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

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) 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

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.