Organocatalytic Synthesis of Lactones by the Oxidation of Alkenoic Acids

Article abstract of DOI:10.1002/cctc.201700837

Along the lines of modern sustainable oxidation, a green and mild organocatalytic synthetic procedure for the synthesis of hydroxylactones from alkenoic acids is described. The reaction includes the activation of H₂O₂ by an organocat

Full text of DOI:10.1002/cctc.201700837

Accepted Article
Title: Organocatalytic Synthesis of Lactones via an Oxidation of
Alkenoic-acids
Authors: Ierasia Triandafillidi, Marianna Raftopoulou, Anatoli Savvidou,
and Christoforos G. Kokotos
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Organocatalytic Synthesis of Lactones via an Oxidation of
Alkenoic-acids
Ierasia Triandafillidi,[a] Marianna Raftopoulou,[a] Anatoli Savvidou[a] and Christoforos G. Kokotos*[a]
Abstract: Along the lines of modern sustainable oxidation, a green
and mild organocatalytic synthetic procedure for the synthesis of
hydroxy-lactones from alkenoic-acids is described. The reaction
includes activation of H2O2 by an organocatalyst (2,2,2-
trifluoromethylacetophenone), followed by the oxidation of an olefinic
group to the corresponding epoxide and intramolecular lactonization
affording a variety of substituted γ- or δ-lactones with multiple
substitution patterns in good to high yields. The product can be
obtained with enough purity after simple extractions, when
conversion is quantitative. Attempts to render the process
asymmetric met with limited success.
Introduction
Lactones are important structural motifs, which are frequently
encountered in natural products, pharmaceuticals, including
antibiotic and antitumor agents, agrochemicals, flavor
components, material and polymer production (Figure 1).[1-3]
Scheme 1. Various retrosynthetic approaches for the synthesis of lactones
found in literature.
Furthermore, lactones are versatile building blocks for the
synthesis of biologically important compounds with antimicrobial
activity, such as (+)-tanikolide and (-)-malyngolide.[4] γ-Lactones
Since lactones constitute a repeatedly occurring scaffold in
are useful intermediates for the synthesis of compounds
nature, a plethora of synthetic methods to access lactones has
presenting inhibitory activity against HIV reverse transcriptase.[5]
been reported utilizing as starting materials a variety of
functional groups, such as carboxylic acids,[7] terminal alkenes[8]
or alkynes,[9] diols[10] or chains that contain some functional
groups (Scheme 1).[11] Despite the utility of all these pathways,
the intramolecular lactonization of alkenoic acids is among the
most common approaches employed and it still constitutes a
challenge for the scientific community. Olefins are among the
most diverse building blocks in organic synthesis and their utility
derives from the wide variety of functionalization reactions that
can participate in. There have been published numerous reports,
taking advantage of metal-catalyzed processes using zinc,[12]
palladium,[13] silver,[14] copper,[15] gold,[16] vanadium[17] or cobalt[18]
(Scheme 2, A). Despite the widespread popularity of these
reactions, the toxicity of metals and high levels of inorganic
waste make their application harmful for the environment and to
Additionally, DAG-lactones are very important compounds as
protein kinase C (PKC) ligands and antitumor agents. [6]
Figure 1. Useful molecules bearing the lactone motif.
be
adopted
by
chemical
industry.
Organocatalytic
halolactonizations have attracted much attention from the
viewpoint of “green” chemistry. Therefore,
a variety of
[a]
I. Triandafillidi, M. Raftopoulou, A. Savvidou, Prof. C. G. Kokotos
Laboratory of Organic Chemistry,
Department of Chemistry,
National and Kapodistrian University of Athens,
Panepistimiopolis 15771, Athens, Greece
E-mail: ckokotos@chem.uoa.gr
organocatalysts have been developed, such as alkyl-[19] or
amino-thiocarbamate,[20] catalysts based on iodine,[7,21]
phosphite,[22]
substituted
imidazoles,[23]
squaramides,[24]
peptides[25] or other (Scheme 2, Β).[26] However, most of them
require cryogenic conditions that limit applications in industry.
Also, in most cases, the developed methodologies can harness
only γ- or δ-lactones with specific substitution pattern. Although
Organocatalysis has presented elegant contributions for the
epoxidation of alkenes,[27] it is quite surprising, that there is
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Organocatalytic synthesis of lactone 2a from alkenoic acid 1a.a
Entry
Catalyst
(mol%)
MeCN/H2O2
(equiv.)
Solvent
Yieldb
(%)
1
2
3
4
5
6
7
8
9
10
0
5
t-BuOH
50
traces
56
5
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
t-BuOH
EtOAc
CHCl3
10
10
10
5
8
12
16
16
12
16
16
16
16
16
16
62
75
Scheme 2. Synthetic methods for the synthesis of lactones from alkenoic
acids.
65
20
20
20
20
20
20
20
73
limited knowledge on the use of hydrogen peroxide as the
oxidant for such
a
tandem epoxidation-lactonization.
85
Very recently, we have reported a cheap, sustainable and
environmentally friendly protocol for various oxidations
employing H2O2 as the oxidant. This procedure has the
advantage that its only by-product is water, while 2,2,2-
trifluoroacetophenone was employed as the organocatalyst to
activate hydrogen peroxide, which by itself is quite poor to
perform oxidations.[28] We had previously employed this protocol
in the synthesis of tetrahydrofurans,[28e] isoxazolines[28g] and
pyrrolidines.[28h] We envisaged we could extend this
organocatalytic oxidative protocol via the introduction of an one-
pot procedure for the isolation of substituted lactones starting
from alkenoic acids. Once the intermediate epoxide is formed,
an intramolecular ring opening reaction would afford the desired
cyclized compound bearing a hydroxy moiety (Scheme 2, C).
75
10
11
12
13
52
MeCN
76
MeOH
CH2Cl2
64
45
[a]
All reactions were carried out with 1a (0.30 mmol), 2,2,2-trifluoro-1-
phenylethanone (x mol%), solvent (0.3 mL), aqueous buffer solution (0.3 mL,
0.6M K2CO3 – 4 x 10-4 M EDTA disodium salt), acetonitrile and 30%
aqueous H2O2. The reaction mixture was left stirring for 18 hours. [b] Isolated
yield.
Results and Discussion
acetamide byproduct, which is also produced, can be removed
by simple aqueous extractions. A variety of solvents were then
tested affording lactone 2a in lower yields (Table 1, entries 9-
13).
Initially, we began our investigation with the use of alkenoic acid
1a, employing our optimized reaction conditions for the
epoxidation of terminal alkenes. Utilizing 10 mol% of 2,2,2,-
trifluoroacetophenone as the organocatalyst and 5 equiv. of
MeCN and H2O2, lactone 2a could be obtained, albeit in
moderate yield (Table 1, entry 1). It has to be highlighted that if
the catalyst is omitted, no reaction is taking place and lactone 2a
is not being formed (Table 1, entry 2). Increasing the amount of
MeCN and hydrogen peroxide had as a consequence an
upsurge in the yield of the product (Table 1, entries 1 and 2-5).
Next the catalyst loading was studied, leading to the
identification of the optimum reaction conditions (Table 1, entries
6-8). It has to be noted that full conversion was observed and no
chromatographic purification is required in this last case, since
the product can be isolated in excellent yield (85%) in high purity
(>95%) after simple extractions. Alternatively, filtration through a
short silica plug can lead to the isolation of pure lactone 2a. The
Once the optimum reaction conditions were found, the
substrate scope of the reaction was sought (Scheme 3 and 4).
Initially, the substitution pattern on the aromatic group was
studied, leading to γ-lactones bearing a tetrasubstituted carbon
atom. In all cases, the desired lactones 2a-f were obtained in
high yield. Thus, the substitution pattern (ortho- or para-
subsitution, as well as electron donating or electron
withdrawing groups) does not affect the outcome of the
reaction. Addition of alkyl moieties on the alkyl backbone
between the alkene and the carboxylic acid does not alter the
efficiency of the reaction, since products 2g and 2h were
obtained in high yield. Thus, polysubstituted γ-lactones can be
synthesized efficiently. Replacing the aromatic group with an
aliphatic chain poses no problem for our methodology and
lactone 2i was isolated in high yield. In an attempt to further
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in slightly lower yields. In all the above cases, Baldwin’s
empirical rules for ring closure are followed, since products 2a-
2k are synthesized via a 5-exo-tet ring closure, which is favored,
while a forbidden 6-endo-tet would have led to the six-
membered ring lactone. Similarly, a favorable 6-exo-tet ring
cyclization is followed for products 2l and 2k.
When the alkene is not 1,1-disubstituted but 1,2-disubstituted,
like in the cases of Scheme 4, γ-lactones were isolated in
excellent yield (2n-2q). Both cis and trans alkenes led to the
corresponding cyclized product. Turning our attention to trans-
disubstituted alkenoic acids, γ-lactones 2s-v were obtained in
good yield and in most cases with high diastereocontrol and
almost full control on the cyclization towards the 5-membered
ring. For compounds 2o-v, the cyclization follows Baldwin’s rules
(5-exo vs 6-endo) leading to γ-lactones instead of δ-lactones.
In an attempt to make this hydrogen peroxide-mediated process
more attractive, we envisaged the use of Shi’s catalyst to render
the process asymmetric.[29] Unfortunately, the corresponding
lactones were isolated in low enantioselectivity, which is in
agreement with our latest finding that probably a dioxirane is not
involved
in
our
catalytic
system.[28f]
To summarize the events that take place, a proposed reaction
mechanism is shown in Scheme 5. Initially, the catalyst (2,2,2-
trifluoroacetophenone) is converted to diol I in the presence of
the aqueous buffer.[28f] When the appropriate pH is employed,
MeCN reacts with H2O2 to afford II, which in conjunction with
H2O2 oxidizes I to perhydrate IV. Another molecule of II reacts
with IV affording the compound V. This could be or can be
transformed into the active oxidant of the protocol, which
epoxides alkenoic-acid 1a. Then, and since the pH is adjusted to
11, the deprotonated carboxylate ring opens the epoxide, and a
simultaneous cyclization occurs leading to lactone 2a.
Scheme 3. Synthetic scope for the synthesis of lactones.
expand the substrate scope, polysubstituted alkenoic acids were
employed. In all cases, the desired polysubstituted lactones 2j
and 2k were obtained in high yields. Moving from γ-lactones to
δ-lactones, which is usually not a trivial task, seems possible
employing our procedure. Six-membered ring lactones 2l and
2m were obtained from the corresponding alkenoic acids, albeit
Scheme 5. Proposed reaction mechanism.
In order to provide a more industrial-friendly process, alkene 1n
was oxidized in a gram scale (Scheme 6). After the reaction was
completed, lactone 2n was isolated in high yield after simple
extractions, bypassing the need for column chromatography.
Scheme 4. Substrate scope for the synthesis of lactones.
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b) R. Bandichhor, B. Nosse, O. Reiser, Top. Curr. Chem. 2005, 243, 43;
c) R. R. A. Kitson, A. Millemaggi, R. J. K. Taylor, Angew. Chem. Int. Ed.
2009, 48, 9426.
[2]
[3]
a) C. W. Jefford, D. Jaggi, A. W. Sledeski, J. Boukouvalas in Studies in
Natural Products Chemistry, Elsevier, Amsterdam, 1989; Vol. 3, part B,
157−171; b) G. Procter in Comprehensive Organic Synthesis, (Eds.: B.
M. Trost, I. Fleming, S. V. Ley), Pergamon, Oxford, 1991; 305−327; c) J.
Libiszowski, A. Kowalski, R. Szymanski, A. Duda, J.-M. Raquez, P.
Degee, P. Dubois, Macromolecules 2004, 37, 52; d) C. K. Williams,
Chem. Soc. Rev. 2007, 36, 1573.
a) I. J. Collins, Chem. Soc., Perkin Trans. 1998, 1, 1869; b) D. M. X.
Donnelly, M. J. Meegan in Comprehensive Heterocyclic Chemistry, (Ed.:
A. R. Katritzky), Pergamon, New York, 1984; Vol. 4, 657; c) T. K. Devon,
A. I. Scott in Handbook of Naturally Occurring Compounds; Academic
Press: New York, 1975; Vol. 1, 249.
Scheme 6. Gram scale reaction.
Conclusions
In conclusion, an effective organocatalytic synthetic protocol for
the organocatalytic synthesis of hydroxy-lactones is described.
Utilizing mild reaction conditions, a metal-free catalyst is
employed to activate hydrogen peroxide leading to a green and
highly sustainable process. When conversion of the starting
material is full, the product can be isolated with enough purity
(95%) by simple extractions. A variety of substitution patterns is
well tolerated leading to either γ-lactones to δ-lactones in good
to excellent yields. Finally, when further substitution is employed,
polysubstituted lactones are obtained. An asymmetric variant
was attempted leading to low enantioselectivities, strengthening
our hypothesis for the reaction mechanism not involving a
dioxirane intermediate. A gram scale reaction enhanced the
industrial character of this method.
[4]
[5]
[6]
I. P. Singh, K. E. Milligan, W. H. Gerwick, J. Nat. Prod. 1999, 62, 1333.
M. A. Siddiqui, V. E. Marquez, Bioorg. Med. Chem. 2007, 15, 283.
J.-H. Kang, Y. Kim, S.-H. Won, S.-K. Park, C. W. Lee, H.-M. Kim, N. E.
Lewin, N. A. Perry, L. V. Pearce, D. J. Lundberg, R. J. Surawski, P. M.
Blumberg, J. Lee, Bioorg. Med. Chem. Lett. 2010, 20, 1008.
S. Eissler, M. Nahrwold, B. Neumann, H.-G. Stammler, N. Sewald, Org.
Lett. 2007, 9, 312976.
a) L. Huang, H. Jiang, C. Qi, X. Liu, J. Am. Chem. Soc. 2010, 132,
17652; b) G. Zhang, L. Cui, Y. Wang, L. Zhang, J. Am. Chem. Soc.
2010, 132, 1474.
[7]
[8]
[9]
C. Shu, M.-Q. Liu, Y.-Z. Sun, L.-W. Ye, Org. Lett. 2012, 14, 4958.
[10] X. Xie, S. S. Stahl, J. Am. Chem. Soc. 2015, 137, 3767.
[11] a) I. Tellitu, S. Serna, M. T. Herrero, I. Moreno, E. Domınguez, R.
SanMartin, J. Org. Chem. 2007, 72, 1526; b) S. K. Murphy, V. M. Dong,
J. Am. Chem. Soc. 2013, 135, 5553; c) J. Wilent, Kimberly, S. Petersen,
J. Org. Chem. 2014, 79, 2303.
[12] L. Filippova, Y. Stenstrom, T. V. Hansen, Tetrahedron Lett. 2014, 55,
419.
[13]
R. M. Trend, Y. K. Ramtohul, E. M. Ferreira, B. M. Stoltz, Angew.
Chem. Int. Ed. 2003, 42, 2892.
Experimental Section
[14] C.-G. Yang, N. W. Reich, Z. Shi, C. He, Org. Lett. 2005, 7, 4553.
[15] C. Sun, Y. Fang, S. Li, Y. Zhang, Q. Zhao, S. Zhu, C. Li, Org. Lett. 2009,
11, 4084.
[16] E. Genin, P. Y. Toullec, S. Antoniotti, C. Brancour, J.-P. Genet, V.
Michelet, J. Am. Chem. Soc. 2006, 128, 3112.
[17] H. Shigehisa, M. Hayashi, H. Ohkawa, T. Suzuki, H. Okayasu, M.
Mukai, A. Yamazaki, R. Kawai, H. Kikuchi, Y. Satoh, A. Fukuyama, K.
Hiroya, J. Am. Chem. Soc. 2016, 138, 10597.
[18] McK. L. Campbell, S. A. Rackley, L. N. Giambalvo, D. C. Whitehead,
Tetrahedron 2015, 71, 3895.
[19] X. Jiang, C. K. Tan, L. Zhou, Y.-Y. Yeung, Angew. Chem. Int. Ed. 2012,
51, 7771.
[20] L. Zhou, C. K. Tan, X. Jiang, F. Chen, Y.-Y. Yeung, J. Am. Chem. Soc.
2016, 138, 10597.
Alkenoic-acid (0.30 mmol) was placed in a round bottom flask and
dissolved in tert-butanol (0.3 mL). 2,2,2-Trifluoro-1-phenylethanone (10.4
mg, 0.06 mmol), aqueous buffer solution (0.3 mL, 0.6M K2CO3 – 4 x 10-
4M EDTA disodium salt), acetonitrile (0.24 mL, 4.80 mmol) and 30%
aqueous H2O2 (0.48 mL, 4.80 mmol) were added consecutively. The
reaction mixture was left stirring for 18 hours at room temperature. The
crude product was quenched with HCl (1N) (5 mL) and extracted with
ethyl acetate (3 x 10 mL). The combined organic layers were dried over
Na2SO4, filtered and concentrated in vacuo. The mixture was purified
using flash column chromatography (10%-40% EtOAc in Pet. Ether) to
afford the desired product.
[21] a) A. C. Boye, D. Meyer, C. K. Ingison, A. N. French, T. Wirth, Org. Lett.
2003, 5, 2157; b) D. C. Braddock, G. Cansell, S. A. Hermitage, Chem.
Commun. 2006, 23, 2483; c) H. Fujioka, S. Matsuda, M. Horai, E. Fujii,
M. Morishita, N. Nishiguchi, K. Hata, Y. Kita, Chem. Eur. J. 2007, 13,
5238; d) T. Dohi, N. Takenaga, A. Goto, A. Maruyama, Y. Kita, Org. Lett.
2007, 9, 3129.
[22] H. Egami, J. Asada, K. Sato, D. Hashizume, Y. Kawato, Y. Hamashima,
J. Am. Chem. Soc. 2015, 137, 10132.
[23] D. C. Whitehead, R. Yousefi, A. Jaganathan, B. Borhan, J. Am. Chem.
Soc. 2010, 132, 3298.
Acknowledgements
The authors gratefully acknowledge the Operational Program
“Education and Lifelong Learning” for financial support through
the
NSRF
program
“ΕΝΙΣΧΥΣΗ
ΜΕΤΑΔΙΔΑΚΤΟΡΩΝ
ΕΡΕΥΝΗΤΩΝ” (PE 2431)” co-financed by ESF and the Greek
State. The authors would like also to thank Dr. Maroula Kokotou
for her assistance in acquiring HRMS data.
[24] J. E. Tungen, J. M. J. Nolsoe, T. V. Hansen, Org. Lett. 2012, 14, 5884.
[25]
D. C. Whitehead, M. Fhaner, B. Borhan, Tetrahedron Lett. 2011, 52,
2288.
[26] a) M. C. Dobish, J. N. Johnston, J. Am. Chem. Soc. 2012, 134, 6068; b)
D. H. Paull, C. Fang, J. R. Donald, A. D. Pansick, S. F. Martin, J. Am.
Chem. Soc. 2012, 134, 11128; c) T. Chen, J. Y. Foo, Y.-Y. Yeung, ACS
Catal. 2015, 5, 4751.
Keywords: organocatalysis • oxidation • alkenoic-acid • lactones
• green chemistry
[27] For selected examples, see: a) W. Adam, R. Curci, J. O. Edwards, Acc.
Chem. Res. 1989, 22, 205; b) S. E. Denmark, D. C. Forbes, D. S. Hays,
J. S. DePue, R. G. Wilde, J. Org. Chem. 1995, 60, 1391; c) D. Yang,
[1]
a) B. Mao, K. Geurts, M. Fananas-Mastral, A. W. van Zijl, S. P. Fletcher,
A. J. Minnaard, B. L. Feringa, Org. Lett. 2011, 13, 948; For reviews, see:
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FULL PAPER
Y.-C. Yip, M.-W. Tang, M.-K. Wong, J.-H. Zheng, K.-K. Cheng, J. Am.
[28]
a) D. Limnios, C. G. Kokotos, ACS Catal. 2013, 3, 2239; b) D. Limnios,
C. G. Kokotos, Chem. Eur. J. 2014, 20, 559; c) D. Limnios, C. G.
Kokotos, J. Org. Chem. 2014, 79, 4270; d) A. Theodorou, D. Limnios, C.
G. Kokotos, Chem. Eur. J. 2015, 21, 5238; e) A. Theodorou, C. G.
Kokotos, Green Chem. 2017, 79, 670; f) E. Voutyritsa, A. Theodorou, M.
G. Kokotou, C. G. Kokotos, Green Chem. 2017, 79, 1291; g) I.
Triandafillidi, C. G. Kokotos, Org. Lett. 2017, 19, 106; h) A. Theodorou,
C. G. Kokotos, Adv. Synth. Catal. 2017, 359, 1577.
Chem. Soc.1996, 118, 491; d) Y. Tu, Z-X. Wang, Y. Shi, J. Am. Chem.
Soc. 1996, 118, 9806; e) Z-X. Wang, Y. Tu, M. Frohn, J.-R. Zhang, Y.
Shi, J. Am. Chem. Soc. 1997, 119, 11224; f) D. Yang, M.-K. Wong, Y.-
C. Yip, X.-C. Wang, M.-W. Tang, J.-H. Zheng, K.-K. Cheng, J. Am.
Chem. Soc. 1998, 120, 5943; g) L. Shu, Y. Shi, J. Org. Chem. 2000, 65,
8807; h) S. E. Denmark, H. Matsuhashi, J. Org. Chem. 2002, 67, 3479;
i) C. P. Burke, Y. Shi, Org. Lett. 2009, 11, 5150; j) D. K. Romney, S. J.
Miller, Org. Lett. 2012, 14, 1138.
[29] For more details, see Supporting Information.
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Entry for the Table of Contents
FULL PAPER
Organo-Lactones. A green
organocatalytic method for the
activation of hydrogen peroxide and
the oxidation of alkenoic acids to
lactones is described.
Ierasia Triandafillidi, Marianna
Raftopoulou, Anatoli Savvidou and
Christoforos G. Kokotos*
Page No. – Page No.
Organocatalytic Synthesis of
Lactones via an Oxidation of
Alkenoic-acids
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