Norephedrine-derived oxazolidinone

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... 

In a broad program of using chiral oxazolidinones in asymmetric synthesis,100 Evans s group published a paper in 1992 on the synthesis and utilization of fV-sulfinyl oxazolidinones as new sulfinylating agent.87 Two chiral auxiliaries were used in the study oxazolidinones derived from (4R, 5S)-norephedrine 74101 and (45)-phenylalanine 75.102 The corresponding fV-sulfinyl oxazolidinones 77 and 78 were obtained either by sulfmylation of the metallated oxazolidinone or by oxidation of the derived N-sulfenamides (Table 15). 

The reaction of the lithiated oxazolidinone derived from (4/f, 5S)-norephedrine 74 and (45)-benzyloxazolidone 75 with arenesulfinyl chloride 76 in THF at -78 °C gave the corresponding Af-sulfinyl oxazolidinones 77 and 78 in modest diastereose-lectivity (32-54% de) in favor of the R diastereomer (Scheme 22). 

An anticonvulsant, CI-1008,(16), was recently developed using the Evans oxazolidinone auxiliary 17 derived from (7.S, 2A)-(-)-norephedrine [45], The route was scaled up to produce several hundred kilogram quantities at production and pilot plant scale and provided early clinical trial malerial (Scheme 2). 

Recently, in a related approach by Evans, chiral oxazolidinones derived from (lR,25)-norephedrine and (5)-phenylalanine were employed to prepare novel, chiral sulfinyl transfer reagents (15) and (16), respectively [26]. 

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... 

Diphenyl carbonate has been chosen as the most convenient phosgene equivalent for the laboratory-scale synthesis (up to 3 mol) of oxazolidin-2-one 711 starting from (IS,2J )-norephedrine 710 [501]. Direct fusion of a 3-amino-D-altritol derivative with diphenyl carbonate to furnish the corresponding oxazolidinone has also been reported [502],... 

The Evans oxazolidinone methodology is quite versatile and quite apart from its use in aldol reactions (section 5.3.3) lends itself well to the asymmetric synthesis of carboxylic acids substituted in the a-position with oxygen, nitrogen, and carbon.ti l The auxiliary shown is derived from (+)-norephedrine and the opposite enantiomers of the products are available from the valine-derived auxiliary. 

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 ... 

One of the most active areas of organoborane chemistry this year has been the application of boron enolates to enantioselective aldol condensations. Thus the enolate (82), derived from (5)-valinol, reacts with aldehydes R CHO to give, after cleavage of the oxazolidinone residue with R OH, the alcohols (83) with an erythro threo selectivity greater than 140 1, whereas the enolate (84), obtained from (IS, 2/ )-norephedrine, gives alcohols (85) with a selectivity of at least 500 1. Somewhat lower levels of selectivity are observed with the azaenolates (86) and (87) which give predominantly threo- and erythro-alcohols (88) and (89), respectively. ... 

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]. 

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