I.~Thermal cycloaddition reactions of pi-delocalized singlet vinylcarbenes.~II.~(4 + 2) Cycloaddition reactions of unactivated 1,3-oxazin-6-ones.~III.~Synthesis and properties of 1,2,7,7a-tetrahydrocycloprop(1,2-c)indol-4-one analogs of CC-1065

Ronald John Wysocki, Purdue University

Abstract

Experimental investigations conducted with the intention of more carefully defining the scope and mechanism of the three-carbon + two-carbon cycloaddition reaction of $\pi$-delocalized singlet vinylcarbenes are detailed. The (3 + 2) cycloaddition reactions of the $\pi$-delocalized singlet vinlycarbene, three-carbon 1,1-/1,3-dipoles generated in a reversible, thermal ring opening of cyclopropenone ketals, with electron-deficient alkenes bearing two geminal electron-withdrawing substituents may proceed with partial, though not complete, loss of substrate olefin geometry in a process in which the rate and stereoselectivity of the reaction has proven independent of the solvent polarity. The experimental observations appear to be consistent with a single-electron transfer/anion-radical and cation-radical mechanism. Unactivated 1,3-oxazin-6-ones participate in well-defined and predictable (4 + 2) cycloaddition reactions with a variety of electron-rich dienophiles including ynamines, enamines, enol ethers, and enol esters. The order of reactivity correlates well with the nucleophilic character of the dienophile. The cycloaddition reaction is regiospecific with exclusive formation of one regioisomer and therefore allows for the synthesis of highly substituted pyridines previously unavailable by other methods. The preparation of 4-methyl-2-propyl-1,3-oxazin-6-one, the scope of its participation in (4 + 2) cycloaddition reactions, and its potential for rubrolone AB ring construction are detailed. (+)-CC-1065 (NSC-298223), an antitumor-antibiotic isolated from cultures of Streptomyces zelensis, possesses exceptionally potent in vitro cytotoxic activity, broad spectrum antimicrobial activity, and confirmed in vivo activity. The synthesis of N-(phenylsulfonyl)- and N-(tert-butyloxycarbonyl)-1,2,7,7a-tetrahydrocycloprop (1,2-c) indol-4-one, N-(phenylsulfonyl)-CI and N-BOC-CI, constituting stable derivatives of the parent spirocyclic cyclopropylcyclohexadienone ring system of the CC-1065 left-hand subunit is described. The approach employed in the total synthesis of the CI agents is based on a final intramolecular alkylation (Winstein Ar-3$\sp\prime$ alkylation) of an appropriately C-3 functionalized 6-hydroxy-3-methylindoline which is indirectly derived from a self-terminating 5-exo-trig aryl radical-alkene cyclization. The incorporation of the parent CI subunit with CDPI$\sb1$ (3-carbamoyl-1,2-dihydro-3H-pyrrolo (3,2-$e$) indole-7-carboxylic acid and CDPI$\sb2$(CDPI dimer) into the total synthesis of CI-CDPI$\sb 1$ and CI-CDPI$\sb 2$ constitutes minimum potent pharmacophores of CC-1065, is detailed. Resolution of 6-benzyloxy-1-(tert-butyloxycarbonyl)-3-(hydroxymethyl)indoline and incorporation into the preparation of (+)- and ($-$)-seco-N-BOC-CI, (+)- and (-)-CI-CDPI$\sb1$, and (+)- and (-)-CI-CDPI$\sb2$ is described. Preliminary DNA binding properties, comparative biological activity, comparative spectroscopic and chemical properties and solvolytic reactivity are presented. Most notably, the CI-based agents were shown to possess the identical sequence-selective DNA binding properties of (+)-CC-1065 and CPI-based agents.

Degree

Ph.D.

Advisors

Boger, Purdue University.

Subject Area

Organic chemistry

COinS