The first total syntheses of the sesquiterpenes (±)-1,10;7,10- bisepoxy-1,10-seco-calamanene and (±)-6,7;7,10-bisepoxy-6,7-seco- calamanene

Article abstract of DOI:10.1055/s-2008-1072733

First total syntheses of the tricyclic sesquiterpenes mentioned in the title containing a benzo-fused 2,8-dioxabicyclo[3.2.1]octane framework, confirming the structures of the natural products, are described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072733

LETTER
1199
The First Total Syntheses of the Sesquiterpenes ( )-1,10;7,10-Bisepoxy-1,10-
seco-calamanene and ( )-6,7;7,10-Bisepoxy-6,7-seco-calamanene
Total
S
yntheses of
.
the Sesquite
S
rpenes rikrishna,* G. Ravi, Hema S. Krishnan
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Received 15 January 2008
and 2 prompted us to investigate the synthesis of these
Abstract: First total syntheses of the tricyclic sesquiterpenes men-
tioned in the title containing a benzo-fused 2,8-dioxabicyc-
lo[3.2.1]octane framework, confirming the structures of the natural
products, are described.
compounds to confirm their structures. Since alternate re-
giostructures 3 and 4 were also possible, a general meth-
odology was investigated for the synthesis of the
compounds 1–4. In continuation of our interest in the syn-
thesis of tricyclic sesquiterpenes containing benzo-fused
oxabicyclo[3.2.1]octanes,3 herein we report the first total
syntheses of the sesquiterpenes 1 and 2.
Key words: natural products, sesquiterpenes, total synthesis, in-
tramolecular acetalisation, dioxabicyclo[3.2.1]octanes
The essential oils derived from plants belonging to the ge-
nus Hedychium are a rich source of a variety of mono- and
sesquiterpenes. In continuation of their phytochemical
investigations1 on the genus Hedychium, Weyerstahl et al.
reported2 the isolation of a number of sesquiterpenes from
the essential oil obtained by hydrodistillation of the rhi-
zomes of the yellow flowering plant Hedychium gardne-
rianum Roscoe, collected from Mungpoo (Darjeeling,
India) at an altitude of 1200 m. The essential oil was found
to contain about 30% of sesquiterpenes, mainly cadinane
derivatives. In addition to several known sesquiterpenes,
they have reported the isolation of two new tricyclic com-
pounds 1,10;7,10-bisepoxy-1,10-seco-calamanene (1)
and 6,7;7,10-bisepoxy-6,7-seco-calamanene (2) as an in-
separable mixture.2 The structures of the compounds 1
and 2 were established based on the analysis of 1H NMR
and 13C NMR spectra of a 3:1 mixture of the compounds
1 and 2 (Figure 1)
O
O
a
87%
HO
MOMO
5
6
90%
b
OH
OH
c
O
MOMO
89%
MOMO
8
7
O
d
O
HO
89%
O
MOMO
O
9
O
1
O
Scheme 1 Reagents and conditions: (a) NaH, MOMCl, THF, 0 °C
to r.t., 1.5 h; (b) CH2=CH(CH2)2MgBr, THF, 0 °C to r.t., ))), 1 h; (c)
PdCl2 (0.5 equiv), CuCl (5 equiv), DMF–H2O (4:1), O2, r.t., 3 h; (d)
3 N HCl, THF, r.t., 2 h.
O
1
2
O
O
To begin with, the synthesis of compound 1 was ad-
dressed starting from the isobutyrophenone 5 obtained
from p-cresol (Scheme 1). It was contemplated that intro-
duction of a 3-oxobutyl side chain followed by an in-
tramolecular acetalisation would lead to compound 1, and
3-butenyl group was identified as the masked 3-oxobutyl
group. Accordingly, the phenolic hydroxy group was pro-
tected as its methoxymethyl (MOM) ether by employing
sodium hydride and methoxymethyl chloride to furnish
the keto ether 6 in 87% yield. Grignard reaction of the
keto ether 6 with but-3-enylmagnesium bromide in THF
furnished the tertiary alcohol 7 in 90% yield. A Wacker
oxidation4 was opted for the conversion of the vinyl group
to an acetyl group in 7. Thus, reaction of the hydroxyole-
O
O
4
3
Figure 1
The presence of an interesting benzo-fused dioxabicyc-
lo[3.2.1]octane framework present in the compounds 1
and 2 coupled with the fact that the structures were as-
signed on the basis of the spectral data of a mixture of 1
SYNLETT 2008, No. 8, pp 1199–1201
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072733; Art ID: D01108ST
x
x.
x
x.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

1200
A. Srikrishna et al.
LETTER
O
O
fin 7 with palladium chloride, copper(I) chloride in a mix-
ture of dimethylformamide (DMF) and water in an
oxygen atmosphere (balloon) for three hours furnished the
hydroxy ketone 8 (in 89% yield),5 which was found to be
in equilibrium with an epimeric mixture of the hemiacetal
9. Finally, hydrolysis of the MOM ether with 3 N aqueous
hydrochloric acid in THF transformed the mixture of 8
and 9 into the tricyclic compound 1 (in 89% yield), which
exhibited 1H NMR and 13C NMR spectral data5 identical
to those reported in the literature.2
a
81%
HO
MOMO
90%
11
12
b
OH
OMOM
c
MOMO
93%
MOMO
92%
14
13
H2 (1 atm)
10% Pd/C
d
O
O
EtOAc, 8 h
OMOM
OMOM
90%
O
HO
e
OHC
1
10
OH
91%
MOMO
MOMO
Scheme 2
15
16
f
86%
O
After successfully accomplishing a four-step efficient
synthesis of the tricyclic sesquiterpene 1, it was readily
identified that hydrogenolytic cleavage of the benzylic
oxygen in 1 would lead to litseachromolaevane A (10), a
sesquiterpene recently reported6,7 from an anti-HIV frac-
tion of the leaves and twigs of Litsea verticillata Hance
(Scheme 2). Accordingly, hydrogenation of the tricyclic
sesquiterpene 1 in ethyl acetate at one atmospheric pres-
sure of hydrogen using 10% palladium over carbon as the
catalyst furnished compound 10 in 90% yield, which ex-
OMOM
O
g
89%
O
MOMO
17
2
Scheme 3 Reagents and conditions: (a) NaH, MOMCl, THF, 0 °C
to r.t., 1.5 h; (b) CH2=CH(CH2)2MgBr, THF, 1 h; (c) MOMCl, i-
Pr2EtN, CH2Cl2, r.t., 12 h; (d) O3/O2, MeOH–CH2Cl2 (1:5), cat.
NaHCO3, –70 °C; Me2S, r.t., 3 h; (e) i-PrMgBr, Et2O, 0 °C to r.t., 0.75
h; (f) PDC, CH2Cl2, r.t., 3 h; (g) 3 N HCl, THF, r.t., 1.5 h.
1
hibited H NMR and 13C NMR spectral data identical to
those reported for the natural product in the literature.6
Next, the synthesis of compound 2 was investigated start-
ing from 2-hydroxy-4-methylacetophenone (11), see
Acknowledgment
Scheme 3. Protection of the phenolic hydroxy group with We thank the Council of Scientific and Industrial Research, New
Delhi for the award of a research fellowship to G.R.
sodium hydride and methoxymethyl chloride transformed
11 into the MOM ether 12.8 Grignard reaction of the keto
ether 12 with but-3-enylmagnesium bromide in THF fur-
nished the tertiary alcohol 13 in 90% yield. Treatment of
the tertiary alcohol 13 with methoxymethyl chloride and
References and Notes
(1) Weyerstahl, P.; Schweiger, R.; Schwope, I.; Hashem, Md. A.
Liebigs Ann. 1995, 1389; and references cited therein.
(2) Weyerstahl, P.; Marschall, H.; Thefeld, K.; Subba, G. C.
ethyldiisopropylamine in methylene chloride furnished
the bis-MOM ether 14.5 Ozonolysis of the olefin in 14 fol-
Flavour Fragr. J. 1998, 13, 377.
lowed by reductive workup with dimethyl sulfide generat-
ed the aldehyde 15. Grignard reaction of the aldehyde 15
with isopropylmagnesium bromide furnished a 1:1
epimeric mixture of the secondary alcohol 16, which on
oxidation with pyridinium dichromate (PDC) in dichlo-
romethane furnished the ketone 17.5 Finally, hydrolysis of
the MOM ethers with 3 N aqueous hydrochloric acid in
THF transformed the ketone 17 into the compound 2,
which exhibited 13C NMR spectral data identical to those
reported for the natural product in the literature.2,9
(3) Srikrishna, A.; Rao, M. S. Synlett 2004, 374.
(4) Tsuji, T. Organic Synthesis with Palladium Compounds;
Springer: New York, 1980, 6–12.
(5) Yields refer to isolated and chromatographically pure
compounds. All the compounds exhibited spectral data (IR,
1H NMR, 13C NMR, and HRMS) consistent with their
structures.
Selected Spectral Data
Alcohol 7: IR (neat): nmax = 3531, 1639, 810 cm–1. 1H NMR
(300 MHz, CDCl3): d = 7.12 (1 H, s), 7.00–6.90 (2 H, m),
5.82–5.72 (1 H, m), 5.15 (2 H, br s), 4.90 (1 H, d, J = 15.9
Hz), 4.86 (1 H, d, J = 9.0 Hz), 3.45 (3 H, s), 3.11 (1 H, br s),
2.29 (3 H, s), 2.30–1.95 (3 H, m), 1.81 (1 H, td, J = 12.9 and
4.2 Hz), 1.70–1.60 (1 H, m), 0.96 (3 H, d, J = 6.6 Hz), 0.72
(3 H, d, J = 6.9 Hz). 13C NMR (75 MHz, CDCl3): d = 152.4
(C), 139.4 (CH), 132.7 (C), 130.5 (C), 129.0 (CH), 128.1
(CH), 114.3 (CH), 114.1 (CH2), 94.5 (CH2), 79.8 (C), 56.0
(CH3), 36.6 (CH2), 36.2 (CH), 28.9 (CH2), 20.9 (CH3), 17.7
(CH3), 16.8 (CH3). HRMS: m/z calcd for C17H26O3Na [M +
In conclusion, we have developed short and efficient syn-
theses of the tricyclic sesquiterpenes ( )-1,10;7,10-bisep-
oxy-1,10-seco-calamanene (1) and ( )-6,7;7,10-bis-
epoxy-6,7-seco-calamanene (2) confirming the structures
of the natural products.
Synlett 2008, No. 8, 1199–1201 © Thieme Stuttgart · New York

LETTER
Na]: 301.1780; found: 301.1776.
Total Syntheses of the Sesquiterpenes
1201
HRMS: m/z calcd for C15H20O2Na [M + Na]: 255.1361;
found: 255.1360.
Compound 1: IR (neat): nmax = 1492, 1262, 1199, 814 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.86 (1 H, d, J = 8.1 Hz),
6.83 (1 H, s), 6.58 (1 H, d, J = 8.1 Hz), 2.50–2.14 (3 H, m),
2.25 (3 H, s), 2.10–1.90 (2 H, m), 1.65 (3 H, s), 1.14 (3 H, d,
J = 6.6 Hz), 1.03 (3 H, d, J = 6.9 Hz). 13C NMR (75 MHz,
CDCl3): d = 150.1 (C), 128.6 (C), 128.5 (C), 128.4 (CH),
123.8 (CH), 116.1 (CH), 106.6 (C), 87.7 (C), 38.9 (CH2),
38.1 (CH2), 30.4 (CH), 24.3 (CH3), 21.0 (CH3), 18.6 (CH3),
16.8 (CH3). HRMS: m/z calcd for C15H20O2Na [M + Na]:
255.1361; found: 255.1359.
Compound 4: IR (neat): nmax = 1624, 1386, 1167, 1078
cm–1. 1H NMR (400 MHz, CDCl3): d = 6.95 (1 H, d, J = 8.0
Hz), 6.63 (1 H, d, J = 8.0 Hz), 6.56 (1 H, s), 2.25 (3 H, s),
2.60–2.20 (4 H, m), 2.10–1.90 (1 H, m), 1.66 (3 H, s), 1.13
(3 H, d, J = 6.9 Hz), 1.03 (3 H, d, J = 6.9 Hz). 13C NMR (100
MHz, CDCl3): d = 152.2 (C), 137.9 (C), 126.0 (C), 123.3
(CH), 120.5 (CH) 116.8 (CH), 106.9 (C), 87.8 (C), 38.9
(CH2), 38.2 (CH2), 30.6 (CH), 24.2 (CH3), 21.1 (CH3), 18.5
(CH3), 16.8 (CH3). HRMS: m/z calcd for C15H20O2Na [M +
Na]: 255.1361; found: 255.1359.
Bis-MOM ether 14: IR (neat): nmax = 1613, 1151, 1016, 923,
817 cm–1. 1H NMR (400 MHz, CDCl3): d 7.30 (1 H, d, J =
8.0 Hz), 6.90 (1 H, s), 6.76 (1 H, d, J = 8.0 Hz), 5.73 (1 H,
ddt, J = 16.8, 10.4, 6.4 Hz), 5.17 (2 H, s, OCH2O), 4.90 (1 H,
d, J = 16.8 Hz), 4.84 (1 H, d, J = 10.4 Hz), 4.75 and 4.70 (2
H, 2 × d, J = 7.2 Hz), 3.47 (3 H, s), 3.41 (3 H, s), 2.32 (3 H,
(6) Cuong, N. M.; Soejarto, D. D.; Pezzuto, J. M.; Fong, H. H.
S. J. Nat. Prod. 2003, 66, 609.
(7) Although litseachromolaevane A (10) was reported as a new
compound in 2003, it is the same as sesquichamaenol
reported earlier from Chamaecyparis forrnosensis Matsum.
See: Ando, M.; Ibe, S.; Kagabu, S.; Nakagawa, T.; Asao, T.;
Takase, K. J. Chem. Soc., Chem. Commun. 1970, 1538.
(8) Nemoto, H.; Miyata, J.; Fukumoto, K. Tetrahedron 1996,
52, 10363.
s), 2.20–1.90 (3 H, m), 1.86–1.70 (1 H, m), 1.68 (3 H, s). 13
C
NMR (100 MHz, CDCl3): d = 154.3 (C), 139.1 (CH), 138.1
(C), 130.0 (C), 127.8 (CH), 122.0 (CH), 115.1 (CH), 113.8
(CH2), 93.9 (CH2), 91.6 (CH2), 80.3 (C), 56.0 (CH3), 55.4
(CH3), 39.1 (CH2), 28.7 (CH2), 24.7 (CH3), 21.2 (CH3).
HRMS: m/z calcd for C17H26O4Na [M + Na]: 317.1729;
found: 317.1717.
(9) In the 1H NMR spectrum of the synthetic sample 2, it was
found that signals due to four methyl groups and two
aromatic protons were identical to those reported in the
literature for the natural compound 2. Since one of the
aromatic resonances (d = 6.59 ppm, d) did not match that
reported (d = 6.89 ppm, d) for 2 [reported in the literature2 on
the basis of the NMR spectrum of a 1:3 mixture (80% pure)
of 2 and 1, where the compound 2 is minor component], the
1H NMR spectrum of a ca. 3:1 mixture of 1 and 2 was
recorded and confirmed that the reported resonance at d =
6.89 ppm is not due to 2. To rule out the other possible
regioisomers completely, synthesis of compounds 3 and 4
were also accomplished5 starting from 2-hydroxy-5-
methylacetophenones and 2-hydroxy-4-methylisobutyro-
phenones employing the same sequence of reactions as
depicted in Schemes 1 and 3, respectively. The 1H NMR and
13C NMR spectra5 of compounds 3 and 4 were found to be
different from those reported in the literature2 for the
compound 2 (Scheme 4).
Ketone 17: IR (neat): nmax = 1711, 1613, 1150, 1015, 923,
817 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.30 (1 H, d, J =
7.9 Hz), 6.89 (1 H, s), 6.75 (1 H, d, J = 7.9 Hz), 5.15 (2 H,
s), 4.73 and 4.71 (2 H, 2 × d, J = 7.2 Hz), 3.45 (3 H, s), 3.39
(3 H, s), 2.50–2.35 (3 H, m), 2.30 (3 H, s), 2.15–2.07 (2 H,
m), 1.66 (3 H, s), 1.00 (3 H, d, J = 6.9 Hz), 0.95 (3 H, d, J =
6.9 Hz). 13C NMR (100 MHz, CDCl3): d = 214.3 (C), 154.0
(C), 138.2 (C), 129.8 (C), 127.5 (CH), 121.9 (CH), 115.2
(CH), 94.0 (CH2), 91.4 (CH2), 79.8 (C), 56.0 (CH3), 55.4
(CH3), 40.8 (CH), 35.6 (CH2), 33.3 (CH2), 24.7 (CH3), 21.2
(CH3), 18.3 (CH3), 18.2 (CH3). HRMS: m/z calcd for
C19H30O5Na [M + Na]: 361.1991; found: 361.1990.
Compound 2: IR (neat): nmax = 1624, 1303, 1160, 907, 802
cm–1. 1H NMR (400 MHz, CDCl3): d = 6.89 (1 H, d, J = 7.9
Hz), 6.59 (1 H, d, J = 7.9 Hz), 6.56 (1 H, s), 2.26 (3 H, s),
2.20–2.08 (4 H, m), 1.90–1.83 (1 H, m), 1.69 (3 H, s), 1.09
(3 H, d, J = 6.7 Hz), 1.08 (3 H, d, J = 6.8 Hz). 13C NMR (100
MHz, CDCl3): d = 151.5 (C), 138.2 (C), 126.5 (C), 122.6
(CH), 120.4 (CH), 116.4 (CH), 111.0 (C), 82.6 (C), 42.8
(CH2), 34.9 (CH2), 34.8 (CH), 21.8 (CH3), 21.2 (CH3), 17.0
(CH3), 16.8 (CH3). HRMS: m/z calcd for C15H20O2Na [M +
Na]: 255.1361; found: 255.1364.
O
O
O
HO
Compound 3: IR (neat): nmax = 1237, 911, 815 cm–1. 1H
NMR (400 MHz, CDCl3): d = 6.92 (1 H, d, J = 7.8 Hz), 6.84
(1 H, s), 6.63 (1 H, d, J = 7.8 Hz), 2.24 (3 H, s), 2.22–2.05 (4
H, m), 1.95–1.83 (1 H, m), 1.69 (3 H, s), 1.09 (3 H, d, J = 6.9
Hz), 1.07 (3 H, d, J = 6.9 Hz). 13C NMR (100 MHz, CDCl3):
d = 149.4 (C), 129.7 (C), 128.8 (CH), 128.7 (C), 123.4 (CH)
115.6 (CH), 111.1 (C), 82.7 (C), 42.7 (CH2), 34.7 (CH), 34.6
(CH2), 21.7 (CH3), 20.7 (CH3), 16.9 (CH3), 16.7 (CH3).
3
O
O
O
HO
4
Scheme 4
Synlett 2008, No. 8, 1199–1201 © Thieme Stuttgart · New York

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