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Synlett 2005(2): 304-308  
DOI: 10.1055/s-2004-836070
LETTER
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of 1,2-Amino Alcohols Using tert-Butanesulfinimines as Chiral Auxiliary

Chang Hong Ko, Doo Young Jung, Min Kyun Kim, Yong Hae Kim*
Center for Molecular Design and Synthesis, Department of Chemistry, School of Molecular Science (BK-21), Korea Advanced Institute of Science and Technology, 373-1, Guseong Dong, Yuseong Gu, Taejon, 305-701, Korea
Fax: +82(42)8695818; e-Mail: kimyh@kaist.ac.kr;
Further Information

Publication History

Received 1 October 2004
Publication Date:
10 December 2004 (online)

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Abstract

Facile and highly stereoselective synthesis of 1,2-amino alcohols has been achieved by the addition of [(dimethylphenyl­silyl)methyl] magnesium chloride to the tert-butanesulfinimines, followed by Fleming-Tamao oxidation of the silicon moiety.

Key words

amino alcohol - enantioselective synthesis - tert-butanesulfinimine - Grignard reagents - nucleophilic addition

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Experimental Procedure for Preparation of [(Dimethyl-phenylsilyl)methyl] Magnesium Chloride ( 1):
Under an argon atmosphere, a suspension of magnesium turnings (0.14 g, 5.83 mmol) in refluxing THF (2 mL) was activated by addition of catalytic amounts of 1,2-dibromo-ethane. Then,(chloromethyl)dimethylphenylsilane (902.1 µL, 5 mmol) was added at such a rate as to maintain a gentle reflux. After the addition was complete, the solution became transparent and grayish. To this solution, additional THF was added to adjust the concentration to be 0.5 M or 1.0 M and the mixture was refluxed for 2 h to give THF solutions of 1. The concentration of THF solution of 1 was determined by the method of Orgura et al. [23]

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Representative Experimental Procedure for the Addi-tion of 1 to tert -Butanesulfinimines (Table 1, Entry 8):
tert-Butanesulfinimine 2a, prepared according to the known procedure, [13] was dissolved in THF and charged with argon. To this solution, [(dimethylphenylsilyl)methyl] magnesium chloride (0.5 M THF), prepared as above, was added dropwise and stirring was continued for 72 h. After TLC analysis indicated the completion of the reaction, the reaction mixture was diluted with Et2O and quenched with sat. NH4Cl aq solution. The organic layer was separated and the aqueous layer was further extracted with Et2O 3 times. The combined organic layer was dried over anhyd MgSO4 and the solvent was evaporated under reduced pressure. The crude product 3a was purified by flash column chromatography using EtOAc-n-hexane = 1:6 as eluents. The product was obtained in 75% yield. To determine diastereoselectivity, 3a was converted to 5a by procedures described below and analyzed with HPLC using racemic 5a, prepared independently as a standard. HPLC conditions: DAICEL AS-H column, 2-propanol-n-hexane = 1:99, 0.5 mL/min flow rate, retention time (major = 12.86 min, minor = 14.90 min). Determination of absolute configuration of major isomer was achieved by HPLC analysis of amino alcohol 6a using both S- and R-6a synthesized independently from the commercially available enantiopure phenyl glycine methyl ester [HPLC conditions: DAICEL OD-H column, 2-propanol-n-hexane = 5:95, 0.5 mL/min flow rate, t R (R) = 15.72 min, t R (S) = 18.99 min, synthetic 6a 15.81 min]. 1H NMR (300 MHz, CDCl3): δ =
-0.02 (s, 3 H), 0.15 (s, 3 H), 1.12 (s, 9 H), 1.42 (m, 2 H), 3.33 (s, 1 H), 4.52 (t, 1 H), 7.23 (m, 5 H), 7.31 (m, 3 H), 7.41 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ = -3.440, -2.249, 22.457, 27.935, 55.172, 56.384, 127.408, 127.618, 128.002, 128.899, 129.190, 133.694, 138.259, 143.481. HRMS (EI): Anal. Calcd for C20H29NOSSi: 359.1739. Found: 359.1742.

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Representative Experimental Procedure for Removal of Sulfinyl Group and Protection as Boc-carbamate (Preparation of 5b):
Compound 3b was dissolved in 1 mL of MeOH at 25 °C. To this solution, 1 mL of 1,4-dioxane and 1 mL of 4 M aq HCl solution was added. The resulting mixture was stirred for 1 h at that temperature. After TLC analysis indicated the complete consumption of 3b, the solvents and HCl were removed by evaporation under reduced pressure. The crude 4b was not purified and directly dissolved in mixed solvents of 1 mL of MeOH and 1 mL of Et3N, followed by addition of 1.5 equiv of (Boc)2O. After 1 h, the solvent was removed and the crude 5b was dissolved in CH2Cl2 and washed with Brine, sat. NH4Cl aq solution and brine successively. The resulting 5b was purified by column chromatography (eluent: EtOAc-n-hexane = 1:8) to give 5b in quantitative yield. 1H NMR (300 MHz, CDCl3): δ = 0.17 (s, 3 H), 0.22 (s, 3 H), 1.23 (m, 2 H), 1.25 (s, 9 H), 4.66 (m, 2 H), 7.05 (d, 2 H), 7.40 (m, 8 H). 13C NMR (75 MHz, CDCl3): δ = -3.100, -2.680, 25.430, 28.299, 51.864, 79.384, 120.666, 127.790, 127.849, 129.0182, 129.236, 131.430, 133.384, 144.214, 154.497. HRMS (EI): Anal. Calcd (433.1073) for C21H28BrNO2Si: C, 70.13; H, 8.24; N, 4.09; Si, 8.20; Br, 18.39. Found: 433.1124. HPLC (DAICEL AS-H column, 2-propanol-n-hexane = 1:99, 0.5 mL/min flow rate) t R(minor) = 16.15 min, (major) = 20.22 min.

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Representative Experimental Procedure for Fleming Oxidation (Table 3, Entry 1): HOAc (1 mL), NaOAc (0.032 g, 0.39 mmol), and KBr (0.045 g, 0.38 mmol) were added to 5a, and the mixture was stirred until the salts were dissolved. The solution was cooled to 0 °C and HOOAc (1.59 mL, 30% in HOAc) was added dropwise with exclusion of light. After the mixture was stirred for 3 h at 25 °C, TLC analysis indicated the completion of the reaction. The mixture was diluted with Et2O and poured into a cooled solution of Na2S2O3 (30 mL, 10%). The organic layer was washed with sat. aq solution of NaHCO3 until no more CO2 gas evolution was detected. The organic layer was dried over anhyd MgSO4 and the solvent was evaporated under reduced pressure. The resulting crude 5a was purified by column chromatography (eluent: EtOAc-n-hexane = 1:2). The spectral data of obtained 5a matched exactly with known compounds. 1H NMR (300 MHz, CDCl3): δ = 1.40 (s, 9 H), 2.39 (s, 1 H), 3.80 (m, 2 H), 4.74 (s, 1 H), 5.30 (s, 1 H), 7.32 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 28.280, 57.079, 66,688, 79.902, 126.525, 127.632, 128.686, 139.621, 156.016.

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HPLC Analysis of 3b-f and Determination of Absolute Configuration. HPLC Conditions:
Compound 3b: DAICEL AS-H column, 2-propanol-n-hexane = 1:99, 0.5 mL/min flow rate, t R (R) = 14.08 min, t R (S) = 17.44 min. Compound 3c: DAICEL AS-H column, 2-propanol-n-hexane = 1:99, 0.5 mL/min flow rate, t R (R) = 19.89 min, t R (S) = 23.11 min. Compound 3d: DAICEL
AS-H column, 2-propanol-n-hexane = 1:99, 0.5 mL/min flow rate, t R (R) = 13.65 min, t R (S) = 15.89 min. Compound 3e: DAICEL AS-H column, 2-propanol-n-hexane = 1:99, 0.5 mL/min flow rate, t R (R) = 14.77 min, t R (S) = 17.01 min. Compound 3f: DAICEL AS-H column, 2-propanol-n-hexane = 1:99, 0.5 mL/min flow rate, t R (R) = 6.23 min, t R (S) = 8.15 min. Determination of absolute configurations: 3b-f were tentatively assigned as (S R , R) in analogy with 3a. [19] The absolute stereochemistry of 3a-f and amino alcohols 6a-f were determined by comparisons with known compounds.