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

Abstract

(S)-Nyasol was selected as the target to demonstrate the efficiency of the copper-catalyzed substitution of secondary propargylic phosphates. The key phosphate (R)-TBDPSO(CH2)2CH(C≡CC6H4OTBS)-(OP(O)(OEt)2) was synthesized from TBDPSO(CH2)2CO2H in four steps. The substitution of the phosphate with 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≡CC6H4OTBS)(C6H4OTBS), were removed, and the acetylene bond was reduced using active Zn to produce the cis olefin. Finally, the HO(CH2)2 moiety was converted to CH2=CH-, thus producing (S)-nyasol with 97% cis selectivity, 94.5% ee, and >99% es. Similarly, dihydro-nyasol was synthesized via hydrogenation of the substitution product followed by construction of the terminal olefin.

Substitution of Secondary Propargylic Phosphates Using Aryl-Lithium-Based Copper Reagents

“…We found the α selective substitution of phosphate 1 with ArMgBr by using CuCN and CuBr•Me 2 S to give acetylenes 2 (Scheme 1) and the γ regioselective reaction with Cu(acac) 2 [29]. The substitution was successfully applied for the synthesis of biologically active compounds [29][30][31][32]. With these results in mind, we focused our attention on aryl lithium compounds (ArLi), with the expectation that several preparations of ArLi would expand the scope of the reagents.…”

Catalytic Dehydrative Transformations Mediated by Moisture-Tolerant Zirconocene Triflate

“…This behaviour stands in contrast to that of rare earth metal triflates, which did not suffer from deactivation by pyridines. 3…”

“…In this context, seminal contributions were made by Kobayashi and co-workers in 1991 through their systematic assessment of the reactivities, properties and applications of rare-earth metal trifluoromethylsulfonate (triflate) complexes. 3 Due to their high activity and easy recovery, these water-tolerant Lewis acidic complexes have since been employed as catalysts for a great number of various bond-forming reactions. Early examples include the use of Sc(OTf) 3 and Yb(OTf) 3 to catalyze Mukaiyama aldol condensations in H 2 O:THF mixtures, enabling the use of commercial aqueous aldehyde solutions, 4 5 as well as catalysis with water as sole reaction medium.…”