Asymmetric Synthesis of 3,4,5,6-Tetrasubstituted Piperidin-2-ones by Three-Component Coupling

Abstract

The asymmetric three-component coupling of α,β-unsaturated esters and alkylidene malonates initiated with a homochiral lithium amide proceeds with high levels of diastereoselectivity, with hydrogenation of the resultant α-substituted β-amino acid derivatives giving a range of differentially protected 3,4,5,6-tetrasubstituted piperidinones with four contiguous stereogenic centres.

conjugate addition - three component coupling - oligomerisation - piperidin-2-one

References

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11

In our hands, oligomeric products have been identified during the conjugate addition of lithium amides to tert-butyl 2,5-dihydrofuran-3-carboxylate. See: Bunnage, M. E.; Davies, S. G.; Roberts, P. M.; Smith, A. D.; Withey, J. M.; Org. Biomol. Chem.; 2004, submitted for publication.

12

The configuration of the minor diastereoisomer arising from this three-component coupling is unknown but is not identical to either diastereoisomer obtained from the stepwise [2+1] reaction manifold.

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18

X-ray crystal structure determination for 15: Data were collected using an Enraf-Nonius DIP2000 diffractometer with graphite monochromated Cu-Kα radiation using standard procedures at 100 K. The structure was solved by direct methods (SIR92), all non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms were added at idealised positions. The structure was refined using CRYSTALS. X-ray crystal structure data for 15 [C₃₈H₄₃NO₄]: M = 577.76, orthorhombic, space group P 21 21 21, a = 11.2640 (2) Å, b = 16.6340 (3) Å, c = 17.0480 (2) Å, V = 3194.21 (9) ų, Z = 4, µ = 0.077 mm^-1, colourless block, crystal dimensions = 0.4 × 0.4 × 0.5 mm. A total of 3793 unique reflections were measured for 3<θ<27 and 3618 reflections were used in the refinement. The final parameters were w R ₂ = 0.0310 and R ₁ = 0.0253 [I>3σ(I)]. Crystallographic data (excluding structure factors) has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC240141. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].