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

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.

kinetic resolution - dynamic kinetic resolution - cinchona­ alkaloid - amino acids - racemization

References

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1b Huerta FF. Minidis ABE. Bäckvall J.-E. Chem. Soc. Rev.  2001,  30:  321 

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7

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.

8

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, t_major = 19.02 min, t_minor = 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).