Synlett 2020; 31(06): 600-604
DOI: 10.1055/s-0039-1690990
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© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of 2,3,6-Trisubstituted Piperidines via Baylis–Hillman Adducts and Lithium Amide through Domino Reaction

Mateo M. Salgado
,
Alejandro Manchado 
,
Carlos T. Nieto
,
David Díez
,
Narciso M. Garrido∗
We are indebted to European Regional Development Fund (FEDER), Spanish Ministerio de Economía y Competitividad (MINECO) for its support (CTQ 2015-68175-R), Junta de Castilla y León (UIC 21), and the Universidad de Salamanca. A.M.C. thanks European Social Fund (FSE) and USAL for his grant.
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Publication History

Received: 31 July 2019

Accepted after revision: 05 September 2019

Publication Date:
24 September 2019 (online)

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Published as part of the ISySyCat2019 Special Issue

Abstract

A convenient asymmetric synthesis of methyl (2S,3S,6R)-6-(4-fluorophenyl)-2-(4-hydroxyphenyl)-piperidine-3-carboxylate is described, starting from Baylis–Hillman adducts. The route involves a domino process: allylic acetate rearrangement, stereoselective Ireland–Claisen rearrangement and asymmetric Michael addition, which provides a δ-amino acid derivative with full stereochemical control. A subsequent chemoselective transformation of one of the side-chain groups allows an effective cyclization leading to biologically interesting polysubstituted piperidines in which the 2,6-aryl groups could be attached sequentially.

Key words

δ-amino acids - asymmetric synthesis - Michael addition - domino reaction - Ireland–Claissen rearrangement - Baylis–Hillman adducts - piperidines - Weinreb amide

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690990.
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  • References and Notes

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  • 12 Compounds 9 and 10; Typical Procedure To a solution of 7 (0.16 g/mL, 0.25 mmol) in acetic acid were added Pd/C 30% (28 mg, 0.028 g/mL) and ammonium formate (0.015 g/mL, 0.42 mmol). The reaction was stirred for 8 h at 50 °C. After being cooled, the reaction mixture was filtered through celite and washed with MeOH. The solvent was evaporated and the resulting mixture was purified by chromatography and 9 and 10 were eluted with hexane/EtOAc 9:1. Compound 9: yellowish solid; yield: 49 mg (60%). IR (layer): 538, 833, 1094, 1157, 1169, 1223, 1265, 1368, 1437, 1510, 1599, 1614, 1717, 1732, 2949, 3397 cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.37 (dd, J = 5.6, 8.5 Hz, 2 H, H-3′′), 7.21 (d, J = 8.5 Hz, 2 H, H-2′), 6.97 (t, J = 8.7 Hz, 2 H, H-2′′), 6.59 (d, J = 8.4 Hz, 2 H, H-3′), 3.94 (d, J = 10.2 Hz, 1 H, H-2), 3.85 (dd, J = 2.4, 11.3 Hz, 1 H, H-6), 3.49 (s, 3 H, COOMe), 2.71 (ddd, J = 3.8, 10.2, 12.3 Hz, 1 H, H-3), 2.17 (dt, J = 3.5, 10.6 Hz, 1 H), 1.88 (ddt, J = 3.7, 6.6, 12.6 Hz, 2 H, H-4A), 1.62 (dq, J = 4.0, 13.8 Hz, 1 H, 4B). 13C NMR (50 MHz, CDCl3): δ = 175.57 (C, COOMe), 164.66 (C, d, J = 241.5 Hz, C-4′′), 156.09 (C, C-4′), 140.13 (C-d, J C-F = 8.05 Hz, C-2′′), 133.26 (C, C-1′), 128.86 (CH, Ar), 128.61 (CH, Ar), 128.45 (CH, Ar), 115.40 (CH d, J C-F = 21.5 Hz, C-3′′), 115.21 (CH, C-3′), 63.88 (CH, C-6), 61.71 (CH, C-2), 51.94 (CH3, COOMe), 49.88 (CH, C-3), 33.47 (CH2, C-5), 29.50 (CH2, C-4). HRMS–FAB: m/z [M + H]+ calcd for C19H21NO3F: 330.1497; found: 330.1500. Compound 10: yellowish solid; yield: 16 mg (20%). IR (layer): 538, 833, 1094, 1157, 1169, 1223, 1265, 1366, 1440, 1512, 1599, 1614, 1718, 1732, 2949, 3397 cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.40 (m, 2 H, H-3′′, H-5′′), 7.05 (m, 4 H, H-2′, H-2′′, H-6′, H-6′′), 6.60 (m, 2 H, H-3′, H-5′), 4.07 (broad s, 1 H, H-2), 3.85 (dd, J = 4.2 and 10.6 Hz, 1 H, H-6), 3.48 (s, 3 H, COOMe), 2.92 (br s, 1 H, H-3), 2.23 (d, J = 8.0 Hz, 1 H, H-4a), 2.03 (m, 2 H, H-5), 1.74 (d, J = 8.0 Hz, 1 H, H-4b). 13C NMR (50 MHz, CDCl3): δ = 174.47 (C, COOMe), 162,22 (C, d, J = 243.5 Hz, C-4′′) 155.30 (C, C-4′), 139.99 (C, C-1′′), 133.30 (C, C-1′), 128.85 (CH, Ar), 128.65 (CH, Ar), 128.49 (CH, Ar), 115.60 (CH d, J C-F = 21.5 Hz, C-3′′), 115.26 (CH, C-3′), 61.70 (CH, C-2), 61.09 (CH, C-6), 51.50 (CH3, COOMe), 44.24 (CH, C-3), 29.02 (CH2, C-5), 28.20 (CH2, C-4). HRMS–FAB: m/z [M + H]+ calcd for C19H21NO3F: 330.1505; found: 330.1500.