Thiol-derived Michael adducts

As early as 1977 Pracejus et al. investigated alkaloid-catalyzed addition of thiols to a-phthalimido acrylates, methylene azlactones, and nitroolefins [56a]. In the former approach, protected cysteine derivatives were obtained with up to 54% ee. Mukaiyama and Yamashita found that addition of thiophenol to diisopropyl mal-eate in the presence of cinchonine (10 mol%) proceeds in 95% yield and that the product, (S)-phenylthiosuccinate, was formed with 81% ee [56b]. The latter Michael adduct was used as starting material for preparation of (R)-(+)-3,4-epoxy-1-butanol. In the course of an asymmetric total synthesis of (+)-thienamycin Ike-gami et al. studied the substitution of the phenylsulfonyl substituent in the azetidi-none 69 by thiophenol in the presence of cinchonidine (Scheme 4.34) [56c]. This substitution probably proceeds via the azetinone 70. In this reaction the phenyl-thioazetidinone 71 was obtained in 96% yield and 54% ee. Upon crystallization, the optically pure substitution product 71 was obtained from the mother liquor... 

In 2009, Enders and Hoffman explored the reactivity of a,(3-unsaturated sulfonates and aromatic thiols in sulfa-Michael additions. When the reactions were catalysed by a chiral bifunctional thiourea derived from quinine, the sulfa-Michael adducts were formed in moderate enantioseleetivities of up to 64% ee, albeit with generally good yields, as shown in Seheme 1.70. 

A chiral bicyclic guanidine derivative was employed as an organocatalyst for the sulfa-Miehael addition of thiols to tert- mty 2-phthalimido acrylates by Tan et ah, providing the expected chiral Michael adducts in excellent yields and enantioselectivities of up to 92% ee, as shown in Seheme 1.71. ... 

Skarzewski reacted acyclic enones with thiols catalyzed by cinchona alkaloids [114]. Cinchonine was the best catalyst evaluated and the Michael adducts were obtained in excellent yields albeit with moderate enantioselectivities. Similar approximations were made by Mukaiyama and coworkers using hydroxyl-proUne derivatives, affording the thio adducts in good yields and good enantioselectivities (up to 88% ee) [115], However, the most effective thiol addition to enones was reported by Deng [116]. In this report (DHQD)2PYR (hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether) was used as catalysts, affording the final compounds in excellent yields and enantioselectivities (Scheme 33.37). 

The quinine derived thiourea 12 was found to be the most efficient catalyst, in terms of conversion and enantioselectivity, in the Michael-Michael cascade process between tra y-3-(2-mercaptoaryl)-2-propenoic acid esters and /ra 5-nitroalkenes [39]. The thiochromanes, containing three new stereocenters, were obtained with excellent enantio- and diastereoselectivity irrespective of the electronic namre and substitution pattern of the aromatic ring in the nitroalkene and in the thiol. Although the first sulfa-Michael step of the process was poorly enantioselective, it was also reversible, so that the enantiomeric mixture of the adducts underwent an efficient dynamic kinetic resolution due to a retro-Michael-Michael-Michael sequence (Scheme 14.10). 

A novel chiral hafnium catalyst, which was readily prepared fromHf(OTf)4 and a proline-derived chiral ligand, has been tested in asymmetric Michael reactions of thiols with 3-(2-alkenoyl)-2-oxazolidinones, affording the corresponding adducts in high yield and enantioselectivity. Although chiral Lewis acids are less reactive than the original Lewis acids in many cases, ligand acceleration has been demonstrated in this as)unmetric Michael addition reaction (eq 18). ... 

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