Asymmetric Synthesis of (2S,3R)-Capreomycidine and the Total Synthesis of Capreomycin IB

Abstract

A 27 step total synthesis of the tuberculostatic macrocyclic peptide antibiotic capreomycin IB has been accomplished. The synthesis features the use of an enolate-aldimine condensation between a chiral glycine aluminum enolate and the benzyl imine of 3-tert-butyldimethylsiloxy-propanal as a means of preparing the cyclic guanidine amino acid (2S,3R)-capreomycidine. Additionally, a Hofmann rearrangement was exacted on a late-stage pentapeptide in order to transform an asparagine residue into a diaminopropanoic acid residue.

Synthesis of Phidianidines A and B

“…Eventually we found that reduction of the azide with activated zinc 10 and ammonium formate in MeOH for 7 h at 25 °C proceeded cleanly to give polar amine 12b that was used without purification. 11a Coupling of 12b with Boc-protected S -methylisothiourea 13 using Et 3 N and AgNO 3 4b, 12 in DMF for 2 h at 0 °C and 5 h at 25 °C afforded protected guanidine 14b in 60% yield from 11b . Deprotection of 14b by stirring in 10:1 CH 2 Cl 2 /TFA for 8 h at 25 °C removed the Boc protecting groups providing phidianidine B ( 1b ) in 92% yield.…”

Synthetic Approaches to α,β‐Diamino Acids

“…The enantiopure Ni(II) complex of benzophenone a-imino glycinate and the aluminum enolate of a chiral oxazinone derived from glycine have been used for the synthesis of fluorinated 2,3-diamino acids (98% d.e.) [7] and capreomycidine [8], respectively. Chiral imines can participate as inductors of asymmetry in the Mannich process.…”

Methods for the Chemical Synthesis of Noncoded α‐Amino Acids found in Natural Product Peptides

“…Demong and Williams reported the asymmetric synthesis of capreomycidine (six steps, 28% yield) en route to his total synthesis of capreomycin IB [247,248]. By invoking an enolate-aldimine strategy, condensation of benzylimine 179 with the lithium enolate of chiral glycinate 180 resulted in an inseparable 3.3 : 1 mixture of diastereomers 181 epimeric at the b-carbon (Scheme 5.45).…”