Synthetic Study on Sespendole, an Indole Sesquiterpene Alkaloid: Stereo­controlled Synthesis of the Sesquiterpene Segment Bearing All Requisite Stereogenic Centers

Abstract

Stereocontrolled synthesis of a sesquiterpene segment with all requisite stereogenic centers for sespendole has been achieved. Synthetic features of our strategy involve (1) highly stereoselective [2,3]-Wittig rearrangement to obtain sterically congested quaternary carbon and (2) isomerization of a spiro epoxide into aldehyde with Cp₂TiCl₂/Mn in a highly stereoselective manner.

natural product synthesis - sespendole - indole sesqui­terpene - [2,3]-Wittig rearrangement - isomerization

References and Notes

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All new compounds were fully characterized by ^¹H NMR, ^¹³C NMR, and IR analyses.
Data for Selected Compounds
Alcohol 12: IR (film): ν_max = 3362, 2954, 2856, 1635, 1472, 1253, 1063, 835 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.04 (3 H, s, CH₃ of TBS), 0.05 (3 H, s, CH₃ of TBS), 0.24 (9 H, s, CH₃ of TMS), 0.88 (9 H, s, CH₃ of t-Bu), 1.02 (3 H, s, CCH _3axCH_3eq), 1.02 (3H, s, CCH_3axCH _3eq), 1.04 (3 H, s, CCH₃), 1.29 [3 H, s, C(CH₂OH)CH ₃], 1.29 (1 H, dt, J = 12.0, 3.5 Hz, CH_bH_cCH_d H _e), 1.55-1.63 (2 H, m, CH_aCH _b H _c), 1.77 (1 H, ddd, J = 14.0, 6.5, 4.5 Hz, CH_hH_iCH _jH_k), 1.82 (1 H, ddd, J = 14.0, 10.0, 6.0 Hz, CH_hH_iCH_j H _k), 2.09 (1 H, ddd, J = 13.0, 10.0, 8.0 Hz, CH_bH_cCH _dH_e), 2.22 (1 H, dddd, J = 13.5, 6.0, 4.5, 1.0 Hz, CH_h H _iCH_jH_k), 2.46 (1 H, dddt, J = 13.5, 10.0, 6.5, 1.0 Hz, CH _hH_iCH_jH_k), 3.57 (1 H, br d, J = 11.0 Hz, CH _xH_yOH), 3.68 (1 H, d, J = 11.0 Hz, CH_x H _yOH), 3.77 (1 H, dd, J = 9.5, 7.0 Hz, TBSOCH_a), 4.71 (1 H, br s, H _mH_nC=C), 4.89 (1 H, br s, H_m H _nC=C). ^¹³C NMR (100 MHz, CDCl₃): δ = -4.7, -3.8, 4.5, 18.1, 19.2, 20.2, 22.7, 25.9, 26.1, 27.6, 28.4, 28.7, 29.9, 46.2, 46.5, 48.4, 68.0, 74.1, 88.9, 108.4, 152.6. ESI-HRMS: m/z calcd for C₂₅H₅₀O₃Si₂Na [M + Na]: 477.3191; found: 477.3202.
Alcohol 2: IR (film): ν_max = 3311, 2955, 2103, 1253, 1097, 1006, 836 cm^-¹. ^¹H NMR (600 MHz, CDCl₃): δ = 0.03 (3 H, s, CH₃ of TBS) 0.04 (3 H, s, CH₃ of TBS), 0.21 (9 H, s, CH₃ of TMS), 0.87 (9 H, s, CH₃ of t-Bu), 0.95 (3 H, s, CCH₃CH ₃), 1.00 (3 H, s, CCH ₃CH₃), 1.26 (3 H, s, CCH₃), 1.33 (1 H, dt, J = 13.0, 3.5 Hz, CH_bH_cCH_d H _e), 1.35 (1 H, td, J = 13.5, 4.0 Hz, CH_gCH _hH_i), 1.41 (3 H, s, CCH₃), 1.60-1.69 (3 H, m, CH_aCH _b H _c, CH_hH_iCH _jH_k), 1.72 (1 H, dq, J = 13.5, 3.5 Hz, CH_gCH_h H _i), 1.81 (1 H, td, J = 14.0, 4.0 Hz, CH_hH_iCH_j H _k), 2.05 (1 H, td, J = 13.0, 5.0 Hz, CH_bH_cCH _dH_e), 2.08 (1 H, tt, J = 12.5, 4.0 Hz, HOCH₂CH _g), 2.20 (1 H, s, CºCH), 3.41 (1 H, br s, HOCH _xH_yCH_g), 3.75 (1 H, dd, J = 11.0, 6.0 Hz, TBSOCH_a), 4.03 (1 H, dd, J = 10.5, 5.0 Hz, HOCH_x H _yCH_g). ^¹³C NMR (100 MHz, CDCl₃): δ = -4.7, -3.7, 4.5, 18.0, 19.9, 21.4, 21.5, 22.4, 25.1, 25.8, 26.0, 26.3, 28.5, 42.9, 44.6, 45.1, 46.2, 66.0, 71.2, 73.9, 87.5, 92.7. ESI-HRMS: m/z calcd for C₂₆H₅₀O₃Si₂Na [M + Na]: 489.3191; found: 489.3210.

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This reaction did not proceed with Cp₂TiCl₂ as a Lewis acid. When the Lewis acid such as MgBr₂˙OEt₂, BF₃˙OEt₂, or AlCl₃ was used for this conversion, the reaction provide lower yield of the desired aldehyde.

<A NAME="RU11210ST-25">25</A> Related reaction for the formation of allylic alcohol from spiro epoxide was reported: Justicia J. Oltra JE. Barrero AF. Guadaño A. González-Coloma A. Cuerva JM. Eur. J. Org. Chem.  2005,  712