Synthesis of helianane, an unusual marine sesquiterpene employing ring-expansion by flash vacuum thermolysis

Article abstract of DOI:10.1016/j.tetlet.2004.10.101

A total synthesis of the marine sesquiterpene helianane 1 is described involving the thermal rearrangement of the benzoxabicyclo[4.2.0]octenone 4 to generate the dienone 5 incorporating the benzoxocane ring system of 1. This dienone was converted to the k

Full text of DOI:10.1016/j.tetlet.2004.10.101

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9653–9655
Synthesis of helianane, an unusual marine sesquiterpene
employing ring-expansion by flash vacuum thermolysis
Subir K. Sabui and Ramanathapuram V. Venkateswaran*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 5 August 2004; revised 15 October 2004; accepted 19 October 2004
Available online 11 November 2004
This paper is respectfully dedicated to Professor G. Mehta for his varied and innovative contributions to organic synthesis
Abstract—A total synthesis of the marine sesquiterpene helianane 1 is described involving the thermal rearrangement of
the benzoxabicyclo[4.2.0]octenone 4 to generate the dienone 5 incorporating the benzoxocane ring system of 1. This dienone was
converted to the key ketone 11, which on interaction with methylmagnesium iodide followed by hydrogenation of the resulting
alkene 18 furnished helianane 1.
Ó 2004 Elsevier Ltd. All rights reserved.
Helianane 1, a novel heterocyclic sesquiterpene, was
isolated from the marine sponge Haliclona fascigera.1
tion could not be achieved. Herein we report an alterna-
tive synthesis of this unusual sesquiterpene.
It contains
a benzoxocane ring system, hitherto
unprecedented in marine natural products. Its closest
ally, the sesquiterpene heliannuol A 2, was isolated from
the plant species Helianthus annus and possesses
the same ring system with two additional hydroxy
groups. Heliannuol A displays significant allelopathic
activity.2 Besides the difference in their source, 1 and 2
also differ in respect of the absolute stereochemistry
at the methyl bearing carbon atom, being S in 1 and R
in 2.
Central to the synthetic design was the thermal rear-
rangement of a benzoxabicylo[4.2.0]octenone 4 to gener-
ate the oxacyclic system. Tricyclic ketone 4 was expected
to give the benzoxocene ring system 5. Saturation of the
olefinic bonds, conversion of the ester functionality to a
gem-dimethyl group and transformation of the carbonyl
function to a methyl group was expected to lead to
helianane 1. The realisation of the above strategy is pre-
sented here.
A synthesis of 1, employing ring-closing metathesis to
generate the oxacyclic eight-membered ring, has been re-
ported.3 We disclose here a synthesis of 1, wherein the
oxocane ring has been developed through a thermal
rearrangement of an oxabicyclo[4.2.0] octene system.
In connection with our previous efforts towards the syn-
thesis of heliannuol A,4 the benzoxocane ring was gener-
ated through ring expansion involving cleavage of the
central bond in a cyclopropane fused seven-membered
ring. We had also synthesised 4-deoxyheliannuol A by
this method,4 hoping to convert this to helianane
through deoxygenation. In the event that transforma-
Photolytic addition of acetylene to 2-ethoxycarbonyl-7-
methyl chromone 35 furnished the required tricyclic
keto-ester 4 in 80% yield. Ring expansion of this keto-
ester was achieved by flash vacuum thermolysis (FVT)
at 520°C at 0.01mmHg and afforded the expected
di-enone 5 in an excellent yield (95%) (Scheme 1).6
Exhaustive hydrogenation of 5 resulted in saturation of
the double bonds and reduction of the ketone to furnish
benzoxocane ester 6 in 94% yield. Reaction of this ester
with methyl iodide in the presence of LDA afforded the
gem-methyl carboxylate 76 in excellent yield (90%). Next
the ester function in 7 was reduced with lithium alumin-
ium hydride in refluxing THF to alcohol 8 in 88%. Con-
version to tosylate 9 and hydride displacement with
sodium cyanoborohydride in HMPA led to the forma-
tion of the benzoxocane 106 in an overall yield of 67%
from the alcohol 8. Benzylic oxidation to benzoxocanone
Keywords: Helianane; Benzoxocane ring system; Flash vacuum
thermolysis.
*
Corresponding author. Tel.: +91 33 24734971; fax: +91 33
24732805; e-mail: ocrvv@mahendra.iacs.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.101

9654
S. K. Sabui, R. V. Venkateswaran / Tetrahedron Letters 45 (2004) 9653–9655
OMOM
O
HO
HO
i
ii
OH
5
O
O
O
1
2
CO2Et
13
12
CO2Et
O
O
O
H
iii
i
OMOM
O
OMOM
O
CO2Et
CO Et
2
4
iv
3
ii
O
O
R
14
CO2Et
15 R = OH
16 R = OTs
17 R = H
v
vi
O
CO Et
2
5
vii
O
Scheme 1. Reagents and conditions: (i) hm, acetylene, acetone, 10h,
80%; (ii) 520°C, 0.01mmHg pressure, 95%.
viii
11,6 proceeded sluggishly in a low yield of 18%
(Scheme 2).
O
O
18
11
ix
An alternative higher yielding method for the synthesis
of 11 involved controlled hydrogenation of 5, which re-
sulted in saturation of the double bonds and reduction
of the ketone giving hydroxy-ester 12 as a mixture of
isomers in 87% yield. Protection of the hydroxy function
as the MOM ether 13 was readily achieved in excellent
yield (95%) through condensation with chloromethyl
methyl ether. Alkylation with methyl iodide in the pres-
ence of LDA furnished the methylated carboxylate 14
(87%), which was reduced to the alcohol 15 (85%) with
lithium aluminium hydride. Conversion to the corre-
sponding tosylate 16 (95%) and displacement with so-
dium cyanoborohydride afforded 176 in 68% yield.
Finally, cleavage of the MOM protecting group with
dimethyl sulfide and BF3ÆEt2O, followed by Jonesꢀ
oxidation of the resultant alcohol, delivered the
benzoxocanone 11 in a yield of 60% from 17 (Scheme 3).
1
Scheme 3. Reagents and conditions: (i) H2, Pd–C (10%), ethanol, 3h,
87%; (ii) MOMCl, i-Pr2NH, DCM, 14h, 95%; (iii) LDA, THF, À78°C
to rt, HMPA, CH3I, 6h, 87%; (iv) LiAlH4, THF, 5h, 85%; (v) p-TsCl,
Py, DMAP, 26h, 95%; (vi) NaBH3CN, HMPA, 130°C, 26h, 68%; (vii)
(CH3)2S, BF3ÆEt2O, À10°C, 2h; Jonesꢀ oxidation, 60% (two steps);
(viii) CH3MgI, ether, reflux, 3h, 96%; (ix) H2, Pd–C (10%), ethanol,
4h, 95%.
With the key benzoxocanone in hand, it only remained
to incorporate a methyl group on the carbonyl carbon
to complete the synthesis of 1. Treatment of ketone 11
with methylmagnesium iodide in refluxing ether pro-
duced the exo-methylene derivative 186 in 96% yield
(Scheme 3). This olefin underwent facile hydrogenation
in excellent yield to furnish helianane 1, whose spectral
features (1H NMR) were consistent with those made
available to us.
i
5
O
In summary we have described a synthesis of helianane,
a sesquiterpene with an unusual bicyclic skeleton
employing flash vacuum thermolysis to generate the
eight-membered oxacyclic ring.
6
CO2Et
ii
iii
Acknowledgements
O
O
CO2Et
R
7
8 R = OH
9 R = OTs
We sincerely thank Professor V. Snieckus for providing
us with a copy of the 1H NMR spectrum of his synthetic
helianane.
iv
v
O
vi
References and notes
O
O
1. Harrison, B.; Crews, P. J. Org. Chem. 1997, 62, 2646–
2648.
10
11
Scheme 2. Reagents and conditions: (i) H2, Pd–C (10%), ethanol, 6h,
94%; (ii) LDA, THF, À78°C to rt, HMPA, CH3I, 5h, 90%; (iii)
LiAlH4, THF, reflux, 88%; (iv) p-TsCl, Py, DMAP, 24h, 96%; (v)
NaBH3CN, HMPA, 130°C, 24h, 70%; (vi) CrO3, glacial CH3COOH,
H2O, 5h, 18%.
2. Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M.
G.; Fronzek, F. R. Tetrahedron Lett. 1993, 34, 1999–
2002.
3. Stefinovic, M.; Snieckus, V. J. Org. Chem. 1998, 63, 2808–
2809.

S. K. Sabui, R. V. Venkateswaran / Tetrahedron Letters 45 (2004) 9653–9655
9655
4. Tuhina, K.; Bhowmik, D. R.; Venkateswaran, R. V. Chem.
Commun. 2002, 634–635.
124.7, 125.9, 130.0, 135.7, 140.3, 152.9; Anal. Calcd for
C14H20O: C, 82.35; H, 9.80. Found: C, 82.13; H, 9.51. For
1
5. Sabui, S. K.; Mondal, P.; Venkateswaran, R. V. J. Chem.
Res. (S) 2002, 428–429.
6. Spectral, analytical data of 5, 7, 10, 11, 17, 18. For 5: IR
11: IR (CHCl3) 1668cmÀ1; H NMR (300MHz, CDCl3) d
1.36 (br s, 6H), 1.41–1.57 (m, 4H), 1.88–1.94 (m, 2H), 2.36
(s, 3H), 6.82 (s, 1H), 7.01 (d, J 8.0Hz, 1H), 7.95 (d, J
8.0Hz, 1H); 13C NMR (75MHz, CDCl3) d 20.7, 21.3, 26.8,
29.5, 32.7, 39.9, 80.5, 125.1, 127.8, 129.4, 131.1, 145.1,
155.2, 200.7; Anal. Calcd for C14H18O2: C, 77.06; H, 8.25.
Found: C, 76.83; H, 7.92. For 17: 1H NMR (300MHz,
CDCl3) d 1.28 (s, 3H), 1.35–1.55 (m, 3H), 1.44 (s, 3H),
1.59–1.75 (m, 2H), 2.13–2.19 (m, 1H), 2.31 (s, 3H), 3.38 (s,
3H), 4.55 (ABq, J 6.5Hz, 2H), 4.97 (dd, J 2.8, 10.4Hz, 1H),
6.74 (s, 1H), 6.97 (d, J 7.7Hz, 1H), 7.31 (d, J 7.8Hz, 1H);
13C NMR (75MHz, CDCl3) d 20.1, 21.4, 27.6, 28.8, 38.0,
38.7, 55.9, 73.9, 81.8, 94.9, 125.5 (2C), 126.0, 135.2, 137.2,
152.6; Anal. Calcd for C16H24O3: C, 72.72; H, 9.09. Found:
C, 72.33; H,8.85. For 18: 1H NMR (300MHz, CDCl3) d
1.30 (s, 6H), 1.38–1.56 (m, 2H), 1.75–1.84 (m, 2H), 2.29 (s,
3H),2.81 (t, J 6.5Hz, 2H), 4.92 (s, 1H), 5.42 (s, 1H), 6.72 (s,
1H), 6.88 (d, J 8.0Hz, 1H), 7.48 (d, J 8.0Hz, 1H); 13C
NMR (75MHz, CDCl3) d 21.1, 26.6, 27.7 (2C), 33.7, 34.1,
81.2, 113.0, 125.6, 127.4, 128.2, 129.9, 138.5, 147.4, 152.2;
Anal. Calcd for C15H20O: C, 83.33; H, 9.25. Found: C,
83.03; H, 8.91.
1
(CHCl3) 1641cmÀ1; H NMR (300MHz, CDCl3) d 1.37 (t,
J 7.2Hz, 3H), 2.40 (s, 3H), 4.32 (q, J 7.2Hz, 2H), 6.45 (m,
2H), 6.96 (d, J 5.4Hz, 1H), 7.10 (d, J 7.8Hz, 1H), 7.44 (s,
1H), 7.81 (d, J 8.1Hz, 1H); 13C NMR (75MHz, CDCl3) d
14.6, 21.8, 62.3, 124.4, 124.5, 127.5, 128.1, 129.1, 132.0,
134.9, 146.5, 149.1, 158.7, 162.6, 191.2; Anal. Calcd for
C15H14O4: C, 69.76; H, 5.42. Found: C, 69.73; H, 5.38. For
1
7: IR (CHCl3) 1745cmÀ1; H NMR (300MHz, CDCl3) d
1.33 (t, J 7.1Hz, 3H), 1.40–1.49 (m, 2H), 1.55 (s, 3H), 1.69–
1.93 (m, 4H), 2.27 (s, 3H), 2.53–2.60 (m, 1H), 2.74–2.82 (m,
1H), 4.29 (q, J 7.1Hz, 2H), 6.77 (s, 1H), 6.85 (d, J 7.3Hz,
1H), 6.99 (d, J 7.5Hz, 1H); 13C NMR (75MHz, CDCl3) d
14.1, 20.8, 24.4, 24.8, 30.8, 31.3, 33.6, 61.0, 85.3, 125.2,
125.5, 130.0,135.2, 136.1, 151.9, 173.6; Anal. Calcd for
C16H22O3: C, 73.28; H, 8.39. Found: C, 72.95; H, 8.03. For
1
10: H NMR (300MHz, CDCl3) d 1.29 (s, 6H), 1.42–1.49
(m, 2H), 1.51–1.61 (m, 4H), 2.12 (s, 3H), 2.58–2.65 (m, 2H),
6.65 (s, 1H), 6.79 (m, 1H), 6.93 (d, J 3.0Hz, 1H); 13C NMR
(75MHz) d 20.9, 23.4, 27.6, 27.7, 31.1, 31.2, 37.4, 80.9,