Asymmetric Strecker Synthesis via a Crystallization-Induced Asymmetric Transformation using a Chiral Auxiliary Wilhelmus H. J. Boesten, Jean-Paul G. Seerden, and Ben de Lange DSM Research Life Sciences-Organic Chemistry and Biocatalysis, The Netherlands

Introduction Experimental Section (cont.) Results (cont.) The synthesis of -amino acids is important The synthesis of amino nitrile (R,S)-3. Optimization trials (Table 1) showed that water at 70 C for 24 because they are used extensively in Ph Ph h produced (R,S)-3 in 93% yield (dr > 99/1). pharmaceuticals, agrochemicals, and as chiral O Ph HN CONH2 HN CONH2 Table 1. Optimization trials for the synthesis of (R,S)-3. NaCN, HOAc ligands. The Strecker reaction is historically one of + + H N CONH H CN CN the most versatile ways to synthesize -amino 2 2 solvent, time, temp H H dr acids, but this method yields only 50% of a single temp time yield (R,S)-3/ solvent(s) ( C) (h) (%) (R,R)-3 enantiomer. Higher yields can be achieved by (R)-1 2 (R,S)-3 (R,R)-3 MeOH rt 20 80 65/35 using chiral auxiliaries, but auxiliaries are often high MeOH/2-PrOH rt 22 51 99/1 2-PrOH rt 22 84 88/12 in cost and low in availability. • A stirred suspension of 1 (400 mmol) in H2O (400 mL) was added 2 PrOH/t-BuOH rt 20 65 96/4 to pivaldehyde 2 (419 mmol) and stirred for 30 min. MeOH/H2O rt 20 69 81/18 H O 55 24 81 85/15 Overview. To solve these problems, we present the 2 • NaCN/HOAc was added at 23–28 °C. The mixture was heated to H2O 60 24 84 96/4 first example of a crystallization-induced H2O 65 24 84 98/2 70 °C and stirred for 24 h. H O 70 24 93 >99/1 asymmetric transformation using optically pure (R)- 2 • After cooling to 30 °C, the product was filtered, washed (500 mL phenylglycine amide 1 as a chiral auxiliary. The H O), dried, and analyzed by 1H NMR. (R,S)-3 diastereomer precipitates out of solution in 2 Discussion 76-93% yield with a diastereomeric ratio (dr) > 99/1. • (R,S)-3 formed as a colorless solid (92.4%, dr > 99/1). A proposed mechanism is shown in Scheme 1. The re-facial attack of CN– to the intermediate imine 4 appears to be preferred, forming (R,S)-3. (R,S)-3 is less soluble and precipitates out of solution; Experimental Section Results (R,R)-3 is more soluble and epimerizes in solution via the imine 4. Scheme 1 General. (R)-Phenylglycine amide 1 was purchased • The absolute configuration of (R,S)- from DSM (Netherlands). The dr of (R,S)-3 and (R,R)- 3 was confirmed by X-ray analysis 3 was determined by 1H NMR using the relative (Fig. 1). integration between the t-Bu signals at 1.05 ppm for (R,S)-3 and 1.15 ppm for (R,R)-3. NMR spectra were Fig. 1. X-ray structure of (R,S)-3. recorded using a Varian VXR-300 spectrometer (300 mHz) and referenced to residual solvent. 100 95 • Solvent, time, and temperature were 90 85 80 optimized. Time was optimized at 30 Percent yield 75 70 min with dr > 99/1 (Fig. 2). 65 0 5 10 15 20 25 30 35 Time (min) Conclusions (R)-phenylglycine amide 1 is an excellent chiral auxiliary in the Fig. 2. Optimization of reaction time. asymmetric Strecker reaction of pivaldehyde 2. In water at 70 C, the (R,S)-3 product was isolated in 93% yield and dr > 99/1. Work is underway to convert (R,S)-3 to (S)-tert-leucine and thereby complete the asymmetric Strecker reaction.