Full details of an enantioselective total synthesis of (+)-duocarmycin A (1) are described in which a solution to the control of the relative and absolute stereochemistry of the remote stereocenters is provided. Catalytic asymmetric dihydroxylation of 15 was employed to introduce the absolute stereochemistry required for the activated cyclopropane, and a diastereoselective Dieckmann-type condensation of 61 was employed to control the absolute stereochemistry of the C6 quaternary center. The complementary diastereoselectivity of a thermodynamic versus kinetic condensation of 61 permitted the divergent synthesis of (+)-duocarmycin A or epi-(+)-duocarmycin A from common intermediates. Final introduction of the reactive cyclopropane was accomplished by transannular spirocyclization of the mesylate 44 upon treatment with base or directly from the corresponding free alcohol itself, duocarmycin D1 (42), upon Mitsunobu activation. Notably, the asymmetric dihydroxylation of 15 employing (DHQD)2-PHAL/(DHQ)2-PHAL was found to proceed with a reverse enantioselectivity than predicted from established models. Employing this approach, the key partial structures (+)-N-BOC-DA (67) and (+)-6-epi-N-BOC-DA (71) and their unnatural enantiomers were also prepared, and a study of their acid-catalyzed solvolysis reactivity, regioselectivity (3:2), and stereochemistry is detailed. Notably, the solvolysis reaction regioselectivity is lower than the characteristic adenine N3 alkylation of duplex DNA, which proceeds with exclusive nucleophilic addition to the least substituted C8 cyclopropane carbon. This may be attributed to the significant destabilizing torsional strain and steric interactions characteristic of the SN2 reaction of a large nucleophile that accompany the abnormal addition of adenine when restricted to the minor groove bound orientation of the reactants.

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