Chiral Auxiliaries in Asymmetric Synthesis

David A. Evans, Gçnter Helmchen and Magnus Rçping
Chiral Auxiliaries in Asymmetric Synthesis
David A. Evans, Harvard University, USA, Gçnter Helmchen, Organisch-Chemisches
Institut der Universitåt Heidelberg, Germany, and Magnus Rçping, Johann Wolfgang
Goethe-University Frankfurt, Germany
The use of chiral auxiliaries in the synthesis of enantiomerically pure compounds
has found wide application for a variety of reactions over the last three decades.
Despite the extensive developments in this area by many academic and industrial
research groups, new auxiliary controlled reactions continue to evolve frequently
[1]. First objectives in this area have been to develop chiral enolate-derived reactions, wherein the chiral auxiliary (Xc) is both readily available and easily recovered after the desired bond construction has been achieved (Scheme 1).
Scheme 1 Diastereoselective synthesis with chiral auxiliaries.
Generally, the major issues which have to be addressed in the development of
diastereoselective transformations using chiral auxiliaries are threefold in nature.
Subsequent to a facile introduction, the chiral auxiliary Xc must provide a strong
predisposition for a highly selective enolization process; it must provide a strong
Asymmetric Synthesis – The Essentials.
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Chiral Auxiliaries in Asymmetric Synthesis
Figure 1 Selected chiral auxiliaries which have been successfully applied in asymmetric
bias for enolate diastereoface selection in the new bond construction; and its nondestructive and mild cleavage must occur without racemization of the desired
products. Today an arsenal of chiral auxiliaries is available meeting the above criteria in full or in part. Of the numerous chiral auxiliaries that have been developed over the past years some of the effectively applied auxiliaries are shown
in Fig. 1. The majority of chiral auxiliaries are derived from inexpensive, chiral
natural sources and most of the diastereoselective reactions reported proceed
with high levels of diastereoselection. The most widely employed auxiliary controlled reactions are the asymmetric alkylations, aldol and Diels-Alder reactions.
From the numerous auxiliary controlled reactions reported, a notable early example of an effective diastereoselective alkylation and Diels-Alder reaction has been
developed by the Helmchen group, using the concave camphor-derived chiral auxiliaries 1 and 2 (Scheme 2) [2]. In this asymmetric alkylation procedure, a selective
deprotonation leads to the corresponding E- or Z- ester enolate, which upon reaction with an alkyl halide and subsequent reduction results in enantiopure pure
alcohols, valuable chiral building blocks and synthons for the synthesis of natural
products. Remarkably, both diastereomers can be selectively obtained starting
from the same chiral camphor derivative by simply changing the solvent.
One of the most utilized type of auxiliaries is the class of chiral oxazolidinones
1, initially developed in the Evans group [3]. These chiral imides have been applied to a wide range of asymmetric transformations and the methodology devel-
David A. Evans, Gçnter Helmchen and Magnus Rçping
Scheme 2 Asymmetric alkylations and Diels-Alder reaction using Helmchen’s camphor-derived auxiliaries.
oped has been most successful in the stereoselective construction of numerous
chiral building blocks, as well as natural products, antibiotics and medicinally important compounds. Subsequent to the initial reports regarding oxazolidininone
1, many structural variants (Fig. 2) have been developed which display different
cleavage reactivity or complimentary diastereoselectivity compared to 1.
Figure 2
Selected succeeding
variations of chiral
N-acyloxazolidinone 1.
Chiral Auxiliaries in Asymmetric Synthesis
Oxazolidinones of type 1, which were initially developed for an efficient asymmetric C–C bond construction in the synthesis of several polyketide-derived natural products, have proved to be a gold standard and have continually been employed by the Evans group and numerous other groups over the last 20 years.
The first asymmetric reactions involving these chiral enolate synthons were the
aldol and alkylation reactions. In these reactions selective enolization to form the Zenolates (Z:E i 100) were achieved using either lithium and sodium amide bases
or dibutylboryl trifluorosulfonate. Subsequent alkylation or aldol reaction of the
corresponding metal enolates resulted in the products with highest levels of asymmetric induction (Scheme 3). Based on these seminal observations many other
reactions employing chiral oxazolidinones have been reported over the years
and the application will continue to be of great importance in the future [4].
Scheme 3
Initial asymmetric alkylation, aldol and Diels-Alder reactions.
The original reports on the asymmetric aldol reactions mediated by boron or
titanium resulted in the syn aldol product with very high diastereoselectivity.
More recent studies by the Evans group have demonstrated an extension of the
aldol process, which employs the same oxazolidinone 1 or the thiazolidine thione
2, in the presence of catalytic amounts of magnesium salts, forming the anti aldol
products, which were previously more difficult to access (Scheme 4) [5].
The significant cost effectiveness and facile scale-up of these magnesium halide
catalyzed anti aldol reactions render them valuable methods for the preparation of
various chiral building blocks and biologically important compounds, especially
as all four diastereoisomers can be prepared from a single isomer of the auxiliary.
David A. Evans, Gçnter Helmchen and Magnus Rçping
Scheme 4
Catalytic diastereoselective anti-aldol reactions.
The application of aldol reactions in natural product synthesis has recently been
highlighted in the synthesis of FR-182877 by Evans, where all stereochemical relationships in the target structure were obtained from chiral oxazolidinone auxiliary controlled aldol reactions. Similar to the syntheses of himachalene [6] and
phomoidride B [7], the asymmetric aldol reaction was the fundamental step for
the construction of the key fragments of FR-182877, which were then united
via a Suzuki coupling, followed by macrolactonization and oxidation. A subsequent Diels-Alder-Hetero-Diels-Alder reaction cascade culminated in the synthesis of hexacyclic FR-182877 (Scheme 5) [8].
Scheme 5 Synthesis of FR-182877 using the auxiliary controlled aldol reactions
and a Diels-Alder reaction cascade.
Chiral Auxiliaries in Asymmetric Synthesis
Asymmetric reactions employing chiral auxiliaries have experienced a remarkable
progress over the past decades. Recent results from our groups, as well as many
others, demonstrate that auxiliary-controlled reactions are still essential tools in
the construction of complex molecular targets. The ready availability of the starting materials, the facile and versatile cleavage, as well as the applicability and reliability in a variety of stereoselective transformations, allows chiral auxiliaries to
endure today as excellent synthetic intermediates in asymmetric synthesis.
CV of David A. Evans
David A. Evans was born in Washington D.C. in 1941. He received his A.B. degree
from Oberlin College in 1963. He obtained his Ph.D. at the California Institute of
Technology in 1967, where he worked under the direction of Professor Robert E.
Ireland. In that year he joined the faculty at the University of California, Los
Angeles. In 1973 he was promoted to the rank of Full Professor and shortly
thereafter returned to Caltech where he remained until 1983. He then joined
the Faculty at Harvard University and in 1990 he was appointed as the Abbott
and James Lawrence Professor of Chemistry.
CV of Gçnter Helmchen
Gçnter Helmchen (b. 1940) is a Full Professor at the University of Heidelberg and
director of the Institute of Organic Chemistry. He pursued undergraduate studies
at the TH Hannover (Dipl.-Chem. 1965). His graduate work, completed in 1971,
was carried out under the guidance of Professor V. Prelog at the ETH Zçrich in
the area of stereochemistry. He then joined the group of H. Muxfeldt for postdoctoral studies in the area of natural product synthesis and carried out a Habilitationsarbeit at the Technical University of Stuttgart (1975–1980). In 1980 he was
appointed Professor C3 at the University of Wçrzburg. In 1985 he moved to
his present position. His interest in catalysis dates back to ca. 1990. His scientific
work has been recognized by a variety of scientific prizes and research awards,
international lectureships and the invitation to join the advisory boards of scientific journals.
CV of Magnus Rçping
Magnus Rçping was born in Telgte, Germany, in 1972. He studied at the Technical University of Berlin, Trinity College Dublin and ETH Zçrich. He obtained his
Ph.D. in 2002 from ETH under the guidance of Professor Dieter Seebach. After
carrying out postdoctoral work with Professor David A. Evans at Harvard University, he joined the Johann Wolfgang Goethe-University Frankfurt as Degussa
Endowed Professor of Chemistry in fall 2004.
David A. Evans, Gçnter Helmchen and Magnus Rçping
Selected References
1. (a) Houben-Weyl, Methods in Organic
Chemistry, Stereoselective Synthesis, G.
Helmchen, R.W. Hoffmann, J. Mulzer,
E. Schaumann (Eds.), Thieme-Verlag,
Stuttgart, 1995; (b) Compendium of Chiral
Auxiliary Applications, G. Roos (Ed.),
Academic Press, New York, 2002.
2. (a) R. Schmierer, G. Grotemeier, G.
Helmchen, A. Selim, Angew. Chem. Int.
Ed. Engl. 1981, 20, 207–208. Functional
Groups at Concave Sites: Asymmetric
Alkylation of Esters with Very High
Stereoselectivity and Reversal of Configuration by Change of Solvent; (b) G.
Helmchen, R. Schmierer, Angew. Chem.
Int. Ed. Engl. 1981, 20, 205–207, Functional Groups at Concave Sites: Asymmetric Diels-Alder Synthesis with Almost
Complete (Lewis-Acid Catalyzed) or High
(Uncatalyzed) Stereoselectivity.
3. D. A. Evans. Aldrichim. Acta 1982, 15,
23–32, Studies in Asymmetric Synthesis.
The Development of Practical Chiral Enolate Synthons.
4. D. J. Ager, I. Prakash, D. R. Schaad,
Aldrichim. Acta 1997, 30, 3–12, Chiral
Oxazolidinones in Asymmetric
(a) D. A. Evans, J. S. Tedrow, J. T. Shaw,
C. W. Downey, J. Am. Chem. Soc. 2002,
124, 392–393, Diasteroselective Magnesium Halide Catalyzed Anti-Aldol Reactions of Chiral N-Acyloxazolidinones; (b)
D. A. Evans, C. W. Downey, J. T. Shaw,
J. S. Tedrow, Organic Lett. 2002, 4, 1127–
1130, Magnesium Halide-Catalyzed AntiAldol Reaction of Chiral N-Acylthiazoldinethiones.
D. A. Evans, D. H. B. Ripin, J. S. Johnson, E. A. Shaughnessy, Angew. Chem.
Int. Engl. 1997, 36, 2119–2121, A New
Strategy for Extending N-Acyl Imides as
Chiral Auxiliaries for Aldol and Diels-Alder
Reactions: Application to an Enantioselective Synthesis of a-Himachalene.
N. Waizumi, T. Itoh, T. Fukuyama J. Am.
Chem. Soc. 2000, 122, 7825–7826, Total
Synthesis of (–)-CP-263,114 (Phomoidride B).
D. A. Evans, J. T. Starr Angew. Chem. Int.
Ed. 2002, 41, 1787–1790, A Cascade
Cycloaddition Strategy Leading to the
Total Synthesis of (–)-FR182877.