A Straightforward Approach towards Functionalized Amino Acids and Pipecolinic Acids via Ruthenium-Catalyzed Allylic Alkylation

Abstract

Chelated amino acid ester enolates react with cis-butene diol substrates via Ru-catalyzed allylic alkylations to functionalized amino acids. The use of [(p-cymene)RuCl₂]₂ as catalyst allows the introduction of Z-configured allylic alcohols in the side chain of the amino acid. They facilitate access to pipecolinic acid and baikiaine derivatives.

Key words

amino acids - allylic alkylation - ruthenium catalysis - cis-butene diol substrates - pipecolinic acid - baikiain

• References and Notes

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• 24 General Procedure for the Ruthenium-Catalyzed Allylic Alkylations A solution of HMDS (335 mg, 2.07 mmol) in THF (2 mL) was prepared in a Schlenk flask under nitrogen. After the solution was cooled to –20 °C, a solution of n-BuLi in hexanes (1.6 M, 1.17 mL, 1.87 mmol) was added slowly. The cooling bath was removed, and stirring was continued for further 10 min. The solution was cooled to –78 °C, and the TFA-protected tert-butyl glycinate (171 mg, 0.75 mmol), dissolved in THF (2 mL), was added to the freshly prepared LHMDS solution. After 10 min a solution of dried ZnCl₂ (123 mg, 0.90 mmol) in THF (2 mL) was added, and stirring was continued for 30 min at –78 °C. A solution was prepared from [(p-cymene)RuCl₂]₂ (6.4 mg, 0.01 mmol) and Ph₃P (5.2 mg, 0.02 mmol) in THF (1 mL). The solution was stirred for 5 min before the allyl substrate (0.50 mmol) was added. The resulting solution was added slowly to the chelated enolate at –78 °C. The mixture was allowed to warm to r.t. overnight. The solution was diluted with Et₂O (20 mL) before 1 M KHSO₄ (10 mL) was added. After separation of the layers, the aqueous layer was extracted thrice with Et₂O, and the combined organic layers were dried over Na₂SO₄. The solvent was evaporated in vacuo, and the crude product was purified by flash chromatography (SiO₂). (Z)-6-[(tert-Butyldimethylsilyl)oxy]-2-(2,2,2-trifluoroacetamido)hex-4-enoic Acid tert-Butyl Ester (2c) ¹H NMR (400 MHz, CDCl₃): δ = 0.07 (s, 6 H), 0.90 (s, 9 H), 1.48 (s, 9 H), 2.68 (m, 2 H), 4.20 (m, 2 H), 4.48 (m, 1 H), 5.34 (dtt, J = 11.4, 7.8, 1.6 Hz, 1 H), 5.72 (dtt, J = 11.4, 5.6, 1.2 Hz, 1 H), 7.15 (d, J = 5.6 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –5.3, 18.4, 25.9, 27.9, 29.5, 52.6, 59.5, 83.4, 123.1, 134.0, 169.2 ppm. Signals of the TFA group could not be observed. HRMS (CI): m/z calcd for C₁₈H₃₂F₃NO₄Si [M]⁺: 411.2053; found: 411.2063. (6R,Z)-6-Acetoxy-2-(2,2,2-trifluoroacetamido)hept-4-enoic Acid tert-Butyl Ester [(R)-7a] (R)-7a was obtained as a 7:3 diastereomeric mixture. Major diastereomer: ¹H NMR (400 MHz, CDCl₃): δ = 1.29 (d, J = 6.2 Hz, 3 H), 1.47 (s, 9 H), 2.02 (s, 3 H), 2.65 (m, 1 H), 2.88 (m, 1 H), 4.44 (m, 1 H), 5.44 (m, 3 H), 7.51 (d, J = 6.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 20.2, 21.1, 27.9, 29.5, 52.7, 66.7, 82.8, 127.3, 132.8, 157.4, 169.2, 171.6 ppm. Minor diastereomer (selected signals): ¹H NMR (400 MHz, CDCl₃): δ = 1.28 (d, J = 6.2 Hz, 3 H), 1.48 (s, 9 H), 2.01 (s, 3 H), 4.52 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 27.9, 52.5, 66.8 ppm. HRMS (CI): m/z calcd for C₁₅H₂₃F₃NO₅ [M + H]⁺: 354.1523; found: 354.1534. GC [l-Chirasil-Val, 80 °C, 10 min, 80 °C → 180 °C (1 °C/min), 40 min]: t _R = 55.69 min (major), t _R = 58.85 min (minor).
• 25 Mitsunobu O. Synthesis 1981; 1
• 26 1-(2,2,2-Trifluoroacetyl)-1,2,3,6-tetrahydropyridine-2-carboxylic Acid tert-Butyl Ester (8g) Alcohol 2g (179 mg, 0.60 mmol) was dissolved in abs. THF (13 mL) and added dropwise to a solution of Ph₃P (254 mg, 0.960 mmol) and diisopropyl azodicarboxylate (196 μL, 204 mg, 0.96 mmol) in abs. THF (33 mL) at 0 °C. The reaction was allowed to warm to r.t. overnight. The solvent was evaporated, and the crude product was purified by column chromatography (silica gel; hexanes–ethyl acetate, 90:10). The desired product 8g (148 mg, 0.530 mmol, 88%) was obtained as a mixture of rotamers (ratio 55:45). Major rotamer: ¹H NMR (400 MHz, CDCl₃): δ = 1.43 (s, 9 H), 2.49 (m, 1 H), 2.73 (m, 1 H), 3.86 (m, 1 H), 4.19 (m, 1 H), 5.33 (dd, J = 6.6, 1.4 Hz, 1 H), 5.64 (m, 1 H), 5.83 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 25.8, 27.8, 42.1, 51.3, 82.6, 122.2, 123.4, 168.3 ppm. Minor rotamer (selected signals): ¹H NMR (400 MHz, CDCl₃): δ = 4.35 (m, 1 H), 4.70 (d, J = 6.0 Hz, 1 H), 5.73 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 26.8, 27.8, 42.5, 54.3, 82.9, 121.9, 122.9, 168.4 ppm. Signals of the TFA group could not be observed. HRMS (CI): m/z calcd for C₁₂H₁₇F₃NO₃ [M + H]⁺: 280.1155; found: 280.1159. Anal. Calcd (%) for C₁₂H₁₆F₃NO₃ (279.26): C, 51.61; H, 5.78; N, 5.02. Found: C, 51.76; H, 5.67; N, 4.98.