Diastereoselective construction of syn-α-oxyamines via three-component α-oxyaldehyde–dibenzylamine–alkyne coupling reaction: application in the synthesis of (+)-β-conhydrine and its analogues

Abstract

A Cu(I)-catalyzed α-oxyaldehyde-dibenzylamine-alkyne coupling reaction was delineated for the construction of α-oxyamines with excellent yields and diastereoselectivity. Crystal structure analysis and theoretical calculations were also supportive of the formation of syn-α-oxyamines as the major products. Application of the methodology addresses the synthesis of (+)-β-conhydrine along with analogs having two different diversity features. A ring size variation allows construction of piperidine and pyrrolidine rings while a variation of side arm functionality is achieved by complete regioselective opening of epoxide by different organocopper ylides (Gilman reagents). A lactam-Cu(I) complexation motif is proposed which allows an intramolecular attack of ylides at the terminal epoxy carbon via the six-membered cyclic transition state. The present work features the synthesis of (+)-β-conhydrine over eight steps in 26% yield and its seven analogs in 21-28% yields.

Cyclometallated Gold(III) Complexes as Effective Catalysts for Synthesis of Propargylic Amines, Chiral Allenes and Isoxazoles

“…Using 2h , amine 3a or 3g and phenylacetylene 4a , products 6a and 6d were obtained in up to 76% yield (Figure 3) and in a diastereomeric ratio of 97: 3 (Table 3, entries 1 and 4). These findings indicated that protection of galactose by O ‐isopropylidene groups has a significant effect on the diastereoselectivity, in which similar observations for α‐oxyaldehydes as substrates have also been reported 21c,25. The absolute configuration of all propargylic amine‐modified sugars was assigned on the basis of X‐ray crystallographic analysis (Figure S2, Supporting Information).…”

Enantioselective syntheses of (R)-pipecolic acid, (2R,3R)-3-hydroxypipecolic acid, β-(+)-conhydrine and (−)-swainsonine using an aziridine derived common chiral synthon

“…Lactam 33 is key intermediate towards the syntheses of b-(+)-conhydrine and its analogues (Scheme 6). 32…”

“…(E)-Ethyl 3-((2S,3R)-1-allyl-3-((tert-butyldimethylsilyl)oxy)-6oxopiperidin-2-yl)acrylate (32). Diol 31 (0.2 g, 0.607 mmol) was dissolved in acetone-water (3 mL, 2 : 1) at 0 C, treated with sodium metaperiodate (0.2 g, 0.9 mmol) and stirred at 15 C for 15 min.…”

Conhydrine: An Account of Isolation, Biological Perspectives and Synthesis

“…The methodology was initially used by Haung et al for the construction of syn-α-oxyamines 11 and further extended to the synthesis of 1,2-amino alcohol (+)-β-conhydrine by Talukdar and co-workers (Scheme 2). 12 The diastereomer 3, synthesized by the reaction of the corresponding alkyne, dibenzylamine, and aldehyde using a copper(I) bromide catalyzed one-pot reaction, was further transformed into epoxide 4 using classical synthetic steps. The regio-and stereoselective opening of epoxide 4 using the Gilman reagent lithium dimethylcuprate, followed by subsequent lithium aluminum hydride (LAH) reduction gave (+)-β-conhydrine.…”