Total synthesis of 4α,5α,10β-trihydroxycadinane and its C4-isomer: Structural revision of a natural sesquiterpenoid

Article abstract of DOI:10.1055/s-2006-951480

An efficient approach to cadinane sesquiterpenes starting from (R)-carvone, employing a ring closing metathesis (RCM) reaction and a modified allylic diazene rearrangement as key steps, is described. The first asymmetric total syntheses of 4α,5α,10β-trihy

Full text of DOI:10.1055/s-2006-951480

LETTER
2655
Total Synthesis of 4a,5a,10b-Trihydroxycadinane and Its C4-Isomer:
Structural Revision of a Natural Sesquiterpenoid
Total
S
ynthesis
i
of
4
a
,5
j
a
,10
b
-
i
Trihydr
n
oxycadinane
g
and Its
C
4-IsomerFang, Fuqiang Bi, Chen Zhang, Guojun Zheng, Yulin Li*
State Key Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000,
P. R. of China
Fax +86(931)8912283; E-mail: liyl@lzu.edu.cn
Received 3 July 2006
The synthetic sequence is depicted in Scheme 2. Selective
Abstract: An efficient approach to cadinane sesquiterpenes start-
hydrogenation of (R)-carvone with Wilkinson’s catalyst
ing from (R)-carvone, employing a ring closing metathesis (RCM)
reaction and a modified allylic diazene rearrangement as key steps,
is described. The first asymmetric total syntheses of 4a,5a,10b-tri-
generated dihydrocarvone 7.7 Aldol reaction of 7 mediat-
ed with lithium diisopropylamide gave the anti-aldol ad-
hydroxycadinane (1) and natural 4b,5a,10b-trihydroxycadinane (2) duct 5 in excellent yield (dr > 95:5).8 Protection of the
were accomplished and the structure of natural product A was re-
vised to 2.
secondary alcohol of 5 produced silyl ether 8. Grignard re-
action of enone 8 with allylmagnesiun bromide furnished
Key words: cadinane sesquiterpenes, synthesis, 4a,5a,10b-tri-
hydroxycadinane, 4b,5a,10b-trihydroxycadinane
the tertiary alcohol 9 as a single diastereomer, which was
oxidized with pyridine chlorochromate (PCC)9 in dichlo-
romethane to provide the diene 4. It is worth noting that
this high yield was achieved only when pyridine (pyri-
Sesquiterpenes of the cadinane series are widely distribut- dine–PCC = 1:1) was added to the reaction system.
ed as plant constituents.1 Cadinane type natural products
show various biological activities.2 Due to the complex
stereochemistry of cadinanes, there are few methods re-
ported in the literature for the stereoselective synthesis of
H
O
RCM
1 and 2
both the cis- and the trans-fused skeletons of this group of
OH
3
TBSO
O
sesquiterpenes.3 Natural product A, whose structure was
proposed as 4a,5a,10b-trihydroxycadinane (1; Figure 1),
was isolated from the leaves of Jasonia candicans by
Ahmed and Mahmoud4 in 1998. Five years later, Kuo and
co-workers reported the isolation of natural product B:
4b,5a,10b-trihydroxycadinane (2; Figure 1)5 from the
roots of Taiwania cryptomerioides. The interesting
structural features and the biological activity of these
cadinanes prompted us to investigate their total synthesis.
4
O
OH
5
6
Scheme 1 Retrosynthetic analysis of cadinanes 1 and 2
O
O
a
b
d
6
OH
OH
H
H
10
7
1
OR
4
5
7
5: R = H
8: R = TBS
c
OH
OH
OH
OH
OH
O
2 (natural product B)
1 (proposed structure
of natural product A)
e
f
Figure 1
TBSO
TBSO
9
4
The retrosynthetic strategy relies on a novel strategy using
the RCM reaction as a key reaction to form the bicyclic
ring system of cadinanes (Scheme 1). Thus diene 4 can be
accessed from precursor 5, which can be easily generated
from (R)-carvone (6).6
O
Mes
N
N Mes
Ru
Cl
Cl
Ph
TBSO
PCy3
11
10
Scheme 2 Reagents and conditions: (a) H2, Rh(Ph3P)3Cl, 82%; (b)
LDA, THF, –78 °C, methacrolein, 93%; (c) TBSCl, imidazole, DMF,
98%; (d) CH2=CHCH2MgBr, Et2O, 0 °C, 99%; (e) PCC, pyridine,
silica gel, CH2Cl2, 98%; (f) Grubbs’ catalyst 11, CH2Cl2, reflux,
100% or bis(tricyclohexylphosphine)benzylidine ruthenium(IV)di-
chloride (12), CH2Cl2, reflux, 62%.
SYNLETT 2006, No. 16, pp 2655–2657
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-951480; Art ID: W14106ST
© Georg Thieme Verlag Stuttgart · New York
0
4
.1
0
.2
0
0
6

2656
L. Fang et al.
LETTER
As expected, the reaction of 4 with Grubbs’ second-gen-
eration catalyst 11 (5 mol%) proceeded smoothly to give
10 in quantitative yield. In contrast, exposure of 4 to first
generation Grubbs’ catalyst 12 under a variety of standard
metathesis conditions was found to be inefficient. A better
yield of 62% was achieved when 12 was added as a 0.01
M dichloromethane solution over 10 hours via a syringe
pump so that the concentration of active catalyst could be
maintained.10
H
H
O
b
c
OH
OR
15
14: R = TBS
3: R = H
a
OH
H
H
O
d
O
OH
OH
Our next step was installation of the C-10 hydrogen to
form a trans-decalin core. Allylic diazene rearrangement
has previously been employed to install angular hydro-
gens in carbocyclic systems via reduction of the corre-
sponding a,b-unsaturated tosylhydrazones.11 However,
since the rearrangement is a suprafacial process, stereo-
electronically preferred axial attack of the hydride on the
tosylhydrazone afforded the undesired b-stereoisomer of
the allylic diazene, which led to cis-fused cadinane ring
systems.11 Therefore, a modified strategy was carried out
to establish the trans-decalin ring fusion (Scheme 3). Re-
duction of the enone 10 with lithium aluminum hydride
produced the b-hydroxyl isomer 13 (dr = 95:5), which was
substituted by TsNHNH2 in nitromethane to provide the
a-stereoisomer of the allylic diazene.12 Interestingly, the
subsequent rearrangement reaction occurred simulta-
neously with the substitution reaction at room tempera-
ture, generating the trans-decalin 14 in 86% yield. The
trans ring fusion was assigned on the basis of the J1,6
coupling constant (10.8 Hz).
OH
1
16
Scheme 4 Reagents and conditions: (a) TBAF, THF, reflux, 96%;
(b) VO(acac)2, t-BuOOH, benzene, 95%; (c) m-CPBA, NaHCO3,
CH2Cl2, 0 °C, 99% (dr = 4:1); (d) LiAlH4, THF, reflux, 96%.
OH
b
Figure 2 ORTEP of 16
a
10
TBSO
H
reduction of the two epoxy groups in 16 with lithium
aluminum hydride afforded triol 1 in 96% yield.
13
1
13
However, the H and C NMR spectral data of our syn-
thetic 115 did not match with those reported for natural
product A. Surprisingly, their spectral data did agree with
those of natural product B. Based on the high stereoselec-
tivity of the last reduction reaction of diepoxy compound
16, we believe that the structure of natural product A re-
ported by Ahmed and Mahmoud4 must be revised and that
the correct structure of natural product A should be com-
pound 2.
N
H
N
H
TBSO
TBSO
14
Scheme 3 Reagents and conditions: (a) LiAlH4, THF, –15 °C, 90%;
(b) p-TsNNH2, MeNO2, 86%.
Treatment of compound 14 with tetrabutylammonium
fluoride (TBAF) gave alcohol 3 (Scheme 4). Hydroxyl-
directed epoxidation of 3 with VO(acac)2 and t-BuOOH
occurred with exquisite facial selectivity to deliver the
epoxy alcohol 15 as a single diastereomer and in excellent
yield.13 Epoxidation of compound 15 with m-chloroper-
oxybenzoic acid (m-CPBA) gave two separable diastereo-
mers 16 and its (9R,10S)-epoxide diastereomer in about
4:1 ratio. The stereochemical assignments of diepoxide 16
and its (9R,10S)-epoxide diastereomer were consistent
with the J8,9 coupling constant (5.7 Hz, 0.0 Hz, respective-
ly) and unambiguously confirmed by the single-crystal X-
ray diffraction analysis14 of 16 (Figure 2). Simultaneous
To confirm the structure of natural product B, we also
synthesized 2 in three steps (Scheme 5). Epoxidation of
both double bonds of the TBS protected diene 14 at –15
°C produced diepoxide 17 in 74% yield. The newly
formed stereocenters in 17 were assigned on the basis of
the J2,3 and J8,9 coupling constants (J = 4.5 Hz, 5.7 Hz, re-
spectively). Treatment of compound 17 with TBAF at
room temperature followed by reduction with lithium alu-
minum hydride gave 4b,5a,10b-trihydroxycadinane (2),16
whose spectral characteristics were consistent with those
of the natural product B.5 Thus, the natural and our syn-
thetic product 2 have the same absolute configuration
(1R,4S,5S,6S,7R,10S).
Synlett 2006, No. 16, 2655–2657 © Thieme Stuttgart · New York

LETTER
Total Synthesis of 4a,5a,10b-Trihydroxycadinane and Its C4-Isomer
2657
(3) For examples, see: (a) Vandewalle, M.; De Clercq, P.
H
O
H
Tetrahedron 1985, 41, 1767. (b) Tietze, L. F.; Beifuss, U.;
Antel, J.; Sheldrick, G. M. Angew. Chem., Int. Ed. Engl.
1988, 27, 703. (c) Davidson, B. S.; Plavcan, K. A.;
Meinwald, J. J. Org. Chem. 1990, 55, 3912. (d) Queiroga,
C. L.; Ferracini, V. L.; Marsaioli, A. J. Phytochemistry 1996,
42, 1097. (e) Barriault, L.; Deon, D. H. Org. Lett. 2001, 3,
1925.
a
b
O
TBSO
TBSO
14
17
OH
H
H
O
(4) (a) Ahmed, A. A.; Mahmoud, A. A. Tetrahedron 1998, 54,
8141. (b) Ahmed, A. A.; Mahmoud, A. A. Tetrahedron
2000, 56, 2725.
(5) Kuo, Y. H.; Chyu, C. F.; Lin, H. C. Chem. Pharm. Bull.
2003, 51, 986.
c
O
OH
OH
OH
18
2
(6) Not many examples have been reported in the literature for
synthesis of cadinanes from carvone: (a) Baranovsky, A.
V.; Jansen, B. M.; Meulemans, T. M.; Groot, A. D.
Tetrahedron 1998, 54, 5623. (b) Takaki, K.; Ohsugi, M.;
Okada, M.; Yasumura, M.; Negoro, K. J. Chem. Soc., Perkin
Trans. 1 1984, 741. (c) Gallagher, M. J.; Sutherland, M. D.
Aust. J. Chem. 1965, 18, 1111.
(7) Ceccarelli, S. M.; Piarulli, U.; Gennari, C. Tetrahedron
2001, 57, 8531.
(8) Martin, S. F.; White, J. B. Tetrahedron Lett. 1982, 23, 23.
(9) (a) Buchi, G.; Egger, B. J. Org. Chem. 1971, 36, 2021.
(b) Defieber, C.; Paquin, J. F.; Serna, S.; Carreira, E. M. Org.
Lett. 2004, 6, 3873.
(10) Quinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6,
4143.
(11) (a) Harapanhalli, R. S. J. Chem. Soc., Perkin Trans. 1 1988,
3149. (b) Chu, M.; Coates, R. M. J. Org. Chem. 1992, 57,
4590. (c) Greco, M. N.; Maryanoff, B. E. Tetrahedron Lett.
1992, 33, 5009.
Scheme 5 Reagents and conditions: (a) m-CPBA, NaHCO3,
CH2Cl2, –15 °C, 74%; (b) TBAF, THF, 89%; (c) LiAlH4, THF, reflux,
96%.
In summary, we have developed a highly efficient ap-
proach to the synthesis of the trans-cadinane skeleton.
The approach relies on the straightforward functionaliza-
tion of (R)-carvone to establish three stereocenters, ring-
closing metathesis to produce the decalin ring system, and
a modified allylic diazene rearrangement to install the req-
uisite trans-fused key intermediate 14. Through the first
asymmetric total synthesis of 4a,5a,10b-trihydroxycadi-
nane (1) and 4b,5a,10b-trihydroxycadinane (2), the incor-
rect structural assignments of natural product A could be
revised to structure B. Also, the absolute configuration of
B was established through this synthesis.
(12) Corey, E. J.; Virgil, S. C. J. Am. Chem. Soc. 1990, 112, 6429.
(13) (a) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc.
1973, 95, 6136. (b) Gallou, F.; MacMillan, D. W. C.;
Overman, L. E.; Paquette, L. A.; Pennington, L. D.; Yang, J.
Org. Lett. 2001, 3, 135.
(14) Atomic coordinates for 16 have been deposited with
Cambridge Crystallographic Data Centre under the
deposition number CCDC no. 617500.
Acknowledgment
We are grateful for the financial support from the National Natural
Science Foundation of China (No. 20272021). The authors want to
thank Dr. Zuosheng Liu (University of Pittsburgh) for suggestions
and preparation of the manuscript.
(15) Spectral data of compound 1: [a]D20 –16 (c = 0.1, CHCl3). IR
(film): 3415, 2963, 2931, 1458, 1380, 1117, 1019 cm–1. 1H
NMR (300 MHz, CDCl3): d = 3.63 (s, 1 H), 2.39 (br s, 1 H),
1.98–2.09 (m, 1 H), 1.82–1.66 (m, 3 H), 1.45–1.54 (m, 4 H),
1.29–1.40 (m, 5 H), 1.23 (s, 3 H), 1.18 (s, 3 H), 0.92 (d, J =
6.9 Hz, 3 H), 0.76 (d, J = 6.9 Hz, 3 H). 13C NMR (75 MHz,
CDCl3): d = 73.1, 72.5, 70.8, 42.5, 42.1, 40.2, 39.2, 33.2,
28.9, 25.6, 23.7, 22.6, 21.4, 19.0, 15.3. HRMS (ES): m/z [M
+ Na]+ calcd for C15H28NaO3: 279.1931; found: 279.1942.
(16) Spectral data of compound 2: mp 185–186 °C; [a]D20 –10
(c = 0.2, CHCl3). IR (film): 3406, 1372, 1154, 1020 cm–1. 1H
NMR (300 MHz, CDCl3): d = 3.60 (br s, 1 H), 2.01 (m, 1 H),
1.82 (m, 1 H), 1.63–1.74 (m, 3 H), 1.50–1.57 (m, 5 H), 1.31–
1.43 (m, 5 H), 1.27 (s, 3 H), 1.20 (s, 3 H), 0.94 (d, J = 7.2 Hz,
3 H), 0.81 (d, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
d = 73.0, 71.3, 70.8, 42.3, 41.8, 40.2, 37.4, 32.4, 28.7, 27.7,
25.6, 21.3, 20.1, 19.0, 15.4. HRMS (ES): m/z [M + Na]+
calcd for C15H28NaO3: 279.1931; found: 279.1929.
References and Notes
(1) For a review, see: Bordoloi, M.; Shukla, V. S.; Nath, S. C.;
Sharma, R. P. Phytochemistry 1989, 28, 2007.
(2) For examples, see: (a) Bordoloi, M. J.; Shukla, V. S.;
Sharma, R. P. Tetrahedron Lett. 1985, 26, 509. (b) Kalsi, P.
S.; Talwar, K. K. Phytochemistry 1981, 20, 511.
(c) Katayama, M.; Marumo, S.; Hottori, H. Tetrahedron
Lett. 1983, 24, 1703. (d) Stipanovic, R. D.; Greenblatt, G.
A.; Beier, R. C.; Bell, A. A. Phytochemistry 1981, 20, 729.
(e) Claeson, P.; Andersson, R.; Samuelsson, G. Planta Med.
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Synlett 2006, No. 16, 2655–2657 © Thieme Stuttgart · New York