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Synlett 2011(12): 1668-1672  
DOI: 10.1055/s-0030-1260933
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Efficient Synthesis of Tetrahydroxylated Pyrrolizidines by Nitrone Cycloaddition Leading to Unnatural Stereoisomers of 7-Deoxycasuarine

Gabriel Podolana, Lucia Kleščíkováa, Lubor Fišera*a, Jozef Kožíšekb, Marek Froncb
a Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovak Republic
e-Mail: lubor.fisera@stuba.sk;
b Institute of Physical Chemistry and Chemical Physics, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovak Republic
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Publication History

Received 11 April 2011
Publication Date:
05 July 2011 (online)

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Abstract

A convenient and efficient method has been used for the synthesis of ten new tetrahydroxylated pyrrolizidines 12a,b, 13a-c, 14a,b, and 15a-c starting from sugar-derived cyclic nitrones prepared from d-xylose, d-arabinose, d-ribose, and l-arabinose, through a five-step reaction sequence. Pyrrolizidine 12a is an enantiomer of 7-deoxycasuarine and pyrrolizidine 12b an enantiomer of the as yet unknown 7-deoxyuniflorine A. This method expands the scope of nitrone cycloadditions and is flexible enough for the synthesis of various stereoisomers of highly polyhydroxylated pyrrolizidines.

Key words

sugar-derived cyclic nitrones - cycloaddition - iminosugars - pyrrolizidines - stereoselective synthesis

    References and Notes

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13

Crystal Data of Compound 11b
C29H33NO4, M = 459.56, monoclinic, P21, a = 13.197 (2) Å, b = 6.0914 (4) Å, c = 16.757 (3) Å, V = 1257.0(2) ų, Z = 2, D x = 1.214 Mg m-³, µ (Cu Kα) = 0.639 mm-¹, F(000) = 492, colorless block, 0.152 × 0.228 × 0.860 mm-³, 15292 diffractions measured (R int = 0.026), 4082 unique, wR2 = 0.0759, conventional R = 0.0284 on I values of 4032 diffractions with I > 2.0 σ(I), (Δ/σ)max = 0.001, S = 1.039 for all data and 311 parameters. Unit cell determination and intensity data collection (θmax = 74.87˚) were performed on a Gemini R diffractometer¹4 at 100 (1) K. Structure solution was done using direct methods¹5 and refinements were achieved by full-matrix least-squares method¹5 on F**2. Further details of the crystal structure investigation can be obtained from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (CCDC deposition no. 818367).

14

Oxford Diffraction(2010). CrysAlis PRO. Oxford Diffraction Ltd, Abingdon, England.

17

Typical Experimental Procedure for Cycloaddition The nitrone (5.39 mmol) was dissolved in THF (50 mL) and methyl acrylate was added (21.56 mmol). The mixture was stirred for 48 h at r.t. The mixture was then concentrated under reduced pressure, and the residue was purified by MPLC (EtOAc-hexanes = 33:66).
Representative Data for Products Compound 9a: [α]D ²5 +41.6 (CHCl3, c 3.04). ¹H NMR (600 MHz, CDCl3): δ = 7.35-7.23 (m, 15 H, OCH2 Ph), 4.60-4.48 (m, 6 H, OCH 2Ph), 4.29 (m, 1 H, H-5), 4.04 (dd, 1 H, H-7, J = 3.9, 5.6 Hz), 3.96 (dd, 1 H, H-6, J = 3.9 Hz), 3.75 (m, 2 H, H-3, H-10b), 3.66 (dd, 1 H, H-9b, J = 4.7, 10.0 Hz), 3.60 (dd, 1 H, H-9a, J = 5.6, 10.0 Hz), 3.55 (dd, 1 H, H-10a, J = 4.5, 12.3 Hz), 3.33 (dd, 1 H, H-8, J = 5.6, 10.8 Hz), 2.32 (ddd, 1 H, H-4b, J = 7.3, 8.8, 15.8 Hz), 2.16 (ddd, 1 H, H-4a, J = 5.6, 7.3, 12.6 Hz). ¹³C NMR (75 MHz, CDCl3): δ = 138.2-127.5 (OCH2 Ph), 87.1 (C-6), 83.8 (C-7), 77.2 (C-5), 73.3, 72.3, 71.7 (OCH2Ph), 69.7 (C-9), 69.6 (C-8), 68.5 (C-3), 63.1 (C-10), 35.4 (C-4). IR: 3238, 3032, 2921, 2852, 1496, 1454, 1357, 1143, 1093, 1078, 1025, 738, 695 cm-¹. TOF MS (ESI): m/z calcd for C29H34NO5 [MH+]: 476.2437; found: 476.2433.
Compound 10a: [α]D ²5 +40.0 (CHCl3, c 0.71); mp 93-95 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 7.37-7.23 (m, 15 H, OCH2 Ph), 4.56-4.50 (m, 6 H, OCH 2Ph), 4.43 (m, 1 H, H-5), 4.24 (m, 2 H, H-10a, H-10b), 4.03 (dd, 1 H, H-7, J = 3.8, 5.8 Hz), 3.96 (dd, 1 H, H-6, J = 3.8 Hz), 3.75 (ddd, 1 H, H-3, J = 3.8, 5.4, 8.9 Hz), 3.65 (dd, 1 H, H-9b, J = 5.0, 9.8 Hz), 3.57 (dd, 1 H, H-9a, J = 5.8, 9.8 Hz), 3.35 (dd, 1 H, H-8, J = 5.8, 10.9 Hz), 3.00 (s, 3 H, OMs), 2.25 (m, 2 H, H-4a,
H-4b). ¹³C NMR (75 MHz, CDCl3) δ = 138.1-127.5 (OCH2 Ph), 86.9 (C-6), 83.9 (C-7), 74.3 (C-5), 73.2, 72.1, 71.8 (OCH2Ph), 70.0 (C-8), 69.7 (C-9), 69.3 (C-10), 68.2 (C-3), 37.5 (OMs), 35.6 (C-4). IR: 3027, 2880, 1497, 1454, 1336, 1178, 1101, 1074, 990, 964, 908, 819, 734, 694, 526 cm-¹. TOF MS (ESI): m/z calcd for C30H36NO7S [MH+]: 554.2212; found: 554.2040.
Compound 11a: [α]D ²5 -10.3 (CHCl3, c 2.10). ¹H NMR (300 MHz, CDCl3): δ = 7.40-7.24 (m, 15 H, OCH2 Ph), 4.75-4.55 (m, 6 H, OCH 2Ph), 4.36 (m, 1 H, H-6), 4.19 (dd, 1 H, H-1, J = 6.3 Hz), 3.98 (dd, 1 H, H-2, J = 6.3, 7.6 Hz), 3.63 (dd, 1 H, H-4b, J = 4.3, 9.4 Hz), 3.55 (dd, 1 H, H-4a, J = 6.6, 9.4 Hz), 3.50 (m, 2 H, H-3, H-8), 3.10 (dd, 1 H, H-5b, J = 3.9, 11.1 Hz), 2.95 (dd, 1 H, H-5a, J = 4.0, 11.1 Hz), 2.17 (ddd, 1 H, H-7β, J = 5.5, 8.3, 13.5 Hz), 1.90 (m, 1 H, H-7α). ¹³C NMR (75 MHz, CDCl3): δ = 140.8-129.0 (OCH2 Ph), 90.9 (C-1), 87.1 (C-2), 74.9 (C-6), 74.7 (C-4), 74.5, 73.8, 73.4 (OCH2Ph), 70.4 (C-3), 68.4 (C-7a), 64.1 (C-5), 41.9 (C-7). IR: 3383, 3030, 2858, 1496, 1453, 1363, 1100, 1067, 1027, 908, 733, 695, 607 cm-¹. TOF MS (ESI): m/z calcd. for C29H34NO4 [MH+]: 460.2488; found: 460.2181.
Compound 12a: [α]D ²5 -14.2 (MeOH, c 0.26). ¹H NMR (300 MHz, CD3OD): δ = 4.55 (m, 1 H, H-6), 4.22 (dd, 1 H, H-1, J = 7.9 Hz), 3.87 (m, 3 H, H-2, H-4a, H-4b), 3.71 (m, 1 H, H-7a), 3.48 (m, 1 H, H-3), 3.35 (m, 2 H, H-5a, H-5b), 2.21 (m, 2 H, H-7α, H-7β). ¹³C NMR (75 MHz, CD3OD): δ = 81.4 (C-1), 76.6 (C-2), 73.5 (C-6), 73.1 (C-3), 69.5 (C-7a), 62.6 (C-5), 60.6 (C-4), 38.4 (C-7). IR: 3269, 2931, 1634, 1435, 1377, 1335, 1097, 1041, 988, 927, 860, 607, 511 cm-¹. TOF MS (ESI): m/z calcd for C29H34NO4 [MH+]: 190.1079; found: 190.1042.
Compound 13a: [α]D ²5 +20.4 (MeOH, c 0.83). ¹H NMR (300 MHz, CD3OD): δ = 4.36 (m, 1 H, H-6), 4.20 (d, 1 H, H-2, J = 2.6 Hz), 4.08 (m, 1 H, H-7a), 3.95 (d, 1 H, H-1, J = 3.8 Hz), 3.85 (dd, 1 H, H-4b, J = 6.4, 11.1 Hz), 3.75 (dd, 1 H, H-4a, J = 6.7, 11.1 Hz), 3.30 (m, 1 H, H-3), 3.20 (dd, 1 H, H-5b, J = 4.1, 11.7 Hz), 2.87 (dd, 1 H, H-5a, J = 3.5, 11.7 Hz), 2.07 (m, 2 H, H-7α, H-7β). ¹³C NMR (75 MHz, CD3OD):
δ = 79.6 (C-2), 77.0 (C-1), 73.9 (C-6), 72.0 (C-3), 68.9 (C-7a), 62.4 (C-5), 61.4 (C-4), 32.9 (C-7). IR: 3238, 2925, 2871, 1645, 1435, 1034, 1251, 1029, 908, 674, 608, 512 cm-¹. TOF MS (ESI): m/z calcd for C29H34NO4 [MH+]: 190.1079; found: 190.1005.
Compound 14a: [α]D ²5 +5.7 (MeOH, c 1.16). ¹H NMR (300 MHz, CD3OD): δ = 4.51 (m, 1 H, H-6), 4.21 (dd, 1 H, J = 3.6 Hz, H-2), 3.91 (m, 2 H, H-4a, H-1), 3.75 (m, 2 H, H-4b, H-7a), 3.05 (m, 2 H, H-3, H-5a), 2.95 (dd, 1 H, J = 4.4, 11.4 Hz, H-5b), 2.07 (ddd, 1 H, J = 4.4, 7.3, 12.4 Hz, H-7β), 1.98 (ddd, 1 H, J = 4.4, 7.3, 12.4 Hz, H-7α). ¹³C NMR (75 MHz, CD3OD): δ = 79.2 (C-1), 75.4 (C-2), 73.3 (C-6), 72.5 (C-3), 68.8 (C-7a), 63.2 (C-5), 61.5 (C-4), 39.1 (C-7). IR: 3329, 3209, 2974, 2910, 2876, 2738, 2475, 2399, 1460, 1323, 1226, 1140, 1098, 1057, 1031, 965, 716, 407 cm-¹. TOF MS (ESI): m/z calcd for C29H34NO4 [MH+]: 190.1079; found: 190.1070.
Compound 15a: [α]D ²5 -15.8 (MeOH, c 1.00). ¹H NMR (600 MHz, CD3OD): δ = 4.55 (m, 1 H, H-6), 4.29 (dt, 1 H, J = 3.9, 8.4 Hz, H-7a), 4.22 (m, 1 H, H-2), 3.96 (d, 1 H, J = 3.9 Hz, H-1), 3.85 (dd, 1 H, J = 5.8, 11.2 Hz, H-4a), 3.80 (dd, 1 H, J = 8.1, 11.2 Hz, H-4b), 3.27 (dd, 1 H, J = 2.7, 11.5 Hz, H-5a), 3.23 (ddd, 1 H, J = 3.4, 5.8, 8.1 Hz, H-3), 2.91 (dd, 1 H, J = 4.2, 11.5 Hz, H-5b), 2.33 (ddd, 1 H, J = 5.1, 7.3, 12.3 Hz, H-7α), 1.77 (ddd, 1 H, J = 3.4, 8.4, 12.3 Hz, H-7β). ¹³C NMR (150 MHz, CD3OD): δ = 80.2 (C-2), 75.7 (C-1), 74.7 (C-6), 72.5 (C-3), 69.9 (C-8), 63.6 (C-5), 60.5 (C-4), 32.6 (C-7). IR: 3261, 2927, 2866, 2709, 1417, 1309, 1282, 1231, 1036, 972, 916, 901, 773, 719, 592, 538 cm-¹. TOF MS (ESI): m/z calcd for C29H34NO4 [MH+]: 190.1079; found: 190.1132.