Oxazolidone and derivs

Table 7. Apparent Kinetic Parameters of Isocyanurate and Oxazolidone Formation Derived by Analysis of DSC Peak Areas... 

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). 

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]... 

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. 

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. 

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. 

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... 

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). 

The nitroso derivatives are generally reasonably stable, except the parent compound of the series, 3-nitroso-2-oxazolidone (m.p. 50°-53°C dec.) and 5-phenyl-3-nitroso-2-oxazolidone (m.p. 76.5°-77.5°C dec., both of which are considered dangerous materials. Probably other unstable members of this class of compounds exist. 

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. 

Oxazolidones, chiral, (1) and (2). Evans et al. have prepared these two chiral 2-oxazolidones by reaction of phosgene with (S)-valinol and (IS, 2R)-norephedrine, respectively, and used them as recyclable chiral auxiliaries for carboxylic acids in cnantioselective reactions of the derived imides. 

Diastereofacial-setective intramolecular Diels-Alder reactions. Trienecarbox-imides derived from ahiral oxazolidones undergo Lewis-acid-catalyzed intramolecular Diels-Alder reactions With high endo- and diastereofacial selectivity (endo/exo 100 1). 

Diphenyl-BINOL-derived chiral aluminum reagents are prepared in situ by addition of Ethylaluminum Dichloride or Diethylaluminum Chloride to 3,3 -diphenyl-BINOL. These chiral aluminum reagents promote the enantioselective Diels-Alder reaction of cyclopentadiene with the oxazolidone dienophile (eq 14). Endo products are obtained with a high level of asymmetric induction (>90% ee) however, a stoichiometric amount of the Lewis acid is required. The preparation and use of a C3 symmetric BINOL-derived boronate has been reported (eq 15). BINOL-B(OAr)3 complexes have recently been developed for the asymmetric Diels-Alder reaction with imines (eq 16). ... 

They also reported the intramolecular version of this asymmetric Diels-Alder reaction [53]. ( , )-Trienecarboximides of type 45 derived from chiral oxazolidones undergo Me2AlCl-catalyzed intramolecular Diels-Alder reactions affording bicyclic compounds 46 with high endo and diastereoselectivity (endolexo = -100 1). The stereochemistry is controlled by the stereogenic center at C4 of the chiral auxiliary (Xc) (Sch. 29). 

If the interaction sites are not present in the solute, they must be added through derivatization. When derivatization is required, the standard approach is to convert an alcohol, amine, or carboxylic acid to an aromatic amide, urea, or carbamate. For example, amphetamine was resolved as its naphthoyl amide (21), a series of ot-methylaryl acetic acid antiinflammatory agents were resolved after conversion to their 1-naphthalenemethyl-amides (22), and aliphatic alcohols can be resolved as 3,5-dinitro-carbamates (23). Other derivatives such as oxazolidones (24) and oxazolidines (25) have also been used. 

Kise and coworkers [492] reported electroreductive intramolecular hydrocoupling of diimines derives from chiral 1,2-diamines giving enantiomerically pure piperazines. They also prepared enantioselectively 3,4-diphenyladipate by electroreductive intermolecular hydrocoupling of chiral A -tra/w-cinnamoyl-2-oxazolidones [493]. 

In order to overcome the problems associated with acid hydrolysis of amides of prolinol, the Evans research group has investigated the diastereoselectivity of the alkylation of imides derived from chiral 2-oxazolidones. Imide enolates are somewhat less nucleophilic than amide enolates, but they have the advantage that their diastereomeric alkylation products are easily separated and the imide linkage is cleaved with a variety of reagents under mild conditions. As shown in Scheme 64, alkylation of the chelated (Z)-enolate of the propionimide derived from (S)-valinol (135) with benzyl bromide occurred in high chemical yield and with high si-face diastereoselectivity. In addition to oxazolidones, imidazoli-diones have proved to be useful chiral auxiliaries for diastereoselective enolate alkylations. ... 

Substituted 2-oxazolidones 165 are useful chiral auxiliaries for diastereoselective functionalization at the a-carbon of their amide carbonyl group. The a-fluoroaldehydes 166 were prepared by a series of reactions electrophilic fluorination of the corresponding oxazolidinone sodium enolates with AMluorobenzenesulfonimine reductive removal of the auxiliary with LiBH4 and Dess-Martin oxidation. The aldehydes are so unstable for isolation that they are converted with (R)-/ -toluenesulfinamide to /7-toluenesul(inimines 167, which are isol-able and satisfactorily enantio-enriched. Chiral sulfinimine-mediated diastereoselective Strecker cyanation with aluminum cyanide provided cyanides 168 in excellent diastereose-lectivity, which were finally derived to 3-fluoroamino acids 169 (see Scheme 9.37) [63]. 

Treatment with phosgene of other 2-aminoaicohois, such as metoproiol (MeOCH2CHj-4-CgH OCHjCH(OH)CHjNHCHMe2 used in the treatment of heart disease), readiiy forms cyclic 2-oxazolidones (such as (3.3) [856a]. Epinephrine and Norepinephrine combine with phosgene to give the anticipated cyclized derivatives [8S6b] ... 

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).

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