Expeditious synthesis of helianane and C-10 halogenated heliananes employing ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2009.06.001

An expeditious synthesis of the marine sesquiterpene helianane enclosing an unusual benzoxocane ring system is described employing ring-closing metathesis as the key step. Helianane has been further converted to the naturally occurring C-10 bromo and chlo

Full text of DOI:10.1016/j.tetlet.2009.06.001

Tetrahedron Letters 50 (2009) 4683–4684
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Tetrahedron Letters
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Expeditious synthesis of helianane and C-10 halogenated heliananes employing
ring-closing metathesis
*
Subir Sabui, Subrata Ghosh, Debayan Sarkar, Ramanathapuram V. Venkateswaran
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An expeditious synthesis of the marine sesquiterpene helianane enclosing an unusual benzoxocane ring
system is described employing ring-closing metathesis as the key step. Helianane has been further con-
verted to the naturally occurring C-10 bromo and chloro derivatives.
Received 7 May 2009
Revised 29 May 2009
Accepted 2 June 2009
Available online 6 June 2009
Ó 2009 Published by Elsevier Ltd.
Keywords:
Helianane
Benzoxocane ring system
Ring-closing metathesis
Helianane 1, an atypical sesquiterpene enclosing a benzoxocane
ring system was isolated from the marine sponge Haliclona
fascigera.1 This is the only aromatic bisabolene structural type to
have been found in marine source. Its closest ally, the allelopathic
sesquiterpene heliannuol A 2, has its origin in the plant species
Helianthus annus.2 Recently 1, along with two halogenated variants
3 and 4, was isolated from another marine sponge Spirastrella
hartmani.3 Although 1 itself is devoid of any biological profile,
the chlorohelianane 4 has been reported to display in vitro activity
against selected human tumour cell lines.
In the event, treatment of this diene with Grubbs 2nd generation
catalyst ‘A’ resulted in the expected cyclisation to afford the
benzoxocene ester 86 in moderate yield (50%), along with the cross-
metathesis product 9 in varying yields. Varying the reaction condi-
tions by further dilution did not improve the yield of 8. Catalytic
hydrogenation of 8 furnished the benzoxocane carboxylate 106 as a
mixture of diastereomers in near quantitative yield. (Scheme 1).
In view of the poor yield in the crucial cyclisation step, an
alternate scheme was fashioned which would lead to a less encum-
bered diene with the possibility of a better yield during the RCM
protocol. This started with the m-cresyl crotyl ether which was
subjected to a Claisen rearrangement employing stannic chloride
as the catalyst following our previously reported conditions7 to
furnish the rearranged styrenol 12 in 80% yield. This was alkylated
The uncommon structural motif present in 1 has been the
subject of synthetic investigations. Snieckus et al. synthesised 1
by generating the eight-membered oxacyclic ring employing
ring-closing metathesis.4a Their method however, involved multi-
step sequences and difficult reaction conditions, not always
accompanied by good yields. Our own various syntheses of 1 had
featured, as the key steps, a FVP ring expansion, selective cleavage
of a cyclopropyl carbinyl radical and application of the Bargellini
condensation.4b–d In view of the current interest in the structure
of 1, arising from the biological activity displayed by chlorohelian-
ane 4, we have devised an expeditious and high yield synthesis of
1, 3 and 4 and present here the details of this investigation.
with ethyl a-bromopropionate and the resultant phenoxy ester 13
was subjected to a further alkylation with allyl bromide in the
presence of LDA to furnish the diene 14 in 80% yield. Ring-closing
metathesis of this diene employing catalyst ‘A’ afforded the ben-
zoxocene carboxylate 156 as a mixture of diastereomers in 90%
yield, which was separable by chromatography. However, further
transformations were carried out with the mixture since separa-
tion was irrelevant in the subsequent reactions. Catalytic hydroge-
nation of 15 yielded the same benzoxocane carboxylate 10 in
almost quantitative yield (Scheme 2).
No attempt was made to effect the separation of the diastereo-
mers in 10 since the next step required the conversion of the ester
functionality to a methyl group to complete the synthesis. This was
carried out as reported in our earlier synthesis of 1.4b Thus, lithium
aluminium hydride reduction of 10 proceeded to afford the alcohol
16 (88%) which was converted to the tosylate 17 (91%) by interac-
tion with toluene-p-sulfonyl chloride. Finally, reduction of 17 with
Alkylation of the styrenol 55 with ethyl
a-bromopropionate in the
presence of potassium carbonate in refluxing acetone furnished the
phenoxy ester 6 in 90% yield. Further alkylation of this ester with
1-bromo-3-butene employing LDA as the base delivered the diene 7
in 80% yield, which was properly set up for ring-closing metathesis.
* Corresponding author. Tel.: +91 33 24734971; fax: +91 33 24732805.
E-mail addresses: ocrvv@iacs.res.in, drvenkatesh46@yahoo.com (R.V. Venkates-
waran).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.06.001

4684
S. Sabui et al. / Tetrahedron Letters 50 (2009) 4683–4684
HO
R
R
a
c
10
R
O
O
OH
O
O
R = H 1
R = Br 3
R = Cl 4
R = OH 16
R = OTs 17
2
d
e
1 R = H
3 R = Br
4 R = Cl
b
Scheme 3. Reagents and conditions: (a) LiAlH4, THF, reflux, 5 h, 88%; (b) p-TsCl, Py,
DMAP, 22 h, 91%; (c) NaBH3CN, HMPA, 130 °C, 20 h, 65%; (d) NBS, acetonitrile, rt,
overnight, 98%; (e) NCS, acetonitrile, rt, overnight, 80%.
a
O
OH
N
CO2Et
sodium cyanoborohydride in HMPA furnished helianane 1 in 65%
yield, which was spectroscopically identical with a previous
sample.4b Overnight treatment of helianane with N-bromosuccini-
mide effected quantitative conversion to bromohelianane 3, whose
spectral data were comparable with those reported (Scheme 3).3,8
Similarly, overnight treatment of 1 with N-chlorosuccinimide fur-
nished chlorohelianane 4 in 80% yield whose spectral data also
were comparable with the reported values.3,8
In summary, we have described an expeditious synthesis of
helianane and the C-10 halogenated heliananes employing simple
reagents and readily accessible reaction conditions to furnish the
target molecules in good overall yield.
6
5
b
Mes
Mes
Cl
N
Ru
Pcy3
O
Cl
Ph
7
CO2Et
A
c
d
Acknowledgements
O
O
WesincerelyacknowledgethefinancialsupportfromtheDepart-
ment of Science and Technology, Government of India. S.G. thanks
the Council of Scientific and Industrial Research, New Delhi for a
research fellowship. We thank Professor Fernando Reyes for provid-
ing us copies of the spectra of C-10 bromo- and chloroheliananes.
CO2Et
CO2Et
8
10
O
CO2Et
O
EtO2C
References and notes
9
1. Harrison, B.; Crews, P. J. Org. Chem. 1997, 62, 2646–2648.
2. Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G. Tetrahedron Lett. 1993,
34, 1999–2002.
3. Martín, M. J.; Berrué, F.; Amade, P.; Fernández, R.; Francesch, A.; Reyes, F.;
Cuevas, C. J. Nat. Prod. 2005, 68, 1554–1555.
Scheme 1. Reagents and conditions: (a) K2CO3, ethyl a-bromopropionate, acetone,
reflux, 7 h, 90%; (b) LDA, 1-bromo-3-butene, HMPA, THF, À78 °C to rt, 7 h, 80%; (c)
Grubbs 2nd generation cat. (15 mmol %), dichloro methane, 9 h, 50%; (d) H2/Pd-C
(10%), ethanol, 4 h, 98%.
4. (a) Stefinovic, M.; Snieckus, V. J. Org. Chem. 1998, 63, 2808–2809; (b) Sabui, S. K.;
Venkateswaran, R. V. Tetrahedron Lett. 2004, 45, 9653–9655; (c) Ghosh, S.;
Tuhina, K.; Bhowmik, D. R.; Venkateswaran, R. V. Tetrahedron 2007, 63, 644–
651; (d) Sen, P. K.; Biswas, B.; Venkateswaran, R. V. Tetrahedron Lett. 2005, 46,
8741–8743.
5. Divakar, K. J.; Rao, A. S. Synth. Commun. 1976, 423.
a
6. All new compounds reported here gave spectral data consistent with the assigned
structures. Selected spectral data: For 8: IR 1749 cmÀ1 1H NMR (300 MHz, CDCl3)
;
O
OH
d 1.23 (t, J = 7.1, 3H), 1.52 (s, 3H), 2.02 (s, 3H), 2.14 (dd, J = 7.3, 14.4 Hz, 2H), 2.25
(s, 3H), 2.35 (dd, J = 6.5, 14.2 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 5.83 (t, J = 6.5 Hz,
1H), 6.78 (d, J = 7.8 Hz, 1H), 6.96 (s, 1H), 7.07 (d, J = 7.8 Hz, 1H); 13C (75 MHz,
CDCl3) d 14.5, 21.3, 21.9, 24.4, 30.0 35.1, 61.4, 94.5, 122.2, 124.9, 125.0, 127.1,
11
12
b
132.2, 137.9, 138.4, 154.3, 174.1. For 10: IR 1751 cmÀ1 1H NMR (300 MHz,
;
CDCl3) d 1.30 (m, 3H), 1.47 (s, 3H), 1.55, 1.60 (2s, 3H) 1.72–1.82 (m, 2H), 1.84–
2.07 (m, 4H), 2.29 (s, 3H), 3.10–3.19 (m, 1H), 4.21 (m, 2H), 6.83, 6.93 (2s, 1H),
6.88 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H). 13C (75 MHz, CDCl3) d 14.5, 19.6,
19.7, 21.1, 22.8, 25.7, 28.8, 30.0, 33.1, 34.7, 40.8, 61.4, 81.2, 81.6, 124.4, 125.2,
126.2, 126.3, 135.3, 135.5, 136.9, 137.0, 153.3, 153.8, 173.8, 174.4. For 15 (one
c
O
13
O
diastereomer): IR 1752 cmÀ1 1H NMR (300 MHz, CDCl3) d 1.24 (m, 6H), 1.31 (m,
;
CO2Et
CO2Et
3H), 2.19 (s, 3H), 2.23 (m, 1H), 2.69 (m, 1H), 3.75–3.76 (m, 1H), 4.20–4.26 (q,
J = 7.2 Hz, 2H), 5.35 (m, 1H), 5.59 (dd, J = 6.3, 10.8 Hz, 1H), 6.74 (s, 1H), 6.82 (d,
J = 8.4 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H); 13C (75 MHz, CDCl3) d 14.3, 19.8, 20.9,
22.3, 33.1, 36.1, 61.3, 82.8, 120.7, 120.8, 125.2, 125.7, 126.8, 136.9, 140.3, 153.0,
173.8. For 3: 1H NMR (300 MHz, CDCl3) d 1.23 (s, 3H), 1.26 (d, J = 6.9 Hz, 3H), 1.
40 (m, 1H), 1.41 (s, 3H), 1.55 (m, 4H), 1.75 (m, 1H), 2.31 (s, 3H), 3.15 (m, 1H),
6.77 (s, 1H), 7.31 (s, 1H); 13C (75 MHz, CDCl3) 21.0, d 21.7, 22.5, 26.5, 29.1, 29.7,
38.0, 39.4, 81.4, 119.7, 127.3, 129.9, 134.9, 141.6, 152.3. For 4: 1H NMR
(300 MHz, CDCl3) d 1.23 (s, 3H), 1.26 (d, J = 6.9, 3H), 1.39 (m, 1H), 1.41 (s, 3H),
1.58 (m, 4H), 1.72 (m, 1H), 2.29 (s, 3H), 3.16 (m, 1H), 6.76 (s, 1H), 7.13 (s, 1H);
13C (75 MHz, CDCl3) d 19.8, 21.2, 21.9, 26.6, 29.2, 29.8, 37.6, 39.5, 81.5, 116.2,
126.8, 127.4, 133.1, 141.3, 151.7.
14
d
e
O
O
CO2Et
CO2Et
10
15
7. Sarkar, D.; Venkateswaran, R. V. Synlett 2008, 5, 653–654.
8. We attribute the minor deviations in the spectral values to a change of solvent in
our case (CDCl3) and possibility of conformational isomers (see Ref. 2).
Scheme 2. Reagents and conditions: (a) SnCl4, dichloro methane, 0 °C to rt, 80%; (b)
K2CO3, ethyl -bromopropionate, acetone, reflux, 6 h, 81%; (c) LDA, allyl bromide,
a
HMPA, THF, À78 °C to rt, 8 h, 80%; (d) Grubbs 2nd generation cat. (1.5 mmol %),
dichloro methane, 24 h, 90%; (e) H2/Pd-C (10%), ethanol, 3 h, 98%;