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Synlett 2011(18): 2685-2688  
DOI: 10.1055/s-0031-1289534
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthetic Studies toward a Biomimetic Linear Precursor of Hirsutellones

Nassima Riache, Idrissa Ndoye, Xu-Wen Li, Bastien Nay*
Muséum National d’Histoire Naturelle, Unité Molécules de Communication et Adaptation des Microorganismes (UMR 7245 CNRS-MNHN), 57 Rue Cuvier (CP 54), 75005 Paris, France
Fax: +33(1)40793135; e-Mail: bnay@mnhn.fr;
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Publication History

Received 4 July 2011
Publication Date:
19 October 2011 (online)

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Abstract

In this paper we describe our efforts to synthesize the polyunsaturated part of a putative linear precursor of hirsutellones from (R)-citronellal, characterized by a terminal (E,Z,E)-triene alcohol. The geometry of this last moiety was installed by the alkyne reduction of an ene-yne-ene, under the Boland conditions [Zn(Ag,Cu), MeOH]. Under these conditions, we found that the presence of a diol functionality at the opposite of the linear chain, facing the alkyne, was necessary for the success of the reduction, an effect attributed to the chelation of an activated zinc species. Then one-pot diol cleavage-Wittig olefination allowed for further functionalization into a valuable α,β-unsaturated ester or Weinreb amide.

Key words

hirsutellones - biomimetic precursor - alkyne reduction - Boland conditions - one-pot reactions - reactivity

    References and Notes

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11

(-)-(6 R )-(3 E )-6,10-Dimethyl-1-(trimethylsilyl)undeca-3,9-dien-1-yne (8)
A 2.5 M solution of n-BuLi (650 µL, 1.23 mmol) in hexane was added dropwise over ca. 10 min at -78 ˚C to a solution of TMSCºCCH2PPh3Br (620 mg, 1.35 mmol) in dry THF (20 mL) under an argon atmosphere. After 20 min, a solution of (R)-citronellal (235 µL, 1.3 mmol) in dry THF (6 mL) was added dropwise over ca. 5 min at -78 ˚C. After 1 h stirring, the mixture was left to warm slowly until 0 ˚C. It was then filtered through a Celite pad and evaporated. The product was purified by silica gel chromatography (pentane), giving the enyne 8 as a colorless oil (268 mg, 87%). In this case, the cumulene 9 was not observed. ¹H NMR (300 MHz, CDCl3): δ = 0.19 [s, 9 H, (CH3)3Si], 0.89 (d, J = 6.6 Hz, 3H, 6-CH3), 1.11-1.22 (m, 1 H, 7-H), 1.30-1.38 (m, 1 H, 7-H), 1.50-1.90 (m, 1 H, 6-H), 1.61 [s, 3 H, C(CH3)2], 1.69 [s, 3 H, C(CH3)2], 1.91-2.02 (m, 3 H, 5-H, 8-H), 2.08-2.15 (m, 1 H, 5-H), 5.09 (t, J = 9.0 Hz, 1 H, 9-H), 5.50 (d, J = 15.9 Hz, 1 H, 3-H), 6.21 (dt, J = 15.9, 7.5 Hz, 1 H, 4-H); ¹³C NMR (75 MHz, CDCl3): δ = 0.0 [(CH3)3Si], 17.6/25.7 [C(CH3)2], 19.4 (6-CH3), 25.5 (C-7), 32.4 (C-6), 36.6 (C-8), 40.5 (C-5), 92.4 (C-1), 104.2 (C-2), 110.7 (C-3), 124.6 (C-9), 131.3 (C-10), 144.9 (C-4). HRMS (ESI+): m/z calcd for C16H29Si [M + H+]: 249.2033; found: 249.2024. IR (neat film on NaCl): ν = 2980, 2914, 2173, 2137, 1452, 1377, 1250, 1084, 957 cm-¹. [α]D ²5 -6
(c 0.3, MeOH).

12

(6 R )-6,10-Dimethylundeca-1,2,3,9-tetraene (9)
Unstable oily compound. ¹H NMR (300 MHz, CDCl3): δ = 0.96 (d, J = 6.7 Hz, 3 H, 6-CH3), 1.20-1.35 (m, 2 H, 7-H), 1.61 [s, 3 H, C(CH3)2], 1.69 [s, 3 H, C(CH3)2], 1.67-1.76 (m, 1 H, 6-H), 1.97-2.05 (m, 2 H, 8-H), 2.05-2.17 (m, 1 H, 5-H), 2.22-2.32 (m, 1 H, 5-H), 5.11-5.15 (m, 3 H, 1-H, 9-H), 5.67-5.78 (m, 1 H, 4-H). ¹³C NMR (75 MHz, CDCl3): δ = 17.6 [C(CH3)2], 19.5 (6-CH3), 25.5 (C-8), 25.7 [C(CH3)2], 32.8 (C-6), 36.6 (C-7), 40.6 (C-5), 90.1 (C-1), 112.4 (C-4), 124.6 (C-9), 131.3 (C-10), 162.1 (C-3), 169.0 (C-2).

14

(+)-(6 R )-9,10-Dihydroxy-6,10-dimethylundeca-3-en-1-yne (10)
A 1 M solution of TBAF in THF (270 µL, 0.27 mmol) was added at r.t. to a solution of enyne 8 (276 mg, 0.111 mmol) in DMF (1.6 mL). After 30 min, the reaction mixture was poured into a sat. aq NH4Cl solution and extracted three times with pentane. After evaporation, the organic extract was purified by silica gel chromatography(pentane), providing the desilylated enyne (193 mg) in 98% yield. A solution of this compound (60 mg, 0.34 mmol) in THF (3 mL) was added to a mixture of H2O (16 µL, 0.88 mmol) and a 2.5 wt% solution of OsO4 in t-BuOH (26 µL, 2.5 µmol) and NMO (45 mg, 0.38 mmol) in THF (1.5 mL). After 2 h, the mixture was diluted in H2O and extracted three times with Et2O. The organic extract was purified by silica gel chromatography (CH2Cl2-MeOH = 9:1), giving diol 10
(45 mg) in 63% yield, as a 1:1 mixture of diastereomers (colorless oil). ¹H NMR (300 MHz, CDCl3): δ = 0.91 [d, J = 6.5 Hz, 3H, 6-(CH3)], 1.17 [s, 3 H, C(CH3)2], 1.22 [s, 3 H, C(CH3)2], 1.32-1.65 (m, 3 H, 8-H, 6-H), 1.93-2.06 (m, 2 H, 7-H), 2.10-2.19 (m, 2 H, 5-H), 2.79 (s, 1 H, 1-H), 3.31-3.37 (m, 1 H, 9-H), 5.49 (d, J = 16.0 Hz, 1 H, 3-H), 6.24 (dt, J = 16.0, 7.4 Hz, 1 H, 4-H). ¹³C NMR (75 MHz, CDCl3): δ = 19.3/19.5 (6-CH3), 23.2 [C(CH3)2], 26.5 [C(CH3)2], 29.1/29.6 (C-8), 32.8/32.9 (C-6), 33.5/33.7 (C-7), 40.2/40.7 (C-5), 65.5 (C-2), 73.2 (C-10), 75.6 (C-1), 78.7/79.0 (C-9), 109.7 (C-3), 145.3 (C-4). HRMS (ESI+): m/z calcd for C13H2O2Na [M + Na+]: 233.1512; found: 233.1506. IR (neat film on NaCl): ν = 3410, 3314, 2955, 2928, 2870, 2859, 1717, 1670, 1458, 1381, 1161, 1068, 960 cm-¹. [α]D ²5 +6
(c 0.1, MeOH).

16

(-)-(9 R )-(2 E ,4 Z ,6 E )-1-[ tert -Butyl(dimethyl)silyloxy]-12,13-dihydroxy-9,13-dimethyltetradeca-2,4,6-triene (13) To a suspension of zinc pellets (1.2 g) in H2O (12 mL), preliminarily stirred for 15 min at r.t., was added Cu(OAc)2 (200 mg). After a further 15 min, AgNO3 (200 mg) was added, and the mixture was stirred vigorously for an additional 30 min. After removal of H2O, the solids were washed, under argon, successively with H2O (3 × 20 mL), MeOH (3 × 20 mL), acetone (3 × 20 mL), and Et2O (3 × 20 mL), furnishing the activated zinc according to Boland.¹5 MeOH (10 mL) and H2O (10 mL) were then added, followed by a solution of the dienyne 12 (78 mg, 0.21 mmol) in MeOH (1 mL). After 48 h stirring at 100 ˚C, the reaction mixture was filtered through a Celite pad. After dilution in H2O (30 mL), the solution was extracted with EtOAc (3 × 5mL). The crude extract was purified by silica gel chromatography (cyclohexane-EtOAc = 4:1), giving 40 mg of compound 13 as a colorless oil (51%). ¹H NMR (300 MHz, CDCl3): δ = 0.10 [s, 6 H, (CH3)2Si], 0.87-0.94 [m,
12 H, (CH3)3CSi, 9-CH3], 1.17-1.27 [m, 9 H, 10-H, 9-H, C(CH3)2], 1.50-1.76 (m, 2 H, 11-H), 1.95-2.08 (m, 1 H, 8-H), 2.11-2.22 (m, 1 H, 8-H), 3.34 (d, J = 8.5 Hz, 1 H, 12-H), 4.27 (d, J = 5.0 Hz, 2 H, 1-H), 5.66-5.81 (m, 2 H, 2-H, 7-H), 5.86-5.99 (m, 2 H, 4-H, 5-H), 6.46 (dd, J = 14.2, 10.1 Hz, 1 H, 6-H), 6.70 (dd, J = 14.7, 10.3 Hz, 1 H, 3-H). ¹³C NMR (75 MHz, CDCl3): δ = -5.3/-5.2 [(CH3)2Si], 18.4 [(CH3)3 CSi], 19.4/19.7 (9-CH3), 23.2 [C(CH3)2], 25.9 [(CH3)3CSi], 26.5 [C(CH3)2], 29.2 (C-11), 33.3/33.4 (C-9), 33.6/33.8 (C-10), 40.2/40.7 (C-8), 63.6 (C-1), 73.1 (C-13), 78.7/79.0 (C-12), 125.2 (C-3), 126.8 (C-4), 127.0 (C-6), 129.3 (C-5), 132.9 (C-2), 134.4 (C-7). HRMS (ESI+): m/z calcd for C22H42O3SiNa [M + Na+): 405.2795; found: 405.2810. IR (neat film on NaCl): ν = 3385, 2955, 2928, 2857, 1647, 1471, 1460, 1375, 1255 cm-¹. [α]D ²5 -1 (c 0.3, MeOH).

17

(-)-(6 R )-(2 E ,8 E ,10 Z ,12 E )-14-[ tert -Butyl(dimethyl)-silyloxy]tetradeca-2,8,10,12-tetraenoic Acid Methyl Ester (18)
Ph3P=CHCO2Me (17 mg, 0.05 mmol) was added at r.t. to a solution of diol 13 (9 mg, 0.023 mmol) in CH2Cl2 (0.5 mL). Three portions of activated MnO2 (41 mg each, Fluka 63548) were added over a period of 12 h. Then, 4 h after the last addition, the mixture was filtered through a pad of Celite. After evaporation, the crude extract was purified by silica gel chromatography (cyclohexane-EtOAc = 9:1), giving 4 mg of ester 18 as a colorless oil (46%). ¹H NMR (300 MHz, CDCl3): δ = 0.10 (s, 6 H, [CH3)2Si], 0.90 (s, 3 H, 6-CH3), 0.94 [m, 9 H, (CH3)3CSi], 1.44-1.79 (m, 3 H, 5-H, and 6-H), 1.95-2.30 (m, 4 H, 4-H and 7-H), 3.74 (s, 3 H, CO2CH3), 4.28 (d, J = 5.0 Hz, 2 H, 14-H), 5.64-5.76 (m, 2 H, 8-H, and 13-H), 5.83 (d, J = 16.8 Hz, 1 H, 2-H), 5.90-5.99 (m, 2 H, 10-H, and 11-H), 6.48 (dd, J = 15.2, 10.1 Hz, 1 H, 9-H), 6.71 (dd, J = 15.2, 9.5 Hz, 1 H, 12-H), 6.92-7.03 (m, 1 H, 3-H). ¹³C NMR (75 MHz, CDCl3): δ = -5.2 [CH3)2Si], 18.8 [(CH3)3 CSi], 19.3 (6-CH3), 25.9 [CH3)3CSi], 29.7 (C-4), 31.9 (C-6), 34.6 (C-5), 40.3 (C-7), 51.3 (CO2 CH3), 63.6 (C-14), 120.9 (C-2), 125.2 (C-12), 127.0 (C-11), 127.2 (C-9), 129.2 (C-10), 133.0 (C-13), 133.9 (C-8), 149.6 (C-3), 186.9 (CO2CH3). HRMS (ESI+): m/z calcd for C22H38O3Na [M + Na+]: 401.2482; found: 401.2491. IR (neat film on NaCl): ν = 2953, 2926, 2854, 1728, 1659, 1464, 1437, 1377, 1257, 1167 cm-¹. [α]D ²5 -7 (c 0.15, MeOH).