A ring closing metathesis-based approach to (±)-herbertene, (±)-α-herbertenol, (±)-β-herbertenol and (±)-herbertenediol

Article abstract of DOI:10.1055/s-2002-19750

An efficient methodology for the synthesis of the aromatic sesquiterpenes (±)-herbertene, (±)-α-herbertenol, (±)-β-herbertenol (±)-herbertenediol and (±)-α-cuparenone, employing a combination of Claisen rearrangement and ring closing metathesis reactions,

Full text of DOI:10.1055/s-2002-19750

340
LETTER
A Ring Closing Metathesis-Based Approach to ( )-Herbertene,
( )- -Herbertenol, ( )- -Herbertenol and ( )-Herbertenediol
A
Ring
Closing
M
.
etathesis-Ba
S
sed Approach
r
to Arom
i
a
tic Se
k
squiterpenesrishna,* M. Srinivasa Rao
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India.
E-mail: ask@orgchem.iisc.ernet.in
Received 30 November 2001
OH
Abstract: An efficient methodology for the synthesis of the aro-
matic sesquiterpenes ( )-herbertene, ( )- -herbertenol, ( )- -her-
bertenol ( )-herbertenediol and ( )- -cuparenone, employing a
combination of Claisen rearrangement and ring closing metathesis
HO
β-herbertenol 3
reactions, is described.
α-herbertenol 2
herbertene 1
Key words: herbertane, aromatic sesquiterpenes, Claisen rear-
rangement, ring closing metathesis
OH
HO
O
O
O
The herbertane group of sesquiterpenes are considered as
chemical markers for the liverworts belonging to the ge-
α-cuparenone 6
herbertenediol 4
herbertenolide 5
nus Herbertus.1a Isolation of the first members of the her-
Figure
bertane group herbertene 1, -herbertenol 2,
-
herbertenol 3, herbertenediol 4 and herbertenolide 5 (Fig-
ure) from Herberta adunca was reported earlier by Mat-
suo and coworkers.1b Recently,1a Asakawa and co-
workers reported the isolation of seven new herbertanes
along with the dimeric herbertanes, mastigophorenes,
from the Japanese liverwort Herbertus sakuraii. The phe-
nolic herbertanes, e.g. 2–4 have been shown to possess in-
teresting biological activity such as growth inhibiting
activity and antilipid peroxidation activity.1 The sesquit-
erpenes cuparanes and herbertanes are interesting synthet-
ic targets owing to the presence of a sterically crowded 1-
aryl-1,2,2-trimethylcyclopentane moiety, and the difficul-
ty associated with the construction of vicinal quaternary
carbon atoms on a cyclopentane ring. Even though there
have been a significant number of reports for the parent
member, herbertene 1,2,3 until recently, the phenolic her-
bertenes have received relatively little attention from syn-
thetic chemists despite their interesting biological
properties.4 Herein, we wish to report a very simple, ring
closing metathesis (RCM)5-based approach to herbertenes
1–4 along with a formal total synthesis of -cuparenone
6(Figure).
OH
R'
O
OH
CHO
R'
R
R'
R
R'
R
R
10
9
8
7
Scheme 1
the aldehyde 11, obtained from 4-methylacetophenone in
three steps, with vinylmagnesium bromide in THF fur-
nished a 1:1 diastereomeric mixture of the dienol 12, in
92% yield (Scheme 2). Oxidation of 12 with pyridinium
chlorochromate (PCC) and sodium acetate furnished the
dienone 13. RCM of the dienone 13 with Grubbs’ catalyst
[PhCH=RuCl2(PCy3)2] in methylene chloride was slow
(18 h, 55–60% conversion), hence the reaction was car-
ried out using dienol 12. Reaction of the dienol 12 with 6
mol% of Grubbs’ catalyst [PhCH=RuCl2(PCy3)2] in meth-
ylene chloride at room temperature for 3 h furnished the
RCM product, cyclopentenol 14, in 97% yield. Oxidation
of the cyclopentenol 14 with PCC and NaOAc in methyl-
ene chloride furnished the cyclopentenone 15, in 93%
It was contemplated that , -disubstituted allyl alcohols 7
can be conveniently converted into 4,4-disubstituted cy-
clopentenones 10 employing a four-step sequence
(Scheme 1), namely, Claisen rearrangement,6 vinylation,
RCM reaction and oxidation.
yield, which exhibited H and 13C NMR spectral data
1
identical to those reported.8a The cyclopentenone 15 has
already been transformed8a into -cuparenone 6, via alky-
lation and hydrogenation.
To demonstrate the feasibility of the sequence, the synthe-
sis of -cuparenone7,8 6 was first investigated starting
from the readily available aldehyde 11.8b Thus, reaction of
After successfully demonstrating the strategy for the
formal synthesis of -cuparenone 6, the same approach
was applied to the synthesis of herbertanes 1–4. The syn-
thetic sequence starting from 3-methylacetophenone, 2-
methoxy-5-methylacetophenone, 4-methoxy-3-methyl-
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0340,0342,ftx,en;D23701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
acetophenone
and
2,3-dimethoxy-5-methylaceto-
phenones 16a–d is depicted in Scheme 3. Thus, Horner-

LETTER
A Ring Closing Metathesis-Based Approach to Aromatic Sesquiterpenes
341
X
CHO
O
O
a
R
R
R
92%
CHO
OH
OH
O
a
b
12
11
Me
R'
Me
R'
Me
c
R'
b
c
R"
16a-d
R"
R"
97%
17a-d X=COOEt
18a-d X=CH2OH
19a-d
OH
OH
O
R
R
14
13
d
c
(slow)
93%
b
Me
R'
Me
R'
R"
R"
21a-d
20a-d
a. R=R'=R"=H
b. R=OMe; R'=R"=H
c. R=R'=H; R"=OMe
d. R=R'=OMe; R"=H
e,f
d
O
O
X
X
R
O
15
(±)-6
(±)-herbertene 1
Scheme 2 (a) CH2=CHMgBr, THF, r.t., 1 h; (b) PCC, NaOAc,
g
(±)-α-herbertenol 2
(±)-β-herbertenol 3
(±)-herbertenediol 4
h
CH2Cl2, r.t., 0.5 h; (c) Grubbs’ catalyst, CH2Cl2, r.t., 3 h; (d) ref. 8a
R
Me
R'
Me
R'
R"
R"
24a-d
Wadsworth-Emmons reaction of the acetophenones
16a–d with triethyl phosphonoacetate and sodium hy-
dride in THF furnished E-crotonates 17a–d in a highly
stereoselective manner, which on regioselective reduction
with lithium aluminium hydride (LAH) at –70 °C in dry
ether furnished the allyllic alcohols 18a–d, in 85–90%
yield. Thermal activation of the alcohols 18a–d and ethyl
vinyl ether in the presence of mercury (II) acetate in a
sealed tube at 180 °C for two days furnished the , -unsat-
urated aldehydes 19a–d, in 60–65%,9–11 which on reaction
with vinylmagnesium bromide in THF furnished dienols10
20a–d as a 1:1 mixture of diastereomers. Reaction of the
dienols 20a–d in methylene chloride with 6–8 mol% of
Grubbs’ catalyst for 4–6 h furnished the cyclopentenols9,10
21a–d via an efficient RCM reaction. Oxidation of the al-
cohols 21a–d with PCC and sodium acetate in methylene
chloride furnished the cyclopentenones10 22a–d, whose
structures were established from their spectral data. The
results are summarised in the Table. Alkylation of the cy-
clopentenones 22a–d with an excess of sodium hydride
and methyl iodide in THF and DMF, followed by hydro-
genation of the cyclopentenones10 23a–d using 10%Pd/C
as the catalyst in ethanol furnished, in 70–77% yield, the
cyclopentanones 24a–d, containing two contiguous qua-
22a-d X=H
23a-d X=CH3
Scheme 3 (a) i. NaH, (EtO)2P(O)CH2COOEt, THF, r.t., 16 h, 89–
96%; ii. LAH, Et2O, –70 °C, 2 h, 90–95%; (b) CH2=CHOEt,
Hg(OAc)2, sealed tube, 180 °C, 48 h, 60–65%; (c) CH2=CHMgBr,
THF, r.t., 1 h; (d) Grubbs’ catalyst, CH2Cl2, r.t., 4–6 h; (e) PCC,
NaOAc, CH2Cl2, r.t., 0.5 h; (f) NaH, MeI, THF–DMF, r.t., 18 h, 75–
76%; (g) H2, 10%Pd/C, EtOH, 1 atm, r.t., 1 h, 100%; (h) references
4e, 4g.
Table Yields of Various Reactions
Aldehyde
Vinylation
(%yield)
RCM
(%yield)
Oxidation
(%yield)
11
12 (92)
14 (97)
15 (93)
19a
19b
19c
19d
20a (92)
20b (93)
20c (90)
20d (92)
21a (97)
21b (97)
21c (95)
21d (97)
22a (94)
22b (92)
22c (92)
22d (90)
1
13
In conclusion, we have developed a convenient and effi-
cient route to the sesquiterpenes ( )-herbertene, ( )- -
herbertenol, ( )- -herbertenol, ( )-herbertenediol and
( )- -cuparenones. The high efficiency of the sequence,
as evident from the Table points to the excellent synthetic
potential of the present methodology.
ternary carbon atoms, which exhibited H and C NMR
spectral data identical to those reported.4e,g Since the ke-
tones 24a–d have already been transformed into ( )-her-
bertene 1, ( )- -herbertenol 2, ( )- -herbertenol 3 and
( )-herbertenediol 4, respectively, the present sequence
constitutes a formal total synthesis of these sesquiterpe-
nes.
Acknowledgement
We thank Professor D. Mukherjee, Indian Association for the Cul-
tivation of Science, Calcutta for providing the copies of the 1H and
13C NMR spectra of compounds 24a–d.
Synlett 2002, No. 2, 340–342 ISSN 0936-5214 © Thieme Stuttgart · New York

342
A. Srikrishna, M. S. Rao
LETTER
Typical Procedure for RCM Rreaction: A solution of the
dienol 20a (50 mg, 0.23 mmol) in CH2Cl2 (4 mL) was added
to a solution of Grubbs' catalyst (15 mg, 8 mol%) in CH2Cl2
(4 mL) under nitrogen atmosphere and stirred for 4 h at room
temperature. Evaporation of the solvent and purification of
the residue on a silica gel column furnished the
References
(1) (a) Irita, H.; Hashimoto, T.; Fukuyama, Y.; Asakawa, Y.
Phytochemistry 2000, 55, 247. (b) Matsuo, A.; Yuki, S.;
Nakayama, M. J. Chem. Soc., Perkin Trans. 1 1986, 701.
(2) For the synthesis of ( )-herbertene, see:
(a) Chandrasekaran, S.; Turner, J. V. Tetrahedron Lett.
1982, 23, 3799. (b) Frater, G. J. Chem. Soc., Chem.
Commun. 1982, 521. (c) Leriverend, M.-L.; Vazeux, M. J.
Chem. Soc., Chem. Commun. 1982, 866. (d) Saha, A. K.;
Das, S.; Mukherjee, D.; Fronczek, F. R. Tetrahedron Lett.
1994, 35, 3353. (e) Mandelt, K.; Fitjer, L. Synthesis 1998,
1523. (f) Poon, T.; Mundy, B. P.; Favaloro, F. G.; Goudreau,
C. A.; Greenberg, A.; Sullivan, R. Synthesis 1998, 832.
(g) Ho, T.-L.; Chang, M.-H. J. Chem. Soc., Perkin Trans. 1
1999, 2479.
cyclopentenol 21a (42 mg, 97%) as a 1:1 diastereomeric
mixture.
(10) All the compounds exhibited spectral data consistent with
their structures. Yields refer to isolated and
chromatographically pure compounds. Selected spectral
data for the aldehyde 19a: IR (neat, cm–1): 2737, 1721, 1636,
1604, 919. 1H NMR (300 MHz, CDCl3 + CCl4): 9.55 (1 H,
br s), 7.30–6.90 (4 H, m), 6.08 (1 H, dd, J = 17.4 and 10.5
Hz), 5.19 (1 H, d, J = 10.3 Hz), 5.10 (1 H, d, J = 17.4Hz.),
2.79 and 2.70 (2 H, 2 d, J = 12.9 Hz.), 2.35 (3 H, s), 1.51
(3 H, s). 13C NMR (75 MHz, CDCl3 + CCl4): 201.9 (CH),
145.4 (C), 145.3 (CH), 138.0 (C), 128.5 (CH), 127.4 (CH),
127.1 (CH), 123.4 (CH), 113.0 (CH2), 53.3 (CH2), 42.9 (C),
26.2 (CH3), 21.8 (CH3). For a 1:1 diastereomeric mixture of
the dienol 20a: IR (neat, cm–1): 3398, 1635, 917. 1H NMR
(300 MHz, CDCl3 + CCl4): 7.24–6.90 (4 H, m), 6.20–6.00
(1 H, m), 5.85–5.75 (1 H, m), 5.15–4.95 (4 H, m), 4.13 (1 H,
br s), 2.34 (3 H, s), 2.05–1.90 (2 H, m), 1.50 (1 H, br s), 1.48
and 1.46 (3 H, CH3). 13C NMR (75 MHz, CDCl3 + CCl4):
147.4 and 147.0 (CH), 146.9 (C), 142.1 and 142.0 (CH),
137.7 and 137.6 (C), 128.3 and 128.2 (CH), 127.4 and 127.3
(CH), 127.0 and 126.9 (CH), 123.8 and 123.7 (CH), 113.5
(CH2), 112.1 and 112.0 (CH2), 70.5 and 70.4 (CH), 48.4
(CH2), 43.8 (C), 25.8 and 25.6 (CH3), 21.8 (CH3). For a 1:1
diastereomeric mixture of the cyclopentenol 21a: IR (neat,
cm–1): 3346, 1605. 1H NMR (300 MHz, CDCl3 + CCl4):
7.30–6.90 (4 H, m), 6.02 (1 H, d, J = 5.1Hz.), 5.88–5.80 (1
H, m), 4.90 (1 H, br s), 2.55–2.35 (1 H, m), 2.34 and 2.32 (3
(3) For enantioselective syntheses, see, (a) Takano, S.; Moriya,
M.; Ogasawara, K. Tetrahedron Lett. 1992, 33, 329.
(b) Tori, M.; Miyake, T.; Hamaguchi, T.; Sono, M.
Tetrahedron: Asymmetry 1997, 8, 2731. (c) Abad, A.;
Agulló Cuñat, A. C.; Perni, R. H. J. Org. Chem. 1999, 64,
1741.
(4) For the synthesis of -herbertenol, -herbertenol and
herbertenediol, see: (a) Fukuyama, Y.; Kiriyama, Y.;
Kodama, M. Tetrahedron Lett. 1996, 37, 1261. (b) Eicher,
T.; Servet, F.; Speicher, A. Synthesis 1996, 863.
(c) Harrowven, D. C.; Hannam, J. C. Tetrahedron Lett. 1998,
39, 9573. (d) Harrowven, D. C.; Hannam, J. C. Tetrahedron
1999, 55, 9333. (e) Pal, A.; Gupta, P. D.; Roy, A.;
Mukherjee, D. Tetrahedron Lett. 1999, 40, 4733.
(f) Degnan, A. P.; Meyers, A. I. J. Am. Chem. Soc. 1999,
121, 2762. (g) Gupta, P. D.; Pal, A.; Roy, A.; Mukherjee, D.
Tetrahedron Lett. 2000, 41, 7563. (h) Srikrishna, A.; Rao,
M. S. Tetrahedron Lett. 2001, 42, 5781. (i) Bringmann, G.;
Pabst, T.; Henschel, P.; Kraus, J.; Peters, K.; Peters, E. M.;
Rycroft, D. S.; Connolly, J. D. J. Am. Chem. Soc. 2000, 122,
9127. (j) Abad, A.; Agullo, C.; Cunat, A. C.; Jimenez, D.;
Perni, R. H. Tetrahedron 2001, 57, 9727. (k)Srikrishna, A.;
Rao, M. S. Tetrahedron Lett. 2002, 43, 151.
(5) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(b) Fürstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013.
(c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18; and references cited therein.
(6) (a) Claisen, L. Ber. 1912, 45, 3157. (b) Lutz, R. P. Chem.
Rev. 1984, 84, 205. (c) Ziegler, F. E. Chem. Rev. 1988, 88,
1423.
H, s), 1.95–1.60 (2 H, m), 1.54 and 1.40 (3 H, s, CH3). 13
NMR (75 MHz, CDCl3 + CCl4): 149.2 and 148.6 (C),
C
143.1 and 142.6 (CH), 137.5 and 137.4 (C), 132.2 and 132.1
(CH), 128.2 and 128.1 (CH), 126.6 and 126.5 (CH), 126.4
and 126.3 (CH), 122.7 and 122.6 (CH), 77.2 (CH), 53.1 and
52.1 (C), 51.3 and 50.8 (CH2), 30.1 and 28.5 (CH3), 21.6
(CH3). For the cyclopentenone 22a: IR (neat, cm–1): 1716,
1586. 1H NMR (300 MHz, CDCl3 + CCl4): 7.65 (1 H, d, J
= 5.7 Hz.), 7.20 (1 H, t, J = 7.5 Hz.), 7.10–6.95 (3 H, m), 6.19
(1 H, d, J = 5.7 Hz.), 2.63 and 2.51 (2 H, 2 d, J = 18.7 Hz.),
2.35 (3 H, s), 1.63 (3 H, s). 13C NMR (75 MHz, CDCl3 +
CCl4): 209.2 (C), 171.1 (CH), 145.2 (C), 138.3 (C), 131.6
(CH), 128.7 (CH), 127.6 (CH), 126.5 (CH), 122.7 (CH), 51.9
(CH2), 48.1 (C), 27.3 (CH3), 21.7 (CH3). For the
(7) For isolation, see: Dev, S.; Chetty, G. L. Tetrahedron Lett.;
1964, 73.
cyclopentenone 23a: IR (neat, cm–1): 1712, 1606, 1594. 1H
NMR (300 MHz, CDCl3 + CCl4): 7.73 (1 H, d, J = 5.7 Hz.),
7.19 (1 H, t, J = 7.6 Hz.), 7.10–6.90 (3 H, m), 6.20 (1 H, d, J
= 5.7Hz.), 2.35 (3 H, s), 1.46 (3 H, s), 1.19 (3 H, s), 0.52 (3
H, s). 13C NMR (75 MHz, CDCl3 + CCl4): 213.8 (C), 168.2
(CH), 143.4 (C), 137.7 (C), 129.4 (CH), 128.3 (CH), 127.6
(2 C, CH), 124.0 (CH), 54.7 (C), 51.5 (C), 26.4 (CH3), 26.0
(CH3), 21.8 (CH3), 20.1 (CH3).
(8) For synthesis: see, (a) Meyers, A. I.; Lefker, B. A. J. Org.
Chem. 1986, 51, 1541. (b) Srikrishna, A.; Sundarababu, G.
Tetrahedron 1990, 46, 3601. (c) Kulkarni, M. G.;
Pendharkar, S. Tetrahedron 1997, 53, 3167: and references
cited therein.
(9) Typical Procedure for Claisen Rearrangement: A solution
of the cinnamyl alcohol 18a (300 mg, 1.85 mmol), ethyl
vinyl ether (532 mg, 7.4 mmol) and a catalytic amount of
mercury (II) acetate ( 50 mg) was heated to180 °C in a
Carius tube under nitrogen atmosphere for 48 h. The reaction
mixture was then cooled, diluted with ether, washed with aq.
NaHCO3 solution and brine, and dried (Na2SO4).
Evaporation of the solvent and purification of the product on
a silica gel column using ethyl acetate–hexane (1:20) as
eluent furnished the aldehyde 19a (226 mg, 65%) as an oil.
(11) Alternately, the aldehydes 19a–d were also obtained (65-
70%) via the orthoester Claisen rearrangement [MeC(OEt)3;
EtCOOH; ] of the alcohols 18a–d followed by conversion
of the resultant esters into aldehydes by reduction (LAH)-
oxidation (PCC) sequence.
Synlett 2002, No. 2, 340–342 ISSN 0936-5214 © Thieme Stuttgart · New York