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

“…Among organofluorine molecules, chiral trifluoromethylated compounds play a unique and significant role in agricultural and medicinal chemistry, as it often imparts enhanced biological activity, metabolic stability, binding interactions, or other desirable changes in physical properties to drug molecules . One such example is ( R )-γ-trifluoromethyl γ-sulfone hydroxamate (Figure ), the potent inhibitor of MMP-3 (stromelysin-1), and the stereogenic carbon center bearing a unique CF 3 group plays a significant role in the structure–activity relationship . Zanda and co-workers reported an approach to access both of the two enantiomerically pure γ-trifluoromethyl γ-sulfone hydroxamates by means of a sulfa-Michael addition of p -methoxythiophenol to chiral 4,4,4-trifluorocrotonamide as the key step, although the chiral-auxiliary-induced sulfa-Michael addition was not efficient and delivered the key intermediates as nearly equimolar mixtures of diastereomers .…”

“…One such example is ( R )-γ-trifluoromethyl γ-sulfone hydroxamate (Figure ), the potent inhibitor of MMP-3 (stromelysin-1), and the stereogenic carbon center bearing a unique CF 3 group plays a significant role in the structure–activity relationship . Zanda and co-workers reported an approach to access both of the two enantiomerically pure γ-trifluoromethyl γ-sulfone hydroxamates by means of a sulfa-Michael addition of p -methoxythiophenol to chiral 4,4,4-trifluorocrotonamide as the key step, although the chiral-auxiliary-induced sulfa-Michael addition was not efficient and delivered the key intermediates as nearly equimolar mixtures of diastereomers . Catalytic asymmetric sulfa-Michael addition (SMA) constitutes a direct and versatile approach toward optically active chiral sulfur compounds, and much attention has been paid to developing enantioselective catalytic protocols for this reaction over the past decades. − However, catalytic asymmetric sulfa-Michael addition to straightforwardly access the optically pure intermediates bearing a sulfur atom and a trifluoromethyl group at the stereogenic center remains a challenge and has met with little success.…”

Efficient Synthesis of 1,4-Thiazepanones and 1,4-Thiazepanes as 3D Fragments for Screening Libraries

“…Methyl-3-mercaptopropionate cyclizes using aziridine with sodium methoxide. This pathway requires several days and may not be compatible with base-sensitive functional groups. , Thiazepanones are also synthesized from cyclization with cysteamine or derivatives under basic conditions with α,β-unsaturated esters, taking 3–7 days and often resulting in low yield. − Our synthesis of 1a using this approach gave similar yields (32%) and reaction time (3 days) . Here we develop cysteamine cyclization reactions with α,β-unsaturated esters to produce 1,4-thiazepanones in short (<3 h) reaction times (Figure , bottom).…”

“…A methyl ester was also tolerated ( 3u ). In contrast, previously reported protocols using either strongly basic or acidic conditions provide limited access to these acid- or base-labile functional groups. − …”