Supplementary Material (ESI) for Chemical Communications
This journal is © The Royal Society of Chemistry 2002
Supplementary Information
First total synthesis of the marine illudalane sesquiterpenoid alcyopterosin E
Bernhard Witulski,* Axel Zimmermann and Nicholas D. Gowans
Fachbereich Chemie, Universität Kaiserslautern, Erwin-Schrödinger-Strasse, D-67663 Kaiserslautern,
Germany. Fax: + 49 631 205 3921; Tel: + 49 205 2032; E-mail: witulski@rhrk.uni-kl.de
General. All reactions were performed under an atmosphere of dry argon. Commercially available reagents were
used without further purification; solvents and gases were dried by standard procedures. Infra-red spectra were
recorded in the range 4000–600 cm-1 on a Perkin–Elmer 1000 series FTIR spectrometer. NMR spectra were
recorded using a Bruker DPX 400 instrument operating at 400 MHz for 1H spectra and 100 MHz for 13C spectra;
J values were recorded in Hz. Low resolution mass spectra were determined using a Finnigan MAT 95 instrument using electron impact ionisation (EI). Microanalyses were recorded using a Perkin–Elmer 240C
Elemental Analyser.
(4,4-Dimethyl-hepta-1,6-diynyl)-dimethyl-phenyl-silane (6)
To a stirred solution of diisopropylamine (3.3 mL, 2.40 g, 24.8 mmol) in dry THF (40 mL) was added n-BuLi
(15.2 mL of a 1.6 M hexane solution) at –78 °C. The solution was brought to 0 °C and stirred for 20 min before
being cooled to –78 °C. Chlorodimethyl(phenyl)silane (3.8 mL, 4.30 g, 24.7 mmol) was added and the solution
was stirred for 20 min before ketone 5 (1.43 g, 10.4 mmol) in dry THF (10 mL) was added. The reaction mixture
was stirred for further 60 min at –78 °C before being allowed to warm to room temperature. The reaction was
quenched by stirring overnight with dilute sulfuric acid (40 mL of a 1.8 M solution in water). The reaction
mixture was extracted with diethyl ether (3 x 40 mL), the organic extracts were combined, washed with water (3
x 40 mL), saturated sodium hydrogen carbonate solution (3 x 40 mL), brine and then dried with MgSO 4 and
evaporated under reduced pressure. The residue was chromatographed (SiO2, hexanes:diethyl ether; 9:1 (v/v)) to
give 2.77 g (98%) of the corresponding silyl protected compound.
Lithiumdiisopropylamine (LDA) was prepared as before with diisopropylamine (0.75 g, 7.45 mmol) and n-BuLi
(5 mL of a 1.6 M hexane solution) in dry THF (12 mL). The silyl protected compound as received above (1.45 g,
5.32 mmol) in dry THF (6 mL) was added to the LDA solution at –78 °C. After 15 min diethyl chlorophosphate
(0.92 mL, 1.10 g, 6.39 mmol) was added and the solution was stirred at room temperature for 2.5 h before being
cooled down to –78 °C. This solution was then transferred by cannula to lithiumdiisopropylamide freshly
prepared from diisopropylamine (1.72 mL, 1.24 g, 12.24 mmol) and n-BuLi (8 mL of a 1.6 M hexane solution)
in dry THF (15 mL). The resulting mixture was allowed to warm to room temperature overnight, quenched with
water (20 mL) and extracted with diethyl ether (3 x 20 mL). The organic extracts were combined, washed with
cold hydrochloric acid (25 mL of a 1 M water solution), water (3 x 15 mL) and saturated sodium hydrogen carbonate solution (3 x 20 mL), dried with MgSO4 and concentrated under reduced pressure. Subsequent
chromatography (SiO2, hexanes:diethyl ether; 8:2 (v/v)) gave diyne 6 as a colourless oil (0.95 g, 70%).
H NMR (400 MHz, CDCl3): δ 0.39 (s, 6H), 1.08 (s, 6 H), 2.00 (t, J = 2.6 Hz, 1H), 2.21 (d, J = 2.6 Hz, 2H), 2.29
(s, 2H), 7.35 - 7.37 (m, 3H), 7.62 - 7.64 (m, 2H); 13C NMR (100 MHz, CDCl3): δ –0.6 (CH3), 26.3 (2 x CH3),
1
31.0 (CH2), 32.4 (CH2), 33.9 (Cq), 70.3 (Cq), 81.9 (CH), 84.7 (Cq), 106.7 (Cq), 127.8 (CH), 129.2 (CH), 133.6
(CH), 137.6 (Cq); IR (neat): νmax(film)/cm-1 3304, 2174, 2115, 1250, 1115, 817.
5,5-Dimethyl-octa-2,7-diynoic acid (7):
Diyne 6 (1.0 g, 3.93 mmol) was dissolved in dry THF (15 mL) and the solution was cooled to –78 °C. After
addition of n-BuLi (6.4 mL of a 1.6 M solution in n-hexane solution) stirring was continued for further 20 min.
Supplementary Material (ESI) for Chemical Communications
This journal is © The Royal Society of Chemistry 2002
The reaction mixture was then warmed to –40°C and dry carbon dioxide was bubbled through the solution until
TLC showed completion of the reaction. The reaction was quenched by pouring over crushed dry ice. The
solution was acidified to pH 3 – 5 with 1 M hydrochloric acid and then extracted with ether (3 x 15 mL). The
combined organic layers were washed with brine, dried with MgSO 4 and concentrated to give the corresponding
acid as an oil (1.04 g, 3.49 mmol, 89%).
To a stirred solution of this acid (0.10 g, 0.34 mmol) in dry THF (3 mL) was added tetrabutylammonium fluoride
(0.53 mL of a 1 M THF solution) at 0 °C. After 1 hour the reaction was quenched with 10 mL of 0.5 M HCl and
extracted with ether (3 x 10 mL). The organic layers were washed with 0.5 M HCl (2 x 10 mL), dried with
MgSO4 and concentrated to give diyne acid 7 as an oil (54 mg, 94%). 1H NMR (400 MHz, CDCl3): δ 1.11 (s, 6
H), 2.03 (t, J = 2.7 Hz, 1H), 2.22 (d, J = 2.8 Hz, 2H), 2.40 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 26.4 (2 x
CH3), 30.9 (CH2), 31.2 (CH2), 34.1 (Cq), 70.8 (Cq), 74.6 (Cq), 81.1 (CH), 89.7 (Cq), 157.8 (Cq); IR (neat):
νmax/cm-1 = 3301, 2237, 1694.
(R)-Pent-3-yne-1,2-diol (9):
Dry dichloromethane (100 mL) was purged with argon for 15 min before CBr 4 (6.3 g, 18.9 mmol) was added. To
this solution triphenylphosphine (4.9 g, 18.8 mmol) was added slowly. The resulting orange solution was cooled
to 0 °C before Zn dust (1.28 g, 20.1 mmol) was added in small portions. Then the mixture was stirred for 48 h
and a colour change from green to light tan was observed. Glyceraldehyde acetonide (S)-8 (1.35 g, 10.3 mmol)
(freshly prepared from ascorbic acid) in CH 2Cl2 (10 mL) was added dropwise to the above mixture. After being
stirred for 2 h, the reaction mixture was poured into hexanes (300 mL). The mixture was filtered over silica gel
and the solvent was removed. Subsequent chromatography (SiO 2, hexanes: diethyl ether, 12:1 (v/v)) afforded the
corresponding dibromoalkene (1.8 g, 6.29 mmol, 61% yield) which was then dissolved in dry THF (10 mL). The
solution was cooled to –78 °C before n-BuLi (12 mL of 1.6 M hexane solution) was added. The reaction mixture
was brought to -20 °C over 3 h before methyl iodide (4.89 g, 35 mmol) was added. The reaction mixture was
brought to room temperature, stirred overnight and then quenched with saturated NH 4Cl solution (2 mL) and
extracted with diethyl ether (5 x 10 mL). The organic fractions were combined, dried with MgSO4 and
concentrated under reduced pressure. Subsequent chromatography (SiO 2, pentane:diethyl ether; 8:2 (v/v))
afforded the protected diol which was immediately dissolved in dry methanol (10 mL). After addition of toluene4-sulfonic acid monohydrate (15 mg) the mixture was stirred for 24 h. The solvent was removed and the crude
residue was purified by chromatography (SiO2, hexanes:diethyl ether; 1:1 (v/v)) and gave diol (R)-9 as a
colourless powder (618 mg, 60%). [α]D22 –9.4 (c 1.0, CHCl3); M.p. 96–98 °C; 1H NMR (400 MHz, CDCl3): δ
1.88 (d, J = 2.1 Hz, 3H), 4.58 (br s, 2H), 4.68 - 4.82 (m, 2H), 5.49 - 5.54 (m, 1H); 13C NMR (100 MHz, CDCl3):
δ 3.4 (CH3), 63.3 (CH), 66.6 (CH2), 77.0 (Cq), 82.4 (Cq). IR (neat): νmax/cm-1 = 3193, 2931, 1455, 1376. Anal.
Calcd. for C5H8O2: C, 59.98; H, 8.01. Found: C, 59.98; H, 8.05.
(R)-Toluene-4-sulfonic acid 2-hydroxy-pent-3-ynyl ester (10):
(R)-9 (220 mg, 2.20 mmol) was dissolved in pyridine/dichloromethane (9:5, 5 mL) and cooled to 0 °C. After
addition of 1.2 equiv. of p-toluenesulfonyl chloride (511 mg, 2.68 mmol) the reaction was stirred for further 6 h
at 0 °C then another 16 h at room temperature. Evaporation of the pyridine/dichloromethane solvent mixture
under vacuum followed by chromatography (SiO2, hexanes:diethyl ether; 7:3 (v/v)) afforded alcohol (R)-10 as an
oil (385 mg, 69%). [α]D22 –16.4 (c 0.2, CHCl3); 1H NMR (200 MHz, CDCl3): δ 1.79 (d, J = 2.2 Hz, 3H), 2.44 (s,
3H), 3.99 (dd, J = 7.2 and 10.2 Hz, 1H), 4.10 (dd, J = 3.8 and 10.2 Hz, 1H), 4.51 - 4.60 (m, 1H), 7.35 (d, J = 8.0
Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H); 13C NMR (50 MHz, CDCl3): δ 3.4 (CH3), 21.5 (CH3), 60.6 (CH), 72.6 (CH2),
75.1 (CH), 83.4 (Cq), 127.9 (CH), 129.8 (CH), 132.4 (CH), 145.0 (C q); MS (EI, 70 eV); m/z (%): 254 (M +, 7),
149 (26), 57 (38), 32 (100).
Supplementary Material (ESI) for Chemical Communications
This journal is © The Royal Society of Chemistry 2002
(R)-5,5-Dimethyl-nona-2,7-diynoic acid 1-(toluene-4-sulfonyloxymethyl)-prop-2-ynyl ester (11):
Propargylic alcohol (R)-10 (360 mg, 1.42 mmol) and acid 7 (380 mg, 2.30 mmol) were dissolved in dry
dichloromethane (4 mL). After addition of a catalytic amount of 4-dimethyl-aminopyridine (12 mg, 0.10 mmol)
the solution was cooled to -78 °C before solid dicyclohexyl carbodiimide (480 mg, 2.30 mmol) was added at
once. The reaction was stirred for further 60 minutes at -78 °C before it was allowed to warm to room
temperature overnight. The reaction mixture was then quenched by filtration over SiO 2. After concentration
under reduced pressure the residue was chromatographed (SiO 2, hexanes:diethyl ether; 10:1 (v/v)) to give ester
(R)-11 as an oil (397 mg, 70%). (R)-11 [α]D22 –13.6 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.04 (s, 6
H), 1.74 (d, J = 2.0 Hz, 3H), 1.97 (t, J = 2.6 Hz, 1H), 2.14 (d, J = 2.6 Hz, 2H), 2.31 (br s, 2 H), 2.39 (br s, 3H),
4.16 - 4.21 (m, 2H), 5.46 - 5.55 (m, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.4 Hz,
2H); 13C NMR (100 MHz, CDCl3): δ 3.6 (CH3), 21.6 (CH3), 26.4 (2 x CH3), 30.9 (CH2), 31.2 (CH2), 34.1 (Cq),
63.0 (CH), 69.1 (CH2), 70.9 (Cq), 71.3 (Cq), 74.2 (Cq), 81.2 (Cq), 85.2 (Cq), 88.8 (Cq), 128.0 (CH), 129.9 (CH),
132.6 (CH), 145.1 (Cq), 152.4 (Cq); MS (EI, 70 eV); m/z (%): 400 (M+, 5), 215 (10), 91 (18), 85 (80), 57 (100);
IR (neat): νmax(film)/cm-1 2954, 2359, 2256, 1766, 1598, 1287.
(R)-Toluene-4-sulfonic acid 5,7,7-trimethyl-1-oxo-3,6,7,8-tetrahydro-1H-indeno[4,5-c]furan-3-ylmethyl
ester (12):
A solution of ester (R)-11 (128 mg, 0.32 mmol) in dry dichloromethane (8 mL) was purged with argon for 15
min. After addition of 10 mol% of [RhCl(PPh3)3] (29 mg, 0.032 mmol) the reaction was stirred for 24 h at 40 °C.
The reaction mixture was quenched by filtering through a plug of silica gel and rinsed twice with
dichloromethane (2 x 15 mL). Subsequent chromatography (SiO 2, hexanes:diethylether, 7:3 (v/v)) afforded (R)12 as a white powder (91 mg, 71%). M.p. 80–82 °C; (R)-12 [α]D22 –89.2 (c 1.00, CHCl3); 1H NMR (400 MHz,
CDCl3): δ 1.14 (s, 3 H), 1.19 (s, 3 H), 2.31 (s, 3 H), 2.45 (s, 3 H), 2.74 (d, J = 3.6 Hz, 2H), 2.99 (br s, 2H), 4.25
(dd, J = 5.4 and 11.5 Hz, 1H), 4.57 (dd, J = 2.4 and 11.5 Hz, 1H), 5.56 (dd, J = 1.9 and 5.2 Hz, 1H), 7.22 (br s,
1H), 7.33 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 17.9 (CH3), 21.6 (CH3),
28.7 (2 x CH3), 40.9 (Cq), 44.7 (CH2), 47.0 (CH2), 68.2 (CH2), 78.1 (CH), 122.4 (Cq), 127.9 (CH), 129.9 (CH),
130.2 (Cq), 131.9 (CH), 132.3 (Cq), 140.7 (Cq), 141.3 (Cq), 145.2 (Cq), 147.3 (Cq), 169.8 (Cq); MS (EI, 70 eV);
m/z (%): 400 (M+, 14), 279 (48), 167 (89), 149 (100), 113 (24). Anal. Calcd. for C 22H24O5S: C, 65.98; H, 6.04.
Found: C, 66.10; H, 6.17.
Compound (S)-12 was prepared following the same procedure: [α]D22 +90.3 (c 1.00, CHCl3).
Alcyopterosine E (1):
To a stirred solution of (R)-12 (58 mg, 0.15 mmol) in dry toluene (5 mL) were added NaNO 3 (123 mg, 1.45
mmol) and tetrabutyl ammonium nitrate (228 mg, 0.75 mmol). The reaction mixture was heated to 110 °C for 5
h. Filtration and subsequent flash chromatography gave Alcyopterosine E (R)-1 (31 mg, 69%) as a colourless oil.
[α]D25 –30.5 (c 2.35, CHCl3); 1H NMR (400 MHz, CDCl3): δ 1.16 (s, 3H), 1.19 (s, 3H), 2.40 (s, 3H), 2.75 (br s,
2H), 3.04 (br s, 2H), 4.57 (dd, J = 6.8 and 12.7 Hz, 1H), 5.06 (dd, J = 2.2 and 12.6 Hz, 1H), 5.66 (dd, J = 2.2 and
6.8 Hz, 1H), 7.27 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 18.0 (CH3), 28.7 (2 x CH3), 41.0 (Cq), 169.7 (Cq),
147.6 (Cq), 141.8 (Cq), 140.5 (Cq), 132.1 (CH), 130.2 (Cq), 122.3 (Cq), 76.9 (CH2), 71.6 (CH), 47.0 (CH2), 44.7
(CH2); MS (EI, 70 eV); m/z (%): 291 (M+, 8), 215 (100), 84 (21), 49 (23); IR (neat): ν max/cm-1 = 2955, 1767,
1642, 1277.
Non-natural (S)-alcyopterosin E was prepared by the same procedure.
(S)-1: [α]D25 + 31.1 (c 2.35, CHCl3).