A simple, ring-closing metathesis reaction based approach to (±)-1,14-herbertenediol and (±)-11-epi-herbertenolide

Article abstract of DOI:10.1016/S0040-4039(01)02051-2

A total synthesis of 1,14-herbertenediol via 11-epi-herbertenolide, and a formal total synthesis of tochuinyl acetate and dihydrotochuinyl acetate, employing a ring-closing metathesis reaction based methodology, are described.

Full text of DOI:10.1016/S0040-4039(01)02051-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 151–154
A simple, ring-closing metathesis reaction based approach to
( )-1,14-herbertenediol and ( )-11-epi-herbertenolide
A. Srikrishna* and M. Srinivasa Rao
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 31 August 2001; revised 16 October 2001; accepted 26 October 2001
Abstract—A total synthesis of 1,14-herbertenediol via 11-epi-herbertenolide, and a formal total synthesis of tochuinyl acetate and
dihydrotochuinyl acetate, employing a ring-closing metathesis reaction based methodology, are described. © 2001 Elsevier Science
Ltd. All rights reserved.
The herbertane group of sesquiterpenes are considered
as chemical markers for the liverworts belonging to the
genus Herbertus.1 Isolation of the first members of the
herbertane group 1a–e and 2a from Herberta adunca
was reported earlier by Matsuo and co-workers.2
Recently,1 Asakawa et al. reported the isolation of
seven new herbertanes 2b and 3–7 along with the
dimeric herbertanes, mastigophorenes, from the
Japanese liverwort Herbertus sakuraii. The phenolic
herbertanes, e.g. 1b–d, are shown to possess interesting
biological activity such as growth inhibiting activity2
and antilipid peroxidation activity.3 Despite their inter-
esting biological properties, until recently the phenolic
herbertanes have received relatively little attention from
synthetic chemists.4 Since its isolation, there has been
only one report5 on the synthesis of herbertenolide 2a.
Recently, Fukuyama and co-workers4g reported the
synthesis of 11-epi-herbertenolide 8 and 1,14-her-
bertenediol 4, employing an intramolecular Heck reac-
tion, during their synthesis of herbertenediol 1d en
route to the dimeric herbertanes, mastigophorenes.
Herein, we wish to report a very simple, ring-closing
metathesis (RCM)6 based approach to 1,14-herbertene-
diol 4 via 11-epi-herbertenolide 8 along with a formal
total synthesis of the marine sesquiterpenes tochuinyl
acetate and dihydrotochuinyl acetate 9 and 10.
It was conceived that a g,g-disubstituted allyl alcohol
11 could be conveniently transformed into the 2,2-dis-
ubstituted cyclopent-3-enecarboxylate 12 employing a
three-step strategy; namely a Claisen rearrangement,
allylation and RCM, as depicted in Scheme 1. To test
the feasibility of this protocol, the readily available allyl
alcohol 13 was chosen as the starting material. Thus,
orthoester Claisen rearrangement of the allyl alcohol 13
with triethyl orthoacetate and propionic acid furnished
the g,d-unsaturated ester 14.7 Alkylation of the ester 14
with lithium diisopropylamide (LDA) and allyl bromide
generated the RCM precursor, diene ester 15. RCM
reaction of the diene ester 15 with 6 mol% of Grubbs’
catalyst in methylene chloride at room temperature
X
OH
15
O
O
Y
X
14
OH
1
3
7
Z
9
Me
OH
5
13
6a,b
4
R
2a. X=O
1a-e
2b. X=H,OH
HO
OH
OH
a.R=Me; X=Y=Z=H
OH
OH
b.R=Me; X=OH; Y=Z=H
c.R=Me; X=Y=H; Z=OH
d.R=Me; X=Y=OH; Z=H
e.R=CHO; X=OH; Y=Z=H
MeOH2C
OH
5
3
7
* Corresponding author. Fax: 91-80-3600683; e-mail: ask@orgchem.iisc.ernet.in
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02051-2

152
A. Srikrishna, M. S. Rao / Tetrahedron Letters 43 (2002) 151–154
OH
R'
COOR"
Claisen
RCM
COOR"
COOR"
R
R R'
R R'
R R'
12
11
Scheme 1.
cleanly furnished the spiro compound 16† in almost
quantitative yield, highlighting the potential of the
strategy (Scheme 2).
focused on the formal total synthesis of tochuinyl ace-
tate and dihydrotochuinyl acetate, 9 and 10, starting
from the readily available8 dimethylcinnamyl alcohol 17
(Scheme 3). The cuparane based marine sesquiterpenes
9 and 10 were isolated from the dendronotid nudi-
branch Tochuina tetraquetra and also from its feed the
To demonstrate the applicability of the present strategy
in natural product synthesis, attention was initially
OH
COOEt
COOEt
COOEt
a
c
b
82%
91%
96%
13
14
15
16
Scheme 2. Reagents and conditions: (a) MeC(OEt)3, EtCOOH, 180°C, 48 h; (b) LDA, THF, −70°C“rt, allyl bromide, 4 h; (c) 6
mol% Grubbs’ catalyst, CH2Cl2, rt, 5 h.
CH2OH
COOEt
H
H
COOEt
COOEt
a
c
b
80%
98%
88%
20
d 82%
17
18
19
Me
CH2OAc
Me
CH2OH
Me
CH2OAc
Me
COOEt
Me
Me
Me
Me
g
e,f
90%
10
9
22
21
Scheme 3. Reagents and conditions: (a) MeC(OEt)3, EtCOOH, 180°C, 48 h; (b) LDA, THF, −70°C“rt, allyl bromide, 4 h; (c) 6
mol% Grubbs’ catalyst, CH2Cl2, rt, 4 h; (d) LDA, THF–HMPA, 0°C“rt, MeI, 8 h; (e) 10% Pd/C, H2 (1 atm), EtOH, rt, 1 h;
(f) LiAlH4, Et2O, rt, 2 h; (g) Ref. 8.
† All the compounds exhibited spectral data consistent with their structures. Selected spectral data for the spiroester 16: IR (neat): wmax/cm−1 1733;
1H NMR (300 MHz, CDCl3+CCl4): l 5.91 (1H, m of d, J=5.4 Hz), 5.65 (1H, d of t, J=5.4 and 2 Hz), 4.15–4.05 (2H, m), 2.78 (1H, m of dd,
J=15.6 and 8.1 Hz), 2.66 (1H, t, J=8.1 Hz), 2.42 (1H, m of dd, J=15.6 and 8.1 Hz), 1.80–1.05 (10H, m), 1.30 (3H, t, J=7.2 Hz); 13C NMR
(75 MHz, CDCl3+CCl4): l 173.7 (C), 135.8 (CH), 127.8 (CH), 59.9 (CH2), 54.6 (CH), 52.3 (C), 38.2 (CH2), 34.0 (CH2), 33.5 (CH2), 26.3 (CH2),
24.1 (CH2), 23.2 (CH2), 14.6 (CH3). For the alcohol 22: IR (neat): wmax/cm−1 3385; 1H NMR (300 MHz, CDCl3+CCl4): l 7.25 (2H, d, J=8.4
Hz), 7.07 (2H, d, J=8.4 Hz), 3.07 and 3.02 (2H, AB quartet, J=11.4 Hz), 2.55–2.40 (1H, m), 2.31 (3H, s), 1.90–1.40 (5H, m), 1.30 (3H, s), 1.11
(3H, s); 13C NMR (75 MHz, CDCl3+CCl4): l 143.4 (C), 135.3 (C), 128.9 (2 C, CH), 126.7 (2 C, CH), 69.4 (CH2), 49.6 (C), 49.3 (C), 37.6 (CH2),
35.1 (CH2), 25.3 (CH3), 21.0 (CH3), 20.4 (CH2), 19.6 (CH3). For the ester 28: IR (neat): wmax/cm−1 1724, 1500, 1250; 1H NMR (300 MHz,
CDCl3+CCl4): l 6.94 (1H, s), 6.87 (1H, d, J=8.1 Hz), 6.63 (1H, d, J=8.1 Hz), 5.79 (1H, d, J=6 Hz), 5.73 (1H, d, J=6 Hz), 3.74 (3H, s),
3.40–3.25 (2H, m), 3.01 (1H, d, J=16.5 Hz), 2.25 (1H, d, J=16.5 Hz), 2.21 (3H, s), 1.49 (3H, s), 1.47 (3H, s), 0.77 (3H, t, J=7.2 Hz); 13C NMR
(75 MHz, CDCl3+CCl4): l 176.2 (C), 156.8 (C), 139.4 (CH), 133.6 (C), 129.8 (CH), 128.4 (C), 127.8 (CH), 126.8 (CH), 111.1 (CH), 59.5 (CH2),
58.9 (C), 55.5 (C), 54.9 (CH3), 46.4 (CH2), 23.4 (CH3), 21.5 (CH3), 20.7 (CH3), 13.7 (CH3). For epi-herbertenolide 8:4g IR (neat): wmax/cm−1 1755;
1H NMR (300 MHz, CDCl3+CCl4): l 7.05 (1H, s), 6.97 (1H, d, J=8.5 Hz), 6.85 (1H, d, J=8.5 Hz), 2.32 (3H, s), 2.45–2.30 (1H, m), 2.15–1.60
(5H, s), 1.25 (3H, s), 1.20 (3H, s); 13C NMR (75 MHz, CDCl3+CCl4): l 172.8 (C), 147.8 (C), 133.7 (C), 128.7 (CH), 128.5 (C), 126.8 (CH), 116.6
(CH), 51.0 (C), 47.7 (C), 39.0 (CH2), 35.7 (CH2), 21.8 (CH3), 21.2 (CH3), 20.1 (CH2), 18.1 (CH3). For 1,14-herbertenediol 4:1,4g IR (neat):
wmax/cm−1 3350; 1H NMR (300 MHz, CDCl3+CCl4): l 6.90 (1H, s), 6.84 (1H, d, J=7.8 Hz), 6.67 (1H, d, J=7.8 Hz), 3.26 (2H, s), 2.55–2.25
(1H, m), 2.25 (3H, s), 2.00–1.70 (3H, m), 1.55 (3H, s), 1.50–1.15 (4H, m), 1.23 (3H, s); 13C NMR (75 MHz, CDCl3+CCl4): l 153.1 (C), 132.7
(C), 129.9 (CH), 128.9 (C), 128.1 (CH), 117.4 (CH), 70.5 (CH2), 51.1 (C), 49.1 (C), 42.5 (CH2), 36.2 (CH2), 24.2 (CH3), 21.3 (CH2), 21.2 (CH3),
20.8 (CH3).

A. Srikrishna, M. S. Rao / Tetrahedron Letters 43 (2002) 151–154
153
CH2OH
COOEt
O
H
H
COOEt
COOEt
MeO
MeO
a,b
MeO
MeO
MeO
c
e
d
86%
87%
76%
95%
26
23
25
24
27
77%
f
OH
OH
O
COOEt
COOEt
O
MeO
MeO
g
b
h
92%
85%
93%
8
4
29
28
Scheme 4. Reagents and conditions: (a) NaH, (EtO)2P(O)CH2COOEt, THF, rt, 16 h; (b) LiAlH4, Et2O, −70°C“rt, 2 h; (c)
MeC(OEt)3, EtCOOH, 180°C, 48 h; (d) LDA, THF, −70°C“rt, allyl bromide, 4 h; (e) 6 mol% Grubbs’ catalyst, CH2Cl2, rt, 4
h; (f) LDA, THF–HMPA, 0°C“rt, MeI, 8 h; (g) 10% Pd/C, H2 (1 atm), EtOH, rt, 1 h; (h) BBr3, CH2Cl2, 0°C“rt, 2 h.
soft coral Gersemia rubiformis.9 The presence of a
cyclopentane ring with two stereogenic vicinal quater-
nary carbon atoms makes the acetates 9 and 10 interest-
ing synthetic targets.8 Thus, orthoester Claisen
rearrangement of the cinnamyl alcohol 17 with triethyl
orthoacetate and propionic acid furnished the pen-
tenoate 18, which on alkylation with LDA and allyl
bromide furnished a 1:1 mixture of the diene 19. Treat-
ment of the diene 19 with 6 mol% of Grubbs’ catalyst
in methylene chloride at room temperature furnished a
1:1 diastereomeric mixture of the cyclopentenecarboxy-
late 20 in near quantitative yield. Alkylation with LDA
and methyl iodide created the second quaternary car-
bon atom and transformed the ester 20 into the ester 21
in a highly stereoselective manner. Hydrogenation of
the cyclopentene moiety using 10% Pd/C as the catalyst
followed by reduction of the ester with lithium alu-
minium hydride (LAH) transformed the cyclopentene-
carboxylate 21 into the primary alcohol 22,† which
exhibited spectroscopic data identical to those reported
earlier.8 Since the alcohol 22 has already been
transformed8 into tochuinyl acetate and dihydro-
tochuinyl acetate 9 and 10, the present sequence consti-
cleanly transformed the diene ester 26 into the
cyclopentenecarboxylate 27, in 95% yield. Alkylation of
the cyclopentenecarboxylate 27 with LDA and methyl
iodide, stereoselectively created the second quaternary
center furnishing the ester 28.† The stereostructure of
the ester 28 was readily established from the upfield
shift of the resonances [3.25–3.40 (2H, m) and 0.77 (3H,
1
t)] due to the ethyl group of the ester in the H NMR
spectrum. The stereoselectivity of the alkylation reac-
tion can be readily explained by the approach of the
electrophile from the less hindered face (anti to the aryl
group) of the intermediate enolate of ester 27. Hydro-
genation of the cyclopentene using 10% Pd/C as the
catalyst transformed the ester 28 into the cyclopentane-
carboxylate 29. Treatment of the ester 29 with boron
tribromide in methylene chloride furnished 11-epi-her-
bertenolide 8,† via hydrolysis of the methyl ether and
lactonization. Finally, reduction of the lactone 8 with
LAH furnished ( )-1,14-herbertenediol 4,† which exhib-
1
ited H and 13C NMR spectroscopic data identical to
those reported.1,4g
In conclusion, we have developed a very simple and
efficient methodology based on the Claisen rearrange-
ment and RCM reactions for the synthesis of herber-
tane sesquiterpenes 1,14-herbertenediol and 11-epi-
herbertenolide, and the marine sesquiterpenes tochuinyl
acetate and dihydrotochuinyl acetate.
tutes
a formal total synthesis of these marine
sesquiterpenes.
After successfully accomplishing the formal total syn-
thesis of the acetates 9 and 10, attention was turned to
the synthesis of 11-epi-herbertenolide 8 and 1,14-her-
bertenediol 4 (Scheme 4). To begin with 2-methoxy-5-
methylacetophenone 23, obtained in two steps from
4-methylphenyl acetate, was transformed into the cin-
namyl alcohol 24 employing a Horner–Wadsworth–
Emmons reaction, followed by regioselective reduction
of the resultant cinnamate with LAH. The orthoester
Claisen rearrangement of the alcohol 24 with triethyl
orthoacetate and propionic acid in a sealed tube at
180°C furnished the ester 25 generating the first quater-
nary carbon atom. Alkylation of the ester 25 with LDA
and allyl bromide generated a 1:1 epimeric mixture of
the diene esters 26. A RCM reaction with Grubbs’
catalyst in methylene chloride at room temperature
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