Effects of temperature and concentration in some ring closing metathesis reactions

Article abstract of DOI:10.1016/S0040-4039(03)00618-X

Ring closing metathesis (RCM) has emerged as a powerful tool to construct macrocyclic ring systems. However, the product distribution of monomer and oligomers is often a problem in the formation of medium to large rings. In the course of synthetic studies on the natural product radicicol and its analogs, we have found that the reaction temperature, along with concentration, has significant impact on the outcome of the product ratio. Specifically, carrying out the RCM reaction in refluxing toluene (110°C) at higher dilution affords improved yields of the monomeric macrocycle. Similar observations for another family of macrolactone natural products, the epothilones, are also reported.

Full text of DOI:10.1016/S0040-4039(03)00618-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3297–3299
Effects of temperature and concentration in some ring closing
metathesis reactions
Kana Yamamoto,a,* Kaustav Biswas,a Christoph Gaula and Samuel J. Danishefskya,b
aLaboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Ave., New York,
NY 10021, USA
bDepartment of Chemistry, Columbia University, Havemayer Hall, 3000 Broadway, New York, NY 10027, USA
Received 24 February 2003; revised 27 February 2003; accepted 28 February 2003
Abstract—Ring closing metathesis (RCM) has emerged as a powerful tool to construct macrocyclic ring systems. However, the
product distribution of monomer and oligomers is often a problem in the formation of medium to large rings. In the course of
synthetic studies on the natural product radicicol and its analogs, we have found that the reaction temperature, along with
concentration, has significant impact on the outcome of the product ratio. Specifically, carrying out the RCM reaction in refluxing
toluene (110°C) at higher dilution affords improved yields of the monomeric macrocycle. Similar observations for another family
of macrolactone natural products, the epothilones, are also reported. © 2003 Elsevier Science Ltd. All rights reserved.
Numerous macrocyclic natural products possess useful
biological activities. Not surprisingly, many macrocy-
clization methods have been developed and applied
toward their total chemical synthesis. In recent years,
the use of ring closing metathesis (RCM) for macrocy-
clization has become increasingly popular.1 During our
studies on natural product-based drug development, we
sought to produce a set of compounds altered by a
single functionality from the parent molecule for SAR
purposes. Recently, we have synthesized analogs of the
natural products radicicol (1) and epothilone 490 (2)
(Fig. 1). In each of these efforts, we took recourse to
utilize RCM as a key step in macrocycle construction.
Interestingly, we observed striking differences in the
behavior of these substrates in the RCM step, notwith-
standing their subtle structural alteration from the par-
ent compounds. Herein, we report our findings, which
show that tuning the reaction temperature and concen-
tration has a significant impact on the outcome of the
product ratio in the RCM, leading to improved yields
in the closure step.
The total synthesis of radicicol2,3 has been achieved as
a part of our program in anticancer drug development
based on Hsp90 inhibitors.4,5 We became interested in
preparing a series of cyclopropyl analogs, isomeric at
the C10% methyl group and the C7%/C8%epoxide (radici-
col numbering) (Scheme 1).6
The key steps in the synthesis of the parent compound
1 involved macrolide formation by RCM of precursor
3. With compound 3, which bears an epoxide at C7%/C8%
position, RCM occurred under mild reaction conditions
(2 mM, CH2Cl2, 42°C) to give the monomeric macro-
cyclic product 6 in good yield (Scheme 1, entry 1).
However, similar conditions (0.5 mM, CH2Cl2, 42°C)
were applied to the cyclopropyl precursor 4, the major-
ity of the isolated products were dimeric 28-membered
macrocycles (entry 2).7 With higher reaction tempera-
tures, the product distribution was improved to a ratio
of ꢀ1:1 (entry 4).8 In an attempt to lower the substrate
concentration, the precursor was added to the reaction
mixture over 7 h (‘infinite dilution’ conditions, the
well-known laboratory practice for promoting macro-
cyclizations).9 In our case, however, the product distri-
Figure 1. Structure of radicicol and epothilone 490.
Keywords: ring closing metathesis; RCM; product distribution; radici-
col; epothilone.
* Corresponding author. Tel.: +1-212-639-5503; fax: +1-212-772-8691;
e-mail: yamamotk@mskcc.org
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00618-X

3298
K. Yamamoto et al. / Tetrahedron Letters 44 (2003) 3297–3299
each product. If the formation of the monomer is
entropically favored over that of the dimer,12 the kinetic
ratio of the two products should shift toward the
monomer at higher temperature. In fact, the ratio
obtained after 5–10 min appears to be a kinetic ratio,13
since runs with longer reaction times resulted in the
formation of more dimer (vide infra). This indicates
that the monomer might eventually revert to the ther-
modynamically favored dimers.
We have also recently described the total synthesis of
epothilone 490, another naturally occurring macrolac-
tone with a 1,3-diene unit.14,15 A key step in the synthe-
sis was the stereospecific RCM of compound 13. The
reaction occurred smoothly under standard reaction
conditions (CH2Cl2, 40°C) to give 16 in 57% yield
(Scheme 2, entry 1). However, while investigating the
applicability of RCM to related congeners for SAR-
level analysis, we encountered similar obstacles as seen
in the radicicol series. Small changes in the substrate
structure (compare 13 with 14 and 15) led to a sharp
drop in yield of the desired cyclic products when the
reactions were carried out in CH2Cl2 at 40°C (entries 2
and 4). Applying the lessons from the aforementioned
radicicol study, the yield of the monomers 17 and 18
was dramatically improved by conducting the metathe-
sis reaction at higher temperature and dilution (entries
3 and 6). The desired macrolides 17 and 18 were
isolated in 66 and 65% yield, respectively. We noted,
however, that unlike the case in the radicicol system,
longer reaction times did not change the product
distribution.
The study described herein demonstrates the possibility
of controlling the product distribution in RCM reac-
tions by altering not only the reaction concentration,
but also the reaction temperature.16 Additionally, the
excellent thermal stability of the second generation
Grubbs catalyst is demonstrated.17 Although it is too
Scheme 1. Construction of the macrocycle via RCM under
different reaction conditions in the radicicol series.
bution was not effected much by this operation, but
was primarily sensitive to the final concentration (entry
5). The above observation can be attributed to the
reversible nature of olefin metathesis.10 Re-subjection
experiments showed that the monomer re-opened to the
acyclic precursor, while the dimers were inert under the
reaction conditions.
Eventually, it was found that the product distribution is
strikingly improved by adjustment of the reaction tem-
perature. Thus, performing the reaction at 110°C in
toluene and quenching after a short period of time
resulted in clean conversion of 4 to the primary cycliza-
tion product 7 (entry 6).11 The yields were significantly
enhanced relative to runs at lower temperature at com-
parable concentrations. The different reaction condi-
tions were also evaluated with the diastereoisomeric
substrate ent-5, and were found to give comparable
outcomes (entries 7 and 8). The substrates without a
protecting group at the C(3)ꢀOH behaved similarly
(entries 9 and 10).
The observations described above may be explained by
the difference of entropy in activation energy leading to
Scheme 2. Construction of the macrocycle via RCM under
different reaction conditions in the epothilone series.

K. Yamamoto et al. / Tetrahedron Letters 44 (2003) 3297–3299
3299
early to assert the generality of the trend reported
herein,18 it was applicable to three independent, highly
functional systems.19
product distribution was found insignificant in our case
(see entries 2 and 3).
9. (a) Knops, P.; Sendhoff, N.; Mekelburger, B.; Voegtle, F.
Top. Curr. Chem. 1991, 161, 1–36; (b) Illumani, G.;
Mandolini, L. Acc. Chem. Res. 1981, 14, 95–102.
10. Selected examples of reversible olefin metathesis: (a)
Marsella, N. J.; Maynard, H. D.; Grubbs, R. H. Angew.
Chem., Int. Ed. 1997, 36, 1101–1103; (b) Xu, Z.; Johan-
nes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.;
Hofilena, G. E.; Hoveyda, A. H. J. Am. Chem. Soc. 1997,
119, 10302–10316; (c) Lee, C. W.; Grubbs, R. H. Org.
Lett. 2000, 2, 2145–2147; (d) Smith, A. B., III; Adams, C.
M.; Kozmin, S. A. J. Am. Chem. Soc. 2001, 121, 990–991;
(e) Wu, Y.; Liao, X.; Wang, R.; Xie, X. S.; De Braban-
der, J. K. J. Am. Chem. Soc. 2002, 124, 3245–3253.
11. General procedure. A stirring solution of diene in anhy-
drous toluene (0.2 mM) under Ar was heated to 110°C
(reflux temperature) and 5–10 mol% Grubbs Ru-dihy-
droimidazolylidene catalyst (Scholl, M.; Ding, S.; Lee, C.
W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956) was
added to the refluxing solution. Stirring was continued
for 5–10 min, and then the flask was immersed in an ice
bath. The reaction mixture was passed through a pad of
silica gel, which was rinsed with methylene chloride,
concentrated, and purified by flash chromatography.
12. Although entropy is generally considered higher for
smaller rings, the calculated values for those larger than
12-membered rings are comparable.9b
13. Typically, RCM produces a thermodynamic distribution
of products, although there are some cases where kinetic
distribution of products is reported.10e
14. Biswas, K.; Lin, H.; Njardarson, J. T.; Chappell, M. D.;
Chou, T. C.; Guan, Y.; Tong, W. P.; He, L.; Horwitz, S.
B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124,
9825–9832.
15. For a detailed study of the behavior of certain ene-diene
systems in ring closing metathesis, see: Paquette, L. A.;
Basu, K.; Eppich, J. C.; Hofferberth, J. E. Helv. Chim.
Acta 2002, 85, 3033–3051.
16. The stereoselectivity of ring closing metathesis reactions
was reported to be altered by temperature: Arisawa, M.;
Kato, C.; Kaneko, H.; Nishida, A.; Nakagawa, M. J.
Chem. Soc., Perkin Trans. 1 2000, 1873–1876.
Acknowledgements
Support for this research was provided by the National
Institutes of Health (CA 28824). Postdoctoral Fellow-
ship support is gratefully acknowledged by K.Y. (The
Helen Hay Whitney Foundation), K.B. (US Army
Breast Cancer Research Program, DAMD-17-98-1-
8155), and C.G. (Deutscher Akademischer Austausch-
dienst, DAAD). Dr. George Sukenick (NMR Core
Facility, Sloan-Kettering Institute) is acknowledged for
NMR and mass spectral analyses. We also thank Dr.
Alex Rivkin for his assistance in preparing compound
14.
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