Enantiospecific synthesis of (+)-herbertene

Article abstract of DOI:10.1016/S0040-4039(01)02365-6

A total synthesis of (+)-herbertene from (+)-camphoric acid is described using a Diels-Alder reaction as the key step.

Full text of DOI:10.1016/S0040-4039(01)02365-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1313–1315
Enantiospecific synthesis of (+)-herbertene
Abhijit Nayek and Subrata Ghosh*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
Received 10 October 2001; revised 5 December 2001; accepted 13 December 2001
Abstract—A total synthesis of (+)-herbertene from (+)-camphoric acid is described using a Diels–Alder reaction as the key step.
© 2002 Elsevier Science Ltd. All rights reserved.
Herbertanes belong to an expanding family1 of
sesquiterpenes possessing a 3-methyl-(1,2,2-trimethyl-
cyclopentyl) cyclohexane skeleton. Herbertene 1, her-
choice of the dienophile 4 will lead to the herbertanes 1,
2 or 3. To demonstrate the feasibility of this protocol,
we herein report a total synthesis of (+)-herbertene. To
date there have only been two reports3a,c on the synthe-
sis of the natural enantiomer (−)-herbertene. However,
(+)-herbertene has not yet been synthesized.
bertenol
2
and herbertene diol
3
are
a
few
representative examples. In recent years, herbertanes
have become popular synthetic targets2, as some mem-
bers of this family exhibit a wide range of biological
activities, such as antifungal, neurotrophic and anti-
lipid peroxidation. The synthesis of these compounds is
associated with the difficulty in the generation of two
adjacent quaternary centers on a cyclopentane ring and
a highly substituted aromatic ring. We have recently
developed a general strategy for the synthesis of these
compounds. The present strategy3, involving construc-
tion of the vicinally substituted cyclopentane ring fol-
lowed by elaboration of one of the substituents to an
aromatic ring, differs from conventional approaches2,4
of annulating the cyclopentane ring at the benzylic
center of a properly substituted aromatic ring. The key
concept in our strategy is the generation of the six-
membered ring through a Diels–Alder reaction of the
dienophile 4 with the diene 5 prepared from the pre-
formed cyclopentane derivative 6. Thus, a proper
The sterically congested cyclopentane derivative 6 was
obtained through two different routes. The first route
begins with the cyclopentane derivative 10, which was
previously prepared5 by us and used as an intermediate
for the total synthesis6 of a cyclopentanoid natural
product. Compound 10 was prepared from acetone as
delineated in Scheme 1. The keto-ester 10 was then
transformed to the ester 67 in two steps through a
Huang–Minlon reduction of the carbonyl group fol-
Scheme 1. Reagents and conditions: (i) ethyl vinyl ether, t-
BuLi, THF, 81%; (ii) NaH, THF, allyl bromide, HMPA,
73%; (iii) hw, CuOTf, Et2O, 88%; (iv) TfOH, CH2Cl2, 84%; (v)
Jones oxidation then CH2N2; (vi) N2H4·H2O, N2H4·HCl,
KOH, digol, 200°C then MeOH, H2SO4, 41%; (vii) LDA,
THF, HMPA, MeI, 77%; (viii) (a) MeOH, H2SO4, 92%; (b)
MeOH, KOH, 89%; (c) hw, t-BuSH, quinoline, C6H6, 59%.
Keywords: aromatization; decarboxylation; Diels–Alder reaction; ter-
penoids.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02365-6

1314
A. Nayek, S. Ghosh / Tetrahedron Letters 43 (2002) 1313–1315
lowed by methylation (LDA-MeI), anticipating that
either the ester 6 or the alcohol 13 could be resolved
using enzymes to provide access to both enantiomers.
In the second route, camphoric acid 11, through its
dimethyl ester, was converted to the monomethyl ester
12 by selective hydrolysis of the secondary ester func-
tionality. Photo-induced decarboxylation8 of the acid
12 then afforded the ester 6.
with those reported in literature.3a Thus, starting with
more readily available (+)-camphoric acid, (+)-her-
bertene,9 [h]D30=+56.85 (c 0.54, CHCl3) was obtained.
As (−)-camphoric acid is also commercially available,
the present route also provides access to the natural
herbertanes.
Acknowledgements
After successfully establishing the desired adjacent qua-
ternary centers on the cyclopentane ring, attention was
given to the construction of the aromatic ring. Toward
this end, the ester 6 was reduced with lithium aluminum
hydride and the resulting alcohol 13 was oxidized to
afford the aldehyde 14 (Scheme 2). Wittig olefination of
the aldehyde 14 with the ylide generated from methallyl
triphenyl phosphonium chloride with n-BuLi afforded
the diene 5 in 46% yield. The Diels–Alder reaction was
carried out by heating a solution of the diene 5 and
maleic anhydride in toluene at 80°C to afford the
adduct 15 as an inseparable mixture of two
diastereoisomers in a 1:2 ratio. Attempted chromato-
graphic purification of the crude product caused
hydrolysis of the anhydride functionality leading to the
isolation of the anhydrides 15 and the corresponding
dicarboxylic acids 16 in 63 and 18% yields, respectively.
As the cyclohexene ring needs to be aromatized for
completion of the synthesis, the mixture of the Diels–
Alder adducts, without further purification, was used
directly for the subsequent steps.
Financial support from Council of Scientific and Indus-
trial Research (CSIR), New Delhi, is gratefully
acknowledged. A.N. thanks CSIR for
Research Fellowship.
a Junior
References
1. Connolly, J. D.; Hill, R. A. In Dictionary of Terpenoids,
1st ed.; Chapman and Hall: London, 1991; Vol. 1, pp.
299–300. Also see: Fraga, B. M. Nat. Prod. Rep. 1992, 9,
217–241; 1993, 10, 397–419; 1994, 11, 533–554; 1995, 12,
303–320; 1996, 13, 307–326; 1997, 14, 145–162; 1998, 15,
73–92.
2. Srikrishna, A.; Rao, M. S. Tetrahedron Lett. 2001, 42,
5781–5782 and references cited therein.
3. This type of approach has recently been reported for the
synthesis of herbertenes: (a) Abad, A.; Agullo, C.; Cunat,
A. C.; Perni, R. H. J. Org. Chem. 1999, 64, 1741–1744; (b)
Ho, T. L.; Chang, M. H. J. Chem. Soc., Perkin Trans. 1
1999, 2479–2482; (c) Tori, M.; Miyako, T.; Sono, M.
Tetrahedron: Asymmetry 1997, 8, 2731–2738.
4. (a) Mukherjee, D.; Dutta Gupta, P.; Pal, A.; Roy, A.
Tetrahedron Lett. 2000, 41, 7563–7566; (b) Mukherjee, D.;
Das, S.; Saha, A. K. Tetrahedron Lett. 1994, 35, 3353–
3354; (c) Takano, S.; Moriya, M.; Ogasawara, K. Tetra-
hedron Lett. 1992, 33, 329–332; (d) Banerjee, A. K.;
Pena-Matheud, C. A.; de Carrasco, M. C. J. Chem. Soc.,
Perkin Trans. 1 1988, 2485–2490; (e) Chandrasekaran, S.;
Turner, J. V. Tetrahedron Lett. 1982, 23, 3799–3802; (f)
Leriverend, M. L.; Vazeux, M. J. Chem. Soc., Chem.
Commun. 1982, 866–867; (g) Frater, G. J. Chem. Soc.,
Chem. Commun. 1982, 521–522.
Hydrolysis of the anhydride mixture afforded the dicar-
boxylic acids 16, mp 117–119°C. The mixture of the
dicarboxylic acids thus obtained was then subjected to
decarboxylation. The conventional decarboxylation
procedure involving Pb(OAc)4 gave a poor yield (25%)
of the diene 17 along with herbertene 1. However,
photodecarboxylation8 afforded the diene 17 in reason-
ably good yield (40%). Aromatization of the cyclohexa-
diene derivative 17 was then effected by heating its
benzene solution at 60°C with DDQ to afford her-
1
bertene 1 in 70% yield. The H and 13C NMR spectro-
scopic data of this sample were found to be identical
5. Patra, D.; Ghosh, S. J. Org. Chem. 1995, 60, 2526–2531.
6. Samajdar, S.; Ghatak, A.; Ghosh, S. Tetrahedron Lett.
1999, 40, 4401–4402.
7. All new compounds reported here were duly characterized
1
on the basis of spectroscopic (IR, H and 13C NMR) and
microanalytical (C, H) data. Spectroscopic data for
selected compounds: Compound 5: 1H NMR (300 MHz,
CDCl3): l 0.82 (3 H, s, Me), 0.89 (3 H, s, Me), 0.97 (3 H,
s, Me), 1.49–1.95 (6 H, m), 1.84 (3 H, s, Me), 4.88 (2 H, br
s), 5.73 (1 H, d, J=15.9 Hz), 6.06 (1 H, d, J=15.9 Hz);
13C NMR (75 MHz, CDCl3): l 19.2 (Me), 20.2 (CH2), 22.1
(Me), 24.2 (Me), 25.8 (Me), 37.3 (CH2), 39.7 (CH2), 44.7
(C), 48.9 (C), 114.5 (CH2), 129.8 (CH), 138.2 (CH), 142.9
(C). Compound 15: IR 1841.9, 1778.2 cm−1; 1H NMR (300
MHz, CDCl3): l 0.81 (3 H, s, Me), 0.98 (3 H, s, Me), 1.07
(3 H, s, Me), 1.44 (1 H, t, J=8.4 Hz), 1.63–2.03 (5 H, m),
1.78 (3 H, br s, Me), 2.17 (1 H, br d, J=10.5 Hz), 2.29 (1
H, br s), 2.63 (1 H, d, J=13.8 Hz), 3.42 (2 H, m) and 5.74
(1 H, br s); 13C NMR (75 MHz, CDCl3): l 17.5 (Me), 19.5
Scheme 2. Reagents and conditions: (i) (a) LiAlH4, Et2O, 84%;
(b) (COCl)2, DMSO, Et3N, CH2Cl2, 89%; (ii) H2C:C(Me)-
CH2PPh3+Cl−, n-BuLi, Et2O, 46%; (iii) maleic anhydride,
C6H5CH3, 80°C, 63%; (iv) NaOH, H2O, EtOH, 94%; (v) hw,
acridine, C6H6, 40%; (vi) DDQ, C6H6, 60°C, 70%.

A. Nayek, S. Ghosh / Tetrahedron Letters 43 (2002) 1313–1315
1315
(CH2), 23.8 (Me), 25.2 (Me), 26.0 (Me), 29.7 (CH2), 37.1
(CH2), 40.4 (CH2), 42.8 (CH), 43.0 (CH), 44.6 (CH), 45.5
(C), 46.2 (C), 125.0 (CH), 137.2 (C), 173.4 (CO), 174.4
20.1 (CH2), 22.2 (Me), 24.7 (Me), 24.8 (Me), 26.9 (Me),
37.2 (CH2), 40.2 (CH2), 44.6 (C), 50.9 (C), 124.5 (CH),
126.4 (CH), 127.7 (CH), 128.2 (CH), 137.1 (C), 147.9 (C).
8. Okada, K.; Okubo, K.; Oda, M. Tetrahedron Lett. 1989,
30, 6733–6736.
1
(CO). Compound 1: H NMR (CDCl3, 300 MHz): l 0.56
(3 H, s, Me), 1.07 (3 H, s, Me), 1.26 (3 H, s, Me),
1.55–1.81 (5 H, m), 2.34 (3 H, s, Me), 2.50 (1 H, m), 6.99
(1 H, m), 7.16 (3 H, m); 13C NMR (75 MHz, CDCl3): l
9. The natural enantiomer, (−)-herbertene, exhibits [h]1D4=
−56 (c 1.4, CHCl3).3a