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988 Chem. Soc. Rev., 2012, 41, 988–999 This journal is c The Royal Society of Chemistry 2012
Cite this: Chem. Soc. Rev., 2012, 41, 988–999
Recent developments in the field of oxa-Michael reactions
Carl F. Nising*aand Stefan Brase*
b
Received 20th June 2011
DOI: 10.1039/c1cs15167c
Oxa-Michael reactions, i.e. addition reactions of oxygen nucleophiles to conjugated systems, have
traditionally received much less attention from the scientific community compared to the addition
of carbon nucleophiles to conjugate acceptor systems (Michael reaction). This was mainly due
to lack of reactivity and selectivity of these reactions. Within the last few years however, there
has been a remarkable increase in publications focussing on method development as well as
applications to natural product synthesis. This tutorial review discusses instructive examples that
have substantially broadened the scope of oxa-Michael reactions.
Introduction
The addition of carbon nucleophiles to conjugate acceptor
systems, which is commonly known as Michael addition, is
nowadays one of the most versatile and widely applied
methods in organic synthesis. Over the last decades, tremen-
dous progress has been made in the fields of stereoselective,
catalytic or broadly applicable Michael reaction protocols,
just to give some examples.1 Until quite recently, hetero-
Michael reactions such as the aza-Michael, sulfa-Michael,
phospha-Michael and oxa-Michael (sometimes also called
oxo- or oxy-Michael) reactions have received considerably
less attention of the synthetic community.2–5 This is rather
astonishing given the fact that the first example of an
oxa-Michael addition, i.e. the addition of an alcohol to a
conjugate acceptor, was published by Loydl as early as 1878
(for nowadays common reaction pathways see Scheme 1).6
Major drawbacks of oxa-Michael reactions typically are
reversibility of the alcohol addition step as well as the
relatively poor nucleophilicity of the employed alcohols. This
renders especially intermolecular oxa-Michael reactions
challenging. On the other hand, this type of reaction offers
tremendous synthetic potential since the products available are
a Bayer Pharma AG, Aprather Weg 18a, D-42113 Wuppertal,Germany. E-mail: [email protected];Fax: +49 202 36 8149; Tel: +49 202 36 5276
bKarlsruher Institut fur Technologie (KIT), Fritz-Haber-Weg 6,Campus Sud, D-76131 Karlsruhe, Germany.E-mail: [email protected]; Fax: +49 721 608 48581;Tel: +49 721 608 42902
Carl F. Nising
Carl Nising was born in 1979in Troisdorf, Germany. Hestudied chemistry at theUniversity of Bonn where hereceived his diploma degree in2003. He then moved to theUniversity of Karlsruhe (TH)where he obtained his PhDunder the supervision ofProfessor Stefan Brase in2006. After performing post-doctoral studies at HarvardUniversity with ProfessorAndrew G. Myers, he joinedBayer Cropscience AG in2007, working in the area of
crop protection research. In July 2011 he moved to BayerPharma AG where he is currently a head of laboratory inmedicinal chemistry. Since 2010 he has also been holding alecturer position at the Karlsruhe Institute ofTechnology (KIT).
Stefan Brase
Stefan Brase studied inGottingen, Bangor (UK) andMarseille and received hisPhD in 1995, after workingwith Armin de Meijere inGottingen. After post-doctoralappointments at UppsalaUniversity (Jan E. Backvall)and The Scripps ResearchInstitute (K. C. Nicolaou),he began his independentresearch career at the RWTHAachen in 1997 (associated toDieter Enders). In 2001, hefinished his Habilitation andmoved to the University of
Bonn as a professor for organic chemistry. Since 2003, he hasbeen a full professor at the Karlsruhe Institute of Technology inGermany. His research interests include methods in drug-discovery (including drug-delivery), combinatorial chemistrytowards the synthesis of biologically active compounds, totalsynthesis of natural products and nanotechnology.
Chem Soc Rev Dynamic Article Links
www.rsc.org/csr TUTORIAL REVIEW
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This journal is c The Royal Society of Chemistry 2012 Chem. Soc. Rev., 2012, 41, 988–999 989
valuable intermediates in organic synthesis. The structural
motif of b-hydroxyketones and a-aminoalcohols can be found
in a variety of natural products and important synthetic
intermediates.7 Moreover, oxa-Michael reactions often grant
efficient access to oxygen-containing heterocycles such as
tetrahydropyrans, chromenes or xanthones which can often
be found within natural products (Fig. 1).8
This prompted us in 2008 to compile a review on oxa-
Michael reactions highlighting the synthetic potential and
limitations of these reactions.9 Since then, the number of
publications dealing with the development of synthetic proto-
cols or the application of oxa-Michael reactions in total
synthesis has increased significantly. For example, various
efficient protocols for organocatalytic oxa-Michael reactions
have been developed (compare Scheme 1, path B) and the
reaction has been successfully embedded in domino reaction
pathways, giving rise to complex heterocyclic systems. In our
opinion, these efforts have substantially broadened the scope
of oxa-Michael reactions. Therefore, this tutorial review aims
at giving an update on the developments in the field within the
last three years. A special focus will be given to (organo)-
catalytic reaction protocols and the application to the synth-
esis of heterocycles and natural products.
New synthetic protocols for oxa-Michael reactions
As outlined in Scheme 1, the oxa-Michael reaction is parti-
cularly suitable for the rapid generation of molecular complexity
when it is embedded in domino reactions. The enolates
generated by addition of alcoholates to conjugate acceptors
are potent nucleophiles which can further react with suitable
electrophiles. Menche et al. used this reactivity to combine
Scheme 1 Common oxa-Michael reaction pathways.
Fig. 1 Synthetic potential of the oxa-Michael reaction.
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990 Chem. Soc. Rev., 2012, 41, 988–999 This journal is c The Royal Society of Chemistry 2012
an oxa-Michael reaction with a Tsuji–Trost coupling
(Scheme 2).10
In this context, readily available homoallylic alcohols 1
react with a conjugate acceptor system 2 giving rise to an
intermediate enolate 3. With the formation of a p-allylcomplex out of the olefinic moiety in 3, an electrophile is
generated which reacts with the previously generated enolate
in an intramolecular allylic substitution reaction leading to
highly substituted tetrahydropyrans 5. This protocol not only
combines an oxa-Michael reaction with a metal-catalyzed
reaction in an unprecedented way, but also generates three
stereogenic centres and thereby rapidly increases molecular
complexity. After much experimentation palladium dibenzyli-
deneacetone (Pd2(dba)3) was identified as one of the suitable
palladium sources together with lithium tert-butoxide as a base.
A selection of tetrahydropyrans that were synthesized employing
nitroolefins as acceptor systems is depicted in Fig. 2. Notably a
high degree of stereocontrol could be achieved given the fact that
up to eight different stereoisomers can potentially be generated in
this process. The already discussed reversibility of oxa-Michael
reactions together with an energetically favoured Zimmerman–
Traxler-type transition state were discussed as key reasons for the
stereocontrol. This seminal work will certainly inspire further
research in the field combining oxa-Michael reactions with other
metal-mediated reactions.
Another key contribution to the field of new synthetic
protocols for the oxa-Michael reaction came from the group
of Feringa. They reported on the direct, non-enzymatic
hydration of enones with high degrees of enantioselectivity
and diastereospecificity.11 Whereas the enzyme-catalyzed
addition of water to conjugate acceptors is well known and
forms part of important processes such as the citric acid cycle,
reports on the non-enzymatic enantioselective addition have
remained very limited.12 Instead, various detour approaches
were developed to overcome the low nucleophilicity of water
and the reversibility of the addition step which prevent high
degrees of stereocontrol. For example, oximes can be used as
water surrogates which display increased nucleophilicity and
can be easily transformed into the target compounds by
reduction.9 A conceptually similar approach is the use of
boron or silicon nucleophiles followed by oxidative cleavage
of the carbon–element bond.13 As part of their studies on
DNA-based asymmetric catalysis, Feringa and coworkers
employed a copper complex which is positioned in close
proximity to a DNA helix through non-covalent interactions.
With this system, a,b-unsaturated acyl imidazoles could be
converted into the corresponding b-hydroxy carbonyl
compounds with up to 72% enantiomeric excess (Scheme 3).
Interestingly, the highest enantiomeric excesses were determined
at low conversion before the reactions reached equilibrium.
Scheme 2 Oxa-Michael/Tsuji–Trost domino reaction.
Fig. 2 Selection of synthesized tetrahydropyrans. Scheme 3 Enantioselective hydration of enones with a DNA catalyst.
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This is due to the reversibility of the water addition step
and the observation that the kinetically preferred
R-enantiomer is also preferentially dehydrated, leading to a
significant decrease in enantiomeric excess after prolonged
reaction times.
By using D2O instead of water, an equilibrium isotope effect
led to even higher conversion and enantiocontrol. Further
investigations of this catalytic system revealed that the
enantioselectivity is depending on the DNA sequence. By
evaluating various self-complementary oligonucleotides it was
established that central AT base pairs gave the best results.
Moreover, all components of the catalytic system (metal
ion, ligand, DNA) seem to be essential for achieving high
reactivity and enantiocontrol. Although the substrate scope
seems to be quite limited for the moment, this work represents
the first example of direct enantioselective oxa-Michael reac-
tions using homogeneous catalysis.
Regarding intramolecular oxa-Michael reactions, an inter-
esting contribution was published by You and coworkers.14
They developed a desymmetrization protocol for cyclohexa-
dienones using chiral phosphoric acids (Scheme 4). After a
preliminary catalyst screening phosphoric acid 10 bearing very
bulky substituents close to the catalytic center was shown to
give the best results. Using optimized reaction conditions, a
variety of cyclohexadienones which are readily available from
aromatic precursors by oxidative dearomatization could be
transformed into the corresponding bicyclic systems with high
yields and enantiomeric excesses.
Interestingly, the substituent at the 4-position of the cyclo-
hexanedione starting material had great influence on the
outcome of the reaction with bulkier substituents lowering
both the enantioselectivity and reactivity. In many cases, the
solid state of the products could be used to further improve the
optical purity in a separate recrystallisation step. In order to
demonstrate the scope of the reaction, an intermediate
obtained through the desymmetrization reaction was used
for an efficient asymmetric synthesis of the natural products
Cleroindicin C, D and F. Regarding possible binding modes
the authors referred to the common bifunctional catalyst
model for chiral phosphoric acids which implies that catalyst
10 forms hydrogen bonds via the acidic proton and the PQO
moiety.15
Organocatalytic oxa-Michael reactions
The majority of contributions to the field of oxa-Michael
reactions in recent years are dealing with organocatalytic
oxa-Michael reaction protocols. This is mainly due to the fact
that organocatalysis has rapidly evolved over the last decade
and that conjugate acceptors which are the starting materials
for oxa-Michael reactions offer various possibilities for
organocatalytic activation (see Scheme 1). Therefore, organo-
catalysis was used to address the open challenge of water
addition to conjugate acceptors, mostly by employing
surrogates with higher nucleophilicity such as oximes or
hydrogen peroxide. On the other hand, oxa-Michael reactions
were often embedded in organocatalytic reaction cascades,
making use of nucleophilic intermediates formed as oxa-
Michael reaction products (Scheme 1). Due to the plethora
of publications in this area we will only discuss a selection in
this review.16
Cordova and coworkers successfully combined an organo-
catalytic oxa-Michael reaction with transition-metal catalysis
for the synthesis of dihydrofurans. The concept of this trans-
formation is depicted in Scheme 5.
It was envisaged that amine catalyzed oxa-Michael reaction
between propargylic alcohols and a,b-unsaturated aldehydes
would lead to enamine intermediates 11 and ent-11. Although
this reaction would typically be reversible and thus lead to low
Scheme 4 Desymmetrization of cyclohexadienones with Brønsted
acids.
Scheme 5 Domino oxa-Michael/carbocyclization reaction.
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992 Chem. Soc. Rev., 2012, 41, 988–999 This journal is c The Royal Society of Chemistry 2012
yields and low stereocontrol, it was reasoned that an ensuing
transition-metal-catalyzed carbocyclization would push the
equilibrium towards C–O bond formation and thus render
the oxa-Michael reaction irreversible. Moreover, it was
expected that enamine 11 would react faster in the carbo-
cyclization step than ent-11 due to less steric hindrance.
Therefore, this process would also represent an example of
organo-catalyzed dynamic kinetic resolution.17 Final isomeri-
zation would then lead to the desired chiral dihydrofurans 12.
After screening various metal sources and chiral amines, a
combination of palladium chloride and amine 13 was
established as the optimal combination (Scheme 6). With this
combination in hand, a variety of a,b-unsaturated aldehydes
could be reacted with propargylic alcohol giving good yields
and excellent stereocontrol.
However, using secondary or tertiary propargylic alcohols
turned out to be more problematic leading to lower yields and
mixtures of diastereoisomers due to the introduction of a
second stereogenic centre.
In an effort to employ alkynals instead of enals in organo-
catalytic domino reactions, Wang and coworkers developed an
efficient access to 4H-chromenes.18 It was reasoned that initial
oxa-Michael addition to an iminium intermediate would lead
to a chiral allenamine which could then act as a nucleophile in
a second reaction step (Scheme 7). Although this approach is
certainly reminiscent of the well-known iminium–enamine
domino reaction using enals, it was complicated by the fact
that alkynals are difficult substrates due to their high reactivity.
Furthermore, chiral allenamines as intermediates are certainly
less studied compared to enamines.
In order to implement this proposed reaction mechanism,
2-(E)-(2-nitrovinyl)phenols 14 were chosen as starting materials
together with a selection of substituted alkynals 15 (Scheme 8).
With these substrates, the reaction leads to 4H-chromenes
featuring one newly generated stereogenic centre as well as
synthetically versatile aldehyde and nitro functionalities. After
optimisation of the reaction conditions and catalyst screening
diarylprolinol silyl ethers turned out to be most effective with
toluene as the optimal solvent. With these conditions in hand,
the scope of the reaction could be further investigated.
It turned out that alkynals bearing aromatic or aliphatic
substituents could be transformed with high yields and
enantiomeric excesses. The same was true for 2-(E)-
(2-nitrovinyl)phenols, where a broad substitution pattern on
the aromatic ring was tolerated. This protocol nicely demon-
strates the power of organocatalytic oxa-Michael reactions
embedded in domino processes for the rapid construction of
molecular complexity.
In further work, the same group extended this concept of
iminium–allenamine chemistry to the oxa-Michael–aldol reaction
between ethyl-2-(2-hydroxyphenyl)-2-oxoacetates and alkynals
to yield 4H-chromenes bearing a quaternary stereogenic centre.19
When taking a closer look at the reaction in Scheme 8 it
becomes obvious that the combination of a salicylic aldehyde
derivative, be it in the form of an ester, imine or nitrovinyl
derivative (as shown) with any kind of conjugate acceptor
(enal, alkynal or nitroolefin), offers an interesting toolbox for
the synthesis of various chromenes through for example
oxa-Michael/aldol, oxa-Michael/aza-Baylis–Hillman or oxa-
Michael/Michael reactions. Indeed, various groups have
worked in this field resulting in numerous publications.19
Aleman and coworkers have published the organo-
catalyzed oxa-Michael/aza-Baylis–Hillman reaction between
salicyl N-tosylimine and alkynals, also using diaryl prolinol
silyl ethers as catalysts (Scheme 9).20
Using this protocol, various 4-amino-4H-chromenes could
be synthesized with high yields and enantiomeric excesses.
In a conceptually similar approach, Xu and coworkers
developed an organocatalytic, enantioselective synthesis of
3-nitro-2H-chromenes through oxa-Michael/Henry reaction
between salicylic aldehydes and nitroolefins (Scheme 10).21
Interestingly, by screening various organocatalysts it turned
Scheme 6 Scope of the domino oxa-Michael/carbocyclization reaction.
Scheme 7 Iminium–allenamine domino reaction.
Scheme 8 Scope of the domino oxa-Michael/Michael reaction for the
synthesis of 4H-chromenes.
Scheme 9 Domino oxa-Michael/aza-Baylis–Hillman reaction.
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out that pyrrolidine–thioimidazole catalyst 18 gave the best
results with regard to yield and enantiomeric excess, whereas
previously discussed diarylprolinol silyl ethers (compare 16,
Scheme 8) turned out to be inefficient. Moreover, benzoic acid
was necessary as a cocatalyst to achieve meaningful enantio-
meric excesses. This was explained with a dual role of catalyst
18. On the one hand, it seems to be involved in the iminium
activation of the aldehyde moiety, which is favoured by the
acid cocatalyst. On the other hand, the basic thioimidazole
moiety could serve to deprotonate the phenolic portion and
thereby promote the oxa-Michael reaction. Under optimized
reaction conditions, several salicylic aldehydes and nitroolefins
could be reacted with medium to good yields and enantiomeric
excesses.
As we have discussed before, the choice of alcohols for oxa-
Michael reactions is often limited to surrogates with higher
reactivity such as phenols or oximes. Consequently, publica-
tions on the application of aliphatic alcohols in oxa-Michael
reactions have remained rather scarce.9 In this context, Vicario
and coworkers recently developed a one-step domino
reaction employing the dihydroxyacetone dimer and various
a,b-unsaturated aldehydes leading to hexahydrofuro[3,4-c]-
furans.22 This reaction is remarkable in several ways. First
of all, four stereogenic centers are formed with a high degree of
stereocontrol. Moreover, a ketone serves as an internal
electrophile whereas in most cases aldehydes are used due to
their higher reactivity. The proposed reaction pathway of this
transformation is depicted in Scheme 11.
The reaction starts with the formation of iminium
intermediate 19, followed by oxa-Michael addition of
dihydroxyacetone which is liberated by retro-dimerization of
dihydroxyacetone dimer 20. The resulting enamine 21 then
reacts in an intramolecular aldol reaction to give furan 22.
Hydrolysis followed by intramolecular hemiacetal formation
then leads to the final hexahydrofuro[3,4-c]furans. In this
reaction pathway, an acid additive such as benzoic acid is
needed to facilitate iminium formation as well as for the
activation of the ketone moiety in intermediate 21. Notably,
the high degrees of stereocontrol observed in this process were
explained by either the fast aldol reaction of 21 or a dynamic
kinetic resolution process (compare Scheme 5) in order to
overcome the reversibility of the oxa-Michael reaction and the
resulting configurational instability. Using optimised reaction
conditions, a variety of enals could be reacted with the
dihydroxyacetone dimer in good yields and excellent stereo-
control (Scheme 12).
In our 2008 review on oxa-Michael reactions we presented
several examples in which water surrogates such as oximes
Scheme 10 Domino oxa-Michael/Henry reaction for the synthesis of
3-nitro-2H-chromenes.
Scheme 11 Reaction pathway for the formation of hexahydrofuro[3,4-c]furans.
Scheme 12 Scope of the hexahydrofuro[3,4-c]furan synthesis.
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994 Chem. Soc. Rev., 2012, 41, 988–999 This journal is c The Royal Society of Chemistry 2012
were used as starting materials due to their higher reactivity.
Shortly after, List and coworkers published an interesting
procedure in which hydrogen peroxide is used in an
organocatalytic oxa-Michael addition to acyclic aliphatic
a,b-unsaturated ketones.23 In the context of developing
enantioselective epoxidation protocols employing hydrogen
peroxide as an oxidant, they realized that peroxyhemiketals
which are formed by oxa-Michael addition of hydrogen
peroxide to the activated enone can be reduced to b-hydroxy-ketones in a one-pot protocol (Scheme 13).
Thus, treatment of enones with catalytic amounts of
cinchona alkaloid derived primary amine 26 (as its salt),
followed by addition of excess hydrogen peroxide, led to
intermediate peroxyhemiketals with high degrees of enantio-
selectivity. These peroxyhemiketals were directly reduced to
the corresponding b-hydroxyketones using triethyl phosphite
in medium yields over two steps. It is interesting to note that
this procedure represents an interesting alternative to proline-
catalyzed aldol reactions which are challenging in the case of
a-unsubstituted aldehydes.
The use of oximes as nucleophiles in (organo)catalytic
oxa-Michael reactions has been pioneered by Jacobsen and
Jørgensen and was already discussed in our previous review.9
In an extension to these studies, Xiao et al. established a useful
protocol for the addition of oximes to b-nitroacrylates(Scheme 14).24 Under optimised reaction conditions, various
aliphatic or aryl b-nitroacrylates can be reacted with p-methoxy-
benzaldehyde oxime in good yields and enantiomeric excesses.
Importantly, the geometry of b-nitroacrylates has a strong
influence on yield and stereocontrol with the (Z)-configuration
giving superior results. The resulting b-nitroesters are versatilesynthetic intermediates since their nitro, ester and alcohol
functionalities offer various options for further derivatization.
Consequently, b2,2-amino acids, oxazolidin-2-ones and
b-lactams could be synthesized in subsequent steps.
N-Heterocyclic carbenes (NHCs) have recently emerged as
broadly applicable organocatalysts in various transformations.25
Scheidt and coworkers have applied NHCs in a highly intriguing
intermolecular oxa-Michael addition of alcohols to various
a,b-unsaturated ketones.26 After optimization it was established
that catalytic amounts of azolium salt 28 (IMes�HCl) in combi-
nation with n-butyllithium and lithium chloride generated the
corresponding b-alkoxy ketones in good yields. As shown in
Scheme 15, a variety of primary and secondary alcohols can be
employed, whereas tertiary alcohols are not suitable substrates,
presumably due to steric hindrance.
The use of a chiral secondary alcohol led to a mixture of
diastereomers, thereby indicating the lack of stereocontrol in
this process. In further studies, it could be established that also
a diverse set of conjugate acceptors can be used, including
substituted enones, a,b-unsaturated esters as well as
b-substituted ynones, thereby demonstrating a broad scope.
With regard to the reaction mechanism, it was postulated that
NHC 28 reacts as a Brønsted base, thus forming an NHC–
alcohol complex (A, Scheme 16).
This complex enables the 1,4-addition of the alcohol giving
rise to enolate B and an imidazolium ion. The lithium counter
ion presumably activates the enone and stabilizes the resulting
enolate. Protonation of the enolate gives rise to the final
product and regenerates the NHC. Interestingly, control
experiments using n-butyllithium without 28 revealed that
significantly lower amounts of the product were formed
together with various side products, underlining the importance
of the NHC. Further studies were directed towards employing
Scheme 13 Synthesis of b-hydroxyketones via peroxyhemiketals.
Scheme 14 Enantioselective addition of oximes to b-nitroacrylates.
Scheme 15 NHC-catalyzed intermolecular oxa-Michael addition.
Scheme 16 Postulatedmechanism of the NHC-catalyzed intermolecular
oxa-Michael reaction.
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chiral NHCs in an enantioselective version of this reaction.
However, only low enantiomeric excesses (10–11%) could be
realized so far. All in all, this work can be seen as a further
milestone in oxa-Michael reactions since it displays a broad
substrate scope, mild reaction conditions and employs a
readily available NHC catalyst. Further applications of this
protocol in the context of domino reactions or natural product
synthesis can certainly be expected in the near future.
Synthesis of oxygen-containing heterocycles
Flavanones are important scaffolds in the context of anti-
tumor and anti-inflammatory therapeutic agents. Moreover,
they can serve as valuable intermediates for pharmaceutical
compounds. Recently, Scheidt and coworkers reported an
organocatalytic enantioselective synthesis of flavanones from
activated a,b-unsaturated ketones using thiourea catalysts.9,27
Feng and coworkers have developed a highly efficient access to
flavanones also using activated a,b-unsaturated ketones and a
chiral nickel (II) complex.28 Optimisation of catalysts and
ligands revealed that N,N0-dioxide complexes based on proline
derivatives as ligands and nickel trifluoroacetylacetonate
(Tfacac) as the metal salt gave the best results. Under these
optimised conditions, a,b-unsaturated ketones with variations
in the phenolic moiety as well as in the olefinic moiety are
suitable substrates for the oxa-Michael reaction (Scheme 17).
Following decarboxylation in a one-pot procedure, flavanones
are obtained in good yields and excellent enantiomeric excesses.
With regard to the efficient synthesis of heterocycles, the
oxa-Michael reaction has proven to be particularly useful for
the synthesis of tetrahydropyran moieties. Consequently, the
reaction has also been used in the total synthesis of complex
natural products.9 Fuwa et al. have published a highly efficient
synthesis of tetrahydropyrans based on a domino olefin cross-
metathesis/intramolecular oxa-Michael reaction.29 The basic
concept of this reaction is that cross-metathesis between a
hydroxy alkene and an enone generates a hydroxy enone
which is then capable of intramolecular oxa-Michael addition.
At this point it was envisioned that promotion of the oxa-
Michael reaction step would require an additional base or a
Lewis acid in order to activate the hydroxy function or a
carbonyl group. However, further optimization showed that
d-hydroxy olefins and vinyl ketones are transformed directly
into the corresponding tetrahydropyrans by using the Hovey-
da–Grubbs second generation catalyst (30) and heating the
reaction mixture in a microwave oven (Scheme 18).
Under the optimized conditions, various tetrahydropyrans
could be synthesized with good yields and high diastereo-
selectivity with 2,6-cis-tetrahydropyrans being the major
isomer. Control experiments indicate that this diastereo-
control originates from kinetic control since the reaction
products do not equilibrate under the reaction conditions.
The role of the cross-metathesis catalyst in the oxa-Michael
reaction also deserves further comment. Further control
experiments with an isolated hydroxy enone (which is
generated in the cross-metathesis step) in the presence of 30
did not yield any product, whereas the same reaction in the
presence of styrene and methyl acrylate gave the target
product in good yield and diastereomeric excess. These results
indicate that an active ruthenium species is generated in situ
during the cross-metathesis step. A successful application
of this protocol for the synthesis of a functionalized bis-
tetrahydropyran was also demonstrated underlining the
versatility of the reaction for natural product synthesis.
Chromans also represent an important class of oxygen
heterocycles since they are present in numerous naturally
occurring structures with biological relevance.30 In the context
of their investigations of phosphine-catalyzed reactions
between salicylaldehydes with allenic ketones and esters, Shi
and coworkers developed an interesting access to functionalized
chromans.31 Reaction of salicylaldimines or salicylaldehydes
with ethyl 2,3-butadienoate catalyzed by tributylphosphine
gives rise to functionalized chromans in good yield and
under mild conditions, albeit with low control of the E/Z-
ratio (Scheme 19).
Scheme 17 Synthesis of flavanones by the Ni(II)-N,N0-dioxide complex.
Scheme 18 Domino cross-metathesis/oxa-Michael reaction.
Scheme 19 Synthesis of functionalized chromans.
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996 Chem. Soc. Rev., 2012, 41, 988–999 This journal is c The Royal Society of Chemistry 2012
In the case of salicylic aldehydes however, E-configurated
chromans were formed exclusively. With regard to the reaction
mechanism, little details have been available so far. Never-
theless, it was postulated that the reaction is initiated by
addition of the phosphine to the allene moiety forming a
zwitterionic intermediate. This intermediate then reacts in a
sequence of nucleophilic addition, oxa-Michael reaction and
phosphine elimination to yield the final products.
Natural product synthesis
Since our initial review, a number of total syntheses of natural
products have been reported using oxa-Michael reactions. The
most important molecules published between 2008 and 2011
are presented in Fig. 3. Due to the large number of relevant
publications, we will only discuss some representative
examples here.32–63
In 2009, Imagawa and Nishizawa et al. reported an
elegant total synthesis of the neurotrophic natural product
neovibsanin B (30).32 One of the key steps in their synthesis is a
domino oxa-Michael/lactonization reaction which was triggered
through fluoride-mediated cleavage of a silyl protecting group
(Scheme 20). This is one of several examples in which depro-
tection of silyl ethers with fluoride sources in the presence
of enone systems directly yields the corresponding oxa-
Michael products.33 This can be explained by the fact that
fluoride-mediated deprotection gives rise to a nucleophilic
alcoholate intermediate which then reacts in an intramolecular
oxa-Michael reaction. In fact, this method seems to be quite
general and should be strategically used in the context of total
synthesis endeavours.
As detailed in the previous chapter, organocatalytic domino
reactions including an oxa-Michael addition step are highly
efficient methods for the synthesis of chromene scaffolds. In
Fig. 3 Selected natural products synthesized using oxa-Michael reactions.
Scheme 20 Total synthesis of neovibsanin B (30).
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this context, Hong et al. applied a quadruple organocatalytic
oxa-Michael/Michael/Michael/aldol-reaction to the straight-
forward total synthesis of the marine metabolite (+)-conicol
(31, Scheme 21).34
In a key step, organo-catalyzed oxa-Michael/Michael
reaction between a suitably substituted 2-(E)-(2-nitrovinyl)-
phenol and 3-methylbut-2-enal led to the corresponding
benzo[c]chromene in excellent yield and enantiomeric excess.
This chromene could then be submitted to a second organo-
catalyzed domino reaction using the same catalyst as before.
In this step, domino Michael/aldol reaction between the
chromene and 4,4-dimethoxy-but-2-enal led to the complete
carbon skeleton of conicol. Importantly, the above mentioned
reaction steps could be combined in one pot, with similar yield
and enantiomeric excess. With the advanced intermediate in
hands, the natural product could be synthesized by means
of several functional group transformations. Again, this
impressive synthesis demonstrates the power of domino
oxa-Michael reactions for the efficient synthesis of oxygen-
containing heterocycles.
In 2006, the disclosure of the cortistatins, a class of
antiproliferative natural products, marked a revival of
steroid-based anticancer lead compounds. Their fascinating
molecular architecture which incorporates a signature abeo-
9(10-19)-androstane-type skeleton together with the impressive
biological activity triggered significant activities by the
synthetic community.35 Consequently, Nicolaou and Chen
developed a synthetic access to cortistatins A and J as well
as analogues thereof.36 In order to build up the central
oxacyclic ring system, they employed an intramolecular
domino oxa-Michael/aldol reaction between a b-hydroxycarbaldehyde and an attached cyclohexenone moiety
(Scheme 22). This base-induced reaction gives rise to an
intermediate incorporating the central cortistatin core in good
yields. Further reactions then led to the final natural products.
Another interesting example for the application of intra-
molecular oxa-Michael reactions in total synthesis comes from
the group of Stratakis.37 In the context of their biosynthesis-
inspired total syntheses of the mycotoxins longianone, patulin
and isopatulin, an oxa-Michael/lactonization sequence was
used for the synthesis of longianone (33, Scheme 23).
Although syntheses of these compounds have been devised
before, these molecules still pose significant synthetic
challenges despite their seemingly simple architecture.
The substrate for the key oxa-Michael reaction, keto enoate
32, is available in two steps from a readily available furan
Scheme 21 Total synthesis of (+)-conicol (31).
Scheme 22 Domino oxa-Michael/aldol reaction in the total synthesis of cortistatins.
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998 Chem. Soc. Rev., 2012, 41, 988–999 This journal is c The Royal Society of Chemistry 2012
precursor. Reaction of 32 with tetra-n-butylammonium
fluoride (TBAF) rapidly results in the formation of an inter-
mediate dihydrofuranone (not shown) which further reacts to
the spirobicyclic compound by lactonization in the presence of
a base. Interestingly, TBAF again turned out to be unique in
its capability to promote the oxa-Michael addition whereas
various acids or bases primarily led to decomposition. The
advanced intermediate could then be transformed into long-
ianone (33) in only one additional oxidative step.
Drug-like molecules and other bioactive molecules
Besides the synthesis of natural products, the oxa-Michael
reaction has been used for drug-like molecules and other
bioactive molecules as well for the synthesis of natural
products analogues/fragments (see e.g. Fig. 4).
The Sodeoka group was able to use the oxa-Michael
reaction for the synthesis of a DEFG-model of the complex
natural product Physalin B.58
In a combinatorial approach, Kapeller and Brase synthe-
sized a number of cannabinoid-like structures using a domino-
oxa-Michael reaction on solid supports.59
Summary and outlook
In this tutorial review we have demonstrated that the oxa-
Michael reaction is an extremely powerful and versatile tool
for the rapid construction of cyclic and acyclic oxygen-
containing building blocks. Although the reaction has been
known for a long time it needs to be stated that the field is far
away from being mature. Overcoming the inherent reactivity
and reversibility issues are only two out of several challenges
discussed before. In our last review from 2008 we stated that
‘‘it can be expected that the true value of this reaction for the
synthesis of carbon-oxygen bonds and heterocyclic moieties
has only started to be revealed’’. The marked increase in
publications dealing with oxa-Michael reactions since then
indicates that this assumption has already turned out to be
correct. Further exciting developments that will further broaden
the scope of the oxa-Michael reaction can be expected in the
near future.
Notes and references
1 T. Tokoroyama, Eur. J. Org. Chem., 2010, 2009; S. Mukherjee,J. W. Yang, S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471;J. Christoffers, G. Koripelly, A. Rosiak and M. Rossle, Synthesis,2007, 1279.
2 For instructive reviews on aza-Michael reactions, see: D. Enders,C. Wang and J. X. Liebich, Chem.–Eur. J., 2009, 15, 11058;J. L. Vicario, D. Badia, L. Carrillo, J. Etxebarria, E. Reyes andN. Ruiz, Org. Prep. Proced. Int., 2005, 37, 513.
3 For sulfa-Michael reactions, see: D. Enders, K. Luttgen andA. A. Narine, Synthesis, 2007, 959.
4 For phospha-Michael reactions, see: D. Enders, A. Saint-Dizier,M. I. Lannou and A. Lenzen, Eur. J. Org. Chem., 2006, 29.
5 In addition to the term oxa-Michael reaction, the terms oxy- and oxo-Michael reaction are also used in the literature. For simplification, theterm oxa-Michael reaction will be used exclusively in this review.
6 F. Loydl, Justus Liebigs Ann. Chem., 1878, 192, 80.7 B. Schetter and R. Mahrwald, Angew. Chem., Int. Ed., 2006,45, 7506.
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Scheme 23 Total synthesis of longianone (33).
Fig. 4 Selected drug-like molecules.
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