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Chiral Tertiary Alcohols Made By Catalytic Enantioselective Addition of Unreactive Zinc Reagents to Poorly Electrophilic Ketones.

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Organometallic Reactions
Chiral Tertiary Alcohols Made By Catalytic
Enantioselective Addition of Unreactive Zinc Reagents
to Poorly Electrophilic Ketones?
Diego J. Ramn and Miguel Yus*
alcohols · asymmetric catalysis · C C coupling ·
enantioselectivity · zinc
owadays, the generation of tertiary carbon-atom stereocenters can be
achieved easily in most cases by using
the appropriate chiral auxiliary, reagent,
or catalyst. However, the approach to
complex compounds bearing quaternary
stereocenters, such as tertiary alcohols
and related systems, is still a challenge
for synthetic organic chemists, and every
enantioselective procedure for the construction of a fully substituted carbon
center is of great value.[1] Among the
different approaches for the synthesis of
this type of compound, such as kinetic
resolution, enantioselective desymmetrization, oxidation, cyclization, electrophilic alkylation, and nucleophilic addition, those which involve stereoselective
C C bond formation are of particular
interest, since one C C bond and one
stereoelement are created in only one
synthetic step.
The simplest approach for the preparation of chiral tertiary alcohols is the
enantioselective addition of organometallic reagents to a ketone.[2] Although
there are several examples of the addition of organolithium[3] and Grignard[4]
reagents to ketones, at least one equivalent of a generally expensive and
difficult-to-prepare chiral ligand is compulsory in all cases. To reduce the
amount of chiral ligand required, an
organometallic reagent with lower nu-
[*] Dr. D. J. Ram"n, Prof. Dr. M. Yus
Departamento de Qu'mica Org)nica
Facultad de Ciencias
Universidad de Alicante
Apdo. 99, 03080-Alicante (Spain)
Fax: (+ 34) 96-590-3549
cleophilic character is usually considered. However, under these new conditions, and to guarantee the success of
the reaction, the chiral system must
determine not only the topological
course of the reaction but also the
chemical reaction itself. This new role
of the catalyst system may be achieved
by either activating the organometallic
reagent or, in the most classical sense, by
activating the carbonyl compound.
Some catalyst systems are able to activate both the nucleophile and the carbonyl compound at the same time.[5]
Organozinc reagents are the ideal
candidates for this type of reaction since
their nucleophilic character is very low.
In fact, it is well known that they do not
add to aldehydes in noncoordinating
solvents. This behavior has permitted
the development of a plethora of chiral
promoters[6] such as amino alcohols,
diols, and disulfonamides, these two last
type of compounds usually in combination with titanium tetraisopropoxide.[7]
In this way the catalyzed enantioselective addition of organozinc reagents to
aldehydes has been achieved with excellent enantioselectivity. However, the
situation is more complicated when the
electrophilic substrate in the reaction is
a ketone. Ketones are less reactive
electrophiles than aldehydes, and the
addition does not take place even when
promoters are used and the reaction is
conducted at high temperatures. Either
the starting ketone is recovered unchanged or products arising from the
reduction of the ketone are obtained.[8]
That was the status until the beginning of 1998, when Dosa and Fu published the first catalytic enantioselective
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200301696
addition of a large excess of diphenylzinc to ketones 1 promoted by 3-exo(dimethylamino)isoborneol (daib, 2) in
the presence of methanol to yield the
corresponding chiral benzyl alcohols 3
(Scheme 1).[9, 10] A simple mechanistic
Scheme 1. Phenylation of ketones according
to Dosa and Fu. RT = room temperature.
study showed that the catalytic cycle, as
well as active species, should be similar
to those described for the corresponding
aldehyde reaction. A phenyl group is
exchanged for a methoxide on the zinc
atom of the chiral Lewis acid, and the
chiral system activates the ketone and
the zinc reagent simultaneously. The
success of this reaction was attributed,
on the one hand, to the increase of the
Lewis acidity of the zinc atom due to the
presence of a methoxide moiety, and, on
the other hand, to the higher reactivity
of diphenylzinc. This reagent does not
Angew. Chem. Int. Ed. 2004, 43, 284 –287
have hydrogen atoms in a-position, and
consequently, the formation of zinc
hydride and subsequent reduction processes are limited or prevented.
By following this approach Cozzi[11]
has been able to perform the alkynylation of ketones with simple acetylene
derivatives, excess dimethylzinc, and the
chiral salen derivative 4 (Scheme 2). In
this case, as previously mentioned, the
activation by the active catalytic species
takes place on both reagents. The chiral
salen 4 is deprotonated to form the
corresponding diphenolate–zinc system,
which is acidic enough to chelate the
ketone effectively. At the same time,
one oxygen atom of the chiral ligand can
chelate the alkynylzinc reagent, activat-
Scheme 3. Alkynylation of a-ketoesters according to Jiang and co-workers. Tf = CF3SO2.
Six years ago we
found that hydroxycamphorsulfonamide
9 catalyzes the enantioselective addition of
different simple dialkylzinc reagents to
ketones in the presence of titanium tetraisopropoxide.[13] The
reaction yielded the
expected tertiary alcohols 12 with good-tomodest yields and
(Scheme 4). A preliminary mechanistic study
showed: a) a small
nonlinear effect (when
Scheme 2. Alkynylation of ketones according to Cozzi.
amount of the chiral
ligand is used) which
ing it and yielding the postulated cata- disappeared when the reaction was
lytic active species.
A simpler alkynylation process was amounts of the chiral ligand; b) the
developed by Jiang's group.[12] They enantioselectivity was independent of
were able to carry out the alkynylation chemical yield; and c) the enantioselecof a-ketoesters by using different sub- tivity was highly dependent on the bulk
stituted acetylenes as the nucleophile of the ligand. All these facts were similar
source and simultaneously as the solvent to those previously described for the
(Scheme 3). In this case, the zinc acety- known reaction with aldehydes. As a
lide is formed as a reactive intermediate consequence, a similar catalytic cycle
in the course of reaction. However, it is and species involved were proposed for
still unclear what is activated: the nu- this new reaction. In other words, the
cleophile, electrophile, or both. Never- catalytic species was postulated to be a
theless, it must be pointed out that the dinuclear titanium complex, in which
reaction works only for highly electro- one titanium atom bears the chiral
philic ketones such as a-ketoesters, ligand and the ketone and the other
titanium atom bears the alkyl moiety,
providing, in general, excellent results.
Angew. Chem. Int. Ed. 2004, 43, 284 –287
and the two metal centers are connected
by two isopropoxy bridges.
The assumption of this dinuclear
catalytic species calls our attention to
the possibility of improving the ligand
by eliminating the floppy isopropoxy
bridges in the catalytic species. The new
ligand would be able to bind to two
titanium atoms at the same time. In this
way, by playing with the length and
angles of the covalent linker, we could
approach both titanium atoms and place
them at the ideal separation for this
addition. In the screening of different
diamines as the covalent linker, o-xylylendiamine emerged as the best one.
The chiral ligand 10 synthesized with
this linker led to improved results, and
this improvement depended on the reaction conditions.[14] However, the results with ketones were not as good as
those with aldehydes, which encouraged
further improvement of the chiral system.
The next idea was to use in the
system a linker with less conformational
freedom such as 1,2-cyclohexanediamine. Walsh's group,[15] coming from
another starting point, and we,[16] as
result of the aforementioned ideas, both
independently synthesized trans-1,2bis(hydroxycamphorsulfonamido)cyclohexane (hocsac, 11). This ligand is an
excellent promoter for the enantioselective addition of dialkylzinc reagents to
any kind of ketones, even dialkyl ketones, with titanium tetraisopropoxide.
The reaction is the fastest and the
conditions are the mildest reported so
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
unsaturated ketone (89 % ee)
in the asymmetric key step in
the synthesis of ( )-frontalin.[17]
The hocsac ligand 11 works
nicely not only for the addition
of dialkylzinc reagents to ketones but also for the addition
of related arylzinc reagents,
and the enantioselectivity remains high (up to 96 % ee).[18]
The high enantioselectivity is
maintained even when arylboronic acids were used as starting
materials for the preparation of
the corresponding arylzinc intermediates in situ.
The final example was reported by DiMauro and Kozlowski, who designed their
chiral salen ligand 13 to be able
to chelate at the same time one
titanium atom, following alkoxy interchange on titanium
tetraisopropoxide, and one
zinc atom, through coordination of the nitrogen atom by
diethylzinc (Scheme 5).[19] In
this way the titanium Lewis
Scheme 4. Alkylation of ketones according to Ram"n and Yus.
acid center activates the aketoester by coordination to
far. The results obtained were compara- the carbonyl oxygen atom, while the
ble to those for the related addition to nucleophile is activated at the same
aldehydes. For example, this ligand has time. Although the reaction is described
been used to promote the addition of only for a-ketoesters, which are very
dimethylzinc to a functionalized a,b- electrophilic ketones, and the results are
Scheme 5. Alkylation of a-ketoesters according to DiMauro and Kozlowski.
2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
still far from excellent, this approach
should impel the search for other, better
catalytic ligands.
As corollary of the results presented
along this short overview on the catalytic enantioselective addition of organozinc reagents to ketones, the answer
to the question formulated in the title is
now totally positive. The final objective
of this article would be achieved if, and
only if, it chemists can be motivated to
apply this very useful addition to the
synthesis of more complicated structures, and also develop new ligands as
promoters for this promising reaction.
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2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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