nucleophiles (homoenolate equivalents) by attack of a nucleophilic catalyst, such as N-heterocyclic carbenes (NHCs), on the aldehyde functionality .
Asymmetric carbon-carbon bond forming reactions using umpolung chemistry are found in nature. Vitamin B1
functions as a cofactor for thiamin diphosphate-dependent
enzymes, including transketolase, pyruvate
decarboxylase, and acetolactate
synthase, to catalyze the formation of stabilized acyl anion intermediates.5
In addition, high enantioselectivities and yields can be obtained using an
asymmetric variant. Stetter6 extended nucleophilic
carbene catalysis to the reaction of acyl anion equivalents with activated Michael acceptors.
TYPES OF UMPOLUNG:
Carbonyl
umpolung
A classic example of polarity inversion is observed in dithiane chemistry. Ordinarily the oxygen atom in the
carbonyl group is more electronegative than the carbon atom and therefore the
carbonyl group reacts as an electrophile at carbon.
This polarity can be reversed when the carbonyl group is converted into a dithiane or a thioacetal 7.
In synthon terminology the ordinary carbonyl group is
an acyl cation and the dithiane is a masked acyl anion.
When the dithiane is derived from an aldehyde such as acetaldehyde the acyl
proton can be abstracted by n-butyllithium in THF at
low temperatures. The thus generated 2-lithio-1, 3-dithiane reacts as a nucleophile in nucleophilic displacement
with alkyl halides such as benzyl bromide, with other carbonyl compounds such
as cyclohexanone or oxiranes
such as phenyl-epoxyethane, shown below. After
hydrolysis of the dithiane group the final reaction
products are α-alkyl-ketones or
α-hydroxy-ketones.8
Enone
umpolung
In ordinary nucleophilic
conjugate additions the β-carbon atom acts as an electrophile.
In special cases this position can be modified to react as a nucleophile. The active catalyst is not palladium compound
but a triazole derived persistent carbene.This
carbene reacts with the α,β-unsaturated
ester at the β-position forming the intermediate enolate9.In
the Baylis-Hillman reaction the same electrophilic β-carbon atom is attacked by a reagent
but resulting in the activation of the α-position of the enone as the nucleophile.
Amine umpolung
The nitrogen atom in the amine group is reacting as a nucleophile by way of its lone pair. This polarity can be
reversed when a primary or secondary amine is substituted with a good leaving
group (such as a halogen atom or an alkoxy group)
10. The resulting N-substituted compound can behave as an electrophile at the nitrogen atom and react with a nucleophile as for example in the electrophilic
amination of carbanions.
Reversible
Umpolung
Reversible umpolung is of greatest
synthetic value. A compound having a C
atom
rendered positive is transformed, into a derivative in which the originally electrophilic C atom has now become nucleophilic11.
Postulates and
Nomenclature of Umpolung Chemistry 12
1. The reactions most
frequently used in organic synthesis are polar in nature, i. e. nucleophilic
or donor (d) and electrophilic or
acceptor
(a) sites are used to make and break bonds.
2. The large majority of
target molecules of organic synthesis contain the heteroatoms
nitrogen and oxygen as functional groups (amino, imino, hydroxy, ether, carbonyl).
3. These heteroatoms impose an alternating acceptor and donor
reactivity pattern.
4. A consequence and
synthetic limitation is the fact that combination of
components
with reactivity.
5. According to the
original proposition, synthons are
"structural units within a molecule which are related to possible
synthetic operations. Thus, the molecule is related with the substrate synthon and the formyl synthon. This is
irrespective of the type of reaction employed (polar, radical pericyclic, transition-metal mediated, photo chemical,
electrochemical).
6. An
a or d"-synthon is, respectively, a synthon with an O- or N-heteroatom at C'
and an
acceptor or donor center at such synthons .An a"-
or
d"-synthon is an acceptor or donor heteroatom (O
or N),
respectively.
7. A reagent is
the
compound or intermediate actually used to carry out the synthetic operation.
Synthetically equivalent reagents or
series of
reactions perform identical transformations.
8. A
reagent
has normal reactivity if it corresponds to a synthon of general type umpolung
is present in a reagent in which a and
d-centers are reversed as compared to functional group.
9.
When
discussing particular transformations, the names of the structural units
under consideration are used with the corresponding
reactivity symbols; newly formed bonds are indicated in bold type.
10. A
reaction or reagent which differentiates between sites of identical
reactivity in a conjugate system called as (ambidoselective).
METHODS OF
REACTIVITY UMPOLUNG:13,14.
·
1.2n-Oxidation
A
process creating an oxygen and/or -nitrogen functionalized carbon skeleton
without formation of a C-C bond is an oxidation (conservative
conversion, non-connective). As can be seen, many classical reactions and their
recent improvements are among the examples: epoxidation,
hydroxylation, oxygenation, amination,
oxidation and imination, ozonolysis,
hydroboration /oxidation,
the Neber, Bayer-Villiger and Criegee-Hock rearrangements the Hofmann-Lomer-Freytag,
and the Barton reaction. We are dealing with cases in which the heteroatoms oxygen and nitrogen have become acceptor
(sextet or septet) sites rather than acting as donors. Umpolung of heteroatom reactivity;
equal polarity at adjacent heteroatoms R-O-O-R, R2N-NR.
Since
the methodology of generating and selectively using reagents with electrophilic N or O is rather limited, there are numerous techniques
which use other acceptor heteroatoms that are
subsequently replaced by oxygen or nitrogen.
·
Exchange and Modification of the
Heteroatom
Nitrogen,
unlike oxygen, has so many oxidation states and occurs in
a
multitude of bonding situations that it can be “modified” to allow for jumping
back and forth between the two reactivity patterns. Organic chemistry is not
restricted to the elements C, H, N; O We can utilize all the
elements of the periodic chart to achieve the goal of
synthesizing C, H, N, O-containing products and to break out of the
reactivity pattern. The most common and best-established systematic way of
reactivity umpolung of N- or O-functionalized
molecules is the temporary exchange of these heteroatoms
by others, which convey opposite reactivity to the carbon
moiety. Thus, we use derivatives of other heteroatoms
like a boat to cross a river.
1.
Heteroatom Exchange
The lack of methods, which clearly introduce
nitrogen and oxygen at donor sites. The use of BrO as an electrophilic substitute heteroatom is a classical solution
to this problem. When the desired C-N bond is formed, the nitrogen acts as a nucleophile, the carbonyl carbon as an electrophile;
The use of
a-chloronitrones and of sr-hetev substituted
oxime and hydrazone
ketone reagents in C-C-bond
forming processes has recently been demonstrated. Sulfur in particular
stabilizes positive and negative charges in the a-position, and there
are numerous ways of removing all three heteroatoms
from a molecule. Allow the coupling of carbon atoms of
the same
polarity recent improvements and promising developments in this general area
are the so called redox condensations with phosphanes and the conversion of
NH2
into the leaving group N (SO2R) 2.The temporary
replacement of the heteroatom oxygen by sulfur for the preparation of 1,2 di-functionalized products.
2.
Heteroatom Modification
In
contrast to oxygen, which can hardly be modified to allow without the help of
heteroatom exchange, nitrogen is a very rich heteroatom
in this respect. There are two fundamental reasons for this nitrogen can make
one more bond with carbon and thus be incorporated "in the middle" of
conjugated systems, and it has many more oxidation states. Thus,
modification of the nitrogen of methylamine in the Schiff-base with benzophenone allows a-N-CH-deprotonation
of umpolung of amine reactivity with pyridoxal in Nature and converts the normal aminoalkylating reactivity of iminium
derivatives. On the other hand, we can convert the amine (oxidation state -3)
into the nitronate (oxidation state +5) and use this
as an amino methyl donor reagent. We need not go all the way to the nitro or diazo group to achieve a-N-CH acidification and a-N-C-donor
properties. Any amine derivative, which bears an electron-withdrawing group
causing a partial positive charge on nitrogen, appears to suffice under
appropriate conditions.
·
Homologation and Its Reversal
Any
compound with a 1.3-functionalization has the normal reactivity pattern with
respect to one of the two functional groups and reactivity umpolung
of the other one. After a reaction with an acceptor at C2, which in
this case is at the same time a d'- and a d'"
center,
the C-C bond leading to C' can be cleaved (reversal of homologation, degradation).
·
Use of Cyclopropanes
Opening
of
a cycloalkane with an odd number of carbon atoms and with substituents by donors and acceptors, respectively,
constitutes yet another principal method of reactivity umpolung.
It
is
related to the homologative method of the previous
section by also rendering normal reactivity the resemblance becomes even closer
if we consider that this kind of process is most likely to occur with cyclopropanes (110 kJ/mol strain release), the next higher
homologues of “cycloethanes”. In the field of
heterocyclic chemistry and natural product synthesis, the construction of
pyrrolines, pyrrolidines,
tetrahydrofurans, lactones and β-lactams is a problem of reactivity umpolung because in all of these five-membered rings, the chain of carbon atoms is Ia
bifunctionalized. It is therefore not
surprising that cyclopropanes have been widely
applied in this area.
·
Acetylenes
Acetylenes
are extremely versatile synthetic intermediates.” The highly reactive,
"strained" triple bond can be attacked by electrophiles
or nucleophiles terminal acetylenes are rather strong
acids and the acetylides obtained by deprotonation are very good, non-hindered nucleophiles. Acetylene itself is therefore a welcome
moiety for the synthesis of bifunctional systems.An
advantageous stereochemical aspect is that disubstituted alkynes can be selectively hydrogenated to (E)
or
(Z)-olefins. If acetylene is attached to a molecule of normal
reactivity a carbon framework with reactivity umpolung.
One finds that the ultimate reagents with reactivity umpolung
are oxirane.
·
Redox
Reactions
The
simplest method of reactivity umpolung is the
addition or removal of electrons in a system, which is electrophilic
or nucleophilic, respectively. This will of course
reverse the reactivity of the species. Thus, we can reduce ketones
and aldehydes to pinacols
and esters to acyloinsby electrochemical
methods
or with metals further reduction leads to olefins which can now be obtained
directly from ketones with lower alkali metal, is
readily accomplished. While we do not normally cleave pinacols and olefins by such simple methods. The
products mentioned-except for the olefin-are bifunctional
and have been made by joining carbon atoms of the same polarity. We formally
obtain these products, if we assume that half of the starting molecules
are converted into reagents with reactivity umpolung
and then couple with the other half of normal reactivity. In
reality, of course, radical anion or cation coupling
furnishes the products in most cases. Therefore, it is difficult to prepare
cross-coupling products in better than statistical amounts, unless we carry out
intramolecular reaction.
·
Direct Umpolung
and Substrate Umpolung 15,16
1. Direct Umpolung
If
reactivity umpolung is observed without using one of
the
methods described above we call it direct umpolung. Carbon monoxide and
isocyanides are simple one-carbon reagents which can be attacked by a donor and
an
acceptor and compare Thus, if carbon monoxide, an olefin and water combine to
give a carboxylic acid under strongly acidic conditions the CO-carbon atom
formally combines with a carbenium ion and OH
Isonitriles are used in the Passerini- and Ugi-reactions to
prepare a-hydroxy and a-amino carboxylic acid
derivatives, respectively; given proper substitution. We realize that it is
arbitrary to say that CO and CNR are reagents with direct umpolung.
2.
Substrate umpolung
By
definition, umpolung must be reversible: the final
goal is to make IO, N-derivatives of normal reactivity. A
reversible umpolung is a
sequence
of operations by which functional group can be temporarily reversed. And this is not
possible with all the methods mentioned in the previous sections. We arrive at
a certain stage of a synthesis where we need to perform the conversions (ah)-(ak), this would be a task much
more difficult than constructing a "small" reagent molecule with
reactivity umpolung. We are here concerned with a
more complex molecule whose functional groups must be compatible with all
operations necessary to achieve the umpolung.
Therefore, this may be called a substrate umpolung.
APPLICATIONS:
1. Synthesis of
(+)-alliacol A
2. In the construction of arteannuin
ring skeletons17
3. Synthesis of
(+)-nemorensic acid
4. Thiamine Catalyzed Benzoin
Reaction 19
5. Synthesis of α-Amino
Acids by Umpolung of Weinreb
Amide Enolates 20
6.Synthesis
of Atorvastatin.21
7.Synthesis
of Nifedipine. 21
RECENT UMPOLUNG REACTIONS CATALYZED BY N-HETEROCYCLIC
CARBENES 18
Fig: NHC as Catalyst
1.Enantioselective
intramolecular Stetter
reaction
2.Enantioselective
synthesis of quaternary stereocenters via intramolecular Stetter reaction.
3.Highly
enantioselective and diastereoselective
intramolecular Stetter
reaction.
4.Synthesis
of Functionized preanthraquinones.
5.NHC
Catalyzed addition of acylstilanes to α,β-unsaturated
systems.
CONCLUSION:
Umpolung
chemistry provides a doorway to otherwise non-accessible reactivity patterns.
The fact that umpolung chemistry reverses the
“normal” traditional reactivity patterns imposed by heteroatoms
in alkyl chains is not only intellectually interesting but synthetically useful
as well. The discovery of NHCs as powerful organocatalysts
reactions has led to unprecedented reaction outcomes with great potential for
the asymmetric construction of interesting natural products. Continue to
dominate both recent antibiotic product launches and companies’ late-stage drug
development pipelines…” It is quite evident that natural products will remain
as our primary source of biologically active pharmacophores.
It is our job as synthetic organic chemists to find efficient routes to these
valuable scaffolds.
REFRENCES:
1. Seebach,
D. Angew. Chem. Int. Ed. Engl. 1979, 91, 259-278.
2. Breslow,
R. J. Am. Chem. Soc. 1958, 80, 3719-3726.
3. Enders, D.; Balensiefer, T. Acc. Chem.
Res. 2004, 37, 534-541.
4. Johnson, J. S. Angew. Chem. Int. Ed.
2004, 43, 1326-1328.
5. Ugai,
T.; Tanaka, S.; Dokawa, S. J. Pharm. Soc. Jpn. 1943, 63, 269-300. (Chem. Abstr.
1951, 45, 5148.)
6.
Stetter, H. Angew. Chem. Int. Ed. Engl. 1976,
15, 639-647.
7.
Mihelcic,
J.; Moeller, K. D. J. Am. Chem. Soc. 2003,125, 36.
8.
Liu, B.; Duan,
S.; Sutterer, A. C.; Moeller, K. D. J.Am. Chem. Soc. 2002, 124, 10101.
9.
Sun, H.; Moeller, K. D. Organic
Letters 2003, 5,3189 and references therein.
10.
Smith, A. B.; Adams, C.M. Acc. Chem.
Res. 2004, 37, 365-377.
11. Chan, A.; Scheidt, K. Org. Lett. 2005, 7, 905-908.
12.
Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1899-1902.
13.
Dieter Seebach,
Methods of Reactivity Umpolung,
Ailyew. Clwm.
Int.
Ed.
Engl. 18, 239-258 (1979).
14.
Seebach
D. (1979). "Methods of Reactivity Umpolung".
Angewandte Chemie
International Edition in English 18 (4): 239–258.
15.
Kerr, M. S.; Rovis,
T. J. Am. Chem. Soc. 2004, 126, 8876-8877.
16.
Hachisu,
Y.; Bode, J.; Suzuki, K. J. Am. Chem. Soc. 2003, 125,8432,
8433.
17.
Mattson, A. E.; Bharadwaj,
A. R.; Scheidt, K. A. J. Am. Chem.Soc.
2004, 126, 2314-2315.
18. Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6,
4363-4366.
19.
Sebastian Hirner, Donata
K. Kirchner and Peter Somfai, Synthesis of α-Amino Acids by Umpolung
of Weinreb Amide Enolates Eur. J. Org. Chem. 2008, 5583–5589
20.
Fischer C., Smith S. W., Powell D. A.,
Fu G. C. (2006). "Umpolung of Michael Acceptors
Catalyzed by N-Heterocyclic Carbenes". Journal
of the American Chemical Society 128 (5)
21. Enders,
Acc. Chem. Res. 2004, 37, 534.
Received on 04.09.2009
Accepted on 07.09.2009
© A &V Publication
all right reserved
Research J. Science
and Tech. 1(1): July-Aug. 2009: 08-12