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Synlett 2004(5): 0779-0782  
DOI: 10.1055/s-2004-817773
LETTER
© Georg Thieme Verlag Stuttgart · New York

Studies on the Synthesis of Croomine: Synthesis of the Tricyclic B,C,D-Ring Core Structure

Karl B. Lindsay, Stephen G. Pyne*
Department of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia
Fax: +61(2)42214287; e-Mail: Stephen_Pyne@uow.edu.au;
Further Information

Publication History

Received 17 December 2003
Publication Date:
10 February 2004 (online)

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Abstract

A convergent and asymmetric synthesis of the tricyclic B,C,D-ring core structure of croomine has been achieved, using aminolysis reactions of chiral vinyl epoxides and the RCM reaction.

Key words

oxazolindone - pyrrolidine - ring-closing metathesis - azepine - Stemona alkaloid

11

(1S,5S,7aS)-5-[(1S)-1-[[(1,1-Dimethylethyl)dimethyl-silyl]oxy]-5-[(methoxyphenyl)methoxy]pentyl]-1-[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]propyl]-5,7a-dihydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one (14): The diene 13 (547 mg, 0.826 mmol) was dissolved in anhyd CH2Cl2 (95 mL), then Grubbs’ 1st generation catalyst (338 mg, 0.413 mmol) was added. The mixture was heated at reflux under N2 for 7 d then cooled, before all volatiles were removed in vacuo to give a black oil. The pure product was obtained by column chromatography (increasing polarity from 10% to 40% EtOAc in pet. sp. as eluant), which gave a black oil. This was dissolved in EtOAc (30 mL) and stirred with activated charcoal for 20 min to remove residual ruthenium, then filtered through celite. Evaporation of the filtrate afforded the title compound (485 mg, 0.785 mmol, 92.6%) as a colorless oil. [α]D 26 -86 (c = 1.0, CHCl3). MS (ES+): m/z (%) = 634.5 (100) [M + 1]. HRMS (ES+): m/z [M + 1] calcd for C34H59NO6Si2: 634.3959; found: 634.3975. 1H NMR (300 MHz, CDCl3): δ = 0.04 [s, 6 H, (CH3)2Si], 0.05 [s, 6 H, (CH3)2Si], 0.86 [s, 9 H, (CH3)3CSi], 0.89 [s, 9 H, (CH3)3CSi], 1.34-1.96 (m, 10 H, H2′, H3′, H4′, H1′′, H2′′), 3.44 (t, J = 6.6 Hz, 2 H, H5′), 3.62-3.74 (m, 3 H, H1′, H3′′), 3.79 (s, 3 H, OCH3), 4.24-4.30 (m, 1 H, H7a), 4.35 (q, J = 6.0 Hz, 1 H, H1), 4.42 (s, 2 H, OCH2Ar), 4.54 (app. t, J = 3.9 Hz, 1 H, H5), 5.85-5.92 (m, 2 H, H6, H7), 6.86 (d, J = 8.7 Hz, 2 H, 2 × ArCH), 7.25 (d, J = 8.7 Hz, 2 H, 2 × ArCH). 13C NMR (75 MHz, CDCl3): δ = -5.4 [q, (CH3)2Si], -4.6 (q, CH3Si), -4.4 (q, CH3Si), 18.0 [s, (CH3)3CSi], 18.3 [s, (CH3)3CSi], 22.2 (t, C3′), 25.8 [q, (CH3)3CSi], 25.9 [q, (CH3)3CSi], 27.9, 29.9, 31.9, 33.6 (t, C2′, C4′, C1′′, C2′′), 55.2 (q, OCH3), 62.3 (t, C3′′), 70.0 (t, C5′′), 70.6 (d, C7a), 71.0 (d, C5), 72.5 (t, OCH2Ar), 73.3 (d, C1"), 82.0 (d, C1), 113.7 (d, 2 × ArCH), 129.2 (d, 2 × ArCH), 129.6, 132.2 (d, C6 and C7), 130.8 (s, ArC), 159.0 (s, ArC), 162.4 (s, C3).

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(3S,9S,9aS)-9-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3-[(1S)-1,4-bis[[(1,1 dimethylethyl)diphenylsilyl]oxy]-butyl]-1H-pyrrolo[1,2-a]azepine (19): The amino alcohol 18 (727 mg, 0.744 mmol) was dissolved in CH2Cl2 (60 mL), then the solution was cooled to 0 °C. Carbon tetrabromide (604 mg, 1.828 mmol) and triphenylphosphine (475 mg, 1.828 mmol) were added, then the mixture was stirred at 0 °C for 10 min, before Et3N (3.70 g, 36.56 mmol) was added. The mixture was stirred at 0 °C for 5 h, then left to stand at 4 °C for 20 h, then stirred at r.t. for 24 h. The mixture was poured into water (50 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated to give a black semi-solid. The pure products were obtained by column chromatography (increasing polarity from 5% to 25% EtOAc in petroleum spirit as eluant), which gave the title compound (451 mg, 0.470 mmol, 63.2%) and the partially stable bromide intermediate. The bromide intermediate was dissolved in CH2Cl2 (10 mL) and Et3N (5 mL), then heated at reflux for 3 h. Work up and column chromatography as described above gave further title compound (128 mg, 0.134 mmol, 17.9%, total yield 81.1%) as a colorless oil. [α]D 24 -35 (c =1.28, CHCl3). MS (ES+): m/z (%) = 958.6(100) [M + 1]. HRMS (ES+): m/z [M + 1] calcd for C61H80NO3Si: 958.5446; found: 958.5452. 1H NMR (300 MHz, CDCl3): δ = 1.07 [s, 9 H, (CH3)3Csi], 1.11 [s, 1 8 H, (CH3)3Si], 0.80-1.80 (m, 13 H, H1, H2, H6, H7, H8a, H2′, H3′), 1.84-2.00 (m, 1 H, H8b), 2.34 (dd, J = 13.2, 9.0 Hz, 1 H, H7a), 2.55 (dd, J = 13.5, 6.6 Hz, 1 H, H7b), 3.10-3.20 (m, 1 H, H9a), 3.28-3.36 (m, 1 H, H5), 3.50 (t, J = 6.0 Hz, 2 H, H4′), 3.76-3.84 (m, 1 H, H9), 3.84-3.92 (dd, J = 7.2, 3.0 Hz, 1 H, H1′), 7.28-7.44 (m, 18 H, SiPh), 7.58-7.73 (m, 12 H, SiPh). 13C NMR (75 MHz, CDCl3): δ = 19.2 [s, (CH3)3CSi], 19.3 [s, (CH3)3CSi], 19.5 [s, (CH3)3CSi], 26.8 [q, (CH3)3CSi], 27.1 [q, (CH3)3CSi], 27.2 [q, (CH3)3CSi], 25.0, 25.1, 26.2, 27.1, 28.1, 30.0, 34.1 (t, C1, C2, C6, C7, C8, C2′, C3′), 48.3 (t, C7), 64.2 (t, C4′), 66.2 (d, C3), 66.7 (d, C9a), 74.0 (d, C9), 76.5 (d, C1′), 127.4, 127.5, 129.4, 129.5 (d, SiPh), 134.2, 134.2, 134.2, 134.5, 134.6, 134.7 (s, SiPh), 136.0, 136.0, 136.0 (d, SiPh).

13

(3S,9S,9aS)-3-[(1S)-1,4-Dihydroxybutyl]-9-hydroxy-1H-pyrrolo[1,2-a]azepine (20): The tri-O-silyl ether 19 (61 mg, 0.0636 mmol) was dissolved in CHCl3 (0.5 mL), then MeOH (4.0 mL) and concd HCl (1.0 mL, 38% w/w) were added. The mixture was heated in a sealed tube at 90 °C for 3 d and then cooled. The mixture was poured into Et2O (40 mL) and extracted with 1 M HCl (3 × 15 mL). The combined aqueous extracts were evaporated to dryness in vacuo to give a gum. This was dissolved in water (2 mL) and applied to basic ion exchange resin (OH form). Elution with water (50 mL) and evaporation of the eluant gave the title compound (13 mg, 0.0534 mmol, 83.9%) as a pale brown gum. [α]D 22 -34 (c = 1.3, MeOH). MS (CI+): m/z (%) = 244(100) [M + 1]. HRMS (CI+): m/z [M + 1] calcd for C13H26NO3: 244.1913; found: 244.1916. 1H NMR (300 MHz, CDCl3): δ = 1.30-2.10 (m, 17 H, H1, H2, H6, H7, H8, H2′, H3′, 2 × OH), 2.85 (ddd, J = 12.3, 6.3, 2.4 Hz, 1 H, H5a), 2.94-3.08 (m, 2 H, H3, H5b), 3.29 (td, J = 6.9, 2.4 Hz, 1 H, H9a), 3.38 (ddd, J = 9.0, 6.3, 2.4 Hz, 1 H, H1′), 3.60-3.76 (m, 2 H, H4′), 3.94 (br d, J = 6.9 Hz, 1 H, H9). 13C NMR (75 MHz, CDCl3): δ = 22.9 (t, C7), 27.9, 28.9, 29.4, 30.1, 32.1, 34.8 (t, C1, C2, C6, C8, C2′, C3′), 52.5 (t, C5), 62.9 (t, C4′), 65.3 (d, C9a), 71.0 (d, C3), 72.6 (d, C9), 72.8 (d, C1′).

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(3S,5S,9S,9aS)-3-[(5S)-tetrahydro-5-oxo-2-furanyl]-5,9-epoxy-1H-pyrrolo[1,2-a]azepine (22): The triol 20 (25 mg, 0.103 mmol) was dissolved in HOAc (2 mL), then TEMPO (5 mg, 0.032 mmol) and BAIB (113 mg, 0.35 mmol) were added. The mixture was stirred at r.t. for 24 h, then Na2S2O3·5H2O (125 mg, 0.504 mmol) was added. After 20 min the mixture was poured into 5% NH4OH solution (40 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were dried (MgSO4) filtered and evaporated in vacuo to give an oil. The pure product was obtained by column chromatography (2% MeOH in CH2Cl2 as eluant), which gave the title compound (7 mg, 0.029 mmol, 28.6%) as a pale yellow semi solid. MS (CI+): m/z (%) = 238 (100) [M + 1]. 1H NMR (300 MHz, CDCl3): δ = 0.80-2.00 (m, 10 H, H1a, H2, H6, H7, H8, H4′a), 2.00-2.14 (m, 1 H, H1b), 2.25 (dddd, J = 12.6, 8.1, 6.9, 5.7 Hz, 1 H, H4′b), 2.53 (dd, J = 9.6, 3.3 Hz, 1 H, H3′a), 2.55 (dd, J = 9.6, 0.9 Hz, 1 H, H3′b), 3.02 (ddd, J = 10.2, 7.5, 5.4 Hz, 1 H, H3), 3.46-3.80 (m, 1 H, H9a), 4.02 (d, J = 1.5 Hz, 1 H, H9), 4.37 (dt, J = 7.8, 7.2 Hz, 1 H, H5′), 4.82 (s, 1 H, H5). 13C NMR (75 MHz, CDCl3): δ = 16.8 (t, C7), 25.4 (t, C4′), 28.8 (t, C3′), 28.9, 29.2 (t, C6, C8), 31.5 (t, C2), 31.6 (t, C1), 68.7 (d, C9a), 70.9 (d, C3), 78.9 (d, C9), 85.3 (d, C5′), 96.0 (d, C5), 177.0 (s, C2).