An acid-catalyzed macrolactonization protocol.

Article abstract of DOI:10.1021/ol026726c

[reaction: see text] An efficient macrolactonization protocol devoid of any base was developed derived from the use of vinyl esters in transesterification. Subjecting a hydroxy acid and ethoxyacetylene to 2 mol % [RuCl(2)(p-cymene)](2) in toluene followed by addition of camphorsulfonic acid or inverse addition provided macrolactones in good yields.

Full text of DOI:10.1021/ol026726c

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ORGANIC
LETTERS
2002
Vol. 4, No. 21
3743-3745
An Acid-Catalyzed Macrolactonization
Protocol
Barry M. Trost* and John D. Chisholm
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received August 13, 2002
ABSTRACT
An efficient macrolactonization protocol devoid of any base was developed derived from the use of vinyl esters in transesterification. Subjecting
a hydroxy acid and ethoxyacetylene to 2 mol % [RuCl2(p-cymene)]2 in toluene followed by addition of camphorsulfonic acid or inverse addition
provided macrolactones in good yields.
With the advent of modern isolation techniques, numerous
large-ring lactones that possess interesting biological activity
have been isolated. The need for dependable methods of
forming such lactones in the presence of sensitive functional-
ity has led to the development of numerous methods.1 The
most recognized of these is the Yamaguchi2 cyclization,
where the ester is activated as a mixed anhydride and
esterification is facilitated by a high concentration of the
acylation promoter 4-(dimethylamino)pyridine (DMAP).
While effective, this can often lead to side reactions with
base-sensitive substrates such as unsaturated acids.3 Exposure
of the activated carboxylic acid derivative in any of these
protocols to base is normally responsible for the undesired
side reactions.
Dixneuf had shown that acetylenes and carboxylic acids
will react in the presence of certain ruthenium catalysts to
form the corresponding vinyl ethers.4 Kita saw this as an
opportunity to activate the carboxylic acid as the ethoxyvinyl
ester, an activating group originally explored by Wasserman.5
Wasserman had used stoichiometric mercury to synthesize
his vinyl esters instead of catalytic ruthenium, and this likely
led to their lack of preparative use.6 In any event, the
ethoxyvinyl esters perform admirably in intermolecular
esterification reactions under acid-catalyzed conditions.
To adapt this method to intramolecular lactone formation,
two questions had to be answered. First, can the ethoxyvinyl
ester be formed in the presence of an alcohol? Second, can
the esterification be performed with catalytic acid under the
high dilution conditions necessary to form large rings?
To address the first question, hydroxycarboxylic acid 1,
which forms a 16-membered macrolactone, also new, was
examined. Initial experiments showed that the activated ester
could be formed under both high dilution conditions (0.005
M) and at higher concentration (0.1 M) without any ester or
macrolactone formation occurring. Evidently, without the
presence of an acid catalyst, the ethoxyvinyl ester is not a
During the course of another investigation, this problem
showed itself to be substantive. To combat its effects, we
attempted to adapt intermolecular esterification methods that
did not require basic conditions to model substrates in the
hope of solving this problem. Our most successful approach
is based upon the work of Dixneuf and Kita.
(1) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org. Chem.
1996, 61, 4560.
(2) Inanaga, J.; Hirata, H.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(3) Hartmann, B.; Kanazawa, A. M.; Depres, J.-P.; Greene, A. E.
Tetrahedron Lett. 1991, 32, 5077.
(4) Ruppin, C.; Dixneuf, P. H. Tetrahedron Lett. 1986, 27, 6323.
(5) Kita, Y.; Maeda, H.; Omori, K.; Okuno, T.; Tamura, Y. Synlett 1993,
273.
(6) Wasserman, H. H.; Wharton, P. S. J. Am. Chem. Soc. 1960, 82, 661.
10.1021/ol026726c CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/14/2002

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With the activated ester in hand, cyclization was attempted.
Heating the activated ester to reflux in toluene at relatively
high dilution (0.005 M) led to a disappointing 22% yield of
the lactone. However, addition of 10 mol % of camphor-
sulfonic acid (CSA) to the dilute solution at room temperature
led to a gratifying 60% yield, along with 11% of the dimeric
product. Other acids such as PPTS and TFA were less
effective in this cyclization. As a standard macrolactonization
protocol starting from the hydroxycarboxylic acid, formation
of the enol ester was followed by either direct addition of
CSA to the reaction mixture or, preferably, slow addition of
the reaction mixture from the enol ester formation to a
toluene solution of CSA.
Scheme 1. Concept
Scheme 2. Initial Experiments
With conditions for cyclization in hand, a study of
substrate generality was undertaken. Toward this purpose, a
number of other hydroxy acid substrates were synthesized.
To add some variety to these substrates, some were synthe-
sized using the ruthenium-catalyzed alkene-alkyne coupling
reaction currently under development in our group.7-9 These
provided hydroxy acids as mixtures of branched and linear
olefin isomers, as shown in Scheme 3.
The use of the Fmoc ester for the synthesis of hydroxy
acid 8 was required because of the facile isomerization of
the triene under basic hydrolysis conditions. Even under the
mild conditions used for the removal of the Fmoc ester, if
the reaction was allowed to proceed for long periods of time
(>3 h), some isomerization was observed. Unsaturated
hydroxy acid 8 would, therefore, provide the most strenuous
test of our methodology.10 The hydroxy acid 15 was
synthesized from the 13-membered ketone following the
literature procedure.11
A summary of the cyclization results are presented in Table
1. The 12-membered hydroxy acid gave almost all dimeric
product, and the 13-membered lactone also gave a poor
result, with about half of the isolated product being dimer.
The lack of any conformational constraint present on these
good electrophile for the alcohol. The ethoxyvinyl ester could
be obtained in relatively pure form by silica gel chromatog-
raphy, but this was accompanied by significant hydrolysis
of the ester. Keeping the TLC Rf fairly high (∼0.6) and
performing the chromatography quickly allowed the hy-
drolysis to be controlled and the activated ester to be isolated
in excellent yield if desired. Synthetically, the enol ester was
not isolated. Instead, the reaction mixture was used directly
for cyclization.
Scheme 3. Synthesis of Substrates by Alkene-Alkyne Coupling
3744
Org. Lett., Vol. 4, No. 21, 2002

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Table 1. Macrolactonization Examples
rings may have contributed to this excessive formation of
dimer. On the other hand, all lactones of 14 or greater
members gave satisfactory results. Both primary and second-
ary alcohols were good substrates for the reaction. Of note
is the unsaturated ester, 18, which underwent no isomeriza-
tion of the sensitive triene. This is in contrast to the
Yamaguchi protocol with DMAP, which resulted in isomer-
ization of approximately 50% of the product (the yields of
the two reactions are comparable). The yield of macrolactone
17 from hydroxy acid 5 via the Yamaguchi cyclization was
also comparable to the method used here when performed
at the same concentration.
(even stoichiometric or larger amounts), this method requires
only a catalytic amount of acids (Lewis and Bronsted). The
excellent chemoselectivity of the process is highlighted by
formation of lactone 18 in 64% yield. Application of this
method to the synthesis of biologically relevant natural
products will be reported in due course
Acknowledgment. We thank the National Science Foun-
dation and National Institutes of Health (GM33049) for their
generous support of our programs. J.D.C. was a NIH
postdoctoral fellow. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of California-
San Francisco supported by the NIH Division of Research
Resources.
Thus, the ruthenium-proton two stage esterification
protocol constitutes an effective macrolactonization method
for rings of 14 members or more. In contrast to other
macrolactonization protocols, which frequently require base
Supporting Information Available: Procedures for Ru-
catalyzed alkene-alkyne coupling and macrolactonization
and characterization data for 2, 4-10, and 17-19. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(7) Trost, B. M.; Indolese, A. J. Am. Chem. Soc. 1993, 115, 4361.
(8) Trost, B. M.; Indolese, A. F.; Muller, T. J. J.; Treptow, B. J. Am.
Chem. Soc. 1995, 117, 615.
(9) Trost, B. M.; Toste, F. D. Tetrahedron Lett. 1999, 40, 7739.
(10) Cf.: Hartmann, B.; Kanazawa, A. M.; Depres, J. P.; Greene, A. E.
Tetrahedron Lett. 1991, 32, 5077.
(11) Clyne, D. S.; Weiler, L. Tetrahedron 1999, 55, 13659.
OL026726C
Org. Lett., Vol. 4, No. 21, 2002
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