Chiral Formamidines. The Total Asymmetric Synthesis of (-)-8-Azaestrone and Related (-)-8-Aza-12-oxo-17-desoxoestrone

Article abstract of DOI:10.1021/jo00043a036

Attachment of the chiral formamidine moiety to 6-methoxy-1,2,3,4-tetrahydroisoquinoline afforded the key chiral, nonracemic precursor 8, upon which the azasteroid skeleton was constructed.Asymmetric alkylation with α-halo esters or β-halo ethers gave 15 and 22, respectively, in high ee's.Cyclization, following enamine formation with cyclopentanedione or cyclopentanone, led to the chiral steroidal skeletons 6 and 5, respectively.The final stereocenters, leading to 8-azaestrone 4 with unnatural absolute configuration (antipodal), were accomplished by intramolecular alkylation of (+)-6b and subsequent reduction and ether cleavage.For the 12-oxosteroid 3, the methyl at C-13 was inserted by initial conjugate reduction of the enone 5 with a copper hydride reagent (Stryker method) requiring the presence of a silyl chloride affording 21.The addition of methyl iodide to C-13 occurred after transforming the triethylsilyl enol ether, 21, to its lithium enolate.Stereochemical assignments for both azasteroids 3 and 4 were confirmed by spectroscopic means including circular dichroism curves.