Alkaloid Synthesis Using Chiral δ-Amino β-Ketoesters:  A Stereoselective Synthesis of (−)-Lasubine II

Abstract

[reaction: see text]A highly stereoselective asymmetric synthesis of the quinolizidinealkaloid (-)-lasubine II from a delta-amino beta-hydroxy ketone, a new polyfunctionalized chiral building block, is described.

Asymmetric synthesis of alkaloids using polyfunctionalized chiral building blocks

“…[3,4-dimethoxy)phenyl]pentanoate (18), with Zn(BH 4 ) 2 gave a 50:6 syn/anti ratio of the ␤-amino alcohol (−)-19 (Scheme 6) [11]. This reduction sets the trans arrangement of the 1-aryl and 3-hydroxy groups found in lasubine II (25).…”

“…Reduction with LiAlH 4 gave (+)-11, and the amino and hydroxyl groups were differentially protected by sequential treatment with trifluoroacetic anhydride (TFAA) and acetic anhydride to furnish (+)-12. [3,4-dimethoxy)phenyl]pentanoate (18), with Zn(BH 4 ) 2 gave a 50:6 syn/anti ratio of the ␤-amino alcohol (−)-19 (Scheme 6) [11]. SCHEME 3 Asymmetric synthesis of monosubstituted piperidines from ␦-amino ␤-ketoesters.…”

“…The phenyl group in 12 was oxidized to the carboxylic acid using NaIO 4 /RuCl 3 , which furnished cis-(2R,4S)-(+)-4-hydroxypipecolic acid (13) in 79% (Scheme 4). The asymmetric synthesis of 25 represents a new and concise entry into the quinolizidine skeleton [11]. trans-(4S,6 R)-4-Hydroxy-6-phenylpiperidin-2one (16) is required for the synthesis of trans-(2R,4R)-(+)-4-hydroxypipecolic acid (17) (Scheme 5) [10].…”

“…Deprotection of the benzyl group and reaction with pyridine and TsCl completes the synthesis of (−)-25. The asymmetric synthesis of 25 represents a new and concise entry into the quinolizidine skeleton [11].…”

Indolizidine and quinolizidine alkaloids

“…76 Addition of the sodium enolate of methyl acetate (4.0 equivalents) proved to be highly diastereoselective (de >95%), affording the (R S ,S )-δ-amino-β-ketoester 181 in 93% yield. 76 Addition of the sodium enolate of methyl acetate (4.0 equivalents) proved to be highly diastereoselective (de >95%), affording the (R S ,S )-δ-amino-β-ketoester 181 in 93% yield.…”