A ring-closing metathesis approach to the bicyclo[4.3.1]decane core of caryolanes

Article abstract of DOI:10.1016/j.tetlet.2010.11.138

A synthesis of highly substituted and sterically congested bicyclo[4.3.1]decenes, a structure embedded in the core 4,7,6-tricyclic system of natural caryolanes, was successfully achieved via a ring-closing metathesis (RCM) reaction of syn-1,3-diene substi

Full text of DOI:10.1016/j.tetlet.2010.11.138

Tetrahedron Letters 52 (2011) 859–862
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A ring-closing metathesis approach to the bicyclo[4.3.1]decane core
of caryolanes
⇑
William P. D. Goldring , Warren T. Paden
School of Chemistry and Chemical Engineering, Queen’s University Belfast, David Keir Building, Stranmillis Road, Belfast, Northern Ireland BT9 5AG, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthesis of highly substituted and sterically congested bicyclo[4.3.1]decenes, a structure embedded in
the core 4,7,6-tricyclic system of natural caryolanes, was successfully achieved via a ring-closing metath-
esis (RCM) reaction of syn-1,3-diene substituted cyclohexanols. The construction of the diene substrates,
starting from 4-acetoxy-3-methyl-2-cyclohexen-1-one, employed diastereoselective copper-mediated
conjugate addition and Grignard reactions. An X-ray crystal structure determination of a key synthetic
intermediate confirmed the relative stereochemistry of the RCM bicyclic product.
Received 14 October 2010
Revised 11 November 2010
Accepted 26 November 2010
Available online 2 December 2010
Dedicated to the memory of Prof. Edward
Piers
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Caryolane
Ring-closing metathesis
Bicyclic ring systems
Cyclohexenone
The caryolane-based natural products, such as 1 and 2, and the
related isomers, have been isolated from a variety of natural
sources from around the world, including the Japanese rootlets of
Panax ginseng,1 the flowers of Asian and European Chrysanthemum
H
H
H
H
OH
OH
OH
indicum L.,2 the Egyptian herbal medicine Cyperus longus3 and the
4
Indonesian medicinal plant Sindora sumatrana MIQ
.
Many mem-
OH
OH
OH
bers of this family of natural compounds exhibit important anti-
HIV, anti-tumour and anti-bacterial properties. Recently, Guo and
co-workers reported the isolation of four related natural caryol-
anes, for example, excogallochaol A (1), from the Chinese man-
grove shrub Excoecaria agallocha L.5 The structural elucidation of
this family of natural products was based, in part, on NMR data
which identified a cis-fused 4,7-bicyclic unit embedded within
these structures. In contrast, the 4,7-bicyclic unit found within
many other natural caryolanes, and related structures, were re-
ported to be trans-fused. These natural structures represent a syn-
thetic challenge which lies in the assembly of the strained
caryolane ring system, with the appropriate stereochemistry. The
core 4,7,6-tricyclic structure of the caryolane ring system has been
the subject of numerous synthetic studies on the rearrangement of
caryophyllene,6 and its derivatives.7 However, we aimed to achieve
a synthesis of this intriguing natural structure using a ring-closing
metathesis (RCM) based approach to construct the bicy-
clo[4.3.1]decene core 3.
1
2
3
The RCM reaction has proven to be a reliable method for the
construction of strained carbo- and heterocyclic ring systems.8 Fol-
lowing the first reports of bridged bicycloalkene formation via
RCM,9 this method was successfully employed in the total synthe-
sis of natural products which possess strained ring systems.10 In
many of these cases the relative stereochemistry and substitution
pattern of the bis-alkenyl substituted cyclic RCM substrates played
a key role in either facilitating or hindering the progress of the
reaction.9,10b–g In related studies, Martin11 and later Mascareñas12
employed syn-1,3-bis-alkenyl substituted six-membered sub-
strates in the RCM formation of bridged bicyclic systems. In these
cases the RCM cyclisation proceeded via a reactive conformation,
favoured by strain or hydrogen-bonding effects.13 However, the
RCM construction of a related bridged bicyclic compound, which
proceeded in the absence of these effects, suggested that other fac-
tors play a more significant role in the success of this reaction.14
In this Letter, a ring-closing metathesis based synthetic route to
the bicyclo[4.3.1]decene core 3 of caryolane ring systems, such as 1
and 2, which does not rely on a conformational bias of the diene
substrate towards a reactive conformation, is described.
⇑
Corresponding author. Tel.: +44 28 9097 4414; fax: +44 28 9097 6524.
E-mail address: w.goldring@qub.ac.uk (W.P.D. Goldring).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.138

860
W. P. D. Goldring, W. T. Paden / Tetrahedron Letters 52 (2011) 859–862
Our retrosynthetic analysis of the bicyclo[4.3.1]decene struc-
OMe
O
O
4 steps
Ref. 15
i, ii
ture 3 revealed the RCM disconnection to 4, shown in Scheme 1.
Sequential Grignard and conjugate addition disconnections of the
vinyl and 3-butenyl groups in 4, respectively, led to the cyclohexe-
none 6, via 5. The conversion of commercially available 3-methyl-
anisole (7) into the cyclohexenone 6 has been reported in the
literature.15 Based on this analysis, the planned forward synthesis
demanded two diastereoselective reactions. The stereochemical
course of the first, a copper-mediated conjugate addition step lead-
ing to 5, was anticipated to proceed opposite to the protected sec-
ondary alcohol. The second was a selective vinyl Grignard addition
step leading to 4. Furthermore, the strategy required a compatible
protecting group for the secondary hydroxy in 5 and 6. The results
of our synthetic studies based on this synthetic plan are described
below.
OAc
8
OTBS
9
7
O
OR
OR
iii
iv
+
OTBS
10
OTBS
OTBS
11a (R = H) 11b
v
12a (R = MOM) 12b
OR
OR
vi
The initial attempt towards
a synthesis of the bicy-
+
or vii
clo[4.3.1]decene core 3 of the caryolanes began with the known
conversion of commercially available 3-methylanisole (7) into
the cyclohexenone 8 (Scheme 2).15 This four-step sequence in-
volved Birch reduction, enol ether hydrolysis, epoxidation and fi-
nally a one-pot elimination-epoxide opening sequence, which
was followed by acetylation of the newly formed secondary alco-
hol. Transesterification of the acetate 8 using Na2CO3 in MeOH fol-
lowed immediately by treatment of the resulting secondary
alcohol with TBSCl in the presence of DMAP and triethylamine
gave the silyl ether 9 in 57% yield over two steps. In our hands
the intermediate alcohol was unstable, which necessitated its
immediate use in the subsequent step. The copper-mediated con-
jugate addition reaction on 9 which led to the ketone 10 first in-
volved the treatment of 4-bromobut-1-ene with magnesium,
followed by the addition of CuBrÁDMS and LiCl to give the corre-
sponding cuprate to which was added the cyclohexenone 9 and
TMSCl. The 1,4-addition product 10 was formed as a single diaste-
reoisomer in 81% yield.16 Based on the literature precedent,15a the
3-butenyl group was added onto the face of the enone 9 opposite
to the TBS protected secondary alcohol, which was reflected in
the relative anti-stereochemical relationship between these groups
in the product 10. Treatment of ketone 10 with vinylmagnesium
bromide gave an inseparable 1.4:1 diastereoisomeric mixture of
the dienes 11 in 85% combined yield. Attempts to separate the dia-
stereoisomers using flash column chromatography were unsuc-
cessful, and therefore this material was used as a mixture in all
subsequent steps. Presumably, the major product 11a, in which
the 3-butenyl and vinyl groups are in a syn-relationship, resulted
from equatorial attack of vinylmagnesium bromide on the ketone
10. In an attempt to separate the tertiary alcohols 11 by chemical
conversion, the diastereoisomeric mixture was treated with MOM-
Cl, DIPEA and TBAI to give an inseparable 1.4:1 diastereoisomeric
mixture of the MOM ethers 12 in 90% combined yield. Undeterred
by this outcome, the mixture of diene diastereoisomers 11 was
treated with 10 mol % of Grubbs’ 1st generation pre-catalyst in
refluxing CH2Cl2 to give the bicyclic product 13 in 66% yield,17
OTBS
13, R = H
14, R = MOM
OTBS
11b, R = H
12b, R = MOM
Scheme 2. Reagents and conditions: (i) Na2CO3, MeOH, rt, 88%; (ii) TBSCl, Et3N,
DMAP, CH2Cl2, rt, 65%; (iii) 4-bromobut-1-ene, Mg, I2, THF, À78 °C; then CuBrÁDMS,
LiCl, TMSCl, THF, À78 °C, 81%; (iv) vinylmagnesium bromide, THF, rt, 85% combined
yield (11a/11b, 1.4:1); (v) 11, MOMCl, DIPEA, TBAI, CH2Cl2, rt, 90% combined yield
(12a/12b, 1.4:1); (vi) 11, Grubbs’ I (10 mol %), CH2Cl2, 40 °C, 66% (13) and 14%
(11b); (vii) 12, Grubbs’ I (10 mol %), CH2Cl2, 40 °C, 60% combined yield (14/12b,
2.2:1).
based on the amount of the syn-diene 11a present in the starting
mixture, together with the anti-diene diastereoisomer 11b in 14%
recovery. Finally, treatment of the mixture of diene diastereoiso-
mers 12 under the RCM conditions described above led to an insep-
arable 2.2:1 mixture of the bicyclic product 14 and recovered anti-
diene 12b in 60% combined yield. In either case, we did not isolate
any of the ruthenium alkylidene corresponding to 11b or 12b, cf.
15; however it is likely that this unproductive intermediate could
account for some of the remaining material balance.
The RCM reaction of the syn-diene 11a to give the bicyclic prod-
uct 13, and the recovery of the anti-diene 11b, suggested that the
relative stereochemistry of the alkene units played a significant
role in governing product formation. Furthermore, the conforma-
tion of the reactive intermediates of 11a must also play an impor-
tant role in the reaction. For example, treatment of the syn-diene
11a with Grubbs’ 1st generation pre-catalyst leads to the ruthe-
nium alkylidene 15 which could adopt two possible chair confor-
mations (Scheme 3). In the bis-equatorial conformation 15-A the
ruthenium alkylidene and alkene groups are unable to move into
[Ru]
OR'
R'O
R
Grubbs' I
11a
R
O
OH
RCM
Grignard
[Ru]
3
15-A
15-B
OH
4
OH
5
(R = OH, R' = TBS)
O
OMe
OH
Cuprate
Ref. 15
OR'
R
OR'
R
OTBS
OH
6
[Ru]
7
13
16
Scheme 1. Retrosynthetic analysis of bicyclo[4.3.1]decene 3.
Scheme 3. Mechanism and conformational analysis of the RCM reaction of 11a.

W. P. D. Goldring, W. T. Paden / Tetrahedron Letters 52 (2011) 859–862
861
a reactive proximity. In contrast, the ruthenium alkylidene and al-
kene groups in the bis-axial conformation 15-B are able to move
into a reactive proximity, leading to the metallacyclobutane 16. Fi-
nally, cycloreversion of 16 leads to the bicyclic product 13.
Following the success of the synthetic studies which led to the
bicyclo[4.3.1]decene 13, we set out to construct the syn-diene 21,
cf. 11a, in order to fully evaluate the potential of the synthetic
route. The synthesis of 21 began with conversion of the acetate 8
into the silyl ether 17 in 62% yield, using a two-step sequence sim-
ilar to the conditions described earlier, using TBDPSCl in place of
TBSCl (Scheme 4). The copper-mediated conjugate addition reac-
tion on 17, using 2-(2-bromoethyl)-1,3-dioxolane under the condi-
tions described by Piers and Oballa,15a gave the ketone 18 as a
single diastereoisomer in 78% yield. The ketone 18 was treated
with vinylmagnesium bromide to give the diastereoisomeric allylic
tertiary alcohols 19 and 20 in 59% and 24% chromatographic yield,
respectively. The major syn-diastereoisomer 19 was isolated as a
colourless solid, and its structure and relative stereochemistry
were confirmed based on a single crystal X-ray structure determi-
nation (Fig. 1).18 Compound 19 possessed a syn-relationship be-
tween the vinyl and dioxolane groups and an anti-relationship
between the dioxolane and silyl ether groups. Therefore, com-
pound 19 possessed the correct stereochemistry for elaboration
of the caryolane structure. Furthermore, we were confident that
the relative stereochemistry of the ketone 10 was analogous to that
of the ketone 18 based on the X-ray data recorded for 19. It is
important to note that the minor anti-diastereoisomer 20 could
not be used to elaborate the caryolane structure 1. Deprotection
of the dioxolane 19 with CeCl3Á7H2O and catalytic NaI in refluxing
acetonitrile19 gave the corresponding aldehyde in 87% crude yield,
which was immediately treated with triphenylphosphonium bro-
mide and n-BuLi in THF to give the syn-diene 21 in 44% yield. We
were pleased to discover that treatment of the diene 21 with
10 mol % of Grubbs’ 2nd generation pre-catalyst in refluxing
CH2Cl2 gave the bicyclic product 22 in 90% yield.
Figure 1. ORTEP representation of 19 at the 50% probability level. The disorder in
the vinyl group was removed for clarity.
the conformation of the substrates towards, for example, the reac-
tive bis-axial conformer 15-B. In fact, analysis of the substitution
pattern of these diene systems suggested that the unproductive
bis-equatorial conformation, for example, 15-A, was favoured.
Therefore, these diene substrates were not predisposed to RCM;
however the reactions were nonetheless successful.
In conclusion, a synthesis of the bicyclo[4.3.1]decene core 22,
found in natural caryolane structures such as 1 and 2, was success-
fully achieved using a RCM based approach. The synthetic route
employed diastereoselective copper-mediated conjugate addition
and Grignard reactions for the construction of the syn-diene RCM
precursor 21. The relative stereochemistry of the bicyclic product
was confirmed based on an X-ray crystal structure of the key syn-
thetic intermediate 19. The results of these synthetic studies sug-
gested that the anti-diene substrates, such as 11b, did not form
the corresponding bicyclic product due to the relative stereochem-
istry of the alkene units, and therefore were not suitable substrates
for RCM. We aim to exploit the results of these ongoing studies,
which led to the bicyclic compound 22, in a synthesis of caryol-
anes. This includes a direct approach to the 4,7,6-tricyclic caryo-
The RCM reactions of the dienes 11a and 21 did not rely on or
benefit from strain or hydrogen-bonding effects which could bias
O
O
O
O
O
i, ii
O
iii
OTBDPS
18
OAc
8
OTBDPS
17
lane system based on
a photochemical [2+2]-cycloaddition
reaction of a diene substrate, such as 21. Our progress in these
areas will be described in due course.
O
O
O
OH
OH
iv
Acknowledgements
+
The authors thank the Department for Employment and Learn-
ing (DEL) for their support of this research (studentship to W.T.P.)
and Professor Paul Raithby, University of Bath, for the X-ray data
recorded for compound 19.
OTBDPS
OTBDPS
20
19 (X-ray)
v, vi
References and notes
OH
OH
vii
1. Iwabuchi, H.; Kato, N.; Yoshikura, M. Chem. Pharm. Bull. 1990, 38, 1405–1407.
2. Yoshikawa, M.; Morikawa, T.; Murakami, T.; Toguchida, I.; Harima, S.; Matsuda,
H. Chem. Pharm. Bull. 1999, 47, 340–345.
3. Xu, F.; Morikawa, T.; Matsuda, H.; Ninomiya, K.; Yoshikawa, M. J. Nat. Prod.
2004, 67, 569–576.
OTBDPS
21
OTBDPS
22
4. Heymann, H.; Tezuka, Y.; Kikuchi, T.; Supriyatna, S. Chem. Pharm. Bull. 1994, 42,
138–146.
5. Wang, J.-D.; Zhang, W.; Li, Z.-Y.; Xiang, W.-S.; Guo, Y.-W.; Krohn, K.
Phytochemistry 2007, 68, 2426–2431.
6. (a) Fitjer, L.; Malich, A.; Paschke, C.; Kluge, S.; Gerke, R.; Rissom, B.; Weiser, J.;
Noltemeyer, M. J. Am. Chem. Soc. 1995, 117, 9180–9189; (b) Barton, D. H. R.;
Scheme 4. Reagents and conditions: (i) Na2CO3, MeOH, rt, 88%; (ii) TBDPSCl, Et3N,
DMAP, CH2Cl2, rt, 71%; (iii) 2-(2-bromoethyl)-1,3-dioxolane, Mg, I2, THF, À78 °C;
then CuBrÁDMS, HMPA, TMSCl, THF, À78 °C, 78%; (iv) vinylmagnesium bromide,
THF, rt, 59% (19) and 24% (20); (v) CeCl3Á7H2O, NaI, CH3CN, 90 °C, 87% (from 19);
(vi) Ph3PCH3Br, n-BuLi, THF, 0 °C, 44%; (vii) Grubbs’ II (10 mol %), CH2Cl2, 40 °C, 90%.

862
W. P. D. Goldring, W. T. Paden / Tetrahedron Letters 52 (2011) 859–862
Nickon, A. J. Chem. Soc. 1954, 4665–4669; (c) Aebi, A.; Barton, D. H. R.;
Burgstahler, A. W.; Lindsey, A. S. J. Chem. Soc. 1954, 4659–4665.
16. The copper-mediated conjugate addition reaction leading to 10 was unreliable;
however the highest yield recorded for this reaction was reported. In contrast,
the related reaction which smoothly led to 18 was reliable and reproducible.
17. Satisfactory spectroscopic data were recorded for all synthesised compounds
reported in this Letter. For example: Data recorded for 13: mmax (film)/cmÀ1
3350, 3008, 2952, 2929, 2856, 1612, 1471 and 1258; dH (400 MHz, CDCl3) 5.83
7. For some examples, see: (a) Choudhary, M. I.; Siddiqui, Z. A.; Nawaz, S. A.; Atta-
ur-Rahman J. Nat. Prod. 2006, 69, 1429–1434; (b) Racero, J. C.; Macías-Sánchez,
A. J.; Hernández-Galán, R.; Hitchcock, P. B.; Hanson, J. R.; Collado, I. G. J. Org.
Chem. 2000, 65, 7786–7791; (c) Collado, I. G.; Hanson, J. R.; Hitchcock, P. B.;
Macías-Sánchez, A. J. J. Org. Chem. 1997, 62, 1965–1969; (d) Abraham, W.-R.;
Ernst, L.; Arfmann, H.-A. Phytochemistry 1990, 29, 757–763.
8. For reviews on the subject, see: (a) Collins, S. K. J. Organomet. Chem. 2006, 691,
5122–5128; (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238.
9. Morehead, A.; Grubbs, R. Chem. Commun. 1998, 275–276, and references
therein.
10. For examples of the RCM-based construction of bridged bicyclic structures in
natural product synthesis, see: (a) Magauer, T.; Mulzer, J.; Tiefenbacher, K. Org.
Lett. 2009, 11, 5306–5309; (b) Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P.
D.; Greene, B.; Yusuff, N.; Wood, J. L. J. Am. Chem. Soc. 2004, 126, 16300–16301;
(c) Voight, E. A.; Seradj, H.; Roethle, P. A.; Burke, S. D. Org. Lett. 2004, 6, 4045–
4048; (d) Watanabe, K.; Suzuki, Y.; Aoki, K.; Sakakura, A.; Suenaga, K.; Kigoshi,
H. J. Org. Chem. 2004, 69, 7802–7808; (e) Washburn, D. G.; Heidebrecht, R. W.;
Martin, S. F. Org. Lett. 2003, 5, 3523–3525; (f) Itoh, T.; Yamazaki, N.; Kibayashi,
C. Org. Lett. 2002, 4, 2469–2472; (g) Tang, H.; Yusuff, N.; Wood, J. L. Org. Lett.
2001, 3, 1563–1566; (h) Scholl, M.; Grubbs, R. H. Tetrahedron Lett. 1999, 40,
1425–1428.
(1H, ddd,
J 11.5, 8.9 and 3.4, CH2CH@CH), 5.31 (1H, dt, J 11.5 and 2.6,
CH2CH@CH), 3.30–3.28 (1H, m, CHOTBS), 2.36–2.27 (1H, m, CHHC@C), 1.97–
1.91 (1H, m, CHHC@C), 1.89–1.75 (3H, m, CHHCH2C@C, CH(OTBS)CHH and
C(4°)(OH)CHH), 1.68 (1H, dd, J 12.9 and 2.5, C(4°)(OH)CHH), 1.57–1.52 (2H, m,
CH(OTBS)CHH and OH), 1.44–1.37 (1H, m, CHHCH2C@C), 1.38 (3H, s, CH3), 1.25
(1H, br s, CHH), 0.92–0.90 (1H, m, CHH), 0.91 (9H, s, SiC(CH3)3), 0.06 (3H, s,
SiCH3), 0.04 (3H, s, SiCH3); dC (100 MHz, CDCl3) 136.0, 130.8, 74.0, 73.6, 42.0,
38.1, 37.4, 32.4, 29.4, 27.4, 25.9, 22.8, 18.2, À4.4, À4.9; m/z (ES) 296.2180 (M+,
2%, C17H32O2Si requires 296. 2172). Data recorded for 22: mmax (CDCl3)/cmÀ1
3594, 3073, 3053, 3014, 2932, 2858, 1601, 1469 and 1262; dH (400 MHz, CDCl3)
7.72–7.68 (4H, m, ArH), 7.45–7.33 (6H, m, ArH), 5.79 (1H, ddd, J 11.4, 8.8 and
3.3, CH2CH@CH), 5.27 (1H, ddd, J 11.4, 2.5 and 1.3, CH2CH@CH), 3.46 (1H, dd, J
2.8 and 2.3, CHOTBDPS), 2.33–2.21 (1H, m, CHHC@C), 1.90–1.82 (4H, m,
CHHC@C, CH2 and C(4°)(OH)CHH), 1.65 (1H, tdd,
J 14.3, 4.0 and 2.2,
CH(OTBDPS)CHH), 1.46–1.40 (2H, m, CH(OTBDPS)CHH and OH), 1.37–1.32
(1H, m, C(4°)(OH)CHH), 1.27–1.23 (1H, m, CHHCH2C@C), 1.24 (3H, s, CH3), 1.10
(9H, s, SiC(CH3)3), 0.92–0.83 (1H, m, CHHCH2C@C); dC (100 MHz, CDCl3) 136.2,
136.1, 135.9, 134.8, 134.2, 130.8, 129.53, 129.48, 127.43, 127.42, 74.9, 73.9,
42.3, 38.6, 37.5, 32.6, 29.5, 27.4, 26.5, 22.7, 19.7; m/z (ES) 443.2366 (M++Na, 6%,
11. (a) Martin, S. F. Pure Appl. Chem. 2005, 77, 1207–1212; (b) Neipp, C. E.; Martin,
S. F. J. Org. Chem. 2003, 68, 8867–8878; (c) Neipp, C. E.; Martin, S. F. Tetrahedron
Lett. 2002, 43, 1779–1782.
C
27H36O2SiNa requires 443.2382).
12. Rodríguez, J. R.; Castedo, L.; Mascareñas, J. L. Chem. Eur. J. 2002, 8, 2923–2930.
13. For a related example, see: Kuznetsov, N. Y.; Khrustalev, V. N.; Godovikov, I. A.;
Bubnov, Y. N. Eur. J. Org. Chem. 2006, 113–120.
14. Srikrishna, A.; Pardeshi, V. H.; Satyanarayana, G. Tetrahedron: Asymmetry 2008,
19, 1984–1991.
18. CCDC 796110 contains the supplementary crystallographic data recorded for
the tertiary alcohol 19 reported in this Letter. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
19. Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco, M.; Sambri, L. J. Org. Chem. 1997,
62, 4183–4184.
15. (a) Piers, E.; Oballa, R. M. J. Org. Chem. 1996, 61, 8439–8447; (b) Polla, M.; Frejd,
T. Tetrahedron 1991, 47, 5883–5894.