Organometallics in Process Chemistry

281 Pages·2004·4.22 MB·English

by  Rob Larsen

Volume Editor
Dr. Robert D. Larsen
Department of Process Research
Merck and Co., Inc.
P.O. Box 2000
Rahway, NJ 07065
USA
E-mail: [email protected]
Editorial Board
Dr. John M. Brown Prof. Pierre Dixneuf
Dyson Perrins Laboratory Campus de Beaulieu
South Parks Road Université de Rennes 1
Oxford OX1 3QY, Av. du Gl Leclerc
E-mail: [email protected] 35042 Rennes Cedex, France
E-mail: [email protected]
Prof. Alois Fürstner Prof. Louis S. Hegedus
Max-Planck-Institut für Kohlenforschung Department of Chemistry
Keiser-Wilhelm-Platz 1 Colorado State University
45470 Mühlheim an der Ruhr, Germany Fort Collins, Colorado 80523-1872, USA
E-mail: [email protected] E-mail: [email protected]
Prof. Peter Hofmann Prof. Paul Knochel
Organisch-Chemisches Institut Fachbereich Chemie
Universität Heidelberg Ludwig-Maximilians-Universität
Im Neuenheimer Feld 270 Butenandstr. 5–13
69120 Heidelberg, Germany Gebäude F
E-mail: [email protected] 81377 München, Germany
E-mail: [email protected]
Prof. Gerard van Koten Prof. Shinji Murai
Department of Metal-Mediated Synthesis Faculty of Engineering
Debye Research Institute Department of Applied Chemistry
Utrecht University Osaka University
Padualaan 8 Yamadaoka 2-1, Suita-shi
3584 CA Utrecht, The Netherlands Osaka 565, Japan
E-mail: [email protected] E-mail: [email protected]
Prof. Manfred Reetz
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1
45470 Mülheim an der Ruhr, Germany
E-mail: [email protected]
Preface
The impact of organometallics on the synthesis of medicinal agents during the
last decade cannot be overstated. Although metals or organometallic species
have been used for sometime in the pharmaceutical industry, the advances in
the variety of reactions and the tremendous selectivity that is often achieved has
expanded the toolbox of reagents available to the medicinal and process chem-
ist. These reagents have helped to streamline the synthetic approaches devel-
oped for medicinal agents as can be seen by the increasingly sophisticated strat-
egies used to synthesize complex drug products. In the areas of asymmetric syn-
thesis, pharmaceuticals can be prepared using methodology only dreamed of a
few decades ago.
This volume will highlight some of the more active areas where organometal-
lics are playing an important role in process chemistry. With the chelation effects
of many chiral ligands, organolithium reagents have become key intermediates in
asymmetric synthesis. Similarly, because of the great propensity of titanium to
chelate and bind to heteroatoms, organotitanium reagents are extremely useful
and versatile in carrying out a number of selective organic transformations. Al-
though the asymmetric hydrogenation of a-amidoacrylates to prepare amino ac-
ids has been known for sometime, the discovery and application of new ligands
and reaction classes have expanded the number of substrates that can be convert-
ed to chiral products with Rh and Ru-mediated reactions. The cyclopropyl group
is a common moiety found in pharmaceutical agents. Metal-mediated methods
for preparing this ring are reviewed herein. Non-reductive means to prepare the
enantiomers of oxy-systems remained elusive until the reports of chiral salen lig-
ands and osmium-mediated reactions over the past two decades. Organopalladi-
um reactions are now so commonly used in the synthesis of complex molecules
that one can forget that palladium was once used only in hydrogenation reac-
tions. The use of metals does come with a price when preparing pharmaceuticals
for human consumption. Because of the potential toxicities of the metals, only
low ppm levels can remain in the active pharmaceutical ingredient. Some of the
methods that have been utilized in process chemistry to remove residual metals
are presented. Organometallics will certainly continue to be used extensively in
the pharmaceutical industry as newer methods and applications are discovered.
Rahway, USA, January 2004 Robert D. Larsen
Contents
Organolithium in Asymmetric Processes
George G. Wu and Mingsheng Huang . . . . . . . . . . . . . . . . . . . . . . 1
Applications of Organotitanium Reagents
David L. Hughes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Rhodium/Ruthenium Applications
Kenzo Sumi and Hidenori Kumobayashi . . . . . . . . . . . . . . . . . . . . 63
Development of Transition Metal-Mediated Cyclopropanation Reactions
Albert J. Delmonte, Eric D. Dowdy, Daniel J. Watson . . . . . . . . . . . . . . 97
Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes
Jay F. Larrow and Eric N. Jacobsen . . . . . . . . . . . . . . . . . . . . . . . . 123
Non-Salen Metal-Catalyzed Asymmetric Dihydroxylation and
Asymmetric Aminohydroxylation of Alkenes. Practical Applications and
Recent Advances
Steven J. Mehrman, Ahmed F. Abdel-Magid, Cynthia A. Maryanoff,
and Bart. P. Medaer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Palladium-Catalyzed Heck Arylations in the Synthesis of
Active Pharmaceutical Ingredients
Mahavir Prashad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Palladium-Catalyzed Cross-Coupling Reactions in the Synthesis
of Pharmaceuticals
Anthony O. King and Nobuyoshi Yasuda. . . . . . . . . . . . . . . . . . . . . 205
Stereospecific Introduction of Cephalosporin Side Chains Employing
Transition Metal Complexes
Joydeep Kant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Removal of Metals from Process Streams: Methodologies and
Applications
Jeffrey T. Bien, Gregory C. Lane, Matthew R. Oberholzer . . . . . . . . . . . 263
Author Index 1–6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Topics Organomet Chem (2004) 6: 1–35
DOI 10.1007/b11769
Organolithium in Asymmetric Processes
George G. Wu · Mingsheng Huang
Chemical Process Research and Development, Schering-Plough Research Institute, Union,
New Jersey 07083, USA
E-mail: [email protected]
Abstract The development of asymmetric processes has been the focus of industrial research
as most of the molecules of pharmaceutical interest contain chiral center(s). Many of the re-
ported processes employ organometallic reagents in their key transformations. This review
surveys chemical processes involving organolithium species in their enantioselective steps
published in the past decade.
Keywords Organolithium · Asymmetric process · Chiral alkylation · Chiral imine addition ·
Chiral aldol/Michael addition
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 Organolithium in Enantioselective Alkylations . . . . . . . . . . . . 2
2.1 Chiral Auxiliary-Mediated Alkylation. . . . . . . . . . . . . . . . . . 3
2.2 Chiral Pool-Based Chemistry. . . . . . . . . . . . . . . . . . . . . . . 11
2.3 Intramolecular Alkylation . . . . . . . . . . . . . . . . . . . . . . . . 14
2.4 Chiral Additive-Mediated Alkylation . . . . . . . . . . . . . . . . . . 14
3 Chiral Nucleophilic Addition of Organolithium Reagents . . . . . . 17
3.1 Addition to C=N Bond . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.2 Alkynylation of Imines and Ketones. . . . . . . . . . . . . . . . . . . 21
3.3 Addition to Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
4 Organolithium in Chiral Aldol Condensations . . . . . . . . . . . . 25
4.1 Auxiliary-Induced Aldol Reaction . . . . . . . . . . . . . . . . . . . . 26
4.2 Lewis Acid-Mediated Aldol Reaction . . . . . . . . . . . . . . . . . . 27
4.3 Catalytic Asymmetric Aldol Condensation. . . . . . . . . . . . . . . 28
5 Organolithium in Chiral Conjugated Additions. . . . . . . . . . . . 29
5.1 Conjugated Addition to a Chiral Acceptor . . . . . . . . . . . . . . . 29
5.2 Auxiliary-Induced Asymmetric Conjugate Additions. . . . . . . . . 30
© Springer-Verlag Berlin Heidelberg 2004
2 G. G. Wu · M. Huang
5.3 Chiral Additive-Mediated Conjugate Addition . . . . . . . . . . . . 32
5.4 Catalytic Asymmetric Conjugate Addition . . . . . . . . . . . . . . 32
6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
1
Introduction
The development of asymmetric processes for drug candidates has become in-
creasingly important as most of the structures of interest contain one or more
chiral centers. There is a wealth of literature on asymmetric processes published
in the past decade. Many of the enantioselective processes reported involve or-
ganolithium species in the asymmetric step. This review will focus on industrial
applications involving the use of organolithium as a nucleophile.
The most commonly used lithium reagents are lithium diisopropyl amide
(LDA), butyllithium, phenylithium, and lithium hexamethyldisilylamide (LiH-
MDS). These lithium reagents are commercially available in bulk quantities and
are easy to handle in the plant. When appropriate, reactions with organolithium
will be contrasted with related cations, such as organosodium, organopotassi-
um, and organozinc reagents. Certain additives, such as LiCl, CuX, and water are
often introduced to organolithium reactions to enhance either the reactivity or
the enantioselectivity.
While this review focuses on the industrial applications of organolithium in
asymmetric syntheses, there are some good reviews of general applications of
organolithium reagents. Advances in chiral lithium amides and enantioselective
protonation as well as asymmetric synthesis via lithium intermediates have been
reviewed previously [1, 2].
2
Organolithium in Enantioselective Alkylations
A majority of the reported enantioselective alkylations can be divided into two
distinct groups – those using a covalently bonded chiral auxiliary and those us-
ing a chiral additive. The auxiliary is generally removed at the end of induction.
However, in some examples, the auxiliary is incorporated as part of the mole-
cule, the so-called chiral pool-based approach. Alkylation using a chiral additive
is more straightforward as it does not require the attachment and removal of the
auxiliary. While primary electrophiles are used in the majority of chiral alkyla-
tions, secondary electrophiles also work well under certain conditions. Chiral
auxiliary-based chemistry has been reviewed previously [3]. New approaches
such as 1,3-asymmetric induction, the use of sterically rigid templates, and in-
tramolecular trans-alkylation have also been developed.
Organolithium in Asymmetric Processes 3
2.1
Chiral Auxiliary-Mediated Alkylation
Diastereoselective processes using covalently bonded chiral auxiliaries have
been widely used in enantioselective alkylation of lithium enolates for asymmet-
ric C-C bond formation. Reactions involving organolithium species often afford
chelation-controlled products. Lithium can be replaced with potassium or sodi-
um as the countercation when chelation is not preferred.
Oxazolidinones are frequently used as chiral auxiliaries for enantioselective
alkylation. For example, Holla et al. of Hoechst have described a short and ster-
eoselective synthesis of (2S)-3-(1¢,1¢-dimethylethylsulfonyl)-2-(1-naphthylme-
thyl)-propionic acid 1, a very potent N-terminal component in aspartyl protease
inhibitors, using an oxazolidinone 2 as an auxiliary [4]. The enantioselectivity
was achieved by a stereoselective alkylation of a lithium enolate of the thioether
oxazolidinone carboximide 3. Enolization with LDA followed by treatment with
1-(bromomethyl)-naphthalene and removal of the auxiliary with concurrent ox-
idation of the thio group produced the alkylated product 1. An overall yield of
37% and 99% optical purity was obtained on a 100-g scale (Scheme 1).
Scheme 1 Stereoselective alkylation using chiral oxazolidinones
Hilpert of Hoffmann-La Roche also used the oxazolidinone auxiliary to estab-
lish two consecutive chiral centers for the synthesis of Trocade, a matrix metal-
loproteinase inhibitor [5]. A first enolization of the cyclopentyl propionic amide
4 with LDA followed by alkylation of the lithium enolate with tert-butyl bromoa-
cetate gave the chelation controlled product 5 in 99.6% ee (Scheme 2). After re-
moval of the auxiliary, the free acid 6 was converted to its corresponding piperi-
dine amide 7. A chemoselective enolization of the amide carbonyl in 7 with a
base followed by alkylation with bromomethyl hydantoin 8 gave either syn- or
anti-succinate 9, depending on the cation of the base used. A lithium base such
as LDA furnished preferentially syn-9 (anti-/syn-=15:85); whereas, potassium
bases like KHMDS afforded predominantly anti-9 (anti-/syn- ratio up to 99:1).
In the second alkylation, it was assumed that the chelation of the lithium enolate
with the adjacent carbonyl group induces the alkylation from the sterically less
hindered face, leading to the syn-9 isomer. In contrast, the potassium enolate
4 G. G. Wu · M. Huang
Scheme 2 Diastereoselective alkylation process for trocade
was assumed to favor the non-chelated, thermodynamically more stable confor-
mation, consequently affording anti- alkylation.
In a related investigation, Hilpert has shown that alkylation of the lithium
enolate of succinic acid 10 with cinnamyl bromide gave a 93:7 mixture favoring
the syn-isomer 11 [5]. As shown in Scheme 3, the syn-isomer 11 was converted
to its corresponding anti-isomer via a second enolization with LDA. These selec-
tivities were rationalized by a chelation effect of the lithium enolate which is
alkylated on the sterically less hindered side leading to syn-isomer 11. A second
deprotonation of 11 to the chelated enolate 12 and protonation again from the
sterically less hindered side affords the anti-13.
Hilper’s methods have provided efficient and practical approaches to the ma-
trix metalloproteinase inhibitor Trocade and to TNF-a converting enzyme in-
hibitor TACE. Both of the processes have been operated in the plant on multi-ton
and multi-kilogram scale [5].
cis-Aminoindanols are another important class of chiral auxiliaries that have
been extensively investigated by various Merck groups. They were originally in-
vestigated because the aminoindanol structure was part of the target molecule,
but have since become important auxiliaries in their own right. The first example
was reported by Askin et al. for the synthesis of hydroxyethylene dipeptide isos-
tere (HDI) inhibitors of HIV-1 protease 14 [6]. As shown in Scheme 4, enolization
Organolithium in Asymmetric Processes 5
Scheme 3 Asymmetric synthesis of TACE
Scheme 4 Diastereoselective synthesis of HIV-1 protease inhibitor
6 G. G. Wu · M. Huang
of 3-phenylpropionic amide of aminoindanol 15 with n-BuLi followed by alkyla-
tion with H C=C(CH I) gave a C symmetry dimer 16. The lithium enolate could
2 2 2 2
also be trapped with an epoxide to give g-hydroxyamide 17 in 90% yield and 98%
ee. The outcome of the R-stereochemistry at the C-2 positions of products 16 and
17 suggested that both the alkyliodide and the epoxide electrophiles approached
from the least hindered face of the lithium enolate. The facial selectivity observed
here is contrasted by those reactions with prolinol amide enolates reported earli-
er [6e]. In the epoxide coupling reactions, Grignard reagents such as isopropyl
magnesium chloride, gave lower yields (~60%) of the desired product.
Another successful application of the rigid tricyclic aminoindanol lithium ac-
etonide was the asymmetric synthesis of the orally active HIV protease inhibitor
Crixivan, one of the leading drugs for the treatment of AIDS [6]. Two alternative
approaches were developed. Both approaches started with enolization of inda-
nol amide 15 with LiHMDS. In the first approach, the lithium enolate was react-
ed with epoxy tosylate 18 to give the epoxy derivative 20. Chemoselectivity was
obtained between the displacement of the tosylate and the opening of the epox-
ide. In the second approach, the lithium enolate was alkylated with an allyl bro-
mide followed by epoxidation to afford 20. In these syntheses, the cis-aminoin-
danol unit remains as a part of the molecule (Scheme 5).
Scheme 5 Diastereoselective alkylation process for crixivan
Alkylation of the cis-aminoindanol-modified glycine enolate 21 with a
number of alkyl halides in the presence of LiCl gave the corresponding alkylated
product 22 in 90~99% diastereoselectivity [7]. Benzylic or naphthyl bromide
gave 99% de and 85% yield. Allylic or primary alkyl halides typically gave 95 to
98% de. The diastereoselectivity was slightly lower (91%) with a secondary acy-
clic iodide. Both the ee and the yield suffered in the absence of LiCl. The auxil-
iary could be effectively removed under epimerization-free conditions. This
provided a practical synthesis of a-amino acids (Scheme 6).
Organolithium in Asymmetric Processes 7
Scheme 6 Diastereoselective alkylation for chiral a-amino acids
In the synthesis of the sidechain of an endothelin receptor antagonist, Song et
al. used (1R,2S)-cis-aminoindanol for a chiral alkylation [8]. As shown in
Scheme 7, enolization of a propionyl amide 23 with LiHMDS followed by alkyla-
tion with benzylchloride gave 2-methyl-3-phenylpropionic amide 24 in 96% de.
Removal of the auxiliary by hydrolysis gave the free acid in 60% overall yield.
Scheme 7 Asymmetric synthesis of endothelin receptor antagonist
(1S,2R)-1-Aminoindanol was also used by Kress et al. as a chiral auxiliary for
an efficient, diastereoselective [2, 3]-Wittig rearrangement of the a-allyloxya-
mide lithium enolate 25 [9]. LiHMDS was found to be a much better base than
NaHMDS, KHMDS, and n-BuLi. Addition of additives, such as HMPA and DM-
PU, was also necessary. After removal of the auxiliary, the resulting optically ac-
tive a-hydroxyl acids were transformed to their corresponding functionalized
amino acid derivatives (Scheme 8).
Pseudoephedrine is another class of chiral auxiliary used in alkylations. For
example, Dragovich et al. of Agouron have employed pseudoephedrine as a chi-