Oxazolidinone amides, with alcohols

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... 

This method, employing methylation by Mel, was used to synthesise pheromones such as (S)-sulcatol 416.176 The oxazolidinone protecting group features a safety-catch which is released by treatment with acid intramolecular assistance to hydrolysis of the secondary amide 415 rapidly generates the free alcohol product 416. 

The phenylalanine-derived oxazolidinone 108 undergoes a diastereoselective aldol reaction with crotonaldehyde to give the syn product 109. Formation of the Weinreb amide, followed by silylation of the crude secondary alcohol, provides 110. The chiral auxiliary is recovered at this stage. Product 110 is a potential precursor of all kinds of monosaccharides and analogs, including 1-deoxynojirimycin (Scheme 13.43) [85]. 

Intramolecular asymmetric induction has also been used in electrochemistry as in the reduction of optically active alcohol esters or amides of a-keto [469,470] and unsaturated [471] acids and oximes [472] and in the oxidation of olefins [473]. A maximum asymmetric yield of 81% was obtained in the reduction of (5 )-4-isopropyl-2-oxazolidinone phenyl-glyoxylate [470]. Nonaka and coworkers [474,475] found that amino acid A-carboxy anhydrides were polymerized with various electrogenerated bases as catalyst to give the poly(amino acids) with high chirality in high yields. Conductive chiral poly(thiophenes) prepared by electropolymerization can be used for chiral anion recognition [476]. 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

Addition of diethyl aluminum chloride at — 78 °C to a,/ -unsaturated oxazolidinone (154) affords an aluminum enolate that, on hydroxylation with (63a), gives the / -ethyl-a-hydroxy amide (155) with high anti selectivity (Equation (38)) <91AG(E)694>. Formation of the enolate of oxazoline thiol ester (156) under chelation (NaHMDS) and stereoelectronic (NaHMDS/HMPA) control gives the syn and anti alcohols (157), respectively, on hydroxylation with (63a) in good to excellent yield and better than 95% diastereoselectivity (Scheme 28) <93JOC6180>. A counterion dependent reversal in stereochemistry has also been reported for the hydroxylation of chiral amide enolates where the auxiliary was 2-pyrrolidinemethanol <85TL3539>. 

Evans exploited this concept of chelation in the transition state with the development of a new generation of chiral auxiliaries based on conversion of amino alcohols to oxazolidinone derivatives. As shown in Table 11.16,229 conversion of these auxiliaries (to give the corresponding conjugated amide 268) gave excellent selectivity in the intramolecular Diels-Alder reaction, which generated mixtures of 269 and 270. Coordination with the Lewis acid catalyst generates a complex in which facial selectivity is enhanced relative to the... 

But the Merck chemists noticed that amino alcohol itself, certainly once protected, has a remarkable similarity to Evans oxazolidinone auxiliaries anyway, and it turns out that this amino alcohol will function very successfully as a chiral auxiliary, which does not need to be removed, avoiding waste and saving steps The amino alcohol was acylated with the acyl chloride, and the amide was protected as the nitrogen analogue of an acetonide by treating with 2-methoxypropene (the methyl enol ether of acetone) and an acid catalyst. The enolate... 

A large variety of propionic acid esters and higher homologs having a chiral alcohol moiety have been used in additions to aldehydes [56, 57]. It turned out, however, that the lithium enolates result in only moderate simple diastereoselectivity and induced stereoselectivity, in contrast with the corresponding boron, titanium, tin, or zirconium enolates and silyl ketene acetals, with which stereoselectivity is excellent. The same feature has been observed in enolates derived from chiral amides and oxazolidinones, as... 

Acyl oxazolidinones 50-52 are easily prepared from commercially available chiral starting materials. As shown in Scheme 4.6, treatment of the amino-acid-derived amino alcohols with diethyl carbonate, followed by N-acylation, affords 54 [6, 46], The removal of the auxiliary following the aldol addition reactions proceeds smoothly under a variety of mild conditions to afford carboxylic acids 56 (UO2H) [47, 50], primary alcohols 57 (LiBH,) [51], esters 58 (Ti(OBn)4) [52], or Weinreb amides 59 [51]. 

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