Diastereoselective Synthesis of Functionally Diverse Substituted Pipecolic ­Acids

Abstract

The synthesis of cis-4-substituted pipecolic acids, 4,5-disubstituted pipecolic acids, and their 6-oxo analogues starting from enantiopure l-aspartic acid is reported. The synthetic strategy involves as key steps, Suzuki-Miyaura and related Pd-mediated couplings, followed by a catalytic hydrogenation with excellent yields and diastereoselectivities. Enolate alkylations provide 4,5-trans-oriented functionalization.

Key words

Suzuki-Miyaura coupling - lactam enolate alkylations - arylpiperidine - piperidinone - pipecolic acid

References and Notes

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13

General Procedure for Suzuki-Miyaura Coupling Under argon, to a solution of 2 (1 equiv) in THF (0.04 M) were added the boronic acid (1.5 equiv), (Ph₃P)PdCl₂ (0.05 equiv) and a 2 M Na₂CO₃ solution (1.5 mL for 0.11 mmol of 2). The mixture was stirred at 40 ˚C overnight. The reaction generally turned black at completion. H₂O was added, and the aqueous layer was extracted three times with Et₂O. The combined organic layers were washed with brine and dried over Na₂SO₄. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography (generally hexane-EtOAc, 8:2).

14

Data for Selected Compound: (2 S ,4 S )-Di- tert -butyl 6-Oxo-4-phenylpiperidine-1,2-dicarboxylate (4a) From 3a (119 mg, 0.32 mmol) was obtained 4a as a white solid (120 mg, 100%); [α]_D -28.6 (c 1.04, CHCl₃); mp 142.5-147.5 ˚C. IR (KBr): 2982, 2934, 1731, 1703, 1605, 1495, 1473, 1459, 1392, 1365, 1283, 1270, 1237, 1153, 1135, 1099, 1042, 1029, 1015 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 7.37 (t, 2 H, J = 7.2 Hz), 7.29 (t, 1 H, J = 7.4 Hz), 7.21 (d, 2 H, J = 7.2 Hz), 4.60 (dd, 1 H, J = 10.0, 6.6 Hz), 3.17-3.08 (m, 1 H), 2.85-2.79 (m, 1 H), 2.64 (dd, 1 H, J = 16.8, 13.0 Hz), 2.59-2.52 (m, 1 H), 2.03-1.94 (m, 1 H), 1.56 (s, 9 H), 1.48 (s, 9 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 170.2, 169.6, 152.1, 141.7, 128.6, 126.9, 126.1, 83.4, 81.9, 58.7, 41.5, 36.7, 33.4, 27.5 ppm. HRMS: m/z calcd for C₂₁H₂₉NO₅: 398.20457; found: 398.19487 [M + Na]⁺.

21

Data for Selected Compound: (2 S ,4 S ,5 R )-Di- tert -butyl 5-Allyl-6-oxo-4-phenylpiperidine-1,2-dicarboxylate (5) From 4a (1.06 g, 2.82 mmol) was obtained 5 as a white solid (904 mg, 77%); [α]_D -133.1 (c 1.41, CHCl₃); mp 115-117 ˚C. IR (KBr): 2980, 1728, 1707, 1457, 1366, 1283, 1248, 1225, 1145, 1028 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.36-7.28 (m, 2 H), 7.28-7.20 (m, 1 H), 7.18-7.08 (m, 2 H), 5.70 (dddd, 1 H, J = 17.0, 10.1, 8.6, 5.7 Hz), 4.97 (d, 1 H, J = 10.1 Hz), 4.85 (d, 1 H, J = 17.1 Hz), 4.47 (dd, 1 H, J = 10.3, 6.2 Hz), 2.92 (dt, 1 H, J = 11.8, 11.8, 3.9 Hz), 2.73 (td, 1 H, J = 11.9, 4.5, 4.5 Hz), 2.66-2.51 (m, 1 H), 2.38 (ddd, 1 H, J = 13.7, 6.1, 4.0 Hz), 2.06-1.93 (m, 2 H), 1.51 (s, 9 H), 1.42 (s, 9 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 171.8, 170.1, 152.3, 141.3, 134.0, 128.4, 126.9, 126.7, 117.4, 83.0, 81.6, 58.4, 49.0, 40.5, 33.5, 32.3, 27.4, 27.4 ppm. HRMS: m/z calcd for C₂₄H₃₃NO₅: 438.23587; found: 438.22464 [M + Na]⁺.

22

Data for Selected Compound: (2 S ,4 R )-Di- tert -butyl 4-Phenylpiperidine-1,2-dicarboxylate (8) From 4a (30 mg, 0.08 mmol) was obtained 8 as a colorless gum (25 mg, 93%); [α]_D -15.6 (c 0.95, CHCl₃). IR (NaCl): 2976, 1738, 1699, 1602, 1478, 1454, 1393, 1366, 1249, 1150, 1028 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ (rotamers) = 7.35-7.31 (m, 2 H), 7.26-7.21 (m, 3 H), 4.25-4.21 (m, 1 H), 3.75-3.56 (m, 2 H), 2.88-2.80 (m, 1 H), 2.28-2.22 (m, 1 H), 2.14-2.02 (m, 2 H), 1.87-1.78 (m, 1 H), 1.49 (s, 9 H), 1.42 (s, 9 H). ^¹³C (100 MHz, CDCl₃): δ = 171.3, 155.4, 144.6, 128.2, 126.6, 126.0, 80.6, 79.7, 56.1, 37.1, 32.4, 29.8, 28.0, 27.6 ppm. HRMS: m/z calcd for C₂₁H₃₁NO₄: 361.22531; found: 362.23232 [M + H]⁺.