Amino oxazolidinone derivatives

The optically active oxazolidinone derivative 3, readily obtainable from serine (see Appendix), is alkylated to give predominantly the cw-product98. The auxiliary is removed by acid hydrolysis to give the 2-amino alcohol. 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

The phenylalanine-derived oxazolidinone featured here enjoys three practical advantages over the valine-derived oxazolidinone developed earlier in this laboratory. First, both the intermediate g-amino alcohol and the derived oxazolidinone are crystalline solids which can be purified conveniently by direct crystallization. Second, the oxazolidinone contains a UV chromophore which greatly facilitates TLC or HPLC analysis when it is employed as a chiral auxiliary. Finally, both enantiomers of phenylalanine are readily available, enabling stereocontrol in either sense simply by using the oxazolidinone derived from the appropriate enantiomer. 

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.

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. 

An interesting innovation involves the use of isopropenyl acetate or acetic anhydride to accomplish irreversible acyl transfer63, as exemplified in the resolution of 1-phenylethanol (12) and the amino diol derivative 3- cr/ butyl-5-(2-hydroxyethyl)-2-oxazolidinone (14) ( ) ... 

As described in Scheme 25, the first method starts with the conversion of an a-amino acid into a p-amino-p-alkyl aldehyde. Then, the chiral aldol condensation between the resulting aldehyde and an oxazolidinone derivative is carried out. In the last step, removal of the oxazolidinone provides the desired product. 

The reaction of methyl thiosalicylate 187 with 2-oxazolidinone 186 yielded 45% of benzothiazepinone 188. The same procedure has been followed to synthesize chiral thiazepine 190 starting from bicyclic oxazolidinone 189 and methyl thiosalicylate 187 (Scheme 31) <2001T2115>. Related reports about cyclization of amino acid derivatives and analogues of 187 have appeared <2004BMC4459>. 

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. 

This coupling procedure with the thioesters proved sensitive to the substitution pattern of both the amino acid and alkene. In contrast, coupling reactions with the M-acyl oxazolidinone derivatives such as 22 proved to be much more effective (Scheme 14) [20]. Mechanistic studies suggested that an alternative pathway was operating in these cases, where reduction of the al-... 

Scheme 14 Alternative acyl-like radical addition reactions with N-acyl oxazolidinone derivatives of amino acids...

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. 

These two examples of thermolysis of 5-oxazolidinone derivatives indicate that cyclic intermediates, 5-oxazolidinones, are most likely involved in the decarboxylative condensation of N-substituted a-amino acids with carbonyl... 

In addition to amino acids, 1,2-amino alcohols can be used as chiral auxiliaries. The synthesis of the amino acid derivative 16 outlined in Scheme 9.15 is a variation of a Strecker reaction. - Evans oxazolidinone chemistry is well documented, which allows for a wide variety of reactions to be performed with a high degree of predictability. In addition to alkylation reactions to introduce the side chain of an amino acid, the nitrogen group can also be introduced in a variety of ways, one of which is illustrated in Scheme 9.16. ... 

An important strategy for achieving substrate control is the use of chiral auxiliaries, which are structures incorporated into reactants for the purpose of influencing the stereochemistry. Two of the most widely used systems are oxazolidinones " derived from amino acids and sultams derived from camphorsulfonic acid. These groups are most often used as carboxylic acid amides. They can control facial stereoselectivity in reactions such as enolate alkylation, aldol addition, and Diels-Alder cycloadditions, among others. The substituents on the chiral auxiliary determine the preferred direction of approach. 

The relative stereochemistry of the amino alcohol functionality in 80 and 81 was established from nOe studies performed on the oxazolidinone derivatives of these two compounds [82],... 

A useful alternative to esterification procedure appears to be the formation of oxazolidinone derivatives using 1,3-dichlorotetrafluoroacetone, as reported recently by Husek and co-workers [246,247] the resulting heterocyclic nitrogen is further acylated with heptafluorobutyric anhydride. This procedure, which is applicable to 20 common amino acids, was found to be both rapid and sensitive [247]. 

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... 

Novel syntheses of amino acids have also employed triethylsilane C-0 bond cleavages of (V, 0-acetals. In this way, Af-methyl-amino acid derivatives are isolated in high yields from the Fmoc or Cbz protected 5-oxazolidinone precursors, using TFA and Ets SiH, or with the Lewis acid AICI3 and Et3SiH (eq 31). A one-pot preparation of (V-methyl-a-amino acid dipeptides can be accomplished from an oxazolidinone, amino acid, TFA, and Et3SiH combination. ... 

Extension of the enamine-mediated carbonyl a-amination strategy to the generation of quaternary stereogenic centers at the a-position of a-branched aldehydes under catalysis by prohne 1 [8, 9], pyrrolidine tetrazole 3 [10, 11], or L-azetidin-2-carboxylic acid 4 [8] has also been explored (Table 11.1). The observed enantio-selectivities ranged from essentially none to >99%. Derivatives of 2-phenylpropanal gave better enantioselectivities than a,a-dialkyl substituted aldehydes. Erase and coworkers [11] employed microwave irradiation to accelerate the rate of proline-catalyzed amination, and found that yields as well as enantioselectivity can be somewhat improved with shorter reaction times. It appears that the pyrrolidine tetrazol 3 was a more effective catalyst than L-proline 1 for the amination of 2-phenylpropanal derivatives [10,11]. Subsequent reduction of adducts and cyclization could be carried out to afford the respective a-amino alcohols or the A-amino-oxazolidinones. 

A mild procedure for the synthesis of (4J ,5S)-4,5-diphenyl-2-oxazolidinone 739 has been described [529]. Compound 739 has been used for the synthesis of optically active amines [530] because of its high stereoselectivity and easy deprotection by hydrogenolysis after the reaction. The procedure can also be used to prepare 2-oxazolidinones from various 2-amino-ethanol derivatives. 

Several examples can serve to illustrate the use of chiral auxiliaries. First, the chiral, heterocyclic, amino-add-derived lactam, (5)-4-(phenylmethyl)-2-oxazolidinone, is capable of conversion into an anion on treatment with butyllithium [CH3(CH2)2CH2Li]. Acylation at nitrogen with propanoyl chloride produces chiral propionamide. 

Chiral oxazoUdinones possess nearly all properties required for economic application on the large scale both enantiomers are available in two steps from d-or L-amino acids they are configurationally stable and easy to recycle. Tailing to measure of chiral oxazolidinone derivatives is possible, as shown in the syntheses of some biological products [10, 11]. 

Asymmetric aldol reactions utilizing chiral auxiliaries or templates have emerged as one of the most reliable methods in organic synthesis. Both syn-and anti-selective aldol reactions have been developed over the years. The field of asymmetric syn aldol reactions has been largely advanced by Evans since his development of dibutylboron enolate aldol chemistry based on amino acid-derived chiral oxazolidinones. This method requires expensive dibutylboron trifiate, hosvever, and the amino acid-derived chiral auxiliary is only readily available in one enantiomer and thus only provides one enantiomer of the syn aldol. Several methods developed on the basis of titanium enolates provide convenient access to both Evans and non-Evans syn aldol products. 

Amino Acid-derived Oxazolidinone and Related Auxiliaries... 

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