Reaction of α , β -dihydroxydihydrocinnamic esters with acetonitrile: a new approach to β -amino- α -hydroxydihydrocinnamic acids

Diols and their derivatives, readily available from cinnamate esters by the Sharpless asymmetric dihydroxylation (AD) reaction, react with acetonitrile in the presence of an acid affording the corresponding β -amino- α -hydroxyacid derivatives. In combination with the AD reaction, this method provides an efficient entry to various phenylisoserine derivatives on multigram scale


Introduction
2][3] There are three general approaches to these compounds: i) direct Sharpless asymmetric aminohydroxylation (AA) of cinnamic acid esters; 1a-d ii) asymmetric carbon-carbon bond formation; 2a-d iii) using other chiral sources, e.g.2,3-dihydroxyesters readily available from Sharpless asymmetric dihydroxylation (AD) 3a,b or aminoacids.3c,d Among these approaches, the synthesis of phenylisoserine from 2,3-dihydroxydihydrocinnamic esters generally proceeds with highest regio-and enantioselectivity.The desired syn geometry is achieved through double inversion at the β-carbon.This transformation requires the activation of the β-hydroxy group followed by the displacement with halide and subsequent reaction with azide or benzoyl isothiocyanate.We now report a simple one-step protocol based on the Ritter reaction 4 for the preparation of various phenylisoserine derivatives from 2,3-dihydroxy-2,3-dihydrocinnamates 1.

Results and Discussion
In a typical procedure (Method A), neat BF 3 •OEt 2 was added dropwise to a stirred solution of (2S,3R)-dihydroxydihydrocinnamic ester 1 in acetonitrile at 0 ºC (Scheme 1).The reaction mixture was stirred at 0 ºC for 4−24 hours.The product was isolated as a mixture of diastereomers: (2R,3S)-2 and (2S,3S)-3 in 76−85% combined yield (Table 1).Based on the characteristic 3 J 2,3 = 8.4-8.6 Hz 3a,5 the major product was assigned to the syn diastereomer 2. We found the highest product ratio (8:1) for the p-methyl derivatives 2c/3c, it was only 6:1 for the pfluoro derivatives 2a/3a.It is worth noting that the reaction time required for completion of the reaction greatly varied from 4 h to 24 h for p-methyl and the p-fluoro derivative, respectively.This may suggest the development of a positive charge at the β-carbon.The high degree of diastereoselectivity of the transformation suggests participation of the neighboring hydroxyl in the stabilization of this charge, i. e. it seems reasonable to assume the cis-disubstituted epoxide as the intermediate (see the proposed mechanism in Scheme 2).

Scheme 1
Figure 1 shows how various acids (both protic and Lewis acids) affect the rate of conversion of 1c into 2c + 3c.The reactions of diol 1c with acetonitrile in the presence of BF 3 •OEt 2 , AlCl 3 or TfOH were monitored by GC.The mixture of diastereomer 2c and 3c was observed in all reactions with approximately the same ratios.Since the reaction with BF 3 •OEt 2 was the fastest and proceeded to completion, this Lewis acid was generally chosen for these transformations.We found that a higher reaction temperature generally accelerates the reaction but affects the ratio of diastereomers 2c and 3c; at 50 °C the diastereomer ratio was 3:1.We attempted to prepare diastereomer 3 by the reaction of acetonitrile with the cyclic orthoacetate 4, formed in situ from diol 1 (Method B), a method known to give the substitution of oxygen at the benzylic position with inversion of configuration.3a,7 Contrary to our expectations, we obtained not only 2 as the major diastereomer, but also the influence of para substituents on the rate of the transformation reversed.In fact, the reaction of 1a (with p-fluoro substituent) went to completion within 2 h, while the p-methyl derivative required over 24 h.The major diastereomers 2 were separated by flash chromatography on silica gel and were subsequently subjected to hydrolysis with 2N HCl at 50 °C for 6 h.The desired products 5 were isolated upon concentration of the reaction mixtures as white powders in 85−94% yield (Scheme 3).Based on the fact that both 1 H and 13 C NMR spectra of amino acid 5b were identical to that of the commercial (2S,3R)-3-phenylisoserine hydrochloride, it was assigned the same syn geometry.Since in our opinion inversion of both stereocenters is not likely and the starting diol had 2S,3R geometry, the specific stereochemistry of the product was also assigned as 2S,3R.Furthermore, chiral HPLC (CHIRALPAK WH00CE) trace of 5b indicated that the retention time of the major peak was identical to that of the commercial (2S,3R)-3-phenylisoserine. The geometry of 5a and 5c was tentatively assigned based on comparison of their NMR spectra with that of 5b.In conclusion, six phenylisoserine derivatives were prepared on multigram scale.This approach provides straightforward entry to various phenylisoserines in stereoselective fashion and practical yields.

Methyl (2S,3R)-3-(acetylamino)-3-aryl-2-hydroxypropanoates (2). Method A:
Neat BF 3 •OEt 2 (31.68 mL, 0.25 mol) was added dropwise to a stirred mixture of diol 1 (0.05 mol) and acetonitrile (30 mL) at 0 ºC.The resulting solution was stirred at 0 ºC for 24 h.The reaction mixture was treated with saturated aq.NaHCO 3 (50 mL), the organic phase was separated, dried over MgSO 4 and concentrated in vacuum to give the desired product as a mixture of diastereomers 2 and 3.The major isomer 2 was separated by flash chromatography on silica gel using hexane/ethyl acetate (4:1) as the eluent.Method B: Diol 1 (10 mmol) was mixed with trimethyl orthoacetate (25 mL), and after addition of a catalytic amount of p-toluenesulfonic acid the resulting mixture was stirred at room temperature for 5 h.The mixture was concentrated under reduced pressure and diluted with dichloromethane (25 mL).To this solution BF 3 •OEt 2 (2.53 mL, 20 mmol) was added dropwise at 0 ºC, and the mixture was stirred at this temperature for 2-24 h and then treated with saturated aq.NaHCO 3 (50 mL).The organic phase was separated, dried over MgSO 4 and concentrated in vacuum to give the desired product as a mixture of diastereomers 2 and 3.

Table 1 .
Conversion of diols 1 into the diastereomer mixtures of aminoalcohols 2 and 3