This Is AuburnElectronic Theses and Dissertations

Synthesis of 10, 11, 12, 12a, 12b, 13-Hexahydro-5H-benzo[f]cyclopropa[d]pyrido[1,2-b] Isoquinoline-5,7(9H)dione and Related Compounds




Tinkleman, Joseph

Type of Degree



Pharmacal Sciences


Agents designed to bind with high DNA sequence selectivity offer great therapeutic opportunities in the treatment of cancer and other genetic disorders. The need for sequence selective agents arises from the fact that the administration of chemotherapeutic agents typically lead to many adverse effects due to their lack of cellular specificity. The natural products (+)-CC-1065 (1), Duocarmycin A (2), and Duocarmycin SA (3) have been shown to selectively alkylate AT-rich regions within the minor groove; whereas, Anthramycin (20) has been shown to selectively alkylate GC-rich areas. Therapeutic interest in these drugs led to the incorporation of several key structural v features into compound 28, which was subsequently modified during the course of this dissertation. The initial target compound was identified as 10, 11, 12, 12a, 12b, 13- hexahydro-5H-benzo[f]cyclopropa[d]pyrido[1,2-b]isoquinoline-5,7(9H)-dione (27). The imine 40 was condensed with the anhydride 38 to afford the diastereomeric mixture of acids 41, which were subsequently reduced and separated to give the pure alcohols 42. The individual alcohols were then activated through methane sulfonate formation followed by debenzylation and cyclization to give the title compound in 50% overall yield. The proceeding target compounds were identified as 9, 10, 11, 11a, 11b, 12- hexahydrobenzo[f]cyclopropa[d]pyrrolo[1,2-b]isoquinoline-5,7-dione (28) and 2-methyl- 1, 2, 10, 10a-tetrahydrobenzo[f]cyclopropa[d]isoquinoline-3,5-dione (98). Analysis of both compounds revealed that the key intermediate, which could be used in both syntheses was identified as 4-bromo-1-benzyloxy-2-naphthoic acid (92). The bromo acid 92 was condensed with either 2-propenyl pyrrolidine (87) or N-methyl-N-butene (101) and the rest of the synthetic routes were carried out under similar conditions to afford the desired final compounds.