2- Oxazolidinone, chiral derivatives

Asymmetric Diels-Alder reactions. Unlike methyl crotonate, which is a weak dienophile, chiral (E)-crotonyl oxazolidinones when activated by a dialkylaluminum chloride (1 equiv.) are highly reactive and diastereoselective dienophiles. For this purpose, the unsaturated imides formed from oxazolidinones (Xp) derived from (S)-phenylalanol show consistently higher diastereoselectivity than those derived from (S)-valinol or (IS, 2R)-norephedrine. The effect of the phenyl group is attributed in part at least to an electronic interaction of the aromatic ring. The reactions of the unsaturated imide 1 shown in equation (I) are typical of reactions of unsaturated N-acyloxazolidinones with cyclic and acyclic dienes. All the Diels-Alder reactions show almost complete endo-selectivity and high diastereoselectivity. Oxazolidinones are useful chiral auxiliaries for intramolecular Diels-Alder... 

Gaul and Seebach showed that lithiated methylthiomethyl-substituted chiral oxazolidi-nones react with aldehydes, ketones, imines and chalcones (Scheme 41). In this case, the oxazolidinone is derived from diphenylvalinol. The products, with two new asymmetric centers, are formed in good yield and excellent diastereoselectivity.A detailed mechanistic study of this and related systems, using computational methods, IR and NMR... 

H. Reactions with Anions of Chiral Oxazolidinones and Derivatives with... 

Saigo and co-workers reasoned that, by analogy, high levels of diastereofacial discrimination could be achieved in the Lewis acid-mediated Diels-Alder reaction of dienes with oxazolidinone 108-derived dienophiles. Indeed, excellent regioselectivities (endo. exo) and diastereoselectivities were reached in the Diels-Alder reaction of 109 with cyclic and acyclic dienes using Et2AlCl as the activator (Scheme 24.28).107 The selectivities obtained actually surpassed those reported with cis-1 -amino-2-indanol 1 as the chiral auxiliary (93% de) (see Scheme 24.16).82 The additional bulk... 

Ghosh et al. reported that the chiral oxazolidinone 87, derived from (1S,2R)-cis-l-amino-2-indanol (86), underwent a highly diastereoselective. vyn-aldol reaction with a variety of aldehydes30 (Scheme 2.1cc). Reaction of the indanolamine 86 with disuccinyl carbonate in acetonitrile gave the oxazolidinone 87, which was deprotonated with -BuLi and reacted with propionyl chloride to provide the N-propionyl derivative 88. Reaction of 88 with n-BioBOTf and... 

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... 

Excellent yields and diastereoselectivities have been obtained in allylations using a new oxazolidinone chiral auxiliary derived from diphenylalaninol [24]. The use of oxazolidinone chiral auxiliaries was sparked by the application of Lewis acids to radical reactions. Bidentate Lewis acids are used to favor one rotamer (44) out of a possible four by forming a chelated intermediate with the two carbonyl groups and through steric interactions imparted by the 4-substituent of the oxazolidinone (Eq. (13.12)). Trapping with the allylstannane can then occur on the face opposite the bulky oxazolidinone-4-substituent. 

A similar allylation has been reported with the chiral auxiliary on the nitrogen of the bromoglycine attached as an imide rather than as an ester (Eq. (13.20)) [30]. A valinol-derived oxazolidinone chiral auxiliary 68 was employed under bidentate Lewis acid conditions (ZnCl2). It was found that ZnCla functions as a radical initiator as well as a Lewis acid in these reactions. The best example provides the allylglycine 69 derivative in 85% yield and the newly formed stereocenter in a ratio of 87 13 (R. S) with a reaction time of 1 h at -78 °C. 

The succinate core can be prepared by alkylation of a simple carboxylic acid (74a or b) with a bromoacetate using the Evans oxazolidinone chiral auxiliary derived from phenylalanine (chapter 27). The branched alkyl group must be present in the substrate for alkylation and the second acid group added in the alkylation so that there is no competition between two carbonyl groups during enolate formation. After hydrolysis (91% yield) the alkylated succinic acid 77 has >95% ee. Notice that the two acid groups are differentiated by this procedure.10... 

The starting material 164 can be made as a single enantiomer by the use of an oxazolidinone chiral auxiliary (chapter 27). Treatment with the chloropurine 167 catalysed by Pd(0) gave only the correct stereoisomer 168 in 63% yield - not a high yield but better than 33% - and deprotection and hydrolysis gave the guanine-derived carbovir19169. 

Diastereoselectivity for the atom transfer sequenee was studied by employing chiral oxazolidinone auxiliaries with 1-hexene and the oxazolidinone imide derived from a-bromopropionic acid, as described in Eq. (23). The results of these studies are reported in Table 1. The major product formed has the R configuration, consistent with model 31. Diastereoselectivity was good to excellent for either R = /-Pr or benzyl. Presumably the auxiliary with R = CH(Ph)2 would give even better se-lectivities in these transformations. 

Among the available methods for the stereoselective synthesis of quaternary proline analogues (7)/ the direct a-functionalisation of (5 )-proline-derived oxazolidinone 5 proposed by Seebach et al. in 1983 has been extensively used in the last thirty years for the production of many bioactive compounds (Scheme 11.1)/ Both a-allq lation and a-condensation reactions proceed stereoselectively with retention of configuration, exemplifying the concept of self-reproduction of chirality . More recently, Germanas and coworkers introduced the cheaper oxazolidinone 6, derived from the condensation of (S)-proline 1 with trichloroacetaldehyde (Scheme 11.1). ... 

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 ... 

Thornton and Siegel have reported that reactions of the titanium enoiates of chiral a-silyloxyketones resulted in excellent syn diastereoselectivity, as shown in Table 2.28, entries 1-4 [55, 56]. Use of tetrakisisopropoxytitanium enoiates also afforded excellent syn diastereoselectivity. In work similar to that with oxazolidinone chiral auxiliaries, these enoiates were generated as lithium enoiates then transmetalated with the appropriate titanium Lewis acid. Large excesses of titanium were necessary for good stereoselectivity. They also noted that carboxylic acid derivatives could be obtained by deprotection and oxidative cleavage. Chiral auxiliary methods are, however, more efficient at providing adducts of this nature. 

Vol. 28, p. 226, ref. 44 for related work). Similar cycloadditions of dienyl pyrrolidinones [le. AT-(peiita-l,3-dienyl)- or -(buta-l,3-dienyl)-pyrolidin-2-one] with the in situ generated acyl nitroso compound derived from benzyl-JV-hydroxy-carbamate with periodate have led to the preparations of racemic pyroUidines 56 and 57 (R = H or Me). The latter compound is thought to exist as a dimer. An asymmetric synthesis of l,S,6-trideoxy-l,5-imino-D-altritol in which the piperidine ring is formed from a pyiidinium ring bearing Seebach s oxazolidinone chiral auxiliary has also been described. ... 

Accordingly, the Evans protocol, when applied to A-propionyl oxazolidinone 51 derived from ephedrine, leads to the predominant formation of the diastere-omeric syw-aldols, again with outstanding stereoselectivity. In this case, the enolate attacks the Re-hce of aldehydes with high preference. The procedure is illustrated in Scheme 4.48 for an aldol addition to a-benzyloxyacetaldehyde yielding the crude product 213 in a diastereomeric ratio of higher than 99 1. After recrystallization, the stereochemically homogeneous aldol adduct 213 was transformed into the Weinreb amide 214 in the course of a total synthesis of the macrolide antibiotic cytovaricin. In the transamination step, the chiral auxiliary 46 was recovered [111]. 

Chiral auxiliaries feature in two amiiKxleoxysugar syntheses. The L-forosamine derivative 54 (Scheme 16) was prepared from the N-acylated oxazolidinone 53 derived from L-phenylalanine, and used in the total synthesis of the macrolide antibiotic lepicidin A. Key steps were asymmetric aldol condensation (step i) and Clurtius reaction (acid to isocyanate with capture by fluorenylmethanol stq) iv). The 5-amino-2,5-dideoxy-D-rhreo-pentoside 57 and 3,5-diamino-2,3,5-trideoxy-l>-e/yrhro-pentoside 58 were synthesized by conventional triflate displacenoent reactions from iodolactone 56,... 

A salient feature of the oxazolidinone auxiliaries is the fact that they are easily synthesized from inexpensive, commercially available starting materials. The L-amino acids valine and phenylalanine provide access to oxazolidi-nones 114 and 115, respectively, while oxazolidinone 116 is conveniently derived from norephedrine. Moreover, their derivatives are typically crystalline, allowing for ease of purification and handling. The general procedure for the preparation of these chiral oxazolidinones is illustrated with the synthesis of the N-propionyl oxazolidinone 127 derived from phenylalanine (130, Scheme 3.20) [86]. 

The reaction has wide scope in respect of the dienophUe / -substituent. The representative less reactive dienophiles, crotonoyl- and cinnamoyl-oxazolidinone, react with cyclopentadiene at -15 °C and 25 °C for 20 h and 24 h giving cycloadducts in 99% ee and 96% ee, respectively. The 3-chloropropenoyl derivative also affords the adduct in high optical purity (96% ee) this adduct is transformed to 2-(methoxycar-bonyl)norbornadiene, a useful chiral building block. Thus, the 3-chloropropenoyl derivative can be regarded as a synthetic equivalent of an acetylene dienophile. 

For the construction of oxygen-functionalized Diels-Alder products, Narasaka and coworkers employed the 3-borylpropenoic acid derivative in place of 3-(3-acet-oxypropenoyl)oxazolidinone, which is a poor dienophile in the chiral titanium-catalyzed reaction (Scheme 1.55, Table 1.24). 3-(3-Borylpropenoyl)oxazolidinones react smoothly with acyclic dienes to give the cycloadducts in high optical purity [43]. The boryl group was converted to an hydroxyl group stereospecifically by oxidation, and the alcohol obtained was used as the key intermediate in a total synthesis of (-i-)-paniculide A [44] (Scheme 1.56). 

The desilylacetylated qrcloadducts, produced from the reactions of trimethylsilyl-diazomethane with 3-crotonoyl-2-oxazolidinone or 3-crotonoyl-4,4-dimethyl-2-oxa-zolidinone, were transformed to methyl traws-l-acetyl-4-methyl-l-pyrazoline-5-car-boxylate through the reactions with dimethoxymagnesium at -20 °C. When the optical rotations and chiral HPLC data were compared between these two esters, it was found that these two products had opposite absolute stereochemistry (Scheme 7.39). The absolute configuration was identified on the basis of the X-ray-determined structure of the major diastereomer of cycloadduct derived from the reaction of trimethylsilyldiazomethane to (S)-3-crotonoyl-4-methyl-2-oxazolidi-none. 

The diastereoselectivity of the zinc iodide catalyzed reaction of the azetidinone I with the trimethylsilyl enolate derivatives of the chiral 3-(l-oxopropyI)oxazolidinones 6 was considerably lower (about 60 40), although independent generation of the zinc enolate, via exchange of the lithium enolate with zinc bromide, afforded the /9-Iactam carboximide derivatives in a ratio (RIS) 80 20177. 

Several other oxazolidinones have been developed for use as chiral auxiliaries. The 4-isopropyl-5,5-dimethyl derivative gives excellent enantioselectivity.91 5,5-Diaryl derivatives are also quite promising.92... 

Unsaturated acyl derivatives of oxazolidinones can be used as acceptors, and these reactions are enantioselective in the presence of chiral to-oxazoline catalysts.321 Silyl ketene acetals of thiol esters are good reactants and the stereochemistry depends on the ketene acetal configuration. The Z-isomer gives higher diastereoselectivity than the Zf-isomer. 

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