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Synlett 2009(1): 71-74  
DOI: 10.1055/s-0028-1087477
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Diastereoselective Synthesis of Functionally Diverse Substituted Pipecolic ­Acids

Stephen Hanessian*, Ludivine Riber, Julien Marin
Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-ville, Montréal, QC, H3C 3J7, Canada
e-Mail: stephen.hanessian@umontreal.ca;
Further Information

Publication History

Received 23 September 2008
Publication Date:
12 December 2008 (online)

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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

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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]+.