A high-yielding low-cost facile synthesis of 2-oxazolidinones chiral auxiliaries
Introduction
Chiral 2-oxazolidinones1 (especially 1) have been shown to be highly versatile chiral auxiliaries through numerous elegant syntheses2 by Evans and others. Unfortunately, their broader application in asymmetric synthesis is seriously hampered by the lack of facile, safe, and low-cost access to the chiral auxiliaries themselves. To circumvent this problem, many efforts3a–m have been made since the late 1980s.
As already noted by previous investigators, the original Et2CO3 procedure3a suffered from such draw-backs as the inconvenience and potential hazards associated with borane, tedious work up, and inconsistent results.3b The subsequent modifications all aimed at circumventing these problems. For instance, LiAlH4,3d CaBH4,3e or LiBH43f (formed in situ from CaCl23e or LiI3f and NaBH4, with the carboxylic acids being transformed into esters before reduction) were employed as reducing agent to replace the borane. Similarly, more reactive (and unfortunately, more expensive) phosgene derivatives such as Cl3CO2CCl,3b,h Cl3CO2COCCl3,3d PhO2CCl,3c and BnO2CCl3f were utilized in place of the Et2CO3 to ensure a facile ring closure. More recent efforts appear to have already given up the base-catalyzed intramolecular ester exchange ring-closure protocol; some3m chose to utilize urea derivatives (prepared at high temperatures not easily accessible using oil baths) with an amino group as leaving group after treatment with nitrite, while others3g,j,l attempted to revert the ester exchange mechanism to the less common alkyloxygen cleavage ones. Since all these modified procedures, while improving the original one in some way, introduced other undesired factors such as expensive reagents or inconvenient conditions, none of them could serve as a clear-cut solution to the aforementioned problem—the ‘bottle-neck’ still remains despite all the exhaustive efforts. The long span of time over which all those efforts were made and the large number of research groups involved in such endeavors seem to insinuate that preparing these chiral 2-oxazolidinones in high yields from cheap phosgene derivatives without problems4 is just impossible.
Section snippets
Results and discussion
Now we have found a clear-cut solution (Scheme 1) to the facile access problem. First, we found from the literature a reduction protocol (NaBH4/H2SO4) reported by Abiko and Masamune5 in 1992, which is apparently the cheapest procedure applicable in the present context but has somehow been ignored by previous investigators. Then an alkoxycarbonylation using EtO2CCl6 is performed without isolating the amino alcohol, directly affording7 the rather pure carbamates 4a,8 4b,3e,9 and 4c3e in near
Experimental
A typical procedure13 is as follows: (S)-(−)-4-Benzyl-2-oxazolidinone 1b. l-Phenylalanine (33.00 g, 200 mmol) was reduced following (but skipping the addition of MeOH) the literature procedure5 up to ‘adding 5N NaOH (200 mL used for this work) and heating for 3 h’. The mixture was cooled to rt with stirring before introducing H2O (150 mL) and NaHCO3 (84.00 g, 1.00 mol), followed by ClCO2Et (21 mL, 210 mmol, cooling with 5°C bath). After stirring at rt for another 1.5 h the mixture was extracted
Acknowledgements
This work was supported by the Chinese Academy of Sciences (CAS ‘Knowledge Innovation’ Project), the Life Science Special Fund of CAS Supported by the Ministry of Finance (Stz 98-3-03), the Major State Basic Research Development Program (G2000077502), the Ministry of Science and Technology of China (970211006-06), and the National Natural Science Foundation of China (29832020).
References (16)
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(1994) - (a) Evans, D. A.; Bartoli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127–2129. (b) For a review, see: Ager, D. J.;...
- See, for example: (a) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. J. Am. Chem. Soc. 1998, 120, 5921–5942....
- (a) Gage, J. R.; Evans, D. A. Org. Synth. 1989, 68, 77–82. (b) Pridgen, L. N.; Prol Jr., J. J. Org. Chem. 1989, 54,...
- We have also tried many bases such as DBU, DMAP, NEt3, NaOH, or run the reaction under acidic conditions (pTsOH, conc....
- MeO2CCl works in exactly the same way except for giving methanol instead of ethanol at the cyclization...
- The carbamates are also accessible by e.g., reducing 5a (Ref. 15) and 5b (Ref. 16) with NaBH4/H2SO4 (Ref. 5). However,...
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