Asymmetric Synthesis

Asymmetric Epoxidation Using Hydrogen Peroxide as Oxidant

Chuan Wang[a] and Hisashi Yamamoto*[a, b]

Chem. Asian J. 2015, 10, 2056 – 2068 Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2056

Focus ReviewDOI: 10.1002/asia.201500293

Abstract: Asymmetric epoxidation is one of the most impor-

tant transformations in organic synthesis. Although tremen-dous progress was achieved in this field in the 1980s and

1990s, it is still desirable from both economical and ecologi-cal views to develop environmentally friendly catalytic epoxi-dation with a broad substrate scope. Hydrogen peroxide isa safe and cheap oxidant, which is easy to handle and gen-

erates water as the sole byproduct. Therefore, asymmetric

epoxidation of olefins using hydrogen peroxide as oxidanthas been a very active research field and has been investi-

gated by many research groups in recent years. In thisreview, the exciting very recent developments of this rapidlygrowing area are surveyed and organized according to thecatalyst systems.

1. Introduction

Asymmetric epoxidation is one of the most important organictransformations, since it provides direct access to various opti-

cally active epoxides, which can be further utilized as precur-

sors for the synthesis of natural products and synthetic ana-logues with biological activities.[1] The milestone discoveries in

this area were accomplished by Sharpless et al. in 1980, whoreported the first titanium-catalyzed asymmetric epoxidation

of allylic alcohols.[2] Being complementary to the Sharplessmethod, the manganese–salen (salen = N,N’-ethylenebis(salicy-

limine)) catalytic system, which was independently developed

in the 1990s by Jacobsen and Katsuki, turned out to be a pow-erful catalyst for highly enantioselective epoxidation of unfunc-

tionalized olefins.[3, 4] Furthermore, Shi et al. reported in 1996the first organocatalyzed asymmetric epoxidation of olefins

using a fructose derivative as catalyst.[5]

These classic methods mentioned above found broad appli-

cations in the synthesis of complex molecules and also evoked

enormous interest from numerous researchers to further devel-op the asymmetric epoxidation reaction. On the one side,

great efforts have been made to design novel catalytic sys-tems, through which the substrate scope of the asymmetric

epoxidation could be significantly expanded. For instance, ourgroup successfully applied bis-hydroxamic acids as ligands in

the enantioselective epoxidation of primary, secondary, and

tertiary allylic and homoallylic alcohols as well as alkenyl sulfo-namides.[6] On the other side, since the Sharpless, Jacobsen–

Katsuki, Shi, and many other successful epoxidation reactionsusually require the use of toxic, costly, or low atom-efficient ox-

idants, such as alkyl peroxide, oxone, sodium hypochlorite, andhypervalent iodine compounds, it is highly desirable from both

an ecological and economical point of view to develop newcatalytic asymmetric epoxidation reactions by employing hy-drogen peroxide as oxidant, which is safe, cheap, easy to

handle, and generates water as the sole byproduct. Therefore,

asymmetric epoxidation of olefins using hydrogen peroxide asoxidant has been a very active research field and has been in-

vestigated by many research groups in recent years. In thisreview the most recent progress, which is not described in the

previous reviews, is surveyed and organized according to the

catalyst systems.[7]

2. Metal-Catalyzed Asymmetric EpoxidationUsing Hydrogen Peroxide as Oxidant

2.1. Titanium-Catalyzed Asymmetric Epoxidation

In 2005, Katsuki et al. reported the first titanium-catalyzed

asymmetric epoxidation of both conjugated and non-conjugat-ed unfunctionalized olefins by employing novel salalen as

ligand (tetradentate [ONNO]-type ligands comprised of an

amine-phenolate and an imine-phenolate subunit).[8] His pio-neering research work evoked further studies in this area. For

instance, Berkessel et al. developed a new structurally simplecis-salalen ligand, which could be readily prepared in two

steps and easily form the active catalyst complex in situ withTi(OiPr)4.[9, 10] Remarkably, this simplified catalyst demonstrates

excellent capability to promote highly enantioselective epoxi-

dation of non-conjugated olefins, while its trans analogue pre-viously developed by the same group was found to be an effi-

cient catalyst for the epoxidation of conjugated olefins.[11]

Under catalysis with these novel Ti--cis-salalen complexes (1–

4), various terminal non-conjugated olefins, which are notori-ously difficult substrates, were successfully used as precursors

for asymmetric epoxidation reactions using aqueous hydrogenperoxide as oxidant (Scheme 1).[9, 10] Generally, the products

were obtained in high enantioselectivities. Furthermore, thefirst titanium–salalen Ti–peroxo complexes were isolated andcharacterized by X-ray crystallography. Interestingly, the peroxo

complexes alone did not affect olefin epoxidation, whereas inthe presence of aqueous hydrogen peroxide the peroxo com-

plexes can promote the epoxidation reaction smoothly.Sun et al. developed a series of biaryl-bridged salalen–titani-

um complexes 5, which served as efficient catalysts for the

asymmetric epoxidation of a variety of aromatic epoxides fur-nishing the products with high enantioselectivities

(Scheme 2).[12] Notably, in the cases of terminal and cis olefinsas substrates, the reactions employing the biaryl-bridged cata-

lysts afforded the products with higher enantiomeric excessesthan the non-bridged titanium complex. However, relatively

[a] Dr. C. Wang, Prof. Dr. H. YamamotoDepartment of ChemistryThe University of Chicago5735 South Ellis Avenue, Chicago, IL 60637 (USA)E-mail : yamamoto@uchicago.edu

[b] Prof. Dr. H. YamamotoMolecular Catalyst Research CenterChubu University1200 Matsumoto, Kasugai, Aichi 487-8501 (Japan)E-mail : hyamamoto@jsc.chubu.ac.jp

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2057

Focus Review

low asymmetric induction was observed in the case of non-conjugated olefins.

Katsuki and co-workers successfully applied the titanium–sal-

alen complex 6 as catalyst for the enantioselective epoxidationof cis-aldehyde enol esters furnishing the products in excellentenantioselectivities (Scheme 3).[13] The authors also demonstrat-

ed that one reaction product was readily converted into thecorresponding 1,2-diol through LiBH4-mediated reduction with-

out erosion of the high enantiomeric excess.Alongside titanium–salalen complexes, more synthetically

accessible titanium—salan complexes have also been investi-

gated as catalysts for asymmetric epoxidation with hydrogenperoxide.[14] Bryliakov and co-workers systematically studied

the influence of the ligand structure on the catalytic activityand selectivity by surveying the performance of a series of

chiral salan ligands with varying steric and electronic proper-ties in the asymmetric epoxidation of aromatic epoxides

(Scheme 4).[15] The results revealed that the electronic effectcontrols the catalytic activity, whereas the steric effect ac-

counts for the facial selectivity of the epoxidation. Generally,the best results with respect to the enantioselectivities were

obtained in the case of Ti complex 7.Recently, Falck and co-workers reported that Ti–salan com-

plex 7 is able to catalyze distal selective epoxidation of conju-gated dienes even in the presence of other olefins and adja-

cent stereocenters (Scheme 5).[16] In this context, a variety of

well-established methods for asymmetric epoxidation weresurveyed for the regioselective epoxidation of conjugateddienes. The reaction using Ti–salan complex 7 or its enantio-mer as catalyst furnished the products with complete regiose-lectivities in favor of the Z- or trisubstituted olefins over E ole-fins. Notably, these reactions also proceeded with high diaster-

eo- or enantioselectivities.

2.2. Scandium-Catalyzed Asymmetric Epoxidation

Feng et al. discovered that the chiral N,N’-dioxide–scandium

complex 8 was able to catalyze the nucleophilic epoxidation ofelectronically deficient olefins, such as a,b-unsaturated ketonesand a,b-unsaturated amides (Scheme 6).[17] The corresponding

products were furnished in high yields and excellent enantio-selectivities under mild reaction conditions. Notably, under the

Chuan Wang was born in Xuzhou (P.R. China)and studied chemistry at the University ofGçttingen (Germany) from 2002 to 2007where he received his Masters degree underthe guidance of Prof. H. Laatsch. Subsequent-ly, he joined the group of Prof. D. Enders atthe RWTH Aachen University (Germany) andin 2010 he obtained his Ph.D. degree. In 2011he undertook postdoctoral research at theJìlich Research Centre (Germany) with Prof. J.Pietruszka. In 2012 he moved to the Universityof Chicago (USA) as a Humboldt postdoctoralfellow with Prof. H. Yamamoto.

Hisashi Yamamoto received his Bachelordegree from Kyoto University (Japan) and hisPh.D. from Harvard University. He became as-sistant professor at Kyoto University and in1977 was appointed as associated professorat the University of Hawaii (USA). In 1980 hemoved to Nagoya University (Japan) as a fullprofessor. In 2002, he moved to the UnitedStates as a professor at the University of Chi-cago. In 2012, he was appointed as professorand director of the Homogeneous Catalyst Re-search Center at Chubu University (Japan).During his research career of over four de-cades, his research group has developeda wide range of synthetic methods, which laid the foundation for modernLewis acid catalysis, Brønsted acid catalysis, and catalytic asymmetric oxida-tion. He has been awarded numerous academic awards and honors includingthe IBM Science Award (1988), the Chemical Society of Japan Award (1995), theNational Prize of Purple Medal (2002), the Yamada Prize (2004), the HumboldtResearch Award (2007), and the Noyori Prize (2012), among others.

Scheme 1. Asymmetric epoxidation of terminal non-conjugated olefins cata-lyzed by Ti–cis-salalen complexes.

Scheme 2. Asymmetric epoxidation of unfunctionalized olefins catalyzed bybiaryl-bridged salalen–Ti complexes.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2058

Focus Review

optimum conditions, the reaction on the gram scalestill afforded excellent results after a prolonged reac-

tion time. Furthermore, both Sc(OTf)3 (OTf = trifluoro-methanesulfonate) and the N,N’-dioxide ligand could

be simply recycled by means of extraction andcolumn chromatography. The authors also studied

the water tolerance of this catalytic system and theresults revealed that the studied reaction still pro-

ceeded smoothly without erosion of enantiomeric

excess values, even if water with 100 times thevolume of hydrogen peroxide used was added to the

reaction mixture. For the mechanism, the authorsproposed that the nucleophilic H2O2 attacks the

Lewis acid activated enone at the ß position and thesubsequent attack of the a-carbon atom at the ele-

trophilic peroxygen atom forms the epoxide.

In 2014, the same research group expanded thesubstrate scope of the scandium-catalyzed epoxida-

tion to 2-arylindene-1,3-diketones under modified re-action conditions (Scheme 7).[18] In this case, the

products were all obtained with high enantiomericexcesses.

2.3. Iron-Catalyzed Asymmetric Epoxidation

Iron-catalyzed asymmetric epoxidation is attractiveowing to the availability, low cost, and low toxicity of

iron salts. Generally, the iron catalysts for asymmetricepoxidation can be classified into two categories:

porphyrin– and non-porphyrin–iron complexes. Thefirst enantioselective epoxidation catalyzed by iron–

porphyrin was reported in 1983 by Groves and

Myers.[19] Since then, a number of different chiraliron–porphyrin complexes have been developed and

applied in epoxidation reactions. The oxidant used inthese catalytic systems is generally iodosyl benzene.

Scheme 3. Asymmetric epoxidation of cis-aldehyde enol esters catalyzed by Ti–trans-sala-len complexes.

Scheme 4. Asymmetric epoxidation of unfunctionalized olefins catalyzed by Ti–trans-salan complexes.

Scheme 5. Distal selective epoxidation of conjugated dienes catalyzed by Ti–trans-salan complexes.

Scheme 6. Asymmetric epoxidation of a,ß-unsaturated carbonyl compoundscatalyzed by N,N’-dioxide–ScIII complexes.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2059

Focus Review

In 2012, Simonneux and his co-workers developed a series of

chiral Halterman iron–porphyrins 9, which are able to promotethe asymmetric epoxidation using hydrogen peroxide as oxi-

dant (Scheme 8).[20, 21] Notably, the sulfonated Halterman iron–porphyrin is water soluble and thus under its catalysis the ep-

oxidation can be conducted under aqueous conditions. How-

ever, the substrate scope of these reactions is narrow and in-cludes only styrene derivatives and 1,2-dihydronaphthalene.

Furthermore, the products are afforded mostly with moderate-ly good enantioselectivities. Therefore, further investigations

are desired in this area to enhance the asymmetric inductionto a synthetically valuable level.

Tetradentate nitrogen-containing ligands, which have elec-

tronic properties that resemble those of porphyrin, alsoproved to be efficient catalysts for the Fe-catalyzed asymmetric

epoxidation of olefins. For instance, Bryliakov and Talsi et al.developed chiral Fe–aminopyridine catalyst 10, which is capa-

ble of promoting highly enantioselective epoxidation of di-verse olefins with aqueous hydrogen peroxide as oxidant

(Scheme 9).[22] Furthermore, the authors also discovered thatthe enantioselectivity of this process increased with growing

steric demand of acidic additives. A plausible mechanism wasproposed by the authors (Scheme 10). Initially, the FeII complexis oxidized to an FeIII intermediate by H2O2. Subsequently, anactive species FeIV complex is formed through a carboxylic acid

assisted heterocyclic cleavage of the O¢O bond. In the nextstep the olefin is epoxidized by the FeIV species to afford theproduct and the FeII intermediate for the next cycle.

Costas and co-workers improved the catalytic behavior of

the Fe–aminopyridine complex significantly by introducing a di-methylamino moiety to the pyridine rings (Scheme 11).[23] The

authors also employed a catalytic amount of carboxylic acid as

cocatalyst, which could improve both yields and enantioselec-tivities of the epoxidation reaction through synergistical coop-

eration with the iron complex leading to more efficient O¢Obond cleavage and the formation of epoxidizing species. After

careful screening of a variety of carboxylic acids, Ibuprofenturned out to be the best coligand. This new epoxidation

Scheme 7. Asymmetric epoxidation of 2-arylindene-1,3-diketones catalyzedby N,N’-dioxide–ScIII complexes.

Scheme 8. Asymmetric epoxidation of unfunctionalized olefins catalyzed byFe–porphyrin complexes.

Scheme 9. Asymmetric epoxidation of olefins catalyzed by Fe–aminopyridinecomplexes.

Scheme 10. Proposed mechanism for the non-porphyrin Fe-catalyzed asym-metric epoxidation of olefins with acidic additives.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2060

Focus Review

method demonstrates a broad substrate scope in-

cluding various enones and cis-b-substituted styr-enes.

Recently, the same research group successfully em-ployed amino acids as synergistical coligands for the

Fe–aminopyridine-complex-catalyzed epoxidation of

a-substituted styrenes, which are challenging sub-strates for asymmetric epoxidation (Scheme 12).[24]

Generally, under optimum conditions, the epoxideproducts were obtained in high enantiomeric excess-

es. The authors’ new observations revealed that thesubstrate spectrum of a catalytic system can besimply expanded through variation of coligands in-

stead of onerous development of novel ligands.Sun et al. developed Fe–aminobenzimidazole com-

plex 12, which proved to be an efficient catalyst for

H2O2-mediated enantioselective epoxidation of chalcone deriv-atives furnishing the products in most cases with high enantio-

selectivities (Scheme 13).[25] This tetradentate N-ligand was alsoemployed in the Mn-catalzyed epoxidation of a,ß-unsaturated

ketones giving similar results in terms of both yields and enan-tioselectivities.

2.4. Manganese-Catalyzed Asymmetric Epoxidation

Mn- and Fe-catalyzed asymmetric epoxidations are similar interms of the ligands employed, the substrate scope, and the

reaction mechanism, however, Mn catalysts generally requirelower catalyst loadings. The use of hydrogen peroxide as oxi-

dant in Mn-catalyzed epoxidation is challenging owing to thecompeting disproportion of hydrogen peroxide. In recent

years a number of tetradentate nitrogen–Mn complexes were

developed by several research groups. Generally, high enantio-selectivities were obtained in the cases of diverse electron-defi-

cient olefins and electron-rich cis olefins, whereas relativelypoor asymmetric induction was achieved in the cases of termi-

nal, trans-disubstituted, and trisubstituted olefins as precursors.Being similar to iron, the manganese–porphyrin complexes

developed by Simonneux et al. were also found to be able cat-

alyze the asymmetric epoxidation of unfunctionalized olefins

with aqueous hydrogen peroxide as oxidant (Scheme 14).[21]

Further improvement is desirable is this field, since the sub-

strate scope was relatively narrow and the level of the asym-metric induction was only moderate.

As early as 2003, Stack et al. reported that a Mn complex

with a tetradentate aminopyridine ligand featuring a cyclohexa-nediamine scaffold was an efficient catalyst for the enantiose-

lective epoxidation of olefins using peracetic acid as oxidant.[26]

In 2011, Bryliakov et al. discovered that this reaction also pro-

ceeded with aqueous hydrogen peroxide as the terminal oxi-

dant and a large excess amount of acetic acid as additive, al-though the products were obtained in lower enantioselectivi-

ties. The same research group also developed a chiral tetraden-tate aminopyridine ligand based on the bis-pyrrolidine struc-

ture, which turned out to be a good ligand for the Mn-catalyzed H2O2-mediated asymmetric epoxidation of electron-

Scheme 12. Asymmetric epoxidation of terminal olefins catalyzed by Fe–aminopyridine complexes.

Scheme 13. Asymmetric epoxidation of olefins catalyzed by Fe–aminobenzimidazolecomplexes.

Scheme 11. Asymmetric epoxidation of diverse olefins catalyzed by Fe–ami-nopyridine complexes.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2061

Focus Review

deficient olefins, thereby yielding the product in moderatelygood enantioselectivities (Scheme 15).[27] Furthermore, the au-

thors also observed that the use of sterically demanding car-boxylic acid instead of acetic acid as additive could improve

the enantioselectivities of this Mn-catalyzed epoxidation reac-tion.

In 2012, Costas et al. also reported a chiral bis-pyrrolidine-

based ligand bearing modified pyridine rings as ligand armsfor the Mn-catalyzed asymmetric epoxidation using hydrogen

peroxide as oxidant (Scheme 16). In this case the productswere provided in high yields albeit with low to moderate

enantioselectivities.[28]

In 2012, Sun et al. described a Mn-catalyzed asym-metric epoxidation by employing a tetradentate N-

ligand containing chiral bis-pyrrolidine and benzimi-dazole moieties (Scheme 17). Under the optimum re-action conditions, high to excellent enantioselectivi-ties were achieved when using chalcones and cis-dis-

ubstituted olefins as substrates.[29] In contrast, rela-tively poor facial control was observed in the cases

of terminal, cis-disubstituted olefins, and a,b-unsatu-rated esters.

Costas et al. and Bryliakov et al. discovered inde-pendently that introduction of electron-donatingsubstituents to the pyridine rings of the aminopyri-

dine ligands led to the enhancement of both the effi-ciency and enantioselectivities of the Mn-catalyzed

epoxidation with hydrogen peroxide as terminal oxi-dant (Schemes 18 and 19).[30, 31] In the cases of a,b-un-saturated carbonyl compounds and chromenes as

substrates the products were yielded with high enan-tioselectivities. Furthermore, Costas et al. studied the

use of the Mn complex for the diastereoselective ep-oxidation of unsaturated steroids and the results re-

vealed that the formation of ß-epoxides was favored whenusing the Mn catalysts.

In 2013, Gao et al. developed a porphyrin-inspired chiralMn–amino-oxazoline complex and applied it successfully in the

asymmetric epoxidation of a variety of olefins using aqueous

hydrogen peroxide as the terminal oxidant (Scheme 20).[32, 33] Inthe cases of trans-stilbene and cyclic olefins such as indene, di-

hydronaphthalenes, as well as chromenes as precursors, theproducts were furnished in good to excellent enantiomeric ex-

Scheme 14. Asymmetric epoxidation of unfunctionalized olefins catalyzedby Mn–porphyrin complexes.

Scheme 15. Asymmetric epoxidation of olefins catalyzed by Mn–aminopyri-dine complexes.

Scheme 16. Asymmetric epoxidation of olefins catalyzed by an Mn–aminopyridine com-plex.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2062

Focus Review

cesses. Moreover, the authors also observed an in-crease in enantioselectivity when the reactions were

conducted in the presence of an acidic additive.

In 2015, Abdi et al. designed chiral Mn complex 22with an N4-ligand based on the diaminocyclohexane

scaffold, which turned out to be an efficient catalystfor the enantioselective epoxidation of chalcones,

indene, and chromenes to give the products in goodenantioselectivities (Scheme 21).[34] The stereochemis-

try of the diaminocyclohexane ligand was not deter-

mined by the authors.

2.5. Tungsten-Catalyzed Asymmetric Epoxidation

Over the last few decades, the use of peroxotung-

states as catalysts for the epoxidation with H2O2 hasattracted much attention as a result of their high ca-

pability for oxygen transfers and low activity for dis-proportion of H2O2. Recently, our group developedthe first tungsten-catalyzed asymmetric epoxidationof allylic and homoallylic alcohols.[35] Under the catal-

ysis of our W–bishydroxamic acid (BHA) catalyticsystem both primary, secondary, and tertiary allylic as

well as homoallylic alcohols were successfully em-ployed as precursors of the asymmetric epoxidation reactionto furnish the products generally with excellent enantioselec-tivities (Scheme 22). Notably, the reactions were performedunder air and in most cases at room temperature, and requir-

ing no anhydrous solvent or preparation of the metal-complexcatalyst prior to the catalytic process.

Moreover, this method demonstrates good chemoselectivityfor primary alcohols over secondary and tertiary alcohols. Forinstance, two farnesol derivatives bearing three olefins and

two alcohol moieties were reacted as precursors of the epoxi-dation reaction; they provided the corresponding products in

almost complete regioselectivities in favor of the oxidation ofthe C=C double bond, which is closer to the primary alcohol

(Scheme 23). These results promised the use of this method inthe late stage of the synthesis of complex molecules.

3. Organocatalyzed Asymmetric Epoxidationusing Hydrogen Peroxide as Oxidant

3.1. Amine-Catalyzed Asymmetric Epoxidation

The reaction of hydrogen peroxide with an a,ß-unsaturated

ketone or aldehyde to form an epoxide was described alreadyin 1921 by Weitz and Scheffer.[36] In 2004, Jørgensen et al. de-

veloped the first secondary-amine-catalyzed asymmetric epoxi-dation of a,b-unsaturated aldehydes with aqueous hydrogen

Scheme 17. Asymmetric epoxidation of olefins catalyzed by an Mn–amino-benzimidazole complex.

Scheme 18. Asymmetric epoxidation of diverse olefins catalyzed by an Mn–aminopyridine complex.

Scheme 19. Asymmetric epoxidation of diverse olefins catalyzed by Mn–aminopyridinecomplexes.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2063

Focus Review

peroxide as oxidant.[37] This method was shown toprovide good yields and high enantioselectivities.Later, the research group of List reported that less

sterically demanding primary amines were to able topromote enantioselective epoxidation of a,b-unsatu-rated ketones.[38, 39] According to the generally accept-

ed mechanism for this type of epoxidation, the reac-tion consists of a cascade of an iminium-mediated

oxa-Michael reaction with H2O2 as nucleophile and anenamine-mediated intramolecular a-oxygenation of

the carbonyl group (Scheme 24).

Recent mechanistic studies on this reaction report-ed by Jørgensen et al. indicate that the hydrate or

peroxyhydrate of the product serves as a phase-transfer catalyst, which can increase the reaction rate

through its autoinductive effect.[40] Relying on thisobservation, the authors discovered that the use of

chloral hydrate as additive accelerated the reactionsignificantly (Scheme 25). Thus, this organocatalyticepoxidation method was greatly improved in termsof the efficiency and applicability in industry.

The seminal work of List et al. demonstrated thatcinchona alkaloid-derived primary amines or their

salts are powerful catalysts for the asymmetric epoxi-dation of a broad substrate scope including a-

branched a,b-unsaturated aldehydes, aliphatic lineara,b-unsaturated ketones, and small, medium andlarge-ring-sized cyclic a,b-unsaturated ketones, which

provide the products generally in high enantioselec-tivities (Scheme 26).[41, 42] Furthermore, this primary-

amine-catalyzed epoxidation was found to havea complete stereoconvergence, since the use of the E

or Z isomer of the olefin as the substrate resulted in

the same enantiomer. These results indicate that E/Zmixtures can be employed as precursors without on-

erous separation. Notably, in the cases of challenging sub-strates such as cyclopentenones and a-branched enals, the use

chiral acids as additives was required to achieve high enantio-selectivities. Limitations of this method are observed in the

cases of aromatic enones, terminal enones, and tri- and tetra-

substituted aliphatic a,b-unsaturated ketones, which failed togive the products or provided the products in low yields.

3.2. Peptide-Catalyzed Asymmetric Epoxidation

Generally, peptide-catalyzed asymmetric epoxidation can beclassified into two categories : 1) Juli�–Colona epoxidation em-

Scheme 20. Asymmetric epoxidation of diverse olefins catalyzed by an Mn–amino-oxazo-line complex.

Scheme 21. Asymmetric epoxidation of diverse olefins catalyzedby an Mn–diaminocyclohexane complex.

Scheme 22. W–BHA-catalyzed asymmetric epoxidation of allylic and homoallylic alcohols.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2064

Focus Review

ploying oligopeptides to control the reactivity of hydrogen

peroxide through a nucleophilic epoxidation mechanism; and2) electrophilic epoxidation using peptide-embedded chiral

carboxylic acids or ketones as catalysts, which can be convert-ed into the corresponding peracids or dioxiranes in situ, re-

spectively (Scheme 27).

In the 1980s, Juli� and Colona introduced poly-l-leucine asa catalyst for the enantioselective epoxidation of chalcone and

its derivatives.[43] Recent studies on this type of reaction basedon NMR spectroscopy and modeling by Berkessel et al. re-

vealed that high enantioselectivity can be achieved with atleast five l-leucine residues, whereas the reaction rate reaches

a plateau at approximately 12 residues.[44] In 2011, Demizu andKurihara et al. synthesized a series of l-leucine-rich heptapepti-

des containing l-serine, d-serine, and l-homoserine derivativesat their third and seventh positions (Scheme 28).[45] These sta-

pled helical heptapeptides turned out to be successful cata-lysts for the asymmetric epoxidation of a,b-unsaturated ke-

tones. Under the optimum reaction conditions, the productswere obtained in good to excellent enantiomeric excesses.

Miller et al. developed a series of peptide-based catalysts

containing aspartic acid for regio- and enantioselective epoxi-dation of allylic alcohols (Scheme 29).[46–48] By using this ap-proach, farnesol and its analogues were selectively epoxidizedat a certain position, which was controlled by the catalysts em-

ployed. Hexapeptide 30 activated the allylic alcohols througha hydroxyl-directing mechanism to provide 2,3-epoxy alcohols

as the major products. In contrast, under the catalysis of pen-

tapeptide 31 the epoxidation proceeded favoring the internalolefin of farnesol giving the 6,7-epoxy alcohol with good regio-

selectivity, albeit with moderate enantioselectivity. Further-more, this method was also applicable to the asymmetric ep-

oxidation of simple allylic alcohols. In the case of cis olefins theproducts were obtained in high yields and enantiomeric ex-

cesses. In the catalytic cycle the terminal carboxylic acid of as-

partic acid is converted into a peracid under the activation ofa stoichiometrical amount of diisopropylcarobodiimide with 1-

hydroxybenzotriazole and N,N-dimethylaminopyridine as cata-lysts. Subsequently, the oxygen atom is transferred from the

peracid to the olefin yielding the epoxide as a product and re-leasing the catalyst for the next catalytic cycle.

The same research group also developed peptide-based cat-

alyst 32, which has a terminal trifluoromethyl ketone and canbe converted into a transient dioxirane with hydrogen perox-

ide as terminal oxidant (Scheme 30).[49] The active species diox-irane turned out to be capable of transferring the oxygen

atom to an olefin in an enantioselective manner. Generally, theproducts were afforded only in moderately good enantiomeric

excess.

3.3. Phase-Transfer-Catalyzed Asymmetric Epoxidation

Chiral phase transfers are also known to be able to catalyze

the asymmetric epoxidation of electron-deficient olefins usinghydrogen peroxide as oxidant. For instance, in 2013 Chen et al.reported an efficient H2O2-mediated epoxidation of ß-trifluoro-methyl ß,ß-disubstituted enones catalyzed by quinidine-de-rived quaternary ammonium salt 33 (Scheme 31).[50] This

method afforded ß-trifluoromethyl a,ß-epoxy ketones bearinga quaternary stereocenter in high yields and excellent stereose-

lectivities. Notably, the catalyst employed could be simply recy-cled through filtration and reused with retained catalytic activi-

ty and selectivity. Furthermore, this reaction was up-scaled to

a gram scale and the product was still obtained with excellentresults. With respect to the mechanism, the authors proposed

a plausible transition state, in which a hydrogen peroxideanion is captured by the catalyst as countercation and the

enone is activated through a hydrogen bond together withp,p stacking.

Scheme 23. W–BHA-catalyzed regioselective epoxidation of the farnesol de-rivatives.

Scheme 25. Secondary-amine-catalyzed asymmetric epoxidation of a,b-unsa-turated aldehydes with chloral hydrate as additive.

Scheme 24. General mechanism for the amine-catalyzed asymmetric epoxi-dation of a,b-unsaturated aldehydes and ketones.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2065

Focus Review

3.4. Oxaziridinium-Salt-Catalyzed Asymmetric Ep-oxidation

Chiral oxaziridinium salts are highly active catalysts

for asymmetric epoxidation of unfunctionalized ole-fins. Generally, this reaction requires oxone as the

stoichiometric oxidant and converts the precatalystiminium salt into an active species, oxaziridinium salt,

which is then able to transfer the oxygen atom to

the olefins. In 2013 Page and co-workers reportedthe first use of hydrogen peroxide as terminal oxi-

dant with diphenyl diselenide as a crucial additive inthe asymmetric epoxidation of a trisubstituted alkene

to provide the product in good yield and enantiose-lectivity (Scheme 32).[51] In the plausible catalytic

cycle benzeneperseleninic acid is generated through

the oxidation of diphenyl diselenide by hydrogenperoxide. Subsequently, the oxaziridinium required

for the enantioselective epoxidation is formed by oxi-dizing the iminium precatalyst with benzenepersele-

ninic acid as oxidant. In the next step the oxygenatom is transferred from the oxaziridinium to the

olefin in a stereoselective manner.

4. Conclusion and Outlook

In this review the most recent advances in the fieldof asymmetric epoxidation using hydrogen peroxide

as oxidant are covered. In recent years, tremendousprogress has been achieved in this area by employ-

ing both transition metals and organocatalysts. Theasymmetric epoxidation using hydrogen peroxide asoxidant provides a simple, direct, and highly stereo-

selective way to access versatile epoxides under mildand environmentally benign reaction conditions. No-

tably, the substrate scope now includes various types

Scheme 26. Primary-amine-catalyzed asymmetric epoxidation of a,b-unsaturated ketonesand aldehydes.

Scheme 27. Peptide-catalyzed asymmetric epoxidations.Scheme 28. Peptide-catalyzed asymmetric epoxidation of a,b-unsaturatedketones.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2066

Focus Review

of alkenes ranging from unfunctionalized olefins and a,b-unsa-turated carbonyl compounds to allylic and homoallylic alco-

hols. Despite the rapid progress in recent years, the asymmet-ric epoxidation using hydrogen peroxide as oxidant is still in

its adolescence with a largely synthetic potential. Further find-ings and contributions in this attractive field are expected to

extend the scope of substrates and to improve thecatalytic turnover and stereoselectivity by developing

new catalytic systems.

Acknowledgements

Japan Science Promotion Foundation (JSP-ACT-C)and the National Institutes of Health (NIH,

2R01M068433) are greatly appreciated for providing

financial support. C.W. thanks the Alexander vonHumboldt Foundation for his postdoctoral fellow-

ship.

Keywords: asymmetric synthesis · catalysis ·epoxidation · hydrogen peroxide · olefins

[1] For recent selected general reviews on asymmetric epoxida-tion, see: a) T. Katsuki, V. S. Martin, Org. React. 1996, 48, 1 –300; b) T. Katsuki in Comprehensive Asymmetric Catalysis,Vol. 2 (Eds. : E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,Berlin, 1999, pp. 621 – 648; c) W. Adam, A. Zhang, Synlett2005, 37, 1047 – 1072; d) E. M. McGarrigle, D. G. Gilheany,Chem. Rev. 2005, 105, 1563 – 1602; e) Q.-H. Xia, H.-Q. Ge, C.-P. Ye, Z.-M. Liu, K.-X. Su, Chem. Rev. 2005, 105, 1603 – 1662;f) O. A. Wong, Y. Shi, Chem. Rev. 2008, 108, 3958 – 3987.

[2] T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102,5974—5976.

[3] W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacobsen, J. Am.Chem. Soc. 1990, 112, 2801 – 2803.

[4] R. Irie, K. Noda, Y. Ito, N. Matsumoto, T. Katsuki, Tetrahedron :Asymmetry 1991, 2, 481 – 494.

[5] a) Y. Tu, Z.-X. Wang, Y. Shi, J. Am. Chem. Soc. 1996, 118,9806 – 9807; b) L. Shu, Y. Shi, Tetrahedron Lett. 1999, 40,8721 – 8724; c) L. Shu, Y. Shi, Tetrahedron 2001, 57, 5213 –5218; d) C. P. Burke, L. Shu, Y. Shi, J. Org. Chem. 2007, 72,6320 – 6323.

[6] Z. Li, H. Yamamoto, Acc. Chem. Res. 2013, 46, 506 – 518.[7] For reviews on epoxidation of olefins with hydrogen perox-

ide, see: a) I. W. C. E. Arends, R. A. Sheldon, Top. Catal. 2002,19, 133 – 141; b) G. Grigoropoulou, J. H. Clark, J. A. Elings,Green Chem. 2003, 5, 1 – 7; c) B. S. Lane, K. Burgess, Chem.Rev. 2003, 103, 2457 – 2474; d) G. De Faveri, G. Ilyashenko,M. Watkinson, Chem. Soc. Rev. 2011, 40, 1722 – 1760; e) A.Russo, C. De Fusco, A. Lattanzi, ChemCatChem 2012, 4, 901 –916.

[8] K. Matsumoto, Y. Sawada, B. Saito, K. Sakai, T. Katsuki,Angew. Chem. Int. Ed. 2005, 44, 4935 – 4939; Angew. Chem.2005, 117, 5015 – 5019.

[9] A. Berkessel, T. Gìnther, Q. Wang, J. M. Neudçrfl, Angew.Chem. Int. Ed. 2013, 52, 8467 – 8471; Angew. Chem. 2013,125, 8625 – 8629.

[10] Q. Wang, J.-M. Neudçrfl, A. Berkessel, Chem. Eur. J. 2015, 21,247 – 254.

[11] A. Berkessel, M. Brandenburg, E. Leitterstorf, J. Frey, J. Lex,M. Sch�fer, Adv. Synth. Catal. 2007, 349, 2385 – 2391.

[12] D. Xiong, X. Hu, S. Wang, C. X. Miao, C. Xia, W. Sun, Eur. J.Org. Chem. 2011, 4289 – 4292.

[13] K. Matsumoto, C. Feng, S. Handa, T. Oguma, T. Katsuki, Tetra-hedron 2011, 67, 6474 – 6478.

[14] a) Y. Sawada, K. Matsumoto, S. Kondo, H. Watanabe, T. Ozawa, K. Suzuki,B. Saito, T. Katsuki, Angew. Chem. Int. Ed. 2006, 45, 3478 – 3480; Angew.Chem. 2006, 118, 3558 – 3560; b) K. Matsumoto, Y. Sawada, T. Katsuki,Synlett 2006, 3545 – 3547; c) K. Matsumoto, Y. Sawada, T. Katsuki, PureAppl. Chem. 2008, 80, 1071 – 1077; d) Y. Shimada, S. Kondo, Y. Ohara, K.Matsumoto, T. Katsuki, Synlett 2007, 2445 – 2447; e) K. Matsumoto, T.

Scheme 29. Peptide-catalyzed regio- and enantioselective epoxidation of allylic alcohols.

Scheme 30. Peptide-catalyzed asymmetric epoxidation of unfunctionalized olefins.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2067

Focus Review

Oguma, T. Katsuki, Angew. Chem. Int. Ed. 2009, 48, 7432 – 7435; Angew.Chem. 2009, 121, 7568 – 7571.

[15] E. P. Talsi, D. G. Samsonenko, K. P. Bryliakov, Chem. Eur. J. 2014, 20,14329 – 14335.

[16] J. L. Jat, S. R. De, G. Kumar, A. M. Adebesin, S. K. Gandham, J. R. Falck,Org. Lett. 2015, 17, 1058 – 1061.

[17] Y. Chu, X. Liu, W. Li, X. Hu, L. Lin, X. Feng, Chem. Sci. 2012, 3, 1996 –2000.

[18] Y. Chu, X. Hao, L. Lin, W. Chen, W. Li, F. Tan, X. Liu, X. Feng, Adv. Synth.Catal. 2014, 356, 2214 – 2218.

[19] J. T. Groves, R. S. Myers, J. Am. Chem. Soc. 1983, 105, 5791 – 5796.[20] P. Le Maux, H. F. Srour, G. Simonneaux, Tetrahedron 2012, 68, 5824 –

5828.[21] N. Amiri, P. Le Maux, H. Srour, H. Nasri, G. Simonneaux, Tetrahedron

2014, 70, 8836 – 8842.[22] O. Y. Lyakin, R. V. Ottenbacher, K. P. Bryliakov, E. P. Talsi, ACS Catal. 2012,

2, 1196 – 1202.[23] O. Cussû, I. Garcia-Bosch, X. Ribas, J. Lloret-Fillol, M. Costas, J. Am.

Chem. Soc. 2013, 135, 14871 – 14878.

[24] O. Cussû, X. Ribas, J. Lloret-Fillol, M. Costas, Angew. Chem.Int. Ed. 2015, 54, 2729 – 2733; Angew. Chem. 2015, 127,2767 – 2771.

[25] X. Wang, C. Miao, S. Wang, C. Xia, W. Sun, ChemCatChem2013, 5, 2489 – 2494.

[26] A. Murphy, G. Dubois, T. D. P. Stack, J. Am. Chem. Soc. 2003,125, 5250 – 5251.

[27] R. V. Ottenbacher, K. P. Bryliakov, E. P. Talsi, Adv. Synth. Catal.2011, 353, 885 – 889.

[28] I. Garcia-Bosch, L. Gûmez, A. Polo, X. Ribas, M. Costas, Adv.Synth. Catal. 2012, 354, 65 – 70.

[29] D. Shen, C. Miao, S. Wang, C. Xia, W. Sun, Eur. J. Inorg. Chem.2014, 5777 – 5782.

[30] R. V. Ottenbacher, D. G. Samsonenko, E. P. Talsi, K. P. Brylia-kov, ACS Catal. 2014, 4, 1599 – 1606.

[31] O. Cussû, I. Garcia-Bosch, D. Font, X. Ribas, J. Lloret-Fillol, M.Costas, Org. Lett. 2013, 15, 6158 – 6161.

[32] W. Dai, J. Li, G. Li, H. Yang, L. Wang, S. Gao, Org. Lett. 2013,15, 4138 – 4141.

[33] W. Dai, S. Shang, B. Chen, G. Li, L. Wang, L. Ren, S. Gao, J.Org. Chem. 2014, 79, 6688 – 6694.

[34] N. C. Maity, P. Kumar Bera, D. Ghosh, S. H. R. Abdi, R. I. Kureshy, N. H.Khan, H. C. Bajaj, E. Suresh, Catal. Sci. Technol. 2014, 4, 208 – 217.

[35] C. Wang, H. Yamamoto, J. Am. Chem. Soc. 2014, 136, 1222 – 1225.[36] E. Weitz, A. Scheffer, Ber. Dtsch. Chem. Ges. 1921, 54, 2327 – 2344.[37] M. Marigo, J. Franz¦n, T. B. Poulsen, W. Zhuang, K. A. Jørgensen, J. Am.

Chem. Soc. 2005, 127, 6964 – 6965.[38] X. Wang, C. M. Reisinger, B. List, J. Am. Chem. Soc. 2008, 130, 6070 –

6071.[39] C. M. Reisinger, X. Wang, B. List, Angew. Chem. Int. Ed. 2008, 47, 8112 –

8115; Angew. Chem. 2008, 120, 8232 – 8235.[40] R. L. Davis, K. L. Jensen, B. Gschwend, K. A. Jørgensen, Chem. Eur. J.

2014, 20, 64 – 67.[41] O. Lifchits, M. Mahlau, C. M. Reisinger, A. Lee, C. FarÀs, I. Polyak, G. Go-

pakumar, W. Thiel, B. List, J. Am. Chem. Soc. 2013, 135, 6677 – 6693.[42] A. Lee, C. M. Reisinger, B. List, Adv. Synth. Catal. 2012, 354, 1701 – 1706.[43] a) S. Juli�, J. Masana, J. C. Vega, Angew. Chem. Int. Ed. Engl. 1980, 19,

929 – 931; Angew. Chem. 1980, 92, 968 – 969; b) S. Juli�, J. Guixer, J.Masana, J. Rocas, S. Colonna, R. Annuziata, H. Molinari, J. Chem. Soc.Perkin Trans. 1 1982, 1317; c) S. Colonna, H. Molinari, S. Banfi, S. Juli�, J.Masana, A. Alvarez, Tetrahedron 1983, 39, 1635 – 1641; d) S. Banfi, S. Co-lonna, H. Molinari, S. Juli�, J. Guixer, Tetrahedron 1984, 40, 5207 – 5211.

[44] a) A. Weyer, D. D�az, A. Nierth, N. E. Schlçrer, A. Berkessel, ChemCatChem2012, 4, 337 – 340; b) A. Berkessel, N. Gasch, K. Glaubitz, C. Koch, Org.Lett. 2001, 3, 3839 – 3842.

[45] Y. Demizu, N. Yamagata, S. Nagoya, Y. Sato, M. Doi, M. Tanaka, K. Naga-sawa, H. Okuda, M. Kurihara, Tetrahedron 2011, 67, 6155 – 6165.

[46] P. A. Lichtor, S. J. Miller, Nat. Chem. 2012, 4, 990 – 995.[47] P. A. Lichtor, S. J. Miller, J. Am. Chem. Soc. 2014, 136, 5301 – 5308.[48] N. C. Abascal, P. a. Lichtor, M. W. Giuliano, S. J. Miller, Chem. Sci. 2014, 5,

4504 – 4511.[49] D. K. Romney, S. J. Miller, Org. Lett. 2012, 14, 1138 – 1141.[50] S. Wu, D. Pan, C. Cao, Q. Wang, F.-X. Chen, Adv. Synth. Catal. 2013, 355,

1917 – 1923.[51] B. R. Buckley, C. E. Elliott, Y. Chan, N. Dreyfus, P. C. B. Page, Synlett 2013,

24, 2266 – 2270.

Manuscript received: March 26, 2015

Accepted Article published: June 9, 2015

Final Article published: July 14, 2015

Scheme 31. Asymmetric epoxidation of ß-trifluoromethyl ß,ß-disubstituted enones cata-lyzed by chiral phase transfer.

Scheme 32. Asymmetric epoxidation catalyzed by a chiral oxazirindiniumsalt.

Chem. Asian J. 2015, 10, 2056 – 2068 www.chemasianj.org Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim2068

Focus Review

本文献由“学霸图书馆-文献云下载”收集自网络，仅供学习交流使用。

学霸图书馆（www.xuebalib.com）是一个“整合众多图书馆数据库资源，

提供一站式文献检索和下载服务”的24 小时在线不限IP

图书馆。

图书馆致力于便利、促进学习与科研，提供最强文献下载服务。

图书馆导航：

图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具