2-Oxazolidone derivatives

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]... 

Farrissey and Nashu105 reported that the reaction of an epoxide with phenyl isocyanate, which previously had been claimed to yield a tetrahydro-l,3-oxazin-2-one,1,106 produced, in fact, a 2-oxazolidone derivative. 

Ito and Terashima obtained good syn selectivity for a two-stage condensation of 3-(2-bromopropion-yl)-2-oxazolidone derivatives and zinc dust with aldehydes (Scheme 13). Syn anti ratios as high as 98 2 were obtained. 

A suspension of the startg. 2-oxazolidone deriv. in tert-huiyl hydroperoxide added dropwise at -5° during 3 hrs. to a stirred soln. of sodium tert-huty peroxide, and warmed to room temp. product. Y 32%. F. e. s. H. Kropf, M. Ball, and H.-J. Franke, Synthesis 1975, 42. 

Firstly, we modified the C(, g-unsaturated acids to be used as dienophiles by converting them into the corresponding 1,3-oxazolidin-2-one (abbreviated as oxazolidone) derivatives 15. 

Since high enantioselectivity was achieved by employing two molar equivalents of the chiral titanium reagent generated from 17b, the asymmetric Diels-Alder reaction of various oxazolidone derivatives of a,8-unsaturated acids and cyclopentadiene was studied. The results are listed in Table 4. With the exception of the acryloyl derivative 15b, various dienophiles reacted with cyclopentadiene to give the endo-adducts 1 in high optical purity. 

On the other hand, the reaction of the oxazolidone derivative of fumaric acid and butadiene was found to proceed in poor enantioselectivity as compared with the reaction carried out in the presence of excess amounts of the chiral titanium reagent, and the cyclohexenedicarboxylic acid derivative was obtained in 32-45% ee. In order to achieve wide applicability for the catalytic procedure, the reaction conditions were... 

Figure 22.4 Separation of racemic propranolol as oxazolidone derivative with a dinitrobenzoylphenylglycine phase [reproduced with permission from I.W. Wainer, T.D. Doyle, K.H. Donn and J.R. Powell, J. Chromatogr., 306, 405 (1984)]. Conditions sample, whole-blood extract, 2.5 h after administration of an 80 mg dose of propranolol racemate, derivatized to oxazolidone with phosgene column, 25 cm X 4.6 mm i.d. stationary phase, 3,5-DNB-phenylglycine, 5 [xm mobile phase, hexane-isopropanol-acetonitrile (97 3 1), 2mlmin fluorescence detector, 290-335 nm IS, internal standard (oxazolidone derivative of pronethalol).

The 17a-carbamate (286) has been cyclised with the 20-oxo-group to give the oxazolidone derivative (287), which was dehydrated to the methylene-oxazolidone... 

An alternative mechanistic explanation for the formation of oxazolidone, derived from the reaction of isocyanate and epoxide, has been given by Gulbins et al. (Reaction 4), Here the oxide anion derived from the epoxy ring attacks the carbonyl (C 0), rather than the imino (C N) double bond as shown in Reaction 2, Ring closure then produces an N-substituted imino-1,3-dioxolane, which isomerises to the 2-oxazolidone. Support for this mechanism was gained from the isomerism of an N-phenyl-2-imino-l,3-dioxolane to the corresponding 2-oxazolidone, using the same reaction conditions. 

The stereochemistry of the amino alcohol anti-680 was unequivocally assigned through its oxazolidone derivatives 681 and 682 prepared with GDI [452]. 

Conventional asymmetric aldol reactions have been performed by using chiral enolates and achiral carbonyl compounds. A chiral boron enolate generated from a chiral oxazolidone derivative (26 and 28), dialkylboron tri-fiate, and diisopropylethylamine reacts stereoselectively with aldehydes to afford the corresponding syn aldol adducts (27 and 29) in good yields with excellent diastereoselectivity (Eqs. (8) and (9)) [12]. The opposite sense of asymmetric induction is achieved by changing the chiral auxiliary. Several other chiral auxiliaries have also been developed for highly diastereoselec-tive synthesis of syn aldol adducts (Eqs. (10)-(13)) [13]. 

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. 

An alternative sequence utilized 2-oxazolidone, which was readily synthesized from urea and ethanolamine, as the glycine equivalent. Subsequent treatment with phosphorous acid and formaldehyde produced iV-phosphonomethyl-2-oxazolidone 12 (16). Upon hydrolysis, and loss of CO2,12 provided the related derivative, iV-phosphonomethylethanolamine 13, which was oxidized at high temperature with a variety of metal catalysts including cadmium oxide (16) or Raney copper (17) to give GLYH3, after acidification. A similar oxidation route has also been reported starting from iV-phosphonomethy 1-morpholine (18). 

Stereoselective Reformatsky reaction. The Reformatsky reaction of the chiral 2-azetidinone 1 with 3-(2-bromopropionyl)-2-oxazolidone (2a) gives essentially a 1 1 mixture of the diastereomers 3a(3 and 3aa. However, introduction of two methyl groups at C4 in 2 markedly improves the (i-diastereoselectivity, as does an increase in the temperature from 0 to 67° (reflux, THF). The highest diastereoselectivity (95 5) is observed with the derivative of 4,4-dibutyl-5,5-pentamethylene-2-oxa-zolidone. The 3p-diastereomer is a useful intermediate to lp-methylcarbapenems.1... 

It is significant to note that the sense of asymmetric induction noted for amide enolates 157 and 158 is the same as that found for the boryl enolates derived from the chiral oxazolidone imides 146 and 145, respectively (cf. Scheme 22). The arguments presented... 

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. 

Further support for this explanation is the fact that the chiral acetate enolates derived from A -acetyl-2-oxazolidone (46). in which the developing Rj <-> CH3 interaction leading to diastereomer A is absent, exhibit only poor diastereofacial selection. 

As can be seen in Table 5, various oxazolidones of acrylic acid derivatives react with cyclopentadiene to afford the endo-adducts in good to high (64-91%) enantioselectivity by the combined use of a catalytic amount of the chiral titanium reagent and MS 4A. 

Due to these limitations Evans et al. focussed on the exploration of imide-derived enolates (165). They expected these systems to react stereoselective in carbon-carbon bond formation and that the derived imides might be readily hydrolized or reduced under the mild conditions required for the construction of complex products, One of the two chiral 2-oxazolidones (175) chosen for study by Evans et al.179) is derived from (S)-valine and was readily prepared from this inexpensive commercially available a-amino acid having an optical purity exceeding 99 %. The preparation of the related imide-derived enolate (165) is shown in the next scheme. Alkylation reactions employing (175) resulted in excellent diastereoface selection, as summarized in Table 4 179). 

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