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

Gabriel Podolan; Lucia Kleščíková; Lubor Fišera; Jozef Kožíšek; Marek Fronc

doi:10.1055/s-0030-1260933

LETTER

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

Gabriel Podolan^a, Lucia Kleščíková^a, Lubor Fišera*^a, Jozef Kožíšek^b, Marek Fronc^b
^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

Abstract

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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

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References

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) Å^³, 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 (θ_max = 74.87˚) were performed on a Gemini R diffractometer^¹4 at 100 (1) K. Structure solution was done using direct methods^¹5 and refinements were achieved by full-matrix least-squares method^¹5 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

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16 Brandenburg K. DIAMOND Crystal Impact GbR; Bonn: 2006.

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.