Volume Editor
Dr. Robert D. Larsen
Department of Process Research
Merck and Co., Inc.
P.O. Box 2000
Rahway, NJ 07065
USA
E-mail: rob_larsen@[Link]
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: [Link]@[Link] 35042 Rennes Cedex, France
E-mail: [Link]@[Link]
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: fuerstner@[Link] E-mail: hegedus@[Link]
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: ph@[Link] 81377 München, Germany
E-mail: knoch@[Link]
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: vankoten@[Link] E-mail: murai@[Link]
Prof. Manfred Reetz
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1
45470 Mülheim an der Ruhr, Germany
E-mail: reetz@[Link]
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