Benzyl-oxazolidinone chiral auxiliary

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. 

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... 

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... 

Vol. 28, p. 226, ref. 44 for related work). Similar cycloadditions of dienyl pyrrolidinones [le. AT-(peiita-l,3-dienyl)- or -(buta-l,3-dienyl)-pyrolidin-2-one] with the in situ generated acyl nitroso compound derived from benzyl-JV-hydroxy-carbamate with periodate have led to the preparations of racemic pyroUidines 56 and 57 (R = H or Me). The latter compound is thought to exist as a dimer. An asymmetric synthesis of l,S,6-trideoxy-l,5-imino-D-altritol in which the piperidine ring is formed from a pyiidinium ring bearing Seebach s oxazolidinone chiral auxiliary has also been described. ... 

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

Cycloaddition to 3-acryloyl-2,2-dialkyloxazolidines (35) proceeded in a highly stereoselective manner (Scheme 6.38) (191), but poorly so when 4-benzyl-5,5-dimethyl-2-oxazolidinone (36) was used as a chiral auxiliary (Scheme 6.39). 

Although the racemization of the a-carbon can now be considered a potential problem, the synthesis of 32-peptides has been achieved in the same way as seen for 33-peptides. As the 32-amino acids cannot be prepared from the analogous a-amino acids, Seebach and co-workers 5,7 opted to use Evans oxazolidinone chemistry to produce enantiomerically pure 32-amino acids. Alkylation of 3-acyloxazolidin-2-ones 17 with A-(chloromethyl)benzamide yielded the products 18 with diastereomeric ratios between 93 7 and 99 1 (Scheme 8). Removal of the chiral auxiliary (Li0H/H202) and debenzoylation (refluxing acid) was followed by ion-exchange chromatography to yield the free 32-amino acids 20 which were converted by standard means into Boc 21 or benzyl ester 22 derivatives for peptide synthesis. 

The C33-C37-unit of (-F)-calyculin A (a marine natural product) is an amide derived from 5-0-methyl-4-deoxy-4-dimethylamino-D-ribonic acid that has been prepared by Evans and co-workers [250]. A-Protection of sarcosine as benzyl carbamate affords acid 118 which is activated and used to iV-acylate the (5)-phenylalanine-derived oxazolidinone. This gives 119 that is methoxymethylated diastereoselectively (98 2) to give 120. Reductive removal of the chiral auxiliary, followed by Swem oxidation forms aldehyde 121 with little racemization if... 

The asymmetric total synthesis of cytotoxic natural product (-)-FRI 82877 was accomplished by D.A. Evans and co-workers." " To establish the absolute stereochemistry, a boron mediated aldol reaction was utilized applying (R)-4-benzyl-A/-propionyl-2-oxazolidinone" as a chiral auxiliary to yield the syn aldol product. 

Diastereoselectivity for the atom transfer sequenee was studied by employing chiral oxazolidinone auxiliaries with 1-hexene and the oxazolidinone imide derived from a-bromopropionic acid, as described in Eq. (23). The results of these studies are reported in Table 1. The major product formed has the R configuration, consistent with model 31. Diastereoselectivity was good to excellent for either R = /-Pr or benzyl. Presumably the auxiliary with R = CH(Ph)2 would give even better se-lectivities in these transformations. 

Charlton [57] demonstrated the use of oxazolidinones as effective chiral auxiliaries the commercially available (4i )-benzyl and (4S)-isopropyl-2-oxazolidinones were /V-acylated with dihydrocinnamic acid to give N-acyloxazolidinones (54 and 55) in yields greater than 80%, Scheme (10). Diastereoselective alkylation with tert-butylbromoacetate gave in each case principally only one diastereomer (56 and 57, respectively) (de>95%). The oxazolidinone moiety could be removed by utilizing LiOH-H2C>2 without affecting the tert-butyl ester. The crude acid was reduced to the corresponding primary alcohol with BH3THF, then... 

Atom-transfer addition of primary and secondary bromide oxazolidinones to alkenes in the presence of Lewis acids has been investigated and the effects of solvent, temperature, and catalyst were determined. The best Lewis acids were found to be Sc(OTf)3 and Yb(OTf)3 and control was possible using chiral auxiliary oxazolidinones. Tertiary bromides did not react (Scheme 37). Stereochemistry of reduction of the cw-mesityl-alkene (53) with BusSnH proceeds to give the ( )-alkene (54) as the major product ( Z = 9 1). Theoretical calculations at the BLYP/6-31G level were undertaken to rationalize the stereochemistry. Asymmetric hydroxylation of the benzylic position of a range of substrates can be achieved by using a chiral dioxomthenium(VI) porphyrin (55). The oxidation proceeds via a rate-limiting H-abstraction to produce a benzylic radical intermediate. ... 

Ytterbium trifluoromethanesulfonate promoted a radical atom-transfer addition of chiral 3-bromoacetyl-2-oxazolidinones to norbornadiene, which afforded the corresponding 5-ex<9-3-bromo-5-nortricycleneacetic acid derivatives in good yields and with high diastereoselectivity (90-96% de, when using the chiral 4-isopropyl- and 4-benzyl-substituted 2-oxazolidinone auxiliaries).133... 

Chiral acyl oxazolidinones also proved effective as auxiliaries on the acceptor component in asymmetric conjugate additions (Equation 17) [100]. Hruby reported a Cu-catalyzed 1,4-addition to phenyl-substituted acceptor 99 that proceeds with high diastereofacial selectivity to furnish 101 in 98 2 dr and 91 % yield. In these studies, low diastereomeric ratios were observed for the corresponding benzyl-substituted oxazolidinones. 

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