Synthesis of Optically Active N-(4-Hydroxynon-2-enyl)pyrrolidines: Key Building Blocks in the Total Synthesis of Streptomyces coelicolor Butanolide 5 (SCB-5) and Virginiae Butanolide A (VB-A)

Abstract

Starting from 5-methylhexanal and (S)-configured N-propargylprolinol ethers, coupling delivered N-(4-hydroxynon-2-ynyl)prolinol derivatives as mixtures of C4 diastereomers. Resolution of the epimers succeeded after introduction of an (R)-mandelic ester derivative and subsequent HPLC separation. Alternatively, suitable oxidation gave the corresponding alkynyl ketone. Midland reagent controlled diastereoselective reduction afforded a defined configured propargyl alcohol with high selectivity. LiAlH4 reduction and Mosher analyses of the allyl alcohols enabled structure elucidation. The suitably protected products are used as key intermediates in enantioselective Streptomyces γ-butyrolactone signaling molecule total syntheses.

Synthesis of (–)-Virginiae Butanolide A (VB-A)

“…Adopting favorable conformations of the carbon backbone (zick zack chain with minimized repulsive interactions), the Newman projections presented below indicate the proximity of R 1 and R 2 of the carbinol and the Mosher ester substituents Ph and OMe. [4] Derivatization of alcohol ent-10 with (R)-MTPA VIII-R affording ester ent-IX and with (S)-MTPA VIII-S affording ester ent-X. Comparison of the 1 H NMR spectra: Protons H-2 and H-3 suffer from upfield shift in ester ent-X and downfield shift in ester ent-IX: H-2 and H-3 are located in R 1 , alcohol ent-10 must be (R)-configured.…”

“…The aromatic protons could not be clearly assigned separately from each other due to their similar chemical shifts 4. The carbon atoms C-13 and C-18, C-14 and C-19, C-15 and C-20, C-16 and C-21 as well as C-21 and 9C-17 could not be clearly assigned separately from each other due to their similar chemical shifts.This article is protected by copyright.…”

“…3 Among the VB (Virginiae butanolide) type compounds, which are characterized by a 2-(1'(S) hydroxyalkyl) substituent, (-)-VB-A was detected as the most active compound regulating virginiamycin M1 and virginiamycin S biosyntheses. 4 In contrast, the SCB/IM-2 GBLs (Streptomyces coelicolor butanolide/Inducing Material-2) incorporate a 2-(1'(R) hydroxyalkyl) chain stimulating, e. g., actinorhodin, undecylprodigiosin as well as showdomycin (S. griseus) and minimycin (S. lavendulae) production. 5 Until now, the configuration of the stereocenters of the Gräfe factors need to be elucidated.…”