An Enantiospecific Formal Total Synthesis of the 5-8-5 Tricyclic Diterpene ent-Fusicoauritone

Abstract

An enantiospecific formal total synthesis of the 5-8-5 tricyclic diterpene fusicoauritone has been accomplished, starting from 5-isopropyl-2-methylcyclopent-1-enemethanol [available in three steps from (R)-dihydrolimonene] employing two ring-closing-metathesis reactions for the construction of the eight- and five-membered rings.

fusicoccanes - limonene - enantiospecific synthesis - cyclooctanoids - ring-closing metathesis

References and Notes

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Yields refer to isolated and chromatographically pure compounds. All the compounds exhibited spectroscopic data (IR, ^¹H NMR, ^¹³C NMR, and HRMS) consistent with their structures.
Selected Spectroscopic Data for (1 S ,8 R ,9 S )-9-Isopropyl-1-methylbicyclo[6.3.0]undec-4-en-3-one (5)
[α]_D ^²6 -196.6 (c 1.4, CHCl₃). IR (neat): ν_max = 3019, 1660 (C=O), 1388, 1369, 1243, 1202, 1152, 839, 768 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 6.49-6.33 (1 H, m, H-3), 6.19 (1 H, d, J = 12.0 Hz, H-4), 2.81 (1 H, d, J = 12.2 Hz, H-2A), 2.90-2.75 (1 H, m), 2.48 (1 H, d, J = 12.0 Hz, H-2B), 2.60-2.34 (1 H, m), 2.04-1.25 (9 H, m), 0.97 (3 H, s, t-CH₃), 0.90-0.85 [6 H, m, CH(CH ₃)₂]. ^¹³C NMR (100 MHz, CDCl₃): δ = 201.2 (C, C=O), 148.2 (CH, C-5), 137.0 (CH, C-4), 54.2 (CH₂, C-2), 46.5 (CH, C-8), 42.1 (CH, C-9), 41.7 (C, C-1), 39.3 (CH₂), 29.3 (CH), 25.8 (CH₂), 24.3 (CH₃), 23.9 (CH₂), 22.2 (CH₂), 21.8 (CH₃), 20.4 (CH₃). HRMS: m/z calcd for C₁₅H₂₄ONa [M + Na]: 243.1725; found: 243.1733.
(1 S ,4 S ,5 R ,8 R ,9 S )-4-Allyl-9-isopropyl-1,5-dimethyl-bicyclo[6.3.0]undecan-3-one (21)
[α]_D ^²¹ +84.2 (c 2.9, CHCl₃). IR (neat): ν_max = 3078, 1694 (C=O), 1386, 1302, 992, 913 cm^-¹. ^¹H NMR (400 MHz, CDCl₃ + CCl₄): δ = 5.64 (1 H, ddt, J = 17.7, 9.9, 7.5 Hz, CH=CH₂), 4.95 (1 H, d, J = 17.7 Hz, CH=CH₂), 4.93 (1 H, d, J = 9.9 Hz, CH=CH₂), 2.46 (1 H, d, J = 11.2 Hz, H-2A), 2.54-2.35 (1 H, m), 2.24-1.76 (6 H, m), 1.76-1.22 (9 H, m), 1.01 (3 H, d, J = 6.7 Hz, s-CH₃), 0.87 (3 H, s, t-CH₃), 0.87
[3 H, d, J = 6.4 Hz, CH(CH ₃)₂], 0.79 [3 H, d, J = 6.7 Hz, CH(CH ₃)₂]. ^¹³C NMR (100 MHz, CDCl₃ + CCl₄): δ = 214.8 (C, C=O), 135.8 (CH, CH=CH₂), 116.3 (CH₂, CH=CH₂), 62.7 (CH, C-4), 53.0 (CH₂, C-2), 47.4 (CH), 46.8 (CH), 44.8 (C, C-1), 42.6 (CH₂), 35.8 (CH₂), 34.6 (CH₂), 31.2 (CH), 28.1 (CH), 24.4 (CH₂), 24.2 (CH₃), 22.5 (CH₂), 21.6 (CH₃), 19.9 (CH₃), 19.8 (CH₃). HRMS: m/z calcd for C₁₉H₃₂ONa [M + Na]: 299.2351; found: 299.2350.
(1 S ,7 S ,8 R ,11 R ,12 S )-12-Isopropyl-1,8-dimethyl-tricyclo[9.3.0.0 ^³,7 ]tetradec-3-en-5-one (23a)
Mp 78-80 ˚C; [α]_D ^²² +3.28 (c 0.5, CHCl₃). IR (neat): ν_max = 1700 (C=O), 1606, 1388, 1342, 1277, 1239, 1187, 918 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 5.89 (1 H, s, C=CH), 2.75 (1 H, d, J = 12.6 Hz, H-2A), 2.66 (1 H, dd, J = 18.8, 6.3 Hz, H-6A), 2.39 (1 H, d, J = 12.6 Hz, H-2B), 2.45-2.38 (1 H, m), 2.08 (1 H, d, J = 18.8 Hz, H-6B), 2.05-1.25 (12 H, m), 1.05 (3 H, d, J = 6.7 Hz, s-CH₃), 0.95 (3 H, s, t-CH₃), 0.86 [3 H, d, J = 6.8 Hz, CH(CH ₃)₂], 0.83 [3 H, d, J = 6.8 Hz, CH(CH ₃)₂]. ^¹³C NMR (100 MHz, CDCl₃): δ = 209.0 (C, C=O), 183.3 (C, C-3), 133.4 (CH, C-4), 53.5 (CH), 47.1 (CH), 44.5 (C), 44.3 (CH₂), 44.1 (CH₂), 42.0 (CH), 39.8 (CH), 39.5 (CH₂), 31.5 (CH₂), 28.3 (CH), 26.3 (CH₂), 25.1 (CH₃), 24.3 (CH₃), 23.6 (CH₂), 22.7 (CH₃), 20.0 (CH₃). HRMS: m/z calcd for C₁₉H₃₀ONa [M + Na]: 297.2194; found: 297.2198.
(1 S ,7 S ,8 R ,11 R ,12 S )-12-Isopropyl-1,4,8-trimethyl-tricyclo[9.3.0.0 ^³,7 ]tetradec-3-en-5-one (28)
Mp 92-94 ˚C; [α]_D ^²² +14.83 (c 1.6, CHCl₃). IR (KBr):
ν_max = 1699 (C=O), 1376, 1347, 1326, 1156, 1083 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.87 (1 H, d, J = 13.0 Hz, H-2A), 2.63 (1 H, dd, J = 18.8, 6.2 Hz, H-6A), 2.31 (1 H, d,
J = 13.0 Hz, H-2B), 2.28-2.18 (1 H, m), 2.05 (1 H, dd, J = 18.8, 2.6 Hz, H-6B), 2.00-1.80 (2 H, m), 1.72 (3 H, s, olefinic CH₃), 1.72-1.22 (10 H, m), 1.04 (3 H, d, J = 6.7 Hz, s-CH₃), 0.97 (3 H, s, t-CH₃), 0.85 [3 H, d, J = 6.8 Hz CH(CH ₃)₂], 0.83 [3 H, d, J = 6.8 Hz, CH(CH ₃)₂]. ^¹³C NMR (100 MHz, CDCl₃): δ = 209.2 (C, C=O), 174.5 (C, C-3), 139.4 (C, C-4), 52.6 (CH), 47.0 (CH), 46.1 (C), 42.9 (CH₂), 42.7 (CH₂), 42.4 (CH), 40.7 (CH₂), 39.2 (CH), 31.8 (CH₂), 28.2 (CH), 26.3 (CH₂), 25.1 (CH₃), 24.4 (CH₃), 23.9 (CH₂), 22.8 (CH₃), 20.0 (CH₃), 9.9 (CH₃). HRMS: m/z calcd for C₂₀H₃₂ONa [M + Na]: 311.2351; found: 311.2352.
Crystal Data for Norhydroxynorfusicoauritone (23a)
X-ray data were collected at 110 K on a SMART CCD-BRUKER diffractometer with graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). The structure was solved by direct methods (SIR 92). Refinement was by full-matrix least-squares procedures on F2 using SHELXL-97. The nonhydrogen atoms were refined anisotropically whereas hydrogen atoms were refined isotropically. C₁₉H₃₀O; MW = 274.43; colorless; crystal system: monoclinic; space group P21; cell parameters, a = 10.383 (2) Å, b = 6.2198 (6) Å, c = 13.4758 (19) Å; β = 111.238 (19)˚, V = 811.2 (2) Å^³, Z = 2, D _c = 1.124 g cm^-³, F(000) = 304, µ = 0.067 mm^-¹. Total number of l.s. parameters = 2853, R1 = 0.058 for 2290 I > 2σ(I) and 0.0762 for all data. wR2 = 0.126, GOF = 1.004, restrained GOF = 1.004 for all data. An ORTEP diagram is depicted in Figure  [²] . Crystallographic data has been deposited with Cambridge Crystallographic Data Centre (CCDC 838173).

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Found to contain variable amount of the 1,3-transposed allylic secondary alcohol (similar to 27).