Oxazolidinone chiral

In an indirect amination process, acyl halides are converted to amino acids. Reaction of the acyl halide with a chiral oxazolidinone leads to a chiral amide, which reacts with the N=N unit of a dialkyl azodicarboxylate [R"02C—N=N—CO2R ]. Hydrolysis and catalytic hydrogenation leads to an amino acid with good enantioselectivity. ... 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted much interest for their various applications in different synthetic transformations.2 Such simple structures, directly related to far better known chiral oxazolidinones,11,12,57 have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations, but mainly in condensation of their /V-acyl derivatives with aldehydes. Chiral OZTs have shown interesting characteristics in anti-selective aldol reactions58 or combined asymmetric addition. 

James R. Gage and David A. Evans 83 DIASTEREOSELECTIVE ALDOL CONDENSATION USING A CHIRAL OXAZOLIDINONE AUXILIARY (2S, 3S )-3-HYDR0XY-3-PHENYL-2-METHYLPROPANOIC ACID... 

Oxazolidinone is a versatile functional group and chiral oxazolidinones, readily prepared from amino acids, are premiere auxiliaries with broad utility in synthetic chemistry ". ... 

In the same work, it was demonstrated that 1% ZnCl2 in [DBIM]BF4 gave 55-97% yields and very high diastereoselectivities endolexo ratio of 100 0) to cycloadducts of chiral oxazolidinones at room temperature. For comparison, 1.4 equivalent of Et2AlCl in CH2CI2 gave a modest 62% cyclo adduct, with a poor endo/exo ratio (endojexo in 48 52). 

Further process optimization by Thiruvengadam and co-workers (Thimvengadam et al., 1999), led to a novel, stereoselective, scalable two-step process devoid of chromatography for chiral 2-azetidinone construction (Scheme 13.4). As above, the titanium-enolate of chiral oxazolidinone 11a was preformed, but now when reacted with well behaved imines of type 16, affords the unexpected anti-addition product. This surprising result was further supported by careful comparison to minor antiproducts obtained in the earlier aldol-addition methodology and determination that the major product was indeed 17a (undesired RSR series). Adjustment of the oxazolidinone absolute stereochemistry to the fortuitously less expensive 2S-series afforded the desired diastereo-mer 17b in 95% de and in 50-70% yield. Recrystallization improved the stereochemical purity to >99% de. 

The first enantioselective synthesis of pregabalin (2) was developed by Yuen and co-workers at Pfizer using Evans chiral oxazolidinone chemistry (Yuen et al., 1994). 

Nonbranched amino acids substituted by a fluoroalkyl chain on a carbon distant at least one methylene from the amino acid function have been prepared as racemates by various methods." Under nonracemic form, co-perfluoroalkyl norvaline and norleucine (Rf = C2F5 or more) have been prepared by bromination of an anion of a fluorinated chiral oxazolidinone (derived from RfCH2CH2C02H). Substitution of the bromine atom by an azide and subsequent reduction yield the desired amino acids (Figure 5.10)." ... 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

Other chiral auxiliaries like Oppolzer s bornanesultam 35 or chiral oxazolidinone 36 gave excellent results in stereocontrol and yield (Figure... 

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

Diastereoselective a-azidation via the chiral oxazolidinone auxiliary provides a valuable means of synthesizing highly substituted phenylglycine 46 (Scheme 18).[811... 

Ceric ammonium nitrate Cerate(2-), hexanitrato-, diammonium Cerate(2-), hexakis(nitrato-O)-, diammonium, (OC-6-11) (16774-21-3), 67,141 Cerium(ill) chloride, heptahydrate (18618-55-8), 69, 89 Cesium carbonate Carbonic acid, dicesium salt (534-17-8), 65, 150 CESIUM THIOLATES, 65, 150 Chiral auxiliary, 65, 173, 183, 203, 215 Chiral oxazolidinone auxiliary, from phenylalanine, 68, 77, 83 Chirasil-Val, 66, 153, 154... 

In a related contribution O Brien described the AA on styrenes and converted the amino alcohols into enantiopure diamines by using a reaction strategy similar to Janda s [83], Further synthetic applications of the AA include a new access to Evans chiral oxazolidinones [84], the enantioselective synthesis of a-amino ketones from silyl enol ethers [85], the stereoselective synthesis of cyclohexyl norstatine [86], and a route towards amino cyclitols by aminohydroxy-lation of dienylsilanes [87]. 

A comparative study involving singlet oxygen, ozone, and 4-phenyl-1,2,4-triazoline-3,5-dione oxidation of chiral oxazolidinone substituted enecarbamates has shed light on the mechanistic intricacies of the oxidative cleavage of alkenyl double bonds.282... 

Overall recovery of the auxiliary was 64%. On cost estimates for scale up work it was found that the previously mentioned chiral auxiliary route exceeded the desired cost by a factor of six, primarily as a result of the cost of the chiral oxazolidinone and a yield of 33% over 10 steps. The route was ultimately replaced with a classical resolution protocol using mandelic acid, and this has been superseded by asymmetric approaches (see Chapter 12). 

Although a large number of chiral dienophiles have been developed (Table 26.2), their ability to provide high asymmetric induction appears to be limited to specific dienes. However, there are some dienophiles that tolerate a wider variety of dienes including menthol derivatives,117 118 camphor derivatives,6 39 40 105 107-113 181 182 and oxazolidinones.120 165 183 184 It should be noted that even these auxiliaries would require an efficient recycle protocol for economic scale up. One exception is the use of sacrificial chiral oxazolidinones, which are relatively inexpensive. This approach has been used in the large-scale preparation of the base cyclohexane unit of Ceralure Bj.168 A procedure has been developed for the preparation of (75,25)-5-norbomene-2-carboxylic acid where the D-panta-lactone auxiliary can be recycled efficiently.185186... 

The capabilities of 5-8 for enantioselective cyclopropanation were determined (34) from reactions at room temperature of d- and/or /-menthyl diazoacetate (MDA) with styrene (Table 1), which allows direct comparison with results from both the Aratani (A-Cu) and Pfaltz (P-Cu) catalysts (19, 24). Cyclopropane product yields ranged from 50 to 75%, which were comparable to those obtained with chiral copper catalysts, but enantiomeric excesses were considerably less than those reported from use of either P-Cu or A-Cu. Furthermore, these reactions were subject to exceptional double diastereoselectivity not previously seen to the same degree with the chiral copper catalysts. Although chiral oxazolidinone ligands proved to be promising, the data in Table 1 suggested that steric interactions alone would not sufficiently enhance enantioselectivities to advance RI12L4 as an alternative to A-Cu or P-Cu. 

Table 1 Preparation of A -acylhydrazones from commercially available chiral oxazolidinones...

In search for control of absolute stereochemistry, the reaction of thio-chalcones was investigated with unsaturated amides bearing an Evans chiral oxazolidinone [223] and dimenthyl fumarate [224, 225]. For the first time with thiocarbonyl compounds, the efficiency of Lewis acid addition was demonstrated, and reactions could be conducted at room temperature. With EtAlCl2 (Table 4, entry 2) or A1C13 (entry 3), levels of induction up to 92% were attained for the endo isomer. Yb(OTf)3 in DMSO also caused the acceleration of the reaction with chiral acrylamides with p-facial selectivity [226]. This group has also reported [227] an intramolecular hetero Diels-Alder reaction with divinyl thioketones and the double bond of an allyloxy group (Table 4, entry 4). 

The initial synthesis of aprepitant (1), which relies on a Tebbe olefination and reduction to install a methyl group on the benzyl ether side chain, is shown in Scheme 3.8,19 The initial steps are from a literature-precedented synthesis of p-fluorophenyl glycine based on conversion of chiral oxazolidinone 33 to azide 34. Formation of morpholinone intermediate 36 proceeds via benzylation and reaction with 1,2-dibromoethane. 

Classical methods for removal of the chiral oxazolidinone moiety such as benzyl alcohol transesterification, caused some epimerization at the newly aminated center. The use of anhydrous LiSH (1 equiv., THF, 20 °C, 10 min) was successful and the cleavage occurred without sensible epimerisation. Treatment of the resulting reaction mixture with THF/CH3C03H (1 1 mixture, 40% in H20) gave the carboxylic acids 44 in 76-85 % yields. Compounds 44 were hydrogenolyzed under classical conditions (H2, Pd/C) to the free a-hydrazino acids which were converted to the a-amino acids 45 by subsequent cleavage of the N-N bond in the presence of Ra-ney-Ni (500 psi, 10% aqueous AcOH) with 80-95 % yield (Scheme 23). 

Recently, a stereoselective synthesis of carbon-linked analogues of a- and 0-ga-lactoserine glycoconjugates has been reported using asymmetric enolate methodology [19]. The key step involved the electrophilic animation of a chiral oxazolidinone enolate with DTBAD. 

In conclusion, the animation of enolates of N-acyloxazolidinones with dibenzyl or di-r-butylazodicarboxylates presented the following properties (i) diastereomeric excesses in the range 80-98% (ii) good chemical yields (iii) efficient route to both chiral a-hydrazino and a-amino acid derivatives and (iv) non-destructive removal of the chiral oxazolidinone auxiliaries. 

Treatment of chiral oxazolidinone with Bu2BOTf and Et3N quantitatively produced a novel doubly borylated enolate, which afforded the double aldol products with high diastereoselectivity in the reaction with aldehydes (Equation (182)).687 688... 

In the presence of Bu4N[Ph3SiF2] and In(OTf)3, tetraallylsilane adds to iV-acylhydrazones bearing a chiral oxazolidinone moiety at room temperature to give allylated products with high diastereoselectivity.127 Dual activation of the reactants by these additives is crucial for the mild allylation. 

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