Synthesis of small and large fused bicyclic compounds by tandem dienyne ring-closing metathesis

Article abstract of DOI:10.1021/ol101233k

(Equation Presented). A tandem ring-closing metathesis reaction using ruthenium catalyst was carried out to synthesize various fused bicyclic compounds containing both small and large rings. Fast ring-closure of the small ring and slow ring-closure of the large ring resulted in the formation of only one isomer. Further manipulation such as the Diels-Alder reaction was carried out to prepare a complex molecule containing multiple rings of different sizes.

Full text of DOI:10.1021/ol101233k

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3442-3445
Synthesis of Small and Large Fused
Bicyclic Compounds by Tandem
Dienyne Ring-Closing Metathesis
Hyeon Park, You-Lee Hong, Yongjoo B. Kim, and Tae-Lim Choi*
Department of Chemistry, Seoul National UniVersity, 599 Gwanak-ro, Gwanak-gu,
Seoul, Korea, 151-747
tlc@snu.ac.kr
Received June 1, 2010
ABSTRACT
A tandem ring-closing metathesis reaction using ruthenium catalyst was carried out to synthesize various fused bicyclic compounds containing
both small and large rings. Fast ring-closure of the small ring and slow ring-closure of the large ring resulted in the formation of only one
isomer. Further manipulation such as the Diels-Alder reaction was carried out to prepare a complex molecule containing multiple rings of
different sizes.
Olefin metathesis (OM) reaction is a powerful tool to create
new carbon-carbon double bonds, and numerous organic
molecules and polymers are efficiently prepared by OM.1
Among the various types of OM reactions, ring-closing
metathesis (RCM) has attracted the most attention from
organic chemists due to its effective synthesis of the various
cyclic molecules.2 In particular, the development of highly
active ruthenium carbene catalysts, such as 1,3 has led to
the broadening of substrate scope for RCM so that it is now
routinely used for the synthesis of various natural products
and new drugs.4 Among the various RCM reactions, mac-
rocyclization5 and tandem RCM to make multiple fused
rings6 enable us to synthesize the molecules with high
complexity making this method more versatile. This is
demonstrated by recent reports where the tandem RCM of
dienyne was successfully carried out for the total synthesis
of many natural products.7 However, this method was so
far limited to the synthesis of fused rings comprising small
or medium sized only.
(1) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013. (c) Handbook of
Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003;
Vol. 1, p 2. (d) Grubbs, R. H. Tetrahedron 2004, 60, 7117.
(2) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993,
115, 9856. (b) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res.
1995, 28, 446. (c) Armstrong, S. K. J. Chem. Soc. Perkin Trans. 1 1998,
371.
Macrocylization is a very important reaction because many
natural products contain large rings. Previously, popular
methods for the macrocyclization were Yamaguchi macro-
lactonization8 and radical-mediated macrocyclization.9 How-
ever, during the past decade, the macrocyclization by RCM
has emerged as a powerful tool because the reaction is highly
functional group tolerant with benign reaction conditions.5
Radical-mediated cascade reactions provide a synthetic
(3) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(4) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4490.
10.1021/ol101233k  2010 American Chemical Society
Published on Web 07/13/2010

access to the bicyclic compounds comprising both the small
and the large rings,10 but controlling these reactions can be
difficult because of problems such as low yield caused by
side reactions and the formation of toxic residues. Therefore,
a more general method for preparing the small and the large
rings in a single reaction would be valuable. We envisioned
if the tandem RCM could be implemented as a general and
efficient platform for the macrocyclization as well, its
synthetic utility would become even greater. Herein, we
report the first general method for synthesizing the fused
bicyclic compounds comprising both the small and the large
rings with high isolated yields by the RCM reaction in a
single operation from the corresponding dienynes.
to form the small ring (kS) is far greater than the rate of
macrocyclization (kM) (Scheme 2). Indeed, a model study
Scheme 2. Scheme for the Selective Tandem RCM
To promote the tandem RCM reaction for the synthesis
of the fused bicyclic compounds comprising the small and
the large rings, we designed a dienyne containing a small
and a long tether. However a potential problem of this
tandem RCM would be that asymmetric dienynes with two
terminal alkenes result in the formation of two different
products with different ring sizes (Scheme 1). This is due to
1
and H NMR confirmed that 2 was the major intermediate
implying the initial formation of the small ring occurred
exclusively without signs of further dimerization or oligo-
merization when monitored during the first 3 h. This suggests
that although catalyst 1 may react with the terminal olefin
on the long tether, no productive RCM occurs. Instead, 1
undergoes fast exchange (kex) ensuring the formation of the
small ring as the first RCM event. Then the slow macrocy-
clization proceeds for a long period of time producing a
single isomer in 82% isolated yield. An alternative mecha-
nism for 1 reacting with the alkyne first is less likely due to
a more congested environment.
Scheme 1. General Pathway for Tandem RCM
To expand the scope of the reaction, various substrates
were subjected to the tandem RCM for the synthesis of
bicyclic[n.3.0] compounds (n ) 12-15). Even though the
second macro-RCM itself was challenging since there was
only one flexible chain, just 5 mol % of 1 in 4 mM toluene
at 50-90 °C was sufficient to promote the tandem RCM
with good to excellent isolated yields of the bicycles (Table
1). In most cases, stereochemistry of olefins on the macro-
cycles is exclusively trans. This selectivity is noteworthy
since E/Z selectivity still remains as a serious issue in the
macro-RCM reactions.12 For the synthesis of a fused
macrolactone (entry 2), changing solvent to 1,2-dichloroet-
hane resulted in better yield than in toluene. Substrates with
additional oxygen in the long tether (entries 3-5) gave
excellent yields favoring the macrocyclization.13 A protected
amine in the long tether also allowed tandem RCM with high
yield (entry 6). A bicycle with a more challenging tetra-
substituted alkene containing bicycle14 was also prepared in
good yield at 90 °C (entry 7). For this compound, small
amount of Z isomer (E/Z ) 8) of the olefin on the macrocycle
was observed.
a nonselective initiation on both tethered alkenes, which will
result in two different bicycles. To prevent this mixture issue,
temporal protection was used by replacing one of two
terminal alkenes with a disubstituted olefin so that the catalyst
would preferentially react with the terminal olefin.6,11 For
the synthesis of the fused bicycles comprising the small and
the large rings by the tandem RCM, we expected that the
selectivity issue might be eliminated if the rate of initial RCM
(5) (a) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942. (b)
Fu¨rstner, A.; Kindler, N. Tetrahedron Lett. 1996, 39, 7005. (c) Lee, C. W.;
Grubbs, R. H. Org. Lett. 2000, 2, 2145. (d) Smith, A. B., III; Kozmin,
S. A.; Adams, C. M.; Paone, D. V. J. Am. Chem. Soc. 2000, 122, 4984. (e)
Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2003, 125, 9582. (f) Gradilas,
A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086. (g) Majumdar,
K. C.; Rahaman, H.; Roy, B. Curr. Org. Chem. 2007, 11, 1339.
(6) (a) Grubbs, R. H.; Kim, S. H.; Bowden, N. J. Am. Chem. Soc. 1994,
116, 10801. (b) Kim, S. H.; Zuercher, W. J.; Bowden, N. B. J. Org. Chem.
1996, 61, 1073.
The compatibility of the tandem RCM for the synthesis
of bicyclic[n.4.0] (n ) 12, 13) compounds was also
(7) For recent applications see (a) Boyer, F.-D.; Hanna, I.; Ricard, L.
Org. Lett. 2004, 6, 1817. (b) Niethe, A.; Fisher, D.; Blechert, S. J. Org.
Chem. 2008, 73, 3088. (c) Siegel, D. S.; Piizzi, G.; Piersanti, G.;
Movassaghi, M. J. Org. Chem. 2009, 74, 9292. (d) For review, see Mori,
M. AdV. Synth. Cat. 2007, 349, 121.
(11) (a) Wu, C.-J.; Madhushaw, R. J.; Liu, R.-S. J. Org. Chem. 2003,
68, 7889. (b) Honda, T.; Namiki, H.; Kaneda, K.; Mizutani, H. Org. Lett.
2004, 6, 87–89. (c) Maifeld, S. V.; Miller, R. L.; Lee, D. J. Am. Chem.
Soc. 2004, 126, 12228. (d) Maifeld, S. V.; Lee, D. Chem.sEur. J. 2005,
11, 6118.
(8) Nakano, A.; Takimoto, S.; Inanaga, J.; Katsuki, T.; Ouchida, S.;
Inoue, K.; Aiga, M.; Okukado, N.; Yamaguchi, M. Chem. Lett. 1979, 1019.
(9) For review on radical cyclizations, see Castle, S. L.; Srikanth, G. S. C.
Tetrahedron 2005, 61, 10377.
(12) (a) Busca, P.; Etheve-Quelquejeu, M.; Valre´y, J.-M. Tetrahedron
Lett. 2003, 44, 9131. (b) Kim, Y. J.; Lee, D. Org. Lett. 2004, 6, 4351. (c)
Conrad, J. C.; Eelman, M. D.; Silva, J. A. D.; Monfette, S.; Parnas, H. H.;
Snelgrove, J. L.; Fogg, D. E. J. Am. Chem. Soc. 2007, 129, 1024.
(13) (a) Fu¨rstner, A. Top. Catal. 1997, 4, 285. (b) Delgado, M.; Martin,
J. D. J. Org. Chem. 1999, 64, 4798.
(10) (a) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. ReV. 1991,
91, 1237. (b) Curran, D. P. Synlett. 1991, 63. (c) Haney, B. P.; Curran,
D. P. J. Org. Chem. 2000, 65, 2007.
(14) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
Org. Lett., Vol. 12, No. 15, 2010
3443

Table 1. Tandem RCM for the Formation of Bicycles
Table 2. Tandem RCM for Larger Ringsa
Comprising Five-Membered Ringsa
a General reaction conditions: under Ar atmosphere, substrate in 4 mM
toluene is added with 5 mol % 1, and the solution was heated to 55-100
°C for 24-48 h. b 10 mol % catalyst used. c 1,2-DCE as solvent. d 8 mol
% catalyst used. e Substrate concentration lowered to 2 mM and 15 mol %
1
a General reaction conditions: under Ar atmosphere, substrate in 4 mM
toluene is added with 5 mol % 1, and the solution was heated to 55-90 °C
for 24 h. b 1,2-DCE as solvent. c Mixture of E/Z ) 8 observed by 1H NMR.
catalyst used. Mixture of E/Z ) 25 observed by H NMR.
The products of enyne metathesis reaction undergo further
transformation such as Diels-Alder reaction.15 However,
there have been no reports of the Diels-Alder reaction with
the fused bicycles produced by the tandem dienyne RCM
reaction because the Diels-Alder reaction in this case is
prevented by conformational strain where the fused bicyles
with Z-olefin on the small rings adopts only a s-trans
conformation.16 We anticipated that our products with E
olefins might adopt a s-cis conformation as well if the
macrocycle is sufficiently flexible. (Scheme 3) Indeed, the
Diels-Alder reaction with maleic anhydride at 90 °C
produced a tetra-cyclic compound comprising three small
rings and one large ring in 76% isolated yield. An NOE study
revealed that the Diels-Alder adduct showed a single
diastereomer with endo selectivity, and the dienophile
investigated, and the similar results were obtained (Table
2). Generally, these reactions required higher temperature
or higher catalyst loading than examples in Table 1. Also
the product yields were slightly lower but still produced only
E olefins on the macrocycles (entries 1-5). A substrate with
a protected amine on its six-membered ring also underwent
tandem RCM (entry 5). Interestingly, the tandem RCM
affording a bicyclic[15.3.1] compound was also successful
even though the product contained a bridgehead olefin on
the six-membered ring (entry 6). This is attributed to a
reduction in the strain exerted by the flexible macrocycle. A
fused bicyclic compound containing a seven-membered ring
was also synthesized as a mixture of E- and Z-isomers (25:
1) (entry 7). However, it required a more dilute condition to
suppress the competing dimerization. Furthermore, the
tandem RCM was slower than that in the previous examples
because the formation of the initial seven-memebered ring
was much slower than that of the five and the six-membered
rings. As a result, a total of 15 mol % of 1 was added in
three portions for 3 days (5 mol % each for a day).
(15) (a) Heerding, D. A.; Takada, D. T.; Kwon, C.; Huffman, W. F.;
Samaren, J. Tetrahedron Lett. 1998, 39, 6815. (b) Rosillo, M.; Dominquez,
G.; Casarrubios, L. J. Org. Chem. 2004, 6, 2084. (c) Lee, H. Y.; Kim,
H. Y.; Tae, H. Org. Lett. 2003, 5, 3439.
(16) For example of Diels-Alder reaction on non-fused bicyclic ring
compound, see Aldegunde, M. J.; Codesido, E. M.; Castedo, L.; Granja,
J. R. Tetrahedron Lett. 2006, 47, 6587.
3444
Org. Lett., Vol. 12, No. 15, 2010

In conclusion, the tandem RCM produced various fused
bicycles comprising both the small and the large rings in a
single reaction. The advantages of this method are generality
and selectivity to produce the fused bicycles with the 5 to
7-membered small rings and the 14 to 17-membered mac-
rocycles in a highly predictive manner. The resulting fused
rings contain a 1,3-diene linked by the flexible tether so that
further manipulation such as the Diels-Alder reaction was
possible. This method can be applicable for the rapid
synthesis of complex organic molecules, especially those
containing the multiple rings of different sizes.
Scheme 3. Diels-Alder Reaction of the Tandem RCM Product
Acknowledgment. The financial support from the Korea
Research Fund (Grants 20090069339) and BK21 is acknowl-
edged.
approached away from the more hindered alkoxy tether.17
This is the first example of the Diels-Alder reaction from
the fused bicyclic compounds, and this method is potentially
useful for the rapid construction of highly complex mol-
ecules.
Supporting Information Available: Details of the ex-
perimental procedure with characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) For similar stereochemistry assignation, see Rega´s, D.; Alfonso,
M. M.; Rodr´ıguez, M. L.; Palenzuela, J. A. J. Org. Chem. 2003, 68, 7845.
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