Enolate acyl oxazolidinone-derived

Stereoselective a-halogenation of enolates is an important approach for the generation of synthetically versatile, chiral building blocks. By use of an auxiliary approach, the acylated oxazolidinone derivatives developed by Evans have been showcased in diastereoselective enolate brominations (Scheme 3.33) [125]. Enolization of 226 (BujBOTf, amine base) and exposure of the boron enolate to NBS affords 228 in 95 5 dr. A key application of the bromo imides is their facile conversion into azides upon treatment with tetramethylguanidinium azide (229). The resulting azides such as 230 (dr=95 5) can readily be elaborated into chiral a-amino acids (see also Chapter 10). 

Conditions for arylation of enolate equivalents have also been developed. In the presence of ZnF2, silyl enol ethers, silyl ketene acetals, and similar compounds react. For example, the TMS derivatives of /V-acyl oxazolidinones can be arylated. 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

Combination of the reagents TiCU, BuaN, and TMSOTf, was reported to be effective for Claisen condensation, as exemplified in Eqs (42) and (43) [129]. When acyl-oxazolidinones were subjected to reaction with TiCU and a tertiary amine, homocoupling reaction at the a-position of the acyl group took place to give succinic acid derivatives [146], The lithium enolate of an ester or amide has been alkylated with an (N,C>)-acetal in the presence of Ti(0-/-Pr)4 (Eq. 44) [147,148]. 

The Nicholas reaction was used to synthesize the p-lactam precursor of thienamycin in the laboratory of P.A. Jacobi and thereby accomplish its formal total synthesis. The necessary p-amino acid was prepared by the condensation of a boron enolate (derived from an acylated oxazolidinone) with the cobalt complex of an enantiopure propargylic ether. The resulting adduct was oxidized with ceric ammonium nitrate (CAN) to remove the cobalt protecting group from the triple bond, and the product was obtained with a 17 1 anti.syn selectivity and in good yield. 

One of the most successful and widely used methods for diastereoselective aldol addition reactions employs Evans imides 17 and the derived dialkyl boryleno-lates [8J. The 1,2-svn aldol adducts are typically isolated in high diastereoisomeric purity (>250 1 dr) and useful yields. More recent investigations of Ti(IV) and Sn(II) enolates by Evans and others have considerably expanded the scope of the aldol process [9], In 1991, Heathcock documented that diverse stereochemical outcomes could be observed in the aldol process utilizing acyl oxazolidinone imides by variation of the Lewis acid in the reaction mixture [10]. Thus, for example, in contrast to the, l-syn adduct (21) isolated from traditional Evans aldol addition, the presence of excess TiCL yields the complementary non-Evans 1,2-syn aldol diastereomer. This and related observations employing other Lewis acids were suggested to arise from the operation of open transition-state structures wherein a second metal independently activates the aldehyde electrophile. 

Michael reaction of an oc,p-unsaturated ketone with a silyl enol ether (Scheme 26) and a Diels-Alder reaction of an oxazolidinone derivative with cy-clopentadiene (Scheme 27) also worked well using MC Sc(OTf)3. Moreover, a Friedel-Crafts acylation proceeded smoothly to produce an aromatic ketone in a good yield (Scheme 28). Friedel-Crafts alkylation and acylation reactions are fundamental and important processes in organic synthesis as well as in indus-... 

Whereas the preceding processes involving ring openings of cyclopropanes provide useful [3+2] entries to cyclopentanes, the use of simpler substrates in [3+2] cycloadditions is made possible by the development of reductive cycloaddition pathways. Such reactions were initially developed in the context of stoichiometric processes, where metallacycles were prepared by oxidative cyclizations of enones and alkynes, followed by either protonation or alkylation of the nickel 0-enolate functionality. Catalytic protocols involving various intramolecular combinations of 7t-systems include formal [3+2] reductive cycloadditions of bis-enones to form bicyclooctanols (Scheme 3-33), of enones with unsaturated acyl oxazolidinones to form triquinane derivatives, and of enals with alkynes to form bicyclooctenols. ... 

The synthesis of both R)- and (5)-enantiomers of 4,4,4-trifluoro-3-methyl-1-butanol (19,20) by Jacobs et al. [54] as building blocks for leuko-triene antagonists Scheme 5.12), demonstrates how oxazolidinone auxiliaries (21) and (22), derived from L-valine and (lS,2/ )-norephedrine, respectively, impart complementary selectivity in alkylation of chelated (Z)-enolates. Similarly, Trova et al. [55] have utilized the iV-acyl oxazolidinone (23), from L-phenylalanine and 3-phenylpropanoyl chloride, for the construction of diastereomeric lactones (24) and (25) as synthons for HIV-1 protease inhibitors Scheme 5.12). Following allylation and hydrolytic removal of the auxiliary, stereocomplementary iodolactonization reactions of... 

Baran and coworkers developed the intermolecular heterocoupling of lithium enolates and elaborated oxidation systems that did not only avoid the (usually undesired) homocoupling but also do not require a large excess of one component [242]. For asymmetric versions, Evans lithium enolates were used and coupled with the lithium enolates of achiral ketones and esters. Two oxidants were studied in detail, Cu(II) and Fe(III), and the choice of the oxidant was found to have a distinct impact on the stereochemical outcome. This is illustrated for cfs-lithium enolate 507 derived from AT-phenacyl oxazolidinone and cfs-enolate 504 of propiophenone. In the Fe(acac)g oxidation system, the formation of 0 tf-coupling product 509 occurs predominantly, whereas syn-513 prevails if Cu(2-ethylhexanoate)2 was used. In both cases, however, diastereomeric mixtures were obtained with typical anti-syn and syn-anti ratios of about 2 1. The proposed mechanism is outlined in a simplified manner in Scheme 4.107 the lithium enolate 504 of the ketone is transmetallated to the iron(III) enolate 505 that might be considered an oxallyl radical 506, wherein the polarity is altered the species 506 features an electrophilic a-carbonyl atom that becomes susceptible to an attack of the nucleophilic AT-acyl oxazolidinone enolate 507. As a result, the radical 508 forms that is finally oxidized to the product 509. The authors... 

Evans has pioneered the use of carboximide-derived enolates in diastereo-selective enolate alkylation reactions [15, 82]. As discussed in subsequent chapters, N-acyl oxazolidinones (such as 114, 115, and 116) enjoy a unique position in asymmetric synthesis as chiral auxiliaries with wide applications in numerous mechanistically unrelated asymmetric transformations, among them aldol (Chapter 4), Diels-Alder (Chapter 17), enolate amination (Chapter 10), and conjugate addition (Chapter 12) reactions. Oxazolidinones 114 and 115 generally lead to Ca-substituted carboximide products in one dia-stereomeric series (cf 119, dr>99 1), while the complementary diastereo-meric adducts such as 122 dr =98 2) can be accessed through the use of oxazolidinone 116 (Scheme 3.18) [82]. 

As carboxylic acid derivatives, the enolates derived from N-acyl oxazolidinones approximate the reactivity patterns of thioesters the derived alkali metal enolates display moderate nucleophilicity [82]. Investigations of these systems have revealed that there is a pronounced difference in alkylation rates between the various alkali metal enolates. Thus, although the reactivity of the lithium enolates is limited (reaction temperatures = 0°C), the corresponding sodium enolates undergo allcylation at lower temperatures (-78 °C). This feature resulted in higher observed diastereoselectivity for the corresponding sodium enolates in the alkylation reactions. 

The chiral acyl oxazolidinones developed by Evans have been demonstrated to function successfully in conjugate addition reactions of titanium enolates to acceptor olefins [99]. A noteworthy example is the addition of 96 to acrylonitrile (Equation 16). Interestingly, although the starting substrate 96 includes both ester and imide groups bearing acidic a-protons, the deprotonation selectively gives the imide-derived enolate. Adduct 98... 

S)-2-Amino-3-methylbutanol [(S)-valinol] derived oxazolidinones, i.e., (S)-3-acyl-4-iso-propyl-2-oxazolidinones 1, have been used extensively for the preparation of a-alkylated acids, aldehydes and alcohols. The enolates are formed by deprotonation with lithium diisopropyl-amide or sodium hexamethyldisilazanide at low temperature in tetrahydrofuran. Subsequent addition of a haloalkane gives alkylation, which occurs from the Si-face2. The diastereoselectivities are usually good (>90 10), and the products are usually purified by flash chromatography and/or recrystallization (see Table 10). Additional examples of alkylation of 1 have been published5 l0 12- 20 22-29 39.44.-47,49.57.70-78... 

S)-4-(l-Methylethyl)-5,5-diphenyl-2-oxazolidinone (3), whose preparation is described here, has several advantages over Evans original auxiliaries i) Derivatives of 3 are more likely to crystallize. In many cases the separation and purification of diastereoisomers can be achieved by simple recrystallization rather than by expensive and time-consuming chromatography, ii) Acylation of 3 can be carried out at 0°C (instead of-78°C for 4 and 5) by deprotonation with BuLi, followed by treatment with an activated carboxylic acid derivative, iii) Lithium enolates of N-acyl derivatives of 3 can be obtained directly by treatment with BuLi at -78°C, in comparison to 4 and 5 when the more expensive... 

Chiral oxazolidinone auxiliaries derived from D-xylose were applied by Koell et al. [156]. The oxazolidinones were acylated with various acid halides furnishing imides, which are substrates for a-alkylation reactions. For example, the butyric acid derivative 213 was deprotonated with LDA to give the (Z)-configured enolate 214, which was reacted with methyl iodide (Scheme 10.71). The methylated product 215 was formed in a moderate yield of 45% and a diastereomeric ratio of 7 1. The approach of the electrophile occurred from the less hindered /-face of the enolate... 

The oxazoline 184 provides an attractive approach to lactacystin as it is a protected form of 3-hydroxyleucine. The other half of the molecule was made in the LeukoSite synthesis by a very different method the alkylation of an Evans chiral auxiliary. This was chosen partly because they wished to vary the alkyl group on the pyrrolidone ring and we use the propyl compound as example. The phenylalanine derived oxazolidinone 193 (chapter 27) was acylated and then the titanium enolate of 194 was alkylated to give 195 with very high selectivity and the chiral auxiliary removed to give the simple acid 196. 

Other oxazolidinones have been used as chiral auxiliaries in asymmetric aldol reactions. Bomane derivatives 1.121 (X = O or S) and 1.122 are readily transformed into V-acyl derivatives. The reactions of their boron or titanium enolates with aldehydes give the same selectivities as Evans s reagents [426, 428, 429, 431, 436], iV-Acylimidazolidinones 1.131 and 1.132 [449, 1270] lead to similar results, but the selectivities observed are somewhat lower. 

Formation of the unexpected oxazolidinone in G18 proved to be crucial because models showed that direct C-acylation of the C-9 enolate derived from G17 was sterically disfavored. However, treatment of G18 with sodium meth-oxide did afford lactone G20 in 70% yield. Enolate G19 is postulated as the intermediate, and as in the case of the actinobolin analogue (E8, Scheme 18), regioisomeric enolization at C-7 is of no consequence, since acylation at that site is a less favored reaction. 

Two new glucose-derived oxazolidinones have been prepared, and converted to iV-acyl derivatives of type 204 (R = Me or Piv). The dialkylboron enolates derived from 204 underwent aldol reactions to give syn-products 205, with diastereomeric ratios between 8 1 and 16 1. The same group has also made the oxazolidinone 206 from D-xylose. When this was treated with Mukaiyama s reagent (2-chloro-l-methylpyridinium iodide) in the presence of an imine, a Staudinger ketene-imine cyclization occurred to give a p-lactam such as 207, the structure of which was confirmed by X-ray crystallography, in >98% de. ... 

The chiral auxiliary is the oxazolidinone (24) derived from IS,2R) norephedrine. Acylation with propionyl chloride gives (25) and this is deprotonated to afford exclusively the internally chelated Z-enolate, which reacts with methallyl iodide from the face opposite the methyl and phenyl groups of the auxiliary. The product (26), a 97 3 mixture of diastereomers, is purified to a ratio of better than 500 1. Reductive removal of the auxiliary and careful oxidation of the primary alcohol under non-racemising conditions affords the chiral (5)-aldehyde (27). This in turn is reacted with the boron enolate of (25), which furnishes with remarkable selectivity the u aldol product (28). The reason for the choice of boron rather than lithium is to invert the facial selectivity of the reaction— the enolate is no longer constrained to be planar by internal chelation and rotates in order to place the bulky dibutyl borinyl group on the opposite side to the methyl and phenyl ... 

In any treatment of auxiliary-based alkylations (as well as aldol additions, enolate oxidations, Mannich and Michael reactions), clearly, the carboximide enolates pioneered by the group of Evans are the center of attention. Developed in the early 1980, JV-acyl derivatives of oxazolidinones 45-47 (Scheme 4.9) became the epitomes of chiral auxiliaries [7,28] with countless applications in natural products and drug syntheses. The enantiomeric oxazolidinones (S)- and (R)-47 derived from the corresponding enantiomer of phenylalanine have the advantage that, when used for various transformations, the corresponding products have a higher tendency to crystallization and were shortly later added [29] to this collection of classics. 

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