The highly active catalyst 2 was used in tandem RCM to make molecules with various ring systems containing α,β-unsaturated carbonyl compounds

Choi, Tae-Lim

Grubbs, Robert H.

English

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Tandem ring-closing metathesis reaction with a ruthenium catalyst
containing a N-heterocyclic ligand
Tae-Lim Choi and Robert H. Grubbs*
Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, USA.
E-mail: rhg@its.caltech.edu
Received (in Cambridge, UK) 12th September 2001, Accepted 29th October 2001
First published as an Advance Article on the web 23rd November 2001
The highly active catalyst 2 was used in tandem RCM to
make molecules with various ring systems containing a,b-
unsaturated carbonyl compounds.
Tandem cyclization reactions build up molecular complexity
rapidly from relatively simple starting substrates.1 Complicated
molecules were synthesized in a single step by carbanion,2
carbocation,3 free radical,4 and Pd coupling reaction5 whose
novelty and efficiency were demonstrated by total syntheses of
many natural products. Olefin metathesis has become a useful
reaction in organic synthesis,6 and our group recently demon-
strated the viability of tandem ring closing metathesis reactions
using catalyst 1.7 Unfortunately, catalyst 1 could not incorpo-
rate more synthetically valuable functionalized olefins such as
a,b-unsaturated carbonyl compounds. However, with the
development of the more active catalyst 2,8 containing a N-
heterocyclic ligand, functionalized olefins could participate in
RCM and cross metathesis reactions.9 Herein, we report tandem
RCM reactions by using catalyst 2, to make synthetically useful
a,b-unsaturated lactones and enones.
Various substrates containing different olefin arrays were
examined for the tandem cyclization and were found to give
moderate to excellent yields (Table 1). Entries 1 through 4
demonstrate the viability of tandem ring-opening/ring-closing
Table 1 Tandem RCM to install functionalized olefinsa
Entry Substrate Concentration Product Yield
1 0.05 M 3: 81%
2 0.05 M 4: 89%
3 0.005 M 5: 45%
4 0.005 M 6: 47%
5 0.03 M 7: 95%
6 0.03 M 8: 86%
7 0.03 M 9: 72%
8 0.015 M 10: 68%
9 0.03 M 11: 100%
10 0.06 M 12: 74%
a 5 mol% catalyst 2 at 40 °C in CH2Cl2 for 6–12 h.
This journal is © The Royal Society of Chemistry 2001
2648 Chem. Commun., 2001, 2648–2649 DOI: 10.1039/b108306f
metathesis. In the case of entries 1 and 2, catalyst 2 reacts with
more reactive terminal olefin and the resulting alkylidene opens
the 5-membered ring. The sequence of tandem events is
completed by ring closing onto the a,b-unsaturated carbonyl
olefin (Scheme 1). Fused tricyclic compounds were also
synthesized from the highly strained norbonene moiety, but the
yields were lower due to competing polymerization (entries 3
and 4).
Another variant of tandem RCM is demonstrated by enyne
tandem ring closing metathesis to form fused bicyclic ring
systems (entries 5 to 10). In these cases, catalyst 2 also reacts
with the terminal olefins preferentially and undergoes rapid
intermolecular enyne metathesis to form the first ring, then
reacts with the a,b-unsaturated carbonyl olefin to close the final
ring (Scheme 2). The fact that 7-membered lactone A is never
observed, implies that during the first RCM event, the newly
formed alkylidene B exclusively reacts with acetylenes over
acrylates. The more challenging trisubstituted a,b-unsaturated
carbonyl olefins were also successfully cyclized (entries 6 and
7). However, an attempt to make a tetrasubstituted a,b-
unsaturated carbonyl olefin afforded less than 10% yield of the
bicycle with the remainder being monocyclized product. This
suggests that disubstituted carbene is formed just as in entry 7,
but preferentially reacts with the terminal olefins of the starting
molecule over the sterically and electronically demanding a-
disubstitued a,b-unsaturated carbonyl olefin. 7,6-Fused bi-
cyclic compounds are available in moderate yield by this
method, (entry 8). Lastly, tandem RCM to make 6,5,6- and
6,6,6-fused tricyclic compounds are shown in entries 9 and 10
which demonstrates that this method has potential applications
in the synthesis of complex natural products.
The highly active catalyst 2 was used in tandem RCM to
make molecules with various ring system. The ability to
incorporate a,b-unsaturated carbonyl olefins makes the tandem
RCM synthetically more valuable since further manipulations
are possible.
The authors would like to thank the NIH for generous support
of this research, and Dr M. Scholl, Dr C. W. Lee, Dr S. D.
Goldberg, Dr F. D. Toste and A.K. Chatterjee for helpful
discussions.
Notes and references
1 L. F. Teitze, Chem. Rev., 1996, 96, 115; T. Hudlickly, Chem. Rev., 1996,
96, 3;  T.-L. Ho, Tandem Reactions in Organic Synthesis, Wiley-
Interscience, New York, 1992.
2 M. Ihara, K. Makita, Y. Tokunaga and F. Fukumoto, J. Org. Chem., 1994,
59, 6008.
3 W. S. Johnson, K. Wiedhaup, S. F. Brady and G. L. Olson, J. Am. Chem.
Soc., 1974, 96, 3979.
4 T. Takahashi, W. Katouda, Y. Sakamoto, S. Tomida and H. Yamada,
Tetrahedron Lett., 1995, 36, 2273.
5 Y. Zhang, G. Wu, G. Angel and E. Negishi, J. Am. Chem. Soc., 1990, 112,
8590; B. M. Trost and Y. Shi, J. Am. Chem. Soc., 1993, 115, 9421.
6 For recent reviews on organic applications, see: R. H. Grubbs, S. J. Miller
and G. C. Fu, Acc. Chem. Res., 1995, 28, 446; M. Schuster and S.
Blechert, Angew. Chem., 1997, 109, 2124; M. Schuster and S. Blechert,
Angew. Chem., Int. Ed. Engl., 1997, 36, 2067; R. H. Grubbs and S.
Chang, Tetrahedron, 1998, 54, 4413; S. K. Armstrong, J. Chem. Soc.,
Perkin Trans. 1, 1998, 371; S. Blechert, Pure Appl. Chem., 1999, 71,
1393; A. Furstner, Angew. Chem., Int. Ed. Engl., 2000, 39, 3013.
7 S. H. Kim, N. B. Bowden and R. H. Grubbs, J. Am. Chem. Soc., 1994,
116, 10801; S. H. Kim, W. J. Zuercher, N. B. Bowden and R. H. Grubbs,
J. Org. Chem., 1996, 61, 1073; W. J. Zuercher, M. Hashimoto and R. H.
Grubbs, J. Am. Chem. Soc., 1996, 118, 6634; W. J. Zuercher, M. Scholl
and R. H. Grubbs, J. Org. Chem., 1998, 63, 4291.
8 M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1,
953.
9 A. K. Chatterjee and R. H. Grubbs, Org. Lett., 1999, 1, 1751; A. K.
Chatterjee, J. P. Morgan, M. Scholl and R. H. Grubbs, J. Am. Chem. Soc.,
2000, 122, 3783; T.-L. Choi, A. K. Chatterjee and R. H. Grubbs, Angew.
Chem., 2001, 113, 1317; T.-L. Choi, A. K. Chatterjee and R. H. Grubbs,
Angew. Chem., Int. Ed. Engl., 2001, 40, 1277; A. K. Chatterjee, T.-L.
Choi and R. H. Grubbs, Synlett, 2001, 1034; T.-L. Choi, C. W. Lee, A. K.
Chatterjee and R. H. Grubbs, J. Am. Chem. Soc., 2001, 123, 10417.
Scheme 1 Ring-opening/Ring-closing tandem RCM.
Scheme 2 Eyn-tandem RCM.
Chem. Commun., 2001, 2648–2649 2649


Tandem ring-closing metathesis reaction with a ruthenium catalyst containing a N-heterocyclic ligand

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Tandem ring-closing metathesis reaction with a ruthenium catalyst containing a N-heterocyclic ligand

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