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

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.

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

References and Notes

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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.

<A NAME="RU26705ST-14">14</A>

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.

<A NAME="RU26705ST-15">15</A> Li W.-S, and Thottathil JK. inventors; US Patent US 5602272 A  19970211.