Mitchell et al.
Two classic reviews by Mandolini9 summarized a large set
of data derived from lactonizations, intramolecular etherifica-
tions, and C-C bond-forming reactions, and reported the
relationship between cyclization efficiency and ring size.
Medium rings represent some of the most difficult challenges
for cyclization strategies; the combination of developing ring
strain and the requirement to restrict rotations around 7-9
flexible bonds ensures unfavorable enthalpic and entropic10
contributions to ∆Gq; cyclization reactions that form medium
rings are therefore often relatively slow. High dilution (or
Ziegler) conditions are often employed to reduce the rate of
competing oligomerization pathways, because relatively inef-
ficient cyclization is anticipated.
SCHEME 1
The RCM reaction converts a diene precursor to two alkene
molecules, one of which is volatile ethylene in most synthetic
sequences, allowing the unfavorable ∆Sq (and ∆Hq) associated
with cyclization to be compensated for entropically. Neverthe-
less, RCM reactions that form medium rings, for example,
cyclooctannulation,11 which is severely enthalpically and en-
tropically disadvantaged, are reported to require high catalyst
loading, high dilution, long reaction times, and importantly some
degree of “gearing” of appropriately placed substituents12 to
deliver acceptable yields of cycloalkene products. These factors
combine to severely restrict scaleability (in principle). Almost
all our insights concerning RCM efficiency come from yield
measurements; there are very few kinetic studies of the RCM
reactions and those that are published involve the formation of
five-membered rings and cyclization is not rate-determining.13
There are no measured effective molarities in the literature; Fogg
has presented a number of expected values of RCM EMs based
on ring size but we are unaware of any experimental determina-
tions of EM for RCM reactions.14
Recently, we showed how we could use metalated difluoro-
alkene chemistry to advance trifluoroethanol rapidly to deliver
a number of sugar-like systems and a glycosyl phosphate
analogue; the synthesis of a cyclooctenone template 1 by RCM15
was a key step (Scheme 1).16
We wished to optimize the RCM reaction by varying the
reaction solvent and temperature and the loading of the
Ruthenium catalyst and by the correct choice of protection (R
in 1) for an allylic hydroxyl group, reporting the results of
qualitative studies in our full synthetic paper. We now wish to
report the results of a study in which substituent effects on RCM
are quantified for the first time, with the two fluorine atoms
acting as reporter groups for the various constituents within
complex reaction mixtures.
In the absence of quantitative information about a wide range
of systems, the optimization of RCM reactions remains a matter
of trial and error rather than one of rational design based on a
detailed understanding of the underlying principles.
A number of authors have reported that allylic substituents
can exert large effects on RCM reaction yield17 and regiochemi-
cal outcome.18 In the most cited paper in the area, Hoye and
(8) (a) Vyboishchikov, S. E.; Thiel, W. Chem.-Eur. J. 2005, 11, 3921.
(b) Castoldi, D.; Caggiano, L.; Panigada, L.; Sharon, O.; Costa, A. M.;
Gennari, C. Chem.- Eur. J. 2005, 12, 51.
(14) For a study that begins to examine a much wider range of systems
and discusses cyclization efficiency, see: Conrad, J. C.; Eelman, M. D.;
Duarte Silva, J. A.; Monfette, S.; Pamas, H. H.; Snelgrove, J. L.; Fogg, D.
E. J. Am. Chem. Soc. 2007, 129, 1024.
(15) (a) Miles, J. A. L.; Mitchell, L.; Percy, J. M.; Singh, K.; Uneyama,
E. J. Org. Chem., 2007, 72, 1575-1587. (b) For a related system, see:
Griffith, G. A.; Percy, J. M.; Pintat, S.; Smith, C. A.; Spencer, N.; Uneyama,
E. Org. Biomol. Chem. 2005, 3, 2701.
(9) (a) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95. (b)
Galli, C.; Mandolini, L. Eur. J. Org. Chem. 2000, 3117.
(10) Buszek and co-workers have measured very small ∆Sq values for a
series of lactonisations forming eight-membered rings; see: Buszek, K. R.;
Jeong, Y.; Sato, N.; Still, P. C.; Muino, P. L.; Ghosh, I. Synth. Commun.
2001, 31, 1781.
(11) For a recent review, see: Michaut, A.; Rodriguez, J. Angew. Chem.,
Int. Ed. 2006, 45, 5740.
(16) For examples of RCM-based syntheses of selectively fluorinated
molecules, see: (a) Butt, A. H.; Percy, J. M.; Spencer, N. S. Chem. Commun.
2000, 1691. (b) Audouard, C.; Fawcett, J.; Griffiths, G. A.; Percy, J. M.;
Pintat, S.; Smith, C. A. Org. Biomol. Chem. 2004, 2, 528. (c) Audouard,
C.; Fawcett, J.; Griffith, G. A.; Kerouredan, E.; Miah, A.; Percy, J. M.;
Yang, H. L. Org. Lett. 2004, 6, 4269. (d) Fustero, S.; Catalan, S.; Piera, J.;
Sanz-Cervera, J. F.; Fernandez, B.; Acena, J. L. J. Org. Chem. 2006, 71,
4010. (e) Fustero, S.; Sanchez-Rosello, M.; Jimenez, D.; Sanz-Cervera, J.
F.; del Pozo, C.; Acena, J. L. J. Org. Chem. 2006, 71, 2706. (f) Fustero,
S.; Bartolome, A.; Sanz-Cervera, J. F.; Sanchez-Rosello, M.; Soler, J. G.;
de Arellano, C. R.; Fuentes, A. S. Org. Lett. 2003, 5, 2523. (g) De Matteis,
V.; van Delft, F. L.; Jakobi, H.; Lindell, S.; Tiebes, J.; Rutjes, F. J. Org.
Chem. 2006, 71, 7527. (h) De Matteis, V.; van Delft, F. L.; Tiebes, J.;
Rutjes, F. Eur. J. Org. Chem. 2006, 1166. (i) Yang, Y. Y.; Meng, W. D.;
Qing, F. L. Org. Lett. 2004, 6, 4257. (j) You, Z. W.; Wu, Y. Y.; Qing, F.
L. Tetrahedron Lett. 2004, 45, 9479.
(12) The literature describes a number of failed attempts to cyclize simple
(often geminally disubstituted) cyclooctene precursors; however, Taylor and
Crimmins found that precursors with appropriately placed vicinal substit-
uents could be cyclized successfully. For successful examples demonstrating
the importance of substituent patterns or gearing, see: (a) Crimmins, M.
T.; Choy, A. L. J. Org. Chem. 1997, 62, 7548. (b) Crimmins, M. T.; Tabet,
E. A. J. Am. Chem. Soc. 2000, 122, 5473. (c) Edwards, S. D.; Lewis, T.;
Taylor, R. J. K. Tetrahedron Lett. 1999, 40, 4267. For unsuccessful attempts
to cyclize less substituted systems, see: (d) Kirkland, T. A.; Grubbs, R. H.
J. Org. Chem. 1997, 62, 7310. (e) Hammer, K.; Undheim, K. Tetrahedron
1997, 53, 2309. For the ROMP of cyclooctene with tungsten alkylidene
catalysis, see: (f) Kress, J. J. Mol. Catal. A 1995, 102, 7. The copious
ROMP literature for cyclooctenes is well reviewed by Ivin; see: (g) Ivin,
K. J. Olefin Metathesis; Academic Press: New York, 1983.
(13) Most of the quantitative studies deal with simple 5- and 6-ring-
forming reactions: (a) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am.
Chem. Soc. 1997, 119, 3887. (b) Bassetti, M.; Centola, F.; Semeril, D.;
Bruneau, C.; Dixneuf, P. H. Organometallics 2003, 22, 4459. See also:
(c) Basu, K.; Cabral, J. A.; Paquette, L. A. Tetrahedron Lett. 2002, 43,
5453. (d) Guo, X.; Basu, K.; Cabral, J. A.; Paquette, L. A. Org. Lett. 2003,
5, 789. (e) Paquette, L. A.; Basu, K.; Eppich, J. C.; Hofferberth, J. E. HelV.
Chim. Acta 2002, 85, 3033.
(17) For reports of significant substitutent effects on RCM outcomes,
see: (a) Castoldi, D.; Caggiano, L.; Bayon, P.; Costa, A. M.; Cappella, P.;
Sharon, O.; Gennari, C. Tetrahedron 2005, 61, 2123. (b) Caggiano, L.;
Castoldi, D.; Beumer, R.; Bayon, P.; Tesler, J.; Gennari, C. Tetrahedron
Lett. 2003, 44, 7913. (c) Kaliappan, K. P.; Kumar, N. Tetrahedron 2005,
61, 7461. (d) Maishal, T. K.; Sinha-Mahapatra, D. K.; Paranjape, K.; Sarkar,
A. Tetrahedron Lett. 2002, 43, 2263. (e) Hyldtoft, L.; Madsen, R. J. Am.
Chem. Soc. 2000, 122, 8444.
2390 J. Org. Chem., Vol. 73, No. 6, 2008