Chiral Building Blocks: Enantioselective Syntheses of Benzyloxymethyl Phenyl Propionic Acids

The synthesis of


Introduction
There is a growing demand from the pharmaceutical industry for single enantiomer compounds and it has been predicted that the sale of single enantiomer therapeutics will grow from US$6.63 billion in 2000 to US$16 billion by 2007 [1].The pharmaceutical industry has a rising demand for chiral intermediates and research reagents because of the continuing imperative to improve drug efficacy.This in turn impacts on researchers involved in synthesis of preclinical drug candidates and the continuing demand by these researchers for effective methods for the synthesis of homochiral building blocks.

Results and Discussion
As part of a collaborative medicinal chemistry effort, we needed to develop an enantioselective synthesis of (2S)-2-(hydroxymethylphenyl) propionic acids for use as chiral building blocks.It was envisaged that an auxiliary-directed stereoselective alkylation of a phenylpropionamide should afford the target compounds after auxiliary removal.The synthesis of the starting phenylpropionic acids is detailed in Schemes 1 and 2. 3-(2-Fluoro-4-methoxyphenyl) propionic acid (5) and 3-(2,4-dimethylphenyl)propionic acid (6) were synthesised from the corresponding benzaldehydes 1 and 2 via Horner/Emmons reaction.Hydrogenation of the resulting α,β-unsaturated esters 3 and 4 followed by hydrolysis afforded the phenylpropionic acids 5 and 6 in high yield.The synthesis of 3-(2-fluoro-4methylphenyl) propionic acid (9) shown in Scheme 2 began from 2-fluoro-4-methylaniline (7) as the benzaldehyde was not commercially available.Diazonium salt formation from the aniline followed by an in situ Heck type coupling with Pd(dba) 2 and methyl acrylate afforded the α,β−unsaturated ester 8 in high yield.Hydrogenation and hydrolysis gave the required acid 9.
Our research plan was to couple a chiral auxiliary onto the required phenylpropionic acid and to direct alkylation from one face of the enolate.We initially used pseudoephedrine as a chiral auxiliary as Myers had reported excellent enantiomeric excesses for the alkylation of pseudoephedrine glycinamide [2].Adapting this method, we successfully coupled 3-(2-fluoro-4-methylphenyl) propionic acid (9) to (S,S)-(+)-pseudoephedrine (10) in the presence of EDC, DIEA to give amide 11 (Scheme 3).Alkylation of 11 with LDA and methoxymethyl chloride (MOMCl) or benzyloxymethyl chloride (BOMCl) gave a mixture of products with low conversion to the desired material.Further work on 11 was abandoned in favour of the approach outlined in Scheme 4.
In 1990, Evans first reported the use of TiCl 4 as a pre-complexation agent with a series of 3acylated-2-oxazolidinones [3].After deprotonation with an amine base, alkylation proceeded almost exclusively from one face of the enolate-titanium complex.Recently, Rawlings and co-workers reported a completely diastereoselective benzyloxymethylation of (4R)-4-isopropyl-3-(3-phenylpropionyl)-2-oxazolidinone as a key step in the asymmetric synthesis of A factor [4].The deployment of BOMCl in this case had the advantage of allowing for reductive removal of the benzyl protecting group after subsequent synthetic operations.Using this procedure we were able to access compounds  4).An X-ray crystal structure of (4R)-4-benzyl-3-[(2S)-2-benzyloxymethyl-3-(2-fluoro-4-methylphenyl)propionyl]-2-oxazolidinone (17) revealed that alkylation had indeed occurred from the least hindered face of the enolate delivering the required S stereochemistry at C2 (Figure 1).Furthermore, the respective minor diastereomers were not observed by 1 H-NMR, HPLC nor LC/MS.Removal of the auxiliary, to give 18-20, was achieved using LiOH•H 2 O and 35% aqueous hydrogen peroxide in degassed tetrahydrofuran/water in good yield [4,5].It should be noted that when 1.0 equivalent of LiOH•H 2 O was used we observed an impurity resulting from attack of the lithium peroxide anion onto the oxazolidinone carbonyl.This by-product was eliminated when 0.9 equivalent of LiOH•H 2 O was used.

Conclusions
The TiCl 4 mediated benzyloxymethylation of a series of N-acyloxazolidinones proceeded with exclusive diastereoselectivity to provide a useful entry to chiral 2-benzyloxymethylphenylpropionic acids.Homochiral products 18 -20 are representative target building blocks.

Experimental
General 1 H-NMR (400 MHz) and 13 C-NMR (100 MHz) were recorded on a Varian UNITY INOVA spectrometer in d-CHCl 3 solutions.LCMS were run on an Applied Biosystems/MDS Sciex API-2000 LC/MS/MS system.HPLC analysis was performed on a Millenium 100 HPLC System and retention times (t R ) are reported at 214 nm.X-ray crystallography was carried out on a Bruker Smart Apex Xray diffractometer.The images were generated using Mercury 1.2.1 from pdb files.Analytical thin layer chromatograms were visualised under UV or with 20% w/v solution of phosphomolybdic acid in ethanol.Flash chromatography was performed with Merck silica gel No. 9385.Anhydrous solvents were purchased from Aldrich Chemical Co. in Sure/Seal TM bottles.The chiral auxiliary was also purchased from Aldrich.