Olefinic-lactone cyclizations to macrocycles

Article abstract of DOI:10.1021/ol802737h

(Chemical Equation Presented) Olefinic-lactone cyclization reactions that result in the generation of macrocycles are described.

Full text of DOI:10.1021/ol802737h

ORGANIC
LETTERS
2009
Vol. 11, No. 2
493-495
Olefinic-Lactone Cyclizations to
Macrocycles
John C. Rohanna and Jon D. Rainier*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East,
Salt Lake City, Utah 84112
rainier@chem.utah.edu
Received November 26, 2008
ABSTRACT
Olefinic-lactone cyclization reactions that result in the generation of macrocycles are described.
Macrocyclic motifs have drawn the attention of synthetic,
biological, and medicinal chemists due to their presence in
a number of biologically active small molecules that include
both natural and non-natural products.1,2 For those scientists
that target their synthesis, when the macrocycle of interest
contains a lactone or lactam, a lactone- or lactam-forming
reaction has been a generally reliable method.3,4 However,
when the target lacks these functionalities, synthetic chemists
have been forced to turn to other, oftentimes less dependable
methods to generate the macrocycle.5 From an awareness
of the difficulties associated with the synthesis of nonlactone
macrocycles, we became interested in using lactone forma-
tion to generate non-lactone macrocycles. As outlined in
Scheme 1, central to the success of this idea would be a
novel olefinic-lactone ring-closing metathesis reaction to give
macrocyclic enol ethers (Scheme 1). To the best of our
Scheme 1
.
The Use of Lactones To Generate Non-Lactone
Macrocycles
(1) For examples of natural products that contain macrocycles see refs
9 and 11 and: (a) Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.;
Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2008, 25, 35. (b) Ishibashi,
M. In Macrolide Antibiotics; Omura, S., Ed.; Academic Press: New York,
2002; pp 57-98.
(2) For recent examples of bioactive non-natural products that contain
macrocycles, see: (a) Shan, D.; Chen, S.; Njardarson, J. T.; Gaul, C.; Ma,
X.; Danishefsky, S. J.; Huang, X.-Y. Proc. Nat. Acad. Sci. U.S.A. 2005,
102, 3772. (b) Metaferia, B. B.; Chen, L.; Baker, H. L.; Huang, X.-Y.;
Bewley, C. A. J. Am. Chem. Soc. 2007, 129, 2434. (c) Anquetin, G.; Horgan,
G.; Rawe, S.; Murray, D.; Madden, A.; MacMathuna, P.; Doran, P.; Murphy,
knowledge, similar cyclizations have not been demonstrated
prior to this work.
To test the viability of the proposed strategy, we examined
the olefinic-lactone cyclization of readily available 13-
membered lactone 5 (eq 1). When 5 was subjected to our
previously disclosed reduced Ti ethylidene conditions for
olefinic-ester cyclizations, we were pleased to isolate dihy-
dropyran 6 in quantitative yield.6
P. V. Eur. J. Org. Chem. 2008, 1953
(3) For a review on macrolactonization, see: Parenty, A.; Moreau, X.;
Capagne, M.-M. Chem. ReV. 2006, 106, 911
.
.
(4) For recent examples of macrolactamization, see: (a) Tan, L.; Ma,
D. Angew. Chem., Int. Ed. 2008, 47, 3614. (b) Qin, H.-L.; Panek, J. S.
Org. Lett. 2008, 10, 2477. (c) Nicolaou, K. C.; Dethe, D. H.; Leung,
G. Y. C.; Zou, B.; Chen, D. Y.-K. Chem. Asian J. 2008, 3, 413. (d) Komano,
K.; Shimamura, S.; Inoue, M.; Hirama, M. J. Am. Chem. Soc. 2007, 129,
14184
.
(5) (a) Prunet, J. Angew. Chem., Int. Ed. 2003, 42, 2826. (b) Gradillas,
A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086.
(6) Iyer, K.; Rainier, J. D. J. Am. Chem. Soc. 2007, 129, 12604.
10.1021/ol802737h CCC: $40.75
Published on Web 12/15/2008
2009 American Chemical Society

Scheme 2. The Ring-Expansion, Reduction, and Oxidation of 8
Having demonstrated the cyclization of 5, we decided to
examine the scope of the reaction. The reaction to generate
a dihydropyran was successful with several other substrates
including 16- and 17-membered lactones 7 and 9, respec-
tively (Table 1, entries 1 and 2).7 We were also pleased to
Table 1. Olefinic Lactone Cyclizations
yield.8 When 8 was sequentially hydrolyzed with SiO2 and
treated with benzoic anhydride, we isolated ketoester 14 in
63% overall yield from lactone 7. Finally, the reduction of
Scheme 3
.
Olefinic-Lactone Cyclizations to (-)-Muscone and
(+)-Muscopyridine
find that the cyclization was not limited to the generation of
6-membered enol ethers as 7-membered ring macrocycle 12
was also prepared from 17-membered lactone 11 (entry 3).
We next decided to demonstrate the utility of the products
from the cyclization reactions. To this goal, we converted
cyclic enol ether 8 into macrocyclic ketone 14, macrocyclic
ketal 13, and macrocyclic pyran 15 as illustrated in Scheme
2. Exposure of 8 to m-CPBA in MeOH gave 13 in 68%
(7) In addition to the tertiary amine in 9, acetals, ethers, and internal
olefins are also amenable to the cyclization conditions. See ref 6 and:
Johnson, H. W. B.; Majumder, U.; Rainier, J. D. J. Am. Chem. Soc. 2005,
127, 848.
494
Org. Lett., Vol. 11, No. 2, 2009

8 using Et3SiH and TFA gave pyran 15 as a single
diastereomer in 87% yield.
cyclization resulted in the generation of macrocyclic dihy-
dropyran 18. Silica gel hydrolysis of the enol ether gave
hydroxyketone 19, which served as a precursor to both
muscone and muscopyridine. (R)-(+)-Muscopyridine resulted
from the oxidation of the secondary alcohol in 19 followed
by pyridine formation.14 (R)-(-)-Muscone came from the
deoxygenation of 19 using Barton-McCombie conditions.15
In summary, we have described a unique and efficient
approach to macrocycles that utilizes an olefinic-lactone
cyclization reaction in the key step. We continue in our study
of the scope and utility of this reaction sequence.
As a further illustration of its utility, we applied the lactone
cyclization, ring expansion sequence to the synthesis of the
natural products (R)-(-)-muscone and (R)-(+)-muscopyri-
dine (Scheme 3).9-12 Our synthesis of both substrates began
with seco-acid 16.13 Yamaguchi macrolactonization of 16
gave 13-membered cyclization precursor 17. Olefinic-lactone
(8) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66,
1380.
(9) Muscopyridine isolation: Schinz, H.; Ruzicka, L.; Geyer, U.; Prelog,
V. HelV. Chim. Acta 1946, 29, 1524
.
(10) For synthetic work to muscopyridine, see: (a) Suwa, K.; Morie,
Y.; Suzuki, Y.; Ikeda, K.; Sato, M. Tetrahedron Lett. 2008, 49, 1510. (b)
Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42, 308. (c) Hagiwara,
H.; Katsumi, T.; Kamat, V. P.; Hoshi, T.; Suzuki, T.; Ando, M. J. Org.
Chem. 2000, 65, 7231. (d) Hadj-Abo, F.; Hesse, M. HelV. Chim. Acta 1992,
75, 1834. (e) Sakane, S.; Matsumura, Y.; Yamamura, Y.; Ishida, Y.;
Maruoka, K.; Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 672. (f) Utimoto,
K.; Kato, S.; Tanaka, M.; Hoshino, Y.; Fujikura, S.; Nozaki, H. Heterocycles
1982, 18, 149. (g) Saimoto, H.; Hiyama, T.; Nozaki, H. Tetrahedron Lett.
1980, 21, 3897. (h) Biemann, K.; Buchi, G.; Walker, B. H. J. Am. Chem.
Acknowledgment. We are grateful to the National Insti-
tutes of Health, General Medical Sciences (GM56677) for
support of this work. We would like to thank the support
staff at the University of Utah and especially Dr. Charles
Mayne (NMR) and Dr. Jim Muller (mass spectrometry) for
help in obtaining data.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Soc. 1957, 79, 5558
(11) Muscone isolation: (a) Walbaum, H. J. J. Prakt. Chem. 1906, 73,
488. (b) Ruzicka, L. HelV. Chem. Acta 1926, 9, 715
.
.
(12) For synthetic work to muscone, see: (a) Eden, I.; Cao, W.; Price,
M.; Colton, M. Tetrahedron 2008, 64, 5497. (b) Knopff, O.; Kuhne, J.;
Fehr, C. Angew. Chem., Int. Ed. 2007, 46, 1307. (c) Bulic, B.; Lucking,
U.; Pfaltz, A. Synlett 2006, 1031, and references contained therein.
(13) Available in eight steps from 10-(tert-butyldimethylsilyloxy)decanal.
See the Supporting Information and: (a) Nagano, H.; Tada, A.; Isobe, Y.;
Yajima, T. Synlett 2000, 1193. (b) Li, G.; Patel, D.; Hruby, V. Tetrahedron:
Asymmetry 1993, 4, 2315. (c) Yokokawa, F.; Asano, T.; Okino, T.; Gerwick,
W. H.; Shioiri, T. Tetrahedron 2004, 60, 6859.
OL802737H
(14) Hagiwara, H.; Katsumi, T.; Kamat, V. P.; Hoshi, T.; Suzuki, T.;
Ando, M. J. Org. Chem. 2000, 65, 7231.
(15) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
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