Isothioureas chiral

Optically active dihydropyranones were synthesized by Smith and co-workers [43] by a highly stereoselective chiral isothiourea-catalyzed intermolecular Michael/lactonization cascade from arylacetic acids and p,7-unsaturated a-ketoesters (Scheme 16.21). This strategy is based on the generation of chiral enolate directly from carboxylic acid activated by the in situ formation of a mixed anhydride and the organocatalyst. 

Another chiral isothiourea, HBTM (S)-ll, previously developed by Birman and Li for the kinetic resolution of aryl cycloalkanols [23], was found by A.D. Smith and coworkers [24] to give excellent yields and enantioselectivities in the Steglich rearrangement of oxazolyl carbonates (Scheme 40.17). The related catalyst (S,R)-12 gave very similar results. 

Scheme 40.17 Enantioselective Steglich rearrangement of O-carbonylated azlactones catalyzed by a chiral isothiourea.

The chiral structural isomer sopromidine (265) was prepared from L-histidine (262) Scheme 5.59.). The amino acid was esteiified and reduced to the chiral alcohol (263) which was converted to the alkyl chloride and hydrogenated to the amine (264), enantiomerically pure (i )(-)-a-methylhis-tamine. Reaction with the isothiourea (256) then gave (265) [317-320]. 

While the alcoholysis of anhydrides outlined above presumably proceeds via non-covalent catalysis, a range of chiral Lewis bases have been used for the desymmetrization of alcohol substrates using covalent strategies. As representative examples of this process, Birman utilized the isothiourea BTM 149 in an asymmetric synthesis of (—)-lobeline via desymmetrization of lobelanidine 167... 

In 2006, Birman and coworkers showed that dihydroimidazo[l,2-a]pyridine (DHIP) derivatives, such as CF3-PIP 20 and Cl-PIQ 22, as well as isothioureas such as benzotetramizole (BTM, 23) and HBTM (47) could serve as effective chiral catalysts for the acylative KR of racemic oxazoHdinones [123]. These catalysts, which rely on 7t-7T and cation-Ti interactions and which had already been successfully used in the enantioselechve acylation of benzylic alcohols, showed impressive selectivities in the case of 4-aryl- and 4-heteroaryl-substituted 2-oxazolidinones (Figure 41.12). 

Reviews have featured recent applications of organocatalysts to asymmetric aldol reactions, including particular focus on catalysis by small molecules. The effects of introduction of a diaryl (oxy)methyl group into chiral auxiliaries, catalysts, and dopants have been discussed and applications of amidine-, isothiourea-, and guanidine-based nucleophilic catalysts for a range of reactions of carbonyl compounds have been highlighted. " ... 

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