Selectivity in the Reduction of Carbonyl Derivatives Containing a Chiral Carbon

Selectivity in the Reduction of Carbonyl Derivatives Containing a Chiral Carbon 

The extent of asymmetric induction in systems containing an adjacent stereogenic center has been discussed by Morrison and Mosher. 61 Cram suggested a model for asymmetric induction in ketones such as 236 that has come to be known as Cram s open chain model (Cram s model), or simply Cram s rule.2 2,263 This model assumes a kinetically controlled reaction (nonequilibrating and noncatalytic) for asymmetric 1,2-addition to aldehydes and ketones. The three groups attached to the chiral center are Rs (small substituent), Rm (middle-sized substituent), and Rl (large substituent). Determining the relative size of the substituents is 

Oishi272 and co-workers studied the diastereoselectivity of several reducing agents that reacted both with a-alkoxy and a-hydroxy ketones (254-see Table 4.7).222 These results indicate a distinct preference for the anti (erythro) diastereomer 256 when Zn(BH4)2 was used for reduction of the keto-alcohol. More anti product was obtained with LiAlH4, but the reaction was less selective. The Cram chelation model for the anti transition state (257) to give 256 was favored over the model for syn selectivity (delivery over the methyl 

The presence of an a-alkoxy substituent does not always lead to Cram selectivity. Reduction of 262a gave 82% of the syn diastereomer, 263.2 Analysis of the Cram cyclic model for 262 (see 264) leads to an incorrect prediction of the anti-diastereomer (265) as the major product. The normal Cram model (see 262b) predicts the correct syn-diastereomer (263) but in reality, the solution to this problem requires that the alkoxy substituent at the C3 position be coordinated with the metal of the reducing agent. In 264, a five-membered 

The Cram open-chain model assumed the presence of a reactive species that led to a higher energy eclipsed conformation in the final product. The Cram open-chain model fails to predict the correct diastereoselectivity for many acyclic molecules that contain heteroatom substituents. 76 The Cram model also fails to predict the correct diastereomer when the relative size Rs and Rm are close. One attempt to correct the deficiencies of the 

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