Development of Bifunctional Thiourea Organocatalysts Derived from a Chloramphenicol Base Scaffold and their Use in the Enantioselective Alcoholysis of meso Cyclic Anhydrides

Abstract

The synthesis of new chloramphenicol‐base‐derived thiourea organocatalysts, (1S,2R)‐12 a–f and (1R,2R)‐15 a–c, and their use in the enantioselective alcoholysis of meso‐anhydrides are described. In particular, hemiesters afforded excellent enantioselectivities if low loadings of (1S,2R)‐12 a–f were used. Almost no enantioselectivities were achieved with the use of (1R,2R)‐15 a–c. This technique was used to synthesize (R)‐(−)‐baclofen.

Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis ofmeso-cyclic anhydrides

“…Similarly as described in [37], with stirring under an atmosphere of nitrogen, alcohol (5 mmol, 10 equiv) was added dropwise to a solution of an anhydride 8 (0.5 mmol, 1 equiv) and 7i (0.05 mmol, 10 mol %) in MTBE (20 mL) at room temperature. The reaction was monitored by using thin-layer chromatography.…”

“…[22–29], while fully synthetic catalysts are rare, only involving Brønsted acid/base catalysts [30], cyclohexanediamine catalysts [31–32], and diphenylethylenediamine catalysts [33–34]. Significant progress in our laboratory has been made in the development of chiral bifunctional urea 1 [35], thiourea 2 and 3 [36–37], sulfonamide 4 [38–40] and squaramide 5 [38–40] catalysts derived from chloramphenicol base (Fig. 1), which showed excellent reactivity and enantioselectivity for this asymmetric transformation.…”

Chiral Thioureas—Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry

“…In a study by Enders and co-workers, tertiary amines (piperidine and pyrrolidine derivatives) were found the best option for domino Michael-Mannich cycloadditions [190]. Chen's group prepared a series of chiral catalysts, including thioureas, using a chloramphenicol base skeleton, and used them in asymmetric transformations [191][192][193]. Chromans can be easily substituted using the Michael addition approach.…”

“…Thiourea-based multivalent organocatalysts offer a great opportunity for preparation of substituted spiro-chroman structures, as exemplified by Michael-acetylation-cascade reaction of 2-oxocyclohexanecarbaldehyde derivatives (Scheme 31) [212]. [187][188][189][190][191][192][193].…”

Chloramphenicol Base: A New Privileged Chiral Scaffold in Asymmetric Catalysis

“…Chen's group also studied the effects of the positions of thiourea and amine moieties between C‐1 and C‐2 of the chloramphenicol base backbone, and regioisomers of organocatalyst 30 were synthesized and evaluated in the desymmetrization of cyclic anhydrides 33 with alcohols. Catalyst 32 has been identified as the best catalyst, providing various hemiesters 34 in high to excellent yields (80–97 % yield) and ee (61–92 % ee).…”