Catalytic Enantioselective Synthesis of Tertiary Thiols From 5H‐Thiazol‐4‐ones and Nitroolefins: Bifunctional Ureidopeptide‐Based Brønsted Base Catalysis

Abstract

The direct catalytic reaction between an enolizable carbonyl compound and an electrophile under proton-transfer conditions has emerged as a challenging versatile transformation in organic synthesis.[1] Over the last years several chiral Brønsted bases have been developed to promote this transformation diastereo-and enantioselectively.[2] However, successful examples are mostly limited to 1,3-dicarbonyl compounds and acidic carbon analogues as the pronucleophilic reaction partners. 5H-Thiazol-4-ones, in contrast, have been well known for a long time and have found several applications in pharmaceutical and medicinal chemistry.[3] Although structurally related to 5H-oxazol-4-ones [4] and 4H-oxazol-5-ones (azlactones), [5] 5H-thiazol-4-ones have, as far as we know, been never been used in asymmetric synthesis in spite of the fact that they may be easily deprotonated [6] and in spite of the importance of thiols and organosulfur compounds in organic synthesis [7] and chemical biology. [8] In this context, whilst chiral secondary thiol derivatives have been the subject of most investigations, tertiary thiols have remained mostly unexplored owing to the insufficient catalytic enantioselective methodology for their preparation in optically pure form. [9] The most general synthesis of organosulfur compounds involves reaction of a sulfur nucleophile with an electrondeficient p-olefin acceptor.[10] By using this approach Zhang and co-workers [11] reported an efficient catalytic asymmetric synthesis of tertiary thiols using chiral Brønsted bases and bsubstituted b-ethoxycarbonyl nitroalkene acceptors. Conversely, tertiary thiols may be produced through conjugate additions of sulfur-based carbon pronucleophiles.[12] For instance, using rhodanines as carbon pronucleophiles and iminium catalysis, Ye and co-workers [13] have recently reported the conjugate addition and the Diels-Alder reaction to a,b-unsaturated ketones and 2,4-dienals, respectively. Tertiary thiols have also been accessed through enantioselective a-sulfenylation of aldehydes, [14a] 1,3-dicarbonyl compounds, [14b] b-keto phosphonates, [14c] and 3-substituted oxindoles.[14d-g] Other methods include thiofunctionalization of unactivated alkenes,[15a] amination of 3-thiooxindoles, [15b] and the aldol [15c] and Mannich [15d] reactions of a-sulfanyl lactones. Accordingly, whilst many methodologies for the enantioselective synthesis of secondary thiols exist, approaches for the asymmetric synthesis of tertiary thiols are clearly necessary to help fill this important gap in organic chemistry. The inherent difficulty associated with the stereoselective construction of quaternary stereogenic centers is probably the reason for the limited number of studies. [16] In connection with our efforts directed towards the asymmetric synthesis of organosulfur compounds, that is, b,b-disubstituted b-mercapto carboxylic acids [17a,b] and thiiranes, [17c] we focused on the enantioselective generation of a tetrasubstituted carbon atom at the a position of a-mercapto carboxylic ...

Organocatalytic Enantioselective α‐Amination of Thiazol‐4‐one‐5‐carboxylates with Azodicarboxylates

“…[c] Determined by HPLC analysis with a chiral stationary phase. A wide range of 2-aryl substituted ethyl 4-oxo-4,5-dihydrothiazole-5-carboxylates, either with electron-withdrawing (entries [8][9][10][11][12] or electron-donating substituents (entries 13-16) on the phenyl ring, underwent the amination reaction in high yields with excellent enantioselectivities (93-98% ee). The ester functionality of the azodicarboxylate 2 has a limited influence on the stereochemical outcome of the reaction (entries 1-4).…”

“…As a nitrogen-sulfur-containing heterocycle, thiazol-4-one has played an important role as a widely exploited pharmacophore in medicinal chemistry having varied biological activity, such as anticancer, [4] antifungal, [5] antimicrobial, [6] anti-inflammatory, [7] antimelanogenic [8] as well as antioxidant activity. These including Brønsted base catalyzed asymmetric Michael addition of thiazol-4-ones to different Michael acceptors, such as α'silyloxy enones, [10] nitroolefins, [11] and maleimides or 1,4-naphthoquinones, [12] phosphine-catalyzed enantioselective γ-additions of thiazol-4-ones to allenoates, [13] as well as Ir-catalyzed asymmetric allylation of substituted thiazol-4-ones. However, only a few examples have been documented for catalytic asymmetric transformations that yield chiral thiazol-4-ones at C-5.…”

“…These including Brønsted base catalyzed asymmetric Michael addition of thiazol-4-ones to different Michael acceptors, such as α'silyloxy enones, [10] nitroolefins, [11] and maleimides or 1,4-naphthoquinones, [12] phosphine-catalyzed enantioselective γ-additions of thiazol-4-ones to allenoates, [13] as well as Ir-catalyzed asymmetric allylation of substituted thiazol-4-ones. [11] As a part of our ongoing research on the development of approaches to biorelevant heterocycles, [16] we herein report the chiral bifunctional squaramide-catalyzed asymmetric electrophilic α-amination of thiazol-4-one-5-carboxylate with azodicarboxylates. Undoubtedly, carbonyl αamination methods were perhaps the most straightforward strategy to access these structures.…”

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

“…The development of novel S -containing substrates has therefore attracted the attention of chemists [1–4]. For example in 2013, Palomo and co-workers introduced 5 H -thiazol-4-ones as a new class of sulfur-containing pro-nucleophiles in a highly enantio- and diastereoselective conjugate addition to nitroalkenes, providing α,α-disubstituted α-mercapto carboxylic acids [5]. Since then, several asymmetric variants using 5 H -thiazol-4-ones as nucleophiles have been disclosed; such as amination [6], allylation [7], conjugate addition to enones [8], and γ-addition with allenoates [9].…”

Understanding the mechanism of procedure-controlled enantioselectivity switch in cinchona alkaloid thiourea catalyzed [3+2] cycloaddition: H-bonds controlled enantioselectivity

“…A variety of new chiral compounds have been synthesized as organocatalysts and showed high efficiency, excellent selectivity and great universality . Among these catalysts, the bifunctional systems [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41], which mimic the natural enzymes, can bind with the substrates on two sites, so are usually more effective. Lately cinchona alkaloid based aminothiourea catalysts, one kind of bifunctional catalysts, are applied in a series of asymmetric reactions and exhibit excellent stereoselectivity [42][43][44][45][46][47][48][49].…”