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.

Key words

propargyl alcohols - allyl alcohols - N-allylprolinol derivatives - O-acetylmandelic acid - enantioselective reduction - Mosher analysis

Publication History

Received: 02 March 2021

Accepted after revision: 24 March 2021

Article published online:
15 April 2021

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The diastereomerically pure alcohols (4R)-20 and (4S)-20 with unknown absolute configuration were converted into the corresponding esters with (R)- and (S)-Mosher acid. The anisotropic shielding effect of the aryl group causes a more intensive upfield shift of adjacent protons upon comparison of the ¹H NMR spectra of both esters. Adopting favorable conformations of the carbon backbone (zigzag chain with minimized repulsive interactions), the Newman projections presented in the Supporting Information indicate the proximity of R¹ and R² of the carbinol and the Mosher ester substituents Ph and OMe. For details, see the Supporting Information. Also see:
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