Direct lactonization of alkenols via osmium tetroxide-mediated oxidative cleavage

Article abstract of DOI:10.1021/ol035057f

(Matrix presented) A highly efficient, mild, and simple protocol is presented for the tandem OsO₄-mediated oxidative cleavage/oxidative lactonization of alkenols to lactones. The protocol couples the OsO ₄-catalyzed oxidative cleavage of olefins with Oxone as the co-oxidant with the direct oxidation of aldehydes in alcoholic solvents to their corresponding esters.

Full text of DOI:10.1021/ol035057f

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3089-3092
Direct Lactonization of Alkenols via
Osmium Tetroxide-Mediated Oxidative
Cleavage
Jennifer M. Schomaker, Benjamin R. Travis, and Babak Borhan*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
borhan@cem.msu.edu
Received June 11, 2003
ABSTRACT
A highly efficient, mild, and simple protocol is presented for the tandem OsO -mediated oxidative cleavage/oxidative lactonization of alkenols
4
to lactones. The protocol couples the OsO -catalyzed oxidative cleavage of olefins with Oxone as the co-oxidant with the direct oxidation of
4
aldehydes in alcoholic solvents to their corresponding esters.
Oxidative chemistry is essential for the success of organic
synthesis as can be attested to by the overwhelming number
of manuscripts published in the area.1-8 Needless to say, the
importance of these reactions cannot be overstated, and the
discovery of new, more efficient and milder reactions with
unique properties would only increase the repertoire of tools
available to organic chemists for tackling syntheses of
complex molecules on both laboratory and industrial scales.
Recently, the use of the convenient and readily available
Oxone as an economical and green oxidant has blossomed
for many transformations in organic synthesis. These include,
but are not limited to, selective oxidations of boron, nitrogen,
phosphorus, and sulfur-containing compounds.9-14 Oxone is
also well-known as a useful reagent for the preparation of
dimethyldioxirane (DMDO) in buffered acetone, which is
used to epoxidize olefins.15,16
We have been engaged in exploring Oxone as a mild
oxidant for the OsO4-mediated oxidative cleavage of olefins
to their corresponding aldehydes and carboxylic acids
(Scheme 1).17,18 Aldehydes are the immediate products
Scheme 1
(1) Bentley, T. W. Org. React. Mech. 1977, 12, 211.
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with Metal Compounds; Plenum Press: New York, 1986.
(7) Muzart, J. Chem. ReV. 1992, 92, 113.
(8) Sheldon, R. A.; Kochi, J. K. Metal-catalyzed Oxidations of Organic
Compounds: Mechanistic Principles and Synthetic Methodology Including
Biochemical Processes; Academic Press: New York, 1981.
(9) Wozniak, L. A.; Stec, W. J. Tetrahedron Lett. 1999, 40, 2637.
(10) Wozniak, L. A.; Koziolkiewicz, M.; Kobylanska, A.; Stec, W. J.
Bioorg. Med. Chem. Lett. 1998, 8, 2641.
obtained in the oxidation of olefins and can be isolated as
the sole product if soluble peroxymonosulfate (nBu4NHSO5)
(11) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117.
(12) Webb, K. S.; Ruszkay, S. J. Tetrahedron 1998, 54, 401.
(13) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287.
(14) Baumstark, A. L.; Beeson, M.; Vasquez, P. C. Tetrahedron Lett.
1989, 30, 5567.
10.1021/ol035057f CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/29/2003

is used for the cleavage of aromatic olefins. Along the same
lines, we have demonstrated that Oxone can be used as a
mild and efficient reagent for conversion of aldehydes to
carboxylic acids, and furthermore, in the presence of
alcoholic solvents, the oxidation proceeds directly to yield
esters (Scheme 1).19 As a continuation of this work, we were
interested in determining whether the oxidative cleavage of
olefins could be coupled with intramolecular trapping by an
alcohol moiety to form lactones. The reaction envisioned is
shown in Scheme 2 (direct conversion of 1 to 2).
Scheme 3
Scheme 2
protected, and the free hydroxyl was oxidized to yield
aldehyde 4. Upon treatment of 4 with either Oxone in DMF
or in MeOH, in situ deprotection of the silyl group occurred
concomitantly with oxidation of the hydroxy aldehyde
intermediate to the lactone 6. Presumably, the oxidation
proceeds via the formation of a hemiacetal intermediate, since
we have demonstrated previously that hydroxy carboxylic
acids do not esterify/lactonize under the given reaction
conditions.19
Olefination of 4 to deliver 5 provided the prerequisite silyl-
protected alkenol poised for a tandem oxidative cleavage/
oxidative lactonization to deliver 6. Treatment of 5 with
catalytic OsO4 (1 mol %) and Oxone in DMF led to the
isolation of 6 in good yields, thus demonstrating the
intramolecular trapping of the unmasked hydroxyl upon
oxidative cleavage of the olefin.
Subsequent experiments focused on the conversion of
alkenols to their corresponding lactones, specifically the
conversion of 4-penten-1-ol and 5-hexen-1-ol to butyro-
lactone and valerolactone, respectively (Table 1, entries 1
and 2). These lactones were obtained in good yields, thus
demonstrating that alkyl-substituted olefins can also undergo
the lactonization in preference to oxidation to carboxylic
acids. Due to the water solubility of the smaller lactones,
these reactions were monitored by using 1,2,3,4-tetra-
methylbenzene or dodecane as an internal standard and
sampling by gas chromatography. Although previous experi-
ence with Oxone/OsO4 systems had shown that DMF was a
very effective solvent for oxidative cleavage of olefins, a
preliminary solvent screen was performed. Acetonitrile,
acetone/water, DMF, methanol, and HMPA were all shown
to yield lactone product. Hexane, glyme, dioxane, and xylene
did not yield appreciable amounts of product. It was later
shown that the yield of oxidative lactonization in solvents
such as acetonitrile and methylene chloride could be
increased, provided that 10-50 equiv of DMF was added.
This is important in facilitating easier workup of water-
soluble or volatile lactones.
Other methods that have been reported for the conversion
of hydroxy olefins to lactones via oxidative cyclization
require stoichiometric chromium or permanganate reagents.
Schlecht and Kim20 have used chromium trioxide in acetic
acid/acetic anhydride, and Chandrasekaran and co-work-
ers21,22 have used a pentavalent (BiPyH2)CrOCl5 reagent to
effect the transformation of various γ- and δ-hydroxy olefins
to the corresponding lactones. However, these particular sets
of reaction conditions are only useful for hydroxy olefins
containing a tertiary alcohol group; otherwise, oxidation of
the alcohol to the corresponding carboxylic acid or ketone
is a major problem. Chandrasekaran and co-workers soon
devised a solution to this problem in the form of cetyltri-
methylammonium permanganate, which can be used in the
oxidative cyclization of primary, secondary, or tertiary
alkenols to the corresponding lactones.23 Chandrasekaran also
reported the use of KMnO4 in the presence of copper sulfate
and a small amount of water as being effective in the
oxidative cyclization of ω-hydroxy alkenes to ω-lactones
under mild conditions.24 We wish to report on our success
in developing a new and mild system for effecting this
transformation involving catalytic OsO4 in the presence of
Oxone as the oxidant.
Our initial efforts centered on the proof of concept depicted
in Scheme 3. Bis-(hydroxymethyl) biphenyl 3 was mono-
(15) Murray, R. W. Chem. ReV. 1989, 89, 1187.
(16) Denmark, S. E.; Forbes, D. C.; Hays, D. S.; Depue, J. S.; Wilde, R.
G. J. Org. Chem. 1995, 60, 1391.
(17) Travis, B. R.; Ciaramitaro, B. P.; Borhan, B. Eur. J. Org. Chem.
2002, 2002, 3429.
(18) Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002,
124, 3824.
(19) Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett.
2003, 5, 1031.
(20) Schlecht, M. F.; Kim, H. Tetrahedron Lett. 1985, 26, 127.
(21) Baskaran, S.; Islam, I.; Raghavan, M.; Chandrasekaran, S. Chem.
Lett. 1987, 1175.
(22) Chakraborty, T. K.; Chandrasekaran, S. Tetrahedron Lett. 1980, 21,
1583.
(23) Rathore, R.; Vankar, P. S.; Chandrasekaran, S. Tetrahedron Lett.
1986, 27, 4079.
(24) Baskaran, S.; Islam, I.; Vankar, P. S.; Chandrasekaran, S. J. Chem.
Soc., Chem. Commun. 1990, 1670.
DMF was chosen as the initial solvent for study due to
fast reaction times and higher yields of product as compared
to other solvents. It was found that the use of a 0.1 M solution
of the alkenol in DMF with 4.0 equiv of Oxone and
3090
Org. Lett., Vol. 5, No. 17, 2003

likely due to the small equilibrium presence of the cyclized
hemiacetals for larger rings. Therefore, following oxidative
cleavage, the oxidation of the intermediate aldehyde to
carboxylic acids predominates. The yield of seven-member
lactones could be improved, provided that conformational
freedom was restricted (Scheme 3 and entry 4 in Table 1).
Attempts to form an eight-member lactone (entry 5) were
unsuccessful and led only to the carboxylic acid product 11a,
albeit in good yield. We were disappointed with these results,
since we had hoped that this protocol could be extended to
the formation of macrocyclic ring systems, thus providing
the opportunity for masking a carboxylic acid as an alkene
during the course of a synthesis. While this might still prove
to be a viable strategy for more highly substituted systems
with preferred conformations that could increase the cyclic
hemiacetal intermediate necessary for lactonization, another
route to larger macrocycles can be pursued by tethering an
alcohol functionality to an endocyclic double bond (Table
1, entry 6).25
Table 1. Oxidative Lactonization of Alkenols
Entries 7 and 8 in Table 1 illustrate the effect of
substitution on the yield of lactonization. The anticipated
Thorpe-Ingold effect26 for alkenol 13 did result in higher
yields of 13a. However surprisingly, the tertiary alcohols
14 and 15 with steric crowding of the hydroxyl groups
reacted efficiently to yield 14a and the spirolactone 15a,
respectively. Fused 5/6 and 6/7 ring systems 16a and 10a,
respectively, could be obtained in good isolated yields (Table
1, entries 10 and 4). Protected benzylic alcohol 17 with an
olefinic appendage was also lactonized under the same
reaction conditions. However, phenolic systems such as 18
did not undergo oxidative lactonization, presumably because
of the tempered nucleophilicity of the hydroxyl group (Table
1, entry 12). Oxidative lactonization of the silyl-protected
alkenol 19 yielded 19a, once again demonstrating the in situ
deprotection/lactonization sequence under the reaction condi-
tions. Aldehyde 20, presumably the intermediate in the
oxidative lactonization of 19, also yields 19a in good yields
upon treatment only with Oxone.
We believe that the lactonization occurs via an initial
cleavage of the alkene 7 to aldehyde 21 (Scheme 4), which
can be either further oxidized to the carboxylic acid 22
(nonproductive process) or trapped intramolecularly by the
alcohol moiety to form the hemiacetal 23. Oxone, which
contains peroxymonosulfate as its active oxidant, is slightly
acidic, and thus equilibration of the hemiacetal 23 to the
hemiperoxymonosulfate acetal 24 can be effected under the
reaction conditions shown in Scheme 4. Baeyer-Villeger-
like rearrangement of 24 can lead to the isolation of lactone
7a.5,27-30 We have some experimental evidence to suggest
the latter to be true. Deprotection of 4 with TBAF leads to
the hydroxy-aldehyde 4a, which exists mainly in the hemi-
acetal form 4b as evident by NMR (see Supporting Informa-
a Isolated yields, unless specified otherwise. b GC yields. c NMR yields.
d Reaction conditions are the same except that OsO4 was omitted.
1.0 mol % OsO4 was effective at converting primary,
secondary, and tertiary alcohols to the corresponding lactones
in good yields (Table 1).
While the formation of five- and six-member lactones was
facile as expected, the yield dropped precipitously on
formation of caprolactone (Table 1, entry 3). Longer chain
alken-1-ols gave no discernible amounts of lactone, and the
carboxylic acids were isolated as the sole products. This is
(25) Das, J.; Chandrasekaran, S. Tetrahedron 1994, 50, 11709.
(26) Sammes, P. G.; Weller, D. J. Synthesis 1995, 1205.
(27) Lethinen, C.; Nevalainen, V.; Brunow, G. Tetrahedron 2001, 57,
4741.
(28) Syper, L. Synthesis 1989, 167.
(29) McNesby, J.; Heller, C. Chem. ReV. 1954, 54, 325.
(30) Godfrey, I.; Sargent, M.; Elix, J. J. Chem. Soc., Perkin Trans. 1
1974, 1353.
Org. Lett., Vol. 5, No. 17, 2003
3091

Scheme 4
Scheme 5
observed difference in reactivity between nBu4NHSO5 and
Oxone is not apparent; however, it could be a result of
Oxone’s much higher water content and its inherent acidity
that could lead to the hydrolysis of silyl ethers. A previous
report by Sabitha and co-workers has demonstrated the ability
of Oxone to deprotect TBDMS groups in aqueous MeOH.31
As such, the tandem oxidative cleavage/oxidative lactoniza-
tion of the tertiary alcohol 25 with nBu4NHSO5 in dichloro-
methane provided lactone 26 in good yields without the
deprotection of the TBS group.
In conclusion, we have shown that a new and mild
osmium-catalyzed tandem oxidative cleavage/oxidative lac-
tonization reaction can be used to prepare lactones from a
wide variety of hydroxy olefins.
tion for spectra). Exposure of 4a/4b to KHSO5 leads to
lactone 6, which can be qualitatively followed by NMR (see
Supporting Information). Detailed mechanistic studies are
ongoing to fully elucidate the mechanism of lactonization,
and thus other mechanistic pathways such as radical-mediated
oxidations cannot be excluded at this time. However, what
is clear is that the path to lactones is not through oxidation
of the olefin to carboxylic acids, followed by an intra-
molecular lactonization event. Carboxylic acids containing
internal hydroxyl groups are immune to lactonization if
placed in identical reaction conditions.19
Acknowledgment. Generous support was provided in part
by Michigan State University Startup funds to B.B. and the
Michigan Economic Development Corporation (GR-183).
J.M.S. is supported by the Michigan State University
Distinguished Fellowship. B.R.T. is supported by a fellow-
ship from the American Chemical Society, Division of
Organic Chemistry.
The use of a soluble form of Oxone (nBu4NHSO5)17 was
briefly studied. Difficulty in separating excess oxidant and
oxidation byproducts from highly polar products was not
trivial, and thus nBu4NHSO5 is not recommended for use
with water-soluble lactones. However, nBu4NHSO5 is a
convenient reagent for more nonpolar substrates and, unlike
the Oxone/DMF system, allows for silyl groups to be retained
during the lactonization (Scheme 5). The reason for the
Supporting Information Available: Detailed experi-
mental procedures and tabulated spectroscopic data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL035057F
(31) Sabitha, G.; Syamala, M.; Yadav, J. S. Org. Lett. 1999, 1, 1701.
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