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Synlett 2003(3): 0333-0336
DOI: 10.1055/s-2003-37112
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Christine Gravier-Pelletier, William Maton, Yves Le Merrer*
Université René Descartes, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France
Fax: +33(1)42868387; e-Mail: Yves.Le-Merrer@biomedicale.univ-paris5.fr;
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Publication History

Received 24 September 2003
Publication Date:
07 February 2003 (online)

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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.

Key words

glycosidases - alkaloids - carbocycles - bicyclic compounds - reductive amination

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8

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

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

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, HA), 3.72 (dd, 1 H, J A ′,A = 10.4 Hz, J A ′,B = 5.0 Hz, HA ′), 3.60 (dd, 1 H, J C,C ′ = 10.0 Hz, J C,B = 5.9 Hz, HC), 3.57 (dd, 1 H, J C ′,C = 10.0 Hz, J C ′,B = 6.4 Hz, HC ′), 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, H7a), 3.26 (dd, 1 H, J 5,6 = J 5,4 = 9.2 Hz, H5), 2.97-2.87 (m, 2 H, HB,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, H3a), 1.86-1.73 (m, 2 H, H3,3 ′), 1.42 (ddd, 1 H, J 7 ′,7 = 14.2 Hz, J 7 ′,6 = 9.5 Hz, J 7 ′,7a = 4.4 Hz, H7 ′), 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 (CA,C), 60.7, 59.4 (C7a,B), 44.9 (C2), 41.9 (C3a), 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, HA ′), 3.56 (dd, 1 H, J A,A ′ = 10.3 Hz, J A,B = 4.6 Hz, HA), 3.60-3.49 (m, 2 H, HC,C ′), 3.24 (dd, 1 H, J 6,7 = J 6,5 = 9.0 Hz, H6), 3.20-3.10 (m, 1 H, HB), 3.06 (ddd, 1 H, J 8a,4a = J 8a,8 = J 8a,8 ′ = ca. 3.2 Hz, H8a), 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, H2 ′), 2.04-1.85 (m, 1 H, H4), 1.81-1.53 (m, 3 H, H4a,3,3 ′), 1.52-1.40 (m, 1 H, H4 ′), 1.38 (s, 6 H, CMe2), 1.40-1.34 (m, 1 H, H8 ′), 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 (CA), 59.8 (CB), 59.4 (CC), 58.8 (C8a), 47.8 (C2), 40.0 (C4a), 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, HA ′), 3.71 (dd, 1 H, J A,A ′ = 10.4 Hz, J A,B = 4.6 Hz, HA), 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, HC), 3.53 (dd, 1 H, J C ′,C = 10.0 Hz, J C ′,B = 7.4 Hz, HC ′), 3.32 (dd, 1 H, J 6,7 = J 6,5 = 9.1 Hz, H6), 3.27-3.14 (m, 1 H, HB), 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, H8a), 2.45-2.31 (m, 2 H, H2 ′,8), 2.04-1.90 (m, 1 H, H4), 1.69-1.54 (m, 1 H, H3), 1.50-1.39 (m, 2 H, H4a,3 ′), 1.37, 1.36 (2 s, 6 H, CMe2), 1.31-1.20 (m, 1 H, H8 ′), 1.07-0.93 (m, 1 H, H4 ′), 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 (CA), 61.4 (CB), 60.6 (CC), 59.2 (C8a), 48.1 (C2), 44.5 (C4a), 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.