Efficient entry into medium-ring keto-lactones. The ruthenium tetraoxide-promoted oxidative cleavage of β-hydroxyethers

Article abstract of DOI:10.1021/ol0342958

(Matrix presented) A new use of ruthenium tetraoxide is reported. The catalytic oxidative cleavage of hexahydro-benzofuran-3a-ols led to nine-membered ring keto-lactones in moderate to good yields and high purity. The reaction is clean and easily performed using catalytic amounts of ruthenium trichloride and an excess of sodium periodate as a cooxidant.

Full text of DOI:10.1021/ol0342958

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1337-1339
Efficient Entry into Medium-Ring
Keto-Lactones. The Ruthenium
Tetraoxide-Promoted Oxidative Cleavage
of â-Hydroxyethers
Helena M. C. Ferraz* and Luiz S. Longo, Jr.
Instituto de Qu´ımica, UniVersidade de Sa˜o Paulo, CEP 05508-900,
Sa˜o Paulo SP, Brazil
hmferraz@iq.usp.br
Received February 19, 2003
ABSTRACT
A new use of ruthenium tetraoxide is reported. The catalytic oxidative cleavage of hexahydro-benzofuran-3a-ols led to nine-membered ring
keto-lactones in moderate to good yields and high purity. The reaction is clean and easily performed using catalytic amounts of ruthenium
trichloride and an excess of sodium periodate as a cooxidant.
The synthesis of medium-ring compounds (those containing
from 8 to 11 atoms) remains a challenge for organic chemists.
Several efforts have been made toward the development of
efficient methods for the preparation of these systems,1 since
they are encountered in many biologically important natural
products such as the medium-ring ethers (+)-obtusenyne,2
(+)-laurallene,3 and (-)-isolaurallene,4 besides the well-
known brevetoxins5 and taxol.6 Medium-ring lactones are
also found in nature. Examples are the octalactins A and
B,7 the nine-membered ring halicholactone and neo-
halicholactone,8 and the cephalosporolides B and C.9 Some
of them are outlined in Figure 1.
Cyclization strategies toward medium-ring lactones are
often inhibited due to entropic factors and transannular
interactions. For instance, the rate of lactonization of
ω-bromo alkanoic acid to the corresponding nine-membered
ring lactone is almost zero.10
Many other methodologies for preparing medium-ring
lactones have been reported11 such as the ionic12 and radical13
cleavage of saturated bicyclic hemiketals, the oxidative
(1) For reviews, see: (a) Yet, L. Chem. ReV. 2000, 100, 2963. (b)
Nubbemeyer, U. Eur. J. Org. Chem. 2001, 1801.
(2) (a) Fujiwara, K.; Awakura, D.; Tsunashima, M.; Nakamura, A.;
Honma, T.; Murai, A. J. Org. Chem. 1999, 64, 2616. (b) Howard, B. M.;
Schulte, G. R.; Fenical, W.; Solheim, B.; Clardy, J. Tetrahedron 1980, 36,
1747. (c) King, T. J.; Imre, S.; O¨ ztuna, A.; Thomson, R. H. Tetrahedron
Lett. 1979, 1453.
(3) (a) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122,
5473. (b) Fukuzawa, A.; Kurosawa, E. Tetrahedron Lett. 1979, 2797.
(4) (a) Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001, 123,
1533. (b) Crimmins, M. T.; Emmite, K. A.; Choy, A. L. Tetrahedron 2002,
58, 1817. (c) Kurata, K.; Furusaki, A.; Sueturo, K.; Katayama, C.; Suzuki,
T. Chem. Lett. 1982, 1031.
(7) (a) Tapiolas, D. M.; Roman, M.; Fenical, W.; Stout, T. J.; Cardy, J.
J. Am. Chem. Soc. 1991, 113, 4682. (b) Buszek, K. R.; Sato, N.; Jeong, Y.
Tetrahedron Lett. 2002, 43, 181.
(8) (a) Niwa, H.; Wakamatsu, K.; Yamada, K. Tetrahedron Lett. 1989,
30, 4543. (b) Critcher, D. J.; Connolly, S.; Wills, M. J. Org. Chem. 1997,
62, 6638. (c) Takemoto, Y.; Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.;
Tanaka, T.; Ibuka, T. Tetrahedron Lett. 2000, 41, 3653.
(9) Ackland, M. J.; Hanson, J. R.; Hitchcock, P. B.; Ratcliffe, A. H. J.
Chem. Soc., Perkin Trans. 1 1985, 843.
(10) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(11) For a review concerning medium-ring lactones, see: Rousseau, G.
Tetrahedron 1995, 51, 2777.
(5) (a) Nicolaou, K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes,
J.; Sato, M.; Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173. (b)
Nicolaou, K. C.; Yang, Z.; Shi, G. Q.; Gunzner, J. L.; Agrios, K. A.; Gatner,
P. Nature 1998, 392, 264.
(6) Nicolaou, K. C.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1995, 34,
2079.
(12) (a) Posner, G. H.; Webb, K. S.; Asirvatham, E.; Jew, S.-S.;
Degl’Innocenti, A. J. Am. Chem. Soc. 1988, 110, 4754. (b) Mahajan, J. R.;
DaSilva, C. R. J. Braz. Chem. Soc. 1990, 1, 87.
(13) (a) Suginome, H.; Yamada, S. Tetrahedron 1987, 43, 3371. (b)
Arencibia, M. T.; Freire, R.; Perales, A.; Rodriguez, M. S.; Sua´rez, E. J.
Chem. Soc., Perkin Trans. 1 1991, 3349.
10.1021/ol0342958 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/28/2003

Table 1. RuO4-Promoted Oxidative Cleavage of 1b-da
Figure 1. Natural medium-ring lactones.
cleavage of unsaturated bicyclic compounds promoted by
ozone, PCC, or mCPBA,14 and the cleavage of bicyclic 1,2-
diols.15 In 1985, Torii and co-workers reported a single
example of the oxidative cleavage of an enol ether by
ruthenium tetraoxide, which led to a ten-membered ring keto-
lactone.16
a Reagents and conditions: 2.4 mol % RuCl3.nH2O, 4.1 equiv of NaIO4,
H2O/CCl4/CH3CN (3:2:2), rt, 75 min.
It is noteworthy that the keto-lactones 3a-d were obtained
with a high degree of purity. No further purification was
necessary, since neither significant impurities nor byproducts
Recently, we reported the preparation of a series of
hexahydro-benzofuran-3a-ols (1a-d) by thallium trinitrate-
promoted cyclization of homoallylic alcohols.17 One of the
possible synthetic applications of these ethers could be the
construction of R,â-unsaturated lactones, an important class
of natural products. For example, the cyclic ether 1a could
be transformed into isomintlactone,18 through dehydration
followed by allylic oxidation.19 Nevertheless, the hydroxyl
group of 1a proved to be very resistant to several dehydration
conditions. We decided then to run a prior oxidation of 1a
to the corresponding lactone 2, which would easily undergo
the desired dehydration. Thus, the cyclic ether 1a was
submitted to treatment with RuO4 generated in situ from
catalytic amounts of ruthenium trichloride (RuCl3‚nH2O) and
an excess of sodium periodate in a biphasic solvent system
(H2O/CCl4/CH3CN ) 3:2:2).20 Somewhat surprisingly,21 the
isolated product was the nine-membered ring keto-lactone
3a, obtained in very good yield (Scheme 1).
1
were detected in the H and 13C NMR spectra of the crude
products.22 Moreover, the simple filtration of the concentrated
organic extracts on a small silica gel pad was sufficiently
efficient to hold the ruthenium dioxide formed during the
course of the reactions.
It has been postulated that the order of reactivity of C-H
bonds toward the RuO4-promoted oxidation of ethers is CH2
> CH.23 However, we observed an inversion of regiochem-
istry in the reaction of the cyclic ethers 1a-d with RuO4,
since carbon 7a (CH) was oxidized in preference to carbon
2 (CH2), as exemplified for 1a in Scheme 2.
Scheme 2
Scheme 1a
Additional evidence of this inversion of regiochemistry
was observed in the RuO4-promoted oxidation of the
(14) (a) Mahajan, J. R.; Arau´jo, H. C. Synthesis 1975, 54. (b) Mahajan,
J. R.; Arau´jo, H. C. Synthesis 1976, 111.
(15) Bond, S.; Perlmutter, P. Tetrahedron 2002, 58, 1779.
(16) Torii, S.; Inokuchi, T.; Kondo, K. J. Org. Chem. 1985, 50, 4980.
(17) Ferraz, H. M. C.; Longo, L. S., Jr.; Zukerman-Schpector, J. J. Org.
Chem. 2002, 67, 3518.
(18) Takahashi, K.; Someya, T.; Muraki, S.; Yoshida, T. Agric. Biol.
Chem. 1980, 44, 1535.
a Reagents and conditions: 2.4 mol % RuCl3‚nH2O, 4.1 equiv
of NaIO4, H2O/CCl4/CH3CN (3:2:2), rt, 75 min (81%).
(19) For a similar sequence leading to mintlactone, see: Ferraz, H. M.
C.; Grazini, M. V. A.; Ribeiro, C. M. R.; Brocksom, U.; Brocksom, T. J.
J. Org. Chem. 2000, 65, 2606.
(20) These conditions were first reported by Sharpless and co-workers
in 1981 and were used to oxidize several functional groups. Carlsen, H. J.;
Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936.
This result prompted us to submit the cyclic ethers 1b-d
to the same treatment. Thus, the keto-lactones 3b-d were
obtained in moderate to good yields, as shown in Table 1.
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Org. Lett., Vol. 5, No. 8, 2003

hexahydro-benzofuran-3-ols 4a and 4b,24 which bear the
hydroxyl group in another position. These ethers afforded,
as the major product, the 2-acetyl-5-methyl-cyclohexanone
(5), which is probably formed by the oxidation of the tertiary
carbon 7a (Scheme 3).
Scheme 4
a
Scheme 3
Although the reaction mechanism remains unclear, the
presence of the hydroxyl group in the cyclic ethers seems to
play an important role in the chemoselectivity displayed by
RuO4.26 It is of note that similar bicyclic ethers, without the
hydroxyl group, afforded exclusively the corresponding
products of oxidation of the secondary carbon.27
The results described herein represent a novel and efficient
procedure for the synthesis of medium-sized lactones. At the
moment, the application of this methodology to the synthesis
of lactones of different sizes is in progress in our laboratory.
a Reagents and conditions: 5.0 mol % RuCl3‚nH2O, 4.1 equiv
of NaIO4, H2O/CCl4/CH3CN (3:2:2), rt, 30 min for 4a and 4 h for
4b (48% for 4a and 40% for 4b).
Acknowledgment. The authors wish to thank FAPESP,
CNPq, and CAPES for financial support. We also thank Prof.
Ronaldo A. Pilli from the University of Campinas for his
help in carrying out the HRMS and Tiago O. Vieira and
Prof. Luiz F. Silva Jr. for fruitful suggestions.
The fact that the equatorial tertiary C-H bonds of 1a-d
and 4a were oxidized faster than the axial tertiary C-H bond
of 4b agrees with the literature information about steric
requirements for the oxidation reaction.25 Moreover, the less
reactive cyclic ether 4b afforded minor amounts of the
oxidation products of secondary carbon 2. The products 6
and 7 were obtained in 12 and 15% yields, respectively.
Supporting Information Available: Experimental pro-
cedures for the RuO4-promoted oxidative cleavage of â-hy-
droxyethers 1a-d and 4a-b and structural data and NMR
spectra of keto-lactones 3a-d. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0342958
(22) For 1H and 13C NMR spectra of keto-lactones 3a-d, see Supporting
Information.
(23) Bakke, J. M.; Frohaug, A. E. J. Phys. Org. Chem. 1996, 9, 310.
(24) Hexahydro-benzofuran-3-ols 4a and 4b were prepared by a previ-
ously reported procedure. Ferraz, H. M. C.; Ribeiro, C. M. R.; Grazini, M.
V. A.; Brocksom, T. J.; Brocksom, U. Tetrahedron Lett. 1994, 35, 1497.
(25) Reactivity of C-H bonds in cyclohexane systems toward RuO4-
promoted oxidations of hydrocarbons: axial secondary C-H, relative rate
) 1; equatorial secondary C-H, relative rate ) 9; axial tertiary C-H,
relative rate ) 47; and equatorial tertiary C-H, relative rate ) 444. Bakke,
J. M.; Bethell, D. Acta Chem. Scand. 1992, 46, 644.
In a preliminary experiment, the oxidative cleavage of the
â-hydroxyether 8 led to the ten-membered ring keto-lactone
9, in a nonoptimized yield of 50% (Scheme 4).
(26) ) Only substrate 4b underwent oxidation of both tertiary and
secondary C-H bonds.
(27) ) Kitagawa, I.; Tsujii, S.; Nishikawa, F.; Shibuya, H. Chem. Pharm.
Bull. 1983, 31, 2639.
(21) For examples of the chemoselectivity displayed by RuO4 in the
oxidation of tetrahydrofuran and tetrahydropyran derivatives, see: Smith,
A. B., III; Scarborough, R. M., Jr. Synth. Commun. 1980, 10, 205.
Org. Lett., Vol. 5, No. 8, 2003
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