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Synlett 2006(1): 0086-0090  
DOI: 10.1055/s-2005-922793
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Enantioselective Synthesis of α-Hydroxy-β-amino Acids Using the Claisen and Curtius Rearrangements

Doo Young Jung, Sol Kang, Sukbok Chang*, Yong Hae Kim*
Center for Molecular Design and Synthesis, 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;
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Publication History

Received 31 August 2005
Publication Date:
16 December 2005 (online)

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Abstract

Highly enantioselective and facile synthesis of α-hydroxy-β-amino acids has been achieved using the Claisen and ­Curtius rearrangements as key reactions. Chiral allylic alcohols were employed, which can be prepared by asymmetric catalysis in both E- and Z-forms; both anti- and syn-α-hydroxy-β-amino acids have been synthesized.

Key words

amino alcohols - amino acids - enantioselective synthesis - Claisen rearrangement - Curtius rearrangement

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Claisen Rearrangement of Allylic Esters 1c; Typical Procedure To a cooled solution of 1c (1 mmol) in THF at -78 °C, was added TMSCl (0.576 mL, 4.5 mmol). The solution was stirred for 5 min and a solution of KHMDS (0.5 M soln in toluene; 8.0 mL) was added rapidly by syringe. The reaction was stirred for 10 min at -78 °C and allowed to warm to r.t. over 1 h. The reaction was quenched with HCl (1 N) and diluted with Et2O. The resulting mixture was partitioned and the resulting aqueous layer was extracted with Et2O (× 2). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed to give the crude carboxylic acid. The crude carboxylic acid was dissolve in MeOH-benzene (1:1, 4 mL). TMS-diazomethane (2.0 M solution in hexane, 1.0 mL, 2.0 mmol) was added dropwise and the solution was stirred for 30 min and then the solvent was removed in vacuo. The crude thus obtained was purified by silica gel column chromatography (EtOAc-hexane, 1:10) to give pure 2c in 86% yield. HPLC (Chiracel AD column, i-PrOH-hexane, 2:98, 1 mL/min) t R 14.1 min, 18.7 min. For anti-isomers, 2a, t R 17.1 min, 23.2 min. 1H NMR (300 MHz, CDCl3): δ = 0.91 (t, 3 H), 1.96 (m, 2 H), 3.63 (m, 1 H), 3.67 (s, 3 H), 4.10 (d, 1 H), 4.26 (d, 1 H), 4.58 (d, 1 H), 5.56 (m, 2 H), 7.21 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 14.0, 26.4, 51.5, 53.3, 73.3, 86.2, 125.7, 127.6, 127.7, 127.9, 128.4, 128.7, 129.1, 129.3, 137.2, 140.2, 172.0. MS (EI): m/z calcd for C21H24O3: 324.1725; found: 323.19.

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α-Hydroxy-β-amino Acids 5a; Typical Procedure To a cooled solution of 2a in CH2Cl2-MeOH (1:1) at -78 °C, O3 was bubbled until the color of the solution changed to a purple color and the bubbling was continued for another 10 min. Then, O3 bubbling was stopped and a stream of nitrogen was applied to the reaction mixture to drive off any residual O3 until the solution became colorless. Then, excess Me2S was added to quench the reaction and the resulting mixture was left to warm to r.t. The solvent was removed in vacuo and the crude mixture was dissolved in t-BuOH and 2-methyl-2-butene (1:1 mixture). To the above solution, a solution of NaH2PO4 (3 equiv) was added followed by dropwise addition of NaClO2 (2 equiv). After 30 min at r.t., the reaction mixture was diluted with EtOAc and acidified with HCl (1 N). The aqueous layer was extracted again with EtOAc (× 2). The resulting organic layer was washed with a sat. aq solution of Na2SO3, dried over MgSO4, filtered, and evaporated in vacuo to give crude 3a. Then 3a was dissolved in toluene, dppa (1.5 equiv), and Et3N (3 equiv) were added, the resulting mixture was stirred for 30 min at r.t., and then heated to reflux. After 3 h, benzyl alcohol (3 equiv) was added and heating was continued for 2 d. The reaction mixture was cooled to r.t. and quenched with an aq solution of NH4Cl. The resulting mixture was extracted with EtOAc (× 3). The resulting organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give crude 4a, which was purified by silica gel column chromatography (EtOAc-hexane, 1:6) to give pure 4a in 71% yield. To confirm the structure and enantiopurity, 4a was converted to the known compound 5a, which was converted to ent-5c. Firstly, it was hydrogenolyzed over Pd(OH)2 under 1 atm of H2. The crude mixture was dissolved in THF, cooled to 0 °C, treated with pyridine (3 equiv), and benzoyl chloride (1.1 equiv) was added dropwise. After 1 h, the reaction was quenched with HCl (1 N) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give crude 5a, which was purified by silica gel column chromatography (EtOAc-hexane, 1:2) to give pure 5a in 81% yield (overall yield from 3a: 58%) The spectra were in accordance with the known compound. [α]D 23 +47.1 (c 1.00, MeOH) {lit. [5b] [α]D 23 -50.2 (c 1.00, MeOH)}; 1H NMR (400 MHz, CD3OD): δ = 3.26 (d, 1 H), 3.86 (s, 3 H), 4.65 (dd, 1 H), 5.75 (dd, 1 H), 6.97 (br d, 1 H), 7.28-7.55 (m, 8 H), 7.78 (d, 2 H). To check the enantiopurity of 5a, it was converted to the ent-5c. To a CH2Cl2 solution of 5a, NMO (2.5 equiv) was added, followed by TPAP (10 mol%). After stirring for 1 h, the reaction mixture was filtered through a short pad of silica gel to give the corresponding α-amino ketone. This compound was treated with tetrabutylammonium borohydride as reported previously [15] to give ent-5c, whose spectral data are identical to those of the known compound 5c. Then ent-5c was reacted with Mosher reagent as described. [5a] The enantiomeric purity of 5c was determined by 1H and 19F NMR spectroscopy.