Oxazolidinones from norephedrine

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. 

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]. 

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... 

The central point of Evans s methodology is the induction of a 7t-enantiotopic facial differentiation through a conformationally rigid highly ordered transition state. Since the dialkylboron enolates of AT-acyl-2-oxazolidinones exhibit excellent syn-diastereoselectivity syn.anti >97 3) when reacted with a variety of aldehydes, Evans [14] studied the aldol condensation with the chiral equivalents 32 and 38. which are synthesised from fS)-valine (35) and the hydrochloride of (15, 2R)-norephedrine (36) (Scheme 9.11), respectively, and presently are commercially available. 

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). 

Evans and coworkers have developed chiral oxazolidinone auxiliaries such as 10 and 11 that are easily obtainable from (5)-vanilol or from (liS, 2R)-norephedrine. As well as the excellent selectivities obtained in aldol reactions, ease of attachment and removal of these auxiliaries has made this method widely popular. The auxiliary may be recovered and reused after cleavage from the aldol product. 

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). 

Lautens and Roy reported a synthesis of iV-(2,4-diaIkyloxazol-5-yl)oxazolidi-nones 288 from substituted A -acetoacetyl oxazolidinones 287 (Scheme 1.77). This reaction was initiated by acid-catalyzed addition of azide to the ketone in 287. It seems that this method is limited in scope to the chiral oxazoUdinone from IR,2S)-(—)-norephedrine. Simple acyclic dialkylamide analogs of 287 were unreactive or decomposed. Simple oxazolidinone analogs of 287 produced isoxazoles or afforded complex mixtures that contained both isoxazoles and 288. For aroylacetyl analogs of 287 (R = aryl), the authors recovered starting material but also encountered epimerization. In general, the yields were acceptable. 

Oxazolidinones are readily prepared from amino alcohols ((l/ ,2iS)-norephedrine, (5)-valinol, (S)-phenylalaninol) and a carbondioxide equivalent, such as phosgene or diethylcarbonate. 

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... 

Typical procedure. (4R,5S)-4-MethYl-5-phenyloxazolidin-2-one [487] To a solution of (IS,2J )-norephedrine (40 g, 0.26 mol) in toluene (400 mL) was added diethyl carbonate (37 mL, 0.32 mol). The mixture was heated to reflux (under Ar) while 40 mL of solvent was removed through the use of a Dean-Stark apparatus. The mixture was allowed to cool for 20 min, and then sodium methoxide (1 g) was added. Upon reheating, an EtOH/toluene azeotropic mixture was removed at 75-77 °C. After 3 h, the reaction was complete and the temperature of the mixture had increased to 125 °C. The mixture was left to stand at room temperature for 16 h, whereupon (4R,5S)-4-methyl-5-phenyloxazdidin-2-one 40.6 g) crystallized and could be collected. The solvent was removed from the filtrate in vacuo and the residue was redissolved in EtOAc (250 mL). This solution was washed with brine (50 mL) and a precipitate was removed by filtration. The solvent was then removed in vacuo and toluene (50 mL) was added to the residue. Removal of the toluene by distillation yielded oily crystals of the oxazolidinone, which were washed with Et20 to afford 4.5 g (total 45 g, 97%). 

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],... 

Typical procedure. (4R,5S)-4-Methyl-5-phenyl-2-oxazolidinone [501] A mechanically stirred mixture of (lS,2R)-norephedrine 710 (151 g, 1.00 mol) ([ajsgg = +33.4 (c = 7, water)), as the hydrochloride salt, diphenyl carbonate (236 g, 1.10 mol), and anhydrous potassium carbonate (152 g, 1.10 mol) was heated at 110 °C for 4-6 h. The resultant mixture was then cooled to <60 °C. Excess diphenyl carbonate was hydrolyzed by adding methanol (600 mL) and heating the mixture under reflux for 0.5 h. Sufficient water (400-600 mL) was then added to dissolve the potassium carbonate. Methanol was removed in vacuo. The product and phenol were extracted into dichloromethane (3 x 1 L). The combined extracts were washed with 2 M aqueous sodium hydroxide (3 x 1 L) to remove the phenol, 1 m aqueous hydrochloric acid (1x1 L), and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 195 g (110% mass balance) of a light-yellow solid. Recrystallization from toluene (600 mL) afforded 145-165 g (82-93%) of oxazolidinone 711 as a white crystalline solid. 

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. ... 

Preparation of Acylated Oxazolidinones The Evans diastereoselective alkylation precursors are generally prepared in two steps starting from the corresponding p-aminoalcohols, which are themselves prepared by reduction of the related optically active a-amino acids (typically valine, phenylalanine, and phenylglycine) or available from natural sources such as norephedrine (Scheme 2.43). The reaction between the... 

---