cis-(-)-Menthyl phenylglycidates in the asymmetric synthesis of taxol side chain

The one-pot azidation and benzoylation of a mixture of cis (-)-menthyl phenylglycidates provide quantitatively the corresponding (2R,3S)-, and (2S,3R)-3-azido-1-((1R,2S,5R)-2-isopropyl-5methylcyclohexyloxy)-1-oxo-3-phenylpropan-2-yl benzoate. Enantiopure (2R,3S)-3-azido-1((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-1-oxo-3-phenylpropan-2-yl benzoate crystallize from MeOH at room temperature in high yields. The reduction of the latter with Zn-TMSCl produces (-)-menthyl 3-benzamido-3-phenyl-2-(trimethylsilyloxy)propanoate which upon simultanious desilylation and hydrolysis provide the taxol side chain N-benzoyl-(2R,3S)-3phenylisoserine.


Results and Discussions
Our retrosynthetic plan for the synthesis of taxol side chain is depicted in Scheme 1. Taxol side chain 5 can be prepared from the hydrolysis of menthyl ester 4 which in turn could be prepared by the reduction of azide 3. One-pot reaction of menthyl glycidate 2 involving azidation and benzoylation will provide azide 3. The mixture (65/35) of phenylglycidates 2 and 2' were converted to 3 and 3' in one-pot by direct treatment with NaN 3 and following benzoylation (Sheme 2).Compound 3 crystallize in high yield from methanol at room temperature.
Zn Cl D Scheme 3. Probable mechanism for the reduction of azides 3 with Zn-TMSCl.
The probable mechanism for the conversion of azide 3 to 4 is depicted in Scheme 3. We assume that single electron transfer from Zn to the Si in TMSCl can give ClZnSiMe 3 .The coordination of azide 3 to the metal centre of the latter through the terminal nitrogen would give intermediate A which synchronously abstracts dimethyl(methylene)silane to produce B. The later is probably in equilibrium with C which eliminates N 2 to give D. The silylation of the latter give 4a or its hydrolysis produce the minor nonsilylated 4.

Conclusions
Thus, the products from the cis diastereoselective asymmetric Darzen condensation of benzaldehyde with (-)-menthyl haloacetate were demonstrated to be useful in the syntheses of the taxol side chain enantiomers.For the first time Zn-TMSCl system was employed in the reduction of the azide 9 functionality of compounds 3-3' to give the corresponding silylated 4-4'.The latter were hydrolysed with KOH in the presence of a phase transfer catalyst such as tetrabutylammonium hydrogensulphate (TBAHS) to give the corresponding enantiopure taxol side chain enantiomers in high overall yields.

Experimental Section
General.Melting points were taken on an Electrothermal Digital melting point apparatus.Infrared spectra were recorded on a Thermo-Nicolet 6700 FTIR.1D and 2D NMR spectra were recorded on a Varian Mercury Plus 400 MHz spectrometer.Elemental analyses were performed on a EuroEA 3000 CHNS analyser.TBAHS (97% pure) were purchased from Aldrich.DMAP (≥99% GC), were Merck quality products.The THF (99% GC) was Riedel-de Haën product.

Reduction of compound 3. General procedure
The mixture of zinc powder (5 mmol, 325 mg) and Me 3 SiCl (5 mmol, 540 mg) in THF (10 mL) was stirred for 5 minutes at room temperature.Benzoylated azide 3 (1 mmol) was added to the mixture and heated at reflux for 24 h.The unreacted zinc powder was filtered and water (10 mL) was added to the cooled mixture and extracted with ethyl acetate (3X10 mL).The organic phase was dried over anhydrous Na 2 SO 4 filtered and the solvent evaporated.The residue was subjected to silica packed column and eluted with ethyl acetate and petroleum ether.

One-pot procedure for the synthesis of (2S,3R)-3-benzamido-2-hydroxy-3-phenylpropanoic acid (+)-5 (Taxol side chain enantiomer)
Menthyl phenylglycidate 2' (3 mmol, 906 mg) was dissolved in a mixture containing MeOH (27 mL), H 2 O (3 mL) and ethylformate (5 mL).NaN 3 (30 mmol, 1950 mg) was added and the reaction mixture was stirred at 60 o C for 90 h.The work up procedure is as described above.To a cooled to 0 o C solution of the nearly pure azidoalcohol (2.72 mmol, 940 mg) in CH 2 Cl 2 (15 mL) and DMAP (2.72 mmol, 332 mg), benzoyl chloride (3.41 mmol, 479 mg) was added drop-wise and the reaction mixture stirred at room temperature for 2 h.The mixture was washed with water (3X15 mL) and the organic phase dried over anhydrous Na 2 SO 4 , filtered and the oily residue, 1060 mg, was dissolved in methanol.The crystalline product was filtered and dried under vacuum to yield 950 mg 3'.To the mixture of zinc powder (10.5 mmol, 687 mg) and Me 3 SiCl (10.5 mmol, 1134 mg) in THF (20 mL) benzoylated azide 3' was added and the mixture refluxed for 24 h.The unreacted zinc powder was filtered and water (15 mL) was added to the cooled mixture and extracted with ethyl acetate (3X15 mL).The organic phase was dried over anhydrous Na 2 SO 4 filtered and the solvent evaporated.To the residue containing the 4' and 4'a (1000 mg, 68/32 by 1 H NMR spectroscopy) dissolved in THF (20 mL) TBAHS (0.21 mmol, 71 mg) and KOH (2.68 mmol, 156 mg) were added successively and the reaction mixture stirred at room temperature for 24 h.Water was added (15 mL) to the mixture and extracted with ethyl acetate (3X10 mL).The layers were separated and the water phase was acidified with 1 N HCl to pH 2 and the precipitated solid filtered to give 371 mg, 69.5% (+)-5