Bicyclic β-hydroxytetrahydrofurans as precursors of medium ring keto-lactones

Article abstract of DOI:10.1021/jo0626109

(Chemical Equation Presented) The reaction of a series of cis-fused bicyclic β-hydroxytetrahydrofurans with ruthenium tetraoxide, generated in situ from ruthenium trichloride and sodium periodate, afforded 9- and 10-membered ketolactones in moderate to good yields, in a clean and straightforward fashion. The starting β-hydroxyethers were obtained from the corresponding 3-alkenols by two alternative procedures, depending on their pattern of substitution: (a) epoxidation by dimethyldioxirane, followed by base-catalyzed cyclization of the resulting epoxyalcohol, and (b) thallium trinitrate-mediated cyclization of the 3-alkenols, a method already described by our group.

Full text of DOI:10.1021/jo0626109

Bicyclic â-Hydroxytetrahydrofurans as Precursors of Medium Ring
Keto-Lactones
Helena M. C. Ferraz* and Luiz S. Longo, Jr.†
Instituto de Qu´ımica, UniVersidade de Sa˜o Paulo, CP 26077, CEP 05513-970, Sa˜o Paulo, SP, Brazil
hmferraz@iq.usp.br
ReceiVed December 19, 2006
The reaction of a series of cis-fused bicyclic â-hydroxytetrahydrofurans with ruthenium tetraoxide,
generated in situ from ruthenium trichloride and sodium periodate, afforded 9- and 10-membered keto-
lactones in moderate to good yields, in a clean and straightforward fashion. The starting â-hydroxyethers
were obtained from the corresponding 3-alkenols by two alternative procedures, depending on their pattern
of substitution: (a) epoxidation by dimethyldioxirane, followed by base-catalyzed cyclization of the
resulting epoxyalcohol, and (b) thallium trinitrate-mediated cyclization of the 3-alkenols, a method already
described by our group.
Introduction
decarestrictines B, E, F, G, H, and J,13 as well as the recently
isolated14 and synthesized15 xestodecalactone A. Some repre-
sentative examples are shown in Figure 1.
Cyclization reactions that lead to medium ring lactones are
often inhibited by both entropic and enthalpic factors, as stated
by Illuminati and Mandolini.16 Therefore, several methods for
circumventing this problem, as well as the competition between
inter- and intramolecular reactions in the preparation of medium
and macrolactones, have been developed.17
Medium ring compounds, those containing 8-11 atoms in
the ring,1 are the subject of continuous interest in organic
synthesis, as they constitute the framework of many natural
products. Thus, several efforts have been made toward the
development of efficient strategies for the synthesis of these
compounds, which can be carbocycles,2,3 lactones,4-6 cyclic
ethers,7 and nitrogen heterocycles,8,9 among others.10 More
particularly, medium ring keto-lactones are found in some
bioactive natural products, such as the polyketide metabolites
diplodialides A and D,11 cephalosporolides B and C,12 and
Ruthenium tetraoxide (RuO4), first introduced in organic
synthesis by Djerassi and Engle,18 has a widespread application
in organic transformations,19 as attested by recent examples, such
† Present address: Universidade Federal de Sa˜o Paulo/Campus Diadema, Rua
Artur Riedel, 275, CEP 09972-270, Diadema, SP, Brazil.
(1) Roxburgh, C. J. Tetrahedron 1993, 49, 10749.
(2) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757.
(3) Minnaard, A. J.; Wijnberg, J. B. P. A.; de Groot, A. Tetrahedron
1999, 55, 2115.
(4) Rousseau, G. Tetrahedron 1995, 51, 2777.
(5) Dra¨ger, G.; Kirschning, A.; Thiericke, R.; Zerlin, M. Nat. Prod. Rep.
1996, 13, 365.
(6) Longo, L. S., Jr.; Bombonato, F. I.; Ferraz, H. M. C. Quim. NoVa
2007, 30, 415.
(7) Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001, 123, 1533
and references cited therein.
(12) (a) Ackland, M. J.; Hanson, J. R.; Hitchcock, P. B.; Ratcliffe, A.
H. J. Chem. Soc., Perkin Trans. 1 1985, 843 (b) Rukachaisirikul, V.; Pramjit,
S.; Pakawatchai, C.; Isaka, M.; Supothina, S. J. Nat. Prod. 2004, 67, 1953.
(13) (a) Go¨hrt, A.; Zeeck, A.; Hu¨tter, K.; Kirsch, R.; Kluge, H.; Thiericke,
R. J. Antibiot. 1992, 45, 66. (b) Grabley, S.; Haummann, P.; Hu¨tter, K.;
Kirsch, R.; Kluge, H.; Thiericke, R. J. Antibiot. 1992, 45, 1176.
(14) Edrada, R. A.; Heubes, M.; Brauers, G.; Wray, V.; Berg, A.; Gra¨fe,
U.; Wohlfarth, M.; Mu¨hlbacher, J.; Schaumann, K.; Brigmann, G.; Proksch,
P. J. Nat. Prod. 2002, 65, 1598.
(15) Bringmann, G.; Lang, G.; Michel, M.; Heubes, M. Tetrahedron Lett.
2004, 45, 2829.
(16) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(17) The general methodology for macrolactones synthesis can often be
applied for medium ring lactones. For a recent review: Parenty, A.; Moreau,
X.; Campagne, J. M. Chem. ReV. 2006, 106, 911.
(8) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131.
(9) Nubbemeyer, U. Top. Curr. Chem. 2001, 216, 125.
(10) Yet, L. Chem. ReV. 2000, 100, 2963.
(11) Wada, K.; Ishida, T. J. Chem. Soc., Perkin Trans. 1 1979, 1154.
(18) Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953, 75, 3838.
10.1021/jo0626109 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/16/2007
J. Org. Chem. 2007, 72, 2945-2950
2945

Ferraz and Longo
SCHEME 2a
a Reagents and conditions: 1.5 of equiv Oxone, 4.0 equiv of NaHCO3,
acetone/H2O (1:1), rt, 5-20 min.
FIGURE 1. Structures of some naturally occurring medium ring keto-
lactones.
to ring contraction products.27 In order to obtain the bicyclic
â-hydroxyethers without a substituent in the cycloalkane ring,
we employed the method described by Murai et al.,28 which
consists of a base-promoted cyclization of epoxyalcohols.
The 3-alkenols 1a-f, used as starting materials, were prepared
from commercially available cyclohexanone and cyclohep-
tanone.29 The epoxidation of the 3-alkenols 1a-f was performed
using Oxone and sodium bicarbonate, following a described
protocol30 (Scheme 2).
SCHEME 1a
The epoxyalcohols 2a-f thus obtained were submitted to
treatment with 10 equiv of KOH in 75% aqueous DMSO
solution.28 The intramolecular reaction, i.e., the opening of the
epoxide by the alkoxide anion, occurs preferentially over an
intermolecular process, providing the reaction is performed at
a high dilution rate. In this way, the expected bicyclic â-hy-
droxyethers 3a-f were obtained in moderate to good yields
(Table 1).
a (a) Epoxidation; (b) cyclization; (c) oxidative cleavage.
The other bicyclic â-hydroxyethers used in this work (3g-
j) were prepared through the already mentioned TTN-mediated
cyclization of 3-alkenols.27
The relative configurations of the diastereomeric â-hydroxy-
ethers shown in Table 1 (entries 2, 3, 5, and 6) were proposed
by comparison of their 1H and 13C NMR data with those of 3h
and 3j.27
as the oxidation of saturated hydrocarbons,20 the oxidative
cleavage of alkenes,21 the R-ketohydroxylation of alkenes,22 the
cis-dihydroxylation of alkenes,23 and the oxidative polycycliza-
tion of polyenes.24 In 1985, Torii et al.25 reported a single
example of the RuO4-promoted oxidative cleavage of an enol
ether, which led to a 10-membered ring keto-lactone.
In this work we wish to report an efficient procedure for
synthesizing a series of bicyclic â-hydroxyethers, as well as
their oxidative cleavage by catalytic RuO4, which showed to
be a clean and straightforward method for the synthesis of 9-
and 10-membered keto-lactones (Scheme 1).26
To check the behavior toward base-promoted cyclization of
epoxides bearing a substituent in the cyclohexane ring, the
3-alkenol 1g, prepared from 4-methyl-cyclohexanone,27 was
transformed into a 3:2 diastereoisomeric mixture of the epoxy-
alcohols 2g and 2g′. Treatment of these epoxides with KOH,
under the same conditions used for the preparation of 3a-f,
led to a mixture of several products. Among them, the expected
â-hydroxyethers 3g and 3g′, the spiro hydroxyether 4, the allylic
alcohol 5, and the glycolic derivative 6 could be partially
Results and Discussion
Preparation of the Bicyclic â-Hydroxytetrahydrofurans.
In a previous paper we reported the preparation of some cis-
fused bicyclic â-hydroxyethers, through a thallium trinitrate
(TTN) mediated cyclization of 3-alkenols bearing an alkyl group
at the cyclohexene ring. Similar unsubstituted alkenols gave rise
1
separated by flash chromatography and identified by H and
13C NMR (Scheme 3).
The formation of the cyclic ethers 3g, 3g′, and 4 can be
rationalized considering a stereoselective diaxial opening of the
oxirane ring. Thus, the isomer 2g, bearing the epoxide and the
methyl group in a cis relationship, can be cyclized through the
more stable conformer I (Figure 2). This 5-endo-trig-like
cyclization affords exclusively the â-hydroxyether 3g. On the
(19) For a review concerning ruthenium tetraoxide-catalyzed oxida-
tions: Plietker, B. Synthesis 2005, 2453.
(20) Drees, M.; Strassner, T. J. Org. Chem. 2006, 71, 1755 and references
cited therein.
(21) Shoair, A. G. F.; Mohamed, R. H. Synth. Commun. 2006, 36, 59.
(22) (a) Plietker, B. Eur. J. Org. Chem. 2005, 1919. (b) Plietker, B. J.
Org. Chem. 2004, 69, 8287 and references cited therein.
(23) Tiwari, P.; Misra, A. K. J. Org. Chem. 2006, 71, 2911.
(24) (a) Go¨ksel, H.; Stark, C. B. W. Org. Lett. 2006, 8, 3433. (b) Caserta,
T.; Piccialli, V.; Gomez-Paloma, L.; Bifulco, G. Tetrahedron 2005, 61, 927.
(25) Torii, S.; Inokuchi, T.; Kondo, K. J. Org. Chem. 1985, 50, 4980.
(26) Part of this work was reported as a preliminary communication:
Ferraz, H. M. C.; Longo, L. S., Jr. Org. Lett. 2003, 5, 1337.
(27) Ferraz, H. M. C.; Longo, L. S., Jr.; Zukerman-Schpector, J. J. Org.
Chem. 2002, 67, 3518.
(28) Murai, A.; Ono, M.; Masamune, T. Bull. Chem. Soc. Jpn. 1977,
50, 1226.
(29) For experimental details and full characterization data of 1a, 1b,
and 1d see ref 27. For a general procedure for the preparation of 1c, 1e,
and 1f, see Supporting Information.
(30) Ferraz, H. M. C.; Muzzi, R. M.; Vieira, T. O.; Viertler, H.
Tetrahedron Lett. 2000, 41, 5021.
2946 J. Org. Chem., Vol. 72, No. 8, 2007

Precursors of Medium Ring Keto-Lactones
TABLE 1. Base-Promoted Cyclization of Epoxyalcohols 2a-fa
FIGURE 2. Conformers of the epoxides 2g and 2g′.
allylic alcohol 5 should be formed from the trans isomer 2g′,
by abstraction of the C6-equatorial proton,31 while a direct
hydroxide opening of the oxirane ring of 2g and/or 2g′ could
give the triol 6.
Oxidative Cleavage of the Bicyclic â-Hydroxytetrahydro-
furans. With the â-hydroxyethers 3a-j in hand, we turned our
attention to the study of the oxidative cleavage of these
substrates by catalytic RuO4. The reaction was performed with
RuO4 generated in situ from ruthenium trichloride (RuCl3‚nH2O)
and excess sodium periodate (NaIO4) in a biphasic solvent
system containing water, carbon tetrachloride, and acetonitrile
(3:2:2 ratio, respectively).32
The hydroxyethers 3a-f afforded the corresponding 9- and
10-membered ring keto-lactones 7a-f, as outlined in Table 2.
The typical workup protocol, addition of distilled water,
extraction with CH2Cl2, and then filtration of the concentrated
organic extracts on a silica gel pad (protocol A), furnished the
keto-lactones 7a and 7b in low yields (entries 1 and 2). In spite
of these yields, no impurities or byproducts were observed by
GC analysis of the crude products. A somewhat modified
workup, quenching with a saturated aqueous sodium thiosulfate
(Na2S2O3) solution,33 extraction with CH2Cl2, and filtration on
Celite (protocol B), allowed a significant improvement in the
yields of the keto-lactones 7a and 7b. Similarly, the â-hydroxy-
ethers 3e and 3f led to the corresponding 10-membered ring
keto-lactones 7e and 7f in better yields using protocol B (entries
5 and 6).
a Reagents and conditions: 1.0 mmol epoxyalcohol, 10 equiv KOH, 20
mL of 75% aq DMSO, 110-120 °C, 2 h. b Minor amounts of the
corresponding glycolic derivative were observed in the crude product of
the reaction. c Ratio determined by GC and/or 1H NMR of the crude product.
SCHEME 3a
As previously reported,26 the â-hydroxyethers 3g-j led to
the corresponding nine-membered keto-lactones 7g-j. These
results are summarized in Scheme 4.34
Bakke and Froehaug35 postulated that the order of reactivity
of carbon-hydrogen bonds vicinal to an ether toward oxidation
by RuO4 is CH2 > CH. The same behavior was reported for
the oxidation of tetrahydrofuran and tetrahydropyran deriva-
tives.36 However, our results demonstrated an inversion of this
regiochemistry in the oxidation of the â-hydroxyethers 3a-j,
(31) Performing the reaction with 4.0 equiv of NaH in anhydrous THF
led to the exclusive formation of the allylic alcohol 5 along with recovered
starting material after 3 h under reflux. It is noteworthy that 5 was the only
regioisomer observed with either KOH or NaH.
(32) The use of acetonitrile, as established by Sharpless and co-workers,
represents a great improvement in the reaction protocol, since this solvent
can prevent coordination of low-valent ruthenium species with carboxylic
acids formed as byproducts during the course of the reaction. Carlsen, H.
J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46,
3936.
a Reagents and conditions: (a) 1.5 equiv of Oxone, 4.0 equiv of NaHCO3,
acetone/H2O (1:1), rt, 10 min; (b) 10 equiv of KOH, 20 mL of 75% aq
DMSO, 110-120 °C, 2 h.
(33) A saturated aqueous solution of sodium sulfite (Na2SO3) is also
used in the workup protocols of ruthenium tetraoxide-mediated oxidations
(see ref 22).
other hand, the cyclization of the trans isomer 2g′ can give either
the hydroxyether 3g′, from the conformer III, or the spiro ether
4, by a 4-exo-trig-like cyclization of IV, since both the
conformations probably have similar stabilities (Figure 2). The
(34) For the 1H and 13C NMR spectra of the keto-lactones 7g-j see ref
26.
(35) Bakke, J. M.; Froehaug, A. E. J. Phys. Org. Chem. 1996, 9, 310.
J. Org. Chem, Vol. 72, No. 8, 2007 2947

Ferraz and Longo
SCHEME 4a
TABLE 2. RuO4-Catalyzed Oxidative Cleavage of
â-Hydroxyethers 3a-fa
a Reagents and conditions: (a) 2.4 mol % RuCl3‚nH2O, 4.1 equiv of
NaIO4, H2O/CCl4/CH3CN (7 mL, 3:2:2, respectively), rt, 75 min, workup
by protocol A; (b) oxidative cleavage.
results obtained by Kitagawa et al.37 These authors reported that
the RuO4/NaIO4 oxidation of the octahydro-3,6-dimethylben-
zofurans, which differ from 3h essentially by the absence of
the hydroxyl group, led to the corresponding bicyclic lactones,
by the anticipated oxidation of the secondary carbon. In our
substrates, it is reasonable to consider the initial formation of a
ruthenate ester with the angular hydroxyl group. This ester might
then participate in a syn methine hydrogen abstraction, followed
by oxidation at that position, to afford the diol depicted in
Scheme 4.
The octahydro-3,6-dimethylbenzofuran-3-ols 9a and 9b,38
which are also â-hydroxyethers but bear the hydroxyl group in
a position different from that of the ethers 3a-j, were submitted
to the same oxidative treatment, in order to verify the role of
the hydroxyl group in the chemoselectivity of the reaction. The
only isolated product from 9a was 2-acetyl-5-methyl-cyclohex-
anone (10),39 again through an oxidation of the tertiary carbon
7a. The ether 9b also led to the â-diketone 10, together with
minor amounts of 11 and 12, produced by oxidation of the
secondary carbon C2.40
The different reactivities of 9a and 9b are in agreement with
the literature information concerning the steric requirements for
the oxidation of cyclic hydrocarbons by RuO4 (reactivity of
C-H bonds: equatorial tertiary . axial tertiary > equatorial
secondary > axial secondary).41 The tertiary equatorial C-H
bond of 9a, as well as those of the ethers 3a-j, is oxidized
faster than the tertiary axial C-H bond of 9b. Therefore, the
less reactive ether 9b allows the oxidation of both tertiary and
secondary carbons. Unfortunately, we could not clarify the role
of the hydroxyl group in the course of the reaction.
A possible mechanism for the oxidation of 9a and 9b by RuO4
is suggested in Scheme 5. The oxidation can occur either in
the tertiary carbon 7a or in the secondary carbon 2. Preferential
oxidation of the C7-H bond of both 9a and 9b leads to the
hemiketal intermediate I, which undergoes oxidation to II and
further cleavage to the â-diketone 10. Alternatively, the oxida-
a Reagents and conditions: 1.0 mmol â-hydroxyether, 3.0 mol %
RuCl3‚nH2O, 4.1 equiv NaIO4, H2O/CCl4/CH3CN (7 mL, 3/2/2, respec-
tively), rt, 90 min. b Diastereoisomeric mixtures of the â-hydroxyethers were
used (see ratios in Table 1). c Protocol A: addition of distilled water,
extraction with CH2Cl2, and filtration on a silica gel pad. Protocol B:
quenching with saturated aqueous Na2S2O3 solution, extraction with CH2Cl2,
and filtration on Celite. d Ratio determined by GC of the crude product.
since carbon 7a (CH) was oxidized preferentially to carbon 2
(CH2), leading to an R-hydroxy-hemiketal (as suggested in
Scheme 4), whose oxidative cleavage could be performed either
by RuO4 or by NaIO4.
It is noteworthy that the oxidation of the â-hydroxyether 3d
(Table 2, entry 4) led to the 10-membered lactone 7d along
with approximately 10% of the bicyclic lactone 8 (assumed
structure). The presence of such an oxidation product, even in
small amounts, was observed exclusively for the substrate 3d.
Although the mechanism of the oxidative cleavage is not
completely understood, the presence of the angular hydroxyl
group in the bicyclic ethers seems to play an important role in
the chemoselectivity displayed by RuO4, when compared to the
(37) Kitagawa, I.; Tsujii, S.; Nishikawa, F.; Shibuya, H. Chem. Pharm.
Bull. 1983, 31, 2639.
(38) Ferraz, H. M. C.; Grazini, M. V. A.; Ribeiro, C. M. R.; Brocksom,
U.; Brocksom, T. J. J. Org. Chem. 2000, 65, 2606.
(39) Descotes, G.; Yvon, Q. Bull. Soc. Chim. Fr. 1968, 8, 3395. Diketone
10 exists predominantly in the enol form: Snider, B. B.; Shi, Z. J. Am.
Chem. Soc. 1992, 114, 1790.
(40) For experimental details and full characterization data of products
11 and 12 see Supporting Information.
(41) Bakke, J. M.; Bethell, D. Acta Chem. Scand. 1992, 46, 644.
(36) Smith, A. B., III; Scarborough, R. M., Jr. Synth. Commun. 1980,
10, 205.
2948 J. Org. Chem., Vol. 72, No. 8, 2007

Precursors of Medium Ring Keto-Lactones
SCHEME 5a
a Reagents and conditions: (a) 5.0 mol % RuCl3‚nH2O, 4.1 equiv of NaIO4, H2O/CCl4/CH3CN (3:2:2), rt, 30 min for 9a and 4 h for 9b; (b) 5.0 mol %
RuCl3‚nH2O, 4.1 equiv of NaIO4, H2O/CCl4/CH3CN (3:2:2), rt, 4 h.
to give a 2:3 mixture of 3e and 3e′ (0.566 g, 3.33 mmol, 75%),
respectively (ratio determined by GC and H NMR in the crude
tion of C2, which occurs only in the ether 9b, gives the
intermediate III, precursor of the minor products 11 and 12.
The possibility of a direct transformation of 11 to 1042 was
excluded by submitting 11 to the same oxidative reactional
conditions: after 4 h of reaction the starting material was
recovered unchanged.
1
product). Analytical samples of the diastereomeric bicyclic â-hy-
droxyethers 3e and 3e′ were obtained performing a second flash
chromatography (gradient elution, 10-50% AcOEt in hexanes).
3e: white solid; mp ) 94.4-94.8 °C; IR (KBr) 3382 cm-1; LRMS
m/z (%) 170 (16, M+); 1H NMR (500 MHz, CDCl3) δ 0.92 (d, J )
6.9 Hz, 3H), 1.26-1.66 (m, 6H, H-OH), 1.77-1.99 (m, 5H), 3.45
(dd, J ) 8.1 and 11.4 Hz, 1H), 3.81 (dd, J ) 2.7 and 11.4 Hz,
1H), 3.93 (t, J ) 7.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 7.8,
23.1, 25.7, 31.2, 33.7, 36.9, 44.1, 72.6, 82.9, 91.9. Anal. Calcd for
C10H18O2: C, 70.55%; H, 10.66%. Found: C, 70.64%; H, 10.65%.
3e′: white solid; mp ) 65.5-65.6 °C; IR (KBr) 3383 cm -1; LRMS
m/z (%) 156 (16, M+); 1H NMR (500 MHz, CDCl3) δ 1.01 (d, J )
7.3 Hz, 3H), 1.27-1.37 (m, 2H), 1.50-1.92 (m, 8H, H-OH),
2.03-2.06 (m, 1H), 3.56 (dd, J ) 2.8 and 8.3 Hz, 1H), 3.75 (dd,
Conclusions
We have demonstrated that the oxidative cleavage of bicyclic
â-hydroxyethers by catalytic RuO4 is a mild and clean method
for the preparation of 9- and 10-membered ring lactones, using
RuCl3 as the source of RuO4 and NaIO4 as the stoichiometric
cooxidant. The bicyclic ethers were easily prepared from
3-alkenols in two steps, i.e., epoxidation with dimethyldioxirane
followed by base-catalyzed cyclization of the resulting epoxy-
alcohol. This method complements the thallium trinitrate-
mediated cyclization of 3-alkenols described earlier by our
group.27 High regioselectivity was observed in the oxidation of
the â-hydroxyethers by RuO4, with large preference for the
oxidation of the tertiary carbon-hydrogen bond, in contrast to
the postulated order of reactivity of the carbon-hydrogen bonds
in ethers.35,36 The application of this methodology to the
synthesis of natural medium ring lactones is in progress in our
laboratory.
J ) 3.0 and 11.2 Hz, 1H), 4.09 (dd, J ) 5.5 and 8.3 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 14.7, 22.7, 25.4, 30.8, 33.2, 33.6, 48.1,
73.4, 84.3, 91.4. Anal. Calcd for C10H18O2: C, 70.55%; H, 10.66%.
Found: C, 70.55%; H, 10.62%.
3â-Ethyl-8arH-octahydro-cyclohepta[b]furan-3ar-ol (3f) and
3r-Ethyl-8arH-octahydro-cyclohepta[b]furan-3ar-ol (3f′). The
reaction was performed following the general procedure, using the
epoxyalcohol 2f (0.389 g, 2.11 mmol) in 75% aqueous DMSO (42
mL) and KOH (1.18 g, 21.1 mmol). The crude product was purified
by flash chromatography (eluent, 50% AcOEt in hexanes) to give
a 7:3 mixture of 3f and 3f′ (0.334 g, 1.82 mmol, 86%), respectively
(ratio determined by GC and 1H NMR in the crude product).
Analytical samples were obtained performing a second flash
chromatography (gradient elution, 10-50% AcOEt in hexanes).
Experimental Section
General Procedure for the Base-Promoted Cyclization of
Epoxyalcohols 2a-f. Preparation of the Bicyclic â-Hydroxy-
ethers 3a-f. To a stirred solution of the epoxyalcohols 2a-f (1
mmol) in 75% aqueous DMSO (20 mL) was added potassium
hydroxide (10 equiv, 0.56 g, 10 mmol). The mixture was stirred at
110-120 °C for 2 h, and water (20 mL) was added dropwise. The
aqueous phase was extracted with AcOEt (three times). The
combined organic extracts were washed with H2O followed by brine
and dried over anhydrous MgSO4, and the solvent was removed
under reduced pressure.
3â-Methyl-8arH-octahydro-cyclohepta[b]furan-3ar-ol (3e)
and 3r-Methyl-8arH-octahydro-cyclohepta[b]furan-3ar-ol (3e′).
The reaction was performed following the general procedure, using
the epoxyalcohol 2e (0.757 g, 4.45 mmol) in 75% aqueous DMSO
(90 mL) and KOH (2.49 g, 44.5 mmol). The crude product was
purified by flash chromatography (eluent, 50% AcOEt in hexanes)
3f: white solid; mp ) 110.5-110.6 °C; IR (KBr) 3380 cm-1
;
LRMS m/z (%) 184 (6.3, M+); 1H NMR (500 MHz, CDCl3) δ 0.94
(t, J ) 7.5 Hz, 3H), 1.26-1.92 (m, 13H, H-OH), 3.48 (dd, J )
8.1 and 11.3 Hz, 1H), 3.80 (dd, J ) 2.4 and 11.3 Hz, 1H), 4.04 (t,
J ) 7.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 13.2, 17.9, 23.1,
25.7, 31.2, 33.6, 37.3, 51.5, 71.6, 83.1, 92.3. Anal. Calcd for
C10H18O2: C, 71.70%; H, 10.94%. Found: C, 71.46%; H, 10.73%.
1
3f′: colorless oil; H NMR (300 MHz, CDCl3) δ 0.91 (t, J ) 7.2
Hz, 3H), 1.15-1.97 (m, 13H, H-OH), 3.68 (dd, J ) 4.0 and 8.6
Hz, 1H), 3.77 (dd, J ) 2.5 and 10.8 Hz, 1H), 4.04 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 12.9, 20.9, 22.4, 24.8, 30.4, 32.3, 33.1,
55.3, 70.0, 83.9, 90.6. Anal. Calcd for C10H18O2: C, 71.70%; H,
10.94%. Found: C, 71.51%; H, 10.83%.
General Procedure for the Ruthenium Tetraoxide-Promoted
Oxidative Cleavage of â-Hydroxyethers 3a-c,e,f (Protocol A).
To 7.0 mL of a 3:2:2 mixture of H2O/CCl4/CH3CN, respectively,
was added 1 mmol of the â-hydroxyethers 3, 4.1 mmol of NaIO4,
(42) An example of the RuO4-promoted oxidation of a formate ester to
the corresponding ketone is described in ref 25.
J. Org. Chem, Vol. 72, No. 8, 2007 2949

Ferraz and Longo
and 2.4-3.0 mol % of RuCl3‚nH2O,43 according to the data shown
in Table 2. The mixture was magnetically stirred at rt for 75-90
min, and 10 mL of distilled H2O was added. The aqueous phase
was extracted with CH2Cl2 (three times), and the combined organic
phases were washed with brine (twice) and concentrated by
removing part of the solvent under reduced pressure. The resulting
residue was then filtered through a small silica gel pad (ap-
proximately 10 cm), washing with CH2Cl2. The filtrate was dried
over anhydrous MgSO4, and the solvent was removed under reduced
pressure affording the corresponding keto-lactones.
Anal. Calcd for C10H16O3: C, 65.19%; H, 8.75%. Found: C,
65.41%; H, 8.67%.
General Procedure for the Ruthenium Tetraoxide-Promoted
Oxidative Cleavage of â-Hydroxyethers 3a,b,d-f (Protocol B).
To 7.0 mL of a 3:2:2 mixture of H2O/CCl4/CH3CN, respectively,
was added 1 mmol of the â-hydroxyethers 3, 4.1 mmol of NaIO4,
and 3.0 mol % of RuCl3‚nH2O,43 according to the data shown in
Table 2. The mixture was magnetically stirred at rt for 90 min,
and 10 mL of a saturated aqueous solution of Na2S2O3 was added.
The resulting solution was filtered under Celite, washing with CH2-
Cl2. The aqueous phase was extracted with CH2Cl2 (three times),
and the combined organic phases were washed with brine (twice)
and dried over anhydrous MgSO4. The solvent was removed under
reduced pressure affording the corresponding keto-lactones.
Oxecane-2,8-dione (7d). The reaction was performed following
the general procedure, stirring the â-hydroxyether 3d (0.178 g, 1.14
mmol), RuCl3‚nH2O (3.0 mol %, approximately 0.007 g), and NaIO4
(1.00 g, 4.67 mmol) in 8.0 mL of a 3:2:2 mixture of H2O/CCl4/
CH3CN at rt for 90 min. The solvent was removed under reduced
pressure, affording the keto-lactone 7d contaminated with ap-
proximately 10% of the â-hydroxylactone 8 (assumed structure)
in 78% overall yield. Spectral data for 7d are in agreement with
the literature.44
8-Methyl-oxonane-2,7-dione (7b). The reaction was performed
following the general procedure, stirring a 3:2 mixture of the
â-hydroxyethers 3b/3b′ (0.050 g, 0.318 mmol), RuCl3‚nH2O (3.0
mol %, approximately 0.002 g), and NaIO4 (0.278 g, 1.30 mmol)
in 2.8 mL of a 3:2:2 mixture of H2O/CCl4/CH3CN at rt for 90 min.
The crude product was purified by flash chromatography (gradient
elution, 0-30% AcOEt in hexanes) affording the keto-lactone 7b
(0.014 g, 0.082 mmol, 26%). 7b: colorless oil; IR (film) 1743,
1
1711 cm-1; LRMS m/z (%) 170 (0.4, M+); H NMR (500 MHz,
CDCl3) δ 1.05 (d, J ) 6.8 Hz, 3H), 1.75-1.95 (m, 4H), 2.31-
2.49 (m, 4H), 3.21-3.28 (m, 1H), 4.01 (dd, J ) 9.5 and 10.7 Hz,
1H), 4.68 (dd, J ) 7.2 and 10.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 13.2, 23.9, 24.5, 35.0, 41.5, 44.8, 66.9, 174.6, 213.8.
Anal. Calcd for C9H14O3: C, 63.51; H, 8.29%. Found: C, 63.65%;
H, 8.31%.
9-Methyl-oxecane-2,8-dione (7e). The reaction was performed
following the general procedure, stirring a 2:3 mixture of the
â-hydroxyethers 3e/3e′ (0.151 g, 0.888 mmol), RuCl3‚nH2O (3.0
mol %, approximately 0.006 g), and NaIO4 (0.779 g, 3.64 mmol)
in 7.0 mL of a 3:2:2 mixture of H2O/CCl4/CH3CN at rt for 90 min.
The crude product was purified by flash chromatography (eluent,
20% AcOEt in hexanes) affording the keto-lactone 7e (0.080 g,
Acknowledgment. We thank FAPESP, CNPq, and CAPES
for financial support. We are grateful to Professor Luiz F. Silva,
Jr. and Marcus V. Craveiro for helpful discussions and Alex-
sandra C. Scalfo for his help in carrying out the HRMS. We
also thank the reviewers of this article for fruitful suggestions.
0.44 mmol, 49%). 7e: colorless oil; IR (film) 1738, 1713 cm-1
;
Supporting Information Available: Experimental procedures
and structural data information for the compounds not described
within the Experimental Section: NMR spectra of 3-alkenols 1a-
g, epoxyalcohols 2a-g, â-hydroxyethers 3a-g, products 4, 5, and
6, and keto-lactones 7a-f. This material is available free of charge
via the Internet at http://pubs.acs.org.
LRMS m/z (%) 184 (4.7, M+); 1H NMR (500 MHz, CDCl3) δ 1.02
(d, J ) 6.8 Hz, 3H), 1.15-1.20 (m, 1H), 1.49-1.64 (m, 1H), 1.60-
1.67 (m, 2H), 1.70-1.80 (m, 1H), 1.83-1.89 (m, 1H), 2.24-2.31
(m, 2H), 2.38 (ddd, J ) 4.3, 5.5 and 14.2 Hz, 1H), 2.69 (ddd, J )
3.8, 9.1 and 14.8 Hz, 1H), 3.30-3.37 (m, 1H), 4.04 (t, J ) 10.6
Hz, 1H), 4.34 (dd, J ) 5.6 and 10.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 12.5, 22.2, 23.1, 25.2, 35.0, 41.9, 43.0, 67.3, 173.1, 214.7.
JO0626109
(43) Calculations for RuCl3‚nH2O were based on n ) 1.
(44) Das, J.; Chandrasekaran, S. Tetrahedron 1994, 50, 11709.
2950 J. Org. Chem., Vol. 72, No. 8, 2007