Halides, alkyl diastereoselectivity with enolate

Optically active, a-branched lactams 30 have been built by means of Meyers chiral auxiliaries [ 10]. The key step included the diastereoselective a-alkylations of the initially formed co-i -sulfonamido oxazolines 26. The R or S configuration in the product 27 was obtained reacting the appropriately configured intermediate aza enolates with alkyl halides, high diastereoselectivities have been reported. Several attempts to achieve a complete ring closure to the lactams 30 (via 29) by an acidic cleavage of the oxazolines 27 failed. Varying mixtures of... 

The enantiomerically pure substituted 1,2-dihydro-4(3//)-pyrimidinone 11 has been employed as a chiral auxiliary for diastereoselective alkylation reactions2. Thus, acylation, followed by enolate formation and alkylation with reactive halides such as halomethanes. (balomethyl)benzenes, 3-halopropenes and 3-halopropynes, affords the alkylation products with high diastereoselectivity (d.r. 93 7 to 99 1) . 

Diastereoselective alkylation of tartaric acid. The enolate (2) of the acetonide of dimethyl (R, R)-tartrate (1) can be generated with LDA in THF-HMPT at — 70° and is sufficiently stable for alkylation with allyl and benzyl halides, but not with other simple alkyl halides, and for addition to acetone (60% yield). The main products (3) of allylation and benzylation have the /ranr-configuration, and thus the substitution occurs with retention of configuration.7... 

Direct alkylation of the enolate of 77a R = cyclopentyl with the alkyl halide 78 was not very diastereoselective so an alternative route was used to allow equilibration to the more stable isomer.11 Carboxylation of the enolate gave 79a and alkylation of this malonate gave a good yield of 80. The benzyl esters were cleaved by hydrogenation and the malonate decarboxylated to give the required anti isomer of 81 in a 4 1 ratio with its syn diastereoisomer. Conversion into Trocade is straightforward. 

The structurally novel bicyclic oxazinone was prepared based on D-glucopyranose. The lithium enolates of these compounds undergo highly diastereoselective alkylation reactions with reactive alkyl halides, in modest yields. Use of the phosphazene P4 base enhanced the yields of these processes, suggesting that metal enolate aggregation is at least partly... 

Diastereoselectivities for alkylation of enolate 6 are outstanding. Alkylation with Mel gives 7 (R = Me) as the major product diastereomer in a ratio of 260 1 with respect to the minor diastereomer 8. A wide range of alkylation reagents have been examined including allylic, benzylic, homoallylic, alkoxymethyl, cyanomethyl, and arylethyl halides. 

A more traveled route to the absolute configuration represented by cyclohexa-1,4-diene 8 involves Birch reduction-alkylation of benzoxazepinone 9.2.5 heterocycle is best prepared by the base-induced cyclization of the amide obtained from 2-fiuorobenzoyl chloride and (5)-pyrrolidine-2-metha-nol. o The molecular shape of enolate 10 is such that the hydrogen at the stereogenic center provides some shielding of the a-face of the enolate double bond. Thus, alkylation occurs primarily at the 3-face of 10 to give 11 as the major diastereomer. The diastereoselectivity for alkylation with methyl iodide is only 85 15, but with more sterically demanding alkyl halides such as ethyl iodide, allyl bromide, 4-bromobut-1-ene etc., diastereoselectivities are greater than 98 2. 

When treated with a strong base such as butyllithium or potassium tert-butoxide, 2-isocyano-tV[(S)-l-phenylethyl]propanamide (1) forms an enolate 2 which is not alkylated at low temperatures. Instead it rearranges on warming and cyclizes to give the enolate of 3,5-dihydro-5-methyl-3-[(,3 )-1-phenylctbylJ-4//-imidazol-4-onc (3) which can be alkylated with benzylic halides with excellent diastereoselectivities4,13. 3-Halopropenes or haloalkanes give much lower diastereoselectivities. 

Seebach and Naef1961 generated chiral enolates with asymmetric induction from a-heterosubstituted carboxylic acids. Reactions of these enolates with alkyl halides were found to be highly diastereoselective. Thus, the overall enantioselective a-alkyla-tion of chiral, non-racemic a-heterosubstituted carboxylic acids was realized. No external chiral auxiliary was necessary in order to produce the a-alkylated target molecules. Thus, (S)-proline was refluxed in a pentane solution of pivalaldehyde in the presence of an acid catalyst, with azeotropic removal of water. (197) was isolated as a single diastereomer by distillation. The enolate generated from (197) was allylated and produced (198) with ad.s. value >98 %. The substitution (197) ->(198) probably takes place with retention of configuration 196>. 

Asymmetric aikyiation of imide etiolates.1 The sodium enolates of 3 and 7 are alkylated with marked but opposite diastereoselectivity by alkyl halides. The selectivity is improved by an increase in the size of the electrophile, with methylation being the least stereoselective process. The asymmetric induction results from formation of (Z)-enolates (chelation) with the diastereoselectivity determined by the chirality of the C4-substituent on the oxazolidone ring (equations I and II). The products can be hydrolyzed to the free carboxylic acids or reduced by LiAlH4 to the corresponding primary alcohols and the unreduced oxazolidone (1 or 2). 

The low reactivity of glycine enolate with unactivated alkyl halides to form a-amino acids could be overcome by stabilizing the nucleophile using m-aminoindanol-derived hippuric acid 53. This key substrate was readily prepared from commercially available azalactone 54 by a one-pot operation (85% yield, 2 steps). The lithium enolate of amide acetonide 53 with a wide range of alkyl halides proceeded in moderate yields (>60%) and excellent diastereoselectivities (>95% de). Assuming that lithium halide would facilitate the dissociation of the amide enolate from the aggregated state and thus enhance its reactivity, 4 equivalents of lithium chloride were used as additive and resulted in a 25% increase in yield (Scheme 24.11). Reactions with secondary halides... 

The diastereoselective alkylation of /V-acyloxazolidinones enolates was examined first. Lithium enolates of 107 were reacted with a variety of alkyl halides, and alkylation products were formed with excellent diastereoselectivities (94-99% de). Hydrolysis gave optically pure carboxylic acids, and the chiral auxiliary was recovered for reuse almost quantitatively.105-106 Highly diastereoselective bromination was also achieved by reaction of the boron enolate of 107 with /V-bromosuccinimide (NBS) (98% de). Optically pure amino acids could be accessed by simple synthetic transformations (Scheme 24.26).106... 

As with the aza-enolate of Figure 10.31, the aza-enolate D in Figure 10.32 contains a polar, covalent N—Li bond that is twisted out of the plane of the enolate. And again as with Figure 10.31, the lithium of this N—Li bond directs the added alkyl halide from, the side of the lithium to the enolate carbon. The kethydrazone E is formed with high diastereoselectivity and, after chromatographic separation, it is obtained in 100% stereochemically pure form. 

The a-protons of iron acyl complexes are acidic and these can be deprotonated with Lithium diisopropylamide (LDA) or with n-butyllithimn. Thus the corresponding enolates are readily functionalized and undergo reaction with alkyl halides, aldehydes, disulfides, trimethylsilyl chloride, and epoxides to afford the corresponding a-derivatized products. " Early work on racemic complexes revealed that these transformations occur in a highly diastereoselective fashion,... 

In addition, the lithium enolate derived from pseudoephedrine propionamide has been shown to undergo highly diastereoselective Mannich reactions with p-(methoxy)phenyl aldimines to form enantiomerically enriched a,p-disubstituted p-amino acids (Table 10). As observed in alkylation reactions using alkyl halides as electrophiles, lithium chloride is necessary for the reaction of aldimines. With respect to the enolate, the stereochemistry of the alkylation reactions is the same as that observed with... 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

The titanium enolate of phenylalanine-derived oxazolidinone (128) reacts with a variety of other electrophiles, including alkyl halides, ortho esters and acetals, with high diastereoselectivity <90JA8215>. The lithium enolate of (128) reacts with diphenyldisulfide to give 2-phenylthio aldehydes or alcohols after reduction with Red-Al or LiBH4, respectively (Scheme 55) <94TL3991>. 

Surprisingly, an X-ray analysis of 2 shows that the r-butyl group has the axial configuration. The enolate of 2 reacts with alkyl halides with high diastereoselectivity to give the rruns-product (3) (also axial). These products (3) can be hydrolyzed to a-substituted /3-amino acids (4) with 6N HCI at 160-180°. This overall process should be applicable to a synthesis of emantiomerically pure /3-amino acids. 

Apparently, deprotonation performed at -78 °C is leading to the 0-, IV-dianion A (Scheme 4). Equilibration of the latter to the thermodynamically more stable Z-enolate B (Scheme 4) upon subsequent warming to room temperature seems to be reasonable, due to the C-alkylated products obtained at 0 °C or even at room temperature. In this temperature range A-alkylation, observed at -78 °C, is effectively suppressed. [lOd] For lithium enolates derived from the glycinamides 5 an influence of lithium halides on rate enhancement and diastereoselectivity is found. [10] Thus, in the absence of LiCl a significant decrease in diastereoselectivity is observed in the alkylation of 5 with ethyl iodide (82 % de without LiCl in comparison to 97 % de upon addition of LiCl (6 equiv)). Lithium bromide (6 equiv) was found to accelerate the rate of enolate alkylation, too, but diastereoselectivity was found to be lower (91-93 % de). 

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