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

Abstract

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.