Catalytic Asymmetric Conjugate Addition of Thiols to α,β‐Unsaturated Thioamides: Expeditious Access to Enantioenriched 1,5‐Benzothiazepines

Abstract

Conjugate addition offers a general strategy for site-specific reactions at carbon-carbon double bonds and is frequently used in organic synthesis. Recent advances in this field have rendered the transformation viable in both a catalytic and asymmetric manner. Although a wide variety of carbon and heteroatom nucleophiles are used in this process, [1][2][3][4][5] the range of electrophiles used has been mostly limited to highly electrophilic conjugate addition acceptors, such as enones, enals, and nitroolefins. a,b-Unsaturated carboxylic acid derivatives exhibit inherently lower electrophilicity at the bcarbon atom and are thus less-common substrates in catalytic asymmetric conjugate addition reactions. We recently found that soft Lewis acids enhance the electrophilicity of a,bunsaturated thioamides 1, thus making them amenable to conjugate addition with in situ generated carbon nucleophiles. [6] To expand the scope of conjugate additions using a thioamide electrophiles, we envisioned that the use of a soft Lewis basic heteroatom nucleophile would preferentially produce an electrophile and nucleophile assembly in an asymmetric environment at the transition state, thereby affording the enantioenriched conjugate-addition product. Herein, we report a catalytic asymmetric conjugate addition (sulfa-Michael reaction) of thiols 2, as a soft nucleophile, to a,b-unsaturated thioamides 1 (Scheme 1). [5,7,8] Optically active sulfides have a wide range of applications in chemistry and biology as chiral auxiliaries, ligands for asymmetric catalysis, and biologically active compounds.

Synthesis of anti-depressant molecules via metal-catalyzed reactions: a review

“…Following side chain addition, a 93% yield of (R)-thiazesim 190 was achieved (Scheme 29). 149 Reboxetine, a selective norepinephrine reuptake inhibitor1 (SNRI), is used to treat depression, narcolepsy, cocaine dependence disorder, and hyperactivity disorder. 150,151 In contrast to its (R,R) enantiomer, (S,S)-reboxetine is much more potent and specic for both nor-epinephrine transporters.…”