CHIRAL DRUGS

CHIRAL DRUGSChemistry and Biological Action

Edited by

GUO-QIANG LINQI-DONG YOUJIE-FEI CHENG

A JOHN WILEY & SONS, INC., PUBLICATION

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Library of Congress Cataloging-in-Publication Data:

Chiral drugs : chemistry and biological action / edited by Guo-Qiang Lin, Qi-DongYou, Jie-Fei Cheng.

p. ; cm.Includes bibliographical references and index.ISBN 978-0-470-58720-1 (hardback)

1. Chiral drugs. 2. Drug development. 3. Structure-activity relationships(Biochemistry) I. Lin, Guo-Qiang, 1943- II. You, Qi-Dong. III. Cheng, Jie-Fei.

[DNLM: 1. Drug Discovery—methods. 2. Pharmaceutical Preparations—chemistry.3. Structure-Activity Relationship. QV 744]

RS429.C483 2011615′.19—dc22

2011002203

Printed in Singapore

oBook ISBN: 978-1-118-07564-7ePDF ISBN: 978-1-118-07562-3ePub ISBN: 978-1-118-07563-0

10 9 8 7 6 5 4 3 2 1

CONTENTS

ABOUT THE EDITORS vii

CONTRIBUTORS ix

INTRODUCTION 1

1 OVERVIEW OF CHIRALITY AND CHIRAL DRUGS 3Guo-Qiang Lin, Jian-Ge Zhang, and Jie-Fei Cheng

2 CHIRAL DRUGS THROUGH ASYMMETRIC SYNTHESIS 29Guo-Qiang Lin and Xing-Wen Sun

3 CHIRAL DRUGS VIA BIOCATALYTICAL APPROACHES 77Jianqiang Wang and Wenya Lu

4 RESOLUTION OF CHIRAL DRUGS 137Qi-Dong You

5 FLUORINE-CONTAINING CHIRAL DRUGS 195Xiao-Long Qiu, Xuyi Yue, and Feng-Ling Qing

6 INDUSTRIAL APPLICATION OF CHIRAL TECHNOLOGIES 253Hui-Yin (Harry) Li, Rui Liu, Carl Behrens, and Chao-Ying Ni

v

vi CONTENTS

7 STRUCTURAL BASIS AND COMPUTATIONALMODELING OF CHIRAL DRUGS 297Deping Wang and Eric Hu

8 PHARMACOLOGY OF CHIRAL DRUGS 323Yongge Liu and Xiao-Hui Gu

9 PHARMACOKINETICS OF CHIRAL DRUGS 347Hanqing Dong, Xiaochuan Guo and Zengbiao Li

10 TOXICOLOGY OF CHIRAL DRUGS 381Guang Yang and Hai-Zhi Bu

11 REPRESENTATIVE CHIRAL DRUGS 401Jiangqin Sun, Dingguo Liu, and Zhimin Wang

INDEX 449

ABOUT THE EDITORS

Professor Guo-Qiang Lin received his BS degree in chemistry from ShanghaiUniversity of Science and Technology in 1964. After completion of his graduatestudy at the Shanghai Institute of Organic Chemistry in 1968, he remained inthe same institute and worked on natural products chemistry. He was promotedto full professorship in 1991. In 2001, he was elected as an Academician of theChinese Academy of Sciences. His research interests include the synthesis ofnatural products and biologically active compounds, asymmetric catalysis, andbiotransformation. He is an Executive Board Member of Editors for TetrahedronPublications, Vice Editor-In-Chief of Acta Chimica Sinica, and Scientia SinicaChimica . He has served as Director of the Division of Chemical Science, NationalNatural Science Foundation of China since 2006.

Dr. Qi-Dong You is the Dean and a Professor of the School of Pharmacy,at China Pharmaceutical University. He received his BS degree in pharmacyfrom the China Pharmaceutical University and completed his PhD degree inmedicinal chemistry at the Shanghai Institute of Pharmaceutical Industry in 1989.He then returned to CPU as a lecturer and associate director of the Department ofMedicinal Chemistry. He spent one year and a half as a senior visiting scholar inthe Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow,UK, before he was promoted to a full professorship in 1995. He is a councilmember of the China Pharmaceutical Association (CPA) and the Vice-Directorof the Division of Medicinal Chemistry of CPA. His research interests includethe design, synthesis, and biological evaluation of new therapeutic agents forcancer and cardiovascular and infectious diseases. He is an Associate Editor ofProgress in Pharmaceutical Sciences and serves on the Editorial Board of theInternational Journal of Medicinal Chemistry and Acta Pharmaceutica Sinica .

vii

viii ABOUT THE EDITORS

Dr. Jie-Fei (Jay) Cheng was born in 1964 in Jiangxi, China. He obtainedhis BS degree in chemistry from the Jiangxi Normal University in 1983 andcontinued his graduate studies at the Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences, under the guidance of Professors Wei-Shan Zhouand Guo-Qiang Lin. After receiving his Master’s degree in chemistry in 1986,he joined the research group of Professor Yoshimasa Hirata and Dr. JunichiKobayashi (now a Professor at Hokkaido University) at the Mistubishi-KaseiInstitute of Life Sciences, Tokyo, Japan. He then moved to Keio Universityto pursue his Ph.D in Professor Shosuke Yamamura’s lab. Since 1993, he hasbeen working at various pharmaceutical companies/biotechs in the United States,focusing on small-molecule drug discovery. He is currently the Director of OtsukaShanghai Research Institute, a fully owned subsidiary of Otsuka PharmaceuticalCo. Ltd, Japan and an adjunct professor at Fudan Univeristy, China.

CONTRIBUTORS

Carl Behrens, Wilmington PharmaTech Company LLC, Newark, DE, USA,and University of Delaware, Newark, DE, USA

Hai-Zhi Bu, 3D BioOptima Co. Ltd, Suzhou, Jiangsu, China

Jie-Fei (Jay) Cheng (Editor), Otsuka Maryland Medicinal Laboratories, Inc.,Rockville, MD, USA, and, Otsuka Shanghai Research Institute, Shanghai,China

Hanqing Dong, OSI Pharmaceuticals, A Wholly Owned Subsidiary of AstellasUS, Farmingdale, NY, USA

Xiao-Hui Gu, Otsuka Maryland Medicinal Laboratories, Inc., Rockville, MD,USA

Xiaochuan Guo, Drumetix Laboratories, LLC, Greensboro, NC, USA

Eric Hu, Gilead Sciences Inc., Foster City, CA, USA

Hui-Yin (Harry) Li, Wilmington PharmaTech Company LLC, Newark, DE,USA, and University of Delaware, Newark, DE, USA

Zengbiao Li, Drumetix Laboratories, LLC, Greensboro, NC, USA

Guo-Qiang Lin (Editor), Key Laboratory of Synthetic Chemistry of NaturalSubstances, Shanghai Institute of Organic Chemistry, Chinese Academy ofSciences, Shanghai, China

Dingguo Liu, Pfizer, San Diego, CA, USA

Yongge Liu, Otsuka Maryland Medicinal Laboratories, Inc., Rockville, MD,USA

ix

x CONTRIBUTORS

Rui Liu, Wilmington PharmaTech Company LLC, Newark, DE, and Universityof Delaware, Newark, DE, USA

Wenya Lu, Department of Chemistry, Iowa State University, Ames, Iowa, USA

Chao-Ying Ni, Wilmington PharmaTech Company LLC, Newark, DE, USA,and University of Delaware, Newark, DE, USA

Feng-Ling Qing, Key Laboratory of Organofluorine Chemistry, Shanghai Insti-tute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China,and College of Chemistry and Chemistry Engineering, Donghua University,Shanghai, China

Xiao-Long Qiu, Key Laboratory of Organofluorine Chemistry, Shanghai Insti-tute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

Jiangqin Sun, Otsuka Shanghai Research Institute, Shanghai, China

Xing-Wen Sun, Department of Chemistry, Fudan University, Shanghai, China

Deping Wang, Biogen IDEC Inc., Cambridge, MA, USA

Jianqiang Wang, ArQule Inc., Woburn, MA, USA

Zhimin Wang, Sundia MedTech Company Ltd., Shanghai, China

Guang Yang, GlaxoSmithKline, R&D China, Shanghai, China

Qi-Dong You (Editor), China Pharmaceutical University, Nanjing, Jiangsu,China

Xuyi Yue, Key Laboratory of Organofluorine Chemistry, Shanghai Institute ofOrganic Chemistry, Chinese Academy of Sciences, Shanghai, China

Jian-Ge Zhang, School of Pharmaceutical Science, Zhengzhou University,Zhengzhou, Henan, China

INTRODUCTION

The book consists of 11 chapters. The first part of the book introduces the gen-eral concept of chirality and its impact on drug discovery and development. Thehistory and the trends of chiral drug development, the technologies for the prepa-ration of chiral drugs, and the industrial applications of chiral technologies arediscussed. This part covers three important chiral technologies, namely, asym-metric synthesis, biocatalytic process, and chiral resolution, and discusses theirimpact on chiral drug development. Without question, fluorine atoms play animportant role in chiral drug discovery and development. The significance andthe preparation of fluorine-containing chiral drugs are the topic of a separatechapter.

The second part of the book mainly deals with some unique aspects of chiraldrugs in terms of pharmaceutical, pharmacological, and toxicological properties.For instance, pharmacology, pharmacokinetic properties, and toxicology of chiraldrugs are discussed in comparison with racemic drugs. Additionally, computa-tional modeling as applied to chiral drug discovery and development is discussed.This part of the book provides a general knowledge of design, synthesis, screen-ing, and pharmacology from the preclinical point of view, hoping to raise interestfrom a broad range of readers.

Finally, Chapter 11 covers 25 representative chiral drugs that have beenapproved or are in advanced clinical trials. Some natural products are notincluded. The most important criteria for their selection are the involvementof chiral processes during their preparation and the significance of chirality intheir development. Every entry contains the trade name, chemical name andproperties, a representative synthetic pathway, pharmacological characterizations,and references.

1

2 INTRODUCTION

This book is intended to introduce chemists to pharmacological aspects ofdrug development and to form a fruitful cooperation among academic syn-thetic chemists, medicinal chemists, pharmaceutical scientists, and pharmacolo-gists from the pharmaceutical and biotechnology industries. The references aftereach chapter will give readers an opportunity for further reading on the topicsdiscussed. This is the first book of its kind to combine synthetic organic chem-istry, medicinal chemistry, process chemistry, and pharmacology in the contextof chiral drug discovery and development.

CHAPTER 1

OVERVIEW OF CHIRALITYAND CHIRAL DRUGSGUO-QIANG LINKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Instituteof Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

JIAN-GE ZHANGSchool of Pharmaceutical Science, Zhengzhou University, Zhengzhou, China

JIE-FEI CHENGOtsuka Shanghai Research Institute, Pudong New District, Shanghai, China

1.1 Introduction 41.2 Overview of chirality 5

1.2.1 Superimposability 51.2.2 Stereoisomerism 51.2.3 Absolute configuration 61.2.4 Determination of enantiomer composition (ee)

and diastereomeric ratio (dr) 81.3 General strategies for synthesis of chiral drugs 9

1.3.1 Enantioselective synthesis via enzymatic catalysis 101.3.2 Enantioselective synthesis via organometallic catalysis 111.3.3 Enantioselective synthesis via organocatalysis 12

1.4 Trends in the development of chiral drugs 141.4.1 Biological and pharmacological activities of chiral drugs 141.4.2 Pharmacokinetics and drug disposition 181.4.3 Regulatory aspects of chiral drugs 211.4.4 Trends in the development of chiral drugs 21

Chiral Drugs: Chemistry and Biological Action, First Edition. Edited by Guo-Qiang Lin,Qi-Dong You and Jie-Fei Cheng. 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

3

4 OVERVIEW OF CHIRALITY AND CHIRAL DRUGS

1.1 INTRODUCTION

The pharmacological activity of a drug depends mainly on its interaction withbiological matrices or drug targets such as proteins, nucleic acids, and biomem-branes (e.g., phospholipids and glycolipids). These biological matrices displaycomplex three-dimensional structures that are capable of recognizing specificallya drug molecule in only one of the many possible arrangements in the three-dimensional space, thus determining the binding mode and the affinity of a drugmolecule. As the drug target is made of small fragments with chirality, it isunderstandable that a chiral drug molecule may display biological and pharma-cological activities different from its enantiomer or its racemate counterpart wheninteracting with a drug target. In vivo pharmacokinetic processes (ADME) mayalso contribute to the observed difference in in vivo pharmacological activitiesor toxicology profiles. One of the earliest observations on the taste differencesassociated with two enantiomers of asparagines was made in 1886 by Piutti [1].Colorless crystalline asparagine is the amide form of aspartic or aminosuccinicacid and is found in the cell sap of plants in two isomeric forms, levo- anddextro-asparagin. The l -form exists in asparagus, beet-root, wheat, and manyseeds and is tasteless, while the d -form is sweet. Thalidomide is another clas-sical example. It was first synthesized as a racemate in 1953 and was widelyprescribed for morning sickness from 1957 to 1962 in the European countriesand Canada. This led to an estimated over 10,000 babies born with defects [2]. Itwas argued that if one of the enantiomers had been used instead of the racemate,the birth defects could have been avoided as the S isomer caused teratogenesisand induced fatal malformations or deaths in rodents while the R isomer exhib-ited the desired analgetic properties without side effects [3]. Subsequent testswith rabbits proved that both enantiomers have desirable and undesirable activ-ities and the chiral center is easily racemized in vivo [4]. Recent identificationof thalidomide’s target solved the long-standing controversies [5]. The chiral-ity story about thalidomide, although not true, has indeed had great impact onmodern chiral drug discovery and development (Fig. 1.1).

1a

NH2O

H2NO

OH

NNH

O

O

O

O

NH2O

H2NO

OH

1b

NNH

O

O

O

O

2a 2b

FIGURE 1.1 Asparagine (1) and thalidomide (2).

OVERVIEW OF CHIRALITY 5

1.2 OVERVIEW OF CHIRALITY

1.2.1 Superimposability

Chirality is a fundamental property of three-dimensional objects. The word “chi-ral” is derived from the Greek word cheir , meaning hand, or “handedness” in ageneral sense. The left and right hands are mirror images of each other no matterhow the two are arranged. A chiral molecule is the one that is not superimposablewith its mirror image. Accordingly, an achiral compound has a superimpos-able mirror image. Two possible mirror image forms are called enantiomers andare exemplified by the right-handed and left-handed forms of lactic acids inFigure 1.2. Formally, a chiral molecule possesses either an asymmetric center(usually carbon) referred to as a chiral center or an asymmetric plane (planarchirality).

In an achiral environment, enantiomers of a chiral compound exhibit identicalphysical and chemical properties, but they rotate the plane of polarized light inopposite directions and react at different rates with a chiral compound or with anachiral compound in a chiral environment. A chiral drug is a chiral molecule withdefined pharmaceutical/pharmacological activities and utilities. The description“chiral drug” does not indicate specifically whether a drug is racemic, single-enantiomeric, or a mixture of stereoisomers. Instead, it simply implies that thedrug contains chiral centers or has other forms of chirality, and the enantiomericcomposition is not specified by this terminology.

1.2.2 Stereoisomerism

In chemistry, there are two major forms of isomerism: constitutional (struc-tural) isomerism and stereoisomerism. Isomers are chemical species (or molecularentities) that have the same stoichiometric molecular formula but different con-stitutional formulas or different stereochemical formulas. In structural isomers,the atoms and functional groups are joined together in different ways. On the

CH3CH3 CH3CH3

OHOH HOHOHH HH

COOHCOOH COOHCOOHCOOHCOOH

OH

3a mirror 3b

HH3C

COOH

HOH

CH3

FIGURE 1.2 Mirror images of lactic acid.

6 OVERVIEW OF CHIRALITY AND CHIRAL DRUGS

other hand, stereoisomers are compounds that have the same atoms connectedin the same order but differ from each other in the way that the atoms are ori-ented in space. They include enantiomers and diastereomers, the latter indicatingcompounds that contain two or more chiral centers and are not superimposablewith their mirror image. Diastereomers also include the nonoptical isomers suchas cis-trans isomers.

Many molecules, particularly many naturally derived compounds, containmore than one chiral center. In general, a compound with n chiral centers willhave 2n possible stereoisomers. Thus 2-methylamino-1-phenylpropanol with twochiral centers could have a total of four possible stereoisomers. Among these,there are two pairs of enantiomers and two pairs of diastereomers. This relation-ship is exemplified by ephedrines (4a, 4b) and pseudoephedrines (4c, 4d) shownin Figure 1.3. In certain cases, one of the stereoisomeric forms of a moleculecontaining two or more chiral centers could display a superimposable mirrorimage, which is referred to as a meso isomer.

HN

CH3

OH

CH3

HN

CH3

OH

CH3

HN

CH3

OH

CH3

HN

CH3

OH

CH3

4a (+)-Ephedrine 4b (−)-Ephedrine 4c (+)-Pseudoephedrine 4d (−)-Pseudoephedrine

enantiomers enantiomers

diastereomers

FIGURE 1.3 Enantiomers and diastereomers.

1.2.3 Absolute Configuration

It is important to define the absolute configuration of a chiral molecule in orderto understand its function in a biological system. Many biological activities areexclusive to one specific absolute configuration. Without a good understandingof absolute configuration of a molecule, it often is hard to understand its chem-ical and biological behavior. As mentioned above, two enantiomers of a chiralcompound will have identical chemical and physical properties such as the sameboiling/melting points and solubility in a normal achiral environment.

The R/S nomenclature or Cahn–Ingold–Prelog (CIP) system for definingabsolute configuration is the most widely used system in the chemistry commu-nity. The key to this system is the CIP priority rule, which defines the substituentpriority based on the following criteria: 1) Higher atomic number or higher atomicmass is given higher priority; 2) when the proximate atom of two or more of thesubstituents are the same, the atomic number of the next atom determines thepriority; 3) double bonds or triple bonds are counted as if they were split intotwo or three single bonds, respectively; 4) cis is given higher priority than trans;

OVERVIEW OF CHIRALITY 7

C

X

Z WY

5

FIGURE 1.4 A central chiral system.

5) long pair electrons are regarded as an atom with atomic number 0; and 6)proximal groups have higher priority than distal groups.

The carbon atom in compound 5 (Fig. 1.4) is defined as a chiral center ifthe four substituents (X, Y, Z, and W) around the center are different. If themolecule is oriented in a way that the lowest-priority group W is pointed awayfrom the observer and the other three groups have a priority sequence X→Y→Zin a clockwise direction, the chiral center will have a R configuration; otherwiseit is defined as an S configuration. The R/S system can be used for other chiralmolecules without a chiral center (e.g., planar chirality) as well [6].

Fischer’s convention with d or l prefix (small cap) is sometimes used for thedescription of the absolute configuration of a molecule, particularly for carbohy-drates or amino acids. For example, d-glyceraldehyde 6a by Fischer’s conventionis shown in Figure 1.5 and is identical to (R)-glyceraldehyde according to CIPrules. By relating compounds to glyceraldehydes, the absolute configuration ofother compounds can be defined. For example, naturally occurring alanine 6d isdesignated as l-form with an S configuration.

Enantiomers do differ from each other in rotating the plane-polarized light,which is referred to as optical activity or optical rotation. When an enantiomerrotates the plane of polarized light clockwise (as seen by a viewer toward whomthe light is traveling), it is labeled as (+). Its mirror-image enantiomer is labeledas the (−) isomer. The (+) and (−) isomers have historically been termedd - and l -, respectively, with d for dextrorotatory and l for levorotatory rota-tion of the lights. This d /l system is now obsolete, and (+/–) should be usedinstead to specify the optical rotation. It should also be pointed out that the opticalrotation (+/–) convention has no direct relation with the R/S or d/l systems. Itis used in most cases for description of relative, not absolute configuration. Thuscompound 3b, which rotates the plane-polarized light in a clockwise direction, isdenoted as R-(+)-lactic acid, while the enantiomer (3a) is referred to S -(–)-lacticacid.

H OHCHO

CH2OH

6a

H NH2

COOH

CH3

H2N HCOOH

CH3

HO HCHO

CH2OH

6b 6c 6d

FIGURE 1.5 Structure of (d)- and (l)-glyceraldehyde and analogs.

8 OVERVIEW OF CHIRALITY AND CHIRAL DRUGS

Absolute configuration is most commonly determined either by X-ray crys-tallography or through chemical conversion to a known compound with definedstereochemistry. Other instrumental procedures for determining absolute stere-ochemistry without derivatization include circular dichroism (CD), vibrationalcircular dichroism (VCD) [7], and optical rotator dispersion (ORD) or specificoptical rotation. The NMR-based method for deducing the absolute configurationof secondary carbinol (alcohol) centers using the “modified Mosher method” [8]was first described by Kakisawa and co-workers [9]. This modified Mosherester analysis relies on the fact that the protons in diasteromeric α-methoxy-α-trifluoromethylphenylacetates display different arrays of chemical shifts in their1H NMR spectra. When correctly used and supported by appropriate data, themethod can be used to determine the absolute configuration of a variety of com-pounds including alcohols, amines, and carboxylic acids [10]. However, it isalways advisable to examine the complete molecular topology in the neigh-borhood of the asymmetric carbon centers and confirm with another analyticalmethod.

1.2.4 Determination of Enantiomer Composition (ee)and Diastereomeric Ratio (dr)

It is important to measure enantiomer composition and diastereomeric ratio fora chiral molecule, in particular a chiral drug, as the biological data may closelyrelate to the optical purity. The enantiomer composition of a sample is describedby enantiomeric excess, or ee%, which describes the excess of one enantiomerover the other. Correspondingly, the diastereomer composition of a diastereomermixture is the measure of an extent of a particular diastereomer over the others.This is calculated as shown in Equations 1 and 2, respectively, for [S ] > [R](Fig. 1.6).

A chiral molecule containing only one enantiomeric form is regarded as opti-cally pure or enantiopure or enantiomerically pure. Enantiomers can be separatedvia a process called resolution (Chapter 4), while in most cases diastereomers canbe separated through chromatographic methods. A variety of methods for deter-mination of optical purity or ee/de value are available [6]. One of the widelyused methods for analyzing chiral molecules is polarimetry. For any compoundof which the optical rotation of the pure enantiomer is known, the ee can bedetermined simply from the observed rotation and calculated by Equations 3 and4 (Fig. 1.7).

ee% =[S] − [R]

[S] + [R]× 100% eq. 1

de% =[S*S] − [S*R]

[S*S] + [S*R]× 100% eq. 2

FIGURE 1.6 Method of calculating enantiomer or diastereomer excess.

GENERAL STRATEGIES FOR SYNTHESIS OF CHIRAL DRUGS 9

[α]D20 =

[α]

L(dm) × c(g/100mL)× 100% Eq. 3

[α]D = measured rotationL = path length of cell (dm)

c = concentration (g/100mL)

D = D line of wavelength of light used for measurement20 = temperature

ee % =(optical purity)

[α]obs

[α]max

× 100% Eq. 4

FIGURE 1.7 ee value is directly determined from the observed rotation.

Chromatography with chiral stationary columns, for example, chiral high-pressure liquid chromatography (HPLC) or chiral gas chromatography (GC), hasalso been utilized extensively for analyzing and determining enantiomeric com-position of a chiral compound. Nuclear magnetic resonance (NMR) spectroscopycan also be used to evaluate the enantiomeric purity in the presence of chiral shiftreagents [6,11] or through its diastereomer derivatives (e.g., Mosher’s esters) [8].

1.3 GENERAL STRATEGIES FOR SYNTHESIS OF CHIRAL DRUGS

Asymmetric synthesis refers to the selective formation of a single stereoisomerand therefore affords superior atom economy. It has become the most power-ful and commonly employed method for preparation of chiral drugs. Since the1980s, there has been progress in many new technologies, in particular, the tech-nology related to catalytic asymmetric synthesis, that allow the preparation ofpure enatiomers in quantity. The first commercialized catalytic asymmetric syn-thesis, the Monsanto process of l-DOPA (9) (Fig. 1.8), was established in 1974by Knowles [12], who was awarded a Nobel Prize in Chemistry in 2001 alongwith Noyori and Sharpless. In the key step of the synthesis of l-DOPA, a goldstandard drug for Parkinson disease, enamide compound 7 is hydrogenated inthe presence of a catalytic amount of [Rh(R,R)-DiPAMP)COD]+BF4 complex,affording the protected amino acid 8 in quantitative yield and in 95% ee. Asimple acid-catalyzed hydrolysis step completes the synthesis of l-DOPA (9).

The discovery of an atropisomeric chiral diphosphine, BINAP, by Noyori in1980 [13] was revolutionary in the field of catalytic asymmetric synthesis. Forexample, the BINAP-Ru(II) complexes exhibit an extremely high chiral recog-nition ability in the hydrogenation of a variety of functionalized olefins andketones. This transition metal catalysis is clean, simple, and economical to oper-ate and hence is capable of conducting a reaction on a milligram to kilogram scalewith a very high (up to 50%) substrate concentration in organic solvents. Both

10 OVERVIEW OF CHIRALITY AND CHIRAL DRUGS

COOH

NHAc

H3CO

AcO7

+ H2

Rh((R,R )-DiPAMP)COD+BF4

−

catalyst

100%

COOHH3CO

AcOH NHAc

895% ee

H3O+

COOHHO

HOH NHAc

L-dopa 9

P

OMe

P

MeO

(R,R )-DiPAMP

COD

FIGURE 1.8 Monsanto process of l-dopa (9).

enantiomers can be synthesized with equal efficiency by choosing the appro-priate enantiomers of the catalysts. It has been used in industrial productionof compounds such as (R)-1,2- propanediol, (S )-naproxen, a chiral azetidinoneintermediate for carbapenem synthesis, and a β-hydroxylcarboxylic acid inter-mediate for the first-generation synthesis of Januvia [14] among others. TheSharpless–Katsuki epoxidation was also published in 1980 [15]. It has also beenused for the chiral drug synthesis on an industrial scale.

Chiral compounds can now be accessed in one of many different approaches:1) via chiral resolution of a racemate (Chapter 4); 2) through asymmetric syn-thesis, either chemically or enzymatically (Chapters 2 and 3); and 3) throughmanipulation of chiral starting materials (chiral-pool material). In the early 1990s,most chiral drugs were derived from chiral-pool materials, and only 20% of alldrugs were made via purely synthetic approaches. This has now been reversed,with only about 25% of drugs made from chiral pool and over 50% from otherchiral technologies [16]. The following is a brief account of catalytic enantiose-lective synthesis with commercial applications.

1.3.1 Enantioselective Synthesis via Enzymatic Catalysis

Enzyme-catalyzed reactions (biotransformation) are often highly enantioselectiveand regioselective, and they can be carried out at ambient temperature, atmo-spheric pressure, and at or near neutral pH. Most of the enzymes used in theasymmetric synthesis can be generated in large quantity with modern molecu-lar biology approaches. The enzyme can be degraded biochemically, thereforeeliminating any potential hazardous caused by the catalysis, providing a supe-rior and environmentally friendly method for making chiral drug molecules. Itis estimated that the value of pharmaceutical intermediates generated by usingenzymatic reactions was $198 million in 2006 and is expected to reach $354.4million by 2013 [17].

GENERAL STRATEGIES FOR SYNTHESIS OF CHIRAL DRUGS 11

(S )-6-hydroxynorleucine (11) is a key intermediate for the synthesis of omapa-trilat (12), an antihypertensive drug that acts by inhibiting angiotensin-convertingenzyme (ACE) and neutral endopeptidase (NEP). 11 is prepared from 2-keto-6-hydroxyhexanoic acid 10 by reductive amination using beef liver glutamatedehydrogenase at 100 g/l substrate concentration. The reaction requires ammoniaand NADH. NAD produced during the reaction is recycled to NADH by theoxidation of glucose to gluconic acid with glucose dehydrogenase from Bacillusmegaterium . The reaction is complete in about 3 h with reaction yields of 92%and >99% ee for (S )-6-hydroxynorleucine 11 (Fig. 1.9) [18].

Gluconic AcidGlucose Dehydrogenase

Glucose

NADNADH

GlutamateDehydrogenase

NH3

HOOH

NH2

O

11

HOONa

O

O

10 12

HSNH

O

N

S

O

H

OOH

FIGURE 1.9 Enzymatic synthesis of chiral synthon (S )-6-hydroxynorleucine (11).

There are some exceptions and limitations to the enzymatic-catalyzed reac-tions. For example, the reaction type may be limited, and reactions may preferablybe conducted in aqueous media and at low substrate concentration. However, alot of new development in the technology of engineering enzymes have been wit-nessed recently [19]. Enzymes can be immobilized and reused in many cycles.Selective mutations of an enzyme can alter the enzyme’s performance or evenmake the opposite enantiomer formation possible.

1.3.2 Enantioselective Synthesis via Organometallic Catalysis

In asymmetric synthesis, a chiral agent should behave as a catalyst withenzymelike selectivity and turnover rate. Transition metal-based catalysts havebeen prevalent in organic synthesis for many years. Since the introductionof the Monsanto process of l-DOPA and BINAP-based ligands, asymmetrichydrogenation has become one of the most important processes in thepharmaceutical industry to synthesize key intermediates or active pharmaceuticalingredients. More than 3,000 chiral diphosphine and many monophosphineligands have been reported, and approximately 1% of those ligands are currentlycommercially available [20]. Besides the asymmetric hydrogenation of olefins,the ligand-mediate asymmetric hydrogenation of ketone to the correspondingalcohol [21] is becoming an indispensable alternative to other known processessuch as transfer hydrogenation and biocatalytic and hydride reduction. However,a lot still remains to be improved in this field in terms of catalyst sensitivity toatmosphere, high cost, and possible toxicity.

12 OVERVIEW OF CHIRALITY AND CHIRAL DRUGS

F

FF

N

NH2 O

N

NN

FF

F

sitagliptin (13)

O

OH

OHN

SO2

N

CF3tipranavir (14)

ONH

O

ramelteon (15)

NH

H3COO

OCH3

NH2

OH

O

NH2

O

aliskiren (16)

NC

HN

OO N

CF3

Cl

taranabant (17)

FIGURE 1.10 Example compounds generated via catalytic asymmetric hydrogenation.

Compounds 13–17 are examples that were generated via catalytic asymmetrichydrogenation. According to reference [22], they are sitagliptin (13), an oral dia-betes drug, tipranavir (14), an HIV protease inhibitor, ramelteon (15), a sleep aid,aliskiren (16), which is a hypertension drug, and taranabant (17), the antiobesityagent (Fig. 1.10).

1.3.3 Enantioselective Synthesis via Organocatalysis

Organocatalysts [23] have emerged as a powerful synthetic paradigm to com-plement organometallic- and enzyme-catalyzed asymmetric synthesis. Althoughexamples of asymmetric organocatalysis appeared as early as the 1970s [24], thefield was not born until the late 1990s and matured at the turn of the new century.Organocatalysis is now widely accepted as a new branch of enantioselectivesynthesis. A survey conducted by MacMillan [25] in 2008 showed only a fewpapers describing organocatalytic reactions before 2000, while the number ofpapers published in 2007 is close to 600. There have been a number of specialissues of journals dedicated to asymmetric organocatalysis [26].

Organocatalysts are loosely defined as low-molecular-weight organicmolecules having intrinsic catalytic activity. If an organocatalyst is modified tocontain a chiral element, the reaction catalyzed by it could become enantiose-lective. Aside from being catalytically active, asymmetric organocatalysis are ingeneral relatively inexpensive and readily available, are stable to atmosphericconditions, and have low toxicity. Many organocatalysts are simple derivativesof commonly available naturally occurring compounds. Representative examples

GENERAL STRATEGIES FOR SYNTHESIS OF CHIRAL DRUGS 13

NH

COOH

N

NH2

O

Ph

19 20N

HOH

18

O OO

OOO

21

R

HN

NH

NH

O

t-Bu H X

N

HO

t-Bu ORX = O, S thiourea-type 22

R

O

OP

R

O

OH

BINOL-BasedPhosphoric acid 23

R

R

N

Br

phase transfer catalysts 24

FIGURE 1.11 Representative organocatalysts.

include alkaloids and their derivatives (e.g., cinchonidine 18) or l-proline (19)and other natural amino acids, which function, for example, as starting materialsfor MacMillan-type catalysts like 20. The chiral ketone (21) generated fromfructose was reported for dioxirane-mediated asymmetric epoxidation [27](Fig. 1.11). A number of privileged organocatalysts, such as 22, 23, and 24have been designed, synthesized, and applied to various asymmetric reactions,which include C-C, C-heteroatom bond formation, oxidation, and reductionreactions.

The versatility of asymmetric organocatalysis is demonstrated by the practicalsynthesis of methyl (2R,3S )-3-(4-methoxyphenyl) glycidate [(–)-27], a key inter-mediate in the synthesis of diltiazem hydrochloride 28, which has been used asa medicine for the treatment of cardiovascular diseases since the 1970s. Methyl(E )-4-methoxycinnamate 25 underwent asymmetric epoxidation with a chiraldioxirane, generated in situ from Yang’s catalyst 26, to provide the product (–)-27in both high chemical (>85%) and optical (>70%ee) yields (Fig. 1.12) [28].

N

S

OMe

OAc

O

Me2N HCl28

MeO

COOMeOxone

25

26

O

MeO

COOMe

(−)-27

O

O

O

O

O

FIGURE 1.12 Asymmetric epoxidation of methyl (E )-4-methoxycinnamate (25).

14 OVERVIEW OF CHIRALITY AND CHIRAL DRUGS

1.4 TRENDS IN THE DEVELOPMENT OF CHIRAL DRUGS

1.4.1 Biological and Pharmacological Activities of Chiral Drugs

Many of the components associated with living organisms are chiral, for example,DNA, enzymes, antibodies, and hormones. The enantiomers of a chiral drugmay display different biological and pharmacological behaviors in chiral livingsystems. This can be easily understood with the example of a drug-receptormodel depicted in Figure 1.13. In possession of different spatial configurations,one active isomer may bind precisely to the target sites (α, β, γ), while aninactive isomer may have an unfavorable binding or bind to other unintendedtargets [29]. Pharmacological effects of enantiomeric drugs may be categorizedas follows [30].

D

CAB

D

ACB

Mirror Plane

Active Enantiomer Inactive Enantiomer

α β γ α β γ

Drug Binding Site Drug Binding Site

FIGURE 1.13 Stereoselective binding of enantiomers of a chiral drug.

1. Both enantiomers act on the same biological target(s), but one isomer hashigher binding affinity than the other: For example, carvedilol (29) is mar-keted as a racemate for the treatment of hypertension and congestive heartfailure [31]. It is a nonselective β- and α-adrenergic receptor blockingagent. Nonselective β-blocking activity resides mainly in the (S )-carvedilol,and the α-blocking effect is shared by both (R)- and (S )-enantiomers[32]. Sotalol (30) is a racemic β-adrenergic blocker. The (R)-enantiomerpossesses the majority of the β-blocking activity, and the (R)- and (S )-enantiomers of sotalol share an equivalent degree of class III antiarrhythmicpotency [33] (Fig. 1.14).

NH

O∗

NH

O

OH

OCH3

∗NH

CH3

HN

OH

CH3

29 30

SH3C

O

O

FIGURE 1.14 Structures of carvedilol (29) and sotalol (30).

TRENDS IN THE DEVELOPMENT OF CHIRAL DRUGS 15

2. Both enantiomers act on the same biological target, but exert opposedpharmacological activities: For example, (–)-dobutamine 31 demonstratedan agonistic activities against α-adrenoceptors, whereas its antipode (+)-dobutamine is an antagonist against the same receptors. The latter also actsas an β1-adrenoceptor agonist with a tenfold higher potency than the (–)isomer and is used to treat cardiogenic shock. The individual enantiomersof the 1,4-dihydropyridine analog Bayk8644 (32) have opposing effects onL-type calcium channels, with the (S )-enantiomer being an activator andthe (R)-enantiomer an antagonist [34] (Fig. 1.15).

HN ∗HO

HOCH3

OH

NH

H3C CH3

H3CO

O CF3

NO

O

31 32

FIGURE 1.15 Structures of (–)-dobutamine (31) and Bayk8644 (32).

3. Both enantiomers may act similarly, but they do not have a synergisticeffect: Two enantiomers of �-3-tetrahydrocannabinol (S )-34 or (R)-34were assayed in humans for psychoactivity. The 1S enantiomer 34had definite psychic actions, qualitatively similar to those of �-1-tetrahydrocannabinol, but quantitatively less potent (1:3 to 1:6). Addingtwo enantiomers together did not increase the effect, confirming thatactivity was solely in one enantiomer and that there was no synergisticeffect between the two isomers [35] (Fig. 1.16).

(1S) 3 -THC 34

H3CO

HN

CH3 O

OH

C5H11 O

OH

C5H11

33 (1R) 3 -THC 34

FIGURE 1.16 Structures of dextromethorphan and �-3-tetrahydrocannabinol(S )-34 or (R)-34.

4. Both enantiomers have independent therapeutic effects through action ondifferent targets: The classical example of this behavior is quinine 35 andquinidine 36 (Fig. 1.17). Quinine, which was originally obtained from thebark of cinchona trees, has been used for the treatment of malaria for

16 OVERVIEW OF CHIRALITY AND CHIRAL DRUGS

centuries. Quinidine, on the other hand, is used as a class 1A antiarrhythmicagent and acts by increasing action potential duration [36].

35 36

N

MeO

HON

N

MeO

HOH

H

N

FIGURE 1.17 Structures of quinine (35) and quinidine (36).

5. One or both enantiomers have the desired effect; at the same time, onlyone enantiomer can cause unwanted side effects: Racemic dropropizine(37) has long been used in human therapy as an antitussive agent. Recentstudies have revealed that (S )-dropropizine possesses the same antitussiveactivity as the racemic mixture, but has much lower selective activity onthe CNS [37]. Therefore, particular clinical significance is attached to drugsof which one enantiomer may contribute side or toxic effects (Fig. 1.18).

NN

∗OH

OH

37

FIGURE 1.18 Structures of dropropizine (37).

6. The inactive enantiomer might antagonize the side effects of the activeantipode: In such cases, taking into account both efficacy and safetyaspects, the racemate seems to be superior to either enantiomer alone. Forexample, the opioid analgesic tramadol (38) is a used as a racemate andis not associated with the classical side effects of opiate drugs, such asrespiratory depression, constipation, or sedation [38]. The (+)-enantiomeris a selective agonist for µ receptors with preferential inhibition ofserotonin reuptake and enhances serotonin efflux in the brain, whereasthe (–)-enantiomer mainly inhibits noradrenaline reuptake. The incidenceof side effects, particularly opioid-mediated effects, was higher with the(+)-enantiomer than with ±-tramadol or the (–)-enantiomer. Therefore,the racemate of tramadol is superior to the enantiomers for the treatmentof severe postoperative pain [39]. Albuterol (39), an adrenoceptoragonist bronchodilator, is the racemic form of 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl) phenol and can increase bronchial

TRENDS IN THE DEVELOPMENT OF CHIRAL DRUGS 17

airway diameter without increasing heart rate. The bronchodilator activityresides in (R)-albuterol. (S )-albuterol, however, is not inert, as it indirectlyantagonizes the benefits of (R)-albuterol and may have proinflammatoryeffects [40] (Fig. 1.19).

OCH3

NCH3

HHO CH3∗

HN CH3

CH3CH3

OH

HO

HO

38 39

FIGURE 1.19 Structures of tramadol (38) and albuterol (39).

It is a difficult task to rationally predict the biological/pharmacological activitydifference for two enantiomers. Fokkens and Klebe developed a simple protocolusing isothermal titration calorimetry in an attempt to semiquantitatively deter-mine the difference in binding affinity of two enantiomers to a protein withoutrequiring prior resolution of the racemates [41]. In some cases, the affinity dif-ference could be explained in terms of differences in the structural fit of theenantiomers into the binding pocket of the protein. [42].

Many attempts were made to develop a quantitative structure-activity rela-tionship between the two enantiomers and a specific target or target families.The ratio of potency or affinity of two enantiomers is defined as the eudismicratio (ER). The more potent enantiomer is generally called the eutomer, and theless potent enantiometer is the distomer. The logarithm of the eudimic ratio isregarded as the eudismic index (EI). Pfeiffer made an initial observation that thelogarithm of the ratio of the activities of the optical isomers was proportional tothe logarithm of the human dose. The generalization that the lower the effectivedose of a drug, the greater the difference in pharmacological effect between theoptical isomers is referred as Pfeiffer’s rule [43]. Indeed, a linear correlationbetween the logarithm of the EI of 14 randomly chosen enantiomeric pairs andthe logarithm of the average human dose was observed.

Eudismic analysis was made for a series of five cholinesterase inhibitors,derivatives of S -alkyl p-nitrophenyl methylphosphonothiolates (R: methylto pentyl), a series of four derivatives of 1,3-dioxolane (R: H, Me, Et,i -propyl) active at the muscarinic receptor, and Pfeiffer’s original set of 14nonhomologous enantiomeric pairs with a computer-aided drug design method[44]. It was concluded that eudismic ratios of potent drugs belonging tohomologous sets can be correlated with their chirality coefficients, which wasdefined as the quantitative index of the dissimilarity between the enantiomersand was calculated from a combination of data from the superimposition ofcomputer-optimized conformations and electrostatic potential (ESP) calculations.Linear correlations were observed between the calculated chirality coefficientsand experimentally determined eudismic ratios for both sets of homologous

18 OVERVIEW OF CHIRALITY AND CHIRAL DRUGS

derivatives. With Pfeiffer’s set (members include atropine, norepinephrine,epinephrine, and methadone) correlation was observed for the first (mostpotent) eight members of the series. The lack of correlation for the less potentcompounds in Pfeiffer’s set was explained as a function of kinetic differencesbecoming more influential than drug-receptor interactions [44].

On the qualitative side, 3D binding molecule modeling studies can point outsome interesting binding differences for two enantiomers. Two enantiomers ofcitalopram were demonstrated to bind to human serotonin transporter in reversedorientation [45].

1.4.2 Pharmacokinetics and Drug Disposition

In addition to the differences in biological activities, stereoisomers may differ intheir pharmacokinetic properties such as absorption, distribution, metabolism, andexcretion (ADME) as a result of chiral discrimination during the pharmacokineticprocesses [46]. The difference in bioavailability, rate of metabolism, metaboliteformation, excretion rate, and toxicity may be further influenced by other factorssuch as the route of administration, the age and sex of the subjects, disease states,and genetic polymorphism in cytochrome P450 (CYP) isoenzymes involved indrug metabolism [47].

Active transport processes may discriminate between the enantiomers, withimplications for bioavailability. For example, a longer plasma half-life in the rab-bit and greater accumulation of propranolol in the heart and brain of the rat werefound for the active (S )-(–)-enantiomer (40) as compared to the correspondingracemate.

Plasma binding capacity for two enantiomers may also be significantly differ-ent, thus influencing drug efficacy. Methadone (41), introduced to treat opioiddependence in 1965, has therapeutic benefits that reside in the (R)-enantiomer.Compared to the (S )-enantiomer of methadone, methadone’s (R)-enantiomershows 10-fold higher affinity for µ and κ opioid receptors and up to 50 times theantinociceptive activity in animal model and clinical studies. Methadone’s enan-tiomers show markedly different pharmacokinetics. The (R)-enantiomer showsa significantly greater unbound fraction and total renal clearance than the (S )-enantiomer. This reflects higher plasma protein binding of the (S )-enantiomer[48] (Fig. 1.20).

O NH

CH3

CH3

H OH H3C ∗ NCH3

CH3

CH3O

40 41

FIGURE 1.20 Structures of (S )-(–)-propranolol (40) and methadone (41).