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

(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)(2)CH[C=C(C6H4-4-OTBS)]OP(O)(OEt)(2) was synthesized from TBDPSO(CH2)(2)CO2H in four steps. Substitution of the phosphate with 4-TBSOC6H4MgBr in the presence of CuBrmiddotMe(2)S 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)(2)CH[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.

Automated summary

This study demonstrates the efficiency of a copper-catalyzed substitution of secondary propargylic phosphates by synthesizing (S)-Nyasol. The key phosphate was synthesized and substituted with stereo- and regioselectivity at the propargylic position. The resulting product was further transformed into (S)-nyasol with excellent selectivity.