Aerobic cascade oxidation of substituted cyclopentane-1,2-diones using metalloporphyrin catalysts

Article abstract of DOI:10.1016/j.tet.2017.12.009

A method for the aerobic cascade oxidation of cyclopentane-1,2-diones using metal porphyrins as catalysts, yielding hydroxydiacids 2, ketoacid 3 and diketoacids 4 which are the intermediates of important biologically active compounds is reported. This method is operationally simple and can be employed under ambient conditions.

Full text of DOI:10.1016/j.tet.2017.12.009

Accepted Manuscript
Aerobic cascade oxidation of substituted cyclopentane-1,2-diones using
metalloporphyrin catalysts
Karolin Maljutenko, Victor Borovkov, Dzmitry Kananovich, Margus Lopp
PII:
S0040-4020(17)31260-7
10.1016/j.tet.2017.12.009
TET 29165
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 September 2017
Revised Date: 29 November 2017
Accepted Date: 5 December 2017
Please cite this article as: Maljutenko K, Borovkov V, Kananovich D, Lopp M, Aerobic cascade oxidation
of substituted cyclopentane-1,2-diones using metalloporphyrin catalysts, Tetrahedron (2018), doi:
10.1016/j.tet.2017.12.009.
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Aerobic cascade oxidation of substituted
cyclopentane-1,2-diones using
metalloporphyrin catalysts
Leave this area blank for abstract info.
Karolin Maljutenko, Victor Borovkov, Dzmitry Kananovich and Margus Lopp
Tallinn University of Technology, Department of Chemistry and Biotechnology, Akadeemia tee 15, Tallinn
12618, Estonia

1
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Tetrahedron
journal homepage: www.elsevier.com
Aerobic cascade oxidation of substituted cyclopentane-1,2-diones using
metalloporphyrin catalysts
Karolin Maljutenko, Victor Borovkov, Dzmitry Kananovich, Ivar Järving and Margus Lopp
Tallinn University of Technology, Department of Chemistry and Biotechnology, Akadeemia tee 15, Tallinn 12618, Estonia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A method for the aerobic cascade oxidation of cyclopentane-1,2-diones using metal porphyrins
as catalysts, yielding hydroxydiacids 2, ketoacid 3 and diketoacids 4 which are the intermediates
of important biologically active compounds is reported. This method is operationally simple and
can be employed under ambient conditions.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Catalysis
Metalloporphyrins
Aerobic oxidation
1. Introduction
or complex biologically active compounds, as a rule, a multi-step
synthesis is necessary. Therefore, the development of catalytic
conditions to assist reaction cascades is of importance.
Currently, the development of sustainable chemical processes
is one of the major challenges in chemical engineering and
applied science. Over the past decades, various transition metal
catalysts have been successfully utilized in combination with
different oxidizing reagents, such as peroxides, hydroperoxides,
peracids and others, to convert alkenes to epoxides or carbonyl
compounds.1,2,3 However, from both economic and ecological
points of view, the use of atmospheric oxygen as a terminal
oxidant is more attractive due to its high natural abundance
(nearly 20% of air is oxygen) and environmental sustainability.
The main limitation for wide application of atmospheric oxygen
in oxidation reactions is its relatively low reactivity in ambient
conditions and lack of selectivity. Therefore, the selection of a
catalyst is vital to carry out aerobic oxidations of different
substrates in an efficient manner. Among known catalysts for
performing aerobic oxidations of organic compounds,4,5 synthetic
metalloporphyrins, mimics of the oxygen carrier and oxidation
catalyst in living organisms, are remarkably efficient and
prospective.6,7 In contrast to natural enzymatic systems, the
selectivity of artificial catalysts is governed by the careful choice
of a transition metal ion and by modifications in the skeleton of
the porphyrin catalyst.6
In the present paper we report the first example of a cascade
air oxidation of reactive organic molecules. Substituted
cyclopentane-1,2-diones (1, Scheme 1) have been chosen as
substrates because of their multiple functional groups sensitive to
oxidation, allowing the formation of oxidation cascades which
result in producing hydroxydiacid 2. Also, the other oxidation
products21-23 of these structures have demonstrated interesting
biological activities (e.g. clionamides22 and dichotomain B.23).
Hydroxydiacids 2 have also been used as precursors for the
synthesis of nucleoside analogues24 and HIV-1 protease
inhibitors.25 On the other hand, ketoacid 3 is also a viable
substrate for the synthesis of γ-lactones26, whilst diketoacid 4 is a
valuable precursor for the synthesis of heterocycles, including
bioactive compounds.27 Moreover, hydroxydiacid 2 contains an
asymmetric center, which may open up additional opportunities
for the elaboration of an enantioselective oxidation approach
using chiral porphyrin catalysts.28,29
We found that enol derivatives 1 can be easily oxidized by air,
using a catalytic amount of metalloporphyrin catalyst (1-5
mol%), affording 2-substituted-2-hydroxydiacids 2, and other
ring-cleaved compounds, such as ketoacids 3 and diketoacids 4.
On the basis of our earlier studies,30,31 we can suggest a following
cascade of occurring aerobic oxidation reactions (Scheme 1): in
all cases the first reaction is the epoxidation of the enol double
bond (formation of intermediate 5). The second oxidation
reaction that may depend on the oxidizing reagent is a Baeyer-
Villiger reaction leading to hydroxydiacid 2 (which easily
Metalloporphyrin-catalyzed air oxidation has so far been used
sparsely in organic syntheses to oxidize various compounds and
functional groups. For example, it has been used in the oxidation
of alkanes,7-13 alkenes,7,11,14-16 aromatic hydrocarbons,7,17,18
steroids,19,20 and aldehydes.11 The listed examples represent only
oxidation
reactions,
without
considering
subsequent
transformations. However, in the preparation of pharmaceuticals

2
Tetrahedron
ACCEPTED MANUSCRIPT
convers to lactone acid 6, route A), or the combination of a
were formed, while diketoacid 4a was not observed (route A and
route B). However, with Co (cat3 and cat6) and with Fe
porphyrin complexes (cat2 and cat5) the reaction yielded mostly
diketoacid 4a and ketoacid 3a (route C and double oxidation
according to route B; Table 1, No. 3, 4, 7 and 8). The yield of
hydroxydiacid 2a was up to 55% in the best case with Mn
catalyst (Table 1, No. 6), for ketoacid 3a the highest yield was
67% (Table 1, No. 2) and for 4a 48% (Table 1, No. 8).
Bayer-Villiger reaction and diol cleavage resulting in ketoacid 3
(route B), or only a diol cleavage reaction yielding the diketoacid
4 product (route C). The reactions proceed under mild conditions,
at ambient temperature and normal air pressure, and the method
is operationally simple (see supplementary info).
A
O
O
O
O
OR1
OH
OH
R2
OR1
OR1
[O]
O
HOOC
COOR1
R2 OH
The substrate was completely consumed in the case of Mn
catalysts (cat1 and cat4; Table 1, No. 2 and 5). However, it the
case of Fe catalysts (cat2 and cat5) and with Co catalysts cat3
and cat6, a certain amount of substrate remained unreacted (from
20 to 49%; Table 1, No. 3, 4, 7 and 8). From Mn catalysts
Mn(TPP)Cl cat4 was more efficient, affording a considerably
higher yield of the target product hydroxyl diacid 2a than cat1;
(55% vs 33%; Table 1, No. 2 and 6). It was also found that cat4
was efficient even with 1 mol% of catalyst (Table 1, No. 6).
However, with preliminary results Mn catalysts had poor
O
COOR1
R2
R2
R2
B
2
6
O
1
5
OR1
OH
OH
R2
1-6 R1=H; R2= a Bn
b
c
d
e
f
Ph
Me
HOOC
R2
C
CH2CH2OBn
CH2CH2OH
CH2CH2NHBoc
CH2COOtBu
Cy
O
3
O
OR1
OH
g
h
i
O
R1OOC
OH
R2
Et
R2
1'a R1=TBS; R2 = Bn
1'j R1=Ac R2= H
O
4
Scheme 1. Reaction oxidative cascade of 1.
chemoselectivity: pathways
equimolecular mixture of compounds 2 and 3 (55% to 42% in the
best case). To follow the formation of 2a and 3a, the kinetics of
these compounds were monitored by H NMR. The obtained
curves clearly indicate that hydroxydiacid 2a and ketoacid 3a
A and B formed an almost
2. Results and discussion
For initial catalyst screening, conventional 3-benzylsubstituted
ketoenol (1a) was a selected as a substrate. The most frequently
used transition metal complexes (Mn, Fe, and Co) of
octaethylporphyrin (OEP) and tetraphenylporphyrin (TPP) were
used as catalysts (Table 1 and Figure 1).
1
form in parallel reactions (Figure 2).
R
R
R
R
R
N
N
N
N
N
N
N
R
R
M
R
M
N
R
R
R
R
OEP-type porphyrins:
TPP-type porphyrins:
cat1 Mn(OEP)Cl M=Mn-Cl
cat4 Mn(TPP)Cl M=Mn-Cl
R=Et
cat2 Fe(OEP)Cl M=Fe-Cl
R=Et
R=Ph
cat5 Fe(TPP)Cl M=Fe-Cl
R=Ph
cat3
Co(OEP)
M=Co
R=Et
cat6
Co(TPP)
M=Co
R=Ph
Figure 1. Used TPP- and OEP-type metalloporphyrin metal
complexes.
Figure 2 Reaction monitoring results.
Table 1. Oxidation of 3-benzyl-cyclopentane-1,2-dione 1
(enol form) with air using different porphyrin metal
complexes as a catalyst.
An effort was made to affect the relative rates of these
reactions by using different solvents and cat4 because of its
highest selectivity towards formation of diacid 2. The results are
presented in Table 2.
No
Catalyst
Loading
mol%
Unreacted
1a,%
Products,%
2a
10
33
-
3a
9
4a
Table 2. Solvent and temperature screening with 1a.
1
-
-
81
-
-
-
No Solvent Temp Time Additive 10 Unreacted 2a,% 3a,%
2
3
4
5
6
7
8
cat1
cat2
cat3
cat4
cat4
cat5
cat6
5
5
5
5
1
5
5
67
30
18
46
42
37
24
oC
[h]
mol%
1a%
30
49
-
40
33
-
1
2
3
4
CDCl3
rt
2
-
-
-
-
3
-
55
54
56
42
46
44
16
-
CH2Cl2 rt
Benzene rt
Toluene rt
2
54
55
-
24
18
-
3
-
9
75
31
20
32
48
(63*) (16*)
5
6
7
8
9
Toluene 5 °C
18
-
-
-
-
-
-
-
11
9
28
61
38
35
-
61
30
59
59
-
8
Toluene 15 °C 18
Toluene 30 °C 18
R
eaction conditions: CDCl3; rt; 5 mol% catalyst; 24 h. Product composition
determined by 1H NMR.
3
The oxidation of 1a without presence of catalyst proceeds, as
expected, considerably slower (81% of unreacted substrate),
without any selectivity (Table 1, No. 1). In reactions with the
catalysts, it was found that formation of different products 2a, 3a
or 4a was highly dependent on the central metal ion of the
porphyrin complex. In the case of the Mn complexes cat1 and
cat4 (Table 1, No. 2, 5 and 6) mostly diacid 2a and ketoacid 3a
Toluene 40 °C
2
6
THF
rt
rt
rt
24
24
2
100
100
69
10 MeOH
11 DMC
-
-
-
31

3
pyridine
squaramide
imidazole
BHT
12 Toluene rt
13 Toluene rt
14 Toluene rt
15 Toluene rt
16 Toluene rt
24
24
24
24
24
100
100
12
-
-
No. 4). These results show that the difference in the substituent-
ACCEPTED MANUSCRIPT
dependent electron density on the double bond of substrates and
steric hindrance that prevents the formation of catalytic
complexes are both important factors for the oxidation reaction
catalysed by porphyrins. Indeed, the substrates with electron
withdrawing groups and bulky substituents, such as phenyl 1b,
CH2CH2NHBoc 1f and CH2COOtBu 1g, make the double-bond
too electron-deficient for the reaction to occur or produce the
excessive bulkiness which inhibits the oxidation (Table 3, No.
3,7 and 8) whilst with electron-donating and less sterically
hindered groups, such as benzyl 1a, methyl 1c, CH2CH2OBn 1d,
CH2CH2OH 1e, Cy 1h and ethyl 1i, the oxidation proceeded
more readily (Table 3, No. 1, 4, 5, 6 and 10).
-
-
35
-
53
-
100
100
TEMPO**
-
-
Catalyst cat4; 1 mol%. The composition of the reaction mixtures was
determined by 1H NMR.
* Isolated yield.
** 1 equivalent
With the initial chlorinated solvents both transformations were
fast but not selective (Table 2, No. 1 and 2). Benzene did not give
any improvement in selectivity (Table 2, No. 3). From the
investigated solvents the best selectivity for 2 was obtained by
using toluene, with a 75/16 ratio of 2a to 3a (Table 2, No. 4). The
selectivity was very sensitive to temperature- both lowering and
increasing of temperature decreased the selectivity towards 2
(Table 2, No. 4-8).
Table 3. Oxidation of substituted substrates 1 with air oxygen
in the presence of porphyrin catalyst cat4.
No
Substrate Time
Conversion to 2a-d
Conversion to 3/4
The use of ether solvent (THF) and alcohol (MeOH)
completely hindered the reaction (Scheme 2, No. 9 and 10,
respectively), while in dimethylcarbonate (DMC) only the
formation of 31% of ketoacid 3 was observed (Scheme 2, No.
11).
1
2
3
4
1a
1’a
1b
1c
18 h
24 h
24 h
24 h
75% (63%*)
16% (16%*) 3a
-
-
-
-
11%
66% 3c
(and 6c 23% )
5
6
1d
1e
1f
48 h
48 h
48 h
48 h
48 h
48 h
24 h
51%*
43%* 3d
Previously it has been shown that external ligands are able to
accelerate porphyrin-catalyzed oxidation reactions.33,34 However,
in our case the addition of pyridine (10 mol%) or a basic and
widely used organocatalyst, squaramide35 (10 mol%), to the
porphyrin complex cat4 (1 mol%) had a negative impact on the
catalytic reaction and no transformation was observed during 24h
at rt (Table 2, No. 12 and 13). Another coordination agent,
methyl imidazole (10 mol%) redirected the reaction towards the
formation of ketoacid 3a (53%) while the conversion to 2a was
35% (Table 2, No. 14).
33%*
-
7
-
-
8
1g
1h
1i
-
-
9
-
40%*
-
86% 4h
16%* 3i
-
10
11
1’j
Catalyst cat4 (Mn(TPP)Cl); 1 mol%. The composition of the reaction
mixtures was determined by 1H NMR.
* Isolated yield
Interestingly, while with most reactive substrates the reaction
resulted in diacids 2 and ketoacids 3, substrate 1h with bulky Cy
group as substituent selectively produced only diketoacid 4h.
In general, there are several possible mechanisms for
metalloporphyrin-catalyzed oxidations, including
a radical
pathway.36 Since there are no additional agents, such as oxygen-
carriers or reductants in our particular cases, a radical mechanism
is the most plausible. In order to support this assumption, the
cat4 mediated reaction was performed in the presence of radical
scavengers. It was found that both BHT (10 mol%) and TEMPO
(1 eq) blocked the reaction completely (Table 2, No. 15 and 16).
This finding supports the radical character of the reaction
according to pathway A (see references37,38) as a new example of
radical Baeyer-Villiger oxidation. The reactivity of other
substrates towards oxidation also corroborates our assumption
(Table 3).
3. Conclusion
The possibility to use environmentally friendly metal
complexes of porphyrin for a cascade aerobic oxidation of
substituted cyclopentane-1,2-diones was demonstrated. The
reactions proceed with moderate to good chemoselectivity to
afford the corresponding oxidation products hydroxy diacids 2,
ketoacids
3 and diketoacids 4. The use of manganese
metalloporphyrins affords diacids 2 with up to 75% yield. This
method is operationally simple, environmentally benign, does not
require the use of harmful oxidants and reductants, and can be
used under ambient conditions. Further studies to increase the
selectivity, to understand the detail mechanism, and to widen the
applicability of this synthetic approach are in progress and will
be reported in due course.
To elucidate the scope of the reaction, the oxidation of
differently substituted enols of cyclopentane-1,2-diones 1 was
carried out by using cat4 as a porphyrin complex. The results are
presented in Table 3. First it was found that enols with protected
OH are unreactive: the free hydroxyl group is necessary for the
oxidation. Thus, substrates 1’a and 1’j did not give any products
after 24 h. (Table 3, No. 2, 11), which means that the hydroxyl
group deprotonation may be the initial step of the reaction. The
phenyl group as a substituent at the enol double bond inhibits the
reaction. The effect of this substituent on the electron density of
the double bond has been studied before.39 In the case of
porphyrin catalysts phenyl substituted substrate 1b is inert in the
oxidation (Table 3, No. 3). At the same time methyl-substituted
diketone 1c afforded tertiary oxidized products in 34% total yield
(2c in 11% yield, and its in situ lactonized derivative 6c in 23%
yield). However, the double oxidation occurred predominantly,
affording ketoacid 3c in 66% yield, after a 24 h reaction (Table 3,
4. Experimental section
1
Full assignment of H and 13C chemical shifts is based on the
1D and 2D FT NMR spectra measured on a 400 MHz or 500
MHz instrument. Residual solvent signals were used as internal
standards. High resolution mass spectra were recorded by using
an Q-TOF LC/MS spectrometer by using ESI ionization. IR
spectra were recorded on a Bruker Tensor 27 FT infrared
spectrophotometer. Mass spectra were measured on a Shimadzu
GCMS – QP 2010 spectrometer using EI (70 eV). Precoated
silica gel 60 F254 plates were used for TLC. Column
chromatography was performed on a preparative purification

4
Tetrahedron
6. Meunier B. Chem. Rev. 1992;92:1411.
system with silica gel Kieselgel 40-63 µm. Purchased chemicals
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7. G. Jiang, Q. Liu, C. Guo, Biomimetic Based Applications, Prof. M.
Cavrak, InTech, China, 2011; Vol. 2, pp 32‒58.
and solvents were used as received. Petroleum ether has a boiling
point of 40-60 °C. The reactions were performed under air
atmosphere. The porphyrins used for the reactions were
commercially obtained from PorphyChem.
8. Guo C-C, Liu X-Q, Li Y, Chu M-F, Zhang X-B. Journal of
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4.1 Synthesis of diacid 2.
11. Jiang G, Chen J, Thu H-Y, Huang J-S, Zhu N, Che C-M. Angew.
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2007;14:660.
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A solution of diketone 1a (18.8 mg, 0.1 mmol) and
Mn(TPP)Cl (0.7 mg, 0.001 mmol) in toluene (0.5 mL) is stirred
overnight (18 h) at room temperature. The reaction progress is
1
monitored by H NMR. After completion, the crude product is
purified with column chromatography (CH2Cl2:MeOH 100:1-
15:1) to afford diacid 2a (15 mg, 63% isolated yield) and
ketoacid 3a (3 mg, 16% isolated yield) as colourless oils.
15. Li XD, Zhu YC, Yang LJ. Chinese Chemical Letters 2012;23:375.
16. Kalajahi SSM, Hajimohammadi M, Safari N. Reac Kinet Mech Cat
2014;113:629.
6.2 Synthesis of diketoacid 4.
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18. Huang G, Yuan RX, Peng Y, Chen XF, Zhao SK, Wei SJ, Guo WX,
Chen X. RSC Adv. 2016;6:48571.
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Trojanowski JQ, Lee VM-Y, Brunden KR, Smith III AB. Bioorg.
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22. Hao X, Wu J, Tian H, Shi Y, Lin J, Tian W. Chin. J. Chem.
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R, Xia C-F, Zhao Q-S. Nat. Prod. Bioprospect. 2014;4:181.
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25. Joshi A, Veron J-B, Unge J, Rosenquist Å, Wallberg H, Samuelsson
B, Hallberg A, Larhed M. J. Med. Chem. 2013;56:8999.
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Legnani L, Gallo E. Chem. Eur. J. 2016; 22:13599.
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A solution of diketone 1 (18.8 mg, 0.1 mmol) and Fe(TPP)Cl
(0.7 mg, 0.001 mmol) in THF (0.5 mL) is stirred overnight (18 h)
1
at room temperature. The reaction progress is monitored by H
NMR. After completion, the crude product is purified with
column chromatography (CH2Cl2:MeOH 100:1-15:1) to afford
ketoacid 3a (12 mg, 60% yield) and diketoacid 4a (3 mg, 20%
yield) as unisolable mixture.
2,5-Dioxo-6-phenylhexanoic acid 4a: 1H NMR (400 MHz,
Chloroform-d) δ 7.39 – 7.17 (m, Bn, 5H), 3.75 (s, CH2-Bn, 2H),
3.14 – 3.06 (m, H-3, 2H), 2.95 – 2.87 (m, H-4, 2H). 13C NMR
(101 MHz, CDCl3) δ 206.0 (C-5), 194.4 (C-2), 159.3 (C-1), 133.6
(s-Bn), 129.4 (o or m-Bn), 128.9 (o or m-Bn), 127.3 (p-Bn), 49.6
(C-6), 36.0 (C-4), 31.2 (C-3). HRMS (ESI) calculated for
C12H12O4, [M - H]-: 219.0663, found 219.0675. MS (m/z): 220,
202, 175, 129, 101, 91, 73, 65, 55. The compound was obtained
as a yellow oil.
4.2 Synthesis of 3-cyclohexyl-2-hydroxycyclopent-2-en-1-one 1h.
A 2N HCl solution (0.43 ml) is added to a solution of 2-((tert-
butyldimethylsilyl)oxy)-3-cyclohexylcyclopent-2-en-1-one (52
mg, 0.18 mmol) in THF (1 mL). After 5 days, 2 mL of water is
added to the reaction mixture and extracted 3x with DCM. The
combined organic phase are washed with brine and dried through
a phase separator. After column chromatography (Petroleum
ether:EtOAc 10:1), compound 1h is obtained as a yellow oil in
70% yield (25 mg, 0.14 mmol). 1H NMR (400 MHz,
Chloroform-d) δ 6.02 – 5.83 (m, 1H), 2.67 (ddd, J = 11.5, 8.0,
3.5 Hz, 1H), 2.42 (d, J = 5.0 Hz, 2H), 2.40 – 2.36 (m, 2H), 1.84 –
1.67 (m, 5H), 1.46 – 1.28 (m, 5H), 1.28 – 1.15 (m, 1H). 13C NMR
(101 MHz, CDCl3) δ 203.6, 152.3, 147.6, 147.6, 38.1, 31.8, 30.2,
26.2, 26.1, 22.8. HRMS (ESI) calculated for C11H16O2, [M + H]+:
181.1223, found 181.1215.
40. Paju A, Laos M, Jõgi A, Päri M, Jäälaid R, Pehk T, Kanger T, Lopp
M. Tetrahedron Lett. 2006;47:4491.
Acknowledgements
This work has been supported by the Estonian Ministry of
Education and Research grants IUT 19-32 and IUT23-7 and
Centre of Excellence in Molecular Cell Engineering (No. 2014-
2020.4.01.15-0013). V.B. and D.K. acknowledge funding from
the European Union’s Seventh Framework Programme for
research, technological development and demonstration under
Grant Agreement No. 621364 (TUTIC-Green).
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