2-oxazolidones, 3-acyl

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

For carboxyl terminal determination of peptides by means of CDI the terminal carboxylic acid group of the peptide is selectively reduced with sodium dihydrobis(2-methoxy-ethoxy)aluminate to an alcohol. Subsequent conversion of the amino alcohol moiety with CDI yields an 7V-acyl-2-oxazolidone derivative, from which the oxazolidone unit can be easily removed and characterized.[56]... 

The chiral boron enolates generated from /V-acyl oxazolidones such as 7 and 8 (which were named Evans auxiliaries and have been extensively used in the a-alkylation reactions discussed in Chapter 2) have proved to be among the most popular boron enolates due to the ease of their preparation, removal, and recycling and to their excellent stereoselectivity.8... 

Usually, (Z)-boron enolates can be prepared by treating /V-acyl oxazolidones with di-K-butylboron triflate and triethylamine in CH2CI2 at 78°C, and the enolate then prepared can easily undergo aldol reaction at this temperature to give a, vy -aldol product with more than 99% diastereoselectivity (Scheme 3-4). In this example, the boron counterion plays an important role in the stereoselective aldol reaction. Triethylamine is more effective than di-wo-propylethyl amine in the enolization step. Changing boron to lithium leads to a drop in stereoselectivity. 

A further step towards improved selectivity in aldol condensations is found in the work of David A. Evans. The work of Evans [3a] [14] is based in some early observations from Meyers laboratory [15] and the fact that boron enolates may be readily prepared under mild conditions from ketones and dialkylboron triflates [16]. Detailed investigations with Al-propionylpyrrolidine (31) indicate that the enolisation process (LDA, THE) affords the enolate 32 with at least 97% (Z>diastereoselection (Scheme 9.8). Finally, the observation that the inclusion of potential chelating centres enhance aldol diastereoselection led Evans to study the boron enolates 34 of A(-acyl-2-oxazolidones (33), which allow not only great diastereoselectivity (favouring the 5yn-isomer) in aldol condensations, but offer a possible solution to the problem of enantioselective total syntheses (with selectivities greater than 98%) of complex organic molecules (see below, 9.3.2), by using a recyclisable chiral auxiliary. 

Acyl-l,3-oxazolidine-2-thiones, chiral (1). Nagao and co-workers1 have prepared the chiral 3-acetyl-l,3-oxazolidine-2-thiones (la and lb) and used them to effect diastereoselective aldol reactions. The two chiral auxiliaries show, as expected, opposite diastereoselectivities, but contrast with the diastereoselectivities observed with chiral 4-alkyl-2-oxazolidones (11, 379-381). This aldol reaction has been used to prepare the chiral azetidinone 4 (equation I) and (-I- )-Prelog-Djerassi lactone. 

Recently, Kunz reported that dialkylaluminum chlorides add in a 1,4-mode to N-(a,f3-unsaturated acyl)oxazolidones (9 Scheme 3),12 while high enantioselectivity is obtained with the chiral N-(a, 3-un-saturated acyl)oxazolinone (11). Typically, higher dialkylaluminum halides (R = ethyl, isobutyl) do not... 

Of similar nature are chiral halogenations using auxiliary groups. Typical examples are the conversion of esters to enantiomerically pure halohydrins (precursors to chiral epoxides) using camphor-10-sulfonic acid derivatives583 and the chiral synthesis of a-amino acid synthons via diastereoselective bromination of TV-acyl oxazolidone derivatives584. 

Asymmetric Diels-Alder reactions. Chiral a,p-unsaturated N-acyl oxazolidones exhibit high diastereoface selection in Diels-Alder reactions, particularly those conducted in the presence of diethylaluminum chloride (1.2 equiv.). 

Asymmetric halogenation of carboxylic acid derivatives has also been achieved by D.A. Evans (refs. 11,12) via chiral N-acyl oxazolidones. For instance, an N-acyl oxazolidone prepared by acylation of the (4S)-benzyl-2-oxazolidone chiral auxiliary derived from (S)-phenylalanine, is converted to its (Z)-dibutyl boron enolate, which is added to a NBS slurry, at low temperature (Fig. 6) ... 

Independent work on asymmetric aldol reactions by Evans et al. led to the development of alternative chiral boron enolates that exhibit >100 1 facial selectivity. A pair of chiral N-acyl-2-oxazolidones (35)... 

Sodium bis(trimethylsilyl) amide Succinic acid esters from 3-acyl-2-oxazolidones via asym. a-carbalkoxymethylation... 

Startg. chiral 3-acyl-2-oxazolidone treated with Na-bis(trimethylsilyl)amide in THF at -78°, the resulting Z-enolate alkylated with 3 eqs. methyl bromoacetate, allowed to warm to —20° over 1-2 h, and quenched at — 50° with 2.5 eqs. acetic acid in ether - intermediate (Y 77% d.e. 95%), treated with 2 eqs. 1 Af Na-methoxide in methanol... 

Highly enantioselective aldol condensation of the chiral A-acyl-oxazolidone via its dibutylboryl enolate with the appropriate aldehyde ... 

Preparation of Isothiocyanates.—A conventional synthetic method is illustrated in the preparation of AT-(isothiocyanato-acyl)-amino-acids, e.g. S C N (CH2) C0 NHCHR C02H, starting from the peptide trimethyl-silyl ester treatment with CSg and an alkyl chloroformate gives an alkoxycarbonyl dithiocarbamate which readily cyclo-eliminates COS and alkanol. Acylation of an amino-acid trimethylsilyl ester with SCN--(CH2) C0 C1 provides an alternative route cyclization of an a-isothio-cyanato-acid (158) to a 2-thio-oxazolidone (159) occurs readily in solution, ... 

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