Organocatalytic Asymmetric Sulfa-Michael Addition of Thiols to 4,4,4-Trifluorocrotonates

Abstract

The first asymmetric sulfa-Michael addition of thiols to 4,4,4-trifluorocrotonates for the construction of a stereogenic center bearing a unique trifluoromethyl group and a sulfur atom has been achieved in high yields and excellent enantioselectivities with a 1 mol % bifunctional organocatalyst. Subsequent transformation led to the expedient preparation of enantioenriched thiochroman-4-one and the key intermediate of the potent inhibitor of MMP-3, (R)-γ-trifluoromethyl γ-sulfone hydroxamate.

Recent advances in asymmetric organocatalysis mediated by bifunctional amine–thioureas bearing multiple hydrogen-bonding donors

“…However, it is surprising that the readily available and inexpensive a,b-unsaturated esters have rarely been employed as the substrates in this reaction, which could probably be attributed to their relatively low electrophilicity. To our knowledge, except for the example of employing (Z)-ethyl 4,4,4-trifluorocrotonate bearing a s-electron-withdrawing CF 3 group as the specific Michael acceptor reported by our group, 39 only one case of a,b-unsaturated ester-involved asymmetric sulfa-Michael addition mediated by the metal-complex at low temperature was achieved. 35a Nevertheless, there were several drawbacks in that catalytic system, especially ortho-substituted thiophenols must be used as the nucleophile in order to obtain higher enantioselective control.…”

“…The expected product was obtained in high yield yet with only moderate enantioselectivity (74% ee). 39 The effects of the ester moiety and geometry of the double bond were then explored. As shown in Scheme 17, the bulkier tert-butyl ester gave higher enantioselectivity, and switching the double bond geometry from E to Z resulted in the formation of the opposite enantiomer with better enantioselectivity.…”

“…39 This could be used as a straightforward method to construct chiral building blocks featuring a sulfur atom and a unique CF 3 group at the stereocenter. A control experiment was performed with ethyl crotonate 25e as the Michael acceptor to probe the role of the CF 3 group played in the above reaction (Scheme 19).…”

“…When the cost-efficient (E)-4,4,4-trifluorocrotonate was employed as the Michael acceptor, only moderate enantioselective control was obtained (Scheme 21). 39 We envisaged that replacement of the ester moiety in (E)-ethyl 4,4,4-trifluorocrotonate with an N-acylpyrazole moiety, which contains an additional hydrogenbonding acceptor, would efficiently improve its reactivity and stereoselectivity via the enhanced hydrogen-bonding interactions between the electrophile and the bifunctional aminethiourea catalyst.…”

Enantioselective bifunctional iminophosphorane catalyzed sulfa-Michael addition of alkyl thiols to unactivated β-substituted-α,β-unsaturated esters

“…To illustrate the case in point, to date there has not been a single report of a highly enantioselective addition of a pro-nucleophilic reagent [a carbon-centered (C–H) or heteroatom-centered (X–H) acid] to unactivated alkyl cinnamate or crotonate esters under organocatalytic conditions. 10 Effectively, these cheap chemical feedstocks are out of reach of existing chiral organocatalysts and accordingly are a very attractive ‘simple’ target class of electrophiles for new enantioselective organocatalytic reaction development (Fig. 1).…”