Oxazolidines, preparation

Diastereoselective addition in Et20/HMPT (1 1) leads to the (5)-aldehyde with an enantiomeric excess of 40%, whereas in -hexane the (2 )-aldehyde is formed with 80% ( ) enantiomeric excess. The (2 )-configured aldehyde is also obtained in benzene and in dichloromethane, but with lower ee values of 50% and 25%, respectively. Inverse results were obtained with a chiral oxazolidine prepared from ( )-cinnamaldehyde and (+)-ephedrine. Here, the (5)-aldehyde with ee = 79% is formed in -hexane, and the (7 )-aldehyde in Et20/HMPT (1 1) with ee = 50% [703], This result may be due to different structures of the organocopper reagent, and hence of the diastereomorphic activated complexes, in nonpolar solvents ( -hexane, benzene, dichloromethane) and in EPD solvents (Et20/HMPT) [703]. 

A chiral oxazolidine prepared from a,j6-unsaturated aldehydes and ( —)- or (-l-)-ephedrine efficiently induced asymmetric cyclopropanation with excess of diazomethane in the presence of palladium acetate, e.g. formation of 24 from ( —)-ephedrine and ( )-cinnamaldehyde 24 was cyclopropanated to give 25 and the auxiliary removed giving... 

Oxazolidines are subject to ring-chain tautomerism. A variety of substituted oxazolidines in the solid state exist in the chain form, based on C NMR experiments <85X5919,92X4979). In solution, the two forms are in equilibrium, the position of which depends on the solvent and the substituents. Oxazolidines prepared from meta- and para-substituted benzaldehydes and 2-amino-2-methyl-propanol, norephedrine, norpseudoephedrine, and serine esters all give good linear plots for the equation log -l-log Ax=h where a are the Hammett-Brown values <93X6701,93JOC1967). 

Oxazolidines are prepared to allow selective protection of the ct- or aj-C02H groups in aspartic and glutamic acids. 

Recently, Lee and co-workers reported an efficient method for the preparation of enantiomerically pure oxazolidin-2-ones from aziridine-2-carboxylates 186 (Scheme 3.68) [128]. This one-pot aziridine ring-opening and subsequent intramolecular cyclization process was highly regio- and stereoselective, affording 187 in high yield. 

Enantiopure a-amino aldehydes are valuable synthons in natural product synthesis [57]. However, problems are often encountered with their configurational instability [58]. Aziridine-2-carboxaldehydes are also a-amino aldehydes and accordingly have a potential synthetic value. We found that M-tritylaziridine-2-carboxaldehyde 56 is a perfectly stable compound and therefore comparable to Garner s aldehyde (ferf-butyl 2,2-dimethyl-4-(S)-formyl-oxazolidine-3-car-boxylate). Aldehyde 56 can readily be prepared from aziridine-2-carboxylic ester 12 by the sequence shown in Scheme 42 [59]. 

Zeijden [112] used chiral M-functionalized cyclopentadiene ligands to prepare a series of transition metal complexes. The zirconium derivative (82 in Scheme 46), as a moderate Lewis acid, catalyzed the Diels-Alder reaction between methacroleine and cyclopentadiene, with 72% de but no measurable enantiomeric excess. Nakagawa [113] reported l,T-(2,2 -bis-acylamino)binaphthalene (83 in Scheme 46) to be effective in the ytterbium-catalyzed asymmetric Diels-Alder reaction between cyclopentadiene and crotonyl-l,3-oxazolidin-2-one. The adduct was obtained with high yield and enantioselectivity (97% yield, endo/exo = 91/9, > 98% ee for the endo adduct). The addition of diisopropylethylamine was necessary to afford high enantioselectivities, since without this additive, the product was essentially... 

Herrmann has prepared several unsymmetrical salts 7 from 1-alkyl-imidazoles (Scheme 6). The chirality was introduced, after N-alkylation of the imidazole by chloro acetonitrile, by addition of enantiomerically pure aminoalcohols onto the nitrile to form an oxazolidine ring [14],... 

In the presence of a catalytic amount of chiral lanthanide triflate 63, the reaction of 3-acyl-l,3-oxazolidin-2-ones with cyclopentadiene produces Diels-Alder adducts in high yields and high ee. The chiral lanthanide triflate 63 can be prepared from ytterbium triflate, (R)-( I )-binaphthol, and a tertiary amine. Both enantiomers of the cycloaddition product can be prepared via this chiral lanthanide (III) complex-catalyzed reaction using the same chiral source [(R)-(+)-binaphthol] and an appropriately selected achiral ligand. This achiral ligand serves as an additive to stabilize the catalyst in the sense of preventing the catalyst from aging. Asymmetric catalytic aza Diels-Alder reactions can also be carried out successfully under these conditions (Scheme 5-21).19... 

In the preparation of (2R,33, 7a3 )-2-phenyl-3-methyl-5-oxo-2,3,5,6,7,7a-hexahydropyrrolo-[2,T ]-oxazole 248, the reaction time is the most important parameter in the /ra r-halometallation. For instance, by stirring 246 with 1 or 2equiv of fer7-butyllithium in EtzO at — 78 °C for 30 min, 247 and the bicyclic lactam 248 were obtained as an equimolar mixture. The latter substance was isolated as a single product when the reaction time was increased to 120min for the reactions of 2-(2 -bromoethyl)oxazolidine 246 with fert-butyllithium (Scheme 36) <1996T10761>. 

In carbohydrate chemistry, the most described method for the preparation of saccharidic thionocarbamates involves preliminary introduction of the amine function on a partially or non-protected saccharidic template. The condensation of amino sugars with carbon disulfide or thiophosgene leads to cyclization in 1,3-oxazolidine- or l,3-oxazine-2-thiones. This reaction involves the formation of an intermediate isothiocyanate, which reacts further with a 3- or y-located hydroxyl group. The viability and facility of this process depends on the saccharidic ring size and the inherent strain. Some major rules can be put into light from the cases studied 30... 

Corey and colleagues215 prepared chiral aluminum complexes from chiral bis(sulfona-mides) and trimethylaluminum. These were successfully applied in the cycloadditions of 3-acryloyl-l,3-oxazolidin-2-one (17a) with substituted cyclopentadienes. Thus, the reaction of 3-acryloyl-l,3-oxazolidin-2-one with 5-(benzyloxymethyl)cyclopentadiene (331) afforded 332 with 94% ee (equation 93). A transition state was proposed based on the X-ray structure of the chiral catalyst and on NMR data of the 1 1 complex between 333... 

Chiral titanium catalysts have generally been derived from chiral diols. Narasaka and colleagues251 developed an efficient catalyst, 406, prepared from TiCl2(OPr- )2 and a (+)-tartaric acid derived 1,4-diol. These authors found that Af-crotonyl-l,3-oxazolidin-2-one (404) reacted with cyclopentadiene in the presence of 10 mol% of 406 to give cycloadduct 405 with up to 91% ee (equation 120)252. 

The Diels-Alder reaction of ethyl 2-benzoylacrylate (450) with cyclopentadiene was effectively catalyzed by magnesium(II) complexes of bis(oxazolidine) 448 and oxazolidine 449 (equation 134). When the catalysts were prepared in refluxing acetonitrile, adduct 451 was obtained with virtually complete endo selectivity for the ethoxycarbonyl group and up to 87% ee282. 

Oxazolidin-5-ones (11.110) are structurally related to oxazolidines, combining the motifs of a lactone and an O-Mannich base. These derivatives have already been discussed in Sect. 8.7.5. However, they serve here as a transition to [3,1 ]benzoxazepin-4-ones as an example of potential prodrugs. Thus, [3,l]benzoxazepin-4-one derivatives (11.111, R = H or Me, R = H, Me, Et, or Ph) were prepared from diclofenac (11.112) [137]. These prodrugs were stable for at least a few hours in simulated gastric juice, but, when administered to rats elicited an anti-inflammatory response comparable to that of diclofenac. One compound (11.111, R = Me, R = Et) was even more active than diclofenac without producing the gastric mucosal injury (ulcers) caused in all rats by diclofenac itself. Here again, there was no indication of whether the mechanism of hydrolysis is chemical or enzymatic. 

Sn2 Reactions with epoxides and aziridines are also synthetically useful. An example of epoxide cleavage with an organocopper reagent with sp carbon moieties is the enantioselective synthesis of (3S, 4S)-4-methyl-3-heptanol (53), an elm bark beetle (Scolytus multistriatus) pheromone [42]. The chiral epoxy oxazolidine 51 [43], prepared from (R)-phenylglycinol, reacted with a propylmagnesium bromide-derived cuprate at —70 °C to afford the oxazolidine 52 in 74% yield (Scheme 9.12). Compound 52 was converted into the target molecular 53 by conventional procedures. 

A range of l,3-oxazolidin-4-ones (93) have been prepared by cyclocondensation of cyanohydrins, R R C(OH)CN, with aldehydes or ketones, R COR, under anhydrous strong acid conditions. The R groups used are mainly simple alkyl and aryl moieties, and the mechanism is discussed. 

To increase the yields of the ring closure reactions, a new method was developed that was successfully applied for the synthesis of alicyclic fused systems of both the parent oxazolidine-2-thione and tetrahydro-1,3-oxazine-2-thione (85S1149). As an example, the synthesis of 2-thioxoperhydro-l,3-benzoxazine 103 is described. The dithiocarbamate 101, prepared from the amino alcohol 100, carbon disulfide and triethylamine, was treated with ethyl chloroformate in the presence of triethylamine, to give the thioxo derivative 103 via the transition state 102 (85S1149). In this way, the fused-skeleton thioxooxazines (91, X = S, 92) can be prepared with considerably higher yields (50-70%) than by the earlier methods (85S1149). 

Lactol 128 has been converted into a variety of racemic C-nucleosides. The unstable aldehyde 130 was prepared from 128 by way of oxazolidine 129. Lactone 131 was also derived from 128 and used as starting material in the synthesis of racemic C-nucleosides. Adducts 77 + 77 were transformed into epoxide 132. Opening of the epoxide, followed by ozonolysis and reduction allowed one to... 

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