Enolate alkylation, stereochemical course

Schemes 3-7 describe the synthesis of cyanobromide 6, the A-D sector of vitamin Bi2. The synthesis commences with an alkylation of the magnesium salt of methoxydimethylindole 28 to give intermediate 29 (see Scheme 3a). The stereocenter created in this step plays a central role in directing the stereochemical course of the next reaction. Thus, exposure of 29 to methanol in the presence of BF3 and HgO results in the formation of tricyclic ketone 22 presumably through the intermediacy of the derived methyl enol ether 30. It is instructive to point out that the five-membered nitrogen-containing ring in 22, with its two adjacent methyl-bearing stereocenters, is destined to become ring A of vitamin Bi2. A classical resolution of racemic 22 with a-phenylethylisocyanate (31) furnishes tricyclic ketone 22 in enantiomerically pure form via diaster-eomer 32.

By contrast, lithium enolates derived from tertiary amides do react with oxiranes The diastereoselectivity in the reaction of simple amide enolates with terminal oxiranes has been addressed and found to be low (Scheme 45). The chiral bicyclic amide enolate 99 reacts with a good diastereoselectivity with ethylene oxide . The reaction of the chiral amide enolate 100 with the chiral oxiranes 101 and 102 occurs with a good diastereoselectivity (in the matched case ) interestingly, the stereochemical course is opposite to the one observed with alkyl iodides. The same reversal is found in the reaction of the amide enolate 103. By contrast, this reversal in diastereoselectivity compared to alkyl iodides was not found in the reaction of the hthium enolate 104 with the chiral oxiranes 105 and 106 °. It should be noted that a strong matched/mismatched effect occurs for enolates 100 and 103 with chiral oxiranes, and excellent diastereoselec-tivities can be achieved. 

Treatment of 23 with potassium hydride in the presence of an alkyl halide and 18-crown-6 in fact gave optically active a-alkylated products 24 in 48% to nearly 73% ee in the absence of any additional chiral source (Table 3.1).17 Thus chirality of optically active 23 was memorized in the enolate intermediate during its alkylation. The stereochemical course of a-methylation and ethylation was inversion. 

Several V- IJ<>c-A-MOM-a-am ino acid derivatives undergo a-methylation in 78% to nearly 93% ee with retention of the configuration upon treatment with KHMDS followed by methyl iodide at —78°C. The substituents of the nitrogen are essential for control of the stereochemistry. How much is the stereochemical course of the reaction affected by an additional chiral center at C(3) of substrates a-Alkylation of A -lioc-A-MOM-L-isoleucine derivative 61 and its C(2)-epimer, D-a/fo-isoleucine derivative 62, were investigated (Scheme 3.16). If the chirality at C(2) is completely lost with formation of the enolate, a-methylation of either 61 or 62 should give a mixture of 63 and 64 with an identical diastereomeric composition via common enolate intermediate K. On the other hand, if the chirality of C(2) is memorized in enolate intermediates, 61 and 62 should give products with independent diastereomeric compositions via diastereomeric enolate intermediates. 

The stereochemical course of a-alkylation of both L-isoleucine and D-allo-isoleucine derivatives 61 and 62 is controlled predominantly by the chiral axis in the enolate intermediate, whereas the adjacent chiral center C(3) has little effect. 

The preparation of ester enolates, their subsequent alkylation and their use as nucleophiles in aldol or Michael reactions are standard procedures in synthesis today. Normally, these are high yield reactions and their stereochemical course can be predicted with confidence, due to the intense investigation effort invested in recent years in this research area. 

Good enantioselectivity was observed in the reaction of aromatic R -substituted silyl enol ethers and tert-alkyl R - and small alkyl R -disubstituted silyl enol ethers (Sch. 9). Interestingly, the absolute stereochemical course for aliphatic silyl enol ethers is the opposite of that for aromatic ethers. The (trimethylsilyl)ethyl group was easily removed without racemization by treatment with hydrogen fluoride-pyridine. 

Enamines are ambident nucleophiles giving C- and N-alkylated products. Acceptable yields of C-alkylated products are obtained by using reactive alkyl halides such as CH3I, ally lie and benzylic halides, and a-halocarbonyl compounds. The resultant iminium ion intermediates no longer behave as a enolates, thus dialkylation is avoided. The stereochemical course of alkylation of the enamine derived from 2-methylcy-clohexanone is depicted below. The reason for the preferred parallel alkylation via a boat-like transition state over antiparallel alkylation via a chair-like transition state is the synaxial RX // CH3 interaction in the latter case. ... 

Predict the stereochemical course of the following enolate alkylations. (Calcimycin-4)... 

The first report of the use of N-acyl oxazolidinones in asymmetric alkylation was by Evans et al. in 1982. The reactions described were found to proceed with high levels of diastereoselectivity and with very good yields (Table 7.2). The primary factor in determining the stereochemical course of the reaction is the geometry of the enolate intermediate. Studies have shown the level of /Z-enolate control transfers directly to the level of diastereoselectivity of the alkylated product. Conveniently, it has also been established that the use of bulky bases (e.g., EDA and NaHMDS) for the deprotonation of A-acyl oxazolidinones strongly favors formation of the Z-(0)-enolate. Another factor influencing the stereochemical course of the reaction is the nature of the auxiliary itself. In particular, the ability of the... 

In particular, there is only one review which places special emphasis on the stereochemical aspects of the alkylation of enolates, i.e., on the influence of a resident asymmetric center on the course of the reaction6. 

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