The first enantiospecific total synthesis of (+)-seychellene

Article abstract of DOI:10.1016/j.tetlet.2006.11.011

The first enantiospecific total synthesis of the tricyclic sesquiterpene (+)-seychellene, starting from (R)-carvone via (S)-3-methylcarvone, has been accomplished employing a combination of an intermolecular Michael addition-intramolecular Michael additio

Full text of DOI:10.1016/j.tetlet.2006.11.011

Tetrahedron Letters 48 (2007) 73–76
The first enantiospecific total synthesis of (+)-seychellene
A. Srikrishna,* G. Ravi and G. Satyanarayana
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 30 August 2006; revised 21 October 2006; accepted 1 November 2006
Available online 21 November 2006
Abstract—The first enantiospecific total synthesis of the tricyclic sesquiterpene (+)-seychellene, starting from (R)-carvone via (S)-3-
methylcarvone, has been accomplished employing a combination of an intermolecular Michael addition–intramolecular Michael
addition sequence and an intramolecular alkylation reaction for the generation of the two vicinal quaternary carbon atoms.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The tricyclic sesquiterpene (ꢀ)-seychellene 1 was isolated
from the patchouli oil (from the leaves of Pogostemon ca-
blin Benth obtained from the Seychelles Islands), as one
of the minor components along with a- and b-patchoul-
enes 2 and 3 and patchouli alcohol 4.1 It was subse-
quently isolated from a variety of species belonging to
Pogostemon and Nardostachys jatamansi. The relative
structure as well as the absolute configuration of seychell-
ene 1 was established by the elegant work of Ourisson
and Wolff.1 The novel structure containing a homoiso-
twistane carbon framework (tricyclo[5.3.1.03,8]undecane
5) incorporating two vicinal quaternary carbon atoms,
which is structurally and biogenetically closely related
to patchouli alcohol 4, attracted the attention of syn-
thetic chemists, and a number of reports appeared on
the synthesis of seychellene 1 in its racemic form.2 How-
ever, so far, there is no report on the enantioselective syn-
thesis of seychellene 1. In continuation of our interest in
the enantiospecific synthesis of tricyclic sesquiterpenes,
such as neopupukeananes, pupukeananes, valeriana-
noids, and patchouli alcohol,3 starting from the readily
available monoterpene (R)-carvone, herein, we report
an efficient methodology for the enantiospecific synthesis
of norseychellene 6 and its extension to the first enantio-
specific synthesis of (+)-seychellene 1.
An intramolecular alkylation reaction of the bicyclic ke-
tone 7 was contemplated for the construction of the tri-
cyclic system containing the two requisite vicinal
quaternary carbon atoms, Scheme 1. An intermolecular
Michael addition followed by intramolecular addition of
the dienolate derived from 2,3-dimethylcyclohexenone 9
to methyl acrylate was conceived for the generation of
the bicyclic ester 8, which could be further elaborated
into 7. Since enone 9 is achiral, 3-methylcarvone 10,
which is readily available from carvone 11,4 was identi-
fied as a chiral equivalent of enone 9, with the isoprop-
enyl group serving as a disposable chiral directing
group.
Initially, the synthesis of norseychellene 6 was ad-
dressed, Scheme 2. Thus, generation of the kinetic lith-
ium dienolate of 3-methylcarvone 10 with 1.1 equiv of
lithium hexamethyldisilazide in hexane followed by
treatment with 1 equiv of methyl acrylate generated
23
the bicyclic ketoester 12, ½aꢁD +82.3 (c 9, CHCl3), via
O
O
R
X
R
COOMe
10
1
1 R = Me
6 R = H
7
8
2
11
8
5
3
7
O
O
OH
O
1
2
3
4
5
11
Scheme 1.
10
9
*
Corresponding author. Tel.: +91 80 22932215; fax: +91 80
23600529; e-mail: ask@orgchem.iisc.ernet.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.011

74
A. Srikrishna et al. / Tetrahedron Letters 48 (2007) 73–76
a tandem intermolecular Michael addition–intramole-
cular Michael addition sequence.5 Simultaneous protec-
tion of the ketone and isomerisation of the olefin bond
of the isopropenyl group in keto ester 12 with 1,2-
ethanediol and a catalytic amount of p-toluenesulfonic
acid (PTSA) in refluxing benzene under Dean-Stark
conditions furnished ketal ester 13 in 90% yield. Ester
13 was then converted into aldehyde 14 employing a
reduction–oxidation protocol in 83% yield. Horner–
Wadsworth–Emmons reaction of aldehyde 14 with tri-
the C-2 ketone is more sterically crowded than the C-10
ketone, and this property was exploited for the selective
reductive removal of the C-10 ketone. Thus, reaction of
diketone 21 with 1,2-ethanedithiol and a catalytic
amount of boron trifluoride diethyl etherate in methyl-
ene chloride furnished thioketal 22 in 98% yield, which
on desulfurisation with Raney nickel in refluxing etha-
nol quantitatively furnished bis-norseychellenone 23.
Since the conventional Wittig reaction was unsuccessful,
methylenation was carried out employing the conditions
developed by Yan and co-workers.6 Accordingly, reac-
tion of ketone 23 with methylene chloride–magne-
sium–titanium chloride in THF gave norseychelleneꢀ 6
in 86% yield, whose structure was established from its
spectral data.
ethyl phosphonoacetate and sodium hydride in THF
24
furnished a,b-unsaturated ester 15, in 97% yield, ½aꢁD
+62.5 (c 13.5, CHCl3). Regioselective hydrogenation
of the disubstituted olefin in 15 using 10% palladium
on charcoal as the catalyst generated ester 16, which
on reduction with lithium aluminium hydride (LAH)
furnished primary alcohol 17, in 99% yield. Next, atten-
tion was turned towards the construction of the third
ring via an intramolecular alkylation reaction. Hydroly-
sis of the ketal in 17 with aqueous acetic acid followed
by treatment of the resultant hydroxyketone 18 with
methanesulfonyl chloride and pyridine in methylene
chloride furnished ketomesylate 19 in 84% yield (2
steps). Intramolecular alkylation of ketomesylate 19
with sodium hydride in refluxing THF furnished the tri-
cyclic ketoneꢀ 20, in 75% yield, whose structure was
established from its spectral data. Ozonolysis followed
by reductive work-up with dimethyl sulfide transformed
ketoolefin 20 into dione 21 in 94% yield. In diketone 21,
After successfully accomplishing the enantiospecific syn-
thesis of norseychellene 6 (obtained from R-carvone in
16 steps with an average yield of 91% in each step),
the methodology was extended to the first enantiospeci-
fic total synthesis of (+)-seychellene 1 employing alde-
hyde 14 as the starting material, Scheme 3. The
requisite methyl group was introduced by converting
24
aldehyde 14 into ketone 24, ½aꢁD +120.2 (c 11.4,
CHCl3), in 89% yield, employing a Grignard reaction–
oxidation protocol. Horner–Wadsworth–Emmons reac-
tion of ketone 24 with triethyl phosphonoacetate and
sodium hydride in refluxing THF furnished the
unsaturated ester 25. Since, selective hydrogenation of
the olefin in 25 was found to be inefficient, a one step,
one electron transfer methodology was adopted for
the direct conversion of the unsaturated ester 25 into
the primary alcohol 26. Accordingly, treatment of the
unsaturated ester 25 with lithium in liquid ammonia fur-
nished a 4:3 diastereomeric mixture of the primary alco-
ꢀ Yields refer to isolated and chromatographically pure compounds.
All the compounds exhibited spectral data (IR, 1H and 13C NMR and
HRMS) consistent with their structures. Selected spectral data for
21
tricyclic ketone 20: ½aꢁD +52 (c 3, CHCl3); IR (neat): mmax 1717 cmꢀ1
;
24
24
hols 26a, ½aꢁD +65.5 (c 14, CHCl3), and 26b, ½aꢁD +68.5
(c 2.7, CHCl3), which were separated by column chro-
matography on silica gel. On the basis of thermo-
dynamic considerations, the R-configuration was
assigned tentatively to the newly created chiral centre
in the major isomer 26a, which was later confirmed by
its conversion to seychellene 1. The same sequence, as
that used for norseychellene 6, was continued with the
major isomer 26a. Thus, hydrolysis of the ketal moiety
in hydroxyketal 26a with aqueous acetic acid followed
by mesylation of the resultant hydroxyketone 27 with
1H NMR (300 MHz, CDCl3 + CCl4): d 3.15 (1H, s), 2.32 (1H, d, J
17.1 Hz), 1.90–1.81 (2H, m), 1.61 (3H, s), 1.54 (3H, s), 1.73–1.47 (4H,
m), 1.40–1.13 (4H, m), 0.95 (3H, s), 0.80 (3H, s); 13C NMR (75 MHz,
CDCl3 + CCl4): d 218.2 (C), 126.1 (C), 125.7 (C), 49.5 (C), 49.2 (CH),
39.1 (CH2), 37.2 (C), 37.1 (CH), 32.4 (CH2), 29.0 (CH2), 27.8 (CH2),
20.2 (CH3), 20.0 (CH3), 19.9 (CH3), 19.6 (CH3), 18.4 (CH2); HRMS:
m/z calcd for C16H24ONa (M+Na): 255.1725; found: 255.1722. For
25
norseychellene 6: ½aꢁD +20.9 (c 2.1, CHCl3); IR (neat): mmax 1639,
883 cmꢀ1; 1H NMR (300 MHz, CDCl3 + CCl4): d 4.81 and 4.60 (2H,
2 · d, J 1.5 Hz), 2.22 (1H, br s), 1.82–1.04 (13H, m), 0.97 (3H, s), 0.83
(3H, s); 13C NMR (75 MHz, CDCl3): d 162.4 (C), 103.5 (CH2), 40.2
(C), 38.4 (CH), 37.8 (CH), 36.3 (CH2), 34.1 (C), 32.2 (CH2), 31.4
(CH2), 28.2 (CH2), 28.0 (CH2), 25.3 (CH3), 20.4 (CH3), 18.0 (CH2).
methanesulfonyl chloride and pyridine in methylene
23
chloride generated ketomesylate 28, ½aꢁD +54.7 (c 3.6,
21
For the tricyclic ketone 29: ½aꢁD +76.0 (c 3.5, CHCl3); IR (neat): mmax
CHCl3), in 91% yield. Intramolecular alkylation reac-
tion of ketomesylate 28 with sodium hydride in refluxing
THF furnished the tricyclic ketoneꢀ 29 in 75% yield,
which on ozonolysis gave dione 30 in 94% yield. Regio-
selective thioketalisation of dione 30, followed by Raney
nickel mediated desulfurisation of thioketal 31 in reflux-
ing ethanol furnished norseychellenoneꢀ 32, whose
structure was established by comparing the spectral data
with that of the racemic compound reported in the liter-
ature. Finally, methylenation of ketone 32 with methyl-
1719 cmꢀ1 1H NMR (300 MHz, CDCl3 + CCl4): d 3.19 (1H, t, J
;
3.0 Hz), 2.38 (1H, d, J 17.1 Hz), 2.10–1.88 (2H, m), 1.80–1.50 (5H,
m), 1.67 (3H, s), 1.60 (3H, s), 1.40 (1H, dd, J 13.8 and 4.5 Hz), 1.35–
1.18 (1H, m), 1.02 (3H, s), 0.86 (3H, s), 0.81 (3H, d, J 6.6 Hz); 13C
NMR (75 MHz, CDCl3 + CCl4): d 218.3 (C), 126.0 (C), 125.5 (C),
49.1 (C), 48.9 (CH), 43.4 (CH), 39.3 (CH2), 38.3 (C), 33.2 (CH2), 29.9
(CH3), 26.8 (CH2), 23.3 (CH2), 20.1 (2C, CH3), 19.7 (CH3), 19.6
(CH3), 18.9 (CH3); HRMS: m/z calcd for C17H27O (M+H): 247.2062;
22
found: 247.2071. For norseychellenone 32: ½aꢁD +38.1 (c 2.7, CHCl3);
IR (neat): mmax 1718 cmꢀ1 1H NMR (300 MHz, CDCl3 + CCl4): d
;
2.21 (1H, br s), 2.05–1.85 (1H, m), 1.85–1.50 (8H, m), 1.45–1.23 (3H,
m), 0.96 (3H, s), 0.94 (3H, s), 0.80 (3H, d, J 6.9 Hz sec-CH3); 13C
NMR (75 MHz, CDCl3 + CCl4): d 222.7 (C), 49.1 (C), 43.9 (CH),
42.9 (CH), 37.4 (C), 33.4 (CH2), 30.6 (CH2), 29.9 (CH), 26.8 (CH2),
24.0 (CH2), 22.8 (CH2), 20.2 (CH3), 19.4 (CH3), 18.6 (CH3); HRMS:
m/z calcd for C14H22ONa (M+Na): 229.1568; found: 229.1563.
ene chloride–magnesium–titanium chloride in THF
23
furnished (+)-seychellene 1, ½aꢁD +27.6 (c 1.7, CHCl3),
which exhibited 1H and 13C NMR spectral data virtually
identical to that reported in the literature2e for the race-
mic compound.

A. Srikrishna et al. / Tetrahedron Letters 48 (2007) 73–76
75
O
O
O
O
a
b
c
O
90%
65%
86%
COOMe
COOMe
11
10
12
13
83%
d,e
O
O
O
O
g
O
f
O
97%
100%
EtOOC
d
CHO
COOEt
16
15
14
99%
O
O
O
O
O
j
h
i
92%
91%
75%
HO
HO
MsO
17
18
19
20
k
94%
O
S
S
O
O
O
n
l
m
86%
98%
100%
6
23
22
21
Scheme 2. Reagents and conditions: (a) (i) MeMgI, Et2O, 0 ꢁC ! rt, 45 min; (ii) PCC, silica gel, CH2Cl2, 6 h; (b) LiHMDS, hexane,
CH2@CHCOOMe, ꢀ70 ꢁC ! rt, 3 h; (c) (CH2OH)2, PTSA, C6H6, reflux, 4 h; (d) LAH, Et2O, 0 ꢁC ! rt, 0.5 h; (e) PCC, NaOAc, CH2Cl2, rt, 0.5 h;
(f) (EtO)2P(O)CH2COOEt, NaH, THF, 0 ꢁC ! rt, 0.5 h; (g) 10% Pd–C, H2 (1 atm), hexane, 4 h; (h) H2O–AcOH (1:1), 60 ꢁC, 1 h; (i) MsCl, py,
CH2Cl2, 0 ꢁC ! rt, 0.5 h; (j) NaH, THF, reflux, 6 h; (k) (i) O3/O2, MeOH:CH2Cl2 (1:4), ꢀ70 ꢁC; (ii) Me2S, 6 h; (l) (CH2SH)2, BF3ÆEt2O, CH2Cl2,
0 ꢁC ! rt, 1 h; (m) Raney Ni, EtOH, reflux, 2 h; (n) Mg, TiCl4, CH2Cl2, THF, 0 ꢁC ! rt, 1 h.
O
O
O
O
O
O
c
O
a
b
O
14
+
94%
93%
89%
HO
HO
O
( 4 : 3 )
26b
24
25
26a
COOEt
O
O
O
d
e
f
26a
90%
91%
75%
HO
MsO
27
28
29
g
94%
O
S
S
O
O
O
j
h
i
100%
98%
86%
1
32
31
30
Scheme 3. Reagents and conditions: (a) (i) MeMgI, Et2O, 0 ꢁC ! rt, 0.75 h; (ii) PCC, NaOAc, CH2Cl2, 0.5 h; (b) (EtO)2P(O)CH2COOEt, NaH,
THF, reflux, 48 h; (c) Li, liq. NH3, THF, EtOH, ꢀ33 ꢁC, 0.5 h; (d) H2O–AcOH (1:1), 60 ꢁC, 1 h; (e) MsCl, py, CH2Cl2, 0 ꢁC ! rt, 0.75 h; (f) NaH,
THF, reflux, 6 h; (g) (i) O3/O2, MeOH:CH2Cl2 (1:4), ꢀ70 ꢁC; (ii) Me2S, 6 h; (h) (CH2SH)2, BF3ÆEt2O, CH2Cl2, 0 ꢁC ! rt, 1 h; (i) Raney Ni, EtOH,
reflux, 2 h; (j) Mg, TiCl4, CH2Cl2, THF, 0 ꢁC ! rt, 1 h.

76
A. Srikrishna et al. / Tetrahedron Letters 48 (2007) 73–76
J. Chem. Soc., Perkin Trans. 1 1990, 2109; (c) Stork, G.;
Baine, N. H. Tetrahedron Lett. 1985, 26, 5927; (d) Welch, S.
C.; Chou, C.-Y.; Gruber, J. M.; Assercq, J.-M. J. Org.
Chem. 1985, 50, 2668; (e) Welch, S. C.; Gruber, J. M.;
Morrison, P. A. J. Org. Chem. 1985, 50, 2676; (f) Jung, M.
E.; McCombs, C. A.; Takeda, Y.; Pan, Y.-G. J. Am. Chem.
Soc. 1981, 103, 6677; (g) Yamada, K.; Kyotani, Y.;
Manabe, S.; Suzuki, M. Tetrahedron 1979, 35, 293; (h)
Frater, G. Helv. Chim. Acta 1974, 57, 172; (i) Fukamiya,
N.; Kato, M.; Yoshikoshi, A. J. Chem. Soc., Perkin Trans.
1 1973, 1843; (j) Mirrington, R. N.; Schmalzl, K. J. J. Org.
Chem. 1972, 37, 2877; (k) Piers, E.; de Wall, W.; Britton, R.
W. J. Am. Chem. Soc. 1971, 93, 5113; For an attempted
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Tetrahedron Lett. 1990, 31, 6839.
In summary, we have developed an efficient enantiospec-
ific methodology for the synthesis of norseychellene
(+)-6, and extended it to the first enantiospecific total
synthesis of ent-seychellene (+)-1 starting from (R)-carv-
one via (S)-3-methylcarvone. A combination of an inter-
molecular Michael addition–intramolecular Michael
addition sequence and an intramolecular alkylation
reaction was strategically employed for the generation
of the tricyclic system containing two vicinal quaternary
carbon atoms. Since the conversion of (R)-carvone to
(R)-3-methylcarvone is also known,4 the present se-
quence is also applicable to (ꢀ)-seychellene.
3. (a) Srikrishna, A.; Kumar, P. R.; Gharpure, S. J. Indian J.
Chem. 2006, 45B, 1909; (b) Srikrishna, A.; Satyanarayana,
G. Tetrahedron Lett. 2006, 47, 367; (c) Srikrishna, A.;
Satyanarayana, G. Tetrahedron: Asymmetry 2005, 16, 3992;
(d) Srikrishna, A.; Satyanarayana, G. Tetrahedron 2005, 61,
8855; (e) Srikrishna, A.; Satyanarayana, G. Org. Lett. 2004,
6, 2337; (f) Srikrishna, A.; Gharpure, S. J. J. Org. Chem.
2001, 66, 4379; (g) Srikrishna, A.; Gharpure, S. J. J. Chem.
Soc., Perkin Trans. 1 2000, 3191; (h) Srikrishna, A.;
Gharpure, S. J. Tetrahedron Lett. 1999, 40, 1035.
Acknowledgements
We thank the Council of Scientific and Industrial Re-
search, New Delhi, for the award of research fellowships
to G.R. and G.S.
References and notes
4. Srikrishna, A.; Hemamalini, P. Indian J. Chem. 1990, 29B,
152.
5. Zhao, R.-B.; Zhao, Y.-F.; Song, G.-Q.; Wu, Y.-L. Tetra-
hedron Lett. 1990, 31, 3559.
1. (a) Wolff, G.; Ourisson, G. Tetrahedron Lett. 1968, 3849;
(b) Wolff, G.; Ourisson, G. Tetrahedron 1969, 25, 4903; (c)
Maheshwari, M. L.; Saxena, D. B. Indian J. Chem. 1974,
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6. Yan, T.-H.; Tsai, C.-C.; Chien, C.-T.; Cho, C.-C.; Huang,
P.-C. Org. Lett. 2004, 6, 4961.
2. (a) Rao, G. S. R. S.; Bhaskar, K. V. J. Chem. Soc., Perkin
Trans. 1 1993, 2813; (b) Hagiwara, H.; Okano, A.; Uda, H.