Diastereoselectivity enolate anion reactions

One of the most important factors for successful diastereoselection in chiral amide enolate alkylation reactions is the presence of strongly chelated ionic intermediates1 3. The chelation serves the purpose of locking the chiral auxiliary in a fixed position relative to the enolate. The metal counterion is chelated between the enolate oxygen and an additional polar group, anionic, carbonyl or ether oxygen attached to the chiral auxiliary. 

When the enones 1 were treated with the ai-haloalkanols 2 and base, the deformylated cfv-prod-ucts rac-3 were obtained exclusively13. Clearly this reaction is initiated by conjugate addition of the O-nucleophile. The diastereoselective step, however, is the subsequent intramolecular displacement of halide by the intermediate enolate anion. 

The nucleophilicity of silyl enol ethers has been examined. Base-induced formation of the enolate anion generally leads to a mixture of (E)- and (Z)-isomers, and dialkyl amide bases are used in most cases. The (EjZ ) stereoselectivity depends on the structure of the lithium dialkylamide base, with the highest EjZ) ratios obtained with LiTMP-butyllithium mixed aggregates in THF. ° The use of LiHMDS resulted in a reversal of the (E/Z) selectivity. In general, metallic (Z) enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. 

When a ketone reacts with a suitable base (secs. 9.1, 9.2) an enolate anion is formed by removal of the a-proton. In the case of an unsymmetrical ketone such as 30, a mixture of (Z)-enolate (31) and ( )-enolate (32) usually results (secs. 9.2.E, 9.5.A). This mixture influences the diastereoselectivity and enantioselectivity of enolate condensation reactions (sec. 9.5). Such a mixture of geometrical isomers generates both syn- and antiproducts upon reaction with aldehydes so it is important to control or at least identify the geometry of the enolate. Several solutions to this problem have been developed, including formation of stable and separable enolate isomers and controlling reaction conditions to maximize production of one isomer. 

There are many reactions that generate a mixture of syn and anti diastereomers, and if the reaction is diastereoselective, one predominates. In Chapter 9, we will see many examples of this in connection with enolate anion condensation reactions. An example is the conversion of alkenes to 1,2-diols. Reaction of... 

Lithium enolates exist as large aggregates and their approach to the electrophile is restricted by steric and electronic considerations, as well as by the relative geometry of the molecule. Despite the structural complexity remarkably good predictions for reactivity and diastereoselectivity can be made based on the steric requirements that would be present in a monomeric system. For example, in most reactions of enolate anions the electrophile will be delivered to the less hindered face of the enolate to give the major product. In all models used to describe reactivity (secs. 9.5.A.iii-9.5.A.v), a monomeric enolate will be shown but the facial and orientational bias of the enolate is clearly influenced by the state of aggregation in solution. 

Ishikawa and colleagues observed a high degree of diastereoselectivity in the addition of enolate anions to (/ )-( )-3,3,3-trifluoroprop-l-enyl p-tolyl sulfoxide (92) [92,93]. For example, reaction with the enolate anion of acetophenone (93) gave product (94) as the major diastereoisomer with 94% de (Scheme 5.31). 

Davis and coworkers have exploited the reactions of chiral JV-sulfinyl-amines in the synthesis of numerous alkaloids. Their route to (—)-epimyr-tine (1098) began with the diastereoselective addition of the enolate anion of methyl acetate to the (Ss)-(4-)-sulfmimine (+)-1128, from which the (Ss,S)-p-amino ester derivative (- -)-1129 was obtained in better than 97% de (Scheme 144). After Claisen condensation of 1129 with ierf-butyl acetate, the sulfmyl group was removed from the resulting P-keto ester (4-)-1130 by treatment with acid, the desuhinylated product then undergoing Mannich cyclization with acetaldehyde. The relative stereochemistry of the sole product, 2,6-a5-disubstituted piperidine (4-)-1131, was corroborated by nOe experiments, which indicated that no epimerization at the stereogenic centers had occurred. After hydrolysis and decarboxylation of... 

The utility of the creation of a y-lactone enolate through 1,4-addition of a carbanion and its interception by an electrophile has also been demonstrated in other classes of natural products, e.g., in the enantioselective synthesis of 10-oxa-l 1-methyl PGE2 analogues22. This synthesis starts with 1,4-addition of the sulfone-stabilized anion from 27 to ( + )-(S )-4-methyl-2-buteno-lide which has been prepared in three steps from (—)-(S)-l,2-epoxypropane. The intermediate enolate 28 is reacted with the acetylenic iodide to give the trisubstituted diastereomeric mixture of lactones 29, which is eventually converted into the pure compound 30, both reactions occurring with high diastereoselectivity. 

The enantio-determining step of nucleophilic additions to a-bromo-a,y -unsaturated ketones is mechanistically similar to those of nucleophilic epoxidations of enones, and asymmetry has also been induced in these processes using chiral phase-transfer catalysts [20]. The addition of the enolate of benzyl a-cyanoacetate to the enone 31, catalysed by the chiral ammonium salt 32, was highly diastereoselective and gave the cyclopropane 33 in 83% ee (Scheme 12). Good enantiomeric excesses have also been observed in reactions involving the anions of nitromethane and an a-cyanosulfone [20]. 

Anions generated from tertiary amides preferentially assumed the Z-configura-tion. Reaction of MA-dimethylamides with 1 equiv. of LDA at -78 °C followed by addition of 1.5 equiv. of di(-)-isobomyl azodicarboxylate 97c gave in each case a 1 1 ratio of diastereomers (/ )-99 and (S)-99 (Table 3.10, entries 7 and 8). Double diastereoselection was tested with chiral enolates enantiomerically pure /V-acyloxazolidinone (S)-100 and its enantiomer (/ )-100 were aminated at -78 °C with 97c (Scheme 47). 

Three new chirality centers are formed with high enantio- and complete diastereoselectivity in the course of the reaction of the enol triflate 37 to the bicyclo [3.3.0]octane derivative 38 (Scheme 11) [15]. In this transformation, the intermediate 39, formed by oxidative addition, leads to the cationic palladium-7r-allyl complex 40, which is finally converted to the isolated product 38 by regio- and diastereoselective nucleophilic addition of an acetate anion. The bicyclic product 38 is of interest as a building block for the synthesis of capnellene sesquiterpenes. 

I n 1993, the first cinchona-catalyzed enantioselective Mukaiyama-type aldol reaction of benzaldehyde with the silyl enol ether 2 of 2-methyl-l -tetralone derivatives was achieved by Shioiri and coworkers by using N-benzylcinchomnium fluoride (1, 12 mol%) [2]. However, the observed ee values and diastereoselectivities were low to moderate (66-72% for erythro-3 and 13-30% ee for threo-3) (Scheme 8.1). The observed chiral inductioncan be explained by the dual activation mode ofthe catalyst, that is, the fluoride anion acts as a nucleophilic activator of the silyl enol ethers and the chiral ammonium cation activates the carbonyl group of benzaldehyde. Further investigations on the Mukaiyama-type aldol reaction with the same catalyst were tried later by the same [ 3 ] and another research group [4], but in all cases the enantioselectivities were too low for synthetic applications. 

The preceding reactions dealt with the use of chiral auxiliaries linked to the electrophilic arene partner. The entering nucleophile can also serve as a chiral controller in diastereoselective SjjAr reactions. This approach was successfully employed for the arylation of enolates derived from amino acids. To illustrate the potential of the method, two examples have been selected. Arylation of Schollkopf s bislactim ether 75 with aryne 77 as electrophilic arylation reagent was demonstrated by Barrett to provide substitution product 81 with good yield (Scheme 8.18) [62, 63]. Aryne 77 arises from the orf/jo-lithiation of 76 between the methoxy and the chlorine atom followed by elimination of LiCl. Nucleophilic attack of 77 by the lithiated species 78 occurs by the opposite face to that carrying the i-Pr substituent. Inter- or intramolecnlar proton transfer at the a-face of the newly formed carbanion 79 affords the anionic species 80. Subsequent diastereoselective reprotonation with the bulky weak acid 2,6-di-f-butyl-4-methyl-phenol (BHT) at the less hindered face provides the syn product 81. Hydrolysis and N-Boc protection give the unnatural arylated amino acid 82. The proposed mechanism is supported by a deuterium-labeling experiment. Unnatural arylated amino acids have found application as intermediates for the construction of pharmaceutically important products such as peptidomi-metics, enzyme inhibitors, etc. [64, 65]. 

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