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Organolithiums in Enantioselective Synthesis . (Series Topics in Organometallic Chemistry Vol. 5.). Edited by David M

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cusses a number of physicochemical
parameters and explains how they can
be measured experimentally or calculated, the reader actually learns little
about the concepts or strategies of
optimizing drug performance by a physicochemical approach. The relevance
and relationships of the different parameters in the realm of physicochemical
properties remains shrouded in mystery,
and the author fails to mention their
importance in early studies of plantderived drugs. The subject of amphiphilic behavior is not mentioned at all.
That rather dull contribution is followed by a really excellent review on the
prediction of “Toxicity and Metabolism”, by M. T. D. Cronin. The author
presents a balanced and critical look at
QSAR methods and rule-based expert
systems, discussing and evaluating their
strengths and weaknesses, illustrated by
examples. This highly informative article ends with a comprehensive bibliography and details of the main providers
of commercial prediction systems.
Suddenly, one has reached the end
of the book, and here one would like to
see the guiding hand of the editors
returning to the general theme and
addressing the question: in what directions must drug research develop during
the coming decades, if one accepts that
the key to greater performance is to be
found in an intelligent combination of
the different technologies described?
The book began with that credo, and at
the end one expects at least the formulation of a hypothesis for consideration,
but nothing is offered. One could imagine that the contributors themselves
might be asked to give their visions for
the future. That would also allow an
opportunity to look at the whole range
of methods from a practical standpoint,
to assess how each of the different
technologies contributes to a sharply
focused research process, and to form a
view about how it can or should develop
in the future.
The usefulness of the book could
certainly have been increased by covering several other topics that it neglects
or fails to treat adequately. Virtual
screening methods are hardly mentioned at all, and an article on earlystage formulation development would
have given additional significance to the
measurement or prediction of physico-
chemical parameters. A separate contribution on methods for predicting pharmacokinetic end-points in the early
stages of research could have been
included, as it is widely recognized that
many drug candidates fail in the later
stages of development because of
unsuitable pharmacokinetic properties.
Lastly, the success of a drug-discovery
program depends on effective data
processing; issues concerning the availability of information and the need to
learn from whatever information is
available for the purpose of prediction
are, unfortunately, too often neglected.
These criticisms are mainly directed
at the failure of the book to live up to
the claims at the beginning, which leaves
the reader rather disappointed at the
end, as there was the possibility that
something new could have emerged.
However, if one reads the book as a
collection of information, it must be said
that it contains some excellent review
articles. Although a few of the articles
are of limited value, they do not greatly
diminish the overall quality, and therefore I have no hesitation in recommending readers to buy the book. It is suitable
for students of chemistry and pharmacology, and for everyone in the pharmaceutical industry who is directly
involved in the search for new drugs
and can benefit from a concise and
mainly up-to-date survey of some
selected techniques and methods.
Nikolaus Heinrich
Schering AG
Berlin (Germany)
, 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Organolithiums in
Enantioselective Synthesis
(Series: Topics in
Chemistry, Vol. 5.).
Edited by David M.
Hodgson. Springer
Verlag, Heidelberg
2003. 320 pp.,
E 235.00.—ISBN
Volume 5 in the Springer series Topics
in Organometallic Chemistry emphasizes the importance of organolithium
compounds in enantioselective synthesis. These compounds are among the
most highly reactive nucleophiles and
are also some of the strongest bases, and
consequently they have applications in
almost every area of organic chemistry.
This volume describes enantioselective
reactions in which organolithium
reagents are used, in particular additions, deprotonations, and rearrangements, which have been developed in
the last few decades and used in organic
After an introductory survey of this
broad subject by the editor, the main
body of the book consists of eight
chapters. In Chapter 1, B. Goldfuss discusses enantioselective additions of
organolithium compounds to aldehydes
and ketones, and also to sterically
strained cyclic ethers and acetals. The
factors that lead to high enantioselectivity in these ligand-controlled additions are discussed. The author describes
work on the development and applications of chiral amine and alcohol ligands
over a period of 30 years. The discussion
covers not only the enantioselectivities
achieved but also the structures of the
chiral modified organolithium systems
used, both in solution and in the solid
phase, as well as their kinetics and the
role of achiral additives. The development of an enantioselective synthesis of
the anti-AIDS drug Efavirenz is a particularly striking example of successful
collaboration on problems of synthesis,
which involves contributions from NMR
studies, X-ray crystallography, and
quantum-mechanical calculations.
Angew. Chem. Int. Ed. 2004, 43, 778 – 781
Chapter 2, by K. Tomioka and coauthors, is concerned with enantioselective 1,4-additions of organolithium compounds to Michael acceptors and 1,2additions to C¼N groups. The authors
discuss the effects of auxiliaries such as
SAMP- or RAMP-hydrazones covalently bonded to the electrophile, and
in the organolithium system the use of,
for example, chiral lithiated sulfoxides.
Chiral amines or aminoethers serve as
external ligands for enantioselective 1,2additions to C¼N groups.
In Chapter 3, D. Hoppe and coauthors describe organolithium compounds with a-O substituents and their
enantioselective syntheses and reactions. These lithium-1-oxyalkanides can
be prepared by tin–lithium exchange,
from thioacetals by reductive lithiation,
or by lithiation of C–H groups. The
latter direct lithiation can be achieved
using dialkyl carbamate functions, even
in cases where there is stabilization by
conjugation. Following reaction with an
electrophile, the alcohol can be released
by reductive removal of the carbamoyl
group. In this way a wide variety of
stereoselective lithiations are possible,
and can be used, for example, in the
synthesis of HIV-protease inhibitors.
Under the influence of suitable external
chiral diamines, in particular ()-spartein, it is possible to obtain enantiomerically pure lithium-1-oxyalkanides. The
authors discuss the mechanisms of the
enantioselective lithiation of alkyl carbamates and of the subsequent reactions. A wide variety of enantioselective
reactions of configurationally labile
lithiated benzyl and alkenyl carbamates
can be carried out by using ()-spartein;
for example, stereoselective homoaldol
additions become possible. The lithiation of propargyl functions via alkynyl
carbamates can be used to synthesize
chiral allenes.
Chapter 4, by P. Beak and coauthors, describes lithiations in the aposition relative to a nitrogen atom and
the subsequent reactions with electrophiles. Such a-lithiations can be promoted by using directing groups, in
particular by introducing amino func-
Angew. Chem. Int. Ed. 2004, 43, 778 – 781
tions into carbamates by BOC-bonding.
By using chiral external ligands such as
()-spartein it is possible to achieve
thermodynamic or kinetic separation of
racemates, or to introduce electrophiles
enantioselectively, for example to prepare a-substituted pyrrolidines. In particular, lithium benzylides with a nitrogen atom in the a-position can serve as
versatile building blocks for the synthesis of alkaloids using covalently
bonded auxiliaries, or by using external
ligands with N-substituted lithium-allyl
anions one can synthesize chiral enamines or (following hydrolysis) chiral asubstituted ketones.
In Chapter 5, S. Nakamura and coauthors discuss a-lithiated organosulfur,
organoselenium, and organophosphorus
compounds. Here again, by using chiral
external ligands, lithiated sulfides, sulfoxides, sulfones, or dithioacetals can be
coupled enantioselectively to electrophiles. Enantioselective Horner–Wadsworth–Emmons olefinations can be
used for the desymmetrization of 4alkylcyclohexanones. a-Lithiated phosphanes or phosphanoxides are especially important as sources for preparing
enantiomerically pure ligands.
Chapter 6, by Hodgson and coauthors, is concerned with enantioselective rearrangements of a-lithiated
ethers. The authors discuss [1,2], [2,3],
and [1,4] Wittig rearrangements, as well
as retro-Brook and phosphate–phosphonate rearrangements. a-Lithiation
with an amide base converts epoxides
into carbenoids, which, following ringopening, give deprotected carbenes
which can undergo 1,2-hydride rearrangements, cyclopropanations, or C–H
insertions. Here again, external chiral
ligands, especially ()-spartein, can be
used to achieve enantioselective reactions.
Chapter 7, by J. Clayden, deals with
the synthesis of compounds with planar
or axial chirality using organolithium
compounds. These in turn can be used to
synthesize a wide variety of ferrocene
and chromarene systems. They also
provide the basis for syntheses of axially
chiral biaryls and other atropisomers, as
well as chiral allenes.
In Chapter 8, J. F. Norman describes
enantioselective carbolithiations, which
are classified into inter- and intramolecular additions to non-activated olefins.
Here again, chiral external ligands, in
particular ()-spartein, can play a valuable role. The volume is completed by
a detailed index.
Inevitably, there are a few instances
of overlapping between the chapters
(e.g., in discussions of a-lithiated
alkoxy groups). However, as the editor
explains in his introduction, these are
not without value, as they provide
insights into a particular topic from
different expert viewpoints. In some
areas the authors discuss not only the
advantages of organolithium chemistry
but also its weaknesses, for example
when one is concerned with stoichiometric reactions compared with catalytic reactions.
To cover this very large subject,
which has grown in size over several
decades and continues to develop rapidly, in such a compact form, as in this
volume, was certainly a demanding task,
but it has been done successfully.
Through the sensible choice of topic
areas and by the arrangement of the
material under different headings (types
of electrophiles in addition reactions,
the nature of the a-heteroatom, types of
rearrangements, chirality of the products), the reader is given easy access to
this complex subject.
As this volume is the first comprehensive survey of enantioselective organolithium reactions, and by describing
many highly topical reactions emphasizes the enormous potential of organolithium reagents in enantioselective synthesis, it will be very useful to every
chemist working in the area of stereoselective synthesis.
Bernd Goldfuss
Institut f5r Organische Chemie
Universit7t K8ln (Germany)
DOI: 10.1002/anie.200385063
, 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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topic, chemistry, organometallic, synthesis, series, organolithiums, edited, enantioselectivity, david, vol
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