A Straightforward Route to Indolizidine and Quinolizidine Analogs as new Potential Antidiabetics

Abstract

New polyhydroxylated indolizidine and quinolizidine analogs of castanospermine are efficiently obtained by a double reductive amination of enantiopure cyclic ketoaldehydes. As rigidi­fied mimics of disaccharides, these compounds are expected to exhibit significant antidiabetic properties.

glycosidases - alkaloids - carbocycles - bicyclic compounds - reductive amination

References

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Satisfactory analytical and/or spectroscopic data were obtained for all new compounds.

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12

In this case, an unexpected lactone, resulting from double bond reduction followed by transketalization and subsequent lactonization, was isolated in a non-reproducible 63% yield (Figure [3] ).

Figure 3

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19

Typical Procedure for the Double Reductive Amination:
To a solution of ketoaldehyde 8 or 12 (387 µmol) in methanol (1 mL), at 0 °C, were successively added sodium cyanoborohydride (753 µmol, 1.9 equiv) and a mixture of primary amine (387 µmol, 1 equiv) and HOAc (387 µmol, 1 equiv) in MeOH (400 µL). After 24 h stirring at 20 °C and concentration in vacuo, a 10% aq solution of NaOH was added and the mixture was extracted with CH₂Cl₂. The combined organic layers were dried (anhyd Na₂SO₄), filtered and concentrated in vacuo. Flash chromatography of the residue afforded the indolizidine or quinolizidine analog in yield ranging from 50% to 75% according to the ketoaldehyde and to the primary amine involved.
Selected physical data for compounds 15, 16a and 16b ([α]_D ²⁰ in CH₂Cl₂ ¹H NMR [250 MHz unless indicated, δ (ppm), J (Hz) and ¹³C NMR (62.5 MHz, δ(ppm)] in CDCl₃. Hydrogen and carbon atoms of the heterocycle have been numbered according to the IUPAC nomenclature rules, and for the N-side chain by A, B and C:
15: [α]_D ²⁰ +24.5 (c 1.1). ¹H NMR (500 MHz): δ = 3.89 (ddd, 1 H, J _{6,7 ′} = 9.5 Hz, J _6,5 = 9.2 Hz, J _6,7 = 5.0 Hz, H₆), 3.75 (dd, 1 H, J _{A,A ′} = 10.4 Hz, J _A,B = 6.2 Hz, H_A), 3.72 (dd, 1 H, J _{A ′,A} = 10.4 Hz, J _{A ′,B} = 5.0 Hz, H_{A ′}), 3.60 (dd, 1 H, J _{C,C ′} = 10.0 Hz, J _C,B = 5.9 Hz, H_C), 3.57 (dd, 1 H, J _{C ′,C} = 10.0 Hz, J _{C ′,B} = 6.4 Hz, H_{C ′}), 3.44 (dd, 1 H, J _4,3a = 10.0 Hz, J _4,5 = 9.2 Hz, H₄), 3.36 (ddd, J _7a,3a = J _{7a,7 ′} = 4.4 Hz, J _7a,7 = 2.9 Hz, 1 H, H_7a), 3.26 (dd, 1 H, J _5,6 = J _5,4 = 9.2 Hz, H₅), 2.97-2.87 (m, 2 H, H_{B,2 ′}), 2.83 (ddd, 1 H, J _{2,2 ′} = 14.8 Hz, J _{2,3 ′} = 9.4 Hz, J _2,3 = 5.6 Hz, H₂), 2.15 (ddd, 1 H, J _{7,7 ′} = 14.2 Hz, J _7,6 = 5.0 Hz, J _7,7a = 2.9 Hz, H₇), 2.13-2.06 (m, 1 H, H_3a), 1.86-1.73 (m, 2 H, H_{3,3 ′}), 1.42 (ddd, 1 H, J _{7 ′,7} = 14.2 Hz, J _{7 ′,6} = 9.5 Hz, J _{7 ′,7a} = 4.4 Hz, H_{7 ′}), 1.38, 1.36 (2 s, 6 H, CMe₂), 0.88 (s, 27 H, t-Bu), 0.05 (s, 18 H, SiMe₂). ¹³C NMR: δ = 109.1 (CMe₂), 83.9 (C₅), 79.1 (C₄), 69.4 (C₆), 63.3, 59.3 (C_A,C), 60.7, 59.4 (C_7a,B), 44.9 (C₂), 41.9 (C_3a), 35.3 (C₇), 29.7 (C₃), 27.0 (CMe₂), 25.9, 18.3, 18.2 (t-Bu), -4.5, -4.8,
-5.4 (SiMe₂). HRMS (CI, CH₄) calcd for C₃₂H₆₈NO₅Si₃ [M⁺ + 1]: 630.4405. Found: 630.4393.
16a: [α]_D ²⁰ +14 (c 1.0). ¹H NMR: δ = 4.12 (dd, 1 H, J _5,4a = 11.1 Hz, J _5,6 = 9.1 Hz, H₅), 3.95 (ddd, 1 H, J _7,8 = 11.0 Hz, J _7,6 = 9.0 Hz, J _{7,8 ′} = 3.8 Hz, H₇), 3.72 (dd, 1 H, J _{A ′,A} = 10.3 Hz, J _{A ′,B} = 6.9 Hz, H_{A ′}), 3.56 (dd, 1 H, J _{A,A ′} = 10.3 Hz, J _A,B = 4.6 Hz, H_A), 3.60-3.49 (m, 2 H, H_{C,C ′}), 3.24 (dd, 1 H, J _6,7 = J _6,5 = 9.0 Hz, H₆), 3.20-3.10 (m, 1 H, H_B), 3.06 (ddd, 1 H, J _8a,4a = J _8a,8 = J _{8a,8 ′} = ca. 3.2 Hz, H_8a), 2.93-2.77 (m, 1 H, H₂), 2.39 (ddd, 1 H, J _{8,8 ′} = 14.7 Hz, J _8,7 = J _8,8a = 3.2 Hz, H₈), 2.26 (ddd, 1 H, J _{2 ′,2} = J _{2 ′,3 ′} = 11.5 Hz, J _{2 ′,3} = 1.9 Hz, H_{2 ′}), 2.04-1.85 (m, 1 H, H₄), 1.81-1.53 (m, 3 H, H_{4a,3,3 ′}), 1.52-1.40 (m, 1 H, H_{4 ′}), 1.38 (s, 6 H, CMe₂), 1.40-1.34 (m, 1 H, H_{8 ′}), 0.88, 0.87 (2 s, 27 H, t-Bu), 0.09, 0.08, 0.06, 0.04, 0.02 (s, 18 H, SiMe₂). ¹³C NMR: δ = 108.7 (CMe₂), 85.4 (C₆), 74.9 (C₅), 68.6 (C₇), 62.9 (C_A), 59.8 (C_B), 59.4 (C_C), 58.8 (C_8a), 47.8 (C₂), 40.0 (C_4a), 37.5 (C₈), 30.2 (C₃), 27.1, 26.9 (CMe₂), 25.9, 18.2 (t-Bu), 22.0 (C₄),
-4.4, -4.7, -5.4, -5.6 (SiMe₂). HRMS (CI, CH₄) calcd for C₃₃H₇₀NO₅Si₃ [M⁺ + 1]: 644.4562. Found: 644.4556.
16b: [α]_{Hg, 365} ²⁰ +5 (c 1.0). ¹H NMR: δ = 3.75 (dd, 1 H, J _{A ′,A} = 10.4 Hz, J _{A ′,B} = 8.2 Hz, H_{A ′}), 3.71 (dd, 1 H, J _{A,A ′} = 10.4 Hz, J _A,B = 4.6 Hz, H_A), 3.81-3.66 (m, 1 H, H₇), 3.59 (dd, 1 H, J _{C,C ′} = 10.0 Hz, J _C,B = 5.3 Hz, H_C), 3.53 (dd, 1 H, J _{C ′,C} = 10.0 Hz, J _{C ′,B} = 7.4 Hz, H_{C ′}), 3.32 (dd, 1 H, J _6,7 = J _6,5 = 9.1 Hz, H₆), 3.27-3.14 (m, 1 H, H_B), 2.97 (dd, 1 H, J _5,6 = 10.8 Hz, J _5,4a = 9.1 Hz, H₅), 2.91-2.80 (m, 1 H, H₂), 2.48 (ddd, 1 H, J _8a,4a = 12.8 Hz, J _{8a,8 ′} = 9.0 Hz, J _8a,8 = 4.0 Hz, H_8a), 2.45-2.31 (m, 2 H, H_{2 ′,8}), 2.04-1.90 (m, 1 H, H₄), 1.69-1.54 (m, 1 H, H₃), 1.50-1.39 (m, 2 H, H_{4a,3 ′}), 1.37, 1.36 (2 s, 6 H, CMe₂), 1.31-1.20 (m, 1 H, H_{8 ′}), 1.07-0.93 (m, 1 H, H_{4 ′}), 0.88, 0.87 (2 s, 27 H, t-Bu), 0.08, 0.07, 0.03, 0.02 (s, 18 H, SiMe₂). ¹³C NMR: δ = 111.3 (CMe₂), 84.2 (C₆), 79.9 (C₅), 70.3 (C₇), 64.2 (C_A), 61.4 (C_B), 60.6 (C_C), 59.2 (C_8a), 48.1 (C₂), 44.5 (C_4a), 38.6 (C₈), 28.5 (C₃), 27.0 (CMe₂), 25.9, 18.2 (t-Bu), 25.6 (C₄), -4.4, -4.9, -5.3, -5.4, -5.6 (SiMe₂). HRMS (CI, CH₄) calcd for C₃₃H₇₀NO₅Si₃ [M⁺ + 1]: 644.4562. Found: 644.4570.