Construction of spiro[5.5]undecanes containing a quaternary carbon atom adjacent to a spirocentre via an Ireland ester Claisen rearrangement and RCM reaction sequence. Total syntheses of (±)-α-chamigrene, (±)-β-chamigrene and (±)-laurencenone C

Article abstract of DOI:10.1016/j.tetlet.2006.01.131

Starting from cyclohexanecarboxylic acid, a combination of an Ireland ester Claisen rearrangement and RCM reactions was exploited for an efficient construction of spiro[5.5]undecanes containing a quaternary carbon atom adjacent to the spirocentre and the

Full text of DOI:10.1016/j.tetlet.2006.01.131

Tetrahedron Letters 47 (2006) 2103–2106
Construction of spiro[5.5]undecanes containing a quaternary
carbon atom adjacent to a spirocentre via an Ireland ester
Claisen rearrangement and RCM reaction sequence.
Total syntheses of ( )-a-chamigrene, ( )-b-chamigrene
and ( )-laurencenone C
A. Srikrishna,* B. Vasantha Lakshmi and Manoj Mathews
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 13 December 2005; revised 18 January 2006; accepted 26 January 2006
Abstract—Starting from cyclohexanecarboxylic acid, a combination of an Ireland ester Claisen rearrangement and RCM reactions
was exploited for an efficient construction of spiro[5.5]undecanes containing a quaternary carbon atom adjacent to the spirocentre
and the methodology was extended to complete total syntheses of three chamigrenes.
Ó 2006 Elsevier Ltd. All rights reserved.
Chamigrenes, which contain a spiro[5.5]undecane car-
bon framework incorporating two vicinal quaternary
carbon atoms, are interesting sesquiterpene natural
products isolated from plant and liverwort as well as
marine sources. Chamigrenes appear to be metabolites
from algae of the genus Laurencia, and most of these
are characterised by the incorporation of chlorine and
bromine atoms.1 The isolation of b-chamigrene 1 was
first reported by Ito et al.2 in 1967 from the leaf oil of
Chamaecyparis taiwanensis, whereas the isolation of a-
chamigrene 2 was reported by Ohta and Hirose3 from
the oil of the fruits of Schisandra chinensis almost at
the same time. Subsequently, a variety of chlorine and
bromine-containing chamigrenes were isolated from
marine sources. Over 120 chamigrenes were isolated
from Laurencia species and from sea hares grazing on
them. Thomson and co-workers reported4 the isolation
of laurencenones A–D 3–6 from Laurencia obtusa,
which contain an enone functionality in the A-ring of
chamigrenes. Several halogenated chamigrenes were
shown to exhibit cytostatic activity and remarkable anti-
microbial activity on both Gram-positive and Gram-
negative bacteria.5 Recently, Cueto and co-workers re-
ported the isolation of several halogenated chamigrenes
Br
O
O
Cl
3 (laurencenone A)
Cl
1 (β-chamigrene)
2 (α-chamigrene)
4 (laurencenone B)
10
6
3
O
O
Cl
8
1
Br
6 (laurencenone D)
O
5 (laurencenone C)
7
*
Corresponding author. Tel.: +91 80 22932215; fax: +91 80 23600529; e-mail: ask@orgchem.iisc.ernet.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.131

2104
A. Srikrishna et al. / Tetrahedron Letters 47 (2006) 2103–2106
from Aplysia dactylomela from the Canary Islands,
some of which were shown to exhibit cytotoxic activity
against HeLa and Hep-2 cancer cell lines.6 Synthesis
of chamigrenes is challenging owing to the presence of
a quaternary carbon adjacent to the spirocentre.5,7,8
Herein, we report an efficient methodology for the con-
struction of spiro[5.5]undecanes containing a quaternary
carbon atom adjacent to the spirocentre, and its applica-
tion to syntheses of ( )-laurencenone C 5, ( )-a-chami-
grene 2 and ( )-b-chamigrene 1.
nished spiroenone 7, whose structure was established
from its spectral data.
After demonstrating the feasibility of the strategy, it was
extended to chamigrenes starting from the readily avail-
able11 isoprene–acrylic acid Diels–Alder adduct 18
(Scheme 3). Accordingly, reaction of the acid 18 with
dimethylallyl alcohol and DCC in the presence of a cat-
alytic amount of DMAP furnished the dimethyl allyl
ester 19 in 95% yield. Generation of the TMS enol ether
of ester 19 with LDA, trimethylsilyl chloride and trieth-
ylamine in THF at ꢀ70 °C followed by refluxing the
reaction mixture for 3 h resulted in the Ireland ester Cla-
isen rearrangement. Hydrolysis of the reaction mixture
with dilute hydrochloric acid followed by esterification
with ethereal diazomethane furnished ester 20 in 92%
yield, whose structure was deduced from its spectral
data. Reduction of ester 20 with LAH followed by oxi-
dation of the resultant primary alcohol with PCC and
silica gel generated aldehyde 21 in 80% yield. A sono-
chemically accelerated Barbier reaction of aldehyde 21
with lithium and allyl bromide furnished the secondary
alcohol 22 in 86% yield. Treatment of the hydroxydiene
22 with 10 mol % of Grubbs’ first generation catalyst
[Cl2Ru(PCy3)2@CHPh] in methylene chloride for 5 h
at room temperature cleanly furnished the spiro com-
pound 23 in 90% yield. Oxidation of the secondary alco-
hol 23 with PCC and silica gel followed by isomerisation
First, as a model study, the synthesis of spiroenone 7,
containing two vicinal quaternary carbon atoms was
investigated starting from cyclohexanecarboxylic acid
8. It was conceived (Scheme 1) that a ring-closing
metathesis (RCM) reaction9 of diene 9 would generate
the spiro system 10, and that diene 9 could be generated
from ester 11. An Ireland ester Claisen rearrangement10
of the dimethylallyl ester 12 was chosen for generation
of ester 11 containing two vicinal quaternary carbon
atoms.
The synthetic sequence is depicted in Scheme 2. Cou-
pling of the acid 8 with dimethylallyl alcohol in methyl-
ene chloride in the presence of dicyclohexylcar-
bodiimide (DCC) and dimethylaminopyridine (DMAP)
produced the dimethylallyl ester 12. Ireland–Claisen
rearrangement of ester 12 was explored via the corre-
sponding trimethylsilyl (TMS) enol ether 13. Thus, gen-
eration of the TMS enol ether 13 of ester 12 with LDA,
trimethylsilyl chloride and triethylamine in THF at
ꢀ70 °C followed by refluxing the reaction mixture for
3 h resulted in the Ireland ester Claisen rearrangement.
Hydrolysis of the reaction mixture with dilute hydro-
chloric acid followed by esterification with ethereal dia-
zomethane furnished ester 14. Ester 14 was then
converted into aldehyde 15 by a two-step protocol,
involving reduction with lithium aluminium hydride
(LAH) in refluxing THF, followed by oxidation of the
resultant primary alcohol 16 with pyridinium chloro-
chromate (PCC) and silica gel in methylene chloride.
Coupling of aldehyde 15 with allyl bromide under Bar-
bier conditions generated the hydroxydiene 9. RCM
reaction of the dienol 9 with Grubbs’ first generation
catalyst furnished the spiro system 10 in an efficient
manner. Oxidation of the alcohol 10 with PCC followed
by isomerisation of the resultant b,c-unsaturated enone
17 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) fur-
Yields refer to isolated and chromatographically pure compounds.
All the compounds exhibited spectral data (IR, 1H and 13C NMR and
mass) consistent with their structures. Selected spectral data for
spiroenone 7: IR (neat): mmax/cmꢀ1: 1676; 1H NMR (300 MHz,
CDCl3 + CCl4): d 6.54 (1H, td, J 10.2 and 4.2 Hz), 5.82 (1H, dt, J
10.2 and 3.9 Hz), 2.30–1.17 (12H, m), 0.96 (6H, s); 13C NMR
(75 MHz, CDCl3 + CCl4): d 206.1 (C), 143.4 (CH), 128.5 (CH), 52.0
(C), 39.8 (C), 39.5 (CH2), 26.1 (2C, CH2), 23.8 (2C, CH3), 23.1 (3C,
CH2); HRMS: m/z calcd for C13H20ONa (M+Na): 215.1412. Found:
215.1420. 3-Methylbut-2-enyl 4-methylcyclohex-3-ene-1-carboxylate
1
19: IR (neat): mmax/cmꢀ1 1735; H NMR (300 MHz, CDCl3 + CCl4):
d 5.40–5.25 (2H, m), 4.53 (2H, d, J 6.9 Hz), 2.50–2.37 (1H, m), 2.25–
2.15 (2H, m), 2.05–1.90 (3H, m), 1.76 (3H, s), 1.71 (3H, s), 1.64 (3H,
s), 1.75–1.60 (1H, m); 13C NMR (75 MHz, CDCl3 + CCl4): d 175.3
(C), 138.1 (C), 133.4 (C), 119.6 (CH), 119.3 (CH), 61.0 (CH2), 39.2
(CH), 29.4 (CH2), 27.7 (CH2), 25.8 (CH3), 25.6 (CH2), 23.6 (CH3),
18.1 (CH3); HRMS: m/z Calcd for C13H20O2Na (M+Na): 231.1361.
Found: 231.1361. Methyl 1-(1,1-dimethylallyl)-4-methylcyclohex-3-
ene-1-carboxylate 20: IR (neat): mmax/cmꢀ1 1727, 914; 1H NMR
(300 MHz, CDCl3 + CCl4): d 5.88 (1H, dd, J 17.4 and 10.8 Hz), 5.32–
5.26 (1H, m), 4.98 (1H, dd, J 10.8 and 1.5 Hz), 4.94 (1H, dd, J 17.4
and 1.5 Hz), 3.63 (3H, s), 2.56–2.45 (1H, m), 2.32–1.80 (4H, m), 1.58
(3H, s), 1.52–1.41 (1H, m), 1.02 (3H, s), 1.017 (3H, s); 13C NMR
(75 MHz, CDCl3 + CCl4): d 175.2 (C), 144.7 (CH), 133.2 (C), 120.2
(CH), 112.3 (CH2), 51.3 (C), 51.0 (CH3), 41.1 (C), 29.0 (CH2), 28.6
(CH2), 25.9 (CH2), 23.3 (CH3), 23.1 (CH3), 23.08 (CH3); HRMS: m/z
calcd for C14H22O2Na (M+Na): 245.1517. Found: 245.1518. 5,5,9-
Trimethylspiro[5.5]undec-8-en-1-one 28: IR (neat): mmax/cmꢀ1 1706;
1H NMR (300 MHz, CDCl3 + CCl4): d 5.27 (1H, br s), 2.53 (1H, td, J
12.3 and 6.9 Hz), 2.30–2.00 (3H, m), 1.92 (1H, td, J 13.2 and 4.8 Hz),
1.86–1.60 (6H, m), 1.51 (3H, s), 1.31–1.23 (1H, m), 0.89 (3H, s), 0.75
(3H, s); 13C NMR (75 MHz, CDCl3 + CCl4): d 213.5 (C), 131.4 (C),
120.7 (CH), 54.8 (C), 40.8 (C), 36.9 (CH2), 35.7 (CH2), 27.9 (CH2),
27.0 (CH2), 26.5 (CH2), 24.9 (CH3), 23.4 (CH3), 23.3 (CH3), 23.1
(CH2); HRMS: m/z calcd for C14H23O (M+H): 207.1749. Found:
207.1709.
O
HO
10
HO
9
7
O
O
COOR
12
11
Scheme 1.

A. Srikrishna et al. / Tetrahedron Letters 47 (2006) 2103–2106
2105
of the resultant b,c-enone 24 with DBU furnished the
key precursor to the chamigrenes, the spirodienone 25,
in 93% yield. An alkylative 1,3-enone transposition12
was considered highly suitable for the conversion of
the enone 25 into laurencenone C 5. After exploring var-
ious conditions, it was found that reaction of the enone
25 with anhydrous cerium chloride and methyllithium13
generated a 1:2 mixture of the 1,2- and 1,4-addition
products 26 and 27, in quantitative yield. Oxidation of
the mixture of 26 and 27 with PCC in methylene chlo-
ride followed by purification on a silica gel column fur-
nished the spiroketone 27 and ( )-laurencenone C 5.
Laurencenone C 5 exhibited spectral data identical to
those reported in the literature.4 In another direction,
treatment of the enone 25 with zinc and potassium
hydroxide14 in refluxing ethanol regioselectively reduced
the enone to generate norchamigrenone 28 in excellent
yield. Reaction of the norketone 28 with methylenetri-
phenylphosphorane (generated from triphenylphospho-
nium bromide and tertiary amyl oxide in benzene and
tertiary amyl alcohol)15,16 or with the Lombardo reagent
(prepared from methylene bromide, zinc and titanium
tetrachloride)17 quantitatively furnished ( )-b-chami-
grene 1. Even though reaction of norchamigrenone 28
with either methyllithium or methylmagnesium iodide
was unsuccessful (contrary to that reported by Plamon-
don and Canonne),8 reaction with a combination
of anhydrous cerium chloride and methylmagnesium
O
TMSO
O
O
COOH
a
b
12
13
8
MeO
O
R
c,d
e
HO
HO
16 R=CH2OH
15 R=CHO
14
9
f
O
O
g
h
17
7
10
Scheme 2. Reagents, conditions and yields: (a) DCC, DMAP
(catalytic), Me2C@CHCH2OH, CH2Cl2, rt, 5 h, 88%; (b) (i) LDA,
THF, TMSCl, NEt3, ꢀ70 °C, 30 min, rt, 6 h; reflux, 3 h; (ii) dil HCl,
40 min; (iii) CH2N2, Et2O, 0 °C, 30 min, 70%; (c) LAH, THF, reflux,
3 h, 75%; (d) PCC, silica gel, CH2Cl2, rt, 0.25 h, 86%; (e) Li,
CH2@CHCH2Br, ))), 0 °C!rt, 1 h, 75%; (f) Cl2(PCy3)2Ru@CHPh
(5 mol %), CH2Cl2, rt, 5 h, 86%; (g) PCC, silica gel, CH2Cl2, rt, 2 h,
86%; (h) DBU, CH2Cl2, rt, 12 h, 79%.
H
a
b
COOH
c,d
O
OMe
H
O
O
O
18
28
19
25
20
21
e
g,h
f
k
HO
X
O
O
23 X = H,OH
24 X = O
22
i
j
O
+ 27
Me
(1:1)
+
( 1 : 2 )
HO
26
Me
O
27
( )-5
l or m
n
o
+
( )-1
28
HO
29
Me
( )-1
( )-2
Scheme 3. Reagents, conditions and yields: (a) DCC, DMAP (catalytic), Me2C@CHCH2OH, CH2Cl2, rt, 5 h, 95%; (b) (i) LDA, THF, TMSCl, NEt3,
ꢀ70 °C, 30 min, rt, 6 h, reflux, 3 h; (ii) dil HCl, 40 min; (iii) CH2N2, Et2O, 0 °C, 30 min, 92%; (c) LAH, Et2O, 0 °C!rt, 2 h, 90%; (d) PCC, silica gel,
CH2Cl2, rt, 0.5 h, 89%; (e) Li, CH2@CHCH2Br, ))), 0 °C!rt, 1 h, 86%; (f) Cl2(PCy3)2Ru@CHPh (10 mol %), CH2Cl2, rt, 5 h, 90%; (g) PCC, silica gel,
CH2Cl2, rt, 2 h, 96%; (h) DBU, CH2Cl2, rt, 6 h, 98%; (i) CH3Li, CeCl3, THF, 0 °C!rt, 2 h; (j) PCC, silica gel, CH2Cl2, 1 h; 100% (from 25) (5:27 1:2);
t
t
(k) Zn, KOH, EtOH, H2O (4:1), reflux, 10 h, 95%; (l) Ph3PCH3Br, AmOꢀK+, C6H6, AmOH, reflux, 10 h, 100%; (m) Zn, TiCl4, CH2Br2, CH2Cl2,
0 °C!rt, 3 h, 100%; (n) CH3MgCl, CeCl3, THF, 0 °C!rt, 3 h 88%; (o) POCl3, py, CH2Cl2, 0 °C!rt, 3 h, 92%.

2106
A. Srikrishna et al. / Tetrahedron Letters 47 (2006) 2103–2106
polymorpha, see: Asakawa, Y.; Tori, M.; Masuya, T.;
Frahm, J.-P. Phytochemistry 1990, 29, 1577–1584.
5. Martin, J. D.; Perez, C.; Ravelo, J. L. J. Am. Chem. Soc.
1986, 108, 7801–7811.
6. Dias, T.; Brito, I.; Moujir, L.; Paiz, N.; Darias, J.; Cueto,
M. J. Nat. Prod. 2005, 68, 1677–1679.
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S. J. Org. Chem. 1984, 49, 1001–1013; Adams, J.; Lepine-
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Lin, W.-Y. Tetrahedron 1996, 52, 13181–13188, and
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8. A very short approach to a-chamigrene via spiroalkyla-
tion was reported by Plamondon and Canonne. However,
1H and 13C spectral data for synthetic ( )-a-chamigrene
reported by these authors is quite different from those
reported by others. See: Plamondon, J.; Canonne, P.
Tetrahedron Lett. 1991, 32, 589–592.
chloride furnished the tertiary alcohol 29 in 88% yield.
Dehydration of the alcohol 29 with phosphorus oxy-
chloride and pyridine furnished a 5:1 mixture of
a- and b-chamigrenes 2 and 1 in 92% yield, which were
separated by column chromatography on silica gel
impregnated with silver nitrate. Both a-chamigrene 2
and b-chamigrene 1 exhibited spectral data identical to
those of the authentic compounds reported5,7 in the
literature.
In summary, we have accomplished efficient total syn-
theses of ( )-laurencenone C 5, ( )-a-chamigrene 2
and ( )-b-chamigrene 1. Starting from the acid 18,
( )-laurencenone C 5 was obtained in an overall yield
of 17% in 10 steps, ( )-a-chamigrene 2 in 32% in 11
steps and ( )-b-chamigrene 1 in 48% in 10 steps. A com-
bination of an Ireland ester Claisen rearrangement and
RCM reactions was employed for the efficient construc-
tion of the requisite two vicinal quaternary carbon
atoms. Extension of the methodology for the enantio-
selective generation of these and related spiro sesquiter-
penes is currently in progress.
9. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
4450; (b) Furstner, A. Angew. Chem., Int. Ed. 2000, 39,
¨
3013–3043; (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18–29.
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94, 5897–5898; (b) Ireland, R. E.; Wipf, P.; Armstrong, J.
D. J. Org. Chem. 1991, 56, 650–657; (c) Gilbert, J. C.; Yin,
J.; Fakhreddine, F. H.; Karpinski, M. L. Tetrahedron
2004, 60, 51–60.
Acknowledgements
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amalini, P. J. Chem. Soc., Perkin Trans. 1 1996, 1305–
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We thank the Council of Scientific and Industrial
Research, New Delhi, for the financial support and
award of a research fellowship to B.V.L.
13. Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett.
1984, 25, 4233–4236.
References and notes
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grenone under standard conditions or with tert-amyl oxide
in the absence of tert-amyl alcohol furnished a very poor
yield of b-chamigrene.
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none
C
from the German liverwort Marchantia