4-Substituted-2-oxazolidinone preparation

Ketone 16 can be prepared from glucose in 6 steps without extensive chromatography purification (Scheme 10.5).78. V-Aryl-substituted oxazolidinone-containing ketone 18 can be synthesized... 

Desymmetrization of AT-Boc-protected serinol has been achieved in good yield and high enantiomeric excess (ee > 99%) by acylation with PPL in vinyl acetate (Fig. 19) (26). The product has been exploited as an intermediate in different ways to prepare (4R)- and (4S)-substituted oxazolidinones known as Evans auxiliaries. These compounds have important tasks as asymmetric inductors for synthesis. 

Tamariz and coworkers [42] have described a versatile, efficient methodology for preparing N-substituted-4,5-dimethylene-2-oxazolidinones 42 (Figure 2.5) from a-diketones and isocyanates and have also studied their reactivity in Diels-Alder reactions. This is a method for synthesizing polycyclic heterocyclic compounds. Some of the reactions of diene 42 are summarized in Scheme 2.18. The nitrogen atom seems to control the regiochemistry of the reaction. 

Scheme 6.81 Transformation of one adduct prepared from the 64-catalyzed asymmetric addition of a-substituted P-keto esters to di-tert-butyl azodicarboxylate (a-hydrazination) into the corresponding oxazolidinone amino acid derivative.

The oxazolidinone-substituted olefin Ic (Scheme 3) constitutes another fortunate substrate for the diastereoselective synthesis of a chiral dioxetane , which is of preparative value for the enantiomeric synthesis of 1,2 diols . For example, the photooxygenation of the enecarbamate Ic produces the asymmetric dioxetane 2c in >95% jt-facial diastereoselectivity. The attack of the O2 occurs from the jt face anti to the isopropyl... 

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)." ... 

Some enantiomerically pure substituted 2-oxazolidinones are excellent as chiral auxiliaries. From the pioneering studies 2 conducted in the early 1980 s of the uses of such auxiliaries has emerged what is perhaps the most widely used method today for the preparation of enantiomerically highly enriched a-alkylalkanoic acids, alcohols and aldehydes, that is, the alkylation of enolates from chiral 3-acylated 2-oxazolidinones followed by auxiliary removal2 59. The early work has been reviewed60-62. These enantiomerically pure cyclic imide auxiliaries have been used not only for alkylations but also in a plethora of a-functionalization reactions, such as diastereoselective aldol, a-hydroxylation, a-amination and Diels-Alder reactions and these are discussed elsewhere in this volume. 

Both, five- and six-membered cyclic carbamates have been synthesized by the reaction of 2-(l-haloalkyl)-oxiranes with C02 and primary aliphatic amines [81]. Notably, 5-substituted 2-oxazolidinones have been prepared in good yield (51-94%) by reacting 2-aminomethyloxiranes with C02 (0.1 MPa), in MeOH, at room temperature [82]. 

A wider range of possibilities of preparing cyclic derivatives is offered by the presence of carboxyl and a-amino groups in the molecule. Substituted 5-oxazolinone (Scheme 4.23) is prepared by refluxing with TFA anhydride, and substituted 5-oxazolidinone (Scheme 4.24)by reaction with (halogenated) acetone [117,118]. Thiohydantoins are formed by reaction with isothiocyanate (Scheme 4.25). If R is methyl or phenyl, then the corresponding methyl- or phenylthiohydantoin is produced. Thiohydantoins are usually not volatile enough and for the purposes of GC analyses must be further modified, e.g., by trimethylsilylation [119,120]. 

Substituted oxazolidin-5-ones are produced by the reaction of amino acids with substituted acetone. Simmons and Wiley [267] applied 1,3-dichlorotetrafluoroacetone, and it is this reagent that has been most often used for the preparation of oxazolidinones [268] (Scheme 5.27). The use of hexafluoroacetone as a reagent is limited as it is gaseous, expensive and the derivatives of the simplest amino acids are too volatile. The former reagent is therefore preferred for cyclizations. 

While this methodology is not intended for the preparation of oxazolidinones that can be generated in a more concise route from their parent a-amino acid (vide supra), it does allow for the preparation of 4-substituted-5,5-dimethyloxazolidin-2-ones in which the parent a-amino acid is either not commercially available or exceedingly expensive. 

Substituted oxazolidin-5-one derivatives, which are prepared from N -protected a-annino dicarboxyhc acids and paraformaldehyde, are employed for dual protection of the a-annino and a-carboxy groups in the synthesis of P-aspartyl and y-glutamyl esters (Scheme 4).Py For this purpose the oxazolidinone derivatives are synthesized by treatment of the Z amino acids with paraformaldehyde in a nnixture of acetic anhydride, acetic acid, and traces of thionyl chloride or by azeotropic distillation of the Z amino acids with paraformaldehyde and 4-toluenesulfonic acid in benzene. The resulting heterocychc compounds are readily converted into the tert-butyl esters with isobutene under acid catalysis. Esterification is achieved with tert-butyl bromidet or with Boc-F.P l Finally, the oxazolidinone ring is opened by alkaline hydrolysis or catalytic hydrogenolysis to yield the tert-butyl esters. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

Substituted 2-oxazolidones 165 are useful chiral auxiliaries for diastereoselective functionalization at the a-carbon of their amide carbonyl group. The a-fluoroaldehydes 166 were prepared by a series of reactions electrophilic fluorination of the corresponding oxazolidinone sodium enolates with AMluorobenzenesulfonimine reductive removal of the auxiliary with LiBH4 and Dess-Martin oxidation. The aldehydes are so unstable for isolation that they are converted with (R)-/ -toluenesulfinamide to /7-toluenesul(inimines 167, which are isol-able and satisfactorily enantio-enriched. Chiral sulfinimine-mediated diastereoselective Strecker cyanation with aluminum cyanide provided cyanides 168 in excellent diastereose-lectivity, which were finally derived to 3-fluoroamino acids 169 (see Scheme 9.37) [63]. 

Enantiomerically pure spiro oxindoles (Scheme 35) were prepared by using solid-supported N-cinnamoyl Evans oxazolidinone (164) [265]. Thus, chiral oxazolidi-none prepared from L-tyrosine was attached to a Merrifield resin and then N-acylated with the required unsaturated acyl chloride such as cinnamoyl chloride (not shown). The resin (165) was then suspended in aqueous dioxane and treated with proline and N-phenyl isatin at 80-90 °C overnight to give a highly substituted spiro compound (167). 

This reaction is arguably the most useful and certainly the most widely used application of the electrophilic C-amination of enolates in organic synthesis. A number of 4- and 4,5-substituted 2-oxazolidinones are commercially available in both enantiomeric forms and the chiral auxiliary is easily recovered.430 Reactions of A-acyloxazolidinonc enolates with azo esters431,432 and arenesulfonyl azides433 are rapid even at very low temperatures (—100°) and the diastereochemical outcome is reliably predictable. The facile removal of the chiral auxiliary and ready conversion of the azide or hydrazino ester functionalities into amines makes these reactions a standard method for the preparation of d- and L-a-amino acids. 

Miscellanea A methodology to prepare a-substituted-P-hydroxy acids and esters has been introduced in solid phase based on an Evans oxazolidinone-based linker to produce enantiospecifk aldol condensations (Figure 15.4). Acids and esters were released by treatment with LiOH and H202 in THF (at -20 °C) or NaOMe in THF, respectively [58, 59], Diels-Alder adducts of oxazolidinone-bound crotonates have also been detached with LiOCH2Ph [60],... 

An alternative to the bis-lactim ether approach is based on condensations of saturated five-membered heterocycles such as imidazolidinone (532) which can now be obtained in an optically pure state by a straightforward classical resolution/ The related oxazolidinone (533) has been obtained from methionine and used to prepare (R)-amino-acids [cf. (528) ] as well as the vinyl substituted derivatives(534) by oxidation and elimination of the sulphur group." Yet more general routes to chiral amino—acids have been reported using a variety of asymmetrically substituted ester enolate equivalents (535) in combination with the electrophilic nitrogen source di-t-butyl... 

Combination Diels-Alder/retro-Diels-Alder reactions have been used to prepare substituted furan derivatives from furans and oxazolidinones. Reaction of a furan or oxazolidinone derivative with a disubstituted alkyne (usual dimethyl acetylenedicarboxylate or diethyl acetylenedicarboxylate) produces the Diels-Alder adduct, which can undergo a retro-Diels-Alder reaction to give the desired furan derivative. 

Oxidative carbonylation of amines affords alkylurea469 and oxamide 470 [192]. Substituted ureas were prepared efficiently in the presence of Pdl2 and KI under CO and CO2 pressure (total 60 atm) [193]. Synthesis of 2-oxazolidinone (471) by the carbonylation of 2-aminoethanol was carried out efficiently using a catalytic system of Pdl2-KI [194]. 

The A -aryl oxazolidinone-bearing ketone catalysts 5 are readily prepared in large quantities from glucose and inexpensive anilines in four steps. Phenyl groups substituted with methylsulfonyl (5a) or alkyls (5b, 5c) consistently provide high enantioselectivity for a variety of cw-olefms and certain terminal olefins. cw-P-Methylstyrenes can be epoxidized with... 

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