Total syntheses of (±)-α-acorenol, β-acorenol, α-epi-acorenol and β-epi-acorenol via an Ireland ester Claisen rearrangement and RCM reaction sequence

Article abstract of DOI:10.1016/j.tetlet.2007.07.163

Total syntheses of (±)-α- and β-acorenols and (±)-α- and β-epi-acorenols, spiro[4.5]decane sesquiterpenes, isolated from the western Australian sandalwood oil, have been accomplished employing a combination of Ireland ester Claisen rearrangement and RCM r

Full text of DOI:10.1016/j.tetlet.2007.07.163

Tetrahedron Letters 48 (2007) 6916–6919
Total syntheses of ( )-a-acorenol, b-acorenol, a-epi-acorenol
and b-epi-acorenol via an Ireland ester Claisen
rearrangement and RCM reaction sequence
A. Srikrishna* and R. Ramesh Babu
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 25 June 2007; revised 14 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—Total syntheses of ( )-a- and b-acorenols and ( )-a- and b-epi-acorenols, spiro[4.5]decane sesquiterpenes, isolated from
the western Australian sandalwood oil, have been accomplished employing a combination of Ireland ester Claisen rearrangement
and RCM reactions for an efficient construction of the spiro[4.5]decane present in acoranes.
Ó 2007 Elsevier Ltd. All rights reserved.
Australian sandalwood oil obtained from Santalum spic-
atum wood, butts and roots is considered very important
in the perfumery industry due to its interesting odour
properties. Recently,1 Braun and co-workers reported
the isolation of a-acorenol 1, b-acorenol 2, a-epi-acore-
nol 3 and b-epi-acorenol 4 from the western Australian
sandalwood oil. Although, a-acorenol 1 and b-acorenol
2 have been known since 1970, and were first isolated
from the wood of Juniperus rigida2 and subsequently
from various essential oils, this isolation of a-epi-acore-
nol 3 and b-epi-acorenol 4 is the first from natural
sources. The structures of the epi-acorenols 3 and 4 were
established from their spectral data in comparison with
those of a- and b-acorenols 1 and 2. Acoranes were the
first sesquiterpene natural products to be isolated from
Nature containing a spiro[4.5]decane carbon frame-
work.3 a-Acorenol 1 was proved to be the biogenetic
precursor of the tricyclic sesquiterpenes cedranoids, for
example, a-cedrene 5. In contrast to other acoranes, so
far only three research groups have reported the synthe-
sis of a- and b-acorenols 1 and 2.4 Herein, we describe
the efficient syntheses of all four acorenols 1–4, starting
from cyclohexane-1,4-dione 6 employing a combination
of an Ireland ester Claisen rearrangement and ring-clos-
ing metathesis (RCM) as key steps for the efficient con-
struction of the spiro[4.5]decane.
As depicted in Scheme 1, it was contemplated that the
RCM reaction5 of diene 7 would generate spiro[4.5]dec-
ane system 8, which would be further elaborated into the
acorenols and epi-acorenols 1–4. The Ireland ester Cla-
isen rearrangement6 of pentenoate 9 was considered
appropriate for the generation of diene 7 containing
the quaternary carbon atom. Ester 9 could be obtained
from cyclohexane-1,4-dione 6 via ester 10.
The synthetic sequence starting from cyclohexane-1,4-
dione 6 is depicted in Scheme 2. A controlled Horner–
Wadsworth–Emmons reaction of dione 6 with sodium
hydride and triethyl phosphonopropionate generated
3
1
H
OH
OH
OH
OH
5
9
7
H
1 (α-acorenol)
2 (β-acorenol) 3 (α-epi-acorenol) 4 (β-epi-acorenol) 5 (α-cedrene)
*
Corresponding author. Tel.: +91 80 22932215; fax: +91 80 23600529; e-mail: ask@orgchem.iisc.ernet.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.163

A. Srikrishna, R. R. Babu / Tetrahedron Letters 48 (2007) 6916–6919
6917
COOR
COOR
O
O
O
COOR
OH
X
O
O
X
O
1-4
8
10
6
7
9
X=protecting group
Scheme 1.
O
CO2Et
CO2Et
O
O
O
OH
a
c
b
d
82%
96%
97%
94%
O
O
O
O
O
O
O
6
11
13
12
9
N
N
O
OTMS
Cl
Cl
Ru
Ph
3
CO2Me
PCy
Grubbs II catalyst
CO2Me
e
f
98%
95%
O
O
O
8
7
O
g
100%
CO2Me
CO2Me
CO2Me
i
h
+ 15
90%
89%
(4 : 1)
O
15
14
16
Scheme 2. Reagents and conditions: (a) (EtO)2P(O)CH(Me)CO2Et, NaH, THF, 0 °C ! rt, 3 h; (b) (CH2OH)2, PTSA, C6H6, reflux (Dean-Stark),
4 h; (c) LiAlH4, Et2O, ꢀ70 ! ꢀ50 °C, 2 h; (d) DCC, DMAP, CH2@CH(CH2)2CO2H, CH2Cl2, rt, 5 h; (e) (i) LDA, THF, TMSCl, NEt3, ꢀ70 °C,
30 min; rt, 4 h; reflux, 5 h; (ii) dil. HCl, 40 min; (iii) CH2N2, Et2O, 0 °C, 30 min; (f) Grubbs0 II catalyst (3 mol %), C6H6, reflux, 3 h; (g) 10% Pd/C, H2
t
(1 atm.), MeOH, rt, 1 h; (h) Ph3P+CH3Brꢀ, AmOꢀK+, C6H6, rt, 1 h; (i) NaOMe, MeOH, reflux, 8 h.
keto ester 11 in 82% yield. Prior to the reduction of the
a,b-unsaturated ester in keto ester 11 to an allyl alcohol,
the keto group was protected as an ethylene ketal by
refluxing with 1,2-ethanediol and a catalytic amount of
p-toluenesulfonic acid (PTSA) in benzene using a
Dean-Stark trap to furnish ketal ester 12 in 96% yield.
Regioselective reduction with lithium aluminum hydride
(LAH) in ether at low temperature transformed ester 12
into allyl alcohol 13 in 97% yield. Allyl alcohol 13 was
then coupled with pent-4-enoic acid using dicyclohexyl-
carbodiimide (DCC) and 4-N,N-dimethylaminopyridine
(DMAP) in methylene chloride to generate the Ireland-
Claisen rearrangement precursor ester 9 in 94% yield.
Generation of the TMS enol ether of ester 9 with
LDA, trimethylsilyl chloride and triethylamine in THF
at ꢀ70 °C followed by refluxing the reaction mixture
for 5 h resulted in the Ireland ester Claisen rearrange-
ment. Hydrolysis of the reaction mixture with dilute
hydrochloric acid followed by esterification with ethe-
real diazomethane furnished keto ester 7 in 95% yield,
whose structure was deduced from its spectral data.7
RCM reaction of diene 7 with 3 mol % of Grubbs’ sec-
ond generation catalyst in refluxing benzene for 3 h
cleanly furnished spiro compound 8 in 98% yield, whose
structure was deduced from its spectral data.7 Before
introducing the methyl group into the cyclohexane ring,
the olefin in the cyclopentene moiety in keto ester 8 was
hydrogenated in a highly stereoselective manner in
methanol at one atmosphere pressure of hydrogen by
employing 10% palladium over charcoal as the catalyst
to generate cis-ester 14 in quantitative yield. Wittig
methylenation of keto ester 14 with methylenetriphenyl-
phosphorane in benzene at room temperature furnished
ester 15 in 89% yield. For the generation of a precursor,
which was suitable for the synthesis of a- and b-acore-
nols 1 and 2, the ester group in 15 was equilibrated in
refluxing methanol with sodium methoxide to furnish
a 1:4 mixture of cis- and trans-esters 15 and 16 in 90%
yield, which were separated by column chromatography
on silica gel.7

6918
A. Srikrishna, R. R. Babu / Tetrahedron Letters 48 (2007) 6916–6919
References and notes
CO2Me
b
OH
OH
1. Braun, N. A.; Meier, M.; Kohlenberg, B.; Valder, C.;
Neugebauer, M. J. Essent. Oil Res. 2003, 15, 381–386.
2. (a) Tomita, B.; Isono, T.; Hirose, Y. Tetrahedron Lett.
1970, 1371–1372; (b) Tomita, B.; Hirose, Y. Tetrahedron
Lett. 1970, 143–144, and references cited therein.
CO2Me
86%
a
95%
17a
1
2
CO2Me
3. Sykora, V.; Herout, V.; Pliva, J.; Sorm, F. Collect. Czech.
Chem. Commun. 1958, 23, 1072–1082; Sorm, F.; Herout, V.
Collect. Czech. Chem. Commun. 1948, 13, 177–206.
16
b
81%
17b
4. For the synthesis of a- and b-acorenols, see (a) Iwata, C.;
Nakamura, S.; Shinoo, Y.; Fusaka, T.; Okada, H.;
Kishimoto, M.; Uetsuji, H.; Maezaki, N.; Yamada, M.;
Tanaka, T. Chem. Pharm. Bull. 1985, 33, 1961–1968; (b)
Iwata, C.; Nakamura, S.; Shinoo, Y.; Fusaka, T.; Okada,
H.; Kishimoto, M.; Uetsuji, H.; Maezaki, N.; Yamada, M.;
Tanaka, T. J. Chem. Soc., Chem. Commun. 1984, 781–782;
(c) Oppolzer, W.; Mahalanabis, K. K.; Battig, K. Helv.
Chim. Acta 1977, 60, 2388–2401; Oppolzer, W. Helv. Chim.
Acta 1973, 56, 1812–1814; (d) Guest, I. G.; Hughes, C. R.;
Ramage, R.; Sattar, A. J. Chem. Soc., Chem. Commun.
1973, 526–527; For the synthesis of epi-acorenols, see:
Iwata, C.; Fusaka, T.; Maezaki, N.; Nakamura, S.; Shinoo,
Y.; Yamada, M.; Tanaka, T. Chem. Pharm. Bull. 1988, 36,
1638–1645.
CO2Me
b
OH
85%
CO2Me
a
18a
3
4
90%
CO2Me
15
OH
b
84%
18b
Scheme 3. Reagents and conditions: (a) PTSA, CH2Cl2, rt, 6 h;
(17a:17b 1:1); (18a:18b 4:1); (b) MeMgI, Et2O, rt, 3 h.
5. (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; (d) Grubbs, R. H. Tetrahedron 2004,
60, 7117–7140.
The 1,4-cis- and trans-esters 15 and 16 were then trans-
formed into epi-acorenols 3 and 4 and into acorenols 1
and 2, respectively, in two steps, as shown in Scheme
3. Thus, isomerisation of the olefin in ester 16 with
PTSA in methylene chloride at room temperature fur-
nished a 1:1 mixture of esters 17a and 17b in 95% yield,
which were separated by column chromatography on
silica gel. Grignard reaction of esters 17a and 17b with
an excess of methylmagnesium iodide furnished a-acore-
nol 1 and b-acorenol 2, respectively.7 In a similar man-
ner, PTSA isomerised the olefin in ester 15 to furnish a
4:1 mixture of esters 18a and 18b in 90% yield, which
were separated by column chromatography on silica
gel. Grignard reaction of esters 18a and 18b with an ex-
cess of methylmagnesium iodide furnished a-epi-acore-
nol 3 and b-epi-acorenol 4, respectively.7 The structure
of a-acorenol 1 was confirmed by comparison with the
1H and 13C NMR spectra of the natural sample, and
similarly the structures of b-acorenol 2, a-epi-acorenol
3 and b-epi-acorenol 4 were confirmed by comparing
their 1H NMR spectral data with those of natural
samples.1
6. (a) Ireland, R. E.; Mueller, R. H. J. Am. Chem. Soc. 1972,
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.
7. 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 ester 7: IR (neat): mmax
/
cmꢀ1 1732, 1717, 1641, 913; 1H NMR (300 MHz, CDCl3 +
CCl4): d 5.54 (1H, ddt, J 17.7 Hz, 11.1 Hz, 7.5 Hz), 5.17
(1H, s), 4.92 (1H, d, J 17.7 Hz), 4.90 (1H, s), 4.88 (1 H, d,
J 11.1 Hz), 3.53 (3H, s), 2.49 (1H, dd, J 11.7 Hz, 2.7 Hz),
2.40–1.50 (10H, m), 1.75 (3H, s); 13C NMR (75 MHz,
CDCl3 + CCl4): d 210.3 (C), 173.7 (C), 143.3 (C), 135.6
(CH), 116.9 (CH2), 116.6 (CH2), 52.0 (CH), 51.2 (CH3),
44.4 (C), 37.7 (CH2), 37.5 (CH2), 31.6 (2 C, CH2), 29.1
(CH2), 19.1 (CH3); HRMS: m/z calcd for C15H22O3Na
(M+Na): 273.1467. Found: 273.1459. For the spiroester 8:
1
IR (neat): mmax/cmꢀ1 1720; H NMR (300 MHz, CDCl3 +
CCl4): d 5.25 (1H, br s), 3.58 (3H, s), 3.10 (1H, dd, J 8.1 Hz
and 5.4 Hz), 2.75–2.10 (6H, m), 2.05–1.67 (4H, m), 1.65
(3H, d, J 2.1 Hz); 13C NMR (75 MHz, CDCl3 + CCl4): d
209.7 (C), 174.7 (C), 143.8 (C), 123.3 (CH), 51.9 (C), 51.4
(CH), 51.3 (CH3), 37.9 (CH2), 37.8 (CH2), 34.5 (CH2), 33.7
(CH2), 28.8 (CH2), 12.9 (CH3); HRMS: m/z calcd for
C13H18O3Na (M+Na): 245.1154. Found: 245.1152. For the
cis-ester 15: IR (neat): mmax/cmꢀ1 1733, 1650, 887; 1H NMR
(300 MHz, CDCl3 + CCl4): d 4.57 (2H, s), 3.64 (3H, s), 2.53
(1H, dd, J 8.4 and 7.2 Hz), 2.30–1.30 (13H, m), 0.96 (3H, d,
J 7.2 Hz); 13C NMR (75 MHz, CDCl3 + CCl4): d 176.3 (C),
148.6 (C), 106.9 (CH2), 53.7 (CH3), 51.2 (CH), 48.4 (C),
41.6 (CH), 41.1 (CH2), 32.4 (CH2), 32.1 (CH2), 32.0 (CH2),
30.4 (CH2), 27.3 (CH2), 15.7 (CH3). For the trans-ester 16:
IR (neat): mmax/cmꢀ1 1733, 1651, 886; 1H NMR (300 MHz,
CDCl3 + CCl4): d 4.57 (2H, s), 3.65 (3H, s), 2.87 (1H, dd, J
8.7 and 5.1 Hz), 2.25–1.70 (8H, m), 1.57–1.15 (5H, m), 0.86
(3H, d, J 7.2 Hz); 13C NMR (75 MHz, CDCl3 + CCl4): d
176.1 (C) 148.8 (C), 107.0 (CH2), 51.2 (CH3), 50.1 (CH),
In conclusion, we have accomplished an efficient total
syntheses of spiro sesquiterpenes acorenols 1–4. A com-
bination of an Ireland ester Claisen rearrangement and
RCM reactions was employed for the efficient construc-
tion of spiro[4.5]decane present in the acorenols. In the
present sequence, the key precursor of the acorenols, the
spiro[4.5]decanecarboxylate 14, was obtained in an over-
all yield of 67%, in seven steps starting from cyclohex-
ane-1,4-dione 6.
Acknowledgement
We thank the University Grants Commission, New
Delhi, for the award of a research fellowship to R.R.B.

A. Srikrishna, R. R. Babu / Tetrahedron Letters 48 (2007) 6916–6919
6919
48.4 (C), 40.0 (CH), 33.4 (CH2), 31.7 (CH2), 31.5 (CH2),
31.3 (CH2), 31.1 (CH2), 25.6 (CH2), 14.6 (CH3); HRMS:
m/z calcd for C14H22O2Na (M+Na): 245.1517. Found:
245.1523. For a-acorenol 1: IR (neat): mmax/cmꢀ1: 3479; 1H
NMR (300 MHz, CDCl3 + CCl4): d 5.40 (1H, br s), 2.35
(1H, d, J 17.4 Hz), 2.10–1.05 (12H, m), 1.66 (3H, s), 1.21
(6H, s), 0.86 (3H, d, J 6.6 Hz); 13C NMR (75 MHz,
CDCl3 + CCl4): d 135.0 (C), 121.4 (CH), 73.7 (C), 54.9
(CH), 45.1 (C), 41.8 (CH), 31.7 (CH3), 30.7 (CH2), 30.3
(CH2), 29.3 (CH2), 28.2 (CH3), 28.1 (CH2), 26.2 (CH2), 23.5
(CH3), 15.1 (CH3); HRMS: m/z calcd for C15H26ONa
(M+Na): 245.1881. Found: 245.1880. For b-acorenol 2: IR
(neat): mmax/cmꢀ1 3459; 1H NMR (300 MHz, CDCl3 +
CCl4): d 5.31 (1H, br s), 2.35 (1H, d, J 16.8 Hz), 2.20–1.05
(12H, m), 1.60 (3H, s), 1.31 (3H, s), 1.25 (3H, s), 0.83 (3H,
d, J 6.9 Hz); 13C NMR (75 MHz, CDCl3 + CCl4): d 133.3
(C), 121.8 (CH), 73.8 (C), 57.6 (CH), 44.5 (C), 41.1 (CH),
33.6 (CH2), 31.9 (CH2), 31.2 (CH3), 30.7 (CH3), 30.2 (CH2),
27.8 (CH2), 26.1 (CH2), 23.5 (CH3), 18.2 (CH3); HRMS:
m/z calcd for C15H26ONa (M+Na): 245.1881. Found:
245.1877. For a-epi-acorenol 3: IR (neat): mmax/cmꢀ1 3468;
1H NMR (300 MHz, CDCl3 + CCl4): d 5.39 (1H, br s), 2.46
(1H, d, J 17.7 Hz), 2.05–1.49 (10H, m), 1.63 (3H, s), 1.50–
1.16 (2H, m), 1.24 (3H, s), 1.23 (3H, s), 0.86 (3H, d, J
6.6 Hz); 13C NMR (75 MHz, CDCl3 + CCl4): d 133.8 (C),
122.1 (CH), 73.4 (C), 60.5 (CH), 44.6 (C), 44.3 (CH), 37.8
(CH2), 32.0 (CH3), 31.5 (CH2), 29.0 (CH3), 28.9(CH2), 27.7
(CH2), 27.1 (CH2), 23.5 (CH3), 17.8 (CH3); HRMS: m/z
calcd for C15H26ONa (M+Na): 245.1881. Found: 245.1885.
1
For b-epi-acorenol 4: IR (neat): mmax/cmꢀ1 3466; H NMR
(300 MHz, CDCl3 + CCl4): d 5.28 (1H, br s), 2.20–1.50
(12H, m), 1.62 (3H, s), 1.28 (3H, s), 1.23 (3H, s), 0.93 (3H,
d, J 7.2 Hz), 0.88–0.78 (1H, m); 13C NMR (75 MHz,
CDCl3 + CCl4): d 133.7 (C), 121.3 (CH), 73.4 (C), 61.3
(CH), 44.9 (C), 42.7 (CH), 40.9 (CH2), 31.5 (CH3), 30.8
(CH2), 29.8 (CH3), 29.2 (CH2), 26.3 (CH2), 24.9 (CH2), 23.5
(CH3), 16.0 (CH3); HRMS: m/z calcd for C15H26ONa
(M+Na): 245.1881. Found: 245.1870.