Chiral auxiliaries oxazolidinones

We (Novartis) reported ] an enantioselective synthesis of (2S,2 71)- zyf/iro-methylphenidate (3) utilizing Evans (S)-4-benzyl-2-oxazolidinone chiral auxiliary to control the diastereofacial selectivity in the hydrogenation of enamine intermediate (65 Scheme 16). Acylation of (S)-4-benzyl-V-phenylace-tyl-2-oxazolidinone (61) with the mixed anhydride 63, followed by deprotection of the V-Boc group with TFA, and neutralization of the reaction mixture with NaHCOs afforded the enamine intermediate 65. Hydrogenation of enamine 65 with 10% Pd-C in ethyl acetate furnished 66 in 95% yield with an excellent diastereoselectivity (97 5). Treatment of 66 with methanol in the presence of EnR afforded the desired... 

Other Reductions. The reductive removal of 2-oxazolidinone chiral auxiliaries with NaBH4 is a mild and chemoselective method that provided the corresponding alcohols in good to excellent yields (75-95%), with complete preservation of stereochem-... 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

Matsumura and his coworkers [38] have employed the 2-pyrrolidone anion, in DMF solution, to deprotonate arylacetic acid esters with subsequent oxidative dimerization of the corresponding carbanions. This study includes a useful comparison between the electrochemical and chemical generation of the 2-pyrrolidone anion (by fluoride anion displacement in A-trimethylsilyl-2-pyrrolidone). The advantage lies with the electrochemical route, which gave yields of final product of 80%, compared with the 30% obtained with the chemically generated base (Scheme 10). The overall process, formation of dimethyl 2,3-diphenylsuccinates, is not only efficient and convenient but also operates with high diastereoselectivity when under the control of an oxazolidinone chiral auxiliary (Scheme 10). 

We have introduced you to this chiral auxiliary before any other because it is more commonly used than any other. It is a member of the oxazolidinone (the name of the heterocyclic ring) family of auxiliaries developed by David Evans at Harvard University, and is easily and cheaply made from the amino acid (S)-valine. Not only is it cheaply made it can also be recycled. The last step of the route above, transesterification with benzyl alcohol, regenerates the auxiliary ready for re-use. synthesis of Evans s oxazolidinone chiral auxiliary from (S)-valine NH2 NH2... 

L. Wessjohn and co-workers successfully applied the CrCl2-mediated Reformatsky reaction for the synthesis of C1-C6 fragment of epothilones. In their approach, they utilized the Evans (R)-4-benzyl-oxazolidinone chiral auxiliary to control the absolute stereochemistry. The chromium-Re/brmafsAy reaction between the (R)-4-benzyl-3-(2-bromoacetyl)-oxazolidinone and 2,2-dimethyl-3-oxo-pentanal occurred with complete chemoselection providing the product with 63% yield and as a single diastereomer. 

Excellent yields and diastereoselectivities have been obtained in allylations using a new oxazolidinone chiral auxiliary derived from diphenylalaninol [24]. The use of oxazolidinone chiral auxiliaries was sparked by the application of Lewis acids to radical reactions. Bidentate Lewis acids are used to favor one rotamer (44) out of a possible four by forming a chelated intermediate with the two carbonyl groups and through steric interactions imparted by the 4-substituent of the oxazolidinone (Eq. (13.12)). Trapping with the allylstannane can then occur on the face opposite the bulky oxazolidinone-4-substituent. 

A similar allylation has been reported with the chiral auxiliary on the nitrogen of the bromoglycine attached as an imide rather than as an ester (Eq. (13.20)) [30]. A valinol-derived oxazolidinone chiral auxiliary 68 was employed under bidentate Lewis acid conditions (ZnCl2). It was found that ZnCla functions as a radical initiator as well as a Lewis acid in these reactions. The best example provides the allylglycine 69 derivative in 85% yield and the newly formed stereocenter in a ratio of 87 13 (R. S) with a reaction time of 1 h at -78 °C. 

Evans Aldol (With Two Oxazolidinone Chiral Auxiliaries)... 

A different approach to enantioselective electrophilic fluorination is the use of chiral auxiliary groups on the substrate this converts the problem into a diastereo-selective fluorination. The ground-breaking work in this field was done since 1992 by the Davis group [207], by fluorination of imide enolates modified by Evans oxazolidinone chiral auxiliary [208] using N-fluoro-o-benzenedisulfonimide (NFTh) as the electrophilic fluorination agent (Scheme 2.94). 

The succinate core can be prepared by alkylation of a simple carboxylic acid (74a or b) with a bromoacetate using the Evans oxazolidinone chiral auxiliary derived from phenylalanine (chapter 27). The branched alkyl group must be present in the substrate for alkylation and the second acid group added in the alkylation so that there is no competition between two carbonyl groups during enolate formation. After hydrolysis (91% yield) the alkylated succinic acid 77 has >95% ee. Notice that the two acid groups are differentiated by this procedure.10... 

The starting material 164 can be made as a single enantiomer by the use of an oxazolidinone chiral auxiliary (chapter 27). Treatment with the chloropurine 167 catalysed by Pd(0) gave only the correct stereoisomer 168 in 63% yield - not a high yield but better than 33% - and deprotection and hydrolysis gave the guanine-derived carbovir19169. 

Scheme 12.23 Asymmetric Diels-Alder reaction using oxazolidinone chiral auxiliary 56.

Scheme 8.2S. a-Amidation of chiral ester enolates using di(ter/-butyl)azodicarboxylate and (a) N-methylephedrine [106] or (b) oxazolidinone chiral auxiliaries [107], Azidation of a chir eno ate... 

Numerous research groups have shown that chiral auxiliaries can be used in free-radical reactions for the generation of new stereogenic centers [34], Sibi and Yamamoto have used oxazolidinone chiral auxiliaries in the presence of bidentate Lewis acid to create bicyclic intermediates and control the outcome of reactions (Scheme 11). 

In the Doi-Takahashi synthesis [37] of spiruchostatin A, the acetate aldol was performed with the Seebach quaternary oxazolidinone chiral auxiliary. The best... 

For an early discussion of the Evans oxazolidinone chiral auxiliaries, see D. A. Evans, J. V. Nelson,... 

Adam W, Bosio SG, Turro NJ (2002) Flighly diastereoselective dioxetane formation in the photooxygenation of enecarbamates with an oxazolidinone chiral auxiliary steric control in the [2+2] cycloaddition of singlet oxygen through conformational alignment. J Am Chem Soc 124 8814-8815... 

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