Synthetic Studies toward a Biomimetic Linear Precursor of Hirsutellones

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.

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

References and Notes

1 Isaka M. Rugseree N. Maithip P. Kongsaeree P. Prabpai S. Thebtaranonth Y. Tetrahedron  2005,  61:  5577 

2 He H. Yang HY. Bigelis R. Solum EH. Greenstein M. Carter GT. Tetrahedron Lett.  2002,  43:  1633 

3 Shiono Y. Shimanuki K. Hiramatsu F. Koseki T. Tetsuya M. Fujisawa N. Kimura K. Bioorg. Med. Chem. Lett.  2008,  18:  6050 

4 Koizumi F, Hasegawa K, Ando K, Ogawa T, and Hara A. inventors; JP Patent  2001147574A2.  ; Chem. Abstr. 2001, 134, 666589

5a Total synthesis of hirsutellone B: Nicolaou KC. Sarlah D. Wu TR. Zhan W. Angew. Chem. Int. Ed.  2009,  48:  6870 

5b Synthesis of the decahydrofluorene core: Tilley SD. Reber KP. Sorensen EJ. Org. Lett.  2009,  11:  701 

5c Construction of the cyclophane core: Huang M. Song L. Liu B. Org. Lett.  2010,  12:  2504 

6 Oikawa H. J. Org. Chem.  2003,  68:  3552 

7 Nay B. Riache N. Evanno L. Nat. Prod. Rep.  2009,  26:  1044 

8 Riache N. Bailly C. Deville A. Dubost L. Nay B. Eur. J. Org. Chem.  2010,  5402 

9 Schlenk A. Schobert R. Chem. Eur. J.  2010,  16:  2599 

10 Khrimyan AP. Gharibyan OA. Streinz L. Wimmer Z. Romanuk M. Badanyan SO. Collect. Czech. Chem. Commun.  1989,  54:  3284 

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).

13 Similar products have been reported by Corey and Ruden with a propargylidene-phosphorus ylide in Wittig reactions: Corey EJ. Ruden RA. Tetrahedron Lett.  1973,  14:  1495 

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).

15 Boland W. Schroer N. Sieler C. Feigel M. Helv. Chim. Acta  1987,  70:  1025 

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).