stituted products,7-9 but all examples reported to date deal
with five-eight-membered rings only. Since direct access
to trisubstituted cycloalkenes of larger ring sizes via RCM
is of eminent importance but known to be very difficult,5,10
we tried to determine if 2-4 could bring compounds of this
type into reach. In an attempt to cyclize diene 5 to the 14-
membered lactone 7 (Scheme 1), however, we noticed that
yield was then exposed to complex 3 in refluxing CH2Cl2
and was thereby cleanly converted into the cyclic monomer
7.12 This example demonstrates that the reversibility of olefin
metathesis is key to success of the formation of highly
substituted macrocycles and illustrates again the superior
performance of 2-4 as compared to 1.
“Second generation” ruthenium carbene complexes also
react with electron-deficient alkenes such as acrylic acid
derivatives which are problematic substrates for the parent
Grubbs catalyst 1.9,13 Notably, however, compounds of this
type undergo either a regular cyclization or a cyclodimer-
ization14 depending on the tether length between the alkene
groups. If the latter pathway is operative, high selectivity
for head-to-tail connected monomer units and (E)-configured
double bonds in the products was observed. This behavior
warrants further study because it may open a novel entry
into lactide antibiotics incorporating these structural elements.
The 16-membered macrodiolide (-)-pyrenophorin 8, an
antifungal agent produced by the plant pathogenic fungi
Pyrenophora aVenae and Stemphylium radicinum,15 is a
prototype member of this family of natural products. Numer-
Scheme 1a
a [a] See Table 1.
the desired ring is only formed in small amounts after a 4 h
reaction time, while the acyclic dimer 6 prevails. On
prolonged heating (40 h), however, 6 almost disappears while
7 becomes the major product (Table 1).
ous syntheses of this γ-oxo-R,â-unsaturated dilactone have
been reported (for a compilation, see Table S-1 in the
Supporting Information).16 Despite the fact that all but one
cleverly exploit the C2-symmetry of the target and employ
rather diverse methodology for the construction of the
macrocyclic ring, most syntheses are rather lengthy and poor
yielding (Table S-1, Supporting Information).
Table 1. Dimerization versus Cyclization of Diene 5a
substrate
catalyst
t (h)
productc
5
1 (10%)
2 (10%)
3 (3%)
3 (6%)
4 (6%)
3 (10%)
17
40
4
40
40
28
6 (79%)
7 (65%)b
5 (25%), 6 (29%), 7 (10%)
7 (57%)b
7 (57%)b
7 (60%)b
(12) The closest precedent to the result reported herein is described by
Hoveyda et al., cf. ref 5. In the course of their synthesis of the antifungal
agent Sch 38516, the formation of a trisubstituted 14-membered lactam is
outlined by using Mo(dNAr)(dCHCMe2Ph)[OCMe(CF3)2]2 as metathesis
catalyst. Although no direct proof has been gained that this particular
cyclization occurs via a discrete intermediate, the authors were also able to
effect a stepwise conversion by first exposing the substrate to the ruthenium
carbene 1. This leads to an acyclic dimer whichsin a separate stepscan
be converted into the desired cyclic monomer by means of Schrock’s
molybdenum catalyst.
6
a All reactions are carried out in refluxing CH2Cl2. b In addition to 7,
traces of 5 and 6 are detected by GC. c The product 7 is invariably obtained
as a 7:1 mixture of isomers.
(13) For related cross-metathesis reactions of acrylates, see: Chatterjee,
A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000,
122, 3783.
(14) For an elegant application of a RCM-based macrodimerization
reaction to a natural product synthesis, see: Smith, A. B.; Kozmin, S. A.;
Adams, C. M.; Paone, D. V. J. Am. Chem. Soc. 2000, 122, 4984.
(15) (a) Isolation: Ishibashi, K. J. Agric. Chem. Soc. Jpn. 1961, 35, 257.
(b) Structure elucidation: Nozoe, S.; Hirai, K.; Tsuda, K.; Ishibashi, K.;
Shirasaka, M.; Grove, J. F. Tetrahedron Lett. 1965, 4675.
To corroborate that the cyclic monomer 7 is formed via
the acyclic dimer 6, substrate 5 was treated with the standard
Grubbs carbene 1.11 As expected, this catalyst effects a
smooth dimerization at the least substituted site but does not
cause any subsequent cyclization, irrespective of the catalyst
loading and the reaction time. Triene 6 thus obtained in 79%
(16) Syntheses of rac-8 as well as formal total syntheses are compiled
in the Supporting Information. For syntheses of (-)-8, see: (a) Seebach,
D.; Seuring, B.; Kalinowski, H.-O.; Lubosch, W.; Renger, B. Angew. Chem.
1977, 89, 270. (b) Seuring, B.; Seebach, D. Liebigs Ann. Chem. 1978, 2044.
(c) Mali, R. S.; Pohmakotr, M.; Weidmann, B.; Seebach, D. Liebigs Ann.
Chem. 1981, 2272. (d) Hatakeyama, S.; Satoh, K.; Sakurai, K.; Takano, S.
Tetrahedron Lett. 1987, 28, 2717. (e) Baldwin, J. E.; Adlington, R. M.;
Ramcharitar, S. H. Synlett 1992, 875. (f) Machinaga, N.; Kibayashi, C.
Tetrahedron Lett. 1993, 34, 841. (g) Matsushita, Y.-I.; Furusawa, H.; Matsui,
T.; Nakayama, M. Chem. Lett. 1994, 1083. (h) Nokami, J.; Taniguchi, T.;
Gomyo, S.; Kakihara, T. Chem. Lett. 1994, 1103. (i) Sugai, T.; Katoh, O.;
Ohta, H. Tetrahedron 1995, 51, 11987.
(9) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S.
P. J. Org. Chem. 2000, 65, 2204. (b) Fu¨rstner, A.; Thiel, O. R.; Blanda, G.
Org. Lett. 2000, 2, 3731.
(10) For a prototype example, see RCM approaches to epothilone B:
(a) Meng, D.; Bertinato, P.; Balog, A.; Su, S.-D.; Kamenecka, T.; Sorensen,
E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 10073. (b) May, S.
A.; Grieco, P. A. Chem. Commun. 1998, 1597. (c) Review: Mulzer, J.
Monatsh. Chem. 2000, 131, 205.
(11) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100. (b) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039.
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Org. Lett., Vol. 3, No. 3, 2001