Synthesis of (S)-Nyasol through a Copper-Catalyzed Propargylic Substitution

Abstract

(S)-Nyasol was selected as a target to demonstrate the efficiency of a copper-catalyzed substitution of secondary propargylic phosphates. The key phosphate (R)-TBDPSO(CH₂)₂CH[C≡C(C₆H₄-4-OTBS)]OP(O)(OEt)₂ was synthesized from TBDPSO(CH₂)₂CO₂H in four steps. Substitution of the phosphate with 4-TBSOC₆H₄MgBr in the presence of CuBr·Me₂S as a catalyst in THF–DME proceeded with both stereo- and regioselectivity at the propargylic position. All the silyl groups in the propargylic product, TBDPSO(CH₂)₂CH[C≡C(C₆H₄-4-OTBS)](C₆H₄-4-OTBS) were removed, and the acetylene bond was reduced by using active Zn to produce the cis-olefin. Finally, the HO(CH₂)₂ moiety was converted into CH₂=CH, giving (S)-nyasol with 97% cis selectivity, 94.5% ee, and >99% enantiospecificity. Similarly, dihydronyasol was synthesized through hydrogenation of the substitution product, followed by construction of the terminal olefin.

Key words

synthesis - nyasol - propargylic substitution - phosphates - copper catalysis - Grignard reagents

Publication History

Received: 25 September 2022

Accepted after revision: 26 October 2022

Accepted Manuscript online:
26 October 2022

Article published online:
25 November 2022

• References and Notes

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