Substrate controlled chiral amine synthesis

Substrate-Controlled Chiral Amine Synthesis via C H Amination... 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

The use of substrate control in rhodium catalyzed C H aminations is covered in detail in Espino and Du Bois recent review of rhodium catalyzed oxidative amina tion [51]. A brief summary of relevant material is provided here, leading to a discussion of recent advances in the synthesis of chiral amines from achiral substrates. Rhodium catalyzed C H amination proceeds via a concerted insertion process rendering it a stereospecific transformation. Thus, the appropriate choice of an enantioenriched starting material can facilitate the synthesis of enantioenriched amines, which would often be particularly difficult to access in any other manner. As exemplified in Scheme 12.9, the C H insertion reaction of enantiomerically pure carbamate 9 was accomplished with complete retention of configuration providing the chiral oxazolidinone 10 in greater than 98% ee [13]. 

Substrate control is another approach for synthesis of anti-Mannich products. The proline-catalyzed Mannich reaction between aldehydes and pre-formed N-Boc-imines affords the syn-Mannich product with exceptionally high diastereoselectivi-ties and enantioselectivities [44]. In contrast, the reaction of aldehyde 83 with N-Boc-imines, generated in situ from the stable a-amido sulfone 84, catalyzed by the commercially available chiral secondary amine 85 provides antt-Mannich product 86 with 96% ee (Scheme 28.7a) [45]. Cyclic iminoglyoxylate 88, readily prepared from commercially available starting materials, is a useful alternative imine electrophile its configuration is locked in the (Z)-form. Because of the (Z)-configuration of imine 88, the anti-selective Mannich reaction proceeds (Scheme 28.7b) [46]. 

Intramolecular rhodium-catalyzed carbamate C-H insertion has broad utility for substrates fashioned from most 1° and 3° alcohols. As is typically observed, 3° and benzylic C-H bonds are favored over other C-H centers for amination of this type. Stereospecific oxidation of optically pure 3° units greatly facilitates the preparation of enantiomeric tetrasubstituted carbinolamines, and should find future applications in synthesis vide infra). Importantly, use of PhI(OAc)2 as a terminal oxidant for this process has enabled reactions with a class of starting materials (that is, 1° carbamates) for which iminoiodi-nane synthesis has not proven possible. Thus, by obviating the need for such reagents, substrate scope for this process and related aziridination reactions is significantly expanded vide infra). Looking forward, the versatility of this method for C-N bond formation will be advanced further with the advent of chiral catalysts for diastero- and enantio-controlled C-H insertion. In addition, new catalysts may increase the range of 2° alkanol-based carbamates that perform as viable substrates for this process. 

The synthesis of y-fluoroalkylated allylic alcohols and amines like 51 starting with chiral fluorinated allylic mesylates 50 has also been reported (Eq. 3) [134]. In this case, the regiochemistry of the addition is controlled by the substrate and the addition of the nucleophile occurs distal to the fluorinated alkyl chain. 

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