Enantiodivergent, Catalytic Asymmetric Synthesis of γ-Amino Vinyl Sulfones

Abstract

A set of diversely substituted N-Boc-gamma-amino vinyl sulfones has been prepared by a four-step procedure from readily available, highly enantiopure anti-N-Boc-3-amino-1,2-alkanediols. This new route, which does not depend on the accessibility of alpha-amino acids as starting materials, is noteworthy for its efficiency, for its generality, and for the fact that both enantiomers of a given gamma-amino vinyl sulfone can be obtained with equal ease.

Metal-dependant stereoselectivity in the Pauson-Khand cyclization of N-propargyl-γ-amino vinyl sulfones

“…To a cold (0ºC), stirred suspension of sodium hydride (6 mg, 0.2 mmol) in anhydrous tetrahydrofuran (1 ml), a solution of the γ-amino vinyl sulfone 1a 7 (50 mg, 0.08 mmol) in tetrahydrofuran (1 ml) was added with the aid of a syringe, and stirring was maintained for 1 h. At this point, propargyl bromide (27 µl, 0.25 mmol) was added in one portion. The reaction was monitored by TLC.…”

“…The resulting mixture was heated to reflux until total disappearance of the starting diol (14 h, TLC monitoring). The solvent was removed at reduced pressure and the residue was purified by column chromatography (silica gel, hexane-ethyl acetate mixtures as eluents) to afford 4.3 g (89% yield) of (S)- (2S,3S)-3-(Benzyloxycarbonylamino)-6-(tert-butyldiphenylsilyloxy)-1-phenylthio-2-hexanol (7). To a solution of oxirane 4b (0.90 g, 1.8 mmol) in anhydrous methanol (18 ml) triethylamine (254 µl, 1.8 mmol) and thiophenol (184 µl, 1.8 mmol) were added sequentially.…”

“…In the context of our long-standing interest in the synthetic applications of scalemic 2-(1-aminoalkyl)oxiranes, 6 we have recently developed a general, high-yielding and enantioselective route to γ-amino vinyl sulfones. 7 In spite of their high biomedical relevance as key components of potent and selective cysteine protease inhibitors, 8 practically nothing is known about the chemistry of these compounds. We decided therefore to investigate the PK cyclization of Npropargyl-γ-amino vinyl sulfones, paying special attention to the stereochemical outcome of the This transformation, however, proved to be more challenging than anticipated.…”

“…In effect, the attempted N-propargylation of 1a by treatment with sodium hydride and propargyl bromide in anhydrous tetrahydrofuran resulted in the irreversible elimination of the phenylsulfinate anion, and the diene 3a was the sole product isolated from the reaction mixture (Scheme 1). Likewise, all attempts to effect the N-propargylation of the epoxide 4a (a synthetic precursor of 1a) 7 were unsuccessful. Better results were obtained by trifluoroacetic acid-mediated cleavage of the Boc group in 1a, followed by reaction of the intermediate trifluoroacetate salt with propargyl bromide in the presence of potassium carbonate.…”

“…The generality of this synthetic sequence was next demonstrated by the preparation of the N-Cbz-N-propargyl-γ-amino vinyl sulfones 2c and 2d. According to the synthetic strategy previously developed by us, 7 the epoxide precursors 4c and 4d were first obtained from transcinnamyl and from trans-crotyl alcohols, respectively, by catalytic Sharpless epoxidation, 10 regioselective opening with azide anion, 11 and Mitsunobu cyclization 6a (Scheme 5). Both 4c and 4d were then submitted to the same synthetic sequence that had allowed the efficient preparation of 2b from 4b: N-propargylation, oxirane ring-opening with thiophenol, oxidation to the hydroxysulfone stage and carbodiimide-mediated dehydration, 7 to provide the target enynes 2c and 2d (Scheme 6).…”