Synthesis of the Tricyclic Core of 5α-Capnellenols Using Asymmetric Heck Reaction-Carbanion Capture Process

Wataru Itano; Takashi Ohshima; Masakatsu Shibasaki

doi:10.1055/s-2006-951537

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Synlett 2006(18): 3053-3056
DOI: 10.1055/s-2006-951537

LETTER

Synthesis of the Tricyclic Core of 5α-Capnellenols Using Asymmetric Heck Reaction-Carbanion Capture Process

Wataru Itano, Takashi Ohshima, Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax: +81(3)56845206; e-Mail: mshibasa@mol.f.u-tokyo.ac.jp;

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Publication History

Received 17 April 2006
Publication Date:
25 October 2006 (online)

Abstract
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Abstract

The tricyclic core of 5α-capnellenols was synthesized using an asymmetric Heck reaction-carbanion capture process and an intramolecular nitrile oxide cycloaddition as key ring construction steps. Moreover, the desired C5-α-OH product was obtained through a retroaldol and aldol epimerization process of the C5-β-OH tricyclic compound.

Key words

asymmetric synthesis - carbanions - cycloadditions - isomerizations - Heck reaction

References and Notes

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7

Analytical Data for 11. Major isomer: R _f = 0.44 (silica gel, EtOAc-hexane, 2 × 1:3). ¹H NMR (500 MHz, CDCl₃): δ = 8.02-7.98 (m, 2 H), 7.60-7.55 (m, 1 H), 7.47-7.42 (m, 2 H), 4.96-4.94 (br s, 1 H), 4.88-4.86 (br s, 1 H), 4.60 (dd, J = 11.0, 6.4 Hz, 1 H), 4.51 (d, J = 7.0 Hz, 1 H), 4.39 (dd, J = 11.0, 8.2 Hz, 1 H), 4.16 (dd, J = 7.0, 6.4 Hz, 1 H), 3.31-3.22 (m, 1 H), 2.76 (ddd, J = 16.8, 11.0, 1.6 Hz, 1 H), 2.49-2.30 (m, 5 H), 1.53-1.45 (m, 2 H), 1.04 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 167.91, 166.34, 152.81, 133.09, 129.97, 129.56 (2 C), 128.42 (2 C), 109.13, 89.30, 66.08, 64.45, 58.58, 55.36, 47.46, 44.25, 34.93, 28.41, 24.47, 20.24.
Minor isomer: R _f = 0.49 (EtOAc-hexane 2 × 1:3). ¹H NMR (500 MHz, CDCl₃): δ = 8.03-8.00 (m, 2 H), 7.60-7.56 (m, 1 H), 7.48-7.44 (m, 2 H), 4.49-4.48 (br s, 1 H), 4.81-4.79 (br s, 1 H), 4.56 (d, J = 7.3 Hz, 1 H), 4.34 (dd, J = 11.0, 5.8 Hz, 1 H), 4.28 (dd, J = 11.0, 6.7 Hz, 1 H), 4.20-4.16 (m, 1 H), 3.01-2.95 (m, 1 H), 2.87 (dd, J = 15.5, 8.3 Hz, 1 H), 2.50-2.34 (m, 3 H), 2.21-2.16 (m, 2 H), 1.55-1.40 (m, 2 H), 1.06 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 167.83, 166.47, 153.63, 133.21, 129.85, 129.56 (2 C), 128.48 (2 C), 106.72, 90.49, 68.14, 61.78, 61.76, 57.96, 49.98, 45.69, 35.30, 28.92, 25.00, 19.67. FT-IR (neat): 2951, 1718, 1451, 1273, 1117, 713 cm^-1. LRMS (ESI, MeOH): m/z = 360.1 [M + Na⁺], 697.2 [2 M + Na⁺]. HRMS-FAB: m/z calcd for C₂₁H₂₃NO₃ [M + H⁺]: 338.1751; found: 338.1760.

9

General Procedure for the Asymmetric Heck Reaction-Carbanion Capture Process. [Pd(allyl)Cl]₂ (1.99 mg, 5.5 µmol, 2.5 mol%) and (S)-BINAP (8.55 mg, 13.7 µmol, 6.3 mol%) were added to a solution of 7 (61.5 mg, 0.218 mmol) in DMSO (1.0 mL, 0.218 M). After degassing, the sodium enolate of 15 (0.33 M, in DMSO, 1.32 mL, 0.436 mmol, 2 equiv) was gradually added to the mixture. The reaction mixture was stirred at r.t. for 1 h, diluted with Et₂O, washed with 1 N aq HCl and brine, dried (Na₂SO₄), and concentrated. The residue was purified twice by silica gel column chromatography (Et₂O-hexane, 1:25) to give 14 (68.5 mg, 82%, 83% ee) as colorless oil (1:1 mixture of diastereomers). R _f = 0.39 (silica gel, EtOAc-hexane, 1:3). FT-IR (neat): 2919, 2849, 1722, 1314, 1249, 1035, 821, 760 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.28-7.24 (m, 2 H), 6.90-6.88 (m, 2 H), 5.54 (dd, J = 5.5, 2.2 Hz, 0.5 H), 5.52-5.48 (m, 1 H), 5.54 (dd, J = 5.5, 2.5 Hz, 0.5 H), 4.91-4.82 (m, 2 H), 4.53-4.49 (m, 2 H), 4.16 (d, J = 17.4 Hz, 0.5 H), 4.14 (d, J = 17.4 Hz, 0.5 H), 4.11 (d, J = 17.4 Hz, 0.5 H), 4.08 (d, J = 17.4 Hz, 0.5 H), 3.81 (s, 3 H), 3.70, 3.66 (s, 1.5 H), 3.63 (d, J = 9.5 Hz, 0.5 H), 3.55 (d, J = 10.4 Hz, 0.5 H), 3.28-3.23 (m, 1 H), 2.38-2.36 (br s, 0.5 H), 2.29-2.17 (m, 2.5 H), 1.72-1.64 (m, 1 H), 1.51-1.41 (m, 1 H), 1.19, 1.15 (s, 1.5 H). ¹³C NMR (126 MHz, CDCl₃): δ = 168.64, 168.57, 159.46, 157.52, 157.40, 141.47, 141.14, 129.60 (2 C), 129.24, 128.92, 128.89, 113.82 (2 C), 106.07, 106.04, 74.58, 74.53, 73.00, 72.97, 61.17, 60.73, 57.22, 57.19, 56.51, 56.34, 55.25, 54.63, 54.17, 52.34, 52.20, 38.35, 38.32, 33.19, 27.68, 27.59. LRMS (ESI, MeOH): m/z = 407.1 [M + Na⁺], 791.2 [2 M + Na⁺]. HRMS-FAB: m/z calcd for C₂₃H₂₈CsO₅ [M + Cs⁺]: 517.0986; found: 517.0981. The allylated product of 14 (Figure [3] , 2.5 mg, 3%) was obtained as the by-product.

14

Analytical Data for 21.
R _f = 0.38 (silica gel, EtOAc-hexane, 1:2). FT-IR (neat): 2958, 2930, 2860, 1719, 1439, 1236, 1076, 831 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 7.12 (s, 1 H), 5.03-5.01 (m, 1 H), 5.00-4.98 (m, 1 H), 4.61 (d, J = 7.7 Hz, 1 H), 4.23 (dd, J = 7.7, 6.8 Hz, 1 H), 3.82 (s, 3 H), 3.17 (dd, J = 6.8, 6.1 Hz, 1 H), 2.47-2.41 (m, 2 H), 2.17 (br d, J = 6.1 Hz, 1 H), 1.61-1.47 (m, 2 H), 1.03 (s, 3 H). ¹³C NMR (126 MHZ, CDCl₃): δ = 169.72, 164.32, 153.56, 153.08, 128.01, 109.12, 90.47, 66.92, 59.97, 55.75, 52.12, 51.79, 37.51, 31.00, 21.20. LRMS (ESI, MeOH): m/z = 281.9 [M + Na⁺]. HRMS-FAB: m/z calcd for C₁₅H₁₇CsNO₃ [M + Cs⁺]: 392.0257; found: 392.0258. [α]_D ²⁰ +36.4 (c 0.22, CHCl₃).

15

(a) Analytical Data for 12. R _f = 0.28 (silica gel, EtOAc-hexane, 2 × 1:2). FT-IR (neat) 3438, 2953, 2925, 1710, 1437, 1222, 1082, 887 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 6.56 (d, J = 2.1 Hz, 1 H), 5.22-5.20 (m, 1 H), 5.03-5.01 (m, 1 H), 3.91-3.89 (m, 1 H), 3.88 (s, 3 H), 3.46 (ddd, J = 6.7, 4.9, 2.1 Hz, 1 H), 3.08 (dd, J = 6.7, 6.7 Hz, 1 H), 2.61-2.54 (m, 1 H), 2.51-2.43 (m, 2 H), 2.16-2.13 (br s, 1 H), 1.97 (ddd, J = 13.2, 9.3, 9.3 Hz, 1 H), 1.51-1.46 (m, 1 H), 1.03 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 209.04, 165.90, 164.46, 155.08, 136.02, 108.31, 81.70, 59.92, 59.01, 57.17, 52.47, 51.12, 31.85, 31.28, 24.25. LRMS (ESI, MeOH): m/z 285.0 [M + Na⁺]. HRMS-FAB: m/z calcd for C₁₅H₁₈CsO₄ [M + Cs⁺]: 395.0254; found: 395.0251. [α]_D ²⁰ +62.5 (c 0.20, CHCl₃). (b) The stereo-chemistry at C5 was confirmed by NOE analysis after protection of the hydroxyl group with a TBS group (Scheme [8] ).

16

Improvement of the C5-OH isomer ratio is still under investigation.

17

The DFT calculation was performed on Gaussian03 with B3LYP/6-31+G(d).

18

(a) Analytical Data for 25.
R _f = 0.33 (silica gel, EtOAc-hexane, 2 × 1:2). FT-IR (neat): 3406, 2924, 2852, 1710, 1438, 1221, 1086, 802 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 6.49 (d, J = 2.2 Hz, 1 H), 3.83 (s, 3 H), 3.77 (dd, J = 7.6, 4.6 Hz, 1 H), 3.39 (ddd, J = 7.0, 4.2, 2.2 Hz, 1 H), 2.99 (dd, J = 7.6, 7.0 Hz, 1 H), 2.16-2.10 (m, 1 H), 2.13 (d, J = 4.6 Hz, 1 H), 1.95-1.89 (m, 1 H), 1.61 (d, J = 4.2 Hz, 1 H), 1.51-1.41 (m, 2 H), 1.20 (s, 3 H), 1.03-0.98 (m, 1 H), 0.64-0.60 (m, 1 H), 0.56-0.52 (m, 1 H), 0.46-0.42 (m, 1 H). ¹³C NMR (126 MHz, CDCl₃): δ = 209.11, 165.87, 164.45, 135.61, 81.70, 59.80, 59.67, 58.79, 52.40, 49.19, 35.06, 31.57, 29.69, 26.35, 15.59, 7.15. LRMS (ESI, MeOH): m/z = 298.8 [M + Na⁺]. HRMS-FAB: m/z calcd for C₁₆H₂₀CsO₄ [M + Cs⁺] 409.0410; found: 409.0399. [α]_D ²⁴ +35.8 (c 0.12, CHCl₃).