Design and Synthesis of 3-Deazaaristeromycin Derivatives 
 
by 
 
Chun Chen 
 
 
 
A dissertation submitted to the Graduate Faculty of 
Auburn University 
in partial fulfillment of the 
requirements for the Degree of 
Doctor of Philosophy  
 
Auburn, Alabama 
December 13, 2010 
 
 
 
 
Copyright 2010 by Chun Chen 
 
 
Approved by 
 
Stewart W. Schneller, Chair, Professor of Chemistry and Biochemistry 
Edward J. Parish, Professor of Chemistry and Biochemistry 
Susanne Striegler, Associate Professor of Chemistry and Biochemistry 
Evert C. Duin, Associate Professor of Chemistry and Biochemistry 
 
 
 
 
 
 
 
 
 
 
Abstract 
 
 
 Analogs of naturally occurring nucleosides have served as structural models for 
the design of antitumor, antiviral, and antibacterial agents. The carbocyclic nucleosides 
aristeromycin and neplanocin A are two examples that show significant broad-spectrum 
antiviral activity. The significant antiviral properties of these two nucleosides have been 
attributed to inhibition of AdoHcy hydrolase, which in turn affects viral mRNA capping 
methylation. However, their clinical potential is limited by toxicity, which is associated 
with phosphorylation of the primary hydroxyl group at 5? position. 3-Deazapurine 
carbocyclic nucleosides (3-deazaneplanocin A and 3-deazaaristeromycin) have been 
shown to retain antiviral activity with significant reduction of toxicity as a result of their 
incapability of undergoing phosphorylation. In the search for effective antiviral agents, 
fluorinated nucleosides and nucleotides, where the fluorine has been introduced into both 
the base and the sugar moiety, have found use in the treatment of viral infections. The 
placement of a fluorine atom can have significant effects on a biological molecule due to 
imparting increased lipophilicity, powerful electronic effects and altered metabolic 
properties. To further explore new antiviral agents retaining 3-deazaaristeromycin-based 
activity while reducing undesired toxicity, modification at the C-3? and C-2? position have 
been recognized as important means to promising compounds. The synthesis and 
biological properties of the 3?-fluoro-3?-deoxy- and 2?-fluoro-2?-deoxy-3-
deazaaristeromycin derivatives 1, 2, 4 and 5 have been investigated. As a logical 
ii 
 
extension of the 3?-deoxy- and 2?-deoxy-3-deazaaristeromycin derivatives 3 and 6 has 
been identified as important target. 
4?-Substituted nucleosides were found to exert potent activity against HIV. In this 
dissertation, the 4?-methyl-3-deazaaristeromycin (7) was sought as an anti-HIV agent and 
an efficient route into the heretofore unknown 4?-alkylated-3-deazaaristeromycin 
framework was developed. The bioassays for all compounds will be forthcoming and 
under study. 
 
 
 
 
 
 
 iii
 
 
 
Acknowledgments 
 
 
Many people have contributed to this dissertation and have given me endless 
support. I am very grateful to each of them all my life. 
First and foremost, I would like to express my sincere gratitude to my research 
advisor, Dr. Stewart W. Schneller, for his continuous support and encouragement with 
valuable knowledge during my graduate career. I also want to thank him for his 
progressive mentorship and dedication to much of the research in this dissertation. My 
gratitude is extended to the distinguished members of my committee including Drs. 
Edward J. Parish, Susanne Striegler, and Evert C. Duin for their intellectual assistance 
and constructive suggestions. 
I am grateful to all Schneller group members for their kind help, useful 
discussions, and friendship. In particular, I would like to thank these lab mates, Drs. Wei 
Ye, Weikuan Li, Chong Liu, Qi Chen and Mingzhu He. I like to thank Drs. Michael 
Meadows and Yonnie Wu for their assistance in obtaining Nuclear Magnetic Resonance 
(NMR) spectroscopy and Mass Spectrometry (MS) data. Additionally, I extend my 
gratitude to Department of Chemistry and Biochemistry and the National Institutes of 
Health for their financial support.  
Finally, I wish to thank my family and friends in China for their infinite love and 
support which made this dissertation possible. Especially, I am deeply indebted to my 
wife and daughter, Jin Gao and Yuelin Chen, for their patience, support, and never-
ending encouragement. 
iv 
 
 
 
 
Table of Contents 
 
 
Abstract............................................................................................................................... ii 
Acknowledgments.............................................................................................................. iv 
Table of Contents ................................................................................................................v 
List of Tables .................................................................................................................... vii 
List of Figures.................................................................................................................. viii 
List of Schemes ................................................................................................................. ix 
Introduction..........................................................................................................................1 
 Introduction of viruses  ...........................................................................................1 
 Viruses and human diseases  ...................................................................................2 
            Prevention and treatment  .......................................................................................3 
            Nucleoside analogs as antiviral agents   .................................................................4 
            Traditional nucleoside derivatives   ........................................................................6 
            Antiviral activity via inhibition of S-adenosylhomocysteine hydrolase  ................8 
            Carbocyclic nucleoside derivatives  ......................................................................15 
            Fluorine-containing nucleoside derivatives  .........................................................25 
            Target design based on the SAH hydrolase inhibition  .........................................28 
Results and Discussion ......................................................................................................33 
Synthesis of (3?R)-3?-deoxy-3?-fluoro-3-deazaaristeromycin (1)   ........................33 
Synthesis of (3?S)-3?-deoxy-3?-fluoro-3-deazaaristeromycin (2)   ........................54 
 v
Synthesis of 3?-deoxy-3?-fluoro-3-deazaaristeromycin (3)   .................................57 
Synthesis of (2?S)-2?-deoxy-2?-fluoro-3-deazaaristeromycin (4)   ........................61 
Synthesis of (2?R)-2?-deoxy-2?-fluoro-3-deazaaristeromycin (5)   ........................64 
Synthesis of 2?-deoxy-3-deazaaristeromycin (6)   ................................................67 
Synthesis of 4?-methyl-3-deazaaristeromycin (7)   ...............................................70 
Conclusion  .......................................................................................................................76 
Experimental .....................................................................................................................78 
References  ......................................................................................................................125 
 
 
 vi
 
 
 
 
 
List of Tables 
 
 
Table 1 Different conditions for regioselective protection of C-2 hydroxyl group  .........43 
Table 2 Different conditions for selective deprotection of 42 ..........................................45 
Table 3 Different conditions for regioselective protection of 43  .....................................47 
 
 
vii 
 
 
 
 
 
 
List of Figures 
 
 
Figure 1 Naturally occurring nucleosides ...........................................................................4 
Figure 2 Examples of coenzymes  ......................................................................................6 
Figure 3 Examples of antiviral nucleosides  .......................................................................7 
Figure 4 Structure of mRNA 5?-terminal cap ...................................................................10 
Figure 5 Carbocyclic nucleosides with antiviral activity  .................................................18 
Figure 6 Structures of neplanocin A, 3-deazaneplanocin A and their decapitated analogs 
DHCA and DHCDA ...........................................................................................22 
 
Figure 7 Structures of aristeromycin, 3-deazaaristeromycin and their decapitated analogs 
DHCaA and 3-deaza-DHCaA  ............................................................................23 
 
Figure 8 Structures of aristeromycin and neplanocin A derivatives .................................25 
Figure 9 Structures of fluorine-containing nucleosides ....................................................26 
Figure 10 Fluorine-containing nucleosides synthesized in the Schneller Laboratory .......28 
Figure 11 Structures of target compounds 1, 2, and 3 ......................................................30 
Figure 12 Analog of 2?-deoxy nucleosides against HIV....................................................31 
Figure 13 Structures of target 2?-deoxy-3-deazaaristeromycin derivatives ......................31 
Figure 14 Structures of 4?-position substituted nucleosides against HIV .........................32 
Figure 15 Structure of 4?-methyl-3-deazaaristeromycin ...................................................32 
Figure 16 Crystallography of 4?-methyl-3-deazaaristeromycin 7 .....................................74 
 
viii 
 
 
List of Schemes 
 
 
Scheme 1 The formation of 5?-terminal capped mRNA ...................................................11 
Scheme 2 The AdoMet cycle ............................................................................................13 
Scheme 3 Mechanism of AdoHcy hydrolase.....................................................................14 
Scheme 4 AdoMet/AdoHcy metabolism ...........................................................................15 
Scheme 5 Comparison of the response of ribo-nucleosides and carbocyclic nucleosides 
towards phosphorylase.....................................................................................16 
 
Scheme 6 Inhibition mechanism of nucleosides and carbocyclic nucleosides on AdoHcy 
hydrolase..........................................................................................................17 
 
Scheme 7 Two metabolism pathways of Ari .....................................................................20 
Scheme 8 Triphosphate of NpcA.......................................................................................21 
Scheme 9 Mechanism of AdoHcy Hydrolase....................................................................29 
Scheme 10 Retrosynthetic analysis of   ( 3? R ) - 3? - deoxy - 3? - fluoro ? 3 -
deazaaristeromycin 1 .......................................................................................34 
 
Scheme 11 Synthesis of 6-chloro-3-deazapurine 11..........................................................35 
Scheme 12 Route A for synthesis of cyclopentenone 13...................................................37 
Scheme 13 Route B for synthesis of cyclopentenone 13...................................................38 
Scheme 14 Reduction and oxidation of unstable aldehyde 24 ..........................................39 
Scheme 15 Route C for synthesis of cyclopentenone 32...................................................40 
Scheme 16 Synthesis of 2, 3-(cyclopentylidenedioxy)-4-vinyl-cyclopentanol 34 ............41 
Scheme 17 Synthesis of mono-protected alcohol 38 .........................................................42 
Scheme 18 Synthesis of mono-protected alcohol 39 from 36 with TBSCl .......................43 
Scheme 19 Synthesis of mono-protected alcohol 44 .........................................................44 
 ix
Scheme 20 Selective deprotection of 42 ...........................................................................45 
Scheme 21 Synthesis of 43 ................................................................................................46 
Scheme 22 Regioselective protection of diol 43................................................................46 
Scheme 23 Synthesis of 1 ..................................................................................................48 
Scheme 24 Revised retrosynthetic analysis of (3?R)-3?-deoxy-3?-fluoro-3 
deazaaristeromycin 1 .....................................................................................49 
 
Scheme 25 Synthesis of mono-protected alcohol 58 and 61 .............................................50 
Scheme 26 Synthesis of 3?-fluoro-cyclopentanol derivative 57 ........................................52 
Scheme 27 Synthesis of 3-deazaadenine derivative 56 .....................................................52 
Scheme 28 Synthesis of (3?R)-3?-deoxy-3?-fluoro-3-deazaaristeromycin 1.......................53 
Scheme 29 Retrosynthetic analysis of 2 ............................................................................54 
Scheme 30 Synthesis of 71 ................................................................................................55 
Scheme 31 Synthesis of (3?S)-3?-deoxy-3?-fluoro-3-deazaaristeromycin 2 .......................56 
Scheme 32 Retrosynthetic analysis of 3?-deoxy-3-deazaaristeromycin 3..........................57 
Scheme 33 Synthesis of 77 ................................................................................................58 
Scheme 34 The mechanism of the Barton deoxygenation.................................................59 
Scheme 35 Synthesis of 79 ................................................................................................60 
Scheme 36 Synthesis of 3?-deoxy-3-deazaaristeromycin 3 ...............................................60 
Scheme 37 Retrosynthetic analysis of  ( 2? S ) - 2? - deoxy - 2? - fluoro ? 3 -
deazaaristeromycin 4 .......................................................................................61 
 
Scheme 38 Synthesis of 2-fluoro cyclopentanol derivative 85..........................................62 
Scheme 39 Synthesis of (2?S)-2?-deoxy-2?-fluoro-3-deazaaristeromycin 4 .......................63 
Scheme 40 Retrosynthetic analysis of 5 ............................................................................64 
Scheme 41 Synthesis of 2-fluoro-cyclopentanol derivative 93 .........................................65 
 x
Scheme 42 Synthesis of (2?R)-2?-deoxy-2?-fluoro-3-deazaaristeromycin 5.......................66 
Scheme 43 Retrosynthetic analysis of 2?-deoxy-3-deazaaristeromycin 6..........................67 
Scheme 44 Synthesis of 2-deoxy-cyclopentanol derivative 99 .........................................68 
Scheme 45 Synthesis of 2?-deoxy-3-deazaaristeromycin 6 ...............................................69 
Scheme 46 Retrosynthetic analysis of 4?-methyl-3-deazaaristeromycin 7 ........................70 
Scheme 47 Synthesis of 4?-methyl-3-deazaaristeromycin 7 ..............................................73 
Scheme 48 Oxidative rearrangement of 108 towards 109.................................................74 
 
 
 xi
 
 
Introduction  
 
Introduction of viruses 
A virus is a small infectious agent that can replicate only inside the living cells of 
organisms. The average virus is about one one-hundredth the size of the average 
bacterium. Virus particles consist of two or three parts: genes made from either DNA or 
RNA, long molecules that carry genetic information; a protein coat that protects these 
genes; and, in some cases, an envelope of lipids that surrounds the protein coat when they 
are outside a cell. A vast number of viruses cause infectious diseases.
1
  
Viral populations do not grow through cell division, because they are acellular; 
instead, they use the machinery and metabolism of a host cell to produce multiple copies 
of themselves, and they assemble in the cell.
2
 The genetic material within viruses, and the 
method, by which the materials is replicated, vary between different types of viruses. 
 Most DNA viruses create copies of their genomes in the cell?s nucleus. If the cell has 
the appropriate receptor on its surface, these viruses enter the cell by fusion with the cell 
membrane or by endocytosis, by which cells absorb a virus from outside the cell by 
engulfing them with their cell membranes. Most DNA viruses are entirely dependent on 
the host cell?s DNA and RNA synthesising machinery, and RNA processing machinery. 
The viral genome must cross the cell?s nuclear membrane to access this machinery. 
RNA viruses are unique because their genetic information is encoded in RNA. 
Replication usually takes place in the cytoplasm. RNA viruses can be classified into 
 
1
about four different groups according to their modes of replication. The polarity of the 
RNA is the key point to determine the replicative mechanism whether the genetic 
material is single-stranded or double stranded. RNA viruses use their own RNA replicase 
enzymes to create copies of their genomes. 
A reverse transcribing virus (retrovirus) is an RNA virus that is replicated in a host 
cell via the enzyme reverse transcriptase to produce DNA from its RNA genome. The 
order of steps from a retroviral gene to a retroviral protein is: RNA ? DNA ? RNA ? 
protein. Retrovirus containing RNA genomes use a DNA intermediate to replicate. They 
use the reverse transcriptase enzyme to carry out the nucleic acid conversion. 
Retroviruses often integrate the DNA produced by reverse transcription into the host 
genome. They are susceptible to antiviral drugs that inhibit the reverse transcriptase 
enzyme, e.g. zidovudine
3
 and lamivudine.
4
 An example of a retrovirus is the human 
immunodeficiency virus (HIV).
5,6
  
 
Viruses and human diseases 
Most viral infections eventually result in the death of the host cell, which is caused by 
cessation of its normal activities because of suppression by virus specific proteins. 
5,7
 
Some viruses cause no apparent changes to the infected cell, in which the virus is latent 
and inactive. However, some of such viruses are the established causes of cancer or other 
diseases.
8
 
Examples of common human diseases caused by viruses include the common cold,
9
 
influenza,
10
 chickenpox
11
 and cold sores.
12
 Some serious diseases, which caused 
epidemics and pandemics in history, such as Ebola,
13
 acquired immune deficiency 
 
2
syndrome (AIDS),
14
 avian influenza
15
 and severe acute respiratory syndrome (SARS)
16
 
are also caused by viruses. In addition, some viruses can result in life-long or chronic 
infections, where the viruses keep on replicating in the body despite the host?s immune 
system defense. For example, hepatitis B virus (HBV) and hepatitis C virus (HCV) are 
common infections. People chronically infected serve as reservoirs of infectious virus. 
These viruses can transmitted through high-risk intimate interaction between infected and 
healthy people. 
The ability of viruses to cause devastating epidemics has led to the concern that 
viruses could be utilized as biological weapons.
17-19
 Thus, an anti-biological terrorism 
plan is very important and necessary to protect society from bioterrorism. 
 
Prevention and treatment 
There are two most effective medical approaches to defend against viral infections: (1) 
vaccination is an effective and comparably inexpensive way of combating infections by 
viruses and (2) antiviral drugs that interfere with the viral replication.  
Vaccines are limited by some disadvantages. First, some vaccines towards certain 
viruses are not available but are urgently needed, for example, for HIV, the hepatitis C 
virus (HCV),
20
 and the Epstein-Barr virus (EBV).
21
 Antiviral drugs are currently the only 
way to treat those viral infections. Secondly, some vaccines have some undesirable side-
effects, such as the hepatitis B virus (HBV) vaccine.
22
 Thirdly, a vaccine may not be 
effective enough to prevent an epidemic viral spread because of rapid virus mutability, 
such as the avian flu in 1997s.
23
 Finally, a vaccine is of little use for people post-
infection.
24-28
 
 
3
With these limitations in mind, more effective antiviral drugs are urgently needed 
because the threat of a viral epidemic or even a pandemic will confront society without 
warning.  
 
Nucleoside analogs as antiviral agents 
Antiviral agents are often nucleoside analogs, which interfere with viral replication. 
Nucleosides are glycosylamines consisting of a heterocyclic nucleobase to a ribose or 
deoxyribose ring. Examples of natural nucleosides include the pyrimidine, cytidine, 
uridine, thymidine, and, purine, guanosine, adenosine and inosine (Figure 1).  
O
N
N
N
N
NH
2
OHHO
HO
O
N
NH
N
N
O
OHHO
HO
NH
2
Adenosine (A) Guanosine (G)
O
HO
N
NH
O
O
H
3
C
HO
Thymidine (T)
O
HO
N
N
NH
2
O
HO
Cytidine (C)
O
HO
N
NH
O
O
HO
OH OH
Uridine (U)
O
N
NH
N
N
O
OHHO
HO
Inosine (I)
N
N
N
N
N
N
H
Purine Pyrimidine
 
Figure 1. Naturally occurring nucleosides 
 
4
 
The naturally occurring nucleosides are the basic building blocks of nucleic acids. 
Nucleosides can be phosphorylated by specific kinases to generate nucleotides that are 
the molecular building-blocks of DNA and RNA. Nucleic acids are polymeric 
macromolecules made from nucleotide monomers. In deoxyribonucleic acid (DNA), the 
purine bases are adenine and guanine and the pyrimidines are thymine and cytosine. 
Ribonucleic acid (RNA) uses uracil in place of thymine.
29,30
 It is well known that DNA 
contains the genetic instructions used in the development and functioning of all 
organisms and some viruses. RNA is transcribed from DNA and is central to protein 
synthesis, which is very important to replicate genomes of most viruses. Natural 
nucleosides are not only serving as building blocks of nucleic acids, but have important 
roles in metabolism. For instance, adenosine is necessary for essential biological 
processes as a key component of ATP, 
31
 coenzyme A, nicotinamide adenine dinucleotide 
phosphate (NADP
+
), flavin adenine dinucleotide (FAD) and nicotinamide dinucleotide 
(NAD
+
) (Figure 2). Consequently, structural modifications within either the heterocyclic 
nucleobase part or sugar part will lead to diverse biological outcomes.
32-35
 
 
5
N
O
OHOH
OP
O
-
O
NH
2
O
N
N
N
N
NH
2
O
OHOH
OP
O
-
O
NAD
+
N
O
OHOH
OP
O
-
O
NH
2
O
N
N
N
N
NH
2
O
OOH
OP
O
-
O
PO
O
O
NADP
+
N
N
N
NH
O
O
O
HO
OH
P
O
P
O
N
N
N
N
NH
2
O
OHHO
FAD
O
O
HO
HO
HS
N
H
N
H
O O
O
OH
CH
3
H
3
C
N
N
N
N
NH
2
O
OHO
OPO
O
O
-
P
O
O
-
P
-
O O
-
O
Coenzyme A
O
O
 
Figure 2. Examples of coenzymes 
 
Traditional nucleoside derivatives 
Nucleoside analogs have antiviral activities because they are fake DNA building 
blocks, which viruses mistakenly incorporate into their genomes during replication. The 
life-cycle of the virus is halted because the newly synthesised DNA is inactive.  
Natural nucleosides all contain D-ribose or 2?-deoxy-D-ribose as their sugar moiety 
and either adenine, guanine, cytosine, uracil or thymine as their heterocyclic base. Two 
major strategies exist to discover new therapeutic nucleosides based on naturally 
occurring nucleosides that have potential antiviral activities. One strategy is modification 
of the sugar moiety and the second is to alter the heterocyclic base.
36,37
  
 
6
Nucleosides have been prominent analogs in antiviral drug discovery. It is reported 
that of the thirty compounds currently marketed in the United States for treatment of viral 
infections, fifteen are nucleosides analogs.
38
 Since the 5-iodo-2?-deoxyuridine (Figure 3) 
was found to have anti-herpetic activity in 1950s,
39
 additional analogs of the natural 
nucleosides have served as structure models in the design of antiviral agents. Many 
nucleoside derivatives have been synthesized and found to have antiviral activities; some 
have been approved by the FDA as antiviral drugs. In this regard, there are clinically used 
antiviral drugs for treating HCV, varicella zoster virus (VZV), herpes simplex virus 
(HSV, acyclovir
40
 and ganciclovir
41
) and HIV (Figure 3).
42
 
N
NH
O
O
HO
I
O
5-Iodo-2'-deoxyuridine
O
HO
NH
N
N
N
O
Didanosine
O
HO
N
N
N
N
NH
2
OHHO
HO
Vidarabine
O
HO
N
OHHO
NN
O
H
2
N
Ribavirin
Trifluridine
NH
N
O
F
F
F
O
O
OH
HO
Emtricitabine
N
N
F
NH
2
O
S
O
OH
(against HSV) (against HSV and VZV)
(against HSV) (against HIV) (against HIV)
(against HCV)
 
Figure 3.  Examples of antiviral nucleosides 
 
 
7
Didanosine and Emtricitabine are both nucleoside analog reverse transcriptase 
inhibitor (RTIs) and are effective against HIV infection in adult and children. 
Emtricitabine is also marketed in a fixed-dose combination with tenofovir. Trifluridine is 
an anti-herpesvirus antiviral drug, which is used primarily for the eye. Vidarabine is 
effective against the HSV and varicella zoster viruses (VZV). Ribavirin is an antiviral 
drug indicated for severe human respiratory syncytial virus (RSV)
43
 infection, hepatitis C, 
and orthopox viruses
42,44
.  
The other approved nucleosides analogs as antiviral agents against HIV include: 3?-
azido-2?,3?-dideoxythemidine (AZT); 2?,3?-dideoxycytidine (ddC); 2?,3?-didehydro-
thymidine (d4T); (-)-?-L-3?-thia-2?,3?-dideoxycytidine (3TC); 2-amino-6-cyclopropyl-
aminopurin-9-yl-2-cyclopentene (ABC).
42
  
 
Antiviral activity via inhibition of S-adenosylhomocysteine hydrolase 
A common characteristic of antiviral nucleosides derivatives is that they are potent 
product inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase. The replication of 
viruses involves the synthesis of viral messenger RNA (mRNA) for the translational 
production of viral proteins that are required for the assembly of the new virions. 
Maturation of mRNA requires methylation of its 5?-terminus to provide a ?cap? structure. 
This is necessary for viral protein translation and replication.  
The starting point is the unaltered 5? end of an RNA molecule. This features a final 
nucleotide followed by three phosphate groups attached to the primary hydroxyl group of  
5? carbon as following: (1) one of the terminal phosphate groups is removed (by a 
phosphatase), leaving two terminal phosphates; (2) GTP is added to the terminal 
 
8
phosphates (by a guanylyl transferase), losing two phosphate groups (from the GTP) in 
the process. This process produces the 5? to 5? triphosphate linkage; (3) the 7-Nitrogen of 
guanine is methylated by a methyl transferase. The methylation leading to a fully 
functional mRNA is catalyzed by N-7 methyltransferases and nucleoside 2?-
methyltransferases, which use AdoMet as the cofactor.
45
 
1) pppN(pN)
n
 ? ppN(pN)
n 
+ Pi 
2) ppN(pN)
n
 + pppG ? G(5? )pppN(pN)
n
 +PPi 
3) G(5?)pppN(pN)
n
 + Adomet ? m
7
 G(5?)pppN(pN)
n
 + AdoHcy 
 
The mRNA methylated 5?-cap has 4 main functions for its successful translation: (1) 
regulation of nuclear export; (2) prevention of degradation by ribonucleases and 
phosphatases; (3) mRNA splicing to ribosome; and (4) the initiation of translation of the 
viral mRNA.
46,47
 Therefore, preventing the 5?-capping process will definitely stop the 
viruses from reproducing.  
The 5?-capped viral mRNA (Figure 4) consists of a N
7
-methylguanosine residue 
linked at its 5?-hydroxy group to the 5?-end of the mRNA strand by an unusual 5?-5? 
triphosphate bridge. Further modification includes methylation of the 2?-hydroxyl group 
of penultimate adenine nucleosides.  
 
 
9
HN
N
N
N
O
CH
3
O
H
2
N
OH
OH
O P O
O
O
P
O
O
O P O
O
O
O
N
O O
PO
O
O
CH
3
O
Base
O O CH
3
P OO
O
mRNA
Guanosine N
7 
methyl group
2'-O methyl cap
5'
5'
N
N
N
H
2
N
 
Figure 4. Structure of mRNA 5?-terminal cap 
 
S-adenosylmethionine (AdoMet) is required as the methyl donor for both the sugar 
and base methylations in the capping of mRNA.
48,49
 S-adenosylmethionine (AdoMet) is 
one of the most versatile co-factors in bio-methyl transfer. The positive sulfur center in 
AdoMet renders the attached methyl as a susceptible donor to bio-nucleophiles, for 
example, -OH, -NH, -SH, and doubles bonds. More than 40 metabolic reactions involve 
the transfer of a methyl group from AdoMet to various substrates. Acceptors include 
nucleic acids, proteins, and lipids. In this instance, the AdoMet S-methyl group is 
transferred in the capping process. In Scheme1, AdoMet is converted to S-adenosyl-
homocysteine (AdoHcy). 
 
10
HN
N
N
N
O
O
H
2
N
OH
OH
O P O
O
O
P
O
O
O P O
O
O
O
Base
O OH
PO
O
O O Base
O OH
P OO
O
mRNA
5'
5'
Ad
S COOH
NH
2
Me
AdoMet
Ad
S COOH
NH
2
Me
AdoMet
Ad
S COOH
NH
2
Me
AdoMet
HN
N
N
N
O
O
H
2
N
OH
OH
O P O
O
O
P
O
O
O P O
O
O
O
Base
O OMe
PO
O
O O Base
O OMe
P OO
O
mRNA
5'
5'
Me
N
7
-Methyl transferase
2'-O-Methyl transferase
2'-O-Methyl 
transferase
Ad
S COOH
NH
2
AdoHcy
+
5'-terminal capped mRNA
 
Scheme 1. The formation of 5?-terminal capped mRNA 
 
The reactions that consume and generate/regenerate AdoMet comprise the AdoMet 
cycle. This cycle consists of four basic steps (Scheme 2). In the first step, the AdoMet 
dependent methylases use AdoMet as a substrate produce AdoHcy and a bio-methylated 
 
11
product that is the 5?-capped methylated mRNA.
50
 AdoHcy is a strong feedback inhibitor 
of methyl transferase and must be metabolized rapidly.
51,52
 This follows with its 
hydrolysis to homocysteine and adenosine by S-adenosylhomocysteine hydrolase. 
Adenosine is further transformed to inosine by adenosine deaminase or it is converted to 
ATP through a series of phosphorylations.
53
 The homocysteine is recycled back to 
methionine catalyzed by methionine synthase through transfer of a methyl group from 5-
methyltetrahydrofolate (THF) or metabolized to cystathionine.
54
 Finally, methionine 
reacts with ATP to give AdoMet under the influence of adenosyltransferase catalyst, 
completing the cycle.
55,56
 
 
12
O
N
N
N
N
NH
2
OHHO
S
Me
NH
2
O
HO
AdoMet
O
N
N
N
N
NH
2
OHHO
S
NH
2
O
HO
AdoHcy
SH
NH
3
O
O
S
NH
3
O
O
CH
3
Homocysteine
Methionine
CH
3
Methyltransferase
methylation of mRNA
AdoHcy
hydrolase
Adenosine
Adenosine
deaminase
Inosine
AMP/ATP
Cystathionine
synthase
Cystathionine
ATP
PPi + Pi
N
5
-methyl FH
4
FH
4
Ado kinase
AdoMet
synthetase
step 1
step 2
step 3
step 4
 
Scheme 2. The AdoMet cycle 
 
Inhibition of AdoHcy hydrolase results in accumulation of AdoHcy, which is both the 
product and feedback inhibitor of the aforementioned essential 5?-capped methylation 
reaction (Scheme 1). With this in mind, inhibition of AdoHcy hydrolase has been 
recognized as a potential target for antiviral drug design for a long time. The mechanism 
of AdoHcy hydrolase was studied thoroughly over the last few decades. Scheme 3 shows 
 
13
the mechanism that is widely accepted.
57-61
 This process begins with crucial selective 
NAD
+
 oxidation of the hydroxyl group at the 3? position to form 3?-ketoAdoHcy and 
NADH. The acidity of C-4? and ?-hydrogen of 3?-ketoAdoHcy results in its enzymatic 
removal. Then the homocysteine group at the 5? position is eliminated and water is added 
to the resultant enone in a Michael addition. Finally, adenosine is obtained via NADH 
reduction of the 3?-keto to a hydroxyl group. 
O
Ade
OHHO
S
NH
2
O
HO
AdoHcy
H
NAD
+
NADH
O
Ade
OHO
S
NH
2
O
HO
H
O
Ade
OHO
S
NH
2
O
HO
E-B:
O
Ade
OHO
H
2
C
H
2
O
O
Ade
OHO
H
2
C
H
HO
NAD
+
NADH
O
Ade
OHHO
H
2
C
H
HO
Ade = Adenine
 
Scheme 3. Mechanism of AdoHcy hydrolase 
 
By blocking AdoHcy hydrolase, the concentration of AdoHcy builds up and the 
AdoMet methylation reaction, whose rate is regulated by intracellular ratio of 
AdoMet/AdoHcy, is suppressed (Scheme 4).
48,54,62
 The higher concentration of AdoHcy 
lowers the ratio of AdoMet/AdoHcy and subsequently inhibits AdoMet transferases. This 
will lead to the inhibition of the transmethylation and, in turn, the formation of 5?-capping 
mRNA, reducing viral protein formation for its replication.
63-65
 
 
 
14
O
N
N
N
N
NH
2
HO OH
X
-
OOC
+
NH
3
X=SMe, AdoMet
cap
cap-Me
     Me 
transferase
X=S, AdoHcy
Adenosine + Homocysteine
AdoHcy Hydrolase
feedback
inhibition 
by
AdoHcy
 
Scheme 4. AdoMet/AdoHcy metabolism 
 
Carbocyclic nucleoside derivatives 
Nucleoside analogs as inhibitors of AdoHcy hydrolase are effective for several 
medicinally important therapies, including antiviral treatment. However, prolonged 
inhibition of the hydrolase will overtake general cellular protein synthesis, leading to 
severe side effects such as toxicity and drug resistance. Thus, clinical application in this 
approach to drug therapy is limited by these inherent and unacceptable side effects. 
Among the most promising antiviral agents based on inhibition of AdoHcy hydrolase 
to overcome these undesirable consequences are the carbocyclic nucleosides
35,66-68
 that 
are nucleosides wherein the more common ribofuranose moiety is replaced by a 
cyclopentane ring. This structure alteration improves the stability of the N-glycosidic 
bond of the ribo-nucleosides against phosphorylases that cause nucleoside breakdown at 
the heterocyclic base and the sugar moiety interface. The consequence of this lysis is a 1?-
 
15
phosphoribose and a heterocyclic base resulting in failure of an intact active nucleosides 
being delivered to the bio-target. The hetero-base to cyclopentyl ring in carbocyclic 
nucleosides leads to nucleoside analogs more resistant to phosphorylsis (Scheme 5). 
O
HO
N
N
N
N
NH
2
OHHO
phosphorylase
O
HO
OHHO
OPO
3
H
2
N
N
N
H
N
NH
2
+
HO
N
N
N
N
NH
2
OHHO
phosphorylase
No phosphorolysis
a carbocyclic nucleoside
a ribo-nucleoside
 
Scheme 5. Comparison of the response of ribo-nucleosides and carbocyclic 
nucleosides towards phosphorylase 
 
In addition to their greater stability, there are other advantages of carbocyclic 
nucleosides, such as a higher lipophilicity for oral uptake and cellular penetration.
69,70
 
The similar structure of the cyclopentyl of carbocyclic nucleosides to the tetrahydrofuran 
ring of ribo-nucleosides renders carbocyclic nucleosides recognizable by the same 
enzymes involved with natural nucleosides as substrates (Scheme 6).
71
  
 
16
O
N
N
N
N
NH
2
OHHO
S
CH
3
HOOC
NH
2
X
N
N
N
N
NH
2
OHHO
SHOOC
NH
2
Nu: Nu-Me
Methyl
transferase
X
N
N
N
N
NH
2
OHHO
SHOOC
NH
2
X
N
N
N
N
NH
2
OHHO
SHHOOC
NH
2
HO
Biofeedback inhibition
AdoHcy
hydrolase
X=CH
2
C-ATPC-AdoMet
AdoMet
AdoHcy, x=O
C-AdoHcy, x=CH
2
+
 
Scheme 6. Inhibition mechanism of nucleosides and carbocyclic nucleosides on 
AdoHcy hydrolase 
 
In addition to their antiviral properties, carbocyclic nucleosides can serve as 
substrates for standard nucleoside processing enzymes (e.g., kinases that convert them to 
nucleotides), leading to anti-tumor and anti-viral candidates.
66-68,72
 
With the promise of carbocyclic nucleosides, numerous related analogs have been 
discovered through isolation from nature or laboratory synthesis in the last few decades. 
Many of these compounds displayed broad-spectrum or specific antiviral activity. Some 
examples (Figure 5) in this category have been found therapeutic potential, such as 
abacavir and carbovir (anti-HIV),
73,74
 entecavir (anti-HBV),
75,76
 carboxentanocin G (anti-
HIV),
77
 aristeromycin and neplanocin A (broad-spectrum).
66-68,72
 
 
17
HO
N
N
N
N
NH
2
OHHO
HO
NH
N
N
N
O
NH
2
Carbovir
HO
NH
N
N
N
HN
NH
2
Abacavir
HO
NH
N
N
N
O
NH
2
HO
Entecavir
HO
NH
N
N
N
O
NH
2
OH
Carboxentanocin G
HO
N
N
N
N
NH
2
OHHO
Aristeromycin (Ari) Neplanocin A (NpcA)
 
Figure 5. Carbocyclic nucleosides with antiviral activity 
 
Aristeromycin (Ari) and neplanocin A (NpcA) are both natural occurring carbocyclic 
analogs of adenosine. Their structures differ by the presence of a double bond between C-
4? and C-6? in NpcA. Neplanocin A was first isolated from the culture broth of 
Ampullariella regularis in 1979
78,79
 while aristeromycin was synthesized
80-85
 before it 
was isolated from a metabolite of Steptomyces citricolor in 1968.
86
 Both aristeromycin 
 
18
and neplanocin A have antiviral potential based on inhibition of AdoHcy hydrolase.
62,87
 
Both Ari and NpcA are phosphorylated by cellular kinases to their 5?-monophosphate-
adenosine, 5?-diphosphate-adenosine and 5?-triphosphate nucleoside derivatives that may 
be the source of their undesirable side effect toxicity.
63,88
 Ari-triphosphate can interfere 
with the metabolic processes involving ATP because of its structural resemblance to ATP. 
Meanwhile, Ari-MP serves as a substrate for AMP deaminase leading to the inosine 
monophosphate (IMP) analog of aristeromycin. In turn, this is converted to carbocyclic 
guanosine monophosphate (GMP), which inhibits the crucial cellular enzyme 
hypoxanthine (guanine)-phosphoribosyltransferase (HGPRTase).
88,89
 This pathway may 
also account for the toxicity and decreased potency of Ari (Scheme 7).
90
  
 
 
19
OH
N
N
N
N
NH
2
HO OH
O
N
N
N
N
NH
2
HO OH
P
-
O
O
-
O
O
N
N
N
N
NH
2
HO OH
PO
O
-
O
P
O
-
O
O
-
O
N
N
N
N
NH
2
HO OH
PO
O
-
O
P
O
O
O
-
P
-
O
O
-
O
O
N
NH
N
N
O
HO OH
P
-
O
O
-
O
Adenosine Kinase
Aristeromycin Ari-MP
Adenylate Kinase
Nucleoside Diphosphate Kinase
Ari-TP
Carbocyclic IMP
AMP deaminase
Interferes with ATP use
O
N
NH
N
N
O
HO OH
P
-
O
O
-
O
Carbocyclic GMP
Inhibits HGPRTase
NH
2
Ari-DP
 
Scheme 7. Two metabolism pathways of Ari 
 
The metabolism of NpcA follows a similar metabolic pathway.
63,90-92
 In that regard, 
the toxicity of NpcA may also be attributed to the fact that the compound is readily 
phosphorylated to its 5?-triphosphate (Scheme 8), which then interferes with host-cell 
RNA synthesis.
89,90,93
  
 
20
OH
N
N
N
N
NH
2
HO OH
O
N
N
N
N
NH
2
HO OH
PO
O
-
O
P
O
O
O
-
P
-
O
O
-
O
Cellular Kinase
Npc A
Npc TP
Incorporation into RNA
 
Scheme 8. Triphosphate of NpcA 
 
With the antiviral activities of Ari and NpcA attributed to their inhibitory effect on 
AdoHcy hydrolase, their toxicity arising from nucleotide formation must be overcome if 
these compounds are to have a potential to provide a structural framework for agent 
design. Thus it became necessary to design similar analogs that are endowed with 
antiviral properties but lacking toxicity.  
The naturally occurring nucleosides most are D-nucleosides analogs, such as 
adenosine, which is the natural product of AdoHcy hydrolysis. Ari and NpcA are both D-
like analogs. Most of the D-like configuration analogs showed higher antiviral activity 
than their L-like counterpart. (-)-5?-norAri (the D-like configuration) is much more potent 
towards cytomegalovirus than (+)-5?-norAri (the L-like configuration).
94,95
 Therefore, the 
D-like 3-deazoaristeromycin analogs are designed and synthesized as a priority in the 
search for new hydrolase inhibitions of S-AdoHcy hydrolase. 
In this regard, 3-deazaneplanocin A and the ?decapitated? analogs of neplanocin A 
and 3-deazaneplanocin A, referred to as DHCA and DHCDA (Figure 6), were 
synthesized.
96-98
 Both DHCA and DHCDA were indeed more selective in their activity 
against vaccinia virus than neplanocin A was.
99
 
 
21
N
N
N
N
NH
2
OHHO
Neplanocin A
HO
N
N
N
N
NH
2
OHHO
N
N
N
NH
2
OHHO
DHCA
DHCDA
N
N
N
NH
2
OHHO
HO
3-Deazaneplanocin A
 
Figure 6. Structures of neplanocin A, 3-deazaneplanocin A and their decapitated 
analogs DHCA and DHCDA 
 
The analogs of 3-deazaaristeromycin,
100
 the ?decapitated? aristeromycin (DHCaA) 
and 3-deaza-DHCaA (Figure 7) were synthesized and maintained the potent antiviral 
activity against vesicular stomatities virus, vaccinia virus, parainfluenza virus, reovirus, 
and rotavirus etc. with less toxicity.
101,102
  
 
22
N
N
N
N
NH
2
OHHO
Aristeromycin
HO
N
N
N
NH
2
OHHO
HO
3-Deazaaristeromycin
N
N
N
N
NH
2
OHHO
DHCaA
N
N
N
NH
2
OHHO
3-Deaza-DHCaA
 
Figure 7. Structures of aristeromycin, 3-deazaaristeromycin and their 
decapitated analogs DHCaA and 3-deaza-DHCaA 
 
The Schneller group also has developed many valuable analogs of aristeromycin and 
neplanocin A derivatives that show greater therapeutic potential without toxicity than 
aristeromycin and neplanocin A. The 5?-deoxy analog of Ari (Figure 8) showed moderate 
antiviral activity against vaccinia virus, vesicular stomatitis virus (VSV)
103
 with little 
toxicity in the assays.
104
 The reason for the reduced toxicity is believed to be due to lack 
of a C-5? hydroxyl and hence no phosphorylation. The Schneller group has also reported 
efficient and stereoselective routes to synthesize (-)-3-deazaaristeromycin,
105
 5?-
homoanaologues of Ari, 5?-homoanaologues of NpcA, and 6-iso analogs of Neplanocin A 
(Figure 8).
104,106,107
 In that series, antiviral activity was shown against a wide variety of 
DNA and RNA viruses, such as the orthopox viruses, vaccinia, cowpox, and 
 
23
monkeypox.
104
 5?-Homoneplanocin A showed noteworthy activity against both HBV and 
HCV.
107
 3-Halo-3-deaza-5?-noraristeromycin analogs possessing a halo atom at the C-3 
position have been synthesized and evaluated in the Schneller laboratory. 3-chloro-3-
deaza-5?-noraristeromycin (a) exhibits activity against HCV. 3-Bromo-3-deaza-5?-
noraristeromycin (b) and 3-iodo-3-deaza-5?-noraristeromycin (c) display marked activity 
against HBV. Compounds a, b and c were also found to have a wide variety of other 
biological properties. 3-Methyl-3-deaza-5?-noraristeromycin (d) showed good activity 
against VSV and VV. 
 
24
N
N
N
N
NH
2
OHHO
H
3
C
5?-Deoxyaristeromycin
N
N
N
N
NH
2
OHHO
HO
N
N
N
N
NH
2
OHHO
HO
5?-Homoaristeromycin
5'-Homoneplanocin
N
N
N
N
NH
2
OHHO
HO
n
n=1, 2
6-isoneplanocin A analogues
HO
N
N
N
NH
2
OHHO
a: R=Cl, 3-chloro-3-deaza-5?-noraristeromycin
b: R=Br, 3-bromo-3-deaza-5?-noraristeromycin
c: R=I, 3-iodo-3-deaza-5?-noraristeromycin
d: R=Me, 3-Methyl-3-deaza-5?-noraristeromycin
R
 
Figure 8. Structures of aristeromycin and neplanocin A derivatives 
 
Fluorine-containing nucleoside derivatives 
In the search for effective antiviral agents, the presence of the small, electronegative 
fluorine substituent has provided promising structural entities with significant antiviral 
properties.
108-112
 As a consequence, fluorinated nucleosides and nucleotides, where the 
 
25
fluorine has been introduced into both the base and the sugar moiety (Figure 9), have 
found use in the treatment of viral infections.
113,114
  
HN
N
O
O
HO
N
N
N
N
NH
2
F
O
HO
N
N
N
N
NH
2
OHHO
Lodenosine
2-Fluoro-8-azaadenosine
O
O
HO
F
Alovudine
F
O
HO
N
N
N
N
NH
2
OHF
2'-deoxy-2'-Fluoro-adenosine
 
Figure 9. Structures of fluorine-containing nucleosides 
 
Fluorine imparts desirable characteristics to drugs by modulating both the 
pharmacokinetics and pharmacodynamics properties of the drug candidate.
115,116
 This is 
the consequence of:  
1) Increased lipophilicity leads to an increase in fat solubility, which improves 
transportation through membranes and increases its bioavailability.  
2) Aid hydrophobic interactions between the drug and binding sites on receptors or 
enzymes. 
3) The electronic effect provided by fluorine?s high electronegativity and small 
atomic radius gives unique properties to its structural framework as expressed by, 
for example, altering both the dipole moment and the pK
a
 of the molecule. 
 
26
4) Altering the drug?s metabolic properties due to the very strong C-F bond leading 
to higher oxidative and thermal stability than present in a carbon-hydrogen bond.  
 
In summary, these properties affect a drug?s metabolism and prolong its half-life. 
Therefore, incorporation of fluorine into a drug can increase lipophilicity, enhance 
absorption into biological membranes, and facilitate docking with drug receptors, all 
leading to a dramatic effect on biological activity. 
In this direction, efficient and stereoselective synthesis of fluorine nucleosides was 
reported by the Schneller group (Figure 10).
110,117
 5?-fluoro-5?-deoxyaristeromycin and 4?-
fluoro-4?-deoxyaristeromycin were evaluated and showed moderate activity against 
measles without toxicity.
117
 This indicated that the replacement of the 5?-hydroxy of 
aristeromycin and 4?-hydroxyl of 5?-noraristeromycin with fluoride can remain potent and 
avoid the undesired phosphorylation and reduced toxicity successfully because the 
fluorine is incapable of phosphorylation. Fluorine-containing nucleosides are 
consideration because the fluorine is incapable of phosphorylation, oxidation, but with 
unique desirable drug characteristics. 
 
 
27
F
N
N
N
N
NH
2
OHHO
5'-fluoro-5'-deoxyaristeromycin
F
N
N
N
N
NH
2
OHHO
4'-fluoro-4'-deoxyaristeromycin
HO
N
N
N
N
NH
2
OHF
(3'R)-3'-fluoro-3'-deoxy-5'-
noraristeromycin
HO
N
N
N
N
NH
2
OHF
(3'S)-3'-fluoro-3'-deoxy-5'-
noraristeromycin
HO
N
N
N
N
NH
2
OH
F
3',3'-difluoro-3'-deoxy-5'-
noraristeromycin
F
 
Figure 10. Fluorine-containing nucleosides synthesized in the Schneller 
Laboratory 
 
Target design based on the SAH hydrolase inhibition 
Seeking analogs that build on this framework, this dissertation research sought to 
structurally unite the biological potential of 3-deazaaristeromycin with fluorine?s 
advantages to create new compounds as antiviral drug candidates.  
As mentioned before, 3-deazaaristeromycin (Figure 11) has significant antiviral 
activity by its inhibition of S-adenosylhomocysteine hydrolase. The mechanism of 
AdoHcy hydrolase (Scheme 9) showed that the hydroxyl group at the C-3? position is 
very important because it is selectively oxidized to form 3? ketoAdoHcy in the first step. 
The inhibition of AdoHcy hydrolase results in the accumulation of AdoHcy and the 
methylation reaction starting from AdoMet to AdoHcy will be suppressed. Consequently, 
 
28
formation of the 5?-capped structure of mRNA is interrupted and the replications of 
viruses are terminated.  
 
O
Ade
OHHO
S
NH
2
O
HO
AdoHcy
H
NAD
+
NADH
O
Ade
OHO
S
NH
2
O
HO
H
O
Ade
OHO
S
NH
2
O
HO
E-B:
O
Ade
OHO
H
2
C
H
2
O
O
Ade
OHO
H
2
C
H
HO
NAD
+
NADH
O
Ade
OHHO
H
2
C
H
HO
Ade = Adenine
X
Ade
OHR
1
S
NH
2
O
HO
AdoHcy
H
NAD
+
NADH
X
Ade
OHO
S
NH
2
O
HO
H
R
2
a: R
1
 = F, R
2
 = H
b: R
1
 = H, R
2
 = F
c: R
1
 = H, R
2
 = H
Further steps
Replacement of the 3'-OH with F or H that is incapable of oxidation inhibits the AdoHcy hydrolase in the first step
 
Scheme 9. Mechanism of AdoHcy hydrolase 
 
Therefore, it is rational design to change the hydroxyl group at C-3? position to 
fluorine or hydrogen that is incapable of oxidation in the first step and inhibit the 
AdoHcy hydrolase. The 3?-fluoro-3?-deoxy- and 3?-deoxy-3-deazaaristeromycin
118,119
 
derivatives 1, 2, 3 were sought as target compounds (Figure 11).  
 
29
N
N
N
NH
2
OHHO
HO
3-Deazaaristeromycin
N
N
N
NH
2
OHF
HO
N
N
N
NH
2
OHF
HO
Target 1
Target 2
N
N
N
NH
2
OH
HO
Target 3
 
Figure 11. Structures of target 1, 2, and 3 
 
A class of 2?-deoxy nucleosides found to be active against DNA viruses, such as HIV, 
was discovered in the late 1970s by Watanabe and Fox.
120
 These compounds are (2?-
fluoro-2?-deoxy-?-D-arabinofuranosyl) pyrimidines substituted in the 5?-position (Figure 
12). With further investigations, the 1?, 2? arrangement between the nucleobase attached 
at the anomeric center and the heteroatom at C-2? is found in numerous biologically 
relevant nucleoside analogues, which are provided as antiviral drugs.
113,121-124
  
 
30
N
HN
O
F
R
O
O
F
OH
HO
R = H, CH
3
, CH
2
CH
3
, I
(Anti-HIV)
 
Figure 12. Analog of 2?-deoxy nucleosides against HIV 
 
The design of target compounds is to change the hydroxyl group at C-2? position to 
fluorine or hydrogen. The 2?-fluoro-2?-deoxy- and 2?-deoxy-3-deazaaristeromycin
118,119
 
derivatives 4, 5, 6 were sought as target compounds (Figure 13). 
N
N
N
NH
2
FHO
HO
N
N
N
NH
2
FHO
HO
Target 4 Target 5
N
N
N
NH
2
HO
Target 6
HO
 
Figure 13. Structures of target 2?-deoxy-3-deazaaristeromycin derivatives 
 
4?-Substituted nucleosides were first investigated by Maag et al. in 1992.
125
 4?-
Azido-2?-deoxynucleosides (Figure 14) were found to exert potent activity against HIV. 
An extensive investigation found that other 4?-position substituent nucleosides also 
exhibited high antiviral activity against HIV.
126-130
 
 
31
O
HO
HO
N
3
Base
4'-azido-2'-deoxynucleosides
O
HO
HO
Base
4'-methyl-2'-deoxynucleosides
O
HO
HO
FH
2
C
Base
4'-fluoromethyl-2'-deoxynucleosides
O
HO
HO
NC
Base
4'-cyano-2'-deoxynucleosides
O
HO
HO
Base
4'-ethynyl-2'-deoxynucleosides 4'-ethynyl-nucleosides
O
HO
HO
Base
OH
Base = Adenine, Inosine, Guanine, Thymine, Uracil, Cytosine
 
Figure 14. Structures of 4?-position substituted nucleosides against HIV 
 
Finally, the 4?-methyl-3-deazaaristeromycin (7) was sought as anti-HIV agent and an 
efficient route into the heretofore unknown 4?-alkylated-3-deazaaristeromycin framework 
was developed (Figure 15). 
4'-methyl-3-deazaaristeromycin  7
N
N
N
NH
2
HO OH
OH
 
Figure 15. Structure of 4?-methyl-3-deazaaristeromycin 
 
 
 
32
 
 
Results and Discussion 
 
Synthesis of (3?R)-3?-deoxy-3?-fluoro-3-deazaaristeromycin (1) 
 
Experimental Design and Synthesis. 
In the introduction part, it was pointed out that the inhibition of AdoHcy hydrolase 
results in the accumulation of AdoHcy and the methylation reaction starting from 
AdoMet to AdoHcy will be suppressed because the AdoHcy will inhibit the methylation 
reaction of viral mRNA. Consequently, formation of 5?-capped mRNA is interrupted and 
viral replication terminated. The mechanism of AdoHcy hydrolase (Scheme 9) has shown 
that the hydroxyl group at the C-3? position is selectively oxidized to form 3? ketoAdoHcy 
in the first step. Therefore, a rational inhibitor design arises by replacing the hydroxyl 
group at the C-3? position of 3-deazaaristeromycin with a fluorine rendering this site 
incapable of oxidation while at the same time adding other advantages as illustrated 
previously in this dissertation. Thus, (3?R)-3?-deoxy-3?-fluoro-3-deazaaristeromycin (1) 
was selected as target compound. The retrosynthetic analysis to 1 is shown in Scheme 
10.
109,131
  
 
33
N
N
N
NH
2
F
OH
HO
H
N
N
N
Cl
F
OTBDPS
TBDPSO
H
N
N
N
Cl
O
O
N
N
H
N
Cl
O
O
OH
+
N
N
N
Cl
HO
OTBDPS
TBDPSO
H
O
O
O
O
OH
HO
HO OH
D-Ribose
1 8
9
101112
13
 
Scheme 10. Retrosynthetic analysis of (3?R)-3?-deoxy-3?-fluoro-3-
deazaaristeromycin 1 
 
The preparation of 1 started from D-ribose and 4-chloro-1H-imidazo[4,5-c]pyridine 
(6-chloro-3-deazapurine, 11). D-ribose is commercially available and its stereochemistry 
is predefined for the purposes here. On the other hand, heterocyclic base 11 is not 
commercially available, but can be synthesized in four steps from the commercially 
available 3-nitropyridine-4-ol (14) (Scheme 11). In that direction, chlorination of alcohol 
14 with phosphorus pentachloride afforded a chloride intermediate that was reacted with 
ethanol to afford 15 in 95% yield. Compound 15 was treated with ammonium acetate 
 
34
under reflux to give amine 16 in 82% yield. The nitro group of 16 was reduced by tin(II) 
chloride (SnCl
2
) in concentrated hydrochloric acid, and followed by a chlorination 
reaction to introduce a chlorine at the 2 position of 16 in one pot leading to 2-chloro-3,4-
diaminopyridine 17 in 70% yield. Finally, 17 was reacted with triethyl orthoformate to 
construct the fused heterocyclic ring product 11 was obtained in 74% yield. Purification 
of crude 6-chloro-3-deazapurine 11 involved filtering and washing by ether, and the solid 
residue was recrystallized twice in methanol/ethyl acetate to give pure 11. 
N
OH
NO
2
N
O
NO
2
N
NH
2
NO
2
N
NH
2
NH
2
Cl
N
N
H
N
Cl
1) PCl
5
, ClCH
2
CH
2
Cl
2) EtOH, 95%
NH
4
OAc, H
2
O
82%
SnCl
2
, Conc. HCl
reflux
70%
CH(OMe)
3
HCOOH, reflux
 74%
14
11
1615
17
 
Scheme 11. Synthesis of 6-chloro-3-deazapurine 11 
 
The requisite D-like cyclopentenone 13 is a very versatile intermediate, which is used 
as multipurpose synthon for the synthesis of carbocyclic nucleosides, and a central 
synthon for the target compounds in this dissertation. Therefore, an efficient, large scale, 
and economic synthesis of cyclopentenone 13 was highly demanded. In this direction, the 
synthesis of 13 was investigated.
132-137
 There are two major synthetic routes that start 
 
35
with D-ribose. Route A
135
 (Scheme 12) and Route B
132,136,138,139
 (Scheme 13). They both 
used for achieving 13. 
In route A (Scheme 12), D-ribose was reacted with acetone in the presence of sulfuric 
acid to give protected 18. A Grignard reaction of 18 with vinyl magnesium bromide 
afforded the triol 19. Oxidation of 19 with sodium periodate gave 20. Subjecting 
aldehyde 20 to a Wittig reaction with methyl triphenylphosphonium bromide and sodium 
hydride afforded the diene 21. With 21 in hand, it was subjected to ring-closing 
metathesis (RCM) reaction conditions with 1 mol% of Grubbs? 1
st
 generation catalyst and 
followed oxidation with pyridinium chlorochromate (PCC) to afford cyclopentenone 13. 
However, it was not an economic and safe scale-up route. When 18 was converted to diol 
19 under Grignard reaction conditions, this reaction need 3.5 equivalents 
vinylmagnesium bromide to give 19. At least 2 equivalents of Grignard reagents were 
consumed and quenched by 2 hydroxyl groups of 18 before the Grignard reagent really 
reacted with aldehyde group of 18. A large scale Wittig reaction of 20 needed a 
considerable amount of sodium hydride (NaH), which could ignite in air (especially upon 
contact with water to release hydrogen) and also is flammable. It was dangerous to 
handle so much NaH in this synthesis, particularly when the reaction was scaled up in the 
lab. So attention changed to route B. 
 
 
36
Ru
Cl
Cl
Ph
P(Cy)
3
P(Cy)
3
O
HO
OH
OH
HO
D-ribose
O
O
O
OH
HO
CH
3
COCH
3
86%
OH
O
O
OH
HO
3.5 eq.C
2
H
4
MgBr
NaIO
4
O
O
O
HO
74%
O
O
NaH, DMSO
CH
3
PPh
3
Br
82%
1) Grubbs' 1st gen. 
catalyst, CH
2
Cl
2
2) PCC
 56% in one-flask
O
O
O
13
18 19
2021
76%
H
2
SO
4
Cy = cyclohexyl
Grubbs' 1st generation catalyst
OH
 
Scheme 12. Route A for synthesis of cyclopentenone 13 
 
Route B (Scheme 13) presented itself as a facile synthesis route for 13. Treatment of 
D-ribose with 2,2-dimethoxypropane and hydrochloric acid in methanol gave primary 
alcohol 22 with diol protection as the isopropylidene unit and methylation at the 
anomeric hydroxyl center. The compound 22 was treated with triphenylphosphine (Ph
3
P) 
and iodine to give iodide 23. Reductive cleavage of 23 with active zinc powder in 
refluxing methanol afforded aldehyde 24, which was quite volatile and unstable. A 
Grignard 1, 2- addition of 24 with vinylmagnesium bromide afforded diene 21. 
 
37
Subjecting 21 to ring-closing metathesis (RCM) conditions with 1 mol% of Grubbs? 1
st
 
generation catalyst and followed by oxidation with pyridinium chlorochromate (PCC) 
provided the desired cyclopentenone 13. 
 
O
HO
OH
OH
HO
O
O
O
OMe
HO
D-ribose
CH
3
COCH
3
, HCl
MeOH, 79%
I
2
, PPh
3
, 
imidazole
reflux
Zn, MeOH
 reflux
O
I
O O
OMe
O O
O
O O
OH MgBr
70%
THF, 84%
1) Grubbs 1st gen. 
catalyst, CH
2
Cl
2
2) PCC
 56% in one-flask
O
O
O
22
24
23
2113
86%
 
Scheme 13. Route B for synthesis of cyclopentenone 13 
 
Compound 24 was very volatile that caused problems when removing the methanol in 
the 23 to 24 step, a necessary procedure to avoid complications in the subsequent 
Grignard process. Also, aldehyde 24 was susceptible to zinc promoted reduction to 
alcohol 25 (Scheme 14) during the reductive cleavage of iodine 23 if the temperature and 
the reaction time was not carefully monitored. Finally, some oxidization of 24 to 26 was 
observed as a consequence of the tedious work-up required.  
 
38
O O
O
24
reduction oxidation
O O
OH
25
O O
O
26
HO
 
Scheme 14. Reduction and oxidation of unstable aldehyde 24 
 
Because of these problems with 24 affected the overall yield, alternatives were 
considered. This led to changing the ribose protecting group from isopropylidene to 
cyclopentylidene to decrease the volatiles of the desired aldehyde.
117
 Thus, a revised 
route C (Scheme 15) arose. Following a procedure similar to that used for synthesizing 
24, 28 was obtained by replacing acetone with cyclopentenone to 27, followed by 
iodination reduction of 28 with active zinc powder afforded aldehyde 29 under a mild 
reduction conditions at 40 ? rather than reflux of Scheme 13. The reaction was traced by 
TLC in order to stop as soon as iodide 28 disappeared. Conversion of 29 into 30 was 
carried out under Grignard conditions with vinyl magnesium bromide. As a mixture of 
diastereomers, diene 30 was subjected to a RCM reaction with 1 mol% of Grubbs? 1
st
 
generation catalyst. This reaction produced an intermediate 31 that was followed by an 
oxidation with active manganese dioxide (MnO
2
) powder at room temperature for 
overnight to give desired cyclopentenone 32. In this latter step, the PCC used in the 
oxidation of Scheme 13 was changed to MnO
2
 because this oxidant provided easier 
work-up than PCC, which generated a muddy pyridine chromate salt containing celite.  
 
39
MeOH, H
2
SO
4
79%
I
2
, PPh
3
, 
Imidazole
reflux
Zn, MeOH
 40?
MgBr
80%
THF, 84%
1) Grubbs 1st gen. 
catalyst, CH
2
Cl
2
2) MnO
2
70% in two steps
O
HO
OH
OH
OH
O
O
O
OMe
OH
O
O
O
OMe
I
O
O
H
O
O
O
OH
O
O
OH
O
O
O
D-ribose
80%
27
32
31 30
29
28
Cyclopantanone
HC(OMe)
3
 
 
Scheme 15. Route C for synthesis of cyclopentenone 32 
 
With cyclopentenone 32 in hand, the isopropylidene cyclopentenone 13 was replaced 
by cyclopentylidene cyclopentenone 32 in the retrosynthetic analysis of 1 (Scheme 10). 
Attention then turned to compound 34 that was synthesized from 32 by two steps 
(Scheme 16). Michael addition of 32 with vinyl magnesium bromide in the presence of 
 
40
copper(?) bromide ? dimethyl sulfide complex (CuBr?Me
2
S), and chlorotrimethylsilane 
(TMSCl) generated ketone 33. Following a literature procedure,
140-142
 Luche reduction of 
33 with NaBH
4
 and cerium(?) chloride heptahydrate (CeCl
3
?7H
2
O) gave alcohol 34 The 
Luche conditions gave a highly diastereoselective 1,2-reduction.
141,142
 That is, the 
secondary alcohol of 34 exists in S-configuration. 
O
O
O
32
OH
O O
O O
O
vinylmagnesium
 bromide
CuBr.Me
2
S
TMSCl
HMPA
NaBH
4
33 34
66%
95%
CeCl
3
  7H
2
O
.
 
 
Scheme 16. Synthesis of 2, 3-(cyclopentylidenedioxy)-4-vinyl-cyclopentanol 34 
 
With the synthesis of the two key intermediates 2, 3-(cyclopentylidenedioxy)-4-vinyl-
cyclopentanol (34) and 6-chloro-3-deazapurine (11), a Mitsunobu coupling reaction 
involving this pair of compounds afforded the desired compound 35 (Scheme 17) along 
with diisopropyl hydrazine-1, 2-dicarboxylate.
131,143-145
 Crude 35 was used directly in the 
next step without further purification. Hydrolysis of 35 with hydrochloric acid in 
methanol gave diol 36. Subjecting 36 to a regioselectively protection of C-2? hydroxyl 
group with 4-methoxybenzyl chloride (PMBCl) resulted in C-2? (37) and C-3? (38). Due 
to their structural similar, these two products were difficult to separate by silica gel 
column chromatography.  
 
41
O
O
OH
N
N
H
N
Cl
PPh
3
N
N
N
Cl
O
O
DIAD
MeOH
HCl
N
N
N
Cl
HO
OH
N
N
N
Cl
HO
OPMB
N
N
N
Cl
PMBO
OH
38
55%
75%
1134
37
PMBCl
+
35
36
+
1'
5'
4'
3'
2'
6'
 
 
Scheme 17. Synthesis of mono-protected alcohol 38 
 
For the purposes of this project, a means to protected C-2? and C- 3? derivatives that 
could be separated was required. Because the hydroxyl groups on C-2? and C- 3? position 
existed in different chemical environments, a few different reaction conditions were 
carried out to regioselectively protect the hydroxyl group at the C-2? position (Table 1). 
However none of the reactions under these conditions could regioselectively protect only 
the hydroxyl group on C-2? position with the consequences being mixtures of products, as 
37 and 38 (Scheme 17) and 39 and 40 (Scheme 18) that were difficult to separate by 
silica gel column chromatography.  
 
42
No. Bases Protectio
n group 
Solvents Reaction 
conditions 
products yield
1 NaH PMBCl THF 
0 ? to RT., 3 h 
37 and 38 low 
2 NaH PMBCl THF 
-78 to - 40?, 5  
h 
37, 38, and 
36 
low 
3 Dibutyltin oxide,  
Tetrabutylammonium 
bromide,  
PMBCl Benzene Reflux, 3 h 37, 38 low 
4 Et3N PMBCl THF 
0 ? to RT., 5 h 
37, 38 80% 
5 Imidazole TBSCl THF 
0 ? to RT., 5 h 
39, 40 
(Scheme 
18) 
77% 
 
Table 1.  Different conditions for regioselective protection of C-2 hydroxyl group 
 
N
N
N
Cl
HO
OH
N
N
N
Cl
HO
OTBS
N
N
N
Cl
TBSO
OH
4039
TBSCl
36
+
 
Scheme 18. Synthesis of mono-protected alcohol 39 from 36 with TBSCl 
 
Further investigations into the regioselective protection of the hydroxyl groups on the 
C-2? and C-3? positions were conducted.
110,146-149
 Scheme 19 shows a new route for this 
purpose. The dihydroxylation of the double bond of 35 with osmium tetraoxide (OsO
4
) 
and N-methylmorpholine-N-oxide (NMO) afforded diol intermediate, which was 
subjected to oxidative cleavage with sodium periodate (NaIO
4
) in one reaction vessel to 
produce an aldehyde. This aldehyde was subjected to reduction with sodium borohydride 
(NaBH
4
) to give primary alcohol 41. Protection of the C-5? hydroxyl of 41 with tert-
 
43
butylchlorodiphenylsilane (TBDPSCl) yielded 42 that was deprotected with hydrochloric 
acid in methanol to selectively remove the cyclopentylidene group to yield 43. 
N
N
N
Cl
O
O
35
N
N
N
Cl
HO
OPMB
TBDPSO
N
N
N
Cl
PMBO
OH
TBDPSO
1) OsO
4
, NMO
3) NaBH
4
N
N
N
Cl
O
O
HO
N
N
N
Cl
O
O
TBDPSO
TBDPSCl
Imidazole
CH
2
Cl
2
2) NaIO
4
60% for three steps
93%
HCl
N
N
N
Cl
HO
OH
TBDPSO
60%
PMBCl
41
42
43
44 45
+
 
Scheme 19. Synthesis of mono-protected alcohol 44 
 
 
44
The desired pure diol 43 was obtained in low yield, being accompanied by triol 46 as 
a consequence of the TBDPS protection group being sensitive to hydrochloric acid 
leading to its removal under the reaction conditions (Scheme 20).  
N
N
N
Cl
HO
OH
TBDPSO
N
N
N
Cl
O
O
TBDPSO
4243
N
N
N
Cl
HO
OH
HO
46
 
 
Scheme 20. Selective deprotection of 42 
Optimized reaction conditions were sought to selectively remove the 
cyclopentylidene unit leaving the TBDPS protection group in tact (Table 2). With 
reaction condition 5, treating 42 with a catalytic amount of 0.6 M hydrochloric acid in 
methanol afforded 43 as the major product, which was along with minimum amounts of 
42 and 46. 
No. Acid Reaction conditions Product Yield
1 HCl (2 M) , pH <1 
0 ? to RT., 5 h 46 
88% 
2 HCl (0.6 M), pH <1 
0 ? to RT., 5 h 
42, 43, and 46  low 
3 Acetic acid 
0 ? to RT., 5 h 
No reaction  
4 Phosphoric acid 
0 ? to RT., 5 h 
42, 43, and 46 low 
5 HCl (0.6 M) catalyst 
amount,  
pH 4-5 
0 ? to RT., 
Overnight 
43 was major 
product 
42, 46 were 
minority 
60% 
 
Table 2. Different conditions for selective deprotection of 42 
 
 
45
An alternative route (Scheme 21) was considered to diol 43 since the hydrolysis of 42 
was difficult to control (Table 2) and monitor by TLC. The new route began with 
deprotection of 41 with hydrochloric acid to provide triol 46 in 88% yield. Triol 46 was 
then treated with 1.1 equivalent of TBDPSCl, imidazole and 4-dimethylaminopyridine 
(DMAP) to selectively protect the C-5? primary alcohol in 86% yield. This route was 
higher yield and more efficiency for synthesis of diol 43 than the route reported in 
Scheme 19. 
46
MeOH
HCl
N
N
N
Cl
HO
OH
TBDPSO
43
N
N
N
Cl
O
O
HO
TBDPSCl
Imidazole
DMAP
N
N
N
Cl
HO
OH
HO
41
88%
86%
 
Scheme 21. Synthesis of 43 
 
With diol 43 available, a renewed effort of regioselective protection of hydroxyl 
group at the C-2? and C-3? was followed (Scheme 22, where PG = protecting group). 
N
N
N
Cl
HO
OH
TBDPSO
N
N
N
Cl
HO
OPG
TBDPSO
N
N
N
Cl
PGO
OH
TBDPSO
43 44:  PG=PMB 45:  PG=PMB
PG
47:  PG=TBS
48:  PG=TBS
49:  PG=TBDPS 50:  PG=TBDPS
 
Scheme 22. Regioselective protection of diol 43 
 
46
 
The reaction conditions of Table 3 were carried out. However, in all cases (PMBCl, 
TBSCl, and TBDPSCl) reactions with 43 in the presence of different bases produced 
mixtures of products, in which either hydroxyl group was protected. Fortunately, the 
mixture of 49 and 50 from reaction of 43 with TBDPSCl in CH
2
Cl
2
 at -40 to 0 ? for 6 
hours could be separated by silica gel column chromatography. This was apparently due 
to a change in product polarity with introduction of the TBDPS groups. 
No. Base Protection 
group 
Solvent Reaction 
conditions 
Product Yield
1 Dibutyltin oxide,  
Tetrabutylammonium 
bromide 
PMBCl 
Benzene Reflux 44, 45 low 
2 NaH, Bu
4
NI PMBCl  THF 
0 ? to RT 
No product 0 
3 NaH PMBCl DMF 
0 ? to RT 
44 and 45 low 
4 NaOC(CH
3
)
3
PMBCl DMF 
0 ? to RT 
44 and 45 low 
5 Et
3
N TBSCl THF 
0 ? to RT 
44 and 45 80% 
6 Imidazole TBSCl THF 
0 ? to RT 
47 and 48 75% 
7 Imidazole, 
DMAP 
TBDPSCl CH
2
Cl
2 -40 to 0? 
49 and 50 82% 
 
Table 3. Different conditions for regioselective protection of 43 
 
When hydroxyl group on C-2? position was protected alcohol to get 49, a Mitsunobu 
reaction of 49 with chloroacetic acid caused C-3? stereo-reversion to ester 51 in 55% 
yield (Scheme 23). Hydrolysis of ester 51 with lithium hydroxide gave alcohol 52, in 
which the C-3? was successfully changed to S-configuration from the R-configuration in 
alcohol 49. Fluorination of 52 with (diethylamino)sulfur trifluoride (DAST) gave 53 in 
50% yield.
108,150-153
 Hydrolysis of 53 with hydrochloric acid removed the TBDPS 
protection groups to yield diol 54. Unfortunately, subsequent amination of 6-chlorine of 
 
47
54 with hydrazine and followed reduction with Raney Nickel did not lead to the desired 
target 1.  
N
N
N
OTBDPS
TBDPSO
Cl
HO
N
N
N
OTBDPS
TBDPSO
Cl
O
O
Cl
N
N
N
OTBDPS
TBDPSO
Cl
DAST
N
N
N
OH
HO
Cl
N
2
H
4
  H
2
O
Raney Ni
N
N
N
OH
HO
NH
2
ClCH
2
COOH
Ph
3
P, DIAD
HO
N
N
N
OTBDPS
TBDPSO
Cl
F
HCl
F
F
49 51
5253
54 1
55%
80%
50%
53%
LiOH
 
Scheme 23. Synthesis of 1 
 
 
48
Although several attempts were carried out and tried to find out the reasons for failure 
to convert 54 to 1, it was concluded that decomposition of 1 might have occurred under 
the harsh conditions of the amination with hydrazine and reduction with Raney Nickel 
under reflux in water for an extended period. Realizing the difficulty to convert the 6-
chlorine of 54 to an amino group at the final stage, a revised retrosynthetic analysis of 
target 1 was developed (Scheme 24). In this regard, a synthetic strategy was foreseen 
with the basic idea being to convert the 6-chloro of 3-deazapurine 11 into an amino 
substituent first. This strategy could avoid the failed amination and reduction reactions at 
the final stage of the previous synthetic route. 
N
N
N
NH
2
F
OH
HO
H
N
N
N
N(Boc)
2
F
OTBDPS
TBDPSO
H
N
N
H
N
N(Boc)
2
F
OTBDPS
TBDPSO
H
1 55
57
OH
+
N
N
H
N
Cl
O
O
OH
34
11 56
HO
OTBDPS
OPMB
58
 
 
49
Scheme 24. Revised retrosynthetic analysis of (3?R)-3?-deoxy-3?-fluoro-3-
deazaaristeromycin 1 
 
The previous key intermediate 34 (Scheme 25) was treated with NaH and PMBCl to 
afford protected 59. Hydrolysis of 59 with hydrochloric acid resulted in diol 60. 
Subjecting 60 to regioselective protection of the C-2 and C-3 hydroxyl groups with 
TBDPSCl gave 58 and 61, which were separated by silica gel column chromatography. 
The ratio of 58 and 61 was 55 : 45 in 75% yield. 
O
O
OH
34
O
O
OPMB
HO
OH
OPMB
HO
OTBDPS
OPMB
+
TBDPSO
OH
OPMB
59
5861
DMF
NaH
PMBCl
86%
HCl
87%
60
TBDPSCl
Imidazole
DMAP
75%
 
Scheme 25. Synthesis of mono-protected alcohol 58 and 61 
 
In Scheme 26, the key intermediate 57 was obtained from alcohol 58 by beginning 
with a Mitsunobu reaction using chloroacetic acid to produce the chloroacetate 62 that 
was hydrolyzed to alcohol 63, in which the configuration at the C-3 was inverted in 
relation to alcohol 58. Introduction of the requisite fluorine atom was accomplished by 
exposure of alcohol 63 to DAST
154
 in CH
2
Cl
2
 to afford fluoro 64. In this fluorination step, 
 
50
the reaction conditions were very careful controlled because the TBDPS group in known 
to be unstable in the presence of fluoride anions.
151-153,155
 When the reaction was carried 
out at -78 ? to -20 ? , the fluorination occurred slowly and in low yield due to a long 
reaction time and the TBDPS group was removed during reaction because of the fluoride 
anions that generated during the decomposition of DAST. Higher reaction temperatures 
also resulted in a rapid removal of the TBDPS group. Finally, an optimized condition was 
found in which the reaction was carried out at 20 ? for about 30 minutes, tracing by 
TLC until the alcohol 63 disappeared, in 65% yield. This step was followed by 
dihydroxylation with osmium tetraoxide and N-methylmorpholine N-oxide, and 
subsequent NaBH
4
 reduction to alcohol 65. The primary alcohol of 65 was protected with 
TBDPS to 66 and removal of the PMB group of 66 with 2, 3-dichloro-5, 6-dicyano-1, 4-
benzoquinone (DDQ) gave the desired 57.  
 
 
 
51
O
OTBDPS
OPMB
O
Cl
OTBDPS
OPMB
HO
OTBDPS
OPMB
F
F
OTBDPS
OPMB
HO
F
OTBDPS
OPMB
TBDPSO
F
OTBDPS
OH
TBDPSO
DAST
65%
62 63
6465
57
66
HO
OTBDPS
OPMB
58
DIAD, Ph
3
P
ClCCOOH
68%
LiOH
85%
1) OsO
4
,NMO
2) NaIO
4
3) NaBH
4
60%
TBDPSCl
DDQ
65%
93%
 
Scheme 26. Synthesis of 3?-fluoro-cyclopentanol derivative 57 
 
To follow Scheme 24, the di-Boc protected derivative of 3-deazaadenine 56 was 
needed and it was prepared through an optimized route developed in the Schneller 
laboratory (Scheme 27). Amination of 6-chloro-3-deazapurine (11) with hydrazine in 1-
propanol under reflux followed reduction with Raney Nickel afforded 3-deazaadenine 67. 
Initial protection of 67 with di-tert-butyldicarbonate [(Boc)
2
O] and DMAP yielded the 
tri-Boc derivative 68,
156
 which could be mono-deprotected to 56 in the presence of tetra-
n-butylammonium fluorine (TBAF) overnight in 63% yield. 
 
52
N
N
N
H
Cl
1) N
2
H
4
n-propanol
N
N
N
H
NH
2
N
N
N
N(Boc)
2
Boc
N
N
N
H
N(Boc)
2
11 67 68 56
2) Raney Ni
     73%
(Boc)
2
O
DMAP
TBAF
75%
84%
 
Scheme 27. Synthesis of 3-deazaadenine derivative 56 
 
Finally, the synthesis of (3?R)-3?-deoxy-3?-fluoro-3-deazaaristeromycin (1) (Scheme 
28) was accomplished via 56 and 57 by calling on a Mitsunobu reaction to 69, which was 
contaminated with reduced DIAD species, and followed by removal of all the protecting 
groups of 69. The reason of overall low yield was that alcohol 57 and 3-deazaadenine 56 
under the Mitsunobu conditions did not react well, which was along with byproduct. 
N
N
N
H
N(Boc)
2
56
F
OTBDPS
OH
TBDPSO
57
+
N
N
N
N(Boc)
2
F OTBDPS
TBDPSO
DIAD
PPh
3
40%
69
HCl
MeOH
N
N
N
NH
2
F OH
HO
1
60%
 
Scheme 28. Synthesis of (3?R)-3?-deoxy-3?-fluoro-3-deazaaristeromycin 1 
 
53
 
 
Synthesis of (3?S)-3?-deoxy-3?-fluoro-3-deazaaristeromycin (2) 
 
Experimental Design and Synthesis. 
As mentioned before, the mechanism of AdoHcy hydrolase (Scheme 9) showed that 
hydroxyl group at C-3? position is very important because it is selectively oxidized to 
form 3? ketoAdoHcy in the first step. Therefore, in continuing to consider the possibilities 
of a fluoro atom at that center would bring antiviral properties, the diastereomer of 1, 
(3?S)-3?-deoxy-3?-fluoro-3-deazaaristeromycin (2) was another target compound. Based 
on the results leading to 1, the retrosynthetic analysis towards 2 is shown (Scheme 29). 
The mono-protected alcohol 58 and di-Boc-3-deazaadenine 56 were seen as start 
materials. 
N
N
N
NH
2
F
OH
HO
H
N
N
N
N(Boc)
2
F
OTBDPS
TBDPSO
H
N
N
H
N
N(Boc)
2
F
OTBDPS
TBDPSO
H
2 70
71
OH
+
56
HO
OTBDPS
OPMB
58
 
Scheme 29. Retrosynthetic analysis of 2 
 
54
 
The intermediate 71 was synthesized from 58 (Scheme 30). Introduction of the 
fluorine atom was accomplished by exposure of 58 to DAST to afford 72. The 
dihydroxylation of the exocyclic double bond of 72 with OsO
4
 and NMO afforded a diol 
intermediate, which was subjected to oxidative cleavage with NaIO
4
 in the reaction 
vessel to produce an aldehyde intermediate. The aldehyde intermediate, without further 
purification, was reduced with NaBH
4
 to give primary alcohol 73. Product 73 was 
protected with TBDPSCl to afford 74. Removal of the PMB group of 74 with DDQ gave 
71.  
HO
OTBDPS
OPMB
58
F
OTBDPS
OPMB
F
OTBDPS
OPMB
HO
F
OTBDPS
OPMB
TBDPSO
72
73
DAST
65%
1) OsO
4
,NMO
2) NaIO
4
3) NaBH
4
60%
TBDPSCl
93%
F
OTBDPS
OH
TBDPSO
DDQ
65%
7471
 
Scheme 30. Synthesis of 71 
 
By Scheme 31, (3?S)-3?-deoxy-3?-fluoro-3-deazaaristeromycin (2) was achieved 
accomplished via 71 and 56 through a Mitsunobu reaction and followed by removal of all 
the protecting groups of 75 with hydrochloric acid. 
 
 
55
 
N
N
N
H
N(Boc)
2
56
+
N
N
N
N(Boc)
2
F OTBDPS
TBDPSO
DIAD
PPh
3
46%
75
HCl
MeOH
N
N
N
NH
2
F OH
HO
2
F
OTBDPS
OH
TBDPSO
71
55%
 
Scheme 31. Synthesis of (3?S)-3?-deoxy-3?-fluoro-3-deazaaristeromycin 2 
 
 
 
56
 
 
Synthesis of 3?-deoxy-3-deazaaristeromycin (3) 
 
Experimental Design and Synthesis. 
Because of the role C-3? hydroxyl center of substrates plays in the metabolic 
processes of AdoHcy hydrolase, deleting the C-3? hydroxyl (hence, removing the 
possibility for oxidation at this site) became a target in this research. Thus, 3?-deoxy-3-
deazaaristeromycin (3) was sought and its retrosynthetic analysis is shown (Scheme 32). 
In this case, mono-protected alcohol 58 and di-Boc-3-deazaadenine derivative 56 were 
projected as start materials. 
N
N
N
NH
2
OH
HO
N
N
N
N(Boc)
2
OTBDPS
TBDPSO
N
N
H
N
N(Boc)
2
OTBDPS
TBDPSO
3 76
77
OH
+
56
HO
OTBDPS
OPMB
58
 
Scheme 32. Retrosynthetic analysis of 3?-deoxy-3-deazaaristeromycin 3 
 
 
57
The intermediate 77 was synthesized from 58 (Scheme 33). Beginning with a Barton 
deoxygenation of 58 to the thiocarbonyl derivative 78, compound 78 was reacted with 
tributyltin hydride (Bu
3
SnH) in the presence of a catalytic amount of 
azobisisobutyronitrile (AIBN) in refluxing toluene. Although the desired deoxygenated 
79 was obtained, the yield was low, varying between 30-50%. As described elsewhere 
herein oxidative cleavage of 79 by OsO
4
-NaIO
4
 produced an aldehyde intermediate that 
was subjected to reduction with NaBH
4
 to primary alcohol 80. This product 80 was 
protected with TBDPSCl to result in 81. Removal of the PMB group of 81 with DDQ 
provided 77. 
O
OTBDPS
OPMB
OPMB
S
S
OTBDPS
78
HO
OTBDPS
OPMB
58
NaH,
CS
2
, MeI
80%
Bu
3
SnH
AIBN
30-50%
OPMB
HO
OTBDPS
79
1) OsO
4
,NMO
2) NaIO
4
3) NaBH
4
60%
OPMB
TBDPSO
OTBDPS
TBDPSCl
93%
OH
TBDPSO
OTBDPS
DDQ
65%
77
81 80
 
Scheme 33. Synthesis of 77 
 
The Barton deoxygenation reaction was further investigated to improve 
deoxygenation of alcohol 58.
157-163
 The mechanism of the Barton deoxygenation (Scheme 
34) shows that it is a free radical reaction and the low concentration of Bu
3
Sn? effects the 
 
58
reaction. A higher concentration of Bu
3
Sn? is helpful to improve the yield. However, the 
radicals also attack double bonds suggesting that the vinyl group in 78 may be susceptible 
to Bu
3
Sn? in a radical chain reaction, which would make it difficult to optimize the 
Barton deoxygenation reaction conditions for the purposes of this project for higher yield. 
R
O
S
S
SnBu
3
?
??
?
?
R
O
S
S
SnBu
3
S
S
SnBu
3
O
R+HBu
3
SnR
Bu
3
Sn H
AIBN
Bu
3
Sn +
H
Initiation:
The catalytic cycle, in which low concentration of the ?SnBu
3
 effects the reaction:
 
Scheme 34. The mechanism of the Barton deoxygenation 
 
 Realizing the difficulty to use Barton deoxygenation, an alternative route was chosen 
to synthesize 79 (Scheme 35).
163
 Alcohol 58 was treated with methanesulfonyl chloride 
(MsCl) to avail 82, which was followed by a reduction with lithium aluminium hydride 
(LiAlH
4
) to give 79 in 45% yield for two steps. 
 
 
 
 
59
HO
OTBDPS
OPMB
58
O
OTBDPS
OPMB
OPMB
OTBDPS
82
79
S
O
O
MsCl
LiAlH
4
Et
3
N
45% for two
steps
 
Scheme 35. Synthesis of 79 
 
In turn, 3?-deoxy-3-deazaaristeromycin (3) (Scheme 36) was achieved via 77 and 56 
under Mitsunobu conditions followed by removal of all the protecting groups of 83 with 
hydrochloric acid. 
N
N
N
H
N(Boc)
2
56
+
N
N
N
N(Boc)
2
OTBDPS
TBDPSO
DIAD
PPh
3
55%
83
HCl
MeOH
N
N
N
NH
2
OH
HO
3
OTBDPS
OH
TBDPSO
77
64%
 
Scheme 36. Synthesis of 3?-deoxy-3-deazaaristeromycin 3 
 
 
 
60
 
 
Synthesis of (2?S)-2?-deoxy-2?-fluoro-3-deazaaristeromycin (4) 
 
Experimental Design and Synthesis. 
As mentioned earlier, the 1?, 2? arrangement between the nucleobase attached at the 
anomeric center and the heteroatom at C-2? was found in numerous biologically relevant 
nucleoside analogues.
121-123
 In that regard, (2?S)-2?-deoxy-2?-fluoro-3-deazaaristeromycin 
(4) became a goal and retrosynthetic analysis for this purpose is shown in Scheme 37. 
The mono-protected alcohol 61 and di-Boc-3-deazaadenine 56 were to be starting 
materials. 
N
N
N
NH
2
F
HO
N
N
N
N(Boc)
2
F
TBDPSO
N
N
H
N
N(Boc)
2
4 84
85
+
56
TBDPSO
OH
OPMB
61
HO
TBDPSO
F
TBDPSO
TBDPSO
OH
 
Scheme 37. Retrosynthetic analysis of (2?S)-2?-deoxy-2?-fluoro-3-
deazaaristeromycin 4 
 
 
61
The 2-fluoro cyclopentanol derivative 85 was synthesized from 61 (Scheme 38). 
Again calling on the Mitsunobu reaction, 61 was treated with chloroacetic acid to 
produce the chloroacetate 86, which was hydrolyzed to alcohol 87. Introduction of the 
fluorine atom was accomplished by exposure of alcohol 87 to DAST in CH
2
Cl
2
 to lead to 
88. This was followed by dihydroxylation with osmium tetraoxide and N-
methylmorpholine N-oxide, and subsequent NaBH
4
 reduction to get alcohol 89. The 
primary alcohol of 89 was protected with TBDPS to 90 followed removal of the PMB 
group of 90 with DDQ gave 85.  
 
TBDPSO
O
OPMB
DAST
65%
86 87
888990
61
DIAD, Ph
3
P
ClCCOOH
68%
LiOH
85%
1) OsO
4
,NMO
2) NaIO
4
3) NaBH
4
60%
TBDPSCl
DDQ
65%
TBDPSO
OH
OPMB
O
Cl
TBDPSO
OH
OPMB
TBDPSO
F
OPMB
TBDPSO
F
OPMB
HO
TBDPSO
F
OPMB
TBDPSO
TBDPSO
F
OH
TBDPSO
85
 
Scheme 38. Synthesis of 2-fluoro cyclopentanol derivative 85 
 
 
62
Calling on the Mitsunobu reaction, (2?S)-2?-deoxy-2?-fluoro-3-deazaaristeromycin (4) 
(Scheme 39) was accomplished via 56 and 85 to 91. This was followed by removal of all 
the protecting groups of 91.  
N
N
N
H
N(Boc)
2
5685
+
N
N
N
N(Boc)
2
TBDPSO F
TBDPSO
DIAD
PPh
3
46%
91
HCl
MeOH
N
N
N
NH
2
HO F
HO
4
55%
TBDPSO
F
OH
TBDPSO
 
Scheme 39. Synthesis of (2?S)-2?-deoxy-2?-fluoro-3-deazaaristeromycin 4 
 
 
 
63
 
 
Synthesis of (2?R)-2?-deoxy-2?-fluoro-3-deazaaristeromycin (5) 
 
Experimental Design and Synthesis. 
As mentioned before, (2?R)-2?-deoxy-2?-fluoro-3-deazaaristeromycin (5) was selected 
as a target compound because its 1?, 2?-cis arrangement is related to numerous 
biologically relevant nucleoside analogues. A retrosynthetic analysis for this purpose is 
shown in Scheme 40 and calls for the mono-protected alcohol 61 and di-Boc-3-
deazaadenine 56 as starting materials. 
N
N
N
NH
2
F
HO
N
N
N
N(Boc)
2
F
TBDPSO
N
N
H
N
N(Boc)
2
5 92
93
+
56
TBDPSO
OH
OPMB
61
HO
TBDPSO
F
TBDPSO
TBDPSO
OH
 
Scheme 40. Retrosynthetic analysis of 5 
 
The 2-fluorocyclopentanol derivative 93 was synthesized from 61 (Scheme 41). The 
introduction of the fluorine atom was accomplished by exposure of 61 to DAST to 
 
64
produce 94. Dihydroxylation of the double bond of 94 with OsO
4
 and NMO afforded a 
diol intermediate, which was subjected to oxidative cleavage with NaIO
4
 in the same 
reaction vessel to produce an aldehyde intermediate. This intermediate, without further 
purification, was subjected to reduction with NaBH
4
 to give 95. Protection of 95 with 
TBDPSCl to 96 and followed removal of the PMB group with DDQ gave 93.  
DAST
65%
94 95
96
61
1) OsO
4
,NMO
2) NaIO
4
3) NaBH
4
60%
TBDPSCl
DDQ
65%
TBDPSO
OH
OPMB
TBDPSO
F
OPMB
TBDPSO
F
OPMB
HO
TBDPSO
F
OPMB
TBDPSO
TBDPSO
F
OH
TBDPSO
93
91%
 
Scheme 41. Synthesis of 2-fluoro-cyclopentanol derivative 93 
 
Finally, (2?R)-2?-deoxy-2?-fluoro-3-deazaaristeromycin (5) (Scheme 42) was 
accomplished via 93 and 56 through a Mitsunobu reaction. This was followed by removal 
of all the protecting groups of 97 with hydrochloric acid to give 5. 
 
65
N
N
N
H
N(Boc)
2
5693
+
N
N
N
N(Boc)
2
TBDPSO F
TBDPSO
DIAD
PPh
3
46%
97
HCl
MeOH
N
N
N
NH
2
HO F
HO
5
55%
TBDPSO
F
OH
TBDPSO
 
Scheme 42. Synthesis of (2?R)-2?-deoxy-2?-fluoro-3-deazaaristeromycin 5 
 
 
 
 
66
 
 
Synthesis of 2?-deoxy-3-deazaaristeromycin (6) 
 
Experimental Design and Synthesis. 
To complete the analog series of this project, 2?-deoxy-3-deazaaristeromycin (6) was 
target compound. Its retrosynthetic analysis was foreseen as Scheme 43 and follows other 
approaches by calling on alcohol 61 and base 56. 
N
N
N
NH
2
HO
N
N
N
N(Boc)
2
TBDPSO
N
N
H
N
N(Boc)
2
TBDPSO
6 98
99
OH
+
56
TBDPSO
OPMB
61
HO
TBDPSO
TBDPSO
OH
 
Scheme 43. Retrosynthetic analysis of 2?-deoxy-3-deazaaristeromycin 6 
 
The 2-deoxycyclopentanol derivative 99 was synthesized from 61 (Scheme 44). 
Barton deoxygenation of 61 began with conversion to the thiocarbonyl derivative 100, 
which was then reacted with Bu
3
SnH in the presence of catalytic amount of AIBN in 
refluxing toluene to the deoxygenated 101. Oxidative cleavage of 101 by OsO
4
-NaIO
4
 to 
 
67
an aldehyde intermediate that was subjected to reduction with NaBH
4
 resulted in alcohol 
102. Protection of 102 with TBDPSCl to 103 was followed by removal of the PMB group 
with DDQ to provide 99. 
TBDPSO
OPMB
OPMB
100
TBDPSO
OH
OPMB
61
NaH,
CS
2
, MeI
80%
Bu
3
SnH
AIBN
30-50%
OPMB
HO
101
1) OsO
4
,NMO
2) NaIO
4
3) NaBH
4
60%
OPMB
TBDPSO
TBDPSCl
93%
OH
TBDPSO
DDQ
65%
99
103 102
TBDPSO
TBDPSO
TBDPSO
TBDPSO
O
S
S
 
Scheme 44. Synthesis of 2-deoxy-cyclopentanol derivative 99 
 
Finally, 2?-deoxy-3-deazaaristeromycin (6) (Scheme 45) was accomplished via 99 and 
56 through a Mitsunobu reaction. This was followed by removal of all the protecting 
groups of 104 with hydrochloric acid to give 6. 
 
68
N
N
N
H
N(Boc)
2
5699
+
N
N
N
N(Boc)
2
TBDPSO
TBDPSO
DIAD
PPh
3
60%
104
HCl
MeOH
N
N
N
NH
2
HO
HO
6
55%
TBDPSO
OH
TBDPSO
 
Scheme 45. Synthesis of 2?-deoxy-3-deazaaristeromycin 6 
 
 
 
 
69
 
 
Synthesis of 4?-methyl-3-deazaaristeromycin (7) 
 
Experimental Design and Synthesis. 
As a potential antiviral agent against HIV mentioned in the introduction, 4?-methyl-3-
deazaaristeromycin (7) was selected as target compound via the retrosynthetic analysis of 
Scheme 46. The intermediate cyclopentylidene cyclopentenone 32 and 6-chloro-3-
deazapurine 11 were set as start points. 
N
N
N
NH
2
HO OH
OH
N
N
N
Cl
O O
N
N
H
N
Cl
O O
+
TfO
O O
O
O
O O
7
32 107
11106
105
 
Scheme 46. Retrosynthetic analysis of 4?-methyl-3-deazaaristeromycin 7 
 
The execution of this route is shown in Scheme 47. Treatment of the cyclopentenone 
32 with methyllithium (MeLi) in THF at -78 ? yielded the tertiary allylic alcohol 108 in 
 
70
85% yield. Subjecting 108 to the known oxidative rearrangement of tertiary allylic 
alcohols by pyridinium dichromate (PDC) afforded 109.
164
 However, the transformation 
of 108 to 4-methylcyclopentenone 109 with PDC proved to be problematic possibly due 
to the steric hindrances of the 2,3-cyclopentylidene group that made it difficult to 
generate the necessary intermediate 116 with PDC (Scheme 48). This steric hindrance 
might have prevented the subsequent 3, 3-sigmatropic rearrangement as well as 
subsequent 4-methylcylcopentenone 109. Upon further analysis of the oxidative 
rearrangement of tertiary allylic alcohols,
165,166
 addition of acetic anhydride led to 
successful PDC oxidation of 108 to 109. This was followed by the conjugate 1, 2-
addition reaction of vinylmagnesium bromide to 109 in the presence of CuBr?Me
2
S as the 
catalyst to obtain the ketone 110. Following a literature procedure,
140-142
 this was 
accelerated by TMSCl and hexamethylphosphoramide (HMPA). Luche reduction of 110 
with NaBH
4
 and cerium(?) chloride heptahydrate (CeCl
3
?7H
2
O) gave alcohol 111. 
The Luche conditions gave a highly diastereoselective 1,2-reduction.
141,142
 X-ray 
crystallography of the eventual target 7 (Figure 16) confirmed the relative configuration 
of the C-4- quaternary stereocenter of 111. Alcohol 111 was converted to its triflate 106 
with trifluoromethanesulfonic anhydride (Tf
2
O) and a subsequent S
N
2 substitution 
reaction of the triflate 106 with a sodium salt of 6-chloro-3-deazapurine 11 in the 
presence of catalytic amount of 18-crown-6 in DMF afforded nucleoside 112. 
Transformation of the vinyl group of 112 to a hydroxyl group followed the usual two step 
sequenced to obtain 113 in 66% yield. Deprotection of 113 with hydrochloric acid 
afforded triol 114. Amination of 114 with hydrazine and subsequent reduction of 115 
 
71
with Raney nickel to produced the desired 4?-methyl-3-deazaaristeromycin (7) (30% yield, 
two steps). 
 
72
O
O
O
MeLi
THF, -78 
o
C
OH
O
O
PDC, Ac
2
O
CH
2
Cl
2
, rt
O
O
O
O
O
O
O
O
HO
N
N
N
H
Cl
a) OsO
4
, NaIO
4
b) NaBH
4
HCl
 Raney Ni
85% 55%
MgBr
CuBr.Me
2
S
THF, -78' C
NaBH
4
70%
86%
32
Pyridine
   Tf
2
O
66%
60%
N
N
N
NH
2
HO OH
OH
55% for 
two steps
O
O
TfO
+
NaH, DMF
18-crown-6
N
N
N
Cl
O O
N
N
N
Cl
O O
OH
N
2
H
4
1-propanol
N
N
N
N
2
H
3
HO OH
OH
30% for 
two steps
7
11 106
108
115
113112
111 110
109
CeCl
3
N
N
N
Cl
HO OH
OH
114
 
Scheme 47. Synthesis of 4?-methyl-3-deazaaristeromycin 7 
 
73
 
OH
O
O
PDC, Ac
2
O
O
O
O
108
109
O
O
O
Cr
O
O
OH
3,3-Sigmatropic
Rearrangement
Cr
O
O
HO
[O]
O
O
O
117116
 
Scheme 48. Oxidative rearrangement of 108 towards 109 
 
In addition to NMR data, the structure of 4?-methyl-3-deazaaristeromycin (7) was 
confirmed by X-ray crystallography (Figure 16).  
 
Figure 16. X-ray crystallography of 4?-methyl-3-deazaaristeromycin 7 
 
74
 
The C-1 was shown as S-configuration that was the reversed R-configuration in 
alcohol 111 obtained from the Luche reduction from 110. The methyl group on C-9 was 
shown as S-configuration. 
 
 
 
 
75
 
 
Conclusion 
 
A common characteristic of antiviral carbocyclic nucleosides derivatives is that they 
are potent inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase. The replication 
of viruses involves the synthesis of viral mRNA that is dependent on S-
adenosylmethionine (AdoMet)-dependent methylation reaction. By blocking AdoHcy 
hydrolase, the concentration of AdoHcy builds up and the AdoMet methylation reaction, 
whose rate is regulated by intracellular ratio of AdoMet/AdoHcy, is suppressed. This will 
lead to the inhibition of the transmethylation and, in turn, the formation of 5?-capping 
mRNA reducing viral protein formation for its replication. Aristeromycin is a potent 
AdoHcy hydrolase inhibitor and shows significant antiviral activity. However, its clinical 
potential is limited by a toxicity arising from 5?-phosphate formation. In order to retain its 
antiviral activity and avoid the undesired phosphorylation that may cause toxicity, further 
structural modifications of 3-deazaaristeromycin were investigated.  
The biofeedback inhibition mechanism of AdoHcy showed that hydroxyl group at C-
3? position is selectively oxidized to form 3? ketoAdoHcy. Replacement of this hydroxyl 
group with hydrogen or fluorine that contains unique desirable drug characteristics might 
inhibit AdoHcy hydrolase efficiently. In this direction, compounds 1, 2, and 3 were 
sought as promising targets. As a logical extension, compounds 4, 5, and 6 were 
identified as important targets since analogs of 2?-deoxy nucleosides were found to 
provide antiviral agents.
113,121-124
 Their synthesis were achieved by a convergent approach, 
in which the desired C-2? or C-3? selective protected sugar moieties were coupled with the 
 
76
3-deazaadenine under the Mitsunobu conditions. The key steps in the synthesis were how 
to selectively protect hydroxyl at C-2? and C-3? with proper protection groups.  
4?-Azido-2?-deoxynucleosides derivatives were found to exert potent activity against 
HIV in 1992. Extensive investigation found that other 4?-position substituent nucleosides 
also exhibited high antiviral activity against HIV. The 4?-methyl-3-deazaaristeromycin (7) 
was sought as anti-HIV agent and an efficient route into the heretofore unknown 4?-
alkylated-3-deazaaristeromycin framework was developed. This synthetic process 
provides a convenient method for synthesis of 4?-position substituent analogs. 
 
 
 
 
 
 
77
 
 
Experimental 
 
Materials and methods  
Melting points were recorded on a Meltemp II point apparatus and are uncorrected. 
1
H and 
13
C NMR spectra were recorded on a Bruker AV 250 Spectrometer (operated at 
250 or 62.9 MHz, respectively) or AV 400 Spectrometer (operated at 400 or 100 MHz, 
respectively). All 
1
H chemical shifts are reported in ? relative to the internal standard 
tetramethylsilane (TMS, ? 0.00). 
13
C chemical shifts are reported in ? relative to CDCl
3
 
(center of triplet, ? 77.23) or relative to DMSO-d (center of septet, ? 39.51). The spin 
multiplicities are indicated by the symbols s (singlet), d (doublet), t (triplet), q (quartet), 
m (multiplet) and br (broad). Elemental analyses were performed by the Atlantic 
Microlabs, Atlanta, Georgia. Reactions were monitored by thin-layer chromatography 
(TLC) using 0.25 mm E. Merck silica gel 60-F
254
 
coated silica gel plates with 
visualization by the irradiation with a Mineralight UVGL-25 lamp or exposure to iodine 
vapor. Column chromatography was performed on Whatman silica gel (average particle 
size 2-25 ?m, 60 ?) and elution with the indicated solvent system. Yields refer to 
chromatographically and spectroscopically (
1
H and 
13
C NMR) homogeneous materials. 
 
4-Ethoxy-3-nitropyridine (15). Compound 14 (15 g, 107 mmol) and PCl
5
 
(25.8 g, 
95%, 118 mmol) were added to ClCH
2
CH
2
Cl (200 mL) sequentially. The resulting 
suspension was heated to reflux for about 3.5 h until the slurry turned into clear solution. 
 
78
The temperature was lowered to 15 ?C by ice-water hath. Absolute ethanol (100 mL) was 
added to the reaction dropwise below 50 ?C. After the addition, the mixture was brought 
to reflux for 1h. Heating was removed and the reaction was cooled to 10 ?C by an ice-
water bath. The mixture stood for 1 h to form precipitate. The solid was collected by 
filtration and washed with ethanol (2 ? 50 mL). Compound 15 (17.1 g, 95%) was 
obtained as white solid after drying in oven at 35 ?C under vacuum. mp 46-48 ?C (lit. 
167,168
 
mp 46.5-48 ?C).  
4-Amino-3-nitropyridine (16). Nitro 15 (17.71 g, 105 mmol) and ammonium acetate 
(24.36 g, 318 mmol) was added to water (200 mL). The resulting slurry was heated to 
reflux for about 6 hours. TLC was used to trace reaction. After TLC showed the 
disappearance of the starting material 15, the heating was removed and the reaction was 
cooled to room temperature. By an ice-water bath, addition of 30% aq. ammonium 
hydroxide (80 mL) to the solution adjusted the pH to 8. The slurry stood in an ice-water 
bath for 1 h to form precipitate. The solid was collected by filtration and was washed 
with cold water (2 ? 50 mL). Compound 16 (12.01 g, 82.0%) was obtained as a yellow 
solid after drying in oven at 100 ?C under vacuum. mp 195-198 ?C. The NMR spectra are 
consistent with literature.
169
 
2-Chloro-3,4-diaminepyridine (17). SnCl
2 
(60 g, 431 mmol) was added to conc. 
HCl (200 mL) and the resulting suspension was heated to 60-70 ?C. The reaction mixture 
became clear solution. Nitro 16 (60 g, 0.43 mol) was then added portion wise slowly at 
this temperature. After the addition, the reaction mixture was brought to reflux and 
allowed to react for another 5 h. After TLC showed the disappearance of the starting 
material 16, the heating was removed and the reaction was cooled to room temperature 
 
79
with an ice-water bath. The cooled mixture was poured over crushed ice (200 g). 3 M 
NaOH and then saturated ammonium hydroxide solution were added to adjust the acidic 
solution to pH 8. The neutralized solution was extracted with ethyl acetate (3?100 mL). 
The combined organic layers were dried (Na
2
SO
4
). Evaporation of the solvent afforded 
17 (43.3 g, 70%) as a yellow solid. mp 185-188 ?C. 
1
H NMR (400 MHz, DMSO-d
6
): 
7.36 (d, J=5.13 Hz, 1H), 6.31 (d, J=5.2 Hz, 1H), 5.29 (br, 2H), 4.46 (br, 2H). 
13
C NMR 
(100 MHz, DMSO-d
6
): 143.6, 137.1, 134.8, 125.9, 107.94.  
4-Chloro-1H-imidazo[4,5-c]pyridine (11). Under a nitrogen atmosphere, compound 
17 (20.0 g, 139 mmol) was added to anhydrous trimethyl orthoformate (200 mL). The 
solution was heated to reflux at about 100 ?C to afford a clear solution. The solution was 
allowed to cool to 90 ?C. Then 8 mL of formic acid was added dropwise at 90 ?C. The 
reaction was brought to reflux again and a solid began to appear in the solution. Reflux 
was allowed for another 2 h. After TLC showed the disappearance of the starting material 
17, the heat was removed and the reaction was cooled to 10 ?C with an ice-water bath. 
The mixture stood for another 1 h in the bath to form a precipitate completely. The 
mixture was filtered and the precipitate was washed with cold ether (2 ? 50 mL). 
Compound 11 (15.83 g, 74%) was obtained as a light yellow solid after drying in oven at 
100 ?C under vacuum. mp 234-237 ?C. 
1
H NMR (400 MHz, DMSO-d
6
): 8.39 (s, 1H), 
8.05 (d, J=5.2 Hz, 1H), 7.51 (d, J=5.2 Hz, 1H). 
13
C NMR (100 MHz, DMSO-d
6
): 144.7, 
141.1, 140.7, 139.5, 135.4, 108.8.  
2,3-O-Isopropylidene-D-ribose (18). To a stirred suspension of D-ribose (15 g, 100 
mmol) in acetone (100 mL) was added dropwise conc. H
2
SO
4
 
(2 mL) at room 
temperature and the reaction mixture was stirred at room temperature for 2.5 h. The 
 
80
mixture was neutralized with solid NaHCO
3
, filtered and evaporated under reduced 
pressure to give colorless oil. The residue was purified by silica gel column 
chromatography (hexane : EtOAc = 1:1) to afford 18 as colorless oil (16.34 g, 86%). The 
NMR spectra are consistent with literature.
135
  
1-[(4R,5S)-5-((1S)-1-Hydroxyallyl)-2,2-dimethyl- [1,3]dioxolan-4-yl]ethane-1,2-
diol (19). To a stirred solution of 18 (16.34 g, 86 mmol) in THF (250 mL) was added 
dropwise vinylmagnesium bromide (400 mL, 400 mmol, 1.0 M solution in THF) at 
?78?C and the reaction mixture was stirred at 0?C for 3 h. After adding water (150 mL) 
at 0?C, the resulting precipitate was removed through a pad of celite. The filtrate was 
extracted with ethyl acetate (3 ? 150 mL), dried, filtered, and evaporated under reduced 
pressure to give an oil, which was purified by silica gel column chromatography (hexane : 
EtOAc = 1:2) to afford 19 as a white solid (14.25 g, 76%). The NMR spectra are 
consistent with literature.
135
  
(3aS,4R,6S,6aS)- and (3aS,4S,6S,6aS)-2,2-Dimethyl-6-vinyltetrahydrofuro[3,4-
d][1,3]dioxol-4-ol (20). To a stirred solution of 19 (14.25 g, 65.3 mmol) in methylene 
chloride (130 mL) was added dropwise an aqueous solution of NaIO
4
 (121 mL, 78 mmol, 
0.65 M solution) at 0?C and the reaction mixture was stirred at room temperature for 40 
min. After water (130 mL) was added, the mixture was extracted with methylene chloride 
(3 ? 100 mL), dried, filtered, and evaporated under reduced pressure to give an oil, which 
was purified by silica gel column chromatography (hexane : EtOAc = 2:1) to give 20 as a 
colorless oil (9 g, 74%). The NMR spectra are consistent with literature.
133,170
  
(4R,5S)-1-(2,2-Dimethyl-5-vinyl-[1,3]dioxolan-4-yl)-prop- 2-en-1-ol (21).  
 
81
Method 1: To a suspension of sodium hydride (4.06g, 102 mmol, 60% dispersion in 
mineral oil) in tetrahydrofuran (100 mL) in was added dimethyl sulfoxide (14.42 mL, 203 
mmol) at 0 ?C. After being stirred for 30 min at room temperature, the mixture was 
transferred to a suspension of methyltriphenylphosphonium bromide (51.8 g, 145 mmol) 
in tetrahydrofuran (300 mL) at 0 ?C, and the mixture was stirred for 1 h at room 
temperature. To this reaction mixture was added a solution of aldehyde 20 (9 g, 48.3 
mmol) in tetrahydrofuran (100 mL) at 0 ?C, and the reaction mixture was stirred at room 
temperature overnight. Diethyl ether was added to the mixture, and a white solid 
precipitated out. The mixture was filtered through a short silica gel pad, washed with 
diethyl ether, and evaporated. The residue was purified by silica gel column 
chromatography (hexane : EtOAc = 8:1) to give diene 21 (7.3 g, 82%) as a colorless oil. 
The NMR spectra are consistent with literature.
133,138
 
Method 2: To a solution of aldehyde 24 (7.92 g, 50.7 mmol) in anhydrous CH
2
Cl
2
 
(100 mL) was added dropwise a solution of vinylmagnesium bromide (60.9 mL, 60.9 
mmol, 1.0 M in THF) at -40 ?C. The reaction was allowed to warm to 0 ?C over 1 h and 
then stirred at this temperature for 2 h. Saturated NH
4
Cl (50 mL) was added to quench 
the reaction. The organic layer was separated, washed with brine, and dried by anhydrous 
Na
2
SO
4
. The solvent was removed by evaporation under reduced pressure and the residue 
purified by silica gel column chromatography (hexane : EtOAc = 8:1) to afford diene 21 
(7.87 g, 84.2%) as a colorless oil. The NMR spectral data agreed with literature.
133,138
 
(3aR,6aR)-2,2-Dimethyl-3a,6a-dihydrocyclopenta[1,3]-dioxol-4-one ((4R,5R)-4,5-
O-isopropylidene-2-cyclopentenone) (13) To a suspension of the Grubbs? 1
st
 catalyst 
benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (223 mg, 0.27 mmol, flushed 
 
82
with N
2
 
three times) in anhydrous CH
2
Cl
2
 
(100 mL) was added a solution of the diene 21 
(5 g, 27.1 mmol) in anhydrous CH
2
Cl
2
 
(50 mL). After being stirred at 24 ?C for 4h, 4 ? 
molecular sieve (20 g), pyridinium dichromate (20.42 g, 54.3 mmol), and acetic acid 
(0.078 mL, 1.36 mmol) were added to the resulting dark brown mixture. The reaction 
mixture was stirred at the same temperature for 12 h and filtered through a silica gel pad 
with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by silica 
gel column chromatography (hexane : EtOAc = 8:1), giving compound 13 (2.34 g, 56.0%) 
as a white solid. The NMR spectral data agreed with literature.
136
 
Methyl-2,3-O-isopropylidene-?-D-ribofuranoside (22). Concentrated hydrochloric 
acid (2 mL) was added to a suspension of D-ribose (15 g, 100 mmol) in acetone (50 mL) 
and methanol (50 mL) at room temperature. The mixture was refluxed for 1 h. The 
reaction was cooled to room temperature, neutralized with pyridine, and partitioned 
between water (100 mL) and ether (50 mL). The separated aqueous phase was extracted 
with ether (2 x 50 mL) and ethyl acetate (3 x 50 mL), and the combined organic phases 
were washed with saturated copper sulfate solution, water, and brine prior to drying and 
solvent evaporation. The residue was distilled to give 17.80 g (79.5%) of 22 as a colorless 
oil as a mixture of anomers. The NMR spectral data agreed with literature.
139
 
Methyl-5-deoxy-5-iodo-2,3-O-isopropylidene-?-D-ribofuranoside (23). A solution 
of these epimers 22 (17.8 g, 88 mmol), imidazole (9 g, 132 mmol), and 
triphenylphosphine (25.4 g, 97 mmol) in toluene (150 mL) and acetonitrile (100 mL) was 
treated portionwise with iodine (24.57.0 g, 97 mmol), refluxed for 5 min, and cooled to 
room temperature. Additional iodine was introduced in approximately 100 mg portions 
until the reaction mixture remained dark-brown in color. After dilution with ether and 
 
83
repeated washing of the organic extracts sequentially with 10% sodium thiosulfate 
solution, water, and brine, the solution was dried over anhydrous MgSO
4
 
and 
concentrated in vacuo to leave a residue, which was filtered through a short plug of silica 
gel, which was eluted with (hexane : EtOAc = 10:1) to give 23 (23.7 g, 86.2%) as a 
colorless oil of the mixture of anomers. The NMR spectral data agreed with literature.
139
 
(2R,4R)-2-Dimethyl-5-vinyl-1,3-dioxolane-4-carboxaldehyde (24). To a stirred 
solution of iodide 23 (23.7 g, 75 mmol) in MeOH (200 mL) at room temperature was 
added zinc powder (5.43 g, 83 mmol, Aldrich, dust, <10 micron) in one batch, followed 
by addition of acetic acid (0.23 mL, 7.54 mmol) in one portion via syringe. The reaction 
mixture was heated to reflux for 5 h. The reaction was cooled to room temperature, 
filtered through a short plug of celite, and washed with a 1:1 mixture of THF/pentane 
(100 mL). The filtrate was concentrated by evaporation under reduced pressure to 
provide a colorless oil, which was purified by silica gel column chromatography (hexane : 
EtOAc = 8:1) to afford the product 24 (7.92 g, 67.2%) as a colorless oil. The NMR 
spectral data agreed with literature.
139
  
((3a?R,6?R,6a?R)-4?-Methoxytetrahydrospiro[cyclopentane-1,2?-furo[3,4-d] 
[1,3]dioxole]-6?-yl)methanol (27). D-ribose (15g, 100 mmol), cyclopentanone (88 mL, 1 
mol), MeOH (100 mL) and trimethylorthoformate (55 mL, 500 mmol) were added to a 
500 mL flask. H
2
SO
4
 (0.5 mL) was also added into flask carefully. The mixture was 
stirred at room temperature for 2 days. Ammonia hydroxide (29.6%) was added to 
neutralize the mixture. The solvent was removed under reduced pressure. The residue 
was dissolved in EtOAc. The organic layer was washed with brine, dried over Na
2
SO
4
, 
and concentrated to give 27 as yellow oil (17.81 g, 78.0%). 
1
H NMR (400 MHz, CDCl
3
), 
 
84
? 4.98 (s, 1H), 4.79 (d, J=6.0 Hz, 1H), 4.55 (d, J=6.0 Hz, 1H), 4.44 (t, J=2.8 Hz, 1H), 
3.67 (m, 2H), 3.44 (s, 3H), 3.29 (dd, J=3.6, 9.6 Hz, 1H), 1.95 (m, 2H), 1.68 (m, 6H). 
13
C 
NMR (100 MHz, CDCl
3
), ? 121.8, 109.8, 88.2, 85.6, 81.5, 64.1, 55.6, 35.8, 35.7, 23.8, 
23.3. Anal. Calcd for C
11
H
18
O
5
: C, 57.38; H, 7.88; Found: C, 57.27; H, 7.96.  
(3a?S,4?S,6a?R)-4?-(Iodomethyl)-6?-methoxytetrahydrospiro[cyclopentane-1,2?-
furo[3,4-d][1,3]dioxole] (28). Compound 27 (17.81 g, 78 mmol) was dissolved in 
MeCN/toluene (1/1, 250 mL). Imidazole (7.97 g, 117 mmol), triphenylphosphine (TPP) 
(22.5 g, 86 mmol) was added. I
2
 (21.8g, 86 mmol) was added in portions until the 
solution turned black. The solution was stirred at room temperature for 2 hours. Water 
(100 mL) and sodium thiosulfate (5 g) were added until the solution turned clear. The 
organic layer was separated, dried over sodium sulfate, concentrated, and purified with 
column chromatography (hexane : EtOAc = 5:1). The product 28 was isolated as 
colorless oil (21.13 g, 80.1%). 
1
H NMR (400 MHz, CDCl
3
), ? 5.06 (s, 1H), 4.71 (d, 
J=5.6Hz, 1H), 4.7 (d, J=5.6 Hz, 1H), 4.45 (m, 1H), 3.37 (s, 3H), 3.3 (m, 1H), 3.18 (m, 
1H), 1.90 (m, 2H), 1.68 (m, 6H). 
13
C NMR (100 MHz, CDCl
3
), ? 123.1, 109.9, 87.9, 85.8, 
82.7, 55.2, 35.8, 35.7, 23.6, 23.2, 6.7. Anal. Calcd for C
11
H
17
IO
4
: C, 38.84; H, 5.04; 
Found: C, 39.08; H, 5.09. 
(2R,3R)-3-Vinyl-1,4-dioxaspiro[4.4]nonane-2-carbaldehyde (29). To a stirred 
solution of iodide 28 (21.13 g, 62 mmol) in MeOH (200 mL) at room temperature was 
added zinc powder (4.47 g, 68 mmol, Aldrich, dust, <10 micron,) in one batch, followed 
by addition of acetic acid (0.23 mL, 7.54 mmol) in one portion via syringe. The reaction 
mixture was heated to reflux for 5 h. The reaction was cooled to room temperature, 
filtered through a short plug of celite, and washed with a 1:1 mixture of THF/hexane (100 
 
85
mL). The filtrate was concentrated by evaporation under reduced pressure to provide a 
colorless oil, which was purified by silica gel column chromatography (hexane : EtOAc = 
2:1) to afford the product 29 (9.07 g, 80.1%) as a colorless oil. 
1
H NMR (400 MHz, 
CDCl
3
), ? 9.55 (d, J=3.2 Hz, 1H), 5.75 (m, 1H), 5.3-5.5 (m, 2H), 4.76 (m, 1H), 4.34 (m, 
1H), 2.09 (m, 2H), 1.75 (m, 6H). 
13
C NMR (100 MHz, CDCl
3
), ? 200.8, 131.2, 121.1, 
120.0, 81.9, 79.4, 36.9, 36.8, 24.1, 23.3.  
1-((2S,3R)-3-Vinyl-1,4-dioxaspiro[4.4]nonan-2-yl)prop-2-en-1-ol (30). Compound 
29 (9.07 g, 49.8 mmol) was dissolved in dichloromethane (50 mL). Vinylmagnesium 
bromide (59.7 mL, 59.7 mmol, 1M in THF) was added at -78 ?C. The mixture was 
warmed to 0 ?C. Saturated NH
4
Cl (40 mL) was added to quench the reaction. The organic 
layer was separated, dried over sodium sulfate, and concentrated using a rotavapor (bath 
temperature <10 ?C). The residue was purified with silica gel column chromatography 
(hexane : EtOAc = 5:1) to give 30 as colorless oil (8.77 g, 83.8%, mixture of two 
diastereomers). 
1
H NMR (400 MHz, CDCl
3
): ? 6.13 (m, 1H), 5.79 (m, 1H), 5.35 (m, 4H), 
4.55 (m, 1H), 4.2 (m, 1H), 4.02 (m, 1H), 2.01 (m, 2H), 1.65 (m, 6H). 
13
C NMR (100 
MHz, CDCl
3
), ? 137.7, 136.9, 134.0, 133.9, 119.8, 119.0, 118.7, 117.2, 116.6, 80.7, 80.6, 
79.0, 78.7, 71.3, 70.9, 37.1, 37.0, 36.9, 36.6, 24.2, 24.1, 23.4, 23.3.  
(3aR,6aR)-3aH-Spiro[cyclopenta[d][1,3]dioxole-2,1?-cyclopentan]-4(6aH)-one 
(32). Compound 30 (8.77 g, 41.7 mmol) was dissolved in dry dichloromethane (100 mL). 
N
2
 was bubbled to remove O2 for 30 minutes. Grubbs 1
st
 generation catalyst (343 mg, 
0.417 mmol) was added. The solution was stirred at room temperature for 12 hours. The 
solution was cooled to 0 ?C and actived MnO
2
 powder (10.88g, 125 mmol) was added. 
The mixture was warmed to room temperature, stirred overnight. Water (200 mL) was 
 
86
added. The organic layer was separated, filtered, dried over Na
2
SO
4
, concentrated, and 
purified with column chromatography (hexane : EtOAc = 2:1) to give 32 as white solid 
(5.28 g, 70.2%), mp 53-55 ?C. 
1
H NMR (400 MHz, CDCl
3
), ? 7.63 (dd, J= 2.4, 4.8 Hz, 
1H), 6.28 (d, J= 6.0 Hz, 1H), 5.23 (dd, J=2.0, 5.2 Hz, 1H), 4.40 (d, J= 5.2 Hz, 1H), 1.86 
(m, 2H), 1.66 (m, 6H). 
13
C NMR (100MHz, CDCl
3
), ? 204.0, 159.9, 135.5, 124.3, 78.2, 
76.2, 37.9, 37.4, 24.1, 23.3. Anal. Calcd for C
10
H
12
O
3
: C, 66.65; H, 6.71; Found: C, 66.79; 
H, 7.02.  
(3aR,6R,6aR)-6-Vinyldihydro-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1?-
cyclopentan]-4(6aH)-one (33). Vinylmagnesium bromide (17.34 mL, 17.34 mmol, 1.0 
M in THF) was added dropwise by syringe to a suspension of CuBr?Me
2
S (0.285 g, 1.39 
mmol) in anhydrous THF (20 mL) at -78 ?C. The reaction mixture was stirred at the same 
temperature for 30 min before a solution of 32 (2.5 g, 13.9 mmol) and TMSCl (3.68 mL, 
29.1 mmol) and HMPA (6.28 mL, 36.1 mmol) in THF (20 mL) were added dropwise via 
a cannula to the above reaction mixture. The reaction mixture was kept stirring at -78 ?C 
for 5 h and warmed to room temperature. Saturated NH
4
Cl (15 mL) and tert-n-
butylammonium fluoride (TBAF, 3.0 mL) were added to quench the reaction and the 
reaction mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc 
(100 mL) and extracted with EtOAc (3?50 mL). The combined organic phases were 
washed with brine, dried with anhydrous MgSO
4
 and concentrated under reduced 
pressure. The residue was purified on silica gel column chromatography (hexane : EtOAc 
= 4:1) to afford 33 as a colorless oil (1.92 g, 66 %): 
1
H NMR (400 MHz, CDCl
3
) ? 5.85 
(m, 1H), 5.17-5.08 (m, 2H), 4.56 (d, J=5.6 Hz, 1H), 4.18 (d, J= 5.2 Hz, 1H), 3,13 (m, 
1H), 2.85 (dd, J=8.40 Hz, 1H), 2.32 (m, J=18.0 Hz, 1H), 1.94-1.65 (m, 8H); 
13
C NMR 
 
87
(100 MHz, CDCl
3
) ? 213.2, 137.3, 122.3, 116.5, 81.6, 77.7, 40.0, 38.8, 36.3, 36.2, 23.9, 
23.1. Anal. Calcd for C
12
H
16
O
3
: C, 69.21; H, 7.74. Found: C, 67.34; H, 7.8.  
2,3-(Cyclopentylidenedioxy)-4-vinyl-cyclopentanol (34). To a stirred solution of 
cyclopentenone 33 (1.92g, 9.2 mmol) and CeCl
3
?7H
2
O (2.93 g, 10.1 mmol) in MeOH (30 
mL) at 0 ?C was added NaBH
4
 
(0.698 g, 18.4 mmol) in small portions. After stirring at 
room temperature for 1 h the mixture was neutralized with conc. HCl, reduced to 2/3 
volume, extracted with brine and ether, and the organic layers combined, dried (MgSO
4
), 
and concentrated to give 34 as a colorless oil (1.84 g, 94.7%). 
1
H NMR (400 MHz, 
CDCl
3
), ? 5.72 (m, 1H), 5.06-5.10 (m, 2H), 4.4 (m, 2H), 4.07-4.13 (m, 1H), 2.76 (m, 1H), 
2.41 (d, J=7.6 Hz, 1H), 1.89-1.96 (m, 4H), 1.7 (m, 6H). 
13
C NMR (100 MHz, CDCl
3
), 
?138.5, 121.6, 115.3, 84.4, 79.0, 71.3, 44.3, 36.3, 35.7, 35.5, 24.2, 23.1. Anal. Calcd for 
C
12
H
18
O
3
: C, 68.54; H, 8.63. Found: C, 68.33; H, 8.60.  
6-Chloro-9-(2?,3?-(cyclopentylidenedioxy)-4?-vinyl-cyclopentyl)-3-deazapurine 
(35). Compound 34 (5 g, 23.8 mmol) was dissolved in THF (50 mL). 11 (5.11 g, 33.3 
mmol), Ph
3
P (12.5g, 47.6 mmol) was added. The solution was cooled to -40 ?C. 
Diisopropyl azodicarboxylate (DIAD) (9.2 mL, 47.6 mmol) was added dropwise. The 
mixture was warmed to room temperature and then heated to 60 ?C for 24 hours. The 
solvent was removed under reduced pressure. The residue was purified by silica column 
(hexane : EtOAc = 5:1 to 2:1) to give crude 35 as a yellow foam (4.53 g, 55.1%). The 
crude product, which contaminated with diisopropyl hydrazine-1,2-dicarboxylate, was 
used in next step without further purification. 
6-Chloro-9-(2?,3?-diol-4?-vinyl-cyclopentyl)-3-deazapurine (36). Compound 35 (5g, 
14.46 mmol) was dissolved in 3 N HCl (0.5 mL) in MeOH solution, stirred at 25 ?C 
 
88
overnight. NaHCO
3
 was added to neutralize the solution until it stopped bubble. The 
mixture was filtered. The solvent was removed under reduced pressure, and the residue 
was purified by silica gel column chromatography (EtOAc) to provide 36 as a white solid 
(3.03 g, 58%), mp 87-89 ?. 
1
H NMR (400 MHz, DMSO-d
6
), ? 8.69 (s, 1H), 8.17 (d, 
J=5.2 Hz, 1H), 7.81 (d, J=5.2 Hz, 1H), 5.97-6.05 (m, 2H), 5.09 (dd, J=10.4, 26.8 Hz, 
1H), 4.71-4.76 (m, 1H), 4.16-4.2 (m, 1H), 3.85-3.9 (m, 1H), 2.52-2.62 (m, 1H), 2.36-2.42 
(m, 1H), 1.86-1.91 (m, 1H). 
13
C NMR (100 MHz, DMSO-d
6
) ?146.5, 143.1, 142.7, 141.5, 
138.5, 137.4, 115.3, 110.8, 84.4, 79.0, 59.4, 44.3, 36.3. Anal. Calcd for C
13
H
14
ClN
3
O
2
: C, 
55.82; H, 5.04. Found: C, 55.51; H, 4.99. 
6-Chloro-9-(2?-(4-methoxybenzyloxy)-3?-hydroxyl-4?-vinyl-cyclopentyl)- 3-deaza 
purine (38). Compound 36 (1.5 g, 5.36 mmol) was dissolved in dry DMF (10 mL). The 
solution was cooled to 0 ?C. NaH (214 mg, 5.36 mmol, 60% in mineral oil) was added in 
one portion. The solution was stirred for 30 minutes. para-Methoxybenzyl chloride 
(PMBCl) (0.8 mL, 5.9 mmol) was added at 0 ?C in one portion. The solution was stirred 
at room temperature for 3 hours. The solvent was removed under reduced pressure. 
Saturated NH
4
Cl solution (10 mL) was added. The mixture was extracted with EtOAc 
(3?50 mL). The combined organic layer was dried over sodium sulfate, concentrated, and 
purified by silica gel column chromatography (hexane : EtOAc = 1:1) to provide 38 as a 
white foam, which mixed with 6-chloro-9-(2?-hydroxyl-3?-(4-methoxybenzyloxy)-4?-
vinyl-cyclopentyl)-purine (37).  
6-Chloro-9-(2?-(tert-butyldimethylsilyl)-3?-hydroxyl-4?-vinyl-cyclopentyl)-3-
deazapurine (39). Compound 36 (1.5 g, 5.36 mmol) was dissolved in dry 
dichloromethane (10 mL). 4-(Dimethylamino)pyridine (DMAP) (33 mg, 0.27 mmol) was 
 
89
added. The solution was treated with imidazole (438 mg, 6.43 mmol), and tert-
butyldimethylsilyl chloride (TBSCl) (0.89 mL, 5.9 mol) at 0 ?C. The solution was then 
warmed to room temperature and stirred for 2 hours. Water (10 mL) was added to quench 
the reaction. The mixture was extracted with EtOAc (3 ?15 mL). The combined organic 
layer was dried over sodium sulfate, concentrated, and purified by silica gel column 
chromatography (hexane : EtOAc = 3:1) to provide 39 as a gum, which mixed with 6-
chloro-9-(2?-hydroxyl-3?-(tert-butyldimethylsilyl)-4?-vinyl-cyclopentyl)-purine (40).  
6-Chloro-9-(2?,3?-(cyclopentylidenedioxy)-4?-hydroxymethyl-cyclopentyl)-3-
deazapurine (41). Compound 35 (2.5 g, 7.23 mmol) was dissolved in MeOH (25 mL). 
Water (24 mL) was added. NaIO
4
 (3.4 g, 15.9 mmol) was added. The mixture was cooled 
to 0 ?C. OsO
4
 (90 mg, 0.36 mmol, 5% mol) was added. The mixture was stirred at 0 ?C 
for 2 hours. The mixture was filtered. MeOH was removed by reduced pressure. The 
residue was extracted with dichloromethane (3 ?50 mL). The organic layer was washed 
with brine, dried over sodium sulfate, concentrated. The residue was dissolved in 
methanol (20 mL). NaBH
4
 (684 mg, 18.1 mmol) was added portionwise at 0 ?C. The 
mixture as stirred at 0 ?C for 1 hour. Saturated NH
4
Cl solution (20 mL) was added. The 
mixture was filtered through celite. The solvent was removed with reduced pressure. The 
residue was extracted with EtOAc (3?20 mL). The combined organic layer was dried 
over sodium sulfate and concentrated. The residue was purified by silica column (hexane : 
EtOAc = 3:1) to provide 41 as a white solid (1.52 g, 60.2%), mp 66-69 ?. 
1
H NMR (400 
MHz, CDCl
3
), ? 8.20 (s, 1H), 8.18 (d, J=2.8 Hz, 1H), 7.63 (d, J=2.8 Hz, 1H), 4.69-4.73 
(m, 1H), 4.59-4.62 (m, 2H), 3.90-3.91 (m, 2H), 2.63-2.68 (m, 1H), 2.53-2.56 (m, 1H), 
2.45-2.5 (m, 1H), 2.06 (m, 4H), 1.73 (m, 4H). 
13
C NMR (100 MHz, CDCl3), ?143.2, 
 
90
143.1, 141.3, 139.2, 138.3, 107.8, 106.4, 84.0, 81.8, 63.5, 63.0, 45.4, 39.0, 37.9, 37.4, 
25.2, 24.1, Anal. Calcd for C
17
H
20
ClN
3
O
3
: C, 58.37; H, 5.76. Found: C, 58.5; H, 5.75.  
6-Chloro-9-(2?,3?-(cyclopentylidenedioxy)-4?-O-(tert-butyldiphenylsilyl)-cyclo 
pentyl)-3-deazapurine (42). Compound 41 (2.5 g, 8.81 mmol) was dissolved in dry 
dichloromethane (20 mL). 4-(Dimethylamino)pyridine (DMAP) (54 mg, 0.44 mmol) was 
added. The solution was treated with imidazole (720 mg, 10.6 mmol), and tert-
butyldiphenylchlorosilane (TBDPSCl) (2.5 mL, 9.69 mol) at 0 ?C. The solution was then 
warmed to room temperature and stirred for 2 hours. Water (10 mL) was added to quench 
the reaction. The mixture was extracted with EtOAc (3?20 mL). The combined organic 
layer was dried over sodium sulfate, concentrated, and purified by silica gel column 
chromatography (hexane : EtOAc = 2:1) to provide 42 as a white soild (4.3g, 93.4%). 
1
H 
NMR (400 MHz, CDCl
3
), ? 8.18 (d, J=8 Hz, 1H), 7.97 (s, 1H), 7.63-7.68 (m, 5), 7.54 (d, 
J=8 Hz, 1H), 7.26-7.46 (m, 5H), 4.93-5.03 (m, 1H), 4.54 (m, 2H), 4.08-4.16 (m, 2H), 
2.65-2.7 (m, 1H), 2.50-2.53 (m, 1H), 2.4-2.45 (m, 1H), 2.01 (m, 4H), 1.83 (m, 4H), 1.08-
1.11 (m, 9H). 
13
C NMR (100 MHz, CDCl
3
), ? 145.2, 143.5, 141.2, 139.1, 137.3, 132.0, 
130.6, 128.4, 107.6, 107.4, 86.0, 88.7, 66.5, 62.0, 45.7, 38.0, 36.9, 36.7, 22.3, 23.0, 19.6. 
Anal. Calcd for C
33
H
38
ClN
3
O
3
Si: C, 67.38; H, 6.51 Found: C, 67.5; H, 6.73.  
6-Chloro-9-(2?,3?-diol-4?-O-(tert-butyldiphenylsilyl)-cyclopentyl)-3-deazapurine 
(43).  
Method 1: Compound 42 (3.0g, 5.1 mmol) was dissolved in 0.6 N HCl (1 mL) in 
MeOH at 0 ? and stirred at 25 ?C overnight. NaHCO
3
 was added to neutralize the 
solution until it no longer bubbled. The mixture was filtered. The solvent was removed 
under reduced pressure, and the residue was purified by silica gel column 
 
91
chromatography (EtOAc:MeOH=2:1) to provide 43 as a white foam (1.6 g, 60.2%), 
which contaminated with 42 and 46. 
Method 2: Compound 46 (2.5 g, 8.81 mmol) was dissolved in dry dichloromethane 
(20 mL). 4-(Dimethylamino)pyridine (DMAP) (54 mg, 0.44 mmol) was added. The 
solution was treated with imidazole (720 mg, 10.6 mmol), and tert-
butyldiphenylchlorosilane (TBDPSCl) (2.5 mL, 9.69 mol) at 0 ?C. The solution was then 
warmed to room temperature and stirred for 2 hours. Water (10 mL) was added to quench 
the reaction. The mixture was extracted with EtOAc (3?20 mL). The combined organic 
layer was dried over sodium sulfate, concentrated, and purified by silica gel column 
chromatography (hexane : EtOAc = 2:1) to provide 43 as a white solid (1.84g, 86%), mp 
55-57 ?. 
1
H NMR (400 MHz, CDCl
3
): 8.20 (s, 1H), 7.95 (d, J=5.6 Hz, 1H), 7.73 (d, 
J=5.6 Hz, 1H), 7.63-7.68 (m, 5), 7.26-7.46 (m, 5H), 5.55 (s, 1H), 5.12 (s, 1H), 4.75 (m, 
1H), 4.31 (d, J=5.6 Hz, 1H), 4.36 (d, J=3.6 Hz, 1H), 3.86 (d, J=5.6 Hz, 2H),1.99 (dd, 
J=5.6, 13.2 Hz, 1H), 1 (s, 9H). 
13
C NMR (100 MHz, CDCl
3
): ?144.7, 141.9, 141.2, 138.6, 
137.4,132.7, 130.5, 128.3, 106.8, 78.4, 76.6, 74.7, 62.7, 61.5, 37.3, 26.0, 18.3. Anal. 
Calcd for C
28
H
32
ClN
3
O
3
Si: C, 64.41; H, 6.18; N, 8.05. Found: C, 64.01; H, 6.22; N, 8.08.  
6-Chloro-9-(2?-(4-methoxybenzyloxy)-3?-hydroxyl-4?-O-( tert-butyldiphenylsilyl)-
cyclopentyl)-3-deazapurine (44). Compound 43 (2.5 g, 4.79 mmol) was dissolved in dry 
DMF (15 mL). The solution was cooled to 0 ?C. NaH (230 mg, 60% in mineral oil, 5.75 
mmol) was added in one portion. The solution was stirred for 30 minutes. para-
Methoxybenzyl chloride (PMBCl) (0.71 mL, 5.3 mmol) was added at 0 ?C in one portion. 
The solution was stirred at room temperature for 3 hours. The solvent was removed under 
reduced pressure. Saturated NH
4
Cl solution (15 mL) was added. The mixture was 
 
92
extracted with EtOAc (3?50 mL). The combined organic layer was dried over sodium 
sulfate, concentrated, and purified by silica gel column chromatography (hexane : EtOAc 
= 3:1) to provide 44 as a white solid, which mixed with 6-chloro-9-(2?- hydroxyl-3?-(4-
methoxybenzyloxy)-4?-O-( tert-butyldiphenylsilyl)-cyclopentyl)-3-deaza-purine (45). 
6-Chloro-9-(2?,3?-diol-4?-hydroxymethyl-cyclopentyl)-3-deazapurine (46). 
Compound 41 (2.5g, 7.23 mmol) was dissolved in 3 N HCl (0.2 mL) in MeOH and 
stirred at 25 ?C overnight. NaHCO
3
 was added to neutralize the solution until it no longer 
bubbled. The mixture was filtered. The solvent was removed under reduced pressure, and 
the residue was purified by silica gel column chromatography (EtOAc : MeOH = 10:1) to 
provide 46 as a white solid (1.78 g, 88%), mp 182-184 ?. 
1
H NMR (400 MHz, CDCl
3
): 
8.11 (s, 1H), 7.92 (d, J=5.6 Hz, 1H), 7.89 (d, J=5.6 Hz, 1H), 5.22 (s, 1H), 5.17 (s, 1H), 
4.78-4.82 (m, 1H), 4.72 (s, 1H), 4.37-4.4 (m, 1H), 4.31-4.34 (m, 1H), 3.83 (d, J=5.6 Hz, 
2H), 2.35-2.42 (m, 2H),1.99-2.02 (m, 1H). 
13
C NMR (100 MHz, CDCl
3
): ?143.2, 142.1, 
141.7, 139.1, 136.3, 106.2, 78.3, 75.2, 74.8, 63.4, 62.5, 37.3, 25.4. Anal. Calcd for 
C
12
H
14
ClN
3
O
3
: C, 50.80; H, 4.97; N, 14.81. Found: C, 50.22; H, 5.01; N, 14.12. 
6-Chloro-9-(2?-(tert-butyldimethylsilyl)-3?-hydroxyl-4?-O-(tert-butyl 
diphenylsilyl)- cyclopentyl)-3-deazapurine (47). Compound 43 (1 g, 1.92 mmol) was 
dissolved in dry dichloromethane (10 mL). 4-(Dimethylamino)pyridine (DMAP) (12 mg, 
0.1 mmol) was added. The solution was treated with imidazole (130 mg, 1.92 mmol), 
and tert-butyldimethylsilyl chloride (TBSCl) (0.32 mL, 2.1 mol) at 0 ?C. The solution 
was then warmed to room temperature and stirred for 2 hours. Water (10 mL) was added 
to quench the reaction. The mixture was extracted with EtOAc (3 ?10 mL). The 
combined organic layer was dried over sodium sulfate, concentrated, and purified by 
 
93
silica gel column chromatography (hexane : EtOAc = 2:1) to provide 47 as a white solid, 
which mixed with 6-chloro-9-(2?- hydroxyl-3?-(tert-butyldimethylsilyl)-4?-O-( tert-butyl 
diphenylsilyl)-cyclopentyl)-3-deazapurine (48). 
6-Chloro-9-(2?-( tert-butyldiphenylsilyl)-3?-hydroxyl-4?-O-( tert-butyldiphenyl 
silyl)-cyclopentyl)-3-deazapurine (49). Compound 43 (1 g, 1.92 mmol) was dissolved in 
dry dichloromethane (10 mL). 4-(Dimethylamino)pyridine (DMAP) (12 mg, 0.1 mmol) 
was added. The solution was treated with imidazole (130 mg, 1.92 mmol), and TBDPSCl 
(0.54 mL, 2.1 mol) at 0 ?C. The solution was then warmed to room temperature and 
stirred for 2 hours. Water (10 mL) was added to quench the reaction. The mixture was 
extracted with EtOAc (3?10 mL). The combined organic layer was dried over sodium 
sulfate, concentrated, and purified by silica gel column chromatography (hexane : EtOAc 
= 3:1) to provide 49 (0.7g, 48%) and 6-chloro-9-(2?- hydroxyl-3?-( tert-
butyldiphenylsilyl)-4?-O-( tert-butyldiphenylsilyl)-cyclopentyl)-3-deazapurine (50) 
(0.49g, 33.6%) as white foam. 49: 
1
H NMR (400 MHz, CDCl
3
): ? 8.33 (s, 1H), 7.82 (d, 
J=5.6 Hz, 1H), 7.34-7.54 (m, 21H), 5.02-5.12 (m, 1H), 4.83 (d, J=5.6 Hz, 1H), 4.28 (m, 
1H), 3.72 (m, 1H), 3.56-3.66 (m, 2H), 2.21-2.34 (m, 2H), 1.78-1.9 (m, 1H), 0.92 (s, 9H), 
0.85 (s, 9H). 
13
C NMR (100 MHz, CDCl
3
): ?145.8, 141.9, 141.2, 138.6, 137.4, 132.8, 
132.7, 130.5, 130.3, 128.6, 128.2, 106.8, 78.4, 77.2, 74.9, 62.7, 61.5, 37.3, 26.1, 25.8, 
17.9. Anal. Calcd for C
44
H
50
ClN
3
O
3
Si
2
: C, 69.49; H, 6.63; N, 5.53. Found: C, 69.01; H, 
6.44; N, 5.21. 50: 
1
H NMR (400 MHz, CDCl
3
): ? 8.51 (s, 1H), 8.00 (d, J=5.6 Hz, 1H), 
7.62-7.7 (m, 6H), 7.29-7.44 (m, 15H), 5.3 (d, J= 6.8 Hz, 1H), 4.93-4.96 (m, 1H), 4.27 (m, 
1H), 4.12 (m, 1H), 3.29-3.31 (m, 1H), 3.17-3.19 (m, 1H), 2.4 (m, 1H), 2.21 (m, 1H), 
1.68-1.78 (m, 1H), 1.16 (s, 9H), 0.84 (s, 9H). 
13
C NMR (100 MHz, CDCl
3
): ?143.7, 
 
94
142.4, 141.5, 137.6, 137.1, 132.6, 132.4, 131.3, 130.8, 128.9, 127.2, 104.6, 78.6, 76.5, 
74.8, 63.6, 62.4, 37.2, 27.2, 26.6, 18.8. Anal. Calcd for C
44
H
50
ClN
3
O
3
Si
2
: C, 69.49; H, 
6.63; N, 5.53. Found: C, 69.33; H, 6.12; N, 5.08 
 (1S,2S,3R,5R)-2-(tert-Butyldiphenylsilyloxy)-5-((tert-butyldiphenylsilyloxy) 
methyl)-3-(4-chloro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentyl-2-chloroacetate (51). 
Compound 49 (2 g, 2.63 mmol) was dissolved in THF (20 mL). Chloroacetic acid (323 
mg, 3.42 mmol), Ph
3
P (1.38g, 5.26 mmol) was added. The solution was cooled to -40 ?C. 
Diisopropyl azodicarboxylate (DIAD) (0.76 mL, 3.94 mmol) was added dropwise. The 
mixture was warmed to room temperature, and then heated to 60 ?C for 24 hours. The 
solvent was removed under reduced pressure. The residue was purified by silica column 
(hexane : EtOAc = 4:1) to give 51 as white foam (1.22 g, 55.2%). The crude product, 
which contaminated with diisopropyl hydrazine-1,2-dicarboxylate, was used in next step 
without further purification. 
(1S,2S,3S,5R)-2-(tert-Butyldiphenylsilyloxy)-5-((tert-butyldiphenylsilyloxy) 
methyl)-3-(4-chloro-1H-imidazo[4,5-c]pyridin-1-yl)cyclopentanol (52). Compound 51 
(1.22g, 1.46 mmol) was dissolved in 1 N LiOH (3 mL) in MeOH (10 mL) and stirred at 
25 ?C for 2 hours. 0.5 N HCl aqueous solution was added to neutralize the solution. 
Water (10 mL) was added and the mixture was extracted with EtOAc (3?10 mL). The 
combined organic layer was dried over sodium sulfate, concentrated, and purified by 
silica gel column chromatography (hexane : EtOAc = 3:1) to provide 52 as white foam 
(1.17g, 80.2%). 
1
H NMR (400 MHz, CDCl
3
): ? 8.33 (s, 1H), 7.82 (d, J=5.6 Hz, 1H), 
7.34-7.54 (m, 21H), 5.02-5.12 (m, 1H), 4.83 (d, J=5.6, 1H), 4.32 (m, 1H), 3.91 (m, 1H), 
3.45-3.56 (m, 2H), 2.21-2.34 (m, 2H), 1.78-1.9 (m, 1H), 0.92 (s, 9H), 0.85 (s, 9H). 
13
C 
 
95
NMR (100 MHz, CDCl
3
): ?145.4, 141.7, 141.1, 138.8, 137.2, 132.6, 132.2, 130.1, 129.7, 
128.3, 128.1, 106.8, 80.3, 76.1, 74.9, 62.7, 61.5, 36.2, 26.1, 25.8, 18. Anal. Calcd for 
C
44
H
50
ClN
3
O
3
Si
2
: C, 69.49; H, 6.63; N, 5.53. Found: C, 69.41; H, 6.52; N, 5.45. 
1-((1S,2S,3R,4R)-2-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy) 
methyl)-3-fluorocyclopentyl)-4-chloro-1H-imidazo[4,5-c]pyridine (53). Compound 52 
(1.17 g, 1.54 mmol) was dissolved in dry dichloromethane (10 mL), pyridine (0.24 mL, 
3.08 mmol) and (diethylamino)sulfur trifluoride (DAST) (0.26 mL, 2.3 mmol) were 
added. The solution was warmed to room temperature under protection of N
2
 for 12 h. 
The reaction was quenched with saturated Na
2
CO
3
 solution (15 mL). The organic layer 
was separated, washed with brine, dried over sodium sulfate, concentrated, and purified 
by silica gel column chromatography (hexane : EtOAc = 3:1) to provide 53 as a white 
foam (0.622 g, 53%). 
1
H NMR (400 MHz, CDCl
3
): ? 8.29 (s, 1H), 7.78 (d, J=5.6 Hz, 1H), 
7.34-7.54 (m, 21H), 4.56 (d, J=5.6, 1H), 4.28 (m, 1H), 3.45-3.56 (m, 2H), 3.40 (m, 1H), 
2.18-2.22 (m, 2H), 1.8-1.9 (m, 1H), 0.93 (s, 9H), 0.88 (s, 9H). 
13
C NMR (100 MHz, 
CDCl
3
): ?146.3, 140.7, 139.9, 138.6, 137.4, 132.8, 132.6, 130.1, 129.9, 128.8, 128.2, 
105.8, 92.3, 80.3, 73.1, 62.7, 61.5, 31.6, 24.3, 25.7, 19.4. Anal. Calcd for 
C
44
H
49
ClFN
3
O
2
Si
2
: C, 69.31; H, 6.48; N, 5.51. Found: C, 69.42; H, 6.48; N, 5.36. 
(1S,2R,3R,5S)-5-(4-Chloro-1H-imidazo[4,5-c]pyridin-1-yl)-2-fluoro-3-(hydroxyl 
methyl)cyclopentanol (54). Compound 53 (0.5g, 0.66 mmol) was dissolved in 1 N HCl 
(0.1 mL) in MeOH, stirred at 25 ?C overnight. Amberlite IRA-400(Cl) ion exchange 
resin was added to neutralize the solution until pH was 7. The mixture was filtered. The 
solvent was removed under reduced pressure, and the residue was purified by silica gel 
column chromatography (EtOAc:MeOH=10:1) to provide 54 as a white solid (0.1 g, 
 
96
53.3%), mp 172-174 ?. 
1
H NMR (400 MHz, DMSO-d
6
) ? 8.23 (s, 1H), 7.88 (d, J=5.6 
Hz, 1H), 7.67 (d, J=5.6 Hz, 1H), 5.46 (d, J=4.4 Hz, 1H), 4.85-4.95 (m, 2H), 4.80(d, 
J=4.4 Hz, 1H), 3.95-4.05 (m, 2H), 3.52-3.65 (m, 2H), 2.3-2.36 (m, 1H), 1.99-2.01 (m, 
1H). 
13
C NMR (100 MHz, DMSO-d
6
): ?149.3, 143.6, 139.2, 137.8, 135.1, 108.7, 94.2, 
79.4, 72.9, 63.9, 32.5, 25.3. Anal. Calcd for C
12
H
13
ClFN
3
O
2
: C, 50.45; H, 4.59; N, 14.71. 
Found: C, 50.33; H, 4.48; N, 14.82.  
(3aS,4S,6R,6aR)-4-(4-Methoxybenzyloxy)-6-vinyltetrahydro-3aH-spiro 
[cyclopenta[d][1,3]dioxole-2,1?-cyclopentane] (59). Compound 34 (3 g, 14.3 mmol) 
was dissolved in dry DMF (15 mL). The solution was cooled to 0 ?C. NaH (685 mg, 17.1 
mmol, 60% in mineral oil) was added in one portion. The solution was stirred for 30 
minutes. p-Methoxybenzyl chloride (PMBCl) (4.15 mL, 28.5 mmol) was added at 0 ?C in 
one portion. The solution was stirred at room temperature for 3 hours. The solvent was 
removed under reduced pressure. Saturated NH
4
Cl solution (40 mL) was added. The 
mixture was extracted with EtOAc (3?50 mL). The combined organic layer was dried 
over sodium sulfate, concentrated, and purified by silica gel column chromatography 
(hexane : EtOAc = 8:1) to provide 59 as a colorless oil (4.06g, 86.2%). 
1
H NMR (400 
MHz, CDCl
3
) ? 7.32 (d, J=8.80 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.68 (m, 1H), 5.03 (m, 
1H), 4.97 (m, 1H), 4.65 (d, J=10.4 Hz, 1H), 4.55 (d, J=10.4 Hz, 1H), 4.43 (t, J=6.4, 5.6 
Hz, 1H), 4.30 (d, J=5.6 Hz, 1H), 3.81 (m, 4H), 2.66 (t, J= 7.2 Hz, 6.75, 1H), 2.03-2.16 
(m, 2H), 1.70-1.94 (m, 8H); 
13
C NMR (100 MHz, CDCl
3
) ? 159.5, 138.9, 130.8, 129.7, 
121.0, 115.0, 114.0, 84.0, 78.5, 77.9, 71.7, 55.5, 44.1, 35.8, 35.6, 32.1, 24.3, 23.3. Anal. 
Calcd for C
20
H
36
O
4
: C, 72.70; H, 7.93. Found: C, 72.35; H, 8.01. 
(1R,2R,3S,5R)-3-(4-Methoxybenzyloxy)-5-vinylcyclopentane-1,2-diol (60).  
 
97
Compound 59 (4.06g, 12.29 mmol) was dissolved in 3 N HCl (0.41 mL) in MeOH 
and stirred at 25 ?C overnight. NaHCO
3
 was added to neutralize the solution until it no 
longer bubbled. The mixture was filtered. The solvent was removed under reduced 
pressure, and the residue was purified by silica gel column chromatography (hexane : 
EtOAc = 3:1) to provide 60 as a colorless oil (2.82 g, 86.7%). 
1
H NMR (400 MHz, 
CDCl
3
) ? 7.26 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 5.77 (m, 1H), 5.05 (m, 1H), 
4.97 (m, 1H), 4.65 (d, J=11.6 Hz, 1H), 4.55 (d, J=11.6 Hz, 1H), 4.02 (t, J=6.4, 5.6 Hz, 
1H), 3.99 (m, 1H), 3.81 (s, 3H), 3.66 (t, J= 6.4, 7.6, 1H), 2.63-2.7 (m, 1H), 2.05-2.09 (m, 
1H), 1.59-1.67 (m, 1H); 
13
C NMR (100 MHz, CDCl
3
) ? 159.7, 138.7, 131.1, 129.5, 121.1, 
114.0, 84.0, 78.5, 77.9, 71.7, 55.5, 44.3, 32.2. Anal. Calcd for C
15
H
20
O
4
: C, 68.16; H, 
7.63 Found: C, 68.14; H, 7.52. 
(1R,2R,3S,5R)-2-(tert-Butyldiphenylsilyloxy)-3-(4-methoxybenzyloxy)-5-vinyl 
cyclopentanol (58) and (1S,2R,3R,5S)-2-(tert-butyldiphenylsilyloxy)-5-(4-methoxy 
benzyloxy)-3-vinylcyclopentanol (61) . Compound 60 (2.82 g, 10.67 mmol) was 
dissolved in dry dichloromethane (20 mL). 4-(Dimethylamino)pyridine (DMAP) (65 mg, 
0.53 mmol) was added. The solution was treated with imidazole (726 mg, 10.67 mmol), 
and TBDPSCl (3.0 mL, 11.74 mol) at 0 ?C. The solution was then warmed to room 
temperature and stirred for 2 hours. Water (20 mL) was added to quench the reaction. 
The mixture was extracted with EtOAc (3?20 mL). The combined organic layer was 
dried over sodium sulfate, concentrated, and purified by silica gel column 
chromatography (hexane : EtOAc = 5:1) to provide 58 (2.2g, 41%) and 61 (1.82g, 34%) 
as colorless oil. 58: 
1
H NMR (400 MHz, CDCl
3
) ? 7.68-7.71 (m, 4H), 7.27-7.42 (m, 6H), 
7.25 (d, J=2 Hz, 2H), 6.86 (d, J=2 Hz, 2H), 5.32-5.42 (m,1H), 4.83 (m, 1H), 4.71-4.81 
 
98
(m, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 3.78 (m, 5H), 2.74-2.8 (m, 
1H), 2.7 (s, 1H), 2.02-2.12 (m, 1H), 1.55-1.65 (m, 1H), 1.07 (s, 9H); 
13
C NMR (100 MHz, 
CDCl
3
) ? 158.1, 138.4, 135.5, 133.5, 131.1, 130.1, 129.7, 127.6, 121.1, 114.0, 84.0, 78.5, 
77.9, 71.7, 55.5, 44.3, 32.2, 25.3, 19.3. Anal. Calcd for C
31
H
38
O
4
Si: C, 74.06; H, 7.62 
Found: C, 75.01; H, 7.53. 61: 
1
H NMR (400 MHz, CDCl
3
) ? 7.68-7.71 (m, 4H), 7.34-
7.43 (m, 6H), 7.25 (d, J=4.8 Hz, 2H), 6.85 (d, J=4.8, 2H), 5.30-5.42 (m,1H), 4.8-4.92 (m, 
2H), 4.41-4.49 (m, 2H), 3.79 (s, 3H), 3.71-3.79 (m, 2H), 2.81-2.9 (m, 1H), 2.49 (s, 1H), 
2.02-2.12 (m, 1H), 1.55-1.65 (m, 1H), 1.07 (s, 9H); 
13
C NMR (100 MHz, CDCl
3
) ? 159.7, 
136.3, 134.1, 133.1, 131.2, 130.3, 129.2, 128.1, 120.9, 114.3, 85.2, 79.3, 77.9, 72.8, 55.5, 
47.3, 33.3, 27.2, 19.4. Anal. Calcd for C
31
H
38
O
4
Si: C, 74.06; H, 7.62 Found: C, 74.55; H, 
7.59. 
(1S,2S,3S,5R)-2-(tert-Butyldiphenylsilyloxy)-3-(4-methoxybenzyloxy)-5-vinyl 
cyclopentyl-2-chloroacetate (62). Compound 58 (2.2 g, 4.38 mmol) was dissolved in 
THF (20 mL). Chloroacetic acid (538 mg, 5.69 mmol) and Ph
3
P (2.3g, 8.75 mmol) were 
added. The solution was cooled to -40 ?C. Diisopropyl azodicarboxylate (DIAD) (1.27 
mL, 6.56 mmol) was added dropwise. The mixture was warmed to room temperature, and 
then heated to 60 ?C for 24 hours. The solvent was removed under reduced pressure. The 
residue was purified by silica column (hexane : EtOAc = 6:1) to give 62 as colorless oil 
(1.72 g, 67.7%). The crude product, which contaminated with diisopropyl hydrazine-1,2-
dicarboxylate, was used in next step without further purification. 
(1S,2R,3S,5R)-2-(tert-Butyldiphenylsilyloxy)-3-(4-methoxybenzyloxy)-5-vinyl 
cyclopentanol (63). Compound 62 (1.72g, 2.97 mmol) was dissolved in 1 N LiOH (5.9 
mL) in MeOH (20 mL) and stirred at 25 ?C for 2 hours. 0.5 N HCl aqueous solution was 
 
99
added to neutralize the solution. Water (10 mL) was added and the mixture was extracted 
with EtOAc (3?20 mL). The combined organic layer was dried over sodium sulfate, 
concentrated, and purified by silica gel column chromatography (hexane : EtOAc = 6:1) 
to provide 63 as a colorless oil (1.27g, 84.8%). 
1
H NMR (400 MHz, CDCl
3
) ? 7.68-7.71 
(m, 4H), 7.27-7.42 (m, 6H), 7.25 (d, J=2 Hz, 2H), 6.86 (d, J=2 Hz, 2H), 5.32-5.42 
(m,1H), 4.83 (m, 1H), 4.71-4.81 (m, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.42 (d, J=11.6 Hz, 
1H), 3.76-3.78 (m, 5H), 2.74-2.8 (m, 1H), 2.7 (s, 1H), 2.02-2.12 (m, 1H), 1.55-1.65 (m, 
1H), 1.07 (s, 9H); 
13
C NMR (100 MHz, CDCl
3
) ? 158.1, 138.4, 135.5, 133.5, 131.1, 
130.1, 129.7, 127.6, 121.1, 114.0, 84.0, 78.5, 77.9, 71.7, 55.5, 44.3, 32.2, 25.3, 19.3. Anal. 
Calcd for C
31
H
38
O
4
Si: C, 74.06; H, 7.62 Found: C, 74.62; H, 7.49. 
tert-Butyl((1S,2R,3R,5S)-2-fluoro-5-(4-methoxybenzyloxy)-3-vinylcyclo 
pentyloxy)diphenylsilane (64). Compound 63 (1.27 g, 2.53 mmol) was dissolved in dry 
dichloromethane (10 mL). Pyridine (0.4 mL, 5.05 mmol) and DAST (0.435 mL, 3.79 
mmol) were added. The solution was warmed to room temperature under protection of N
2
 
for 12 h. The reaction was quenched with saturated Na
2
CO
3
 solution (15 mL). The 
mixture was extracted with EtOAc (3?20 mL). The combined organic layer was dried 
over sodium sulfate, concentrated, and purified by silica gel column chromatography 
(hexane : EtOAc = 6:1) to provide 64 as a colorless oil (0.83g, 65.1%). 
1
H NMR (400 
MHz, CDCl
3
) ? 7.68-7.71 (m, 4H), 7.27-7.42 (m, 6H), 7.25 (d, J=2 Hz, 2H), 6.86 (d, J=2 
Hz, 2H), 5.32-5.42 (m,1H), 4.83 (m, 1H), 4.71-4.81 (m, 1H), 4.49 (d, J=11.6, 1H), 4.42 
(d, J=11.6 Hz, 1H), 3.81-3.92(m, 2H), 3.76 (s, 3H), 2.81-2.89 (m, 1H), 2.7 (s, 1H), 2.02-
2.12 (m, 1H), 1.55-1.65 (m, 1H), 1.07 (s, 9H); 
13
C NMR (100 MHz, CDCl
3
) ? 158.1, 
138.4, 135.5, 133.5, 131.1, 130.1, 129.7, 127.6, 121.1, 114.0, 85.2, 79.2, 77.9, 71.7, 55.5, 
 
100
44.3, 33.1, 25.3, 19.3. Anal. Calcd for C
31
H
37
FO
3
Si: C, 73.77; H, 7.39 Found: C, 74.02; 
H, 7.38. 
((1R,2R,3S,4S)-3-(tert-Butyldiphenylsilyloxy)-2-fluoro-4-(4-methoxybenzyloxy) 
cyclopentyl)methanol (65). Compound 64 (2 g, 3.96 mmol) was dissolved in MeOH (20 
mL). Water (13 mL) and NaIO
4
 (1.86 g, 8.72 mmol) were added. The mixture was cooled 
to 0 ?C. OsO
4
 (50 mg, 0.198 mmol, 5% mol) was added. The mixture was stirred at 0 ?C 
for 2 hours. The mixture was filtered. MeOH was removed by reduced pressure. The 
residue was extracted with dichloromethane (3?50 mL). The organic layer was washed 
with brine, dried over sodium sulfate, and concentrated. The residue was dissolved in 
methanol (20 mL). NaBH
4
 (375 mg, 9.91 mmol) was added portionwise at 0 ?C. The 
mixture as stirred at 0 ?C for 1 hour. Saturated NH
4
Cl solution (20 mL) was added. The 
mixture was filtered through celite. The solvent was removed with reduced pressure. The 
residue was extracted with EtOAc (3?15 mL). The combined organic layer was dried 
over sodium sulfate, concentrated. The residue was purified by silica column (hexane : 
EtOAc = 5:1) to provide 65 as a colorless oil (1.22 g, 60.3%). 
1
H NMR (400 MHz, 
CDCl
3
) ? 7.68-7.71 (m, 4H), 7.27-7.42 (m, 6H), 7.25 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 
Hz, 2H), 4.49 (d, J=11.6 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 3.81-3.92(m, 2H), 3.76 (s, 
3H), 3.31-3.40(m, 2H), 2.81-2.89 (m, 1H), 2.7 (s, 1H), 1.71-1.85 (m, 2H), 1.14 (s, 9H); 
13
C NMR (100 MHz, CDCl
3
) ? 158.1, 138.4, 133.5, 131.1, 130.1, 129.7, 127.6, 121.1, 
85.2, 79.2, 77.9, 71.7, 61.2, 55.5, 44.3, 33.1, 25.3, 19.3. Anal. Calcd for C
30
H
37
FO
4
Si: C, 
70.83; H, 7.33 Found: C, 70.23; H, 7.45. 
tert-Butyl(((1R,2R,3S,4S)-3-(tert-butyldiphenylsilyloxy)-2-fluoro-4-(4-methoxy 
benzyloxy)cyclopentyl)methoxy)diphenylsilane (66). Compound 65 (1.22 g, 2.4 mmol) 
 
101
was dissolved in dry dichloromethane (10 mL). 4-(Dimethylamino)pyridine (DMAP) (15 
mg, 0.12 mmol) was added. The solution was treated with imidazole (163 mg, 2.4 mmol), 
and TBDPSCl (0.68 mL, 2.64 mol) at 0 ?C. The solution was then warmed to room 
temperature and stirred for 2 hours. Water (10 mL) was added to quench the reaction. 
The mixture was extracted with EtOAc (3 ?10 mL). The combined organic layer was 
dried over sodium sulfate, concentrated, and purified by silica gel column 
chromatography (hexane : EtOAc = 8:1) to provide 66 as a colorless oil (1.67g, 93.2%). 
1
H NMR (400 MHz, CDCl
3
): ? 7.68-7.71 (m, 8H), 7.27-7.42 (m, 12H), 7.25 (d, J=8.4 Hz, 
2H), 6.86 (d, J=8.4 Hz, 2H), 4.56 (d, J=5.6 Hz, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.42 (d, 
J=11.6 Hz, 1H), 4.28 (m, 1H), 3.76 (s, 3H), 3.45-3.56 (m, 2H), 3.40 (m, 1H), 2.18-2.22 
(m, 2H), 1.8-1.9 (m, 1H), 0.93 (s, 9H), 0.88 (s, 9H). 
13
C NMR (100 MHz, CDCl
3
): ? 
158.1,138.4, 134.1, 133.5, 132.3, 131.1, 130.1, 130.4, 129.7, 128.5, 127.6, 121.1, 85.2, 
79.2, 77.9, 71.7, 61.2, 55.5, 44.3, 33.1, 25.3, 25.1, 19.3, 19.1. Anal. Calcd for 
C
46
H
55
FO
4
Si
2
: C, 73.95; H, 7.42 Found: C, 73.83; H, 7.24. 
(1S,2S,3R,4R)-2-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy) 
methyl)-3-fluoro-cyclopentanol (57). Compound 66 (1.67 g, 2.24 mmol) was dissolved 
in 19:1 dichloromethane/H
2
O (20 mL). DDQ (634 mg, 2.79 mmol) was added in one 
portion. The mixture was stirred at room temperature for 2 hours. Saturated Na
2
CO
3
 
solution (20 mL) was added. The mixture was extracted with EtOAc (3 ?15 mL) and the 
organic layer was separated, washed with saturated Na
2
CO
3
 solution (20 mL), brine (20 
mL), dried over sodium sulfate, concentrated and purified by silica gel column 
chromatography (hexane : EtOAc = 5:1) to provide 57 as a colorless oil (1.46 g, 65.1%). 
1
H NMR (400 MHz, CDCl
3
): ? 7.68-7.71 (m, 8H), 7.27-7.42 (m, 12H), 4.56 (d, J=5.6 Hz, 
 
102
1H), 4.28 (m, 1H), 3.46-3.56 (m, 2H), 3.40 (m, 1H), 2.28-2.32 (m, 2H), 1.8-1.9 (m, 1H), 
0.91 (s, 9H), 0.87 (s, 9H). 
13
C NMR (100 MHz, CDCl
3
): ? 138.3, 134.2, 133.6, 132.2, 
131.1, 130.1, 130.6, 127.5, 85.1, 79.3, 77.9, 61.2, 44.2, 33.1, 25.3, 25.1, 19.3, 19.1. Anal. 
Calcd for C
38
H
47
FO
3
Si
2
: C, 72.80; H, 7.56 Found: C, 72.91; H, 7.53. 
1H-Imidazo[4,5-c]pyridin-4-amine (67). Compound 11 (22.4 g, 146 mmol) was 
added to a mixture of anhydrous hydrazine (99%, 45.8 mL) and propan-1-ol (100 mL). 
The solution was brought to reflux for 8 h. The reaction was cooled to room temperature 
and the residual hydrazine and propan-1-ol was evaporated under reduced pressure. 
Water (100 mL) was added to dissolve the residue. Raney nickel (25.7 g) was added 
portionwise. The mixture was heated to reflux for 1 h. After the reaction had completed, 
the reaction mixture was filtered through a celite pad. The filtrate was evaporated under 
reduced pressure to afford 67 as a white solid (14.28 g, 73%). The NMR spectral data 
agreed with literature.
156
 
tert-Butyl 4-(bis(tert-butoxycarbonyl) amino) -1H ?imidazo [4,5-c] pyridine-1-
carboxylate (68). To 67 (6 g, 44.7 mmol) and 4-(dimethylamino)pyridine (DMAP) (546 
mg, 4.47 mmol) was added 100 mL of dry THF. To the resulting suspension was added 
(Boc)
2
O (39 g, 179 mmol). The reaction mixture was stirred for 2 days at room 
temperature under a nitrogen atmosphere. TLC analysis (hexane : EtOAc = 3:2) was used 
to monitor the reaction progress. Solvent was removed by evaporation under reduced 
pressure to give yellow oil. The crude product was purified by silica gel column 
chromatography (hexane : EtOAc = 1:1) to give 68 (16.4 g, 84.2%) as a white foam. 
1
H 
NMR (400 MHz, CDCl
3
): 8.47 (s, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.88 (d, J=5.6 Hz, 1H), 
1.73 (s, 9H), 1.40 (s, 18H). 
13
C NMR (100 MHz, CDCl
3
): 150.9, 147.1, 144.7, 143.5, 
 
103
142.7, 138.4, 136.7, 109.67, 91.0, 83.1, 28.0, 27.8. Anal. Calcd for C
21
H
30
N
4
O
6
: C, 58.05; 
H, 6.96; N, 12.89. Found: C, 58.15; H, 6.89; N, 12.77. 
4-(bis(tert-Butoxycarbonyl)amino)-1H-imidazo[4,5-c]pyridine-1-carboxylate (56). 
Compound 68 (5 g, 11.5 mmol) was dissolved in 100 mL of dry THF under N
2
. Bu
4
NF 
(43.3 mL, 43.3 mmol, 1 M in THF) was added and the reaction mixture was stirred for 12 
h. TLC analysis was used to monitor the reaction progress. Water (100 mL) was added. 
After extraction with EtOAc (3 ? 100 mL), the combined organic layers were washed 
with brine (100 mL), dried over anhydrous Na
2
SO
4
, filtered and the solvent was removed 
under reduced pressure. The crude product was purified by silica gel column 
chromatography (hexane : EtOAc = 1:3) to afford 56 (2.89 g, 75%) as a white foam. 
1
H 
NMR (400 MHz, CDCl
3
): 8.31 (d, J=5.6 Hz, 1H), 8.30 (s, 1H), 7.61 (d, J=5.6 Hz, 1H), 
1.35 (s, 18H). 
13
C NMR (100 MHz, CDCl
3
): 149.8, 147.1, 144.7, 143.5, 142.7, 138.4, 
136.7, 109.67, 89.6, 84.2, 27.7. Anal. Calcd for C
16
H
22
N
4
O
4
: C, 57.47; H, 6.63; N, 16.76. 
Found: C, 57.32; H, 6.54; N, 16.88.  
1-((1R, 2S, 3R, 4R)-2-(tert-Butyldiphenylsilyloxy)-4-((tert-butyl diphenylsilyloxy) 
methyl)-3-fluorocyclopentyl)-4-(N,N-di-(tert-butyl-O-carbonyl)amino)-1H-imidazo 
[4,5-c]pyridine (69). Compound 57 (2 g, 3.19 mmol) was dissolved in THF (20 mL). 56 
(1.6 g, 4.79mmol) and Ph
3
P (1.67g, 6.38 mmol) were added. The solution was cooled to -
40 ?C. Diisopropyl azodicarboxylate (DIAD) (0.93 mL, 4.79 mmol) was added dropwise. 
The mixture was warmed to room temperature, and then heated to 60 ?C for 24 hours. 
The solvent was removed under reduced pressure. The residue was purified by silica gel 
column chromatography (hexane : EtOAc = 2:1) to give crude 69 as yellow oil (1.2 g, 
 
104
39.8%). The crude product, which contaminated with diisopropyl hydrazine-1,2-
dicarboxylate, was used in next step without further purification. 
1-((1R,2S,3R,4R)-2-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy) 
methyl)-3-fluorocyclopentyl)-1H-imidazo[4,5-c]pyridin-4-amine (1). Compound 69 
(1.2g, 1.27 mmol) was dissolved in 1 N HCl (0.127 mL) in MeOH and stirred at 25 ?C 
overnight. Amberlite IRA-400(Cl) ion exchange resin was added to neutralize the 
solution until pH was 7. The mixture was filtered. The solvent was removed under 
reduced pressure, and the residue was purified by silica gel column chromatography 
(EtOAc : MeOH : NH
3
?H
2
O = 20:2:1) to provide 1 as a white solid (0.2 g, 59.7%), mp 
246-249 ?. 
1
H NMR (400 MHz, DMSO-d
6
) ? 8.13 (s, 1H), 7.82 (d, J=6 Hz, 1H), 7.64 (d, 
J=6 Hz, 1H), 6.14 (br, 2H), 5.46 (d, J=2 Hz, 1H), 4.85-4.95 (m, 2H), 4.80(d, J=2 Hz, 
1H), 3.95-4.01 (m, 2H), 3.51-3.63 (m, 2H), 2.31-2.36 (m, 1H), 1.97-2.00 (m, 1H). 
13
C 
NMR (100 MHz, DMSO-d
6
): ?152.3, 140.7, 140.6, 136.8, 135.2, 108.7, 94.2, 79.4, 72.9, 
63.9, 32.5, 25.3. Anal. Calcd for C
12
H
15
FN
4
O
2
: C, 54.13; H, 5.68; N, 21.04. Found: C, 
54.24; H, 5.62; N, 20.98. 
tert-Butyl((1S,2S,3R,5S)-2-fluoro-5-(4-methoxybenzyloxy)-3-vinylcyclopentyloxy) 
diphenylsilane (72). Compound 72 was prepared from 58 by the same procedure as 
described for the synthesis of compound 64. 
1
H NMR (400 MHz, CDCl
3
) ? 7.66-7.71 (m, 
4H), 7.37-7.42 (m, 6H), 7.25 (d, J=2 Hz, 2H), 6.86 (d, J=2 Hz, 2H), 5.32-5.42 (m,1H), 
4.83 (m, 1H), 4.69-4.72 (m, 1H), 4.49 (d, J=11.6 Hz, 1H), 4.42 (d, J=11.6 Hz, 1H), 3.81-
3.92(m, 2H), 3.76 (s, 3H), 2.81-2.89 (m, 1H), 2.7 (s, 1H), 2.02-2.12 (m, 1H), 1.55-1.65 
(m, 1H), 1.07 (s, 9H); 
13
C NMR (100 MHz, CDCl
3
) ? 158.2, 138.5, 135.6, 133.8, 131.2, 
 
105
130.2, 129.6, 127.5, 121.2, 114.1, 85.1, 79.1, 78.0, 71.8, 55.5, 44.5, 33.1, 25.3, 19.3. Anal. 
Calcd for C
31
H
37
FO
3
Si: C, 73.77; H, 7.39 Found: C, 73.89; H, 7.42. 
((1R,2S,3S,4S)-3-(tert-Butyldiphenylsilyloxy)-2-fluoro-4-(4-methoxybenzyloxy) 
cyclopentyl)methanol (73). Compound 73 was prepared from 72 by the same procedure 
as described for the synthesis of compound 65. 
1
H NMR (400 MHz, CDCl
3
) ? 7.67-7.71 
(m, 4H), 7.26-7.41 (m, 6H), 7.24 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.48 (d, 
J=11.6 Hz, 1H), 4.43 (d, J=11.6 Hz, 1H), 3.80-3.91(m, 2H), 3.75 (s, 3H), 3.32-3.41(m, 
2H), 2.82-2.89 (m, 1H), 2.7 (s, 1H), 1.71-1.82 (m, 2H), 1.14 (s, 9H); 
13
C NMR (100 MHz, 
CDCl
3
) ? 158.2, 138.3, 133.6, 131.2, 130.1, 129.6, 127.5, 121.2, 85.3, 79.1, 78.0, 71.6, 
61.3, 55.4, 44.2, 33.2, 25.4, 19.2. Anal. Calcd for C
30
H
37
FO
4
Si: C, 70.83; H, 7.33 Found: 
C, 70.64; H, 7.39. 
tert-Butyl(((1R,2S,3S,4S)-3-(tert-butyldiphenylsilyloxy)-2-fluoro-4-(4-methoxy 
benzyloxy)cyclopentyl)methoxy)diphenylsilane (74). Compound 74 was prepared from 
73 by the same procedure as described for the synthesis of compound 66.
 1
H NMR (400 
MHz, CDCl
3
): ? 7.69-7.72 (m, 8H), 7.29-7.42 (m, 12H), 7.27 (d, J=8.4 Hz, 2H), 6.87 (d, 
J=8.4 Hz, 2H), 4.57 (d, J=5.6 Hz, 1H), 4.50 (d, J=11.6 Hz, 1H), 4.43 (d, J=11.6 Hz, 1H), 
4.28-4.30 (m, 1H), 3.75 (s, 3H), 3.46-3.55 (m, 2H), 3.39-3.41 (m, 1H), 2.19-2.23 (m, 2H), 
1.8-1.9 (m, 1H), 0.94 (s, 9H), 0.89 (s, 9H). 
13
C NMR (100 MHz, CDCl
3
): ? 158.2, 138.5, 
134.2, 133.4, 132.2, 131.2, 130.2, 130.4, 129.7, 128.6, 127.7, 121.2, 85.3, 79.3, 77.8, 71.7, 
61.3, 55.4, 44.2, 33.2, 25.4, 25.2, 19.3, 19.0. Anal. Calcd for C
46
H
55
FO
4
Si
2
: C, 73.95; H, 
7.42 Found: C, 73.91; H, 7.33. 
(1S,2S,3S,4R)-2-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy) 
methyl)-3-fluorocyclopentanol (71). Compound 71 was prepared from 74 by the same 
 
106
procedure as described for the synthesis of compound 57. 
1
H NMR (400 MHz, CDCl
3
): 
?7.68-7.71 (m, 8H), 7.27-7.42 (m, 12H), 4.56 (d, J=5.6 Hz, 1H), 4.28 (m, 1H), 3.46-3.56 
(m, 2H), 3.41 (m, 1H), 2.27-2.31 (m, 2H), 1.8-1.9 (m, 1H), 0.92 (s, 9H), 0.88 (s, 9H). 
13
C 
NMR (100 MHz, CDCl
3
): ? 138.5, 134.3, 133.7, 132.4, 131.1, 130.2, 130.7, 127.6, 85.2, 
79.4, 77.9, 61.3, 44.3, 33.2, 25.4, 25.3, 19.5, 19.2. Anal. Calcd for C
38
H
47
FO
3
Si
2
: C, 
72.80; H, 7.56 Found: C, 72.89; H, 7.44. 
1-((1R,2S,3S,4R)-2-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy) 
methyl)-3-fluorocyclopentyl)-4-(N,N-di-(tert-butyl-O-carbonyl)amino)-1H-
imidazo[4,5-c]pyridine (75). Compound 75 was prepared from 71 and 56 by the same 
procedure as described for the synthesis of compound 69, which was used in next step 
without further purification. 
(1S,2S,3R,5R)-5-(4-amino-1H-imidazo[4,5-c]pyridin-1-yl)-2-fluoro-3-(hydroxyl 
methyl)cyclopentanol (2). Compound 2 was prepared from 75 by the same procedure as 
described for the synthesis of compound 1. Mp 248-250 ?. 
1
H NMR (400 MHz, DMSO-
d
6
) ? 8.15 (s, 1H), 7.81 (d, J=6 Hz, 1H), 7.63 (d, J=6 Hz, 1H), 6.13 (br, 2H), 5.45 (d, J=2 
Hz, 1H), 4.84-4.94 (m, 2H), 4.79(d, J=2 Hz, 1H), 3.96-4.01 (m, 2H), 3.50-3.62 (m, 2H), 
2.32-2.36 (m, 1H), 1.97-2.00 (m, 1H). 
13
C NMR (100 MHz, DMSO-d
6
): ?152.4, 140.9, 
140.6, 136.9, 135.3, 108.8, 94.3, 79.5, 73.0, 63.9, 32.6, 25.4. Anal. Calcd for 
C
12
H
15
FN
4
O
2
: C, 54.13; H, 5.68; N, 21.04. Found: C, 54.18; H, 5.62; N, 20.89. 
O-(1R,2S,3S,5R)-2-(tert-Butyldiphenylsilyloxy)-3-(4-methoxybenzyloxy)-5-
vinylcyclopentyl S-methyl carbonodithioate (78). A solution of compound 58 (2 g, 
3.98 mmol) and imidazole (27 mg, 0.4 mmol) in dry THF (20 mL) was added NaH (318 
mg, 7.96 mmol, 60% in mineral oil). The reaction was stirred for 30 min, after which 
 
107
time CS
2
 (0.6 mL, 9.95 mmol) was added. MeI (1.0 mL, 15.91 mmol) was then added 
after another 40 min. The mixture was stirred for 40 min. It was quenched with CH
2
Cl
2
 
(20 mL), poured into water (20 mL), and extracted with CH
2
Cl
2
 (3 ? 20 mL). The organic 
phase was dried with anhydrous Na
2
SO
4
 and then evaporated to dryness. The residue was 
submitted to silica gel column chromatography (hexane : EtOAc = 6:1) to yield 78 as a 
yellow oil (1.89 g, 50.1%). 
1
H NMR (400 MHz, CDCl
3
) ? 7.68-7.71 (m, 4H), 7.34-7.37 
(m, 6H), 7.28 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.32-5.42 (m,1H), 4.83 (m, 1H), 
4.71-4.81 (m, 1H), 4.53 (d, J=11.6 Hz, 1H), 4.45 (d, J=11.6 Hz, 1H), 3.76-3.82 (m, 5H), 
2.72-2.6 (m, 1H), 2.7 (s, 1H), 2.42 (s, 3H), 2.01-2.10 (m, 1H), 1.54-1.57 (m, 1H), 1.01 (s, 
9H); 
13
C NMR (100 MHz, CDCl
3
) ? 215.4, 157.9, 137.3, 135.3, 133.2, 131.2, 130.3, 
129.6, 127.5, 121.2, 114.1, 83.8, 79.2, 77.8, 71.6, 55.4, 44.2, 33.8, 25.3, 19.9, 19.4. Anal. 
Calcd for C
33
H
40
O
4
S
2
Si: C, 66.85; H, 6.8 Found: C, 66.76; H, 6.64. 
tert-Butyl-((1R,2S,4S)-2-(4-methoxybenzyloxy)-4-vinylcyclopentyloxy) diphenyl 
silane (79).  
Method 1: To a refluxing solution of Bu
3
SnH (4.2 mL, 15.94 mmol) in dry toluene 
(10 mL) was added dropwise a solution of compound 78 (1.89 g, 3.19 mmol) and AIBN 
(52 mg) in dry toluene (10 mL). The reaction was stirred for 30 min, and then the 
reaction mixture was extracted with CH
2
Cl
2
 (3 ? 50 mL). The organic phase was dried 
with anhydrous Na
2
SO
4
 and concentrated to dryness. The residue was submitted to silica 
gel column chromatography (hexane : EtOAc = 6:1) to provide 79 as a light yellow oil 
(725 mg, 46.7%). 
1
H NMR (400 MHz, CDCl
3
) ? 7.68-7.71 (m, 4H), 7.34-7.37 (m, 6H), 
7.28 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.32-5.42 (m,1H), 4.81-4.82 (m, 1H), 
4.71-4.80 (m, 1H), 4.53 (d, J=11.6 Hz, 1H), 4.45 (d, J=11.6 Hz, 1H), 4.11-4.16 (m, 1H), 
 
108
3.84-3.91 (m, 1H), 3.82 (s, 3H), 3.40-3.51 (m, 2H), 1.75-1.82 (m, 1H), 1.65-1.72 (m, 1H), 
1.52-1.58 (m, 1H), 0.88 (s, 9H) 
13
C NMR (100 MHz, CDCl
3
) ?157.8, 137.2, 135.2, 133.3, 
131.2, 130.2, 129.5, 127.4, 121.1, 119.9, 79.4, 76.2, 70.3, 55.2, 44.1, 36.2, 33.7, 25.2, 
19.5. Anal. Calcd for C
31
H
38
O
3
Si: C, 76.5; H, 7.78 Found: C, 76.66; H, 7.70. 
Method 2: MsCl (0.19 mL, 2.39 mmol) was added dropwise over 15 min to a cooled 
(0 ?C) and stirred solution of 58 (1 g, 1.99 mmol) and Et
3
N (0.33 mL, 2.39 mmol) in 
CH
2
Cl
2
 (10 mL). After the mixture had stirred for another 0.5 h at that temperature, H
2
O 
(10 mL) was added, and the mixture was extracted with CH
2
Cl
2
 (2 ? 10 mL). The organic 
extract was washed with H
2
O (2 ? 10 mL) and brine (1 ? 5 mL), and dried. Solvent 
removal in vacuo afforded the residue containing the crude mesylate 82. A solution of the 
above mesylate 82 in THF (10 mL) was added dropwise to a suspension of LiAlH
4
 (0.159 
g, 4.18 mmol) in THF (10 mL) at room temperature. After the mixture had heated at 
reflux for 4 h, it was cooled with ice water, and treated with sat. aq Na
2
SO
4
 (1.5-2.0 mL). 
The white gelatinous precipitate was filtered, the precipitate was washed with Et
2
O, and 
the filtrate was concentrated in vacuo. This gave a residue, which was purified by silica 
gel column chromatography (hexane : EtOAc = 7:1) to afford 79 as a colorless oil (0.43g, 
44.8%);  
((1S,3R,4S)-3-(tert-Butyldiphenylsilyloxy)-4-(4-methoxybenzyloxy) cyclopentyl) 
methanol (80). Compound 80 was prepared from 79 by the same procedure as described 
for the synthesis of compound 65. 
1
H NMR (400 MHz, CDCl
3
) ? 7.66-7.70 (m, 4H), 
7.32-7.36 (m, 6H), 7.24 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.55 (d, J=11.6 Hz, 
1H), 4.47(d, J=11.6 Hz, 1H), 4.12-4.17 (m, 1H), 3.88-3.92 (m, 1H), 3.82 (s, 3H), 3.41-
3.51 (m, 2H), 1.74-1.80 (m, 2H), 1.67-1.71 (m, 2H), 1.53-1.59 (m, 1H), 0.89 (s, 9H) 
13
C 
 
109
NMR (100 MHz, CDCl
3
): ?156.7, 134.1, 133.5, 131.4, 130.3, 129.6, 127.7, 121.4, 79.3, 
76.3, 70.7, 68.2, 54.9, 44.3, 36.1, 32.9, 25.1, 19.4. Anal. Calcd for C
30
H
38
O
4
Si: C, 73.43; 
H, 7.81 Found: C, 73.33; H, 7.76. 
tert-Butyl(((1S,3R,4S)-3-(tert-butyldiphenylsilyloxy)-4-(4-methoxybenzyloxy) 
cyclopentyl ) methoxy)diphenylsilane (81). Compound 81 was prepared from 80 by the 
same procedure as described for the synthesis of compound 66. 
1
H NMR (400 MHz, 
CDCl
3
) ? 7.76-7.82 (m, 8H), 7.44-7.49 (m, 12H), 7.21 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 
Hz, 2H), 4.54 (d, J=11.6 Hz, 1H), 4.46(d, J=11.6 Hz, 1H), 4.11-4.15 (m, 1H), 3.87-3.90 
(m, 1H), 3.83 (s, 3H), 3.40-3.49 (m, 2H), 1.74-1.79 (m, 2H), 1.62-1.66 (m, 2H), 1.52-
1.58 (m, 1H), 0.91 (s, 9H), 0.89 (s, 9H) 
13
C NMR (100 MHz, CDCl
3
) ?156.8, 134.2, 
134.0, 133.5, 132.5, 131.4, 130.2, 130.1, 129.5, 128.3, 127.6, 121.3, 79.3, 76.5, 70.8, 68.1, 
54.8, 44.2, 36.1, 32.8, 25.3, 25.2, 19.6, 19.4. Anal. Calcd for C
46
H
56
O
4
Si
2
: C, 75.78; H, 
7.74 Found: C, 75.66; H, 7.73.
 
(1S,2R,4S)-2-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy) methyl) 
cyclopentanol (77). Compound 77 was prepared from 81 by the same procedure as 
described for the synthesis of compound 57. 
1
H NMR (400 MHz, CDCl
3
) ? 7.75-7.81 (m, 
8H), 7.45-7.49 (m, 12H), 4.11-4.15 (m, 1H), 3.77-3.82 (m, 1H), 3.41-3.48 (m, 2H), 1.68-
1.72 (m, 2H), 1.61-1.66 (m, 2H), 1.53-1.57 (m, 1H), 0.90 (s, 9H), 0.88 (s, 9H) 
13
C NMR 
(100 MHz, CDCl
3
) ? 134.3, 134.1, 133.7, 132.7, 131.4, 130.4, 130.1, 127.7, 79.4, 76.5, 
68.2, 44.3, 36.2, 32.7, 25.3, 24.1, 19.6, 19.4. Anal. Calcd for C
38
H
48
O
3
Si
2
: C, 74.95; H, 
7.94 Found: C, 74.88; H, 7.86. 
1-((1R, 2R, 4S)-2-(tert-Butyldiphenylsilyloxy) -4-((tert-butyldiphenylsilyloxy ) 
methyl) -cyclopentyl) -4- (N,N-di- (tert-butyl-O-carbonyl)amino)-1H-imidazo[4,5-c] 
 
110
pyridine (83). Compound 83 was prepared from 77 and 56 by the same procedure as 
described for the synthesis of compound 69, which was used in next step without further 
purification. 
(1R,2R,4S)-2-(4-Amino-1H-imidazo[4,5-c]pyridin-1-yl)-4-(hydroxymethyl) cyclo 
pentanol (3). Compound 3 was prepared from 83 by the same procedure as described for 
the synthesis of compound 1. Mp 221-224 ?. 
1
H NMR (400 MHz, DMSO-d
6
) ? 8.12 (s, 
1H), 7.77 (d, J=6 Hz, 1H), 7.63 (d, J=6 Hz, 1H), 6.15 (br, 2H), 4.11-4.15 (m, 1H), 3.77-
3.82 (m, 1H), 3.41-3.48 (m, 2H), 1.68-1.72 (m, 2H), 1.61-1.66 (m, 2H), 1.53-1.57 (m, 
1H). 
13
C NMR (100 MHz, DMSO-d
6
): ?155.2, 141.6, 141.7, 135.2, 135.0, 108.5, 79.3, 
72.9, 63.8, 41.1, 32.6, 25.2. Anal. Calcd for C
12
H
16
N
4
O
2
: C, 58.05; H, 6.5; N, 22.57. 
Found: C, 58.14; H, 6.63; N, 22.21. 
(1R,2R,3R,5S)-2-(tert-Butyldiphenylsilyloxy)-5-(4-methoxybenzyloxy)-3-vinyl 
cyclopentyl 2-chloroacetate (86). Compound 86 was prepared from 61 by the same 
procedure as described for the synthesis of compound 62, which was used in next step 
without further purification. 
(1R,2R,3R,5S)-2-(tert-Butyldiphenylsilyloxy)-5-(4-methoxybenzyloxy)-3-vinyl 
cyclopentanol (87). Compound 87 was prepared from 86 by the same procedure as 
described for the synthesis of compound 63. 
1
H NMR (400 MHz, CDCl
3
) ? 7.65-7.72 (m, 
4H), 7.35-7.42 (m, 6H), 7.24 (d, J=4.8 Hz, 2H), 6.84 (d, J=4.8 Hz, 2H), 5.35-5.44 
(m,1H), 4.7-4.93 (m, 2H), 4.42-4.48 (m, 2H), 3.8 (s, 3H), 3.73-3.79 (m, 2H), 2.82-2.89 
(m, 1H), 2.5 (s, 1H), 2.01-2.09 (m, 1H), 1.56-1.61 (m, 1H), 1.05 (s, 9H); 
13
C NMR (100 
MHz, CDCl
3
) ? 159.6, 136.2, 134.2, 133.2, 131.3, 130.2, 129.3, 128.1, 120.9, 114.2, 85.1, 
 
111
79.2, 77.8, 72.7, 55.4, 47.2, 33.2, 27.1, 19.4. Anal. Calcd for C
31
H
38
O
4
Si: C, 74.06; H, 
7.62 Found: C, 74.03; H, 7.51. 
tert-Butyl((1R,2S,3S,5R)-2-fluoro-3-(4-methoxybenzyloxy)-5-vinylcyclo 
pentyloxy)diphenylsilane (88). Compound 88 was prepared from 87 by the same 
procedure as described for the synthesis of compound 64.
 1
H NMR (400 MHz, CDCl
3
) ? 
7.69-7.72 (m, 4H), 7.27-7.42 (m, 6H), 7.25 (d, J=2 Hz, 2H), 6.86 (d, J=2 Hz, 2H), 5.32-
5.42 (m,1H), 4.83-4.92 (m, 2H), 4.39-4.44 (m, 2H), 3.81-3.92(m, 2H), 3.76 (s, 3H), 2.80-
2.86 (m, 1H), 2.5 (s, 1H), 2.02-2.12 (m, 1H), 1.55-1.65 (m, 1H), 1.08 (s, 9H); 
13
C NMR 
(100 MHz, CDCl
3
) ? 158.2, 138.6, 135.4, 133.4, 130.9, 130.3, 129.5, 127.6, 121.2, 114.1, 
85.3, 79.3, 78, 71.6, 55.4, 44.3, 33.1, 25.2, 19.5. Anal. Calcd for C
31
H
37
FO
3
Si: C, 73.77; 
H, 7.39 Found: C, 73.82; H, 7.33. 
((1R,2R,3S,4S)-2-(tert-Butyldiphenylsilyloxy)-3-fluoro-4-(4-methoxybenzyloxy) 
cyclopentyl)methanol (89). Compound 89 was prepared from 88 by the same procedure 
as described for the synthesis of compound 65. 
1
H NMR (400 MHz, CDCl
3
) ? 7.67-7.70 
(m, 4H), 7.28-7.41 (m, 6H), 7.25 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.41-4.48 (m, 
2H), 3.80-3.88(m, 2H), 3.74 (s, 3H), 3.69-3.72(m, 2H), 2.81-2.89 (m, 1H), 2.5 (s, 1H), 
1.71-1.85 (m, 2H), 1.14 (s, 9H); 
13
C NMR (100 MHz, CDCl
3
) ? 157.9, 138.3, 133.4, 
131.2, 129.8, 129.6, 127.5, 121.2, 85.3, 79.1, 77.8, 71.5, 61.4, 55.2, 44.2, 32.8, 25.4, 19.6. 
Anal. Calcd for C
30
H
37
FO
4
Si: C, 70.83; H, 7.33 Found: C, 70.63; H, 7.44. 
tert-Butyl(((1R,2R,3S,4S)-2-(tert-butyldiphenylsilyloxy)-3-fluoro-4-(4-methoxy 
benzyloxy)cyclopentyl)methoxy)diphenylsilane (90). Compound 90 was prepared from 
89 by the same procedure as described for the synthesis of compound 66. 
1
H NMR (400 
MHz, CDCl
3
): ? 7.69-7.72 (m, 8H), 7.23-7.33 (m, 12H), 7.26 (d, J=8.4 Hz, 2H), 6.93 (d, 
 
112
J=8.4 Hz, 2H), 4.57 (d, J=5.6 Hz, 1H), 4.47-4.51 (m, 2H), 4.26 (m, 1H), 3.75 (s, 3H), 
3.66-3.72 (m, 2H), 3.41 (m, 1H), 2.19-2.23 (m, 2H), 1.81-1.89 (m, 1H), 0.94 (s, 9H), 0.89 
(s, 9H). 
13
C NMR (100 MHz, CDCl
3
): ? 158.5,138.3, 134.2, 133.4, 132.2, 131.2, 130.4, 
130.1, 129.7, 128.6, 127.5, 121.2, 85.2, 79.2, 77.9, 71.8, 61.2, 55.6, 44.3, 33.2, 25.3, 25.1, 
19.2, 19.0. Anal. Calcd for C
46
H
55
FO
4
Si
2
: C, 73.95; H, 7.42 Found: C, 73.78; H, 7.32. 
(1S,2S,3R,4R)-3-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy) 
methyl)-2-fluorocyclopentanol (85). Compound 85 was prepared from 90 by the same 
procedure as described for the synthesis of compound 57. 
1
H NMR (400 MHz, CDCl
3
): ? 
7.69-7.73 (m, 8H), 7.32-7.42 (m, 12H), 4.66 (d, J=5.6 Hz, 1H), 4.28-4.31 (m, 1H), 3.71-
3.79 (m, 2H), 3.23-3.26 (m, 1H), 2.29-2.32 (m, 2H), 1.82-1.92 (m, 1H), 0.91 (s, 9H), 0.87 
(s, 9H). 
13
C NMR (100 MHz, CDCl
3
): ? 138.2, 134.1, 133.5, 132.1, 131.3, 130.3, 130.7, 
127.6, 85.2, 79.2, 77.2, 61.3, 44.3, 33.2, 25.3, 25.2, 19.3, 19.0. Anal. Calcd for 
C
38
H
47
FO
3
Si
2
: C, 72.80; H, 7.56 Found: C, 72.81; H, 7.44. 
1-((1R,2S,3R,4R)-3-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy) 
methyl)-2-fluorocyclopentyl)-4-(N,N-di-(tert-butyl-O-carbonyl)amino)-1H-imidazo 
[4,5-c]pyridine (91). Compound 91 was prepared from 85 and 56 by the same procedure 
as described for the synthesis of compound 69, which was used in next step without 
further purification. 
(1R,2S,3R,5R)-3-(4-amino-1H-imidazo[4,5-c]pyridin-1-yl)-2-fluoro-5-(hydroxyl 
methyl) cyclopentanol (4). Compound 4 was prepared from 91 by the same procedure as 
described for the synthesis of compound 1. Mp 238-241 ?. 
1
H NMR (400 MHz, DMSO-
d
6
) ? 8.13 (s, 1H), 7.69 (d, J=6 Hz, 1H), 6.84 (d, J=6 Hz, 1H), 6.14 (br, 2H), 5.46 (d, J=2 
Hz, 1H), 4.81-4.92 (m, 2H), 4.80(d, J=2 Hz, 1H), 3.92-4.00 (m, 2H), 3.71-3.79 (m, 2H), 
 
113
2.32-2.37 (m, 1H), 1.98-2.02 (m, 1H). 
13
C NMR (100 MHz, DMSO-d
6
): ?151.8, 141.5, 
141.3, 135.5, 135.1, 108.6, 94.1, 78.8, 72.8, 62.8, 32.4, 24.9. Anal. Calcd for 
C
12
H
15
FN
4
O
2
: C, 54.13; H, 5.68; N, 21.04. Found: C, 54.14; H, 5.61; N, 20.93. 
tert-Butyl((1R,2R,3S,5R)-2-fluoro-3-(4-methoxybenzyloxy)-5-vinylcyclopentyloxy) 
diphenylsilane (94). Compound 94 was prepared from 61 by the same procedure as 
described for the synthesis of compound 64. 
1
H NMR (400 MHz, CDCl
3
) ? 7.7-7.74 (m, 
4H), 7.29-7.42 (m, 6H), 7.26 (d, J=2 Hz, 2H), 6.87 (d, J=2 Hz, 2H), 5.34-5.43 (m,1H), 
4.83-4.92 (m, 2H), 4.4-4.45 (m, 2H), 3.81-3.90(m, 2H), 3.73 (s, 3H), 2.81-2.86 (m, 1H), 
2.51 (s, 1H), 2.06-2.14 (m, 1H), 1.53-1.63 (m, 1H), 1.07 (s, 9H); 
13
C NMR (100 MHz, 
CDCl
3
) ? 157.3, 137.5, 135.1, 133.3, 130.9, 130.3, 129.6, 127.6, 121.3, 114.2, 85.3, 79.3, 
78, 71.5, 55.6, 44.3, 33.2, 25.1, 19.5. Anal. Calcd for C
31
H
37
FO
3
Si: C, 73.77; H, 7.39 
Found: C, 73.71; H, 7.29. 
((1R,2R,3R,4S)-2-(tert-Butyldiphenylsilyloxy)-3-fluoro-4-(4-methoxybenzyloxy) 
cyclopentyl)methanol (95). Compound 95 was prepared from 94 by the same procedure 
as described for the synthesis of compound 65. 
1
H NMR (400 MHz, CDCl
3
) ? 7.67-7.70 
(m, 4H), 7.27-7.38 (m, 6H), 7.25 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.42-4.48 (m, 
2H), 3.82-3.89(m, 2H), 3.73 (s, 3H), 3.69-3.72(m, 2H), 2.82-2.88 (m, 1H), 2.49 (s, 1H), 
1.71-1.85 (m, 2H), 1.13 (s, 9H); 
13
C NMR (100 MHz, CDCl
3
) ? 157.4, 138.3, 133.3, 
131.2, 130.1, 129.5, 127.5, 121.3, 85.4, 79.1, 77.9, 71.5, 61.4, 55.3, 44.3, 32.7, 25.5, 19.7. 
Anal. Calcd for C
30
H
37
FO
4
Si: C, 70.83; H, 7.33 Found: C, 70.71; H, 7.41. 
tert-Butyl(((1R,2R,3R,4S)-2-(tert-butyldiphenylsilyloxy)-3-fluoro-4-(4-methoxy 
benzyloxy) cyclopentyl) methoxy) diphenylsilane (96). Compound 96 was prepared 
from 95 by the same procedure as described for the synthesis of compound 66. 
1
H NMR 
 
114
(400 MHz, CDCl
3
): ? 7.7-7.74 (m, 8H), 7.25-7.33 (m, 12H), 7.26 (d, J=8.4 Hz, 2H), 6.92 
(d, J=8.4 Hz, 2H), 4.56 (d, J=5.6 Hz, 1H), 4.46-4.50 (m, 2H), 4.25 (m, 1H), 3.75 (s, 3H), 
3.64-3.70 (m, 2H), 3.40 (m, 1H), 2.17-2.22 (m, 2H), 1.82-1.89 (m, 1H), 0.93 (s, 9H), 0.88 
(s, 9H). 
13
C NMR (100 MHz, CDCl
3
): ? 159.1, 138.3, 134.2, 133.3, 132.1, 131.1, 130.3, 
130.1, 129.5, 128.4, 127.1, 121.1, 85.4, 79.5, 77.3, 71.8, 61.1, 55.4, 44.2, 33.2, 25.3, 25.1, 
19.2, 19.0. Anal. Calcd for C
46
H
55
FO
4
Si
2
: C, 73.95; H, 7.42 Found: C, 73.87; H, 7.36. 
(1S,2R,3R,4R)-3-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy) 
methyl)-2-fluorocyclopentanol (93). Compound 93 was prepared from 96 by the same 
procedure as described for the synthesis of compound 57. 
1
H NMR (400 MHz, CDCl
3
): ? 
7.66-7.70 (m, 8H), 7.28-7.37 (m, 12H), 4.62 (d, J=5.6 Hz, 1H), 4.24-4.27 (m, 1H), 3.71-
3.76 (m, 2H), 3.21-3.25 (m, 1H), 2.29-2.3 (m, 2H), 1.81-1.88 (m, 1H), 0.91 (s, 9H), 0.87 
(s, 9H). 
13
C NMR (100 MHz, CDCl
3
): ? 137.6, 134.5, 133.4, 132.1, 131.4, 130.2, 130.8, 
127.5, 85.3, 79.1, 77.1, 61.3, 44.1, 32.9, 25.4, 25.2, 19.3, 19.2. Anal. Calcd for 
C
38
H
47
FO
3
Si
2
: C, 72.80; H, 7.56 Found: C, 72.68; H, 7.53. 
1-((1R,2R,3R,4R)-3-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenyl silyloxy) 
methyl)-2-fluorocyclopentyl)-4-(N,N-di-(tert-butyl-O-carbonyl)amino)-1H-
imidazo[4,5-c]pyridine (97). Compound 97 was prepared from 93 and 56 by the same 
procedure as described for the synthesis of compound 69, which was used in next step 
without further purification. 
(1R,2R,3R,5R)-3-(4-Amino-1H-imidazo[4,5-c]pyridin-1-yl)-2-fluoro-5-(hydroxyl 
methyl)cyclopentanol (5). Compound 5 was prepared from 97 by the same procedure as 
described for the synthesis of compound 1. Mp 239-242 ?. 
1
H NMR (400 MHz, DMSO-
d
6
) ? 8.14 (s, 1H), 7.67 (d, J=6 Hz, 1H), 6.82 (d, J=6 Hz, 1H), 6.15 (br, 2H), 5.44 (d, J=2 
 
115
Hz, 1H), 4.79-4.89 (m, 2H), 4.75(d, J=2 Hz, 1H), 3.90-3.97 (m, 2H), 3.70-3.79 (m, 2H), 
2.31-2.36 (m, 1H), 1.98-2.02 (m, 1H). 
13
C NMR (100 MHz, DMSO-d
6
): ?151.6, 141.3, 
141.1, 135.1, 135.0, 107.9, 94.4, 78.6, 72.5, 62.6, 32.4, 24.8. Anal. Calcd for 
C
12
H
15
FN
4
O
2
: C, 54.13; H, 5.68; N, 21.04. Found: C, 54.05; H, 5.59; N, 20.94. 
O-(1S,2R,3R,5S)-2-(tert-Butyldiphenylsilyloxy)-5-(4-methoxybenzyloxy)-3-vinyl 
cyclopentyl S-methyl carbonodithioate (100). Compound 100 was prepared from 61 by 
the same procedure as described for the synthesis of compound 78. 
1
H NMR (400 MHz, 
CDCl
3
) ? 7.68-7.71 (m, 4H), 7.34-7.37 (m, 6H), 7.28 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 
Hz, 2H), 5.32-5.42 (m,1H), 4.81-4.92 (m, 2H),4.47-4.53 (m, 2H), 3.78 (s, 3H), 3.71-3.76 
(m, 2H), 2.81-2.91 (m, 1H), 2.5 (s, 1H), 2.42 (s, 3H), 2.01-2.10 (m, 1H), 1.54-1.57 (m, 
1H), 1.01 (s, 9H); 
13
C NMR (100 MHz, CDCl
3
) ? 216.3, 157.1, 136.8, 135.3, 133.8, 
131.3, 130.3, 129.7, 127.5, 121.3, 114.2, 83.8, 79.5, 77.6, 71.4, 55.3, 44.2, 33.6, 25.3, 
19.7, 19.2. Anal. Calcd for C
33
H
40
O
4
S
2
Si: C, 66.85; H, 6.8 Found: C, 66.72; H, 6.71. 
tert-Butyl((1S,2R,4S)-4-(4-methoxybenzyloxy)-2-vinyl cyclo pentyloxy) diphenyl 
silane (101). Compound 101 was prepared from 100 by the same procedure as described 
for the synthesis of compound 79. 
1
H NMR (400 MHz, CDCl
3
) ? 7.68-7.71 (m, 4H), 
7.34-7.37 (m, 6H), 7.28 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 5.32-5.42 (m,1H), 
4.82-4.88 (m, 2H), 4.48-4.53 (m, 2H), 4.12-4.16 (m, 1H), 3.84-3.91 (m, 1H), 3.79 (s, 3H), 
3.42-3.51 (m, 2H), 1.76-1.83 (m, 1H), 1.66-1.73 (m, 1H), 1.53-1.59 (m, 1H), 0.89 (s, 9H) 
13
C NMR (100 MHz, CDCl
3
) ?157.6, 137.3, 135.2, 133.4, 131.3, 130.3, 129.6, 127.6, 
121.3, 119.7, 79.4, 76.4, 70.3, 55.3, 44.3, 36.2, 33.7, 25.3, 19.6. Anal. Calcd for 
C
31
H
38
O
3
Si: C, 76.5; H, 7.78 Found: C, 76.56; H, 7.87. 
 
116
((1R,2S,4S)-2-(tert-Butyldiphenylsilyloxy)-4-(4-methoxybenzyloxy) cyclopentyl) 
methanol (102). Compound 102 was prepared from 101 by the same procedure as 
described for the synthesis of compound 65. 
1
H NMR (400 MHz, CDCl
3
) ? 7.64-7.71 (m, 
4H), 7.30-7.35 (m, 6H), 7.26 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 4.42-4.48 (m, 
2H), 4.12-4.17 (m, 1H), 3.88-3.92 (m, 1H), 3.78 (s, 3H), 3.66-3.69 (m, 2H), 1.68-1.74 (m, 
2H), 1.64-1.67 (m, 2H), 1.54-1.60 (m, 1H), 0.89 (s, 9H) 
13
C NMR (100 MHz, CDCl
3
): 
?156.3, 134.2, 133.5, 131.6, 130.3, 129.7, 127.7, 121.6, 79.3, 76.2, 70.7, 68.2, 54.8, 44.3, 
36.1, 32.8, 25.2, 19.3. Anal. Calcd for C
30
H
38
O
4
Si: C, 73.43; H, 7.81 Found: C, 73.37; H, 
7.71. 
tert-Butyl(((1R, 2S, 4S)-2-(tert-butyldiphenylsilyloxy)-4-(4-methoxy benzyloxy) 
cyclopentyl)methoxy)diphenylsilane (103). Compound 103 was prepared from 102 by 
the same procedure as described for the synthesis of compound 66. 
1
H NMR (400 MHz, 
CDCl
3
) ? 7.78-7.84 (m, 8H), 7.41-7.51 (m, 12H), 7.22 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 
Hz, 2H), 4.41-4.51 (m, 2H), 4.13-4.16 (m, 1H), 3.87-3.90 (m, 1H), 3.7 (s, 3H), 3.66-3.69 
(m, 2H), 1.73-1.78 (m, 2H), 1.64-1.68 (m, 2H), 1.51-1.57 (m, 1H), 0.91 (s, 9H), 0.89 (s, 
9H) 
13
C NMR (100 MHz, CDCl
3
) ?156.6, 134.1, 134.0, 133.5, 132.6, 131.4, 130.1, 130.1, 
129.5, 128.2, 127.4, 121.3, 79.3, 76.6, 70.8, 68.2, 54.8, 44.2, 36.2, 32.7, 25.3, 25.1, 19.5, 
19.2. Anal. Calcd for C
46
H
56
O
4
Si
2
: C, 75.78; H, 7.74 Found: C, 75.71; H, 7.62. 
(1S,3S,4R)-3-(tert-Butyldiphenylsilyloxy)-4-((tert-butyl diphenyl silyloxy) methyl) 
cyclopentanol (99). Compound 99 was prepared from 103 by the same procedure as 
described for the synthesis of compound 57. 
1
H NMR (400 MHz, CDCl
3
) ? 7.73-7.79 (m, 
8H), 7.42-7.48 (m, 12H), 4.12-4.16 (m, 1H), 3.71-3.79 (m, 1H), 3.42-3.47 (m, 2H), 1.68-
1.72 (m, 2H), 1.61-1.65 (m, 2H), 1.52-1.58 (m, 1H), 0.91 (s, 9H), 0.89 (s, 9H) 
13
C NMR 
 
117
(100 MHz, CDCl
3
) ? 135.4, 134.7, 133.2, 131.6, 132.4, 130.3, 130.2, 127.3, 78.8, 76.5, 
68.3, 44.3, 36.9, 32.9, 25.3, 24.1, 19.6, 19.4. Anal. Calcd for C
38
H
48
O
3
Si
2
: C, 74.95; H, 
7.94 Found: C, 75.03; H, 7.88. 
1-((1R,3S,4R)-3-(tert-Butyldiphenylsilyloxy)-4-((tert-butyldiphenylsilyloxy) 
methyl)-cyclopentyl)-4-(N,N-di-(tert-butyl-O-carbonyl)amino)-1H-imidazo[4,5-c] 
pyridine (104). Compound 104 was prepared from 99 and 56 by the same procedure as 
described for the synthesis of compound 69, which was used in next step without further 
purification. 
(1S,2R,4R)-4-(4-Amino-1H-imidazo[4,5-c]pyridin-1-yl)-2-(hydroxymethyl) 
cyclopentanol (6). Compound 6 was prepared from 104 by the same procedure as 
described for the synthesis of compound 1. Mp 223-226 ?. 
1
H NMR (400 MHz, DMSO-
d
6
) ? 8.13 (s, 1H), 7.68 (d, J=6 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 6.12 (br, 2H), 4.12-4.16 
(m, 1H), 3.77-3.82 (m, 1H), 3.71-3.79 (m, 2H), 1.68-1.72 (m, 2H), 1.61-1.66 (m, 2H), 
1.51-1.55 (m, 1H). 
13
C NMR (100 MHz, DMSO-d
6
): ?155.3, 141.5, 140.8, 135.3, 135.1, 
108.3, 79.2, 72.8, 63.7, 41.3, 32.6, 25.3. Anal. Calcd for C
12
H
16
N
4
O
2
: C, 58.05; H, 6.5; N, 
22.57. Found: C, 58.08; H, 6.48; N, 22.61.  
(3aR,4S,6aR)-4-Methyl-4,6a-dihydro-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1?-
cyclopentan]-4-ol (108). MeLi (31.2 mL, 1.6 M, 49.9 mmol) was added to a solution of 
32 (5.0 g, 27.7 mmol) in dry THF (50 mL) at -78 ? dropwise. After stirring at -78 ? for 
30 min, the reaction mixture was warmed to room temperature and stirred for 1 h. The 
reaction was quenched by the addition of aqueous NH
4
Cl (50 mL) at 0 ?, the aqueous 
phase was extracted with ethyl acetate (3 ? 50 mL), and the combined organic layers 
were dried over MgSO
4
, filtered, and concentrated in vacuo. The residue was purified 
 
118
through silica gel column chromatography (hexane : EtOAc = 5:1) to give 108 (4.63 g, 
85%) as a white solid: mp 43-44 ?; 
1
H NMR (400 MHz, CDCl
3
): ? 5.81 (d, J=9.2 Hz, 
1H), 5.74 (d, J=9.2 Hz, 1H), 5.04-5.07 (m, 1H), 4.24 (d, J=9.2 Hz, 1H), 3.09 (s, 1H), 
1.79-1.84 (m, 4H), 1.61-1.70 (m, 4H), 1.33 (s, 3H); 
13
C NMR (100 MHz, CDCl
3
) ?142.3, 
131.7, 114.8, 84.9, 81.9, 80.3, 78.9, 39.3, 37.9, 20.3, 20.1; Anal. Calcd for C
11
H
16
O
3
: C, 
67.32; H, 8.22. Found: C, 67.18; H, 8.13.  
(3aS,6aS)-6-Methyl-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1?-cyclopentan]-4(6aH) 
-one (109). A mixture of 108 (3.43 g, 17.6 mmol), PDC (13.26 g, 35.3 mmol), 4 ? 
molecular sieves (3.0 g), and Ac
2
O (7.84 mL, 141 mmol) in dichloromethane (100 mL) 
was stirred at room temperature overnight. The solvent was removed in vacuo and the 
residue partitioned between saturated aqueous Na
2
CO
3
 (100 mL) and CH
2
Cl
2
 (100 mL). 
The aqueous layer was washed with CH
2
Cl
2
 (2 ? 100 mL) and the combined organic 
layers were dried over MgSO
4
, filtered, and concentrated in vacuo. The residuewas 
purified by silica gel column chromatography (hexane : EtOAc = 10:1) to afford 109 
(1.87 g, 54.8%) as a white solid: mp 80-81 ?. 
1
H NMR (400 MHz, CDCl
3
) ? 5.99 (s, 
1H), 4.96 (d, J=5.6 Hz, 1H), 4.41 (d, J=5.6 Hz, 1H), 2.2 (s, 3H), 1.68-1.86 (m, 4H), 
1.62-1.67 (m, 4H); 
13
C NMR (100 MHz, CDCl
3
) ? 202.8, 184.3, 174.8, 130.0, 116.0, 80.7, 
37.3, 35.9, 24.9, 20.5, 20.1; Anal. Calcd for C
11
H
14
O
3
: C, 68.02; H, 7.27. Found: C, 68.18; 
H, 7.26.  
(3aS,4S,6aS)-4-methyl-4-vinyldihydro-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1?-
cyclopentan]-6(6aH)-one (110). Vinylmagnesium bromide (10.95 mL, 10.95 mmol, 1.0 
M in THF) and HMPA (3.2 mL, 18.25 mmol) were added to a suspension of CuBr?Me2S 
(150 mg, 0.73 mmol) in dry THF (20 mL) at -78 ? over 10 min. After stirring at -78 ?  
 
119
for 15 min, a solution of 109 (1.42 g, 7.3 mmol) and TMSCl (1.94 mL, 15.33 mmol) in 
dry THF (20 mL) was added dropwise over 30 min. The reaction mixture was stirred at -
78 ? for 2 h, and then quenched by the addition of saturated NH
4
Cl (10 mL). The 
reaction mixture was extracted with EtOAc (3 ? 40 mL), the combined organic phases 
were dried over MgSO
4
, filtered, and concentrated in vacuo. The residue was purified by 
silica gel column chromatography (hexane : EtOAc = 10:1) to give 110 (1.13 g, 69.8%) 
as a colorless oil. 
1
H NMR (400 MHz, CDCl
3
) ? 5.66-5.73 (m, 1H), 4.99-5.04 (m, 2H), 
4.4-4.43 (d, J=5.6 Hz, 1H), 4.11-4.22 (d, J=5.6 Hz, 1H), 1.94 (d, J=7 Hz, 2H), 1.68-1.86 
(m, 4H), 1.62-1.67 (m, 4H), 1.12 (s, 3H); 
13
C NMR (100 MHz, CDCl
3
) ? 213.6, 142.9, 
114.4, 113.3, 82.8, 79.2, 44.5, 41.6, 36.7, 34.6, 25.0, 21.9, 21.7; Anal. Calcd for C
13
H
18
O
3
: 
C, 70.24; H, 8.16. Found: C, 70.11; H, 8.09. 
(3aS, 4S, 6R, 6aR)-4-Methyl-4-vinyltetrahydro-3aH-spiro[cyclopenta[d] [1,3] 
dioxole-2,1?-cyclopentan]-6-ol (111). CeCl
3
?7H
2
O (1.43 g, 4.95 mmol) was added to a 
solution of 110 (1 g, 4.5 mmol) in MeOH (10 mL) at -30 ?. After stirring for 15 min at -
30 ?, NaBH
4
 (340 mg, 9.0 mmol) was added carefully and the reaction mixture was 
warmed to room temperature for 30 min. The mixture was neutralized with conc. HCl, 
reduced to 2/3 volume, extracted with brine and ether. The organic layers combined, 
dried (MgSO
4
), and concentrated. The residue was purified by silica gel column 
chromatography (hexane : EtOAc = 5:1) to give 111 (866 mg, 85.8%) as a colorless oil. 
1
H NMR (400 MHz, CDCl
3
) ? 5.66-5.73 (m, 1H), 4.99-5.03 (m, 2H), 4.37 (t, J=6.0 Hz, 
1H), 4.22 (d, J=5.5 Hz, 1H), 3.99-4.03 (m, 1H), 2.41 (d, J=10.0 Hz, 1H), 1.94-1.98 (m, 
5H), 1.52-1.72 (m, 5H), 1.11 (s, 3H); 
13
C NMR (100 MHz, CDCl
3
) ? 143.9, 112.9, 111.2, 
 
120
84.7, 78.5, 70.8, 44.2, 41.9, 35.9, 33.9, 25.2, 21.3, 20.99; Anal. Calcd for C
13
H
20
O
3
: C, 
69.61; H, 8.99. Found: C, 69.73; H, 8.82. 
4-Chloro-1-((3aS,4S,6S,6aR)-4-methyl-4-vinyltetrahydro-3aH-spiro[cyclopenta 
[d][1,3]dioxole-2,1?-cyclopentane]-6-yl)-1H-imidazo[4,5-c]pyridine  (112). Tf
2
O (1.5 
mL, 8.92 mmol) was added to a solution of 111 (1 g, 4.46 mmol) and pyridine (1.44 mL, 
17.83 mmol) in dry dichloromethane (10 mL) at 0 ?. After stirring for 50 min at 0 ?, 
cold dichloromethane (10 mL) and ice-water (20 mL) were added. The aqueous layer was 
washed with cold dichloromethane (15 mL) and the combined organic phases were dried 
over MgSO
4
, filtered, and concentrated to give the crude triflate 106, which was dried in 
vacuo at 0 ? for 1 h. A solution of 11 (1.3 g, 8.47 mmol), NaH (357 mg, 8.92 mmol, 
60% dispersion in mineral oil), and 18-crown-6 (2.36 g, 8.92 mmol) in DMF (15 mL) 
was heated at 70 ?  for 4 h and then cooled to 0 ?. To this mixture was added the 
solution of previously prepared triflate in DMF (5 mL), and the reaction mixture was 
allowed to stir at 0 ?  for 12 h and then at room temperature for 2 days. DMF was 
removed in vacuo and the residue was purified by silica gel column chromatography 
(hexane : EtOAc = 5:1) to give 112 (882 mg, 55%) as a colorless oil. 
1
H NMR (400 MHz, 
CDCl
3
) ? 8.09 (s, 1H), 7.65 (d, J=5.6 Hz, 1H), 7.55 (d, J=5.6 Hz, 1H), 5.95-6.01 (m, 1H), 
5.06-5.14 (m, 3H), 4.98-5.02 (m, 1H), 4.69 (d, J=6.5 Hz, 1H), 2.64-2.69 (m, 1H), 2.26- 
2.3 (m, 1H), 1.80-1.82 (m, 2H), 1.64-1.69 (m 2H), 1.48- 1.59 (m, 4H), 1.26 (s, 3H); 
13
C 
NMR (100 MHz, CDCl
3
) ?149.8, 139.7, 137.2, 136.7, 132.3, 122.6, 114.8, 113.0, 108.1, 
84.9, 83.9, 61.5, 46.3, 42.8, 36.1, 34.2, 25.1, 21.9, 21.7; HRMS calcd for C
19
H
22
ClN
3
O
2
 
359.1488, found 359.1438. 
 
121
((3aR, 4S, 6S, 6aS) -4- (4-Chloro-1H-imidazo [4,5-c] pyridin-1-yl)-6-methyl 
tetrahydro-3aH-spiro[cyclopenta[d][1,3]dioxole-2,1?-cyclopentane]-6-yl)methanol 
(113). Compound 112 (882 mg, 2.45 mmol) was dissolved in MeOH (8 mL). Water (8.3 
mL) was added. NaIO
4
 (1.15 g, 5.39 mmol) was added. The mixture was cooled to 0 ?C. 
OsO
4
 (31 mg, 0.12 mmol, 5% mol) was added. The mixture was stirred at 0 ?C for 2 
hours. The mixture was filtered. MeOH was removed by reduced pressure. The residue 
was extracted with dichloromethane (3?10 mL). The organic layer was washed with 
brine, dried over sodium sulfate, concentrated. The residue was dissolved in methanol (10 
mL). NaBH
4
 (232 mg, 6.13 mmol) was added portionwise at 0 ?C. The mixture as stirred 
at 0 ?C for 1 hour. Saturated NH
4
Cl solution (10 mL) was added. The mixture was 
filtered through celite. The solvent was removed with reduced pressure. The residue was 
extracted with EtOAc (3 ?10 mL). The combined organic layer was dried over sodium 
sulfate, concentrated. The residue was purified by silica gel column chromatography 
(hexane : EtOAc = 3:1) to provide 113 as a white foam (587 mg, 65.8%). 
1
H NMR (400 
MHz, CDCl
3
), ? 8.27 (s, 1H), 8.22 (d, J=5.6 Hz, 1H), 7.57 (d, J=5.6 Hz, 1H), 4.74-4.78 
(m, 1H), 4.63-4.65 (m, 1H), 4.46-4.48 (d, J= 6.4 Hz, 1H), 3.61 (d, J=5.6 Hz, 2H), 2.62-
2.68 (m, 1H), 2.31-2.37 (m, 1H), 1.65-1.8 (m, 8H), 1.2 (s, 3H); 
13
C NMR (100 MHz, 
CDCl
3
) ?149.9, 139.6, 137.1, 132.2, 122.7, 113.2, 108.2, 84.7, 83.9, 67.5, 61.5, 46.2, 42.6, 
36.2, 34.3, 25.2, 21.9, 21.7; Calcd HRMS for C
18
H
22
ClN
3
O
3
: 363.1377, Foud: 363.1367. 
(1R,2S,3S,5S)-5-(4-Chloro-1H-imidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)-3-
methylcyclopentane-1,2-diol (114). Compound 113 (587 mg, 1.61 mmol) was dissolved 
in 2 N HCl (1 mL) in MeOH at 0 ?C and stirred at 25 ?C overnight. NaHCO
3
 was added 
to neutralize the solution until it no longer bubbled. The mixture was filtered. The solvent 
 
122
was removed under reduced pressure, and the residue was purified by silica gel column 
chromatography (EtOAc : MeOH = 2:1) to provide 114 as a white solid (287 mg, 59.7%), 
mp 184-186 ?. 
1
H NMR (400 MHz, DMSO-d
6
), ? 8.56 (s, 1H), 8.13 (d, J=5.6 Hz, 1H), 
7.82 (d, J=5.6 Hz, 1H), 4.82-4.92 (m, 1H), 4.53-4.57 (m, 1H), 3.9-3.93 (m, 1H), 3.51 (d, 
J=5.6 Hz, 1H), 3.44 (d, J=5.6 Hz, 1H), 3.29 (s, 1H), 2.09-2.18 (m, 1H), 2.01-2.07 (m, 
1H), 1.12 (s, 3H). 
13
C NMR (100 MHz, DMSO-d
6
) ? 149.3, 138.4, 136.8, 132.1, 119.2, 
108.4, 75.7, 74.5, 69.4, 60.4, 44.4, 36.7, 18.4; Calcd HRMS for C
13
H
16
ClN
3
O
3
: 297.0965, 
Foud: 297.0961.  
(1R,2S,3S,5S)-5-(4-Amino-1H-imidazo[4,5-c]pyridin-1-yl)-3-(hydroxymethyl)-3-
methylcyclopentane-1,2-diol (7). To a mixture of anhydrous hydrazine (99%, 1 mL) and 
propan-1-ol (3 mL) was added 114 (287 mg, 1.87 mmol). The solution was brought to 
reflux for 8 h. The reaction was cooled to room temperature and the residual hydrazine 
and propan-1-ol was evaporated under reduced pressure. Water (5 mL) was added to 
dissolve the residue. Raney nickel (0.8 g) was added portionwise. The mixture was 
heated to reflux for 1 h. After the reaction had completed, the reaction mixture was 
filtered through a celite pad. The filtrate was evaporated under reduced pressure and the 
residue was purified by silica gel column chromatography (EtOAc : MeOH : NH
3
?H
2
O = 
20:2:1) to provide 7 as a white solid (76 mg, 30.3%), mp 208-209 ?. 
1
H NMR (400 
MHz, MeOD), ? 8.21 (s, 1H), 7.64 (d, J=6 Hz, 1H), 7.0 (d, J=6 Hz, 1H), 4.56-4.78 (m, 
1H), 4.53-4.57 (m, 1H), 3.94 (d, J=6 Hz, 1H), 3.51 (d, J=5.6 Hz, 1H), 3.48 (d, J=5.6 Hz, 
1H), 2.08-2.13 (m, 1H), 1.98-2.05 (m, 1H), 1.13 (s, 3H). 
13
C NMR (100 MHz, MeOD) ? 
176.5, 153.3, 142.3, 140.4, 128.2, 99.7, 77.5, ,76.0, 70.6, 62.7, 45.7, 37.7, 20.1. Calcd 
HRMS for C
13
H
18
N
4
O
3
: 279.1469, Foud: 279.1457.
 
123
 
 
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