Studies on stereoselective synthesis of phenylglycine using D-glucopyranosylimine as chiral template

Zhou Guobin^a,b , Zhang Pengfei^a,*, Pan Yuanjiang^b,*
(^aDepartment of Chemistry, Hangzhou Teachers College, Hangzhou 310036; ^bDepartment of Chemistry, Zhejiang University, Hangzhou 310027, China)

Supported by the National Natural Science Foundation of China (No. 20376016) and the Natural Science Foundation of Zhejiang Province (No. 202075)

Phenylglycine and its derivatives have been shown to be active on receptors in cloned cell lines, neonatal rat spinal cord, neonatal and adult rat cortex and to be competitive antagonists at mGluRla expressed in either Chinese hamster ovary cells or baby hamster kidney cells ^[1,2]. In addition, it and its derivatives have received much interest for their utilization in synthetic and medicinal chemistry^[3-7].
    A variety of asymmetric synthetic methods have been developed^[8-14] for peparation of phenylglycine and its derivatives. Particularly, Kunz' group developed a Strecker synthesis of amino acids using O-pivaloyl-D-galactosylamines as chiral auxiliaries. D-glucopyranosyl amine II is the derivative generated from D-glucose which is, friendly to environment and can be repeatedly used by reclaiming, have been used to synthesize oligosaccharides, glycoconjugates and glycoproteins etc. (Figure 1)^[16-18] Compared to D-galactosylamine I, the only difference between I and II is the position of hydroxy attaching to the atoms (C-4) and all functional groups necessary for the stereodifferentiation are the same in II (Figure 1). However, D-glucopyranosyl amine is more stable, less expensive than D-galactosylamine. Under such consideration, the authors studied on the synthesis of the amino acids by using D-glucopyranosylaldimines as chiral auxiliaries. We have synthesized successfully a series of D-glucopyranosyl aldimines. In order to confirm their conformations, we choose the 2-hydroxyl-N-(2,3,4,6-tetra-O-pivaloyl-b-D-glucopyranosyl)benzylideneamine as an example for the X-ray (Figure 2). We can find that the structure of D-glucopyranosylaldimine is evidently dissymmetrical from the Figure 2, and which provide the foundation of structure for synthesis of the optically active phenylglycine.

Figure 1

Figure 2

    Herein we wish to report the N- (2,3,4,6-tetra-O-pivaloyl- D-glucopyranosyl) aldimine as a chiral template for the stereocontrolled synthesis of phenylglycine. The synthesis of phenylglycine 5 is outlined in Scheme 1

Scheme 1

    The key step is the reaction of N-(2,3,4,6-tetra-O-pivaloyl- D-glucopyranosyl)aldimine 1 with trimethylsilyl cyanide. This conversion was induced by the tin tetrachloride Lewis acid in dichloromethane with the addition of a small quantity of triethylamine at low temperature and was monitored by TLC. After the reaction for 6 hours, thea-amino nitrile 2 was obtained almost quantitatively and was characterized by HPLC, Polarimeter, ¹H NMR, ¹³C NMR and MS spectrometer.
    Then the D-phenylglycine hydrochloride 4 could be detached from the carbohydrate moiety by treating 2 with dry hydrogen chloride in formic acid at room temp. The 4 was obtained successfully and could be easily separated from pivaloylated glucose derivatives 3 by simple extraction procedure. The pivaloylated glucose derivative 3 was restored to the starting auxiliary carbohydrate.
    In our experiment, we carried out the reaction of nucleophilic addition in the presence of tin tetrachloride Lewis acid in anhydrous tetrahydrofuran, there is a lot of white deposits in the solution and the reaction does not occur. so we tried to use dichloromethane as solvent and then the a-amino nitrile 3 could be obtained but the ultimate product 6 was racemic. In order to increase the ratio of diastereomer, we tried to add a small quantity of triethylamine into the dichloromethane, the results showed that the ratios of diastereomers were considerably increased. So we deduced that the mechanistic rationalization may be as the following:

Figure 3

    The preferred formation of the S-configured diastereomer of 1 can be rationalized by an attack of cyanide from Si side of imine. In the transition state (Figure 3), the tin have two octahedral coordination which are occupied by the imine nitrogen and carbonyl oxygen of the (C-2) pivaloyloxy group respectively, and one of the four chlorines may be substituted by triethylamine nitrogen when the triethylamine was introduced, the steric obstacle would increase considerably, so the tendency of the SN2'-type attack of trimethylsilyl cyanide from Si side facing the ring oxygen increases.
    In conclusion, a novel effective configurationally stable chiral template in the stereocontrolled synthesis of phenylglycine has been developed and the use of trimethylsilyl cyanide (TMSCN) instead of HCN as cyano anion source provides a promising and safer route to these compounds. This synthetic method is efficient, economical and friendly to environment and provides high yield and high stereoselectivity. Further studies along this line are now in progress.

EXPERIMENTAL
Melting points were determined on a X₄-Data microscopic melting point apparatus. Microanalyses were obtained using Carlo—Erba 1106.¹H NMR spectra were obtained at 500MHZ (AVANCE DMX500) in D₂Oor CDCl₃ using TMS as an internal standard. IR spectra were recorded on a Perkin Elmer 683 spectrometer at r. t. Mass spectra were obtained by electron impact at 70ev (HP5989B). X-ray measurements were made on a Rigaku RAXIS RAPID imaging plate area detector with graphite monochromated Mo-K radiation.
    Procedure for preparation of α-amino nitrile 2: To a solution of trimethylsilyl cyanide (0.198g, 2mmol) and tin tetrachloride (0.521g, 2mmol) in dichloromethane (20ml) added will a small quantity of triethylamine (0.05g, 0.5 mmol) at -40ºC, a solution of the imine 2 (0.906g, 1.5mmol) in dichloromethane (1ml) was added slowly and after half an hour, then the solution was slowly warmed to -18ºC, the reaction was monitored by TLC, when completed, extracted with HCl, washed with NaHCO₃ and water, dried with MgSO₄ and concentrated in vacuo. The remaining residue was analyzed by HPLC and recrystallized from n-heptane to give the pure diastereomers the N-(2,3,4,6-Tetra-O-pivaloyl-D-glucosyl ) a-amino nitrile(0.870g, 92%) m. p 152-155ºC; Anal. Calcd for C₃₄H₅₀N₂O₉: C, 64.74; H, 7.99; N, 4.44. Found: C, 64.73; H, 7.86; N, 4.61; %ee=87.5%; [a]_D²⁰= +30.1(C=0.6,CHCl₃), m/z (ESI): 631.3(M⁺+H);¹H NMR (DCCl₃, 500MHz) d: 7.55 (d, J=1.7Hz, 2H ), 7.41(m, J=5.2Hz, 2H ), 7.31(t,1H ), 5.45(t, J=9.4Hz, 1H ), 5.26(t, J=9.6Hz, 1H ), 5.14(t, J=9.2Hz, 1H ), 4.75(d, J=8.8Hz,1H ), 4.23(m, 2H ), 3.92(m, 1H ),1.96(s, 1H), 1.07-1.33(m, 36H ); ¹³C NMR (DCCl₃, 500MHz) d: 178.5, 177.9, 176.8, 176.5, 130.1, 129.5, 128.8, 127.9, 94.7,73.5, 72.3, 70.8, 68.5, 62.3, 44.2, 39.0-39.2, 27.3-27.4; IR (KBr, cm^-1) n: 2979, 2245, 1744, 1633, 1481, 1398, 1279, 1139, 1033.941, 893.
    Procedure for preparation of D-phenylglycine 5^[11]: A dry hydrogen chloride was bubbled through a solution of 2(0.63g) in formic acid (20ml) for 24h at room temp, then, the solution was concentrated in vacuo, filtered through silica gel (20g) with light petroleum ether/ethyl acetate (1:1) .The silica gel was dried, extracted four times with 2NHCl (400ml), the combined acidic solution were concentrated to a volume of about diluted with conc. HCl (10ml) and heated to 80ºC for 48h. After concentratied to dryness, 4 (0.17g) was obtained. Then treatment of 4 with ion-exchange resin delivered the free 5(0.11g): m.p 296-298ºC, %ee=88.2%, [a]_D²⁰= -138.5(C=2, 2NHCl) m/z (ESI): 152.2(M⁺+H);¹H NMR (D₂O, 500MHz) d: 7.79(d, J=7.6Hz, 2H ), 7.64(t, 1H), 7.49(m, J=7.6Hz, 2H ), 5.50(s, 1H); ¹³C NMR (D₂O, 500MHz): d191.9, 135.2, 133.2, 129.0, 128.2, 65.5; IR( KBr, cm^-1) u:3457, 2802-3000, 2105, 1690, 1608, 1592, 1412, 1251, 1154, 955, 740, 700.

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