Proposed Mechanism for the Enantioselective Alkynylation of an Aryl Trifluoromethyl Ketone, the Key Step in the Synthesis of Efavirenz

Abstract

The rationalization of observations made during optimization of the zinc-mediated enantioselective addition of cyclopropylacetylene (2) to ketoaniline 8 in the presence of (1R,2S)-1-phenyl-2-(pyrrolidin-1-yl)­propan-1-ol (3) to afford amino alcohol 11 has enabled us to propose a mechanism for this transformation. The proposed mechanism has been used as the basis for the development of a spreadsheet-based mass-balance simulation, which has proved useful in predicting the effects of stoichiometry changes and in process troubleshooting.

Flow Asymmetric Propargylation: Development of Continuous Processes for the Preparation of a Chiral β‐Amino Alcohol

“…Although (1 S ,2 R )‐ N ‐pyrrolidinylnorephedrine ( L5 ) gave promising diastereoselectivity, we noticed that the reaction was plagued by formation of substantial amounts of the α‐allenic carbinol regioisomer 4 ( 1 : 4 =1.7:1). To our delight, the formation of wrong regioisomer 4 could be largely suppressed to <5 % by using achiral additive trifluoroethanol (Table , entry 7), which also improved diastereoselectivity to 23:1 and increased reaction rate.…”

Epoxydibenzo[b,f][1,5]diazocines: From a Hidden Structural Motif to an Efficient Solvent-Free Synthetic Protocol

“…They noticed that some byproducts 43 possessed the epoxydiazocine skeleton, although no spectral analyses for 43 were provided. Further optimization studies on large-scale Efavirenz synthesis and in-depth investigation of mechanistic aspects conducted by Warm and Griffiths 30 allowed the isolation of epoxydiazocine 43a as a byproduct in 12% yield (Scheme 9 ), and further elucidate its structure by spectroscopic methods and X-ray crystal structure analysis.…”

Flow Asymmetric Propargylation: Development of Continuous Processes for the Preparation of a Chiral β‐Amino Alcohol

“…Although (1S,2R)-N-pyrrolidinylnorephedrine (L5)g ave promising diastereoselectivity,w en oticed that the reaction was plagued by formation of substantial amounts of the aallenic carbinol regioisomer 4 (1:4 = 1.7:1). To our delight, the formation of wrong regioisomer 4 could be largely suppressed to < 5% by using achiral additive trifluoroethanol ( Table 1, entry 7), [16] which also improved diastereoselectivity to 23:1 and increased reaction rate.…”

“…To our delight, the formation of wrong regioisomer 4 could be largely suppressed to < 5% by using achiral additive trifluoroethanol (Table 1, entry 7), [16] which also improved diastereoselectivity to 23:1 and increased reaction rate. To our delight, the formation of wrong regioisomer 4 could be largely suppressed to < 5% by using achiral additive trifluoroethanol (Table 1, entry 7), [16] which also improved diastereoselectivity to 23:1 and increased reaction rate.…”