Cram addition

The procedure shown here describes the preparation of a-silyl ketones from aldehydes and acyl chlorides. The a-silyl ketones undergo Cram addition of various nucleophiles to produce diastereoselectively p-hydroxysilanes. These compounds are then subjected directly to elimination in situ under basic or acidic conditions to produce the corresponding alkenes. 

Figure 49 Anti-Cram addition of MeMgBr to a-phenylpropanal mediated by the bulky aluminum...

Fig. 12.2 Cram (Felkin) addition vs anti - Cram addition - Open chain modei...

The addition of methylmagnesium iodide to 2-phenylpropanal is stereoselective in producing twice as much syn-3-phenyl-2-butanol as the anti isomer (entry 5). The stereoselective formation of a particular configuration at a new stereogenic center in a reaction of a chiral reactant is called asymmetric induction. This particular case is one in which the stereochemistry can be predicted on the basis of an empirical correlation called Cram s rule. The structural and mechanistic basis of Cramls rule will be discussed in Chapter 3. 

A number of years ago an empirical relationship, now called Cram Jr rule, was recognized. When R, R, and R differ in size, and the molecule is oriented such that the largest group is anti to the carbonyl oxygen, the major product arises from addition of the nucleophile syn to the smaller substituent. ... 

Addition of Grignard reagents to ketones and aldehydes was one of the reactions which led to the formulation of Cram s rule. Many ketones and aldehydes have subsequently been examined to determine the degree of stereoselectivity. Cram s rule is obeyed when no special complexing functional groups are present near the reaction site. One series of studies is summarized in Table 8.2. 

By application of Cram s rule or a more recent model on the reactivity of a-chiral aldehydes or ketones, a prediction can be made, which stereoisomer will be formed predominantly, if the reaction generates an additional chiral center. 

In his original paper,2 Cram disclosed an alternative model that rationalizes the preferred stereochemical course of nucleophilic additions to chiral carbonyl compounds containing an a heteroatom that is capable of forming a complex with the organometallic reagent. This model, known as the Cram cyclic or Cram chelate model, has been extensively studied by Cram9 and by others,410... 

Formation of C-C Bonds by Addition to Chiral Acyclic Carbonyl Compounds 1.3.1.3.1. Addition to Acyclic a-Alkyl-Substituted Carbonyl Compounds Cram-Selective 1,2-Asymmetric Induction... 

In addition to the boron trifluoride-diethyl ether complex, chlorotrimcthylsilanc also shows a rate accelerating effect on cuprate addition reactions this effect emerges only if tetrahydrofuran is used as the reaction solvent. No significant difference in rate and diastereoselectivity is observed in diethyl ether as reaction solvent when addition of the cuprate, prepared from butyllithium and copper(I) bromide-dimethylsulfide complex, is performed in the presence or absence of chlorotrimethylsilane17. If, however, the reaction is performed in tetrahydrofuran, the reaction rate is accelerated in the presence of chlorotrimethylsilane and the diastereofacial selectivity increases to a ratio of 88 12 17. In contrast to the reaction in diethyl ether, the O-silylated product is predominantly formed in tetrahydrofuran. The alcohol product is only formed to a low extent and showed a diastereomeric ratio of 55 45, which is similar to the result obtained in the absence of chlorotrimethylsilane. This discrepancy indicates that the selective pathway leading to the O-silylated product is totally different and several times faster than the unselective pathway" which leads to the unsilylated alcohol adduct. A slight further increase in the Cram selectivity was achieved when 18-crown-6 was used in order to increase the steric bulk of the reagent. 

Addition of 15-crown-5 to the higher-order cuprate led to a reagent that is totally unrcac-tive towards 2-phenylpropanal even at room temperature18. If, however, boron trifluoride-diethyl ether complex was added as additional ingredient, the reactivity was restored and, furthermore, the Cram selectivity increased to 90 10 (Table 4). Analogous results could be obtained by placing the crown-ether effect within the cuprate itself, as in reagent 10. 

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