REVIEW

DOI: 10.1002/adsc.201300882

Oxidative Alkene Cleavage by Chemical and Enzymatic Methods

Aashrita Rajagopalan,a Miguel Lara,a and Wolfgang Kroutila,*
a
Department of Chemistry, Organic and Bioorganic Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
Fax: (+ 43)-316-380-9840; phone: (+ 43)-316-380-5350; e-mail: [email protected]

Received: September 30, 2013; Published online: October 31, 2013

Abstract: The cleavage of alkenes to the correspond- 1 Introduction

ing carbonyl products is a widely employed method 2 Alkene Cleavage by Chemical Methods
in organic synthesis, especially to introduce oxygen 2.1 Ozonolysis
functionalities into molecules, remove protecting 2.2 Metal-Based Methods
groups and tailor large molecules. Chemical methods 2.3 Electrocatalytic Anodic Cleavage
available for alkene cleavage include, for instance, 2.4 Singlet Oxygen
ozonolysis, several metal-based variants (KMnO4, 2.5 Hypervalent Iodine
OsO4, RuO4, etc.), electrochemical alternatives, sin- 2.6 m-Chloroperbenzoic Acid
glet oxygen, hypervalent iodine and organic mole- 2.7 N-Hydroxyphthalimide and Molecular Oxygen
cules in combination with oxygen. Furthermore, sev- 3 Alkene Cleavage by Enzymes
eral enzymatic methods for alkene cleavage have 3.1 Heme-Dependent Alkene Cleaving Enzymes
been described to establish safe, mild and selective 3.2 Non-Heme Iron-Dependent Alkene Cleaving
oxidation methods. Various heme and non-heme Enzymes
iron-dependent enzymes catalyse the alkene cleavage 3.3 Non-Iron Metal-Dependent Alkene Cleaving
at ambient temperature and atmospheric pressure in Enzymes
an aqueous buffer, showing good chemo- and regio- 4 Conclusion
selectivities in selected cases. Quite recently some
Cu-, Mn- and Ni-dependent enzymes have been
identified for this reaction. This review gives an over-
view of the different chemical and enzymatic meth- Keywords: alkenes; biocatalysis; chemical methods;
ods available for the cleavage of alkenes. cleavage reactions; oxidation

1 Introduction sweet odours of spearmint leaves, caraway seeds and

the camphor tree. There are several methods and re-
Alkenes can undergo a wide range of reactions in- actions known for alkene cleavage. These include
cluding electrophilic addition of acids or carbocations, chemical methods like the classical ozonolysis and
rearrangements of carbocations, hydrogenation and metal-based variants. Additionally, several enzymes
oxidation; the oxidation of alkenes permits the incor- have been reported in the literature for alkene cleav-
poration of new functionalities into the molecule such age. The chemical as well as the enzymatic methods
as alcohols, acids, aldehydes or ketones and provides are reviewed below.
opportunities for further synthetic elaboration.[1]
Alkene cleavage is an important synthetic tool (i) to
remove protecting groups; (ii) to tailor large mole- 2 Alkene Cleavage by Chemical Methods
cules or (iii) to intoduce carbonylic functional
groups.[2] Moreover, the synthesis of a large number 2.1 Ozonolysis
of bioactive compounds involves alkene cleavage as
the key step to yield the corresponding carbonyl com- Among the arsenal of oxidation methods available to
pounds. Many compounds found in nature possess al- date, ozonolysis of C=C double bonds giving access to
dehyde or ketone functional groups. Aldehydes have aldehydes or ketones is certainly the most widely ap-
mostly pungent odours, whereas ketones tend to smell plied methodology (Scheme 1).[3,4]
sweet. Vanillin and cinnamaldehyde are examples of Ozone adds as an electrophile to an alkene to give
naturally occurring aldehydes. The ketones carvone the unstable cyclic molozonide which immediately re-
and camphor are responsible for the characteristic arranges to the more stable ozonide. Ozonides are ex-

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 REVIEW Aashrita Rajagopalan et al.

In an interesting alternative, pyridine (2–3 equiva-

Aashrita Rajagopalan did her lents) was employed instead of using the reducing
bachelor degree in biotech- agent, leading overall to the desired aldehydes/ke-
nology at SASTRA University, tones as well as molecular oxygen as formal side
India and continued with MSc product.[7] The reaction is hypothesised to involve nu-
work in biotechnology at Ham- cleophile-promoted fragmentation of carbonyl oxides
burg University of Technology via formation of zwitterionic peroxy acetals.
in Germany. After her master If the ozonide is cleaved in the presence of an oxi-
thesis at TU Delft, the Nether- dising agent such as hydrogen peroxide, the products
lands, she started her PhD at will be ketones and/or carboxylic acids (pathway b in
the University of Graz in the Scheme 1). Carboxylic acids are formed instead of al-
Marie Curie FP7 initial training dehydes since the initially formed aldehyde is imme-
network BIOTRAINS under the supervision of diately oxidised to the corresponding carboxylic acid
Wolfgang Kroutil. During her studies she did several by hydrogen peroxide.
industrial internships in companies like BIOCON
India Ltd., Dr. Reddys Biologics, Richter-Helm
Biotec etc to name a few. 2.2 Metal-Based Methods
Miguel Lara earned his master 2.2.1 KMnO4
degree at the University of
Granada (Spain). After several Alkenes are oxidised to 1,2-diols by a basic solution
years in the pharmaceutical in- of potassium permanganate at around 25 8C or
dustry, he moved to Austria. He below.[8] If the basic solution of potassium permanga-
did his doctoral studies at the nate is heated or if the solution is acidic, the reaction
University of Graz under the will not stop at the diol stage; instead, the alkene will
supervision of Wolfgang Krou- be cleaved, and the reaction products will be ketones
til. He then worked as a post- and carboxylic acids (Scheme 2A) whereby terminal
doctoral researcher in the group alkenes give CO2 as product. The reaction proceeds
of Nadia Mçsch-Zanetti, University of Graz, in inor- by forming a cyclic manganate ester which is not
ganic chemistry before he went to the competence stable under the conditions employed and undergoes
centre kwood. Currently he is working as project a cyclic fragmentation process resulting in breaking
manager in the company Lenzing AG in Upper Aus- the C C bond between the two oxygens.[9]
tria. In the Lemieux–von Rudolff oxidation double
bonds are readily oxidised in an aqueous solution of
Wolfgang Kroutil is full profes- periodate containing catalytic amounts of permanga-
sor at the University of Graz, nate (Scheme 2B).[10] The permanganate reacts with
Austria. He did his masters the olefin following a [3+2] cycloaddition to generate
studies at the TU Graz and his a cyclic intermediate which is hydrolysed to afford
doctoral studies at the Universi- the corresponding cis-diol and Mn(V) oxide. The peri-
ty of Exeter (S. M. Roberts) odate then re-oxidises the consumed permanganate
and TU Graz (Kurt Faber). and finally cleaves the formed diol to the correspond-
After a Postdoc in industry ing aldehyde and/or ketone. MnO4 oxidises intermedi-
(Syngenta) he worked as ate aldehydes to the corresponding carboxylic acids.
a R&D manager (Krems
Chemie). In 2000 he became an
assistant professor at the University of Graz, in 2003 2.2.2 Ruthenium-Based Cleavage
associate and in 2013 full professor. His research in-
terest is to cut chemical synthesis short or turn it In an alternative method catalytic amounts of RuO2
more efficient by using biocatalysts. Bio-oxidation or RuCl3 were employed together with stoichiometric
and reduction as well as C C bond formations are amounts of an oxidant like oxone or NaIO4. RuO4,
some of his research topics. which is generated in situ, acts in the same fashion as
MnO4 in the previous method (Section 2.2.1) per-
plosive[5,6] and hence are seldom isolated, but they are forming cis-hydroxylation of the double bond.[8b,11]
easily cleaved to carbonyl products, for example, in Since RuO4 oxidises an eventually formed aldehyde
the presence of a reducing agent such as zinc or di- to the corresponding carboxylic acid, several new pro-
methyl sulphide (pathway a in Scheme 1) leading to tocols have been developed for the synthesis of alde-
ketones and/or aldehydes. hydes avoiding their over-oxidation to acids.[12] For in-

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Oxidative Alkene Cleavage by Chemical and Enzymatic Methods

Scheme 1. Ozonolysis of alkenes followed by work-up with reducing or oxidising agents.

Scheme 2. Alkene cleavage by KMnO4. A) Cleavage em- Scheme 3. Selected examples of ruthenium-based protocols
ploying acidic conditions; B) Lemieux–von Rudolff oxida- for alkene cleavage.
tion employing stoichiometric amounts of NaIO4 and cata-
lytic amounts of KMnO4.
2.2.3 Osmium Tetroxide

stance, one protocol involves the use of acetonitrile In the Lemieux–Johnson oxidation catalytic amounts
and water (volume ratio 1.5:1) as the homogeneous of OsO4 perform the dihydroxylation of the C=C
solvent system, ruthenium trichloride as the catalyst double bond.[16] Stoichiometric amounts of NaIO4 re-
(3.5 mol%), oxone as the primary oxidant and sodium oxidise Os(VI) to OsACHTUNGRE(VIII) and cleave the formed
bicarbonate as the buffer to maintain the neutral con- glycol to generate the corresponding aldehyde and/or
ditions to cleave trans-stilbene (Scheme 3A).[12] An- ketone (Scheme 4A).[17,18] Cleavage of olefins by
other protocol involves sodium periodate as the ter- OsO4-NaIO4 sometimes suffered from low yields due
minal oxidant to cleave cyclooctene and two immisci- to the formation of side products. However, the addi-
ble liquid phases as the solvent system, i.e., 1,2-di- tion of 2,6-lutidine effectively suppresses the forma-
chloroethane and water[13] (Scheme 3B). In case of tion of a-hydroxy ketone side products, accelerates
mono-substituted aliphatic olefins, the optimised reac- the rate of the desired reaction, and dramatically im-
tion system included the use of the homogeneous sol- proves the reaction yield. In addition, 2,6-lutidine
vent system of CH3CN-H2O (volume ratio 6:1) and serves as a weak base to neutralise the acid generated
2 equivalents of NaIO4 (Scheme 3C). Ruthenium in the reaction to prevent the cleavage of acid-labile
nanoparticles immobilised on hydroxyapatite have protecting groups (Scheme 4B).[19] OsO4 has also been
also been reported as an effective catalyst for cis-di- employed microencapsulated in a polyurea matrix.
hydroxylation and cleavage of alkenes.[14] A catalytic These microcapsules have been used as recyclable cat-
amount of a composite material, RuO2/BaTi4O9, in alysts in the dihydroxylation and the cleavage of ole-
combination with NaIO4 in EtOAc-H2O has been fins.[20]
shown to efficiently cleave alkenes, affording ketones, Several groups have investigated the use of OsO4
aldehydes and/or carboxylic acids in high yields.[15] to perform the alkene cleavage without intermediate
1,2-diol formation. By using either hydrogen peroxide
or tert-butyl hydrogen peroxide as co-oxidant the
direct oxidation of olefins could be achieved, albeit in
low yields.[21] More recently a mild, organometallic al-

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 REVIEW Aashrita Rajagopalan et al.

Scheme 4. OsO4-based alkene cleavage. A. Lemieux–Johnson oxidation. B. Optimised cleavage of olefins by OsO4 and
NaIO4 in the presence of 2,6-lutidine.

1 1
ternative using oxone (KHSO5 · 2 KHSO4 · 2 K2SO4) as opened by H2O2 to the hydroperoxide which led to
the co-oxidant has been proposed to be used with acetophenone formation via Grob fragmentation
OsO4.[22] Oxone is known to be an effective oxidant (Scheme 5).[24]
for numerous transformations. In this system it fulfils
three functions: (i) it oxidises the initially formed
osmate back to OsACHTUNGRE(VIII), (ii) it promotes the cleavage 2.2.5 Ceric Ammonium Nitrate
to an intermediate aldehyde, and (iii) oxidises the al-
dehyde to the carboxylic acid. In another recent pro- The selective carbon-carbon double bond cleavage of
tocol, the use of iodobenzene diacetate PhIACHTUNGRE(OAc)2 as chalcones and other olefins was achieved employing
the oxidant in dichloromethane enabled a clean cleav- K10-montmorillonite clay-supported ceric ammonium
age of 1,2-diols to aldehydes in the presence of OsO4 nitrate (CAN) and molecular oxygen as oxidant in
as catalyst, NMO and 2,6-lutidine. Olefinic bonds methanol medium (Scheme 6).[25] The catalyst was re-
were cleaved in acetone/water to yield the corre- cycled without any loss of activity and selectivity.
sponding carbonyl compounds.[23]

2.2.4 Titanium Zeolite

Transition metals can be incorporated by isomorphous

substitution into the framework of zeolites and relat-
ed molecular sieves for use as selective oxidation cat-
alysts. Titanium-containing zeolites have been applied
for alkene cleavage of a-methylstyrene with hydrogen Scheme 6. Clay-supported ceric ammonium nitrate-catalysed
cleavage of C=C double bonds.
peroxide as oxidant leading first to epoxidation. In
acetonitrile as solvent the intermediate epoxide was
2.2.6 Chromium

The oxidation of carbon-carbon double bonds with

different chromium(VI) reagents is often complicated
by various side reactions.[26] Only in special cases
were good yields of the corresponding carbonyl com-
pounds obtained, for instance, if the double bond had
one or more phenyl or alkoxy substituents. In general
it has been observed that in a partially aqueous
medium chromic acid favoured cleavage of C=C
double bonds whereas under anhydrous conditions
Scheme 5. a-Methylstyrene oxidation by titanium-containing other pathways were favoured like the attack at allylic
zeolites and H2O2 forming various products. positions or partial oxidation of the double bond to

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Oxidative Alkene Cleavage by Chemical and Enzymatic Methods

form epoxides, diol derivatives or ketols; rearrange- 2.2.9 Iron and Mn-Porphyrin Derivatives
ments of the intermediate oxidation products have
also been observed. In the case of compounds without Iron complexes like hemin chloride lead in general to
alcohol or aldehyde functional groups, the chro- a mixture of various oxidation products.[31]
mium(V) complex [(BiPy)H2CrOCl5] effected a fairly Modification of tetrakis(4-hydroxyphenyl)porphyrin
clean cleavage of C=C double bonds under anhydrous [TPP-(OH)4] with poly(ethylene glycol) chain as four
conditions at room temperature, usually without any side arms led to a compound which is soluble in both
complicating side reactions.[27] However, attempted organic and water solutions. The corresponding man-
cleavage of simple alkyl-substituted olefins in general ganese porphyrin complex MnCl-TPP-(PEO750)4
led to mixtures of products. Alcohols and aldehydes proved to be an excellent catalyst for the cleavage of
containing C=C double bonds gave only the corre- C=C bonds, yielding the corresponding carbonyl com-
sponding carbonyl compounds and carboxylic acids, pounds with sodium periodate as oxidant.[32] The
respectively, in good yields without cleavage. cleavage involved most likely the epoxide intermedi-
ate, which was subsequently hydrolysed to yield the
1,2-diol followed by C C cleavage (Scheme 8). Com-
2.2.7 Palladium-Based Cleavage paring the rate of cleavage of the alkene and its cor-
responding epoxide, the second one reacted much
PdCl2 can be employed as catalyst for the aerobic faster, suggesting that the rate-limiting step of this
alkene cleavage of styrene to yield benzaldehyde cleavage is the epoxide formation.
using a supercritical carbon dioxide and poly(ethylene
glycol) (PEG) biphasic system. PEG effectively im-
mobilises and stabilises the catalyst. This biphasic 2.3 Electrocatalytic Anodic Cleavage
system facilitated product separation and catalyst re-
cycling.[28] Electrocatalytic anodic cleavage of electron-deficient
substituted unsymmetrical and symmetrical stilbenes
in acetonitrile-water mixtures resulted in the forma-
2.2.8 Gold-Based Cleavage tion of the corresponding aldehydes in high yields em-
ploying a high oxidation potential triphenylamine
Gold(I)-catalysed cleavage of alkenes with tert-butyl electrocatalyst (Scheme 9).[33] The oxidation pathway
hydrogen peroxide (TBHP) as the oxidant in the apparently involved the corresponding 1,2-diols,
presence of neocuproine afforded ketones or alde-
hydes as products (Scheme 7).[29] Thereby neocu-
proine served as the bidentate nitrogen ligand for
gold allowing the successful transformation of several
styrene derivatives. Also gold nanoclusters stabilised
by a hydrophilic polymer [poly(N-vinyl-2-pyrrolidone)
(Au:PVP)] have been reported for oxygenative cleav-
age of alkenes.[30]

Scheme 8. Cleavage catalyzed by MnCl-TPP-(PEO750)4.

Scheme 7. Gold(I)-catalysed cleavage of alkenes employing

TBHP in the presence of neocuproine serving as ligand.

Scheme 9. Electrocatalytic anodic oxidation of stilbenes.

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 REVIEW Aashrita Rajagopalan et al.

which were converted to the aldehydes in high yield

under the same conditions. In another approach
anodic bromo-formyloxylation, followed by an anodic
1,2-diol cleavage, resulted in overall double bond
cleavage of cyclohexene to hexane-1,6-dial or its ace-
tals.[34]

2.4 Singlet Oxygen

Singlet oxygen (1O2) is a versatile reagent for oxida-

tion reactions. For example, [2+2] cycloaddition was
observed with electron-rich alkenes. The formed diox-
etane products were in general sensitive molecules
that thermally decomposed in a chemiluminescent Scheme 11. Alkene cleavage employing iodosylbenzene.
process to the corresponding carbonyl compounds.
Many experimental studies have suggested that
[2+2] cycloadditions with singlet oxygen occurred via cleavage in the presence of water at room tempera-
the stepwise mechanism depicted in Scheme 10. ture (Scheme 11).[37] The method is supposed to be
Thereby it was observed that (i) both stereospecific as safer than ozonolysis and probably cheaper than tran-
well as non-stereospecific dioxetane formation hap- sition metals. It works well for electron-rich olefins.
pened, (ii) if ene and [2+2] adduct formation compete, In a subsequent protocol the hypervalent iodine was
increasing solvent polarity favours dioxetane forma- used only in catalytic amounts produced in situ from
tion, and (iii) methanol trapping products are formed iodomesitylene (2,4,6-Me3C6H2I, 1–10 mol%) using
under conditions where the dioxetane product is m-chloroperbenzoic acid (mCPBA) as terminal oxi-
stable, arguing for interception of either an exciplex dant with 48% aqueous HBF4 (2.2 equiv.) in CH2Cl2-
or zwitterion precursor.[35] The thermolysis of alkyl- hexafluoroisopropyl alcohol-H2O 9:3:1. If aldehydes
and/or phenyl-substituted dioxetanes produces car- got formed they were oxidised further to the corre-
bonyl fragments, whereby one is produced in an sponding acids under these conditions.[38]
exited state. Two mechanistic extremes have been
proposed to describe the thermal decomposition of
substituted dioxetanes, namely via a (a) diradical or 2.6 m-Chloroperbenzoic Acid
(b) concerted pathway (Scheme 10B).[36]
The cleavage of terminal C=C double bonds of gemi-
nal biarylethenes was performed employing m-chloro-
2.5 Hypervalent Iodine perbenzoic acid (mCPBA) in dichloromethane with-
out the need of any catalyst (Scheme 12A).[39] Addi-
In an attempt to improve the yield and to look for tionally, 2,4-substituted enynes were converted to the
more environmentally benign methods for the cleav- corresponding ynone systems under mild reaction
age of C=C double bonds, new methodologies have conditions (Scheme 12B). This approach was found to
been developed. For instance, activated iodosylben- be suitable to introduce functionalities to the benzo-
zene monomers have been employed for alkene phenone and ynone architectures.

Scheme 10. A) Singlet oxygen stepwise [2+2] cycloaddition mechanism. B) Mechanistic pathways for the (thermal) decompo-
sition of dioxetanes.

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Oxidative Alkene Cleavage by Chemical and Enzymatic Methods

amples show that biocatalytic alkene cleavage can be

employed efficiently for the transformation of various
non-natural organic molecules.[42] The enzymes per-
forming alkene cleavage are grouped here based on
their cofactor dependence. Most of the alkene cleav-
ing enzymes known are heme or non-heme iron-de-
pendent enzymes.[43] However, recent examples of cer-
tain Mn-, Cu- and Ni-dependent alkene cleaving en-
zymes are also included.

3.1 Heme-Dependent Alkene Cleaving Enzymes

The heme-dependent enzymes are either peroxidases

or oxygenases, thus requiring either hydrogen perox-
ide or molecular oxygen as oxidant. In the case of
Scheme 12. A) Alkene cleavage by mCPBA of geminal heme peroxidases, alkene cleavage is only observed
biaryl ethenes and B) of 2,4-substituted enynes.
as a side reaction. Heme-containing enzymes partici-
pate in a strikingly diverse range of chemistry; yet all
2.7 N-Hydroxyphthalimide and Molecular Oxygen biological oxidation reactions catalysed by these en-
zymes involve similar high oxidation state intermedi-
In recent work another metal-free alkene cleavage ates whereby their reactivity is modulated by the pro-
methodology was reported employing N-hydroxyph- tein environment.[44] In this review, the heme-depen-
thalimide (NHPI) as catalyst for an aerobic cleavage dent alkene cleaving enzymes are divided based on
at the expense of molecular oxygen (Scheme 13).[40] the oxidant.
In all examples reported the C=C double bond is ad-
jacent to a (substituted) phenyl or naphthyl moiety.
3.1.1 Heme-Dependent Enzymes Requiring Oxygen
as Oxidant

Tryptophan 2,3-dioxygenase (TDO)[45–47] and indole-

ACHTUNGREamine 2,3-dioxygenase (IDO)[45,47,48] are heme-depen-
dent dioxygenases which cleave the C=C double bond
of the pyrrole ring of tryptophan to afford N-formyl-
Scheme 13. Cleavage of a C=C double bond adjacent to an kynurenine (Scheme 14A); thereby both oxygen
aromatic moiety at the expense of molecular oxygen using atoms are incorporated from molecular oxygen. TDO
N-hydroxyphthalimide. and IDO catalyse essentially the same reaction,
whereby IDO displays a broader substrate scope
(Scheme 14B). The enzymatic C=C double bond
3 Alkene Cleavage by Enzymes cleavage of natural rubber [i.e., poly-(cis-1,4-iso-
prene)] and synthetic rubbers was observed using
Enzymes are also just catalysts following the rules of a purified protein from Xanthomonas sp., currently
chemistry. Nevertheless, since all enzymes possess named as rubber oxygenase (RoxA).[49] RoxA consists
a protein backbone, these biocatalysts will be treated of two heme prosthetic groups located in the protein
here in a separate section. Reasons to employ biocat- scaffold and a conserved sequence motif which is
alysts include (i) safe reaction conditions, (ii) ability to a distinctive feature of the cytochrome c peroxidases.
operate under mild conditions for the sake of unsta- RoxA showed high regioselectivity since it was capa-
ble products and (iii) to functionalise/modify complex ble of cleaving poly-(cis-1,4-isoprene) at regular inter-
precursor molecules in a chemo-, regio- and stereo- vals, principally cutting off three isoprene units per
specific fashion. Additionally, the rising popularity of step (Scheme 14C).
natural products during the last decades has triggered
off significant research activities to use biocatalysts
for the production of, for instance, natural flavour 3.1.2 Enzymes Requiring Hydrogen Peroxide as
compounds.[41] Enzymes can efficiently activate the Oxidant (Heme Peroxidases)
most innocuous oxidant, molecular oxygen, and cata-
lyse the alkene cleavage at ambient temperature and Peroxidases are ubiquitously found in microorgan-
atmospheric pressure in aqueous buffer. Recent ex- isms, plants, and animals and possess a ferric proto-

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 REVIEW Aashrita Rajagopalan et al.

Scheme 14. Heme-dependent oxygenases employed for alkene cleavage.

porphyrin IX (protoheme) as the prosthetic group.[50] (Scheme 15D).[54] Substrates with free phenolic moiet-
The alkene cleavage is mainly a secondary activity of ies led to poylmerisation. Even for plant-cell cultures
the peroxidases, thus the alkene cleavage products are (e.g., Camellia sinensis, Nicotiana tabacum, Catharan-
in general side-products. thus roseus and Daucus carota) biocatalytic alkene
In the chloroperoxidase (CPO)-catalysed oxidation cleavage of indene derivatives was observed in the
of conjugated dienoic esters, alkene cleavage was ob- presence of H2O2.[55] However, significant conversions
served as a side reaction (13%) with tert-butyl hydro- were observed even in absence of biocatalyst
gen peroxide under aerobic conditions (Scheme 15E).
(Scheme 15A).[51] Cleavage of 3-methylindole and 3-
ethylindole was observed employing horseradish per-
oxidase (HRP) to yield the corresponding ring- 3.2 Non-Heme Iron-Dependent Alkene Cleaving
opened ortho-acyl formanilides and oxindoles on Enzymes
a 50-mg scale with H2O2 under aerobic conditions
(Scheme 15B).[52] The radical oxidation was initiated All non-heme iron-dependent enzymes require molec-
by the addition of a catalytic amount of H2O2, where- ular oxygen for alkene cleavage. Nevertheless, each
by its concentration was maintained low (30 mM) to enzyme activates dioxygen in a different manner; ad-
avoid enzyme deactivation. Using exclusively oxygen ditionally it was also postulated that the same enzyme
as oxidant the alkene cleavage products were the may cleave the olefinic functionalities via different
main products for substrates like isoeugenol, t-anet- mechanisms depending on the substrate (see below
hole and indene.[31c] Both myeloperoxidase (MPO) for carotenoid cleavage oxygenases). The non-heme
and the peroxidase from Coprinus cinereus (CiP) oxygenases are grouped here based on whether they
have been found to catalyse the Ca=Cb double bond cleave an aromatic C=C double bond or an aliphatic
cleavage of various substituted styrene precursors, C=C double bond.
forming significant amounts of substituted benzalde-
hydes (Scheme 15C).[53] The alkene cleavage is the
most prominent reaction when catalysed by CiP, 3.2.1 Non-Heme Iron Oxygenases Cleaving Aliphatic
whereas MPO forms a larger amount of epoxide. C=C Double Bonds
Lignin peroxidase (LiP) transformed phenolic pro-
tected vanillin precursors like o-ethylisoeugenol to Several non-heme iron oxygenases are able to differ-
the corresponding benzaldehyde derivatives entiate between various C=C double bonds within the

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Oxidative Alkene Cleavage by Chemical and Enzymatic Methods

Scheme 15. Heme-dependent peroxidases described in alkene cleavage.

same molecule. Remarkably, even from many conju- quire an Fe(II) centre which is bound to four highly
gated double bonds only a single defined alkene func- conserved and catalytically essential histidine resi-
tionality is cleaved. This is a feature that is not ach- dues.[56] CCDs often exhibit substrate promiscuity,
ievable easily by established chemical methods. Caro- thus also derivatives of the natural substrate are
tenoid cleavage dioxygenases (CCDs) are widespread transformed. Thereby they retain their perfect regio-
in bacteria, plants and animals and catalyse, as their selectivity, cleaving only a specific C=C double bond
name already implies, the cleavage of the C=C double of the carotenoid chain. Depending on the enzyme,
bond of carotenoids to give apocarotenoids. They re- the alkene cleavage can occur either at the central

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 REVIEW Aashrita Rajagopalan et al.

Scheme 16. Cleavage of aliphatic C=C by non-heme iron-dependent oxygenases.

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Oxidative Alkene Cleavage by Chemical and Enzymatic Methods

C=C double bond of the carotenoid substrates (i.e., cleavage), and (b) cleavage of one bond neighboured
C-15=C-15’ position, central cleavage) or at another by only one carbon with a hydroxy group (extradiol
more outer position (i.e., excentric cleavage) cleavage). The intradiol dioxygenases cleaving the C=
(Scheme 16A). C double bond between the phenolic hydroxy groups
The AtCCD1 from Arabidopsis thaliana cleaves yield muconic acid derivatives (Scheme 17A[62] and
a variety of carotenoids symmetrically at the 9,10 and/ Scheme 17B[63]), whereas the extradiol dioxygenases
or 9’,10’ double bond to form a (di-)aldehyde and one result in the formation of 2-hydroxymuconaldehyde
or two C13 products, depending on the carotenoid sub- (Scheme 17C,[62b,64] Scheme 17D[65]). In the example in
strate (Scheme 16B).[57] The products of the alkene Scheme 17E the p-hydrochinone is cleaved to yield
cleavage of carotenoids and apocarotenoids constitute a hydroxy-a-keto-diacid.[66] The extradiol 3-hydroxy-
important natural flavours for the aroma industry; ACHTUNGREanthranilate-3,4-dioxygenase (HAD) catalyses the ox-
hence the possibility to exploit AtCCD1 in biocataly- idative ring opening of 3-hydroxyanthranilate to yield
sis has attracted the interest of academia and industry. 2-amino-3-carboxymuconic semialdehyde[67]
Four isoenzymes of the lignostilbene-a-b-dioxyge- (Scheme 17F). It is remarkable that both the intradiol
nase (LSD) from Sphingomonas paucimobilis were and extradiol dioxygenases require a mononuclear
identified and purified.[58] The four enzymes contain
one equivalent of iron, and they are constituted by
two subunits: isoenzyme I (aa), isoenzyme II (ab),
isoenzyme III (bb), and isoenzyme IV (gg). All isoen-
zymes transform a stilbene-type substrate possessing
trans-configuration and bearing a hydroxy substituent
in the para-position of the aromatic ring
(Scheme 16C).
Two stilbene oxygenases from Novosphingobium
aromaticivorans DSM 12444 (NOV1 and NOV2) se-
lectively cleave trans-stilbene-type substrates bearing
a hydroxy or a methoxy moiety in the para-position
of the phenyl ring.[57c] The two stilbene oxygenases
were classified as monooxygenases (Scheme 16D). In
another study, a novel enzyme was identified from
Pseudomonas putida IE27 when the microorganism
was cultivated from soils containing isoeugenol as the
sole carbon source. The enzyme was purified and as-
sayed for the catalytic reaction in vitro, demonstrating
high activity for the alkene cleavage of isoeugenol to
yield vanillin in the presence of molecular oxygen.[59]
Consequently, the enzyme was named after its sub-
strate as isoeugenol oxygenase (Scheme 16E).
In case of the Fe(II)-dependent b-diketone dioxy-
genase from Acinetobacter johnsonii (Dke1),[60] the
enol form of the 2,4-pentanedione is cleaved, giving
equimolar amounts of methylglyoxal and acetate and
consuming one equivalent of molecular oxygen
(Scheme 16F).

3.2.2 Enzymes Cleaving Aromatic C=C Double

Bonds

The selective cleavage of aromatic C=C bonds cannot

be performed by chemical means. The catechol dioxy-
genases catalyse the cleavage of catechols and substi-
tuted catechols as a central step in the bacterial deg-
radation of aromatic compounds.[61] For catechol, two
types of ring cleavage have been found: (a) oxygena-
tive cleavage of the bond between the two carbon Scheme 17. Aromatic C=C cleavage by non-heme iron-de-
atoms bearing the two hydroxy groups (intradiol pendent oxygenases.

Adv. Synth. Catal. 2013, 355, 3321 – 3335  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim asc.wiley-vch.de 3331
 REVIEW Aashrita Rajagopalan et al.

iron centre with no additional cofactors, whereby the

intradiol dioxygenase is Fe(II)-dependent while the
extradiol dioxygenase is FeACHTUNGRE(III)-dependent.[61]

3.3 Non-Iron Metal-Dependent Alkene Cleaving

Enzymes

Although most alkene cleaving enzymes are iron-de-

pendent, there are some exceptions. For instance, the
2,3-dihydroxybiphenyl-1,2-dioxygenase (DHBD) be-
longs to the extradiol ring cleavage dioxygenases and
catalyses the meta-cleavage of the hydroxylated bi-
phenyl ring.[68] Even though related enzymes have
found to be Fe-dependent, an Mn(II)-dependent,
thermostable 2,3-dihydroxybiphenyl 1,2-dioxygenase
was first reported from Bacillus sp. JF8[69]
(Scheme 18A). The homoprotocatechuate 2,3-dioxy-
genase (2,3-HPCD) cleaves the aromatic ring of its
substrate with insertion of both atoms of oxygen from
O2 to form a-hydroxy-d-carboxymethyl cis-muconic
semialdehyde (Scheme 18B).[70] The enzyme isolated
from Arthrobacter globiformis was found to be
Mn(II)-dependent.[71]
Quercetinase is an induced extracellular dioxyge-
nase produced by Aspergillus flavus when grown on
rutin, a flavonoid glycoside, and is Cu(II)-depen-
dent.[61,72] The enzyme oxidatively cleaves the hetero-
cyclic ring of quercetin to yield carbon monoxide and
the phenolic ester, 2-protocatechuoylphloroglucinol
carboxylic acid (Scheme 18C). Cleavage of acireduc-
tone to 2-keto-4-thiomethylbutyrate and formic acid
is an unusual transformation step in the l-methionine
salvage pathway (Scheme 18D).[61] Acireductone di-
ACHTUNGREoxygenase (ARD) (which catalyses two C C cleavag-
es) contains a single iron(II) cofactor, whereas dioxy-
genase ARD’ (which catalyses one C C cleavage) Scheme 18. Alkene cleavage by non-iron metal-dependent
contains a single nickel(II) cofactor.[73,74] oxygenases.
A cell-free extract of the white rot fungus Trametes
hirsuta FCC 047 was found to cleave the C=C double
bonds adjacent to the aromatic ring of several sty- regioselective methods are required; on the other
rene-type molecules (Scheme 18E).[42] It is noteworthy hand, most established chemical methods are broadly
that other C=C double bonds are not transformed, applicable. From this review one can deduce that in-
thus, the enzyme distinguishes between double bonds nocuous molecular oxygen is the desired oxidant of
adjacent to a phenyl group and others.[42e] The bio- the future. The enzymatic methods in general already
transformation was optimised and carried out under work with molecular oxygen as oxidant. Some en-
oxygen pressure to enhance the reaction rate. The zymes are highly specific concerning their regioselec-
enzyme was recently identified to be MnACHTUNGRE(III)-depen- tivity, thus their cleaving site. Nevertheless, by the
dent.[75] choice of biocatalyst, alternative cleavage sites can be
targeted. Various types of enzymes are known for spe-
cific alkene cleavage reactions. Unfortunately, the
4 Conclusion specific enzymes are in general not easily accessible
for a synthetic chemist, since no commercial source
Chemical methods for alkene cleavage are well estab- exists in general. Consequently, either exchanges be-
lished although there is a strong need for safer and/or tween groups or open catalyst libraries would be de-
environmentally benign alternatives requiring less sirable. Furthermore, the stability of some enzymes
hazardous reagents. Additionally more chemo- and needs to be improved to withstand elevated substrate

3332 asc.wiley-vch.de  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Synth. Catal. 2013, 355, 3321 – 3335
Oxidative Alkene Cleavage by Chemical and Enzymatic Methods

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achieve selective, environmental benign and safe [8] a) S. Lai, D. G. Lee, Synthesis 2001, 1645–1648; b) D.
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