Organocatalytic one-pot oxidative cleavage of terminal diols to dehomologated carboxylic acids

Article abstract of DOI:10.1021/ol3021429

The organocatalytic one-pot oxidative cleavage of terminal 1,2-diols to one-carbon-unit-shorter carboxylic acids is described. The combination of 1-Me-AZADO (cat.), NaOCl (cat.), and NaClO₂ caused smooth one-pot oxidative cleavage under mild conditions. A broad range of substrates including carbohydrates and N-protected amino diols were converted without epimerization. Terminal triols and tetraols respectively underwent cleavage of their C-2 and C-3 moieties to afford their corresponding two- and three-carbon-unit-shorter carboxylic acids.

Full text of DOI:10.1021/ol3021429

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5006–5009
Organocatalytic One-Pot Oxidative
Cleavage of Terminal Diols to
Dehomologated Carboxylic Acids
Masatoshi Shibuya,*,† Ryusuke Doi, Takuro Shibuta, Shun-ichiro Uesugi, and
Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, 6-3 Aobayama, Sendai 980-8578, Japan
m-shibu@ps.nagoya-u.ac.jp; y-iwabuchi@m.tohoku.ac.jp
Received August 1, 2012
ABSTRACT
The organocatalytic one-pot oxidative cleavage of terminal 1,2-diols to one-carbon-unit-shorter carboxylic acids is described. The combination of
1-Me-AZADO (cat.), NaOCl (cat.), and NaClO2 caused smooth one-pot oxidative cleavage under mild conditions. A broad range of substrates
including carbohydrates and N-protected amino diols were converted without epimerization. Terminal triols and tetraols respectively underwent
cleavage of their C-2 and C-3 moieties to afford their corresponding two- and three-carbon-unit-shorter carboxylic acids.
The 1,2-diol is a useful structural motif in organic syn-
thesis that offers flexible access to various functional
groups, such as R-hydroxy-carbonyl1,2 or R-dicarbonyl
compounds,3 epoxides,4 alkenes,5 and others6,7 on the basis
of judicious choices of reagents and conditions. Because of
our research interest in developing nitroxyl radical/oxoam-
monium salt-catalyzed alcohol oxidation processes,8,9 we
examined the applicability of TEMPO oxidation to the
selective conversion of 1,2-diols to 2-hydroxy acids using
the primary alcohol selectivity of TEMPO.1a,c During our
experimentation, we found that terminal 1,2-diols are
cleanly converted to dehomologated carboxylic acids via
the oxidative decarboxylation of R-keto-carboxylic acids.
† Present address: Department of Basic Medicinal Sciences, Graduate
School of Pharmaceutical Sciences, Nagoya University, Chikusa, Nagoya
464-8601, Japan.
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r
10.1021/ol3021429
Published on Web 09/19/2012
2012 American Chemical Society

We now describe the first organocatalytic one-pot oxida-
tive cleavage of terminal 1,2-diols to dehomologated
carboxylic acids with a wide range of substrate applic-
abilities, featuring the combineduse of cat.1-Me-AZADO/
cat.NaOCl/NaClO2.
Nitroxyl-radical-catalyzed alcohol oxidation has at-
tracted much attention owing to its versatile utility sup-
ported by diverse sets of catalyst and terminal oxidant
availabilities.10ꢀ13 2,2,6,6-Tetramethylpiperidine 1-oxyl
(TEMPO, 1) is a representative of this type of catalyst. A
less hindered class of nitroxyl radical 2-azaadamantane
N-oxyls (AZADOs) (2, 3),8a,b,f,g 9-azabicyclo[3.3.1]-nonane
N-oxyl (ABNO) (4),8c and 9-azanoradamantane N-oxyl
(Nor-AZADO) (5)8e have been developed as more reactive
nitroxyl radical catalysts (Figure 1).
carboxylic acid has been published;14 however, it focused
on the development of a column-flow alcohol oxidation
system using immobilized TEMPO with few examples of
oxidative cleavage. Stark et al. have also recently reported
TPAP-catalyzed vicinal diol cleavage to carboxylic acids
as a new synthetic method.15 Because of the efficiency and
mildness of the nitroxyl-radical-catalyzed method as well
as its eco- and user-friendliness, we thought it useful to
clarify the scope of nitroxyl-radical-catalyzed oxidative
cleavage.16 Furthermore, highly active AZADOs could
expand the scope of TEMPO-catalyzed oxidative cleavage.
Comparing 1-Me-AZADO (3) with TEMPO (1), we
examined the substrate applicability of this method
(Table 1).17ꢀ19 As expected, the simple 1,2-diols 6a, 7a,
and 8a efficiently underwent the desired reaction using
either catalyst. The phenylacetylene 9a yielded its corre-
sponding one-carbon-unit-shorter carboxylic acid 9c accom-
panied by less than 5% benzoic acid under the 1-Me-
AZADO-catalyzed conditions, whereas 12% benzoic acid
was obtained under the TEMPO-catalyzed conditions
(entry 4). For the entries 5ꢀ7, 9, and 10, the differences
between 1-Me-AZADO and TEMPO became clear. The
conversions from 2-hydroxy acids to one-carbon-unit-
shorter carboxylic acids were more efficiently promoted
under the 1-Me-AZADO-catalyzed conditions than under
Figure 1. Structures of nitroxyl radicals.
In light of the inherent stereodiscriminable properties of
TEMPO,1 we first evaluated the possibility of TEMPO-
catalyzed oxidation to conduct the selective oxidation of
1,2-diols to their corresponding 2-hydroxy acids, employing
cat.NaOCl/NaClO2 (Zhao’s procedure),13b,d which offers
an efficient one-pot oxidation of primary alcohols to their
corresponding carboxylic acids. While attempting the oxida-
tion of 1,2-diol 6a under Zhao’s conditions, we unexpectedly
found that smooth and clean oxidative CꢀC cleavage from
the 2-hydroxy acid 6b to the one-carbon-unit-shorter car-
boxylic acid 6c takes place (Scheme 1).
At the outset of this reaction, only 2-hydroxy acid was
detected by analytical TLC. As the reaction approached
completion, CꢀC bond cleavage took place exclusively to
afford the one-carbon-unit-shorter carboxylic acid 6c with-
out any intermediate other than the 2-hydroxy acid 6b being
detected. One report including a nitroxyl-radical-catalyzed
direct cleavage reaction from 1,2-diol to dehomologated
Scheme 1. Unexpected Oxidative Cleavage
TEMPO-catalyzed conditions. Thus, the corresponding
2-hydroxy acids were obtained after 24 h under the
TEMPO-catalyzed conditions in moderate yield (the
yields are shown in Table 1). No epimerization of an
adjacent stereocenter was detected under either set of
catalyst-catalyzed conditions (entries 5ꢀ10). Note that
the methoxy diol 13a and the N-protected amino diols 14a
and 15a efficiently underwent one-pot oxidative cleavage
without racemization under the 1-Me-AZADO-catalyzed
conditions (entries 8ꢀ10).20,21 The optically active diols
13a and 14a were prepared by Sharpless asymmetric
epoxidation and acid-catalyzed nucleophilic ring opening
(10) (a) de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Synthesis
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Ragan, J. A.; Ripin, D. H. B. Chem. Rev. 2006, 106, 2943–2989. (c)
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Z. J.; Tschaen, D. M. Org. Synth. 2005, 81, 195–203.
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to one-carbon-unit-shorter carboxylic acid: (a) Parker, K. A.; Lim,
Y. H. J. Am. Chem. Soc. 2004, 126, 15968–15969. (b) Koizumi, Y.;
Kobayashi, H.; Wakimoto, T.; Furuta, T.; Fukuyama, T.; Kan, T.
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Org. Lett., Vol. 14, No. 19, 2012
5007

from the corresponding allylic alcohol (see Supporting
Information). These results showcase the use of this
method for preparing optically active R-amino acids and
R-alkoxy acids. The piperidinodiol 15a was also prepared
from D-mannitol according to Kamal’s report,22 which in-
dicates the use of this one-pot oxidative cleavage as a
preparation method for R-amino acids from a chiral pool.
Unfortunately, 16a having a sensitive trisubstituted olefin
under oxidative conditions and the internal diol 17a did
not afford the desired products.
Table 1. Scopes of TEMPO- and 1-Me-AZADO-Catalyzed
One-Pot Oxidative Cleavagesa
To investigate the applicability of this one-pot oxidative
cleavage to terminal triols and tetraols, we examined the
reactions of the triol 18 and the tetraol 20(Scheme 2). Two-
and three-carbon dehomologations effectively proceeded
to afford the corresponding carboxylic acids.
To probe the reaction mechanism, we examined the
reactivity of oxoammonium salts (1-Me-AZADOþXꢀ),
which are active species of 1-Me-AZADO (3), NaOCl,23
and NaClO2,24,25 toward the 2-hydroxy acid 7b and the
keto acid 7e (Scheme 3). Neither 1-Me-AZADOþClꢀ nor
NaOCl-NaClO2 caused the CꢀC bond cleavage of the
2-hydroxy acid 7b (eqs 1, 2). Although 1-Me-AZADOþClꢀ
also did not cause the CꢀC bond cleavage of the keto acid
7e, NaClO2 did promote the CꢀC bond cleavage of the
keto acid 7e (eqs 3, 4). These results show that CꢀC bond
(17) AZADO (2) also smoothly catalyzed one-pot oxidative cleavage.
By mixing the hydroxy ketone 7f and the hydroxyamine of AZADO
(AZADOH) and NaClO2, neither CꢀC bond cleavage nor alcohol
oxidation occurred, which indicates that the oxidation of a secondary
alcohol prior to a primary alcohol could shut down the catalytic cycle
(eq 2). NaOCl generated from NaClO2 by the oxidation of an aldehyde
to a carboxylic acid is necessary for the regeneration of oxoammonium
species in this reaction (eq 1). Thus, we used 1-Me-AZADO (3) because
of its moderate bulkiness as a catalyst.
(18) The catalytic efficiency of 1-Me-AZADO is shown in the
Supporting Information (Table S1). 7a effectively underwent the one-
pot oxidative cleavage with 1 mol % 1-Me-AZADO.
(19) In our previous study,8b sometiomes one-pot oxidation of
primary alcohols to carboxylic acids suddenly stopped in low ion
concentration buffter (<0.1 M ion concentration) accompanied by
acidification of the reaction mixture. It was confirmed that one-pot
oxidation proceeded in 1 M phosphate buffer with high reproducibility.
(20) 13a and 14a were prepared from the corresponding 90% ee 2,3-
epoxy alcohol. The enantiomeric excess of 13c obtained from either the
1-Me-AZADO- or TEMPO-catalyzed reaction was determined to be
90% ee. The enantiomeric excess of 14c obtained from the 1-Me-
AZADO (3) catalyzed reaction was also determined to be 90% ee,
although the TEMPO (1) catalyzed condition afforded 87% ee 14c.
(21) Optically pure 15c was obtained from chiral 15a under either the
1-Me-AZADO (3)- or TEMPO (1)-catalyzed conditions.
(22) Kamal, A.; Vangala, S. R. Tetrahedron 2011, 67, 1341–1347.
(23) Veisi, H. Synlett 2007, 2607–2608 and references cited therein.
(24) de Ferreira, M. L. Synlett 2011, 5, 730–731 and references cited
therein.
(25) Mohamed, M. A.; Yamada, K.; Tomioka, K Tetrahedron Lett.
2009, 50, 3436–3438.
a Conditions: 10 mol % nitroxyl radical, 10 mol % NaOCl, and
3 equiv of NaClO2 were added in MeCN and buffer (pH 6.8, 1.0 M)
at rt. b Isolated yield. c Carboxylic acids were isolated as methyl esters
after treatment with CH2N2. d The numbers in paretheses are the
yields of the corresponding 2-hydroxy acids. e 6 equiv of NaClO2 were
used.
5008
Org. Lett., Vol. 14, No. 19, 2012

With the above results taken into consideration, an
overall plausible reaction mechanism is shown in Scheme 4.
1,2-Diols are oxidized to 2-hydroxy acids which are the only
intermediates detectable by analytical TLC under the reac-
tion conditions. Immediately after 2-hydroxy acids are oxi-
dized to keto acids by the oxoammonium species, the CꢀC
bond is smoothly excised by NaClO2. The one-pot oxidative
cleavage is completed in four oxidative steps: oxidation of
primary alcohols to aldehydes, oxidation of aldehydes to
carboxylic acids, oxidation of hydroxyl acids to keto acids,
and oxidative cleavage of keto acids to one-carbon-unit-
shorter carboxylic acids.
Scheme 2. One-Pot Oxidative Cleavage of Triol and Tetraol
In summary, we have developed cat.1-Me-AZADO/cat.
NaOCl/NaClO2 for the useful one-pot oxidative cleavage
reaction of 1,2-diols to dehomologated carboxylic acids
under mild conditions. 1-Me-AZADO (3) more effectively
catalyzed the reaction than TEMPO (1). Sensitive groups
such as double bonds, triple bonds, acetonides, and N-Boc
groups were compatible with these reaction conditions.
This one-pot oxidative cleavage proceeded without the
epimerization of adjacent stereocenters. Furthermore, this
method was applicable to terminal triols and tetraols. This
reaction will be a useful transformation for 1,2-diols and
will also expand the use of nitroxyl radical catalysts.
Scheme 3. Reactivity of Oxoammnium Salts, NaOCl, and
NaClO2
Scheme 4. Plausible Overall Mechanism
Acknowledgment. This work was partly suppported by
a Grant-in-Aid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocatalysis”
from the Ministry of Education, Culture, Sports, Science
and Technology, Japan, by a Grant-in-Aid for Scientific
Research (B) (No. 21390001), and by a Grant-in-Aid for
Young Scientists (A) (No. 23689001) from the Japan Society
for the Promotion of Science (JSPS).
cleavage of 2-hydroxy acids is caused by NaClO2 via the
keto acid. Next, to investigate the difference in reaction
rate between the 1-Me-AZADO-catalyzed and TEMPO-
catalyzed conditions, the 2-hydroxy acid 10b was treated
with either 1-Me-AZADOþClꢀ or TEMPOþClꢀ. 10b was
completely oxidized to the corresponding keto acid 10e by
1-Me-AZADOþClꢀ within 1 h (eq 5). On the other hand,
56% 2-hydroxy acid 10b was recovered after treatment
with TEMPOþClꢀ for 1 h (eq 6). These results indicate
that the difference in reaction rate between 1-Me-AZADO
(3)-catalyzed and TEMPO (1)-catalyzed conditions re-
flects the rate of oxidation from the 2-hydroxy acid to the
keto acid.
Supporting Information Available. General experimen-
tal procedure, characterization data, and copy of NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5009