Synlett 2003(12): 1927-1930  
DOI: 10.1055/s-2003-41500
CLUSTER
© Georg Thieme Verlag Stuttgart · New York

Dynamic Kinetic Resolution for Asymmetric Synthesis of α-Alkyl Amino Acids via Dual-Function Catalysis of Modified Cinchona Alkaloids

Jianfeng Hang, Li Deng*
Department of Chemistry, Brandeis University, 415 South St., Waltham, MA 02454-9110, USA
Fax: +1(781)362516; e-Mail: deng@brandeis.edu;
Further Information

Publication History

Received 21 July 2003
Publication Date:
19 September 2003 (online)

Abstract

The electronic property of the N-protecting group of N-carboxyanhydrides (NCA) is found to have a significant influence on the rate of racemization of NCA with modified cinchona alkaloid­s. Consequently, modified cinchona alkaloids can be applie­d as dual-function catalysts to catalyze both the racemization and alcoholytic kinetic resolution of alkyl NCA bearing an electron-withdrawing N-protecting group, leading to a dynamic kinetic resolution­ converting racemic alkyl NCAs to the corresponding amino esters in 59-75% ee and 75-87% yield. Upon recrystallization­, the amino ester can be obtained in greater than 99% ee and 53% yield from the racemic NCA.

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Experimental Procedure for the Preparation of 1h: To a suspension of the racemic β-(2-thienyl)-alanine (1.712 g, 10.0 mmol) in anhyd THF (16.0 mL) at 50 °C was added triphosgene (1.01 g, 3.40 mmol, 1.02 equiv) in one portion. After 1 h, 2 aliqouts of triphosgene (0.1 equiv/aliquot) were added to the reaction mixture at 1 h intervals. The reaction mixture was stirred at 50 °C for a total of 3 h, after which time a clear solution was formed. The solution was cooled to r.t., then concentrated to approximately 12 mL and then poured into hexanes (40 mL). The resulting mixture was stored in a freezer (-20 °C) overnight. The white crystals formed during this time were collected and dried under vacuum to give the corresponding NCA (1.763 g, 89% yield), which was used for the next step without further purification. To a solution of the NCA (8.94 mmol) in anhyd THF (25.0 mL) at -30 °C, dichloroacetyl chloride (1.12 mL, 1.3 equiv) was added. A solution of N-methyl morpholine (NMM, 1.47 mL, 1.5 equiv) in THF (5.0 mL) was introduced dropwise to the reaction mixture over a period of 30 min. The resulting mixture was stirred at -30 °C for a total of 3 h, and then acidified by HCl (4.0 M in dioxane) until the pH of the mixture was approximately 3. The resulting mixture was allowed to warm to r.t. The precipitate (NMM hydrochloride) was removed by filtration under N2 atmosphere through dry Celite 521 (3.0 g). The Celite was washed with anhyd THF (10 mL). The filtrate was concentrated and the residue was subjected to recrystallization from Et2O/hexanes at -20 °C overnight. The light brown solid was collected and dried under vacuum to give the desired product 1h [2.63 g, 85% yield, 76% overall yield from racemic β-(2-thienyl)-alanine]; mp 76-78 °C.
IR (CHCl3): 1356, 1434, 1738, 1799, 1869 cm-1.
1H NMR (400 MHz, CDCl3) δ: 3.62 (dd, J = 15.3, 2.4 Hz, 1 H), 3.89 (dd, J = 15.3, 5.5 Hz, 1 H), 5.11 (dd, J = 5.5, 2.4 Hz, 1 H), 6.82-6.88 (m, 1 H), 6.94-7.00 (m, 1 H), 7.04 (s, 1 H), 7.22-7.28 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.7, 60.9, 63.8, 126.6, 127.8, 128.7, 131.9, 146.9, 162.2, 163.9.
HRMS (EI): m/z calcd for C10H7NO4SCl2: 306.9473, found: 306.9472.

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Experimental Procedure for the Dynamic Kinetic Resolution of 1h: At r.t., a mixture of (DHQD)2AQN (0.04 mmol, 0.2 equiv) and 4 Å molecular sieves (20 mg) in anhyd Et2O (12.0 mL) was stirred for 10 min, then a solution of 1h in Et2O (0.125 M, 1.60 mL, 0.20 mmol) and a solution of allyl alcohol in Et2O (0.125 M, 1.60 mL, 0.20 mmol) were added to the mixture simultaneously over a period of 2 h by using a syringe pump (SAGE instruments, model 355). The resulting mixture was stirred at r.t for another hour, after which the reaction mixture was washed with aq HCl (2.0 N, 2 × 3.0 mL) and brine (3.0 mL), and then concentrated. The crude product was subjected to flash chromatography on silica gel, eluting with hexanes-EtOAc (9:1). Amino ester 2h was isolated as a white solid (55.8 mg, 87% yield). The ee was determined to be 75% by HPLC analysis [Daicel Chiralpak AS, hexanes-isopropyl alcohol (90:10), 1.0 mL/min, λ 220 nm, tmajor = 19.02 min, tminor = 11.93 min]. [α]D 23 =
-32.7° (c 2.0, CHCl3); mp 103-105 °C.
IR (CHCl3): 1434, 1540, 1670, 1729, 3301 cm-1,
1H NMR (400 MHz, CDCl3): δ = 3.40-3.54 (m, 2 H), 4.62-4.74 (m, 2 H), 4.80-4.90 (m, 1 H), 5.26-5.44 (m, 2 H), 5.84-6.00 (m, 2 H), 6.78-6.86 (m, 1 H), 6.90-7.00 (m, 1 H), 7.06-7.16 (m, 1 H), 7.16-7.24 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 31.5, 53.7, 66.0, 66.7, 119.6, 125.2, 127.1, 127.2, 131.0, 136.1, 163.6, 169.6.
HRMS (EI): m/z calcd for C12H14NO3SCl2: 322.0071, found: 322.0061.
Compound 2h (55.8 mg, 75% ee) was recrystallized from EtOAc (0.30 mL) and hexanes (1.0 mL) to give a white solid (34.3 mg, 53% yield from 1h, 99.4% ee).