Arabinosylamine in Asymmetric Syntheses of Chiral Piperidine Alkaloids

Abstract

The stereodifferentiating potential of arabinosyl ald­imines was utilized in stereoselective syntheses of 2-substituted ­dehydropiperidinones and their further transformation to 2,6-cis-substituted piperidinones. The absolute configuration was proven by X-ray analysis and by the synthesis of the enantiomerically pure alkaloid (+)-dihydropinidine. The presented method offers the ­possibility to synthesize piperidine derivatives enantiomeric to those obtained by the application of the corresponding galactosyl­amine auxiliary.

carbohydrate auxiliaries - arabinosylamine - domino Mannich-Michael reaction - piperidine alkaloids - conjugate cuprate addition

References

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Compoumd 6d: [a]_D ²⁵ +66.6 (c 1, CHCl₃). ¹H NMR (200 MHz, CDCl₃): d = 6.90 (d, 1 H, J _H-6,H-5 = 7.3 Hz, CH=CH), 5.55 (t, 1 H, J _{H-2 ′ ,H-1 ′} = 9.5 Hz, J _{H-2 ′ ,H-3 ′} = 9.5 Hz, H-2¢),
5.30-5.20 (m, 1 H, H-4¢), 5.13 (dd, 1 H, J _{H-3 ′ ,H-2 ′} = 10.0 Hz, J _{H-3 ′ ,H-4 ′}= 3.2 Hz, H-3¢), 4.93 (d, 1 H, J _H-5,H-6 = 7.3 Hz, CH=CH), 4.44 (d, 1 H, J _{H-1 ′ ,H-2 ′} = 9.3 Hz, H-1¢), 4.02 (dd, 1 H, J _{H-5 ′ a,H-5 ′ b} = 13.2 Hz, J _{H-5 ′ a,H-4 ′} = 2.0 Hz, H-5¢a), 3.80-3.70 (m, 1 H, PrCHN), 3.67 (d, 1 H, J _{H-5 ′ b,H-5 ′ a} = 13.2 Hz, H-5¢b), 2.60 (dd, 1 H, J _H-3a,H-3b = 16.6 Hz, J _H-3a,H-2 = 6.3 Hz, CHHC=O), 2.34 (d, 1 H, J _H-3b,H-3a = 16.6 Hz, CHHC=O), 2.00-1.75 [m, 1 H, (CHH)₂CH₃], 1.65-1.50 (m, 1 H, (CHH)₂CH₃), 1.30-1.10 (m, 27 H, piv CH₃), 0.86 [t, 3 H, J = 7.3 Hz, (CH₂)CH ₃] ppm. ¹³C NMR (50.3 MHz, CDCl₃): δ = 192.15 (C=O), 177.21, 176.76 (pivC=O), 149.92 (CH=CH), 99.79 (CH=CH), 92.13 (C-1¢), 71.13, 67.97, 66.06 (C-2¢, C-3¢, C-4¢), 66.22 (C-5¢), 53.48 (PrCHN), 38.97 (CH₂C=O), 38.89, 38.82, 38.77 (pivC_quart.), 32.66 [(CH₂)CH₃], 27.21, 27.13, 27.02 (piv-CH₃), 18.90 [(CH₂)CH₃], 13.81 [(CH₂)CH₃] ppm; X-ray analysis: P2₁2₁2₁(orthorhombic), a = 9.8895(13) Å, b = 10.1820(11) Å, c = 30.614(4) Å, V = 3082.7(6) ų, z = 4, F(000) = 1136, CAD4 Enraf Nonius, Cu-K_α, SIR-92, SHELXL-97. Further details of the crystal structure analysis are available on request from the Cambridge Crystallographic Data Centre quoting the deposit number CCDC 229785.

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15

X-ray analysis: P1(triclinic), a = 10.1869(6) Å, b = 13.1017(12) Å, c = 15.5126(12) Å, V = 1901.1(3) ų, z = 2, F(000) = 716, CAD4 Enraf Nonius, Cu-K_α, SIR-92, SHELXL-97. Further details of the crystal structure analysis are available on request from the Cambridge Crystallographic Data Centre quoting the deposit number CCDC 229786.

16

Compound 10: [α]_D ²⁵ +11.1 (c 1, EtOH). ¹H NMR (200 MHz, DMSO): δ = 9.07 (br s, 1 H, NH), 8.68 (1 H, NH), 3.15-2.80 (m, 2 H, H-1, H-6), 1.90-1.00 (m, 13 H, CH₂, CH₃), 0.87 [t, 3 H, J = 7.1 Hz, (CH₂)₂CH ₃] ppm. ¹³C NMR (50.3 MHz, DMSO): δ = 55.98, 52.52 (C-2, C-6), 34.82, 29.78, 27.05, 22.01, 18.75, 17.86 (CH₂, CH₃), 13.68 [(CH₂)₂ CH₃] ppm.

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