Chiral Compounds

HANS-ULRICH BLASER, Solvias AG, Basel, Switzerland

ANDREAS PFALTZ, University of Basel, Department of Chemistry, Switzerland

HELMA WENNEMERS, University of Basel, Department of Chemistry, Switzerland

1. Introduction. . . . . . . . . . . . . . . . . . . . . 11.1. Properties of Enantiomers . . . . . . . . 21.2. Absolute Configuration at Stereogenic

Centers . . . . . . . . . . . . . . . . . . . . . . 31.3. Other Stereogenic Elements. . . . . . . 42. Analysis of Chiral Compounds . . . . . . 42.1. Optical Rotation . . . . . . . . . . . . . . . 42.2. NMR-Spectroscopic Analysis . . . . . . 52.3. Chromatographic Analysis. . . . . . . . 53. Occurrence, Significance and Synthetic

Options . . . . . . . . . . . . . . . . . . . . . . . . 63.1. Occurrence and Significance . . . . . . 63.2. Synthetic Options. . . . . . . . . . . . . . . 74. Resolution of Racemates and Chiral

Pool Approach . . . . . . . . . . . . . . . . . . . 84.1. Resolution of Racemates . . . . . . . . . 84.2. Chiral Pool Approach . . . . . . . . . . . 105. Stoichiometric Enantioselective

Synthesis . . . . . . . . . . . . . . . . . . . . . . 105.1. Chiral Reagents . . . . . . . . . . . . . . . . 115.2. Chiral Auxiliaries . . . . . . . . . . . . . . 12

6. Enantioselective Catalysis . . . . . . . . . 127. Catalysis with Soluble Metal

Complexes (Homogeneous Catalysis) 157.1. Hydrogenation of Olefins, Ketones

and C¼N Functions . . . . . . . . . . . . . 167.2. Oxidation Reactions. . . . . . . . . . . . . 187.3. Addition Reactions to C¼C, C¼O,

and C¼N Moieties . . . . . . . . . . . . . . 207.4. Miscellaneous Transformations . . . . 217.5. Future Developments . . . . . . . . . . . . 228. Heterogeneous Catalysis . . . . . . . . . . 229. Organocatalysis . . . . . . . . . . . . . . . . . 239.1. Covalent Binding: Aminocatalysis . . 239.2. Hydrogen–Bonding Catalysis . . . . . . 249.3. Ion Pair Formation: Catalysis with

Lewis Bases, Brønsted Acids, andPhase-Transfer Cations . . . . . . . . . . 25

9.4. Further Aspects and FutureDevelopments. . . . . . . . . . . . . . . . . . 26

10. Enzymatic Transformations . . . . . . 26

1. Introduction

Chirality is an all-encompassing phenomenon.In Nature, both macroscopic and microscopicobjects can be chiral. Actually, most naturalmolecules, plants, animals, and humans arechiral. The concept of chirality has played anessential role in the development of stereochem-ical models. More importantly, it has a stronginfluence on our daily life, i.e., the application ofchiral bioactive compounds, such as pharma-ceuticals, agrochemicals, or flavors and fra-grances. In molecular terms, chirality is ageometric property of a particular subclass ofstereoisomers. A molecule is termed chiral,when it can exist in two forms (the enantiomers)which have the same chemical structure but are

non-superimposable mirror images. Chiralcomes from the Greek word ‘‘cheir’’ (hand), asthe right and left hand possess this property, andfor this reason one also speaks of left- and right-handed molecules [1].

Chiral molecules are also called opticallyactive, because molecular chirality results inoptical activity, i.e., the ability to rotate theplane of polarized light. This phenomenon wasfirst observed in 1815 by the French scientistBIOT while studying the interaction of planepolarized light with solutions of organic mate-rials, such as sugar or camphor. However, thelink between optical activity and molecularstructure did not become apparent until muchlater. An important milestone was the discoveryof PASTEUR in 1848: Ammonium sodium tartrate

� 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim10.1002/14356007.a18_177.pub2

can crystallize in two distinct types of crystals,which he could separate manually. When dis-solved, each type of crystal exhibited similaroptical activity but in opposite direction. Thisfundamental discoverywas the starting point forthe development of a molecular basis for thephenomenon of ‘‘chirality’’ in particular andstereochemistry in general, with far-reachingimplications in organic and biochemistry. SoonPASTEUR recognized the tendency of living sys-tems to produce chiral molecules — he calledthem dissymmetric — not as racemic (50:50)mixtures but enantiomerically pure (100:0). Inaddition, he correctly stated that enantiomeri-cally pure (or enantioenriched) compounds canonly be produced artificially in the presence of aphysical or chemical chiral agent (in the case ofthe tartrate, the agent was PASTEUR himself, whomanually separated the left- and the right-hand-ed crystals). Although PASTEUR suspected thatthis phenomenon has its basis in the molecularstructure, the final explanation was provided byVAN’T HOFF in 1874. Following KEKULE’s struc-tural theory that carbon is always tetravalent,VAN’T HOFF proposed that a carbon atom at-tached to four substituents leads to tetrahedralgeometry. Consequently, when all substituentsare different, such as in lactic acid, the moleculeis chiral because it is non-superimposable on itsmirror image (Fig. 1). A carbon with four dif-ferent groups attached is called a stereogeniccenter (sometimes also asymmetric atom orcenter of chirality), and its presence is mostoften the cause that a molecule is chiral.

1.1. Properties of Enantiomers

The two enantiomers of lactic acid, like all pairsof enantiomers, have the same physical and

chemical properties, such as melting points orretention times in HPLC, and their NMR or IRspectra are identical. However, enantiomersbehave differently in the presence of other chiralmolecules or agents. For instance, enantiomersdo not migrate identically on chiral chro-matographic phases, and the NMR spectra ofenantiomers are affected differently by chiraladditives. Because enantiomers rotate polarizedlight to the same extent but in opposite direc-tions a 1:1 mixture of enantiomers is opticallyinactive. Such a mixture is called a racemate ora racemic mixture. Enantiomers can be separat-ed when the barrier of racemization, i.e., ofinterconversion, is high enough (> 100 kJ/molat room temperature). Molecules may adopt avariety of different conformations, which oftenare chiral. When assessing chirality, a time-averaged structure is considered, and the mostsymmetric possible conformation should bereferred to.

Although Nature frequently exhibits a highdegree of symmetry in terms of general mor-phology, at themolecular level the naturalworldis highly asymmetric. Enzymes, proteins, poly-saccharides, nucleic acids, andmany other basiccomponents of plants and animals are chiral andoccur in enantiopure form. Interestingly, thebasic building blocks in biological systems havethe same handedness: Most amino acids have L

and most sugars have D configuration (seebelow). The origin of homochirality in biologyis the subject of much debate but most scientistsassume that Earth life’s ‘‘choice’’ of chiralitywas purely random. The implications of thechiral nature on the properties of biologicalsystems are profound. For example, enzymesor proteins distinguish between the two enan-tiomers of a chiral drug leading to sometimesdramatically different effects. This can be

Figure 1. A) Stereogenic center; B) Absolute configuration of lactic acid

2 Chiral Compounds

understood by imagining an enzyme as having aglove-like cavity that binds a substrate. If theglove is right-handed, then one enantiomer fitsinside and is bound, whereas the other enantio-mer has a poor fit and is unlikely to bind.Similarly, because our sensory receptors in-volved in taste and smell are also chiral, en-antiomers of chiral compounds often taste andsmell differently (e.g., natural L-asparagine isbitter, whereas artificial D-asparagine is sweet).

1.2. Absolute Configuration atStereogenic Centers

Due to the abundance and importance of op-tically active compounds, various systems ofnomenclature have been developed to specifythe absolute configuration, i.e., the spatial ar-rangements of the substituents. The first de-scription is based on the direction in which thematerial rotates the plane of light. Compoundsthat rotate the plane of polarized light to the right(clockwise) are assigned the configuration (þ)and termed dextrorotatory; those rotating to theleft (counterclockwise) are designated (�) orlevorotatory. This, however, does not allowconnecting the absolute configuration of differ-ent molecules. A first solution was offered byROSANOFF who developed a system that relatedall molecules containing stereogenic carbonatoms to either (þ)- or (�)-glyceraldehyde.Molecules that can be connected to (þ)-glycer-aldehyde are designated D and those that arecorrelated with (�)-glyceraldehyde are denotedL. The D-(þ)-isomer of glyceraldehyde wasassigned, arbitrarily, the configuration depictedin Figure 2A. The absolute configuration ofnatural amino acids and sugars was assignedon this basis. It was not until 1951 thatBIJVOET [10] succeeded in experimentally deter-mining the absolute configuration of a moleculeby using a specializedX-ray diffractionmethod.

The compound investigated was (þ)-sodiumrubidium tartrate, and from its configuration itwas deduced that the original guess for (þ)-glyceraldehyde was actually correct.

Although the D/L system remains in commonuse in amino acids and carbohydrate chemistry— it is convenient to have the same label ofchirality for all compounds of a given type ofstructure — it is very cumbersome and oftenimpossible to correlate each stereogenic centerof interest to glyceraldehyde via chemical deg-radation. For this reason a new system wasdeveloped that labels each stereogenic centerR or S according to a procedure by which itssubstituents are assigned a priority, according tothe Cahn–Ingold–Prelog priority rules (CIP),based on atomic numbers [11]. If the center isoriented in such a way that the lowest priority ofthe four is pointed away from the viewer, twocases are possible: If the priority of the remain-ing three substituents decreases in clockwisedirection, it is labeled R (for rectus) (Fig. 2B); ifit decreases counterclockwise, it is S (forsinister).

The R/S system has no direct relation to the(þ)/(�) system. An R isomer can be eitherdextrorotatory or levorotatory, depending onthe nature of the substituents. It also does notcorrelate to the D/L system. Nevertheless, incertain classes of structurally related com-pounds, D and L correlate well with R and S.For example, naturally occurring L-amino acids(i.e., correlated to L-glyceraldehyde) havemostly S configuration because the priorityfor the substituents are usually the same:NH2 > COOH > R > H.

As the CIP system labels each stereogeniccenter in a molecule in an unambiguous mannerand can also be applied to chiral moleculeswithout stereogenic centers, it has greater gen-erality than the D/L system. This is important formolecules with more than one stereogenic cen-ter. The number of stereoisomers is 2n (or 2n-1

Figure 2. A) Absolute configuration of glyceraldehyde; B) Cahn–Ingold–Prelog priorities

Chiral Compounds 3

pairs of enantiomers) where n is the number ofstereogenic centers. An exception to the ruleoccurs for C2-symmetrical molecules and n¼ 2,because the (R,S)-form (calledmeso) has a planeof symmetry and is therefore NOT chiral(despite having stereogenic centers), and thusonly three stereoisomers exist as depicted inFigure 3. Changing the absolute configurationof one ormore centers inmolecules with severalstereogenic centers leads to diastereomers. Dia-stereomers, such as (R,R)- and (R,S)-tartaricacid have different relative spatial arrangementsof atoms and therefore differ in all of theirphysical and chemical properties.

1.3. Other Stereogenic Elements

Not only carbon atoms can show chirality butany molecule containing an atom bound to fourdifferent tetrahedrally arranged substituents ischiral. Pyramidal nitrogen atoms do not, ingeneral, induce optical activity because racemi-zation via inversion is rapid. Phosphorus, arse-nic, and sulfur compounds with three differentsubstituents undergo inversion more slowly andoften exhibit optical activity.

Besides stereogenic centers there are a fewother stereogenic elements that will lead tochiral molecules. Of practical importance areaxial and planar chirality. Axial chirality is usedto refer to stereoisomerism resulting from thenonplanar arrangement of four groups in pairs

along a chirality axis. Atropisomerism due torestricted rotation of ortho-substituted biphe-nyls is an example (Fig. 4A). The configurationis specified by the stereodescriptors Ra and Sa.Planar chirality results from the arrangement ofout-of-plane groups with respect to a plane(chirality plane). This is illustrated inFigure 4B by the disubstituted ferrocenes(chirality plane¼ substituted ring). The config-uration is specified by the stereodescriptors RP

and SP.

2. Analysis of Chiral Compounds

There are several reliable methods to determinethe enantiomeric purity of a chiral compound,and all rely on the interaction with a chiralmedium or compound.

2.1. Optical Rotation

Until the introduction of reliable spectroscopictechniques, measuring the optical activity of asolution of the chiral analyte was the obviousmethod of choice. In order to determine theenantiopurity of a given sample, it is necessaryto know the specific rotation [a] of the purechiral compound in question. The specificrotation is a standardized figure defined for aparticular concentration of the sample, c(g/100 mL) at a temperature T (�C) with light

Figure 3. Absolute configuration of tartaric acid

Figure 4. Stereogenic elementsA) Axial chirality; B) Planar chirality

4 Chiral Compounds

of wavelength l by the equation

½a�Tl ¼ 100a

lc

wherea is the observed rotation in degrees and lthe sample path length in decimeters. The spe-cific rotation is often measured by using lightcorresponding to the D line of sodium (l ¼589 nm) and expressed as [a]D. As opticalrotation gives a direct measure of the excess ofthemajor enantiomer (the rest is canceled by theopposite enantiomer), the enantiomeric purityof a compound, also called optical purity, is stilltoday expressed as enantiomeric excess, ee (%)defined as

ee ¼ j%R�%Sj

Although polarimetry has been used exten-sively to determine enantiomeric purity, thelimitations of this method should be recognized.The specific rotation is concentration, tempera-ture, andwavelength dependent. In addition, thepresence of even small amounts of an impuritywith a high specific rotation can givemisleadingresults. Furthermore, molecules that formstrong associates can show a nonlinear correla-tion between a and ee values.

For these reasons and because of an ever-increasing demand for more reliable and preciseanalytical techniques, other methods have beendeveloped. These are based on chromatographicand spectroscopic procedures relying on thegeneration of a diastereomeric interaction thatis either covalent or noncovalent. Because thesemethods measure the composition of thesample, some authors prefer to define theenantiomeric purity by the enantiomeric ratio(er ¼ R/S) of a given sample.

2.2. NMR-Spectroscopic Analysis

NMR spectroscopy, with 1H NMR being themost widely used technique, is a flexible andreliable method to determine the enantiomericexcess. A mixture of enantiomers is either deri-vatized to give spectroscopically distinguish-able diastereomers or the NMRmeasurement iscarried out in the presence of a chiral additive.

In the first case, a derivative is usually chosenthat contains a sharp, readily observable signal,such as the methoxy moiety in a-methoxyphe-nylacetic acid, which has been used extensively

to analyze both amines and alcohols. TheMosh-er reagent, (R)-or (S)-a-methoxy-a-(trifluoro-methyl)phenylacetic acid (MTPA), is a usefulalternative because it is more stable towardacid- or base-catalyzed racemization. MTPAderivatives can in addition to 1H NMR also beanalyzed by 19F NMR and are suitable foranalysis by GC and HPLC.

Other options are the use of a chiral solvatingagent and lanthanide shifts reagents. A rangeof chiral solvating agents, such as the commer-cially available aryl trifluoromethyl methanolsand 1-arylethylamines, have found widespreadapplication. Lanthanide shifts reagents inducegenerally larger shifts than those observed withchiral solvating agents, but line broadeningeffects may cause difficulties. Several praseo-dymium and europium complexes based oncamphor derivatives are commercially avail-able and have been used extensively.

However, for routine analysis of enantiomer-ic composition these spectroscopic methodshave almost completely been replaced by chro-matographic analysis using GC or HPLC onchiral stationary phases.

2.3. Chromatographic Analysis

Suitable substrates, such as amines or alcoholscan be derivatized with an optically pure car-boxylic acid leading to diastereomeric amidesand esters, respectively, which may be analyzedby conventional GC or HPLC. This strategy isnow used only in special cases. The more ver-satile alternative is the use of chiral stationaryphases (CSP) which are commercially availablein a wide variety for both GC and HPLC allow-ing separation of almost any chiral compound.The most commonly used materials includePirkle-type, derivatized polysaccharides,macrocyclics (such as cyclodextrins, glycopep-tides, and crown ethers), ligand-exchange, pro-tein, and other polymer-based CSPs. The mostversatile materials are cellulose derivatives,such as Chiralcel and amylose derivatives usedin Chiralpak columns [12].

Chromatographic methodologies havealmost entirely replaced other analytical meth-ods due to the advantages of speed (especiallyfor GC and supercritical HPLC) and operationalsimplicity.

Chiral Compounds 5

3. Occurrence, Significance andSynthetic Options

3.1. Occurrence and Significance

Many of Nature’s most important types of mo-lecules, such as enzymes, proteins, polysacchar-ides, nucleic acids, and many other basic com-ponents of plants and animals are chiral and,with some exceptions, occur as only one enan-tiomer and in enantiomerically pure form (ee�99%). An exception is, for example, lactic acid,which naturally occurs both in the (R)- and the(S)-form. Today, the most important large-scaleapplications of enantiomerically pure com-pounds are as bioactive ingredients indrugs [13], agrochemicals [14], feed and foodadditives, and as flavors and fragrances.

Clearly, if a chiral molecule is directed to-wards a biological target, the two enantiomersshould be viewed as distinct compounds that arecapable of acting in different ways. The poten-cy, absorption, transport, degradation, and ex-cretion of the two enantiomers can be quitedifferent within the body. Although this mayoften not be a problem, in the worst scenario theunwanted enantiomer can be highly toxic. Aparticularly tragic case was the sedative thalid-omide (Fig. 5), which was sold as a racemateand in the 1950s led to severe malformations inchildren. It was later found that this was due tothe teratogenic nature of the (S)-enantiomer.This case and other observations led to anincreased pressure for enantiomerically purecompounds even though it was found that for

thalidomide, applying only the (R)-enantiomerwould not have helped, since racemization read-ily occurs in the body [15].

In 1988 the FDA announced a set of guide-lines addressing these stereochemical topics inrelation to the submission of new drug applica-tions [16]. Consequently, the use of racemateshas drastically been reduced (see Fig. 6) and ananalysis carried out in 2006 by scientists fromAstraZeneca, GlaxoSmithKline, and Pfizer con-firmed this trend: Of 128 compounds underdevelopment in the three companies, 69(54%) were molecules containing at least onestereogenic center and of these chiral molecules67 were being developed as single enantiomers,only two as racemates [17].

This trend makes the efficient synthesis ofenantiopure chiral chemicals an important top-ic. The presence of a chiral agent is necessary toobtain preferentially the desired enantiomer. Inall practically useful synthetic strategies, thisagent is an enantiopure chiral molecule able to

Figure 5. Structure of thalidomide

Figure 6. Proportion of chiral drugs approved as racemate in from 1985 to 2001 (adapted from [18])& Achiral; & Single enantiomer; & Racemates

6 Chiral Compounds

interact with the substrates during the synthesisof the chiral target molecule.

3.2. Synthetic Options

There are four general approaches for producingenantiopure (ee � 99%) or enantioenrichedcompounds:

1. Resolution of racemates via separation of thetwo enantiomers. This can be achieved byclassical crystallization of diastereomericadducts (usually salts), HPLC on a chiralstationary phase usingmoving simulated bedtechnology, or (catalytic) kinetic resolution.

2. Chiral pool approach using chiral buildingblocks from natural products for the con-struction of the final molecule.

3. Stoichiometric enantioselective syntheses,performed either with chiral reagents or withthe help of covalently bound chiral auxili-aries, (often from the chiral pool) whichrender the reactions diastereoselectively.

4. Enantioselective catalysis where achiralstarting materials are transformed to enan-tioenriched products by chiral catalysts. Ef-fective catalysts are either synthetic (chemo-catalysis) or of natural origin (biocatalysis)

In the following discussion, the focus is onthe strengths and weaknesses of various ap-proaches in the context of synthetic and indus-trial applicability. However, the development ofan effective new synthesis for even a simplechiral molecule can be quite time consumingand tedious. This is illustrated in an over-view [19] on synthetic approaches to enantio-merically enriched 4-hydroxycyclohex-2-en-1-one (HCEO, 1), an important chiral buildingblock for complex natural products.

Even for this rather simple building block, 25different approaches are described includingracemate resolution, the use of chiral auxiliariesas well as modern catalytic asymmetric proce-dures, such as enantioselective reduction, enzy-matic kinetic resolution, and organocatalysis.However, in practice only three methods areroutinely used (Fig. 7).

Figure 7. Useful synthetic routes and key enantioselective step(s) for the synthesis of enantiomerically enriched4-hydroxycyclohex-2-en-1-one (1)A) Lipase catalyzed kinetic resolution route from a racemate (three steps to (S)-HCEO, four steps to (R)-HCEO);B) Chiral poolroute from (�)-quinic acid (six steps to protected (S)-HCEO, six steps to (R)-HCEO); C) Proline catalyzed aminoxylation routefrom 1,4-cyclohexanedione (four steps to (S)-HCEO or (R)-HCEO)

Chiral Compounds 7

The choice of the optimal method to preparea chiral target molecule depends on a number ofconsiderations, such as nature of the chemicalreaction, goal of the synthesis, know-how of theinvestigators, time frame, available manpower,equipment, etc. As a rule, synthesis of racemiccompounds followed by chromatographic reso-lution is usually the method of choice when aproduct has to be synthesized fast and in smallamounts, such as in the discovery phase ofbioactives. Enantioselective synthetic methodsare chosen for a large-scale production process.However, its development is much more com-plex and time consuming.

No matter which option is chosen, the fol-lowing criteria influence the selection:

. Maturity of the enantioselective step. Whatlevel of enantioselection can be expected,how well are scope and limitations known?

. Commercial availability of both enantiomersof the chiral auxiliary. For industrial applica-tions, this means that, e.g., chiral ligands mustbe available on kilogram scale.

. Cost (for industrial applications) and effortneeded for the over-all synthesis.

. Familiarity and experience of the investiga-tors with a particular methodology ortransformation.

4. Resolution of Racemates andChiral Pool Approach

4.1. Resolution of Racemates

Since the synthesis of racemic products is usu-ally better established and easier, resolution ofracemates is still the method of choice in manyinstances, even though it means that 50% of thesynthesized material has to be discarded orrecycled, e.g., via racemization. Consequently,in a multistep synthesis, the resolution stepshould occur as early as possible in the sequencein order to save expensive reagents. Althoughcrystallization of diastereomeric adducts can beapplied on any scale, separation via HPLC isprobably most important in the early phase ofproduct development and restricted to small tomedium scale, high value products. In bothcases, large amounts of solvents have to be

handled. In kinetic resolution the chiral cata-lysts react at different rates with the two en-antiomers; the product and unreacted startingmaterials have to be separated.

The resolution approach gives a maximumyield of 50% and the unwanted enantiomer hasto be discarded unless recycling via racemiza-tion is feasible. This is often possible and infavorable cases can occur in situ — a strategycalled dynamic kinetic resolution.

Resolution via Crystallization. The classi-cal resolution of racemates via crystallization ofdiastereomeric adducts is still predominant inthe production of chiral drugs. This methodolo-gy requires the use of an enantiomerically pureresolving agent leading to a diastereomer adductthat is separated by crystallization. Cleavage ofthe adduct gives the enantioenriched substratethat has to be separated from the resolvingagent, which may be recovered. Quite often,several crystallizations are necessary to achievesufficiently high enantiopurity leading to sig-nificant yield losses and relatively high processcosts.

Chiral carboxylic acids and amines are mostoften used as resolving agents because they arereadily available, and their acidic/basic proper-ties allow easy separation of the resolving agentfrom the enantiomer of interest. Commonlyused carboxylic acid resolving agents includetartaric acid (and related analogues), camphor-sulfonic acid, mandelic acid, and pyroglutamicacid. Chiral amines used as resolving agentsinclude the cheap a-methylbenzylamine andalkaloids, such as brucine and cinchonidine,ephedrine, and pseudoephedrine.

A good example of the use of classicalresolution is shown in Figure 8 for synthesis of(S)-naproxen — the only a-arylpropionic acidanti-inflammatory agent marketed as single en-antiomer. N-alkyl-D-glucamine (NAG) is usedas the resolving agent. The efficiency of theprocess is high because the unwanted (R)-na-proxen can be easily racemized, and the resolv-ing agent is recycled with a high recoveryrate [20].

Finding the right resolution agent and crys-tallization conditions is very much a trial-and-error approach and can be time consuming.More systematic searches have been developedrecently [21, 22] and are increasingly combined

8 Chiral Compounds

with high-throughput screening. Decisive forsuccess is a sufficient enrichment with only oneor two crystallizations and an effective recy-cling of the chiral auxiliary, the solvent and, ifpossible, the unwanted enantiomer. In suitablecases, the unwanted enantiomer can be race-mized in situ (crystallization-induced asymmet-ric transformation), leading, theoretically, to100% yield [23].

Resolution by HPLC. Although HPLC isfirmly established as analytical technique, thelarge-scale separation on a chiral stationaryphase using simulated moving bed (SMB) tech-nology is still in the emerging stage [24, 25].

SMB is a continuous process using severalchromatographic columns where the sampleinlet and the analyte exit positions are movedcontinuously, giving the effect of a moving bed.This technology leads to savings of both the(expensive) chiral stationary phase and solventbut, on the negative side, requires substantialcapital investments.

Resolution by HPLC and crystallizationwere compared for the synthesis of the thioureaderivative (3), a building block for the drugAMG221 (4) (Fig. 9) [26]. 2-Aminonorbornane(2) (obtained in two steps) was needed to per-form the resolution via crystallization with thechiral acid 5, and after two additional steps 3

Figure 8. Resolution of naproxen via crystallization with N-alkyl-D-glucamine (NAG)

Figure 9. Enantiomer separation of a chiral intermediate: Comparison of crystallization vs. chromatography

Chiral Compounds 9

was obtained. The chromatographic separationwas possible with 3, which was obtained in twosteps from the startingmaterial. In this study, theresolution by HPLC is the better technique dueto fewer chemical steps and higher efficiency ofresolution. This shows that to achieve optimalresults the synthesis has to be adapted to theresolution method.

Kinetic Resolution. In kinetic resolution,the chiral catalyst reacts at different rates withthe two enantiomers and is therefore a specialcase of enantioselective catalysis. Because atbest only 50% yield is possible, this variant hasbeen less investigated, and only few catalytictransformations have gained importance.

By far the most widely used type of reactionis the resolution using hydrolases, e.g., for thehydrolysis of esters or amides or the acylation ofalcohols or amines (! Enzymes, 5. Enzymes inOrganic Synthesis, Section 4.3; ! Biocataly-sis, 3. Nonimmobilized Biocatalysts in Indus-trial Fine Chemical Synthesis, Section 2.3). Anexample is shown in Figure 7A. It is possible toachieve dynamic kinetic resolution by combin-ing a hydrolase with an organometallic racemi-zation catalyst. This is not trivial because theoptimal conditions (solvent, additives, temper-ature) for the two catalysts can be quite differ-ent. Very good results have been reported for thepreparation of chiral alcohols and amines [27].

One of the few practically useful chemoca-talytic kinetic resolutions is the Co/salen cata-lyzed hydrolysis of epoxides [28] (see Fig. 10).As the diol is much more water soluble, separa-tion is relatively easy. This option can be moreeconomical than asymmetric epoxidation and isoften competitive with biocatalytic methods.Indeed, Rhodia-Chirex [29] has developed the

catalytic system and produces several epoxideswith this technology.

4.2. Chiral Pool Approach

Nature provides a wide range of chiral mole-cules called ‘‘chiral pool’’ that can be used as astarting point for asymmetric synthesis. Of par-ticular relevance in asymmetric synthesis arealkaloids, terpenes, carbohydrates, a-amino-,and a-hydroxyacids. There are numerous ex-amples of starting materials in syntheses, manyof which have important industrial applications(see special chapters in refs. [2, 4, 5]). Anexample is shown in Figure 7B and many ofthe most useful chiral ligands and auxiliarieshave been prepared starting from naturalproducts [30].

Starting materials from the chiral pool areoften chosen in the early phases of drug devel-opment but, depending on the commercialavailability of the starting material, can also beused for large-scale production. Because naturalproducts often have high enantiomeric purity,no further enrichment is usually necessary. Arecent complication is that products of animalorigin must be declared for the production ofmedicinal products in order to minimize therisk of transmitting animal spongiformencephalopathy.

5. Stoichiometric EnantioselectiveSynthesis

Stoichiometric enantioselective synthesis in-volves the use of stoichiometric quantities ofa chiral moiety, either as a reagent or a residue

Figure 10. Kinetic resolution of epoxides via Co/salen catalyzed hydrolysis

10 Chiral Compounds

covalently attached to the substrate. The chiralauxiliaries are not incorporated in the targetmolecule but are removed from the chiral prod-uct after the new stereogenic center has beenestablished and are either recycled or discarded.Research in these fields was strongest in the late1970s and 1980s when the intrinsically moreattractive catalytic methods were not (yet) per-forming well. The stoichiometric methodolo-gies were more predictable, less structure sen-sitive and often more robust. For these reasons,they still play a considerable role in total syn-thesis and when first amounts of a new com-pound must be prepared in a short time, such asin the discovery phase for bioactives.

5.1. Chiral Reagents

Although there are many examples of chiralreagents in asymmetric synthesis [31], this ap-proach has lost some of its importance due to theenormous progress in enantioselective cataly-sis. Some useful chiral reagents are shown inFigure 11. Reagents based on hydridoaluminateor hydridoborate complexes often achieve veryhigh ee values for the reduction of ketones,exemplified with BINAL-H [32] and with(1R)-B-3-pinanyl-9-borabicyclo[3.3.1]nonane,commercially available as Alpine borane [33].Similarly, boron-containing reagents [34], suchas diisopinocampheylborane (Ipc2BH) or deri-vatives thereof with R ¼ Cl or allyl have beenshown to be versatile and highly selective forthe enantioselective reduction of a variety of

functional groups, allylation of aldehydes aswell as the asymmetric hydroboration of a rangeof substituted alkenes. An industrial example isthe synthesis of the LTD4 antagonist L-708,738by Merck [35] on a 350 g scale, using Ipc2BClreduction of an aryl ketone for introducing thelone stereocenter. The reagent was preparedprior to use from BH2Cl�SMe2 and (þ)-(R)-pinene.

The so-called CBS reduction is a reliable andindustrially popular choice for enantioselectivereduction of ketones [36]. It can be debatedwhether this is really a reagent or actually acatalyst as the proline-derived oxazaborolidine(CSB reagent) is used in combination with astoichiometric reductant (typically BH3�SMe2or BH3�THF) giving the borane adduct (Fig. 11).However, the oxazaborolidine is typically usedat high catalyst loadings (5–20mol%) and somesubstrates require stoichiometric quantities toreach satisfactory enantioselectivities. Thereaction has been used industrially for the prep-aration of a number of intermediates on themulti-kilogram scale as well as for the produc-tion of an active ingredient [37] as shown inFigure 12.

A variety of chiral amide bases related to theclassic lithium amides (see examples in Fig. 11)are useful for desymmetrization of prochiralketones or deracemization of racemicketones [38]. The base selects between enantio-topic protons in a kinetically controlled depro-tonation, and a stereoselective addition of anelectrophile then leads to the desired chiralproduct.

Figure 11. Structures of selected chiral reagents

Chiral Compounds 11

5.2. Chiral Auxiliaries

The chiral auxiliary approach to asymmetricsynthesis has been refined to such an extent thatit now provides a versatile and often highlypredictable route to a wide range of opticallypure compounds, especially on the laboratoryscale. Despite impressive progress in catalyticmethodologies, for many transformations chiralauxiliaries often represent the only selectivemethod available [39]. Industrial applicationsare more cumbersome, and cost and efficientrecycling of the auxiliary are critical. Someversatile chiral auxiliaries developed over thepast years are shown in Figure 13. Successfultypes of chiral auxiliaries are the oxazolidinonesdeveloped by EVANS [40]. The most widelyemployed auxiliary controlled reactions are en-antioselective alkylations, aldol, and Diels–Al-der reactions [41, 42].

Because of its chemical reactivity and ver-satility, reactions with carbonyl groups are es-pecially suitable for this strategy. As depicted inFigure 14, the role of the auxiliary is to create achiral environment near the reacting centers andto confer a preferred conformation on an en-olate, enamide, or enonemoiety in the substrate.This is often associated with the formation of a

metal chelate, allowing preferential attack at oneof the two diastereotopic faces of the C¼C bondof the reactive intermediate (see discussion inSection Basis for Enantiodiscrimination). Thereactivity of the carbonyl group is then exploitedto facilitate the removal of the auxiliary.

GLORIUS [43] described an effective auxilia-ry-based method for the heterogeneous hydro-genation of substituted pyridines — a reactionfor which no enantioselective catalytic methodis available. A variety of substituted piperidinesare accessible with good yields and enantios-electivities, and oxazolidinone auxiliary caneasily be cleaved of and recycled (Fig. 15).

6. Enantioselective Catalysis

Enantioselective catalysis is a relatively youngbut rapidly expanding field. This is true forchemocatalytic methods as well as for theapplication of biocatalysts in organic synthesis.As the application of biocatalysts is describedelsewhere (! Enzymes, 5. Enzymes inOrganicSynthesis, Chap. 2; ! Biocatalysis, 2. Immo-bilized Bioctalysts; ! Biocatalysis, 3. Nonim-mobilized Biocatalysts in Industrial Fine Chem-ical Synthesis), the discussion is focused onchemocatalysis. Up to 1985, only few catalystswere known that gave enantioselectivities ofmore than 90% [44]. However, now there are

Figure 12. Industrial application of a CBS-reduction on production scale

Figure 13. Selected chiral auxiliaries (for a complete listsee [41])

Figure 14. Diastereoselective synthesis with chiral auxili-aries (Aux*)

12 Chiral Compounds

a large number of chiral catalysts available thatare able to catalyze a variety of transformationwith ee values > 98% [3, 6].

Over the years, three types of enantioselec-tive chemocatalysts have proven to be syntheti-cally useful. Homogeneous metal complexescontaining bidentate ligands with a chiral back-bone carrying two coordinating heteroatoms arethe most versatile enantioselective chemocata-lysts. For noblemetals, especially Rh, Pd,Ru, Ir,and Os these are P or N atoms; for metals, suchas Ti, B, Zn, Co, Mn, or Cu ligands withcoordinatingOorN atoms are usually preferred.The methodology has received its due recogni-tion in the 2001 Nobel Prize to KNOWLES andNOYORI for enantioselective hydrogenation andto SHARPLESS for enantioselective oxidation ca-talysis [45]. The transfer of the results obtainedfor a particular substrate to even a close analogremains a challenge due to the low tolerance forstructure variation even within a class of sub-strates (substrate specificity).

Heterogeneous metallic catalysts modifiedwith chiral auxiliaries and phase transfer cata-lysts are also useful for certain syntheticapplications.

Organocatalysis, i.e., the use of small organ-ic molecules as catalysts is now a hot researchtopic with immense potential for organic syn-thesis and hopefully also for industrialapplications.

Chiral polymeric and gel-type materials [46]and immobilized metal complexes [47] are not(yet) practically useful for synthetic purposes.

In addition to the requirements for any en-antioselective method described above, the fol-lowing criteria have also to be fulfilled tomake acatalyst useful for organic synthesis:

. The chemoselectivity and/or functional grouptolerance is important when multifunctionalsubstrates are involved.

. The catalyst productivity, given as turnovernumber (TON) or as substrate to catalyst ratio(s/c) determines catalyst costs. For industrialapplications, TONs should be > 1 000 forsmall-scale, high-value products and> 50 000 for large-scale or less expensiveproducts (catalyst reuse increases theproductivity).

. The catalyst activity, given as turnover fre-quency for > 95% conversion (TOF, h�1),determines the production capacity. For hy-drogenations, TOFs ought to be > 500 h�1

for small-scale and > 10 000 h�1 for large-scale products.

. Catalyst separation and trace metal contami-nation. Catalyst separation was mentionedonly once as a major obstacle when develop-ing a homogeneous catalytic process [7]. Dis-tillation, product crystallization, and extrac-tion are the techniques most frequently ap-plied to remove the catalyst. Only in rarecases, catalysts are recycled; usually the noblemetal residues are sent back to the catalystproducer. Trace metal contamination is moreof an issue, especially for pharmaceuticalapplications and when the homogeneous cat-alyst is used at a late stage in the synthesis. Inthis case, metal scavengers have shown to bean effective but relatively expensive solu-tion [48]. Several companies, such as JohnsonMatthey, Evonik, or Phosphonics offer tailor-made scavengers for different metals andmetal complexes.

Basis for Enantiodiscrimination. Enantio-selective synthesis is based on the interaction ofan enantiopure chiral moiety with the reactant(s). The effect of this interaction is the creationof two diastereomeric entities, which (at least inprinciple) have different energies and differentprobabilities of formation. For the resolution ofracemates, it is the interaction of the resolution

Figure 15. Diastereoselective hydrogenation of pyridines using a chiral auxiliary

Chiral Compounds 13

agent with the two enantiomers. In the case ofenantioselective synthesis, where the startingmaterial is not chiral, it is the energy differencebetween the two diastereomeric transition statesleading to the S- and R-products that determinesthe level of enantioselection (Fig. 16A). Enan-tioselection results from the preferential attackon one of the enantiotopic faces of a C¼Xmoiety or by preferential reaction of an enan-tiotopic group Y (Fig. 16B). Practically usefulselectivities require an energy difference in theorder of 8–12 kJ/mol. This can be quite difficultto realize, particularly when relatively weakinteractions between the chiral auxiliary andthe reactants are involved, which is usually thecase in enantioselective catalysis. Because theseinteractions can be rather subtle, most enantio-selective transformations are quite substratespecific, i.e., even small structural changes ineither reactant(s) or the chiral moiety can lead todifferent results.

The attractive interactions between a catalystand substrate(s) are responsible for the rateacceleration effect; although selectivity can of-ten be explained by steric repulsion, it can also

be due to weak attractive forces. These inter-actions include hydrogen bonding, electrostaticeffects, p–p, cation–p, hydrophobic, and Vander Waals forces. Destabilization by steric re-pulsion ismost effective as a defining element ofstereocontrol in strongly bound and conforma-tionally restricted catalyst–substrate com-plexes [49]. Examples are organometallic com-plexes or secondary amines in which reactionintermediates are bound to the catalyst throughwell-defined covalent interactions. However,stereocontrol via weak attractive forces can alsoplay a role. Three well understood examplestaken from [49] are schematically presented inFigure 17. In each case, the relatively strongbinding interaction leads to activation of thesubstrate. In case of Figure 17A and B, specificsteric repulsion leads to shielding of one face ofthe reactant and preferential attack from theunshielded side. In case of Figure 17C, there isa binding interaction via anH-bond and reactionfrom the same side is favored. Similar modelsalso serve to explain stereocontrol in a hetero-geneous reaction, where the adsorption on themetal surface as well as a hydrogen bond playsan important role (Fig. 18).

Noncovalent interactions are not onlygenerally weaker but also less directional andless distance dependent leading to a lack ofconformational order. This may be overcomeby multiple noncovalent cooperative interac-tions, because this can afford the conformation-al constraint required for high stereoinduction.This cooperative model of binding is a definingfeature of biological as well as synthetic

Figure 16. A) Energy diagram for enantioselective trans-formations; B) Preferential attack of enantiotopic face orgroup

Figure 17. EnantiodiscriminationA), B) Repulsive interaction; C) Attractive interactions

14 Chiral Compounds

receptors and also underlies enzymatic cataly-sis. An example is schematically shown inFigure 19 for the thiourea catalyzed Streckerreaction where the orientation of both reactantsis controlled through various hydrogen bonds.Enantiocontrol via ion pair formation as postu-lated for catalysis with Lewis bases, Brønstedacids, and phase transfer cations (but can also beinvoked for crystallization) is much more diffi-cult to rationalize.

From this discussion, it is possible to extractsome conclusions regarding the various meth-odologies to obtain enantiopure products. Ac-cording to DALKO [50], organocatalytic reac-tions proceed either by a much ‘‘tighter’’ or amuch ‘‘looser’’ transition structure than chiralmetal complex-mediated reactions. The formerclass involves compounds, which are acting ascovalently bonded reagents, with bonding ener-gies exceeding 60 kJ/mol (an extreme case isthe chiral auxiliaries strategy, where a separatereaction step is needed to release the product).The latter class includes reactions via noncova-lent complexes, usually via ion pairing or

H-bonds with interactions below 12 kJ/mol. Inaddition, many organocatalysts have more thanone active center, usually a Lewis base and aBrønsted acid allowing activation of both donorand acceptor reactant. The catalytic activity(i.e., the turnover frequency) is lower when verystrong bonds between catalyst and substrate(s)have to be formed and broken (to release theproduct). Indeed, with a few notable exceptions,organocatalytic reactions often require ratherhigh catalyst loadings and often have longreaction times.

7. Catalysis with Soluble MetalComplexes (Homogeneous Catalysis)(! Catalysis, Homogeneous)

Homogeneous catalysts usually consist of acentral metal ion, one or more chiral ligand(s), and an anion. The metal has the activatingfunction (redox and/or Lewis acid activity),whereas the chiral ligand is responsible forenantiocontrol. However, it has to be stressedthat all components of a given catalytic system(metal, ligand, anion, additives, solvents, etc.)are needed to reach the observed catalytic effect,i.e., selectivity and activity. In each case, theseparameters as well as the reaction conditionshave to be carefully optimized in order to arriveat the best overall catalyst performance.

Today, an impressive number of chiral li-gands are recorded in the literature to achievevery high enantioselectivity for a variety ofcatalytic transformations [3, 6]. Most classesof chiral catalysts have a preferred applicationspectrum (type of reaction and substrate), whichis sometimes quite broad as, e.g., for dipho-sphine complexes and sometimes narrow as,e.g., for metal porphyrins. Only few chiralligands are used on a regular basis in synthesis,and these are termed ‘‘privileged ligands’’ [51].A selection of such ligands is shown in Fig-ure 20. The usefulness of a catalyst or ligand canbe negatively affected if it is extremely air and/or moisture sensitive. Modular ligands are pre-ferred because the effort required to adapt theligand structure to the desired transformation ismuch lower than for ligands with little structuralvariability. Ligands with a wide scope (andwell-defined and known limitations), low

Figure 18. Model for the stereoface selection for theheterogeneous hydrogenation of pyridines (see Fig. 15);hydrogen is added to the adsorbed face of the molecule

Figure 19. Stereocontrol via multiple H-bonding interac-tions (adapted from [49])

Chiral Compounds 15

substrate specificity, good functional group tol-erance, and stability have a greater chance ofbeing applied.

As space limitations do not allow describingthe state-of-the-art of homogeneous catalysiscomprehensively, the synthetic and industrialpotential of enantioselective reactions is sum-marized in Table 1 for selected transformationsonly [52]. In all cases, catalytic systems havebeen developed that give, in favorable cases, eevalues up to 90–99%. Reactions are classifiedaccording to whether large-scale industrialapplications have been realized or seem likely(such applications are the ultimate goal ofcatalyst development) and according to thesynthetic scope for the construction of complexmolecules in preparative organic synthesis. Theclassification is subjective and due to personalexperience.

7.1. Hydrogenation of Olefins,Ketones and C¼N Functions

Enantioselective hydrogenation of olefins andketones are the best-studied reactions with themost industrial applications [53]. Over the lastFigure 20. Generic structures of privileged ligand types

Table 1. Classification of synthetic and industrial potential of selected transformations

Application Synthetic scope Type of transformation

Many large-scale medium . hydrogenation of enamides and itaconates

. hydrogenation of b-functionalized C¼O

Several large-scale narrow to medium . hydrogenation of C¼C–COOR and C¼C–CH–OH

. hydrogenation of a-functionalized and aryl C¼O

. hydrogenation of C¼N–Ar

Some large-scale narrow to high . hydrogenation of other C¼C and C¼O

. hydrogenation of and addition to various C¼N

. dihydroxylation and epoxidation of C¼C

. oxidation of aryl sulfides

. epoxide opening (kinetic resolution)

. isomerization and cyclopropanation of C¼C

Selected larger-scale possible broad . transfer hydrogenation/reduction of C¼O

. (hetero) Diels–Alder reactions

. Michael additions, allylic substitution

. aldol and ene reactions

. various addition reactions to C¼O and C¼N

Niche applications possible narrow . aminohydroxylation of C¼C

. hydrocarbonylation, hydroboration, hydrosilylation and hydrocyanation of C¼C

. cross coupling, metathesis, Heck reaction, C–H insertion

16 Chiral Compounds

decades, a few privileged substitution patternshave evolved that almost guarantee high enan-tioselectivities; generic structures are shown inFigure 21. Except for the aryl ketones, all thesesubstrates have functional groups that can co-ordinate to the metal, leading to rigid and stableintermediates, consequently to better enantio-control, and in many cases to an increase incatalyst activity. With few exceptions, Rh andRu chiral diphosphin complexes are the pre-ferred catalysts but the optimal complex (metal,ligand, anion, etc.) has to be determined for eachsubstrate.

Hydrogenation of enamides (Fig. 21A,X¼NR, Y¼C, W¼R), especially of a-dehy-droamino acid derivatives (R1¼COOR), is dueto the success of KNOWLES [54] for L-dopasynthesis (Fig. 22) not only the best-known test

reaction but has also a high potential for theproduction of pesticides or pharmaceuticals.The ee values obtained using different ligandsshow that the results are sensitive to ligandstructure, and bidentate ligands (such as di-pamp, Fig. 22) have a clear advantage. Theoriginal motivation for developing this reactiontype was the production of a-amino acids.However, except for small-scale applicationsor complex structures, the preparation of theenamide substrates was too expensive and mostlarge-scale amino acids are now produced viabiocatalytic methods. Many different substratesof type Figure 21A, such as enamides or itaconicacid derivatives can be hydrogenated with eevalues between 95 and 99% with moderate tovery high catalyst activity and productivity. Ingeneral, more and larger substituents lead to adecrease in catalyst activity both when directlyattached to C¼C or when bound to X or W.Preferred catalysts are Rh diphosphine com-plexes with P-chiral ligands, phospholanes, orferrocene derived ligands.

The hydrogenation of allylic alcohols anda,b-unsaturated acids (Fig. 21B) is anotherclass of transformations with a high industrialsuccess rate. With few exceptions, the catalystsof choice are Ru diphosphine complexes withbiaryl backbones. Although very high TONsand TOFs have been achieved for simple allylicalcohols, more complex substrates and a,b-unsaturated acids are reduced with lower effi-ciency. Rh complexes can also be used effec-tively for sterically hindered a,b-unsaturatedacids as shown for an intermediate of aliskirendeveloped by Speedel and produced now onlarge scale for Novartis. Competitive produc-tion processes have been developed bySolvias [55], DSM [56], and BASF [57] (seeFig. 23). The process developed byDSMshows,that also monodentate ligands (e.g., phosphra-midite) can have excellent performance.

The hydrogenation of alkenes without ‘‘pri-vileged’’ functional groups is much more diffi-cult and requires more effort to achieve goodenantioselectivity. Of special interest are Ircatalysts with P^N ligands, such as phosphi-nooxazolines (phox, Fig. 20) [58].

The hydrogenation of ketones using Rh andRu diphosphine catalysts is the most versatileand efficient method for the synthesis of a largevariety of chiral alcohols. Although Rh

Figure 21. Olefins and ketones with privileged substitutionpatternsA) Enamides or itaconic acid derivatives; B) Allylic alco-hols and a,b-unsaturated acids; C) b-Keto acid derivatives;D) (Cyclic) aryl ketones

Figure 22. Production of an intermediate of L-dopa fortreating Parkinson’s disease; reaction conditions and com-parison of different ligands

Chiral Compounds 17

diphosphine catalysts are often substrate specif-ic, several Ru/biaryl diphosphine complexeshave a broader scope. These catalysts are effec-tive for the hydrogenation of functionalizedketones, such as b-keto esters, 2-amino, and2-hydroxyketones with high ee values and oftenreasonable TONs and TOFs. The Ru/binap/chi-ral diamine catalysts [59] are very active for thehydrogenation of aryl ketones (TOF up to2.4�106) and are also suitable for a,b-unsatu-rated ketones. Transfer hydrogenation usingiPrOH/base or HCOOH/NEt3 as reducing sys-tems has proven to be a reliable method for thereduction of aryl ketones and especially the Ru/dpenTs catalyst [59] is frequently applied inpreparative synthesis. Catalyst activities andproductivities are usually lower for transferhydrogenation catalysts even though in a fewcases TONs up to 5 000 and TOFs of 3 000–6 000 h�1 were described. Unfunctionalized al-kyl ketones are still problematic substrates, eevalues> 90% have only been reported for a fewcases.

Figure 24 shows a selection of ketones forwhich industrial hydrogenation processes havebeen developed. Takasago produces an inter-mediate for penem antibiotics [60] on a scale of50–120 t/a via a hydrogenation involvingdynamic kinetic resolution of an existing stereo-genic center with high enantio- and diastereos-electivities (de) (Fig. 24A). (R)-1,2-Propane-diol [61], an intermediate for (S)-oxfloxazin, isproduced by Takasago on a 50 t/a scale(Fig. 24B). Boehringer-Ingelheim [62] has de-

scribed medium scale production processes foradrenaline (R ¼ OH) and phenylephrine (R ¼H; Fig. 24C). The Rh/mccpm catalyst achieveshigh TONs and TOFs, but only moderate eevalues which increase to > 99% after precipi-tation of the free base. Finally, Chemi [63] hascarried out the hydrogenation of ethyl 4-chlor-oacetoacetate on a > 100 kg scale using a Ruheterobiaryl diphosphine catalyst (Fig. 24D).

Even though chiral amines are importantintermediates for biologically active com-pounds, the asymmetric hydrogenation of C¼Nhas been investigated less systematically thanthat of C¼C and C¼O groups. However, inrecent years, various Rh, Ir and Ru complexeshave been investigated which provide reason-able enantioselectivities [64]. With few excep-tions, Rh complexes have relatively low catalystactivities and productivities whereas some Ircomplexes have high initial rates but tend todeactivate. Up to now, only few industrial ap-plications have been reported. The reactionemployed in the metolachlor process (Fig. 25)is the largest enantioselective catalytic produc-tion process and, with TONof> 2�106 and TOF> 400 000 h�1, the Ir/Josiphos complex is alsoone of the most active enantioselectivecatalysts.

7.2. Oxidation Reactions

Catalytic oxidationswith industrial potential areepoxidation as well as dihydroxylation and,

Figure 23. Synthesis of an intermediate of aliskiren (several t/a scale): Different process conditions employed by differentcompanies

18 Chiral Compounds

with a more narrow potential, sulfide oxidation.The enantioselective oxidation of olefins is anelegant way of introducing oxygen and in somecases nitrogen functions into a molecule. Theepoxidation of allylic alcohols (SHARPLESS ep-oxidation) using Ti/dialkyl tartrate catalysts and

hydroperoxides as oxidant is arguable one of themost widely used catalytic reactions and hasbeen applied in numerous multistep synthesesof bioactive compounds and intermediates [65].In the presence of molecular sieves, the catalystis effective for a variety of substituents at theC¼C bond and tolerates most functional groupswith good to high enantioselectivities but ratherlow activity. However, there are still only fewexamples for applications on a larger scale. Themost important is the production of glycidol(Fig. 26) developed by Arco and later operatedby PPG-Sipsy [66]. The reaction has been care-fully optimized and was run with cumyl hydro-peroxide as oxidant. Potential problems of theSharpless epoxidation are the handling of or-ganic peroxides (tert-butyl or cumyl hydroper-oxide) on large scale, the rather low catalyticactivity and productivity, and the isolation andpurification of the epoxy alcohols.

The epoxidation of unfunctionalized olefinsusing cheap NaOCl as oxidizing agent has beendeveloped by JACOBSEN and was developed in-dustrially by Rhodia Chirex [67]. Mn/salen type

Figure 24. Selected industrial ketone hydrogenation production processesA) Intermediate for peneme antibiotics (Takasago); B) Intermediate of (S)-oxfloxazin (Takasago); C) Production of adrenalin(R ¼ OH) or phenylephrine (R ¼ H) (Boehringer-Ingelheim); D) Hydrogenation of ethyl 4-chloroacetoacetate (Chemi)

Figure 25. Synthesis of an intermediate for (S)-metola-chlor. Produced on a > 10 000 t/a scale since 1996 (Ciba-Geigy, now Syngenta)

Chiral Compounds 19

catalysts give good results for cis-disubstitutedolefins results with ee values up to > 97% andmoderate to good catalytic activity [68]. Theasymmetric dihydroxylation (AD) of olefinsdeveloped by SHARPLESS leads to cis-diols withhigh to very high enantioselectivities using Os/cinchona complexes [69]. This reaction hasbeen applied in numerous lab-scale syntheses,and a catalyst/oxidant mixture (AD-mix) isavailable from Strem. However, its applicationon a commercial scale seems to be challenging.K3Fe(CN)6-K2CO3, the oxidant used in thecommercially available AD-mixture is prob-lematic on larger scale.

The oxidation of aromatic or heteroaromaticsulfides using Ti/catalysts exhibits good enan-tioselectivities but usually low TONs (2–20)and TOFs (1–5 h�1) [70]. Two industrial appli-cations have been reported, one developed byAstraZeneca [71] for the chiral switch of esome-prazole (Fig. 27).

7.3. Addition Reactions to C¼C,C¼O, and C¼N Moieties

Addition reactions are among the most impor-tant classes of synthetic transformations

covering a wide range of substrates and re-agents. For many addition reactions, enantiose-lective catalytic versions have been developed[52].

Addition reactions to olefins can be usedboth for the construction and the functionaliza-tion of molecules. Accordingly, chiral catalystshave been developed for different types ofreactions with often high enantioselectivity.Unfortunately, most have either a narrow syn-thetic scope or are not yet developed for imme-diate industrial application due to insufficientactivities and/or productivities, and most of theligands are not available on technical scale. Themost common classes of substrates for theaddition of various H–X fragments are styrenesand other functionalized olefins; very oftenregioselectivity is an issue. Of interest are hy-drocarbonylation, hydrosilylation, hydrobora-tion, and hydrocyanation reactions, which havean interesting synthetic potential but also somedrawbacks. For the foreseeable future, they willbe used industrially at best in niche applications.

Both the Michael addition and the Diels–Alder reaction have broad synthetic scope, how-ever, most investigations were carried out usingmodel substrates or for proof-of-conceptsyntheses of natural products. The cyclopropa-nation of olefins, actually one of the first com-mercial enantioselective processes (Sumitomo/ARATANI), and the insertion of carbenes inC–H bonds also have synthetic potential butinvolve the handling of diazo compounds.

Addition reactions to carbonyl groups arecentral in synthetic methodology. Even thoughnumerous catalysts with high enantioselectivity

Figure 26. Industrial synthesis of glycidol on multi t/ascale (discontinued)

Figure 27. Production process for esomeprazole, multi t/a scale

20 Chiral Compounds

have been developed in the last years, there areonly few industrial applications. Most catalystshave low tomedium catalytic activity andTONsof 5–100.

Of synthetic interest are the aldol, ene andhetero Diels–Alder reactions which are cata-lyzedmost effectively by early transitionmetalsand lanthanide complexes. The addition reac-tions of ZnR2 and similar reagents to aldehydesin the presence of catalytic amounts of aminoalcohols or early transition metal complexes isone of the classical model reactions butwith fewsynthetic applications. The synthesis of chiralcyanohydrins as versatile building blocks bycatalytic addition of cyanide to C¼O groupshas seen much progress in the last few years.The most effective catalysts are early transitioncomplexes with O and N ligands which achieveee values of up to 90–95% albeit with modestTON and TOF. A drawback is the need fortrimethylsilylcyanide as cyanation reagent be-cause there are only few cases where HCN orKCN works well. Industrial applications havebeen reported for the Au catalyzed aldol reac-tion as an interesting approach to b-hydroxyamino acids, an ene reaction for an intermediatefor Trocade, a collagenase inhibitor, and thenitroaldol reaction.

Addition Reactions to C¼N Groups. Sev-eral addition reactions to C¼N groups havebeen developed in recent years with a highsynthetic potential, but with few exceptionsindustrial use is not yet feasible. A notableexception is the Strecker reaction where inparallel to cyanohydrin synthesis progress hasbeen impressive in recent years. Feasiblecatalysts are Al, Ti, Zr, and Sc/binol complexes,Ti/tripeptide and Al/salen catalysts, typical eevalues are 85–95%, TONs 10–50 but TOFs areoften < 1 h�1.

7.4. Miscellaneous Transformations

Even though many of the reactions briefly dis-cussed below form new C–C bonds enantiose-lectively, none has been developed to technicalmaturity. Major issues are in many cases cata-lyst activity and productivity and especially forthe versatile Heck and metathesis reactions therelatively narrow synthetic scope for making

chiral molecules. Nucleophilic allylic substitu-tion reactions with C- and N-nucleophiles cata-lyzed by various Pd and Ir complexes have beenapplied not just in model studies but also for thesynthesis of natural products and pharmaceuti-cal-relevant molecules. Indeed, Dow Chirotechhas commercialized two ligands but no large-scale application has been reported. The Ni-catalyzed cross-coupling reactions tolerate onlyfew functional groups. The asymmetric Heckreaction is still in an exploratory phase eventhough some syntheses of natural products havebeen reported. In the last few years, the Ru andMo catalyzed metathesis of olefins has been oneof the hottest research topics in organic synthe-sis. Several chiral catalysts have been developedwith an interesting but narrow synthetic scopebecause only rather special substrate structuresare feasible. With the exception of allylic sub-stitution, all these methodologies will find atbest industrial niche applications.

Finally, the Rh/binap catalyzed isomeriza-tion of allylamines depicted in Figure 28deserves special mention. The technology hasbeen developed by Takasago [72] for the pro-duction of L-menthol (> 1 000 t/a), hydroxydi-hydrocitronellal (40 t/a), D- and L- citronellol(20 t/a) and methoprene (juvenile hormone,20 t/a) and is now the second largest applicationof a homogeneous chiral catalyst. Crucial for thehigh catalyst productivity were the purificationof the starting material and the efficient catalystrecycling after distillation. Catalyst loss witheach recycle was reported to be ca. 2%. BesidesO2, H2O, and CO2, the presence of amines in

Figure 28. Rh/bianp catalyzed isomerization of allyl aminein the synthesis of L-menthol

Chiral Compounds 21

concentrations as low as 0.07% affect thecatalyst performance negatively.

7.5. Future Developments

The number of industrial applications of metal-based homogeneous catalysts is likely to in-crease significantly in the future. First, aftermore than 20 years of successful academic andindustrial research it is highly probable that weare now in the steeper part of the usual S-shapedlearning curve for technical applications.Second, there are many indications that devel-opment chemists in large pharmaceutical andchemical companies responsible for the choiceof process technology have a greater awarenessfor the potential of enantioselective catalysis.Third, many specialized technology companies,such as Solvias, Rhodia-Chirex, or Dow Chir-otech have evolved offering know-how andexperience in catalytic process developmentand producing technical quantities of the chiralligands. This gives also smaller companies notbeing able to develop the technology access tocatalytic processes and ligands.

8. Heterogeneous Catalysis

Heterogeneous enantioselective catalysts un-doubtedly have operational advantages overhomogeneous variants concerning handling andseparation [73]. However, there are only few

heterogeneous systemswhich can compete withalternative synthetic methods. In Table 2 threetypes of practically useful chiral heterogeneouscatalysts are listed and characterized.

Up to now, only a cinchona modified Ptcatalyst has been used on an industrial scale forthe production of a chiral intermediate for ACEinhibitors [74] (see Fig. 29). However, severalfeasibility studies show that this catalyst systemis competitive for the hydrogenation of a-ketoesters and other ketones with an activatinggroup in the alpha position. Ni-catalysts modi-fied with tartaric acid are suitable for the hydro-genation of b-ketoesters and related ketones butare probably not active enough to compete withthe Noyori catalysts.

A large number of homogeneous complexeshave been immobilized on different types ofsupports and carriers [75]. Although it is nottrivial to maintain the catalytic performance ofthe homogeneous analogs, there are increasingexamples where good enantioselectivities canbe obtained. In many cases, the catalysts can bereused several times but metal leaching can be asignificant problem. No immobilized metalcomplex has so far been applied to industriallyrelevant targets on larger scale even thoughseveral heterogenized catalysts would, in prin-ciple, be viable candidates. Major reasons arethe higher complexity of heterogeneous systemsleading to a poor predictability of the catalyticperformance, the significant higher costs forcatalyst preparation and, especially for

Table 2. Schematic view and important properties of chiral heterogeneous catalysts

Adsorbed chiral modifier

on supported active

metal

M–L complex covalently attached

to functional carrier or solid

support

M–L complex adsorbed on an organic or inorganic

solid support

Applicability

problems

. restricted

. solvent dependent

. narrow scope

. broad

. ligand synthesis

. preparation on large scale

. restricted

. solvent dependent

. competition with substrates, solvents, and salts

22 Chiral Compounds

immobilized chiral ligands, that most of thesecatalysts are not commercially available.

9. Organocatalysis

Organocatalysis, i.e., the application of chirallow molecular mass organic molecules as cat-alysts, is currently the most active area ofresearch in synthetic chemistry. Although theability of small chiral organic molecules, suchas cinchona alkaloids or amino acids to catalyzevarious reactions in a stereoselective fashionwas appreciated very early, it was not until twoseminal reports by LIST, LERNER, and BARBAS

[76] and MACMILLAN and co-workers [77] oncatalysis by chiral secondary amines that the fullpotential of this approachwas recognized. Sincethen the number of publications has developedin an exponential fashion and it is now clear thatthis methodology offers alternatives to metal-catalyzed processes for a wide range of enan-tioselective transformations [78]. In addition,organocatalysis has some attractive benefitsbecause compared to metal-based catalyst, or-ganic catalysts are relatively nontoxic, readilyaccessible (often from the chiral pool), andgenerally more stable. These properties allowreactions to be performed without special pre-cautions, such as air and water exclusion, whichis often required for the preparation and han-dling of organometallic catalysts, leading tooperational simplicity. On the other hand, mostorganocatalysts are significantly less active thanmetal-based catalysts and often high catalystloadings (typical are s/c ratios of 10–20) andlong reaction times (often 1–2 days) are required

in order to get good conversions. This is not aproblem for laboratory applications, but itmightbe challenging for larger scale use.

Because organocatalysis develops rapidlyand encompasses almost all areas of organicsynthetic chemistry, it is not possible to give acomprehensive overview. Instead, the focus lieson a number of catalyst types that over the yearshave proven to be extraordinarily versatile and,in analogy to the privileged ligands, could becalled ‘‘privileged catalysts’’ [51].

9.1. Covalent Binding:Aminocatalysis

Catalysis by secondary amines started the re-vival of organocatalysis [79]. The five mem-bered ring amines shown in Figure 30 catalyzean astonishing number of transformations ofaldehydes or ketones with enantioselectivitiesof 90–99% ee. Two modes of activation havebeen identified. For carbonyl compounds able to

Figure 29. Intermediate for various ACE inhibitors, produced on a multi-ton scale by Ciba-Geigy (discontinued)

Figure 30. Structures of privileged secondary aminecatalysts

Chiral Compounds 23

form enols, catalysis is based on the reversibleformation of an enamine with increased nucleo-philicity (enamine catalysis, see Fig. 17C) [80].

Transformations include additions to C¼O(aldol), C¼N (Mannich), C¼C (Michael),N¼N, and N¼O bonds, as well as nucleophilicsubstitution for the introduction of oxygen,halogen, or sulfur in a-position. a,b-Unsaturat-ed carbonyl compounds that cannot formenamines react to the iminium adduct with amuch higher electrophilic reactivity (iminiumcatalysis, see Fig. 17B) [81], catalyzing trans-formations, such asMichael and cycloadditions,Friedel–Craft type reactions with heteroarenes,epoxidations, or conjugate reductions. Themostused catalysts are proline and derivatives there-of and MACMILLAN’s imidazolidinone catalystsas shown in Figure 30.

Industrial applications are slowly appearingin the literature, and an impressive examplehas been described by Merck [82] for the syn-thesis of telcagepant. The Michael addition inFigure 31 was carried out on a > 100 kg scale,demonstrating the feasibility of aminocatalysisalso for larger scale preparations even though arather high catalyst loading and a long reactiontime were necessary.

9.2. Hydrogen–Bonding Catalysis

Catalysis by neutral, organic, small moleculescapable of binding and activating substratessolely via noncovalent interactions, particularlyH-bonding, has emerged as an importantapproach in organocatalysis [83]. The mostprevalent catalyst of this type are (thio)ureaderivatives (see Fig. 32), often asmultifunction-

al catalysts with a basic amine. Reactions en-compass Claisen rearrangement, Strecker reac-tions, and other addition reactions to C¼Nbonds. Recently, a Roche team [84] describedthe synthesis of an intermediate for the P2X7

receptor antagonist via methanolysis of an an-hydride on pilot scale (Fig. 33); enrichment to97% ee was possible via simple trituration.

Due to their modular nature, peptides com-posed of 2–50 amino acids are another attractivecatalyst platform [85]. Catalyzed reactions cov-er almost all classes of organic transformations.A particularly impressive reaction is the dimer-ization of a bisphenol derivative catalyzed by atetrapeptide where the enantiotopic OH-groupsare separated by almost 10 A

�with up 95%

ee [86]. Industrial applications have been

Figure 31. 1,4-Addition of nitromethane to an a, b-unsaturated aldehyde via aminocatalysis

Figure 32. Structures of effective urea (X¼O)and thiourea(X ¼ S) derivatives

24 Chiral Compounds

reported for the so-called Julia epoxidation ofchalcone derivatives catalyzed by polyleucine[87].

9.3. Ion Pair Formation: Catalysiswith Lewis Bases, Brønsted Acids, andPhase-Transfer Cations

Lewis bases, Brønsted acids, and phase-transfercations, although seemingly different catalyst,form a tight ion pair with the activated substrateallowing stereodifferentiation. This phenome-nonwas termed asymmetric counterion directedcatalysis (ACDC) [88]. In the case of Lewisbases, mostly tertiary amines, the substrate isactivated by deprotonation, whereas Brønstedacids activate by protonation. In phase-transfercatalysis (PTC) (! Phase-Transfer Catalysis,the water insoluble substrate is usually depro-tonated with an aqueous base and forms a tightion with the PTC cationic catalyst in the organicphase.

The application of various chiral Lewis baseshas been reviewed [89, 90]. Arguably the mostversatile bases are the cinchona alkaloids (seeFig. 34), which due to the presence of OHfunctions (X and/or Z ¼ OH) often act asbifunctional catalysts [91]. Other bases withlow nucleophilicity, such as phosphinamides oramine N-oxides are being developed. A mal-onate Michael addition catalyzed by 1 mol%desmethylquinidine (Z ¼ OH in Fig. 34) on

100 g scale has been described by a Merckteam [92] with 88% yield and 95% ee (�20�C,20 h).

Chiral Brønsted acids are able to catalyzenumerous transformations involving imine andcarbonyl activation, such as Friedel–Crafts,Pictet–Spengler, Strecker, cycloaddition reac-tions, transfer hydrogenations, and reductiveaminations [93, 94]. Binol phosphates substitut-ed with bulky R-groups (see Fig. 35A) are by farthe most applied acids but when sensitive sub-strate classes are involved, chiral dicarboxylicacids are of particular value.

Phase-transfer catalysis, i.e., reactions car-ried out under biphasic conditions, was one ofthe first industrial applications of organocata-lysts [95]. Catalysts based on cinchona alkaloidcations (aralkylated at the quinuclidine nitro-gen) and MARUOKA’s [96] biaryl-based ammo-nium catalysts (see Fig. 35B) are preferred for avariety of enantioselective carbon–carbon orcarbon–heteroatombond-forming reactions.Anessential issue for optimal performance is therational design of catalysts allowing the gener-ation of a well-defined chiral ion pair that reactswith electrophiles in a stereoselectively [97].Various reactions have been implemented onindustrial scale. A recent example is the synthe-sis of non-proteinogenic amino acids on pilotscale (Fig. 36) [98]. Enantioselectivity is not

Figure 33. Thiourea catalyzed methanolysis of ananhydride

Figure 34. Structures of cinchona alkaloids

Figure 35. Structures of atropisomeric biaryl backbone-based Brønsted acid (A) and PT catalysts (B)

Chiral Compounds 25

particularly high, but crystallization of a saltafter imine hydrolysis led to > 99% ee.

9.4. Further Aspects and FutureDevelopments

In addition to the work summarized above,several lines of research are developing. Otherconcepts include singly occupied molecularorbital (SOMO) catalysis, an extension of thefruitful iminium chemistry [99]. Besides amine-based catalysts, chiral carbenes [100] andylides [101] have proven to be versatile cata-lysts. A number of organocatalysts has beendeveloped for various oxidation reactions [102].An early example is the sugar-based oxidationcatalysts, for which a first industrial applicationon the 100 kg scale has been described byDSM [103]. Although turnover numbers ofmany organocatalysts are low, the catalysts arenot very sensitive and usually quite stable;immobilization strategies should help to bringcatalyst costs down. Indeed, first results arepromising [104, 105], even though large-scaleapplications have not yet been described. Anevolving field is the application of organocata-lysts to cascade or domino reactions, i.e., aconsecutive series of reaction steps, which oftenproceed via highly reactive intermediates andare catalyzed by the same catalyst [106, 107].Finally, the combination of chiral organocata-lysts (especially chiral anions) with achiralmetal catalysts is an interesting approach, espe-cially in cases where there is no effective chiralmetal complex known, such as in Fe catalyzedimine hydrogenation [108].

There is no doubt that the area of organoca-talysis will expand in a rapid pace. It is likelythat further activation modes will be discoveredallowing the effective catalysis of ever moretransformations. It is also easy to predict that the

applications in preparative chemistry for thesynthesis of chiral intermediates not just on thelaboratory but also on industrial scale will soonbecome frequent.

10. Enzymatic Transformations(! Enzymes, 1. General;! Enzymes, 5. Enzymes in OrganicSynthesis; ! Biocatalysis, 3.Nonimmobilized Biocatalysts inIndustrial Fine Chemical Synthesis)

Over the last decade, the application of bioca-talysts for the synthesis of chiral molecules hasincreased significantly and encompasses nownot just kinetic resolution using hydrolases (seeSection 4.1) but also oxidation [109], reduc-tion [110], and other reaction types. Neverthe-less, the increase is mostly restricted to applica-tions on larger scale and for established andalready marketed products. In total synthesisand on the laboratory scale, classical methodsare still the preferred option in most cases. Thisis because finding and developing an efficientbiocatalyst, especially when the starting mate-rial is not a close analog to the natural substrateis work intensive.

From the industrial point of view, the ex-pected progress is due to two facts: First, avariety of techniques have been developed toengineer enzymes genetically via directed evo-lution to adapt them to catalyze a specific reac-tion [111]. By repeated cycles of gene mutagen-esis, expression, screening for catalytic perfor-mance and selection, an enzyme is developedthat has the required performance concerningactivity, enantioselectivity, stability, or lowerproduct inhibition. In addition, several compa-nies have developed methodologies to expressthese enzymes on the scale needed for a com-mercial production. Secondly, technology com-panies, such as Daicel [112] or Codexis [113]offer broad enzyme screening kits selected forspecific transformations, such as C¼O andC¼N reductions. This allows a much fasterscreening of potential candidates and a fasterdecision on the feasibility of a synthetic scheme.

Many cases have been described where theapproach of enzyme evolution has beenapplied to develop more efficient production

Figure 36. PT catalyzed allylation (catalyst see Fig. 35B, R¼ 3,4,5-F3C6H2, R1 ¼ nBu)

26 Chiral Compounds

processes [114]. However, this approachrequires much know-how, not just in chemistrybut also in biology and information technologyand a rather expensive infrastructure. It istherefore restricted to specialized or large com-panies. Furthermore, enzyme evolution is usu-ally applied to improved syntheses of existingproducts with an already established marketwhere cost and/or ecology of production areessential.

The case history of sitagliptin is described insome more detail because it serves well toillustrate these points. In October 2006, sita-gliptin was approved by the FDA as DPP-4inhibitor for the treatment of type 2 diabetesand is now being marketed by Merck under thebrand names Januvia and Janumet. The devel-opmentwork started in 2002 andwas carried outunder an immense time pressure [115]. Becauseprior work had established an efficient three-step route to the triazole portion of themolecule,development efforts focused on accessing theb-amino acid functionality. As shown inFigure 37, two chemocatalytic approaches wereevaluated by process chemists. The first attempt(Fig, 37A) was made with a diastereoselectiveheterogeneous hydrogenation using a chiralauxiliary. This was considered a more predict-able strategy and indeedworkedwell. However,introducing and removing the auxiliary added

further synthetic steps and the chiral auxiliarycould not be reused. The second approach(Fig. 37B) was the unprecedented enantioselec-tive hydrogenation of an unprotected enamine.This reaction was developed with the help ofhigh throughput experimentation and providedthe basis for the first generation productionprocess. Later a variant was described by aMerck/Takasago team [116], which avoided theisolation and purification of the enamine butrequired a higher catalyst loading (seeFig. 38A).

Finally, an elegant biochemical process wasdisclosed by a Codexis/Merck team [117],which not only provides very high enantioselec-tivities but avoids the need for further purifica-tion (Fig 38B). Starting from an enzyme that hadthe catalytic machinery to perform the desiredchemistry but lacked any activity toward thepro-sitagliptin ketone, various approaches, suchas substrate walking, modeling, and mutationwere applied to create a transaminase withmarginal activity for the synthesis of the desiredchiral amine. This variant was then furtherengineered via directed evolution for practicalapplication in a production setting. A massiveR&D effort was needed in order to reach thisambitious goal but it is clear that this technologyhas the potential to replace the hydrogenationroute used [118].

Figure 37. Substrate (A) and catalyst (B) controlled hydrogenation of sitagliptin precursors

Chiral Compounds 27

There is little doubt that the use of biocata-lysts for enantioselective syntheses of bothsimple intermediates and complex chiral com-pounds will increase even further, once thesetechnologies are implemented on a routinebasis. However, racemate resolution and stoi-chiometric as well as chemocatalytic methodsremains probably the method of choice in manycases when time and development efforts arelimited and for transformation where enzymesdo not work well.

References

General References1 IUPAC: http://goldbook.iupac.org/index.html, (accessed March

5, 2012).

2 R.S. Atkinson (ed.): Stereoselective Synthesis, John Wiley &

Sons, New York 1995.

3 E.N. Jacobsen, H. Yamamoto, A. Pfaltz (eds.): Comprehensive

Asymmetric Catalysis, Springer, Berlin 1999.

4 A.Ager (ed.):Handbook of Chiral Chemicals, 2nd ed., Taylor&

Francis, Boca Raton 2006.

5 M. Christmann, S. Brase (eds.): Asymmetric Synthesis - The

Essentials, Wiley-VCH, Weinheim 2007.

6 I. Ojima (ed.): Catalytic Asymmetric Synthesis, 2nd ed., Wiley-

VCH, Weinheim 2000.

7 H.U. Blaser, E. Schmidt (eds.): Asymmetric Catalysis on Indus-

trial Scale, Wiley-VCH, Weinheim 2003.

8 H.U. Blaser, H.-J. Federsel (eds.): Asymmetric Catalysis on

Industrial Scale II, Wiley-VCH, Weinheim 2010.

9 E. Francotte, W. Lindner (eds.): Chirality in Drug Research:

Methods and Principles in Medicinal Chemistry, Wiley-VCH,

Weinheim 2006.

Specific References10 J.M. Bijvoet, A.F. Peerdeman, A.J. van Bomnel, Nature 168

(1951) 270.

11 R.S. Cahn, C. Ingold, V. Prelog, Angew. Chem. Int. Ed. Engl. 5

(1966) 385.

12 A. Thayer, C&EN 83 (2005) no. 36, 49.

13 A.M. Rouhi, C&EN 82 (2004) no. 24, 47.

14 G.M. Ramos Tombo, H.U. Blaser in G.T. Brooks, T.R. Roberts

(eds.): Pesticide Chemistry and Bioscience, Royal Society of

Chemistry, Cambridge 1999, p. 33.

15 G.W. Muller, Chemtech 27 (1997) no. 1, 21.

16 W.H. de Camp, Chirality 1 (1989) 2.

17 J.S. Carey, D. Laffan, C. Thomson, M.T. Williams, Org.

Biomol. Chem. 4 (2006) 2337.

18 A.M. Rouhi, C&EN 81 (2003) no. 18, 56.

19 A.R. Burns, R.J.K. Taylor, Synthesis (2011) no. 5, 681.

20 P.J. Harrington, E. Lodewijk, Org. Process. Res. Devel. 1

(1997) 72.

21 A. Bruggink in A.N. Collins, G.N. Sheldrake, J. Crosby (eds.):

Chirality in Industry II, John Wiley & Sons, New York 1997,

p. 81.

22 B. Kaptein, T. Vries, J.W. Nieuwenhuijzen, R.M. Kellogg, R.F.

P. Grimbergen, Q.B. Broxterman, in A. Ager (ed.): Handbook

of Chiral Chemicals, 2nd ed., Taylor & Francis, Boca Raton

2006, p. 97.

23 N.G. Anderson, Org. Process Res. Devel. 9 (2005) 800.

24 M. McCoy, C&EN 78 (2000) no. 25, 17.

25 G.J. Quallich, Chirality 17 (2005) S120.

26 S. Caille, J. Boni, G.B. Cox, M.M. Faul, P. Franco, S. Khattabi,

L.M.Klingensmith, J.F. Larrow, J.K. Lee,M.J.Martinelli, L.M.

Miller, G.A. Moniz, K. Sakai, J.S. Tedrow, K.B. Hansen, Org.

Process Res. Devel. 14 (2010) 133.

27 H. Pellissier, Tetrahedron, 67 (2011) 3769.

28 J.M. Keith, J.F. Larrow, E.N. Jacobsen, Adv. Synth. Catal. 343

(2001) 5.

29 L. Aouni, K.E. Hemberger, S. Jasmin, H. Kabir, J.F. Larrow, I.

Le-Fur, P.Morel, T. Schlama, inH.U. Blaser, E. Schmidt (eds.):

Asymmetric Catalysis on Industrial Scale, Wiley-VCH,

Weinheim 2003, p. 165.

Figure 38. Amination processes to sitagliptinA) Chemical approach (structure of dm-segphos see Fig. 24, Ar ¼ 3,5-xylyl); B) Biocatalytical approach

28 Chiral Compounds

30 H.U. Blaser, Chem. Rev. 92 (1992) 935.

31 L.A. Paquette (ed.): Handbook of Reagents for Organic Syn-

thesis, Chiral Reagents for Asymmetric Synthesis, John Wiley

& Sons, Chichester 2003.

32 R. Noyori, Pure Appl. Chem. 53 (1981) 2315.

33 M.M. Midland, D.C. McDowell, R.L. Hatch, A. Tramontano,

J. Am. Chem. Soc. 102 (1980) 867.

34 H.C. Brown, P.V. Ramachandran, Pure & Appl. Chem. 63

(1991) 307.

35 D.R. Sidler, J.W. Sager, J.J. Bergan, K.M.Wells, M. Bhupathy,

R.P. Volante, Tetrahedron: Asymmetry 8 (1997) 161.

36 E.J. Corey, C.J. Helal, Angew. Chem. Int. Ed. 37 (1998) 1986.

37 B. Schaub, CHEManager 3 (2008) 23.

38 P.J. Cox, N.S. Simpkins, Tetrahedron: Asymmetry 2 (1991) 1.

39 Y. Gnas, F. Glorius, Synthesis (2006) no. 12, 1899.

40 D.A. Evans, Aldrichimica Acta 15 (1982) 23.

41 D.A. Evans, G. Helmchen, M. Ruping in M. Christmann, S.

Brase (eds.): Asymmetric Synthesis - The Essentials, Wiley-

VCH, Weinheim 2007, p. 3.

42 G. Roos (ed.): Compendium of Chiral Auxiliary Applications,

Academic Press, New York 2002.

43 F. Glorius, N. Spielkamp, S. Holle, R. Goddard, C.W.

Lehmann, Angew. Chem. Int. Ed. 43 (2004) 2850.

44 J.D. Morrison (ed.): Asymmetric Synthesis, vol. 5, Academic

Press, New York 1985.

45 W.S. Knowles, R. Noyori, K.B. Sharpless, Angew. Chem. Int.

Ed. 41 (2002) 1998.

46 H.U. Blaser, M. Studer in E.N. Jacobsen, H. Yamamoto, A.

Pfaltz (eds.): Comprehensive Asymmetric Catalysis, Springer,

Berlin 1999, p. 1353.

47 P. McMorn, G.J. Hutchings, Chem. Soc. Rev. 33 (2004)

108.

48 C.J. Welch, J. Albaneze-Walker, W.R. Leonard, M. Biba, J.

DaSilva, D. Henderson, B. Laing, D.J. Mathre, S. Spencer, X.

Bu, T. Wang, Org. Process. Res. Devel. 9 (2005) 198.

49 R.R. Knowles, E.N. Jacobsen, Proc Natl Acad Sci USA 107

(2010) 20678.

50 P.I. Dalko (ed.): Enantioselective Organocatalysis, Wiley-

VCH, Weinheim 2007, p. 1.

51 Q.-L. Zhou (ed.): Privileged Chiral Ligands and Catalysts,

Wiley-VCH, Weinheim 2011.

52 H.U. Blaser, B. Pugin, F. Spindler, J. Mol. Catal. A: Chemical,

231 (2005) 51 and references therein.

53 J.G. de Vries, C.J. Elsevier (eds.): Handbook of Homogeneous

Hydrogenation, Wiley-VCH, Weinheim 2007.

54 W.S. Knowles in H.U. Blaser, E. Schmidt (eds.): Asymmetric

Catalysis on Industrial Scale, Wiley-VCH, Weinheim 2003,

p. 23.

55 T. Sturm, W. Weissensteiner, F. Spindler, Adv. Synth. Catal.

345 (2003) 160.

56 J.A.F. Boogers, U. Felfer, M. Kotthaus, L. Lefort, G. Stein-

bauer, A.H.M. deVries, J.G. de Vries,Org. Process Res. Devel.

11 (2007) 585.

57 BASF, WO 2006097314, 2006 (F. Hettche, M. Volkert, C.

Jackel).

58 S.J. Roseblade, A. Pfaltz, Acc. Chem. Res. 40 (2007) 1402.

59 T. Ohkuma,M. Kitamura, R. Noyori in I. Ojima (ed.):Catalytic

Asymmetric Synthesis, 2nd ed., Wiley-VCH, Weinheim 2000,

p. 1.

60 H. Kumobayashi, Recl. Trav. Chim. Pays-Bas 115 (1996)

201.

61 M. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T.

Miura, H. Kumobayashi, Adv. Synth. Catal. 343 (2001) 264.

62 F.D. Klingler, Acc. Chem. Res. 40 (2007) 1367.

63 T. Benincori, S. Rizzo, F. Sannicolo, O. Piccolo in Proceedings

of the ChiraSource2000 Symposium, The Catalyst Group,

Spring House, USA, 2000.

64 F. Spindler, H.U. Blaser inC.Bolm,M.Beller (eds.):Transition

Metals for Organic Synthesis, 2nd ed., vol. 2, Wiley-VCH,

Weinheim 2004, p. 113.

65 R.A. Johnson, K.B. Sharpless in I. Ojima (ed.): Catalytic

Asymmetric Synthesis, 2nd ed., Wiley-VCH, Weinheim

2000, p. 231.

66 W.P. Shum, M.J. Cannarsa in A.N. Collins, G.N. Sheldrake, J.

Crosby (eds.): Chirality in Industry II, John Wiley & Sons,

Chichester 1997, p. 363.

67 C.H. Senanayake, E.N. Jacobsen in K.G. Gadamasetti (ed.):

Process Chemistry in the Pharmaceutical Industry, Marcel

Dekker Inc, New York 1999, p. 347.

68 E.N. Jacobsen, M.H. Wu in E.N. Jacobsen, H. Yamamoto, A.

Pfaltz (eds.): Comprehensive Asymmetric Catalysis, Springer,

Berlin 1999, p. 649.

69 R.A. Johnson, K.B. Sharpless in I. Ojima (ed.): Catalytic

Asymmetric Synthesis, 2nd ed., Wiley-VCH, Weinheim

2000, p. 357.

70 H.B. Kagan in I. Ojima (ed.): Catalytic Asymmetric Synthesis,

2nd ed., Wiley-VCH, Weinheim 2000, p. 327.

71 H.J. Federsel, M. Larsson in H.U. Blaser, E. Schmidt (eds.):

Asymmetric Catalysis on Industrial Scale, Wiley-VCH, Wein-

heim 2003, p. 413.

72 S. Akutagawa, K. Tani in I. Ojima (ed.): Catalytic Asymmetric

Synthesis, 2nd ed., Wiley-VCH, Weinheim 2000, p. 145.

73 H.U. Blaser, B. Pugin in K. Ding (ed.): Handbook of Asymmet-

ric Heterogeneous Catalysis, Wiley-VCH, Weinheim 2008,

p. 413.

74 H.U. Blaser, M. Studer, Acc. Chem. Res. 40 (2007) 1348.

75 H.U. Blaser, B. Pugin in G. Ertl, H. Knozinger, F. Schuth, J.

Weitkamp (eds.): Handbook of Heterogeneous Catalysis, 2nd

ed., Wiley-VCH, Weinheim 2008, p. 3603.

76 B. List, R.A. Lerner, C.F. Barbas III, J. Am. Chem. Soc. 122

(2000) 2395.

77 K.A. Ahrendt, C.J. Borths, D.W.C. MacMillan, J. Am. Chem.

Soc. 122 (2000) 4243.

78 P.I. Dalko (ed.): Enantioselective Organocatalysis, Wiley-

VCH, Weinheim 2007.

79 P.Melchiorre,M.Marigo, A. Carlone, G. Batoli,Angew. Chem.

Int. Ed. 47 (2008) 6138.

80 B. List, Chem. Commun. 2006, 819.

81 G. Lelais, D.W.C.MacMillan in K.Mikami, M. Lautens (eds.):

New Frontiers in Asymmetric Catalysis, John Wiley & Sons,

New York 2007, p. 313.

82 F. Xu, M. Zacuto, N. Yoshikawa, R. Desmond, S. Hoerrner, T.

Itoh, M. Journet, G.R. Humphrey, C. Cowden, N. Strotman, P.

Devine, J. Org. Chem. 75 (2010) 7829.

83 A.G. Doyle, E.N. Jacobsen, Chem. Rev. 107 (2007) 5713.

84 X. Huang, S. Broadbent, C. Dvorak, S-H. Zhao, Org. Process

Res. Devel. 14 (2010) 612.

85 E.A.ColbyDavie, S.M.Mennen, Y.Xu, S.J.Miller,Chem. Rev.

107 (2007) 5759.

86 C.A. Lewis, J.L. Gustafson, A. Chui, J. Balsells, D. Pollard, J.

Murry, R.A. Reamer, K.B. Hansen, S.J. Miller, J. Am. Chem.

Soc. 130 (2008) 16385.

87 A. Gerlach, T. Geller, Adv. Synth. Catal. 346 (2004) 1247.

88 S. Mayer, B. List: Angew. Chem. Int. Ed. 45 (2006)

4193.

89 M. Shibasaki, M. Kanai in K. Mikami, M. Lautens (eds.): New

Frontiers in Asymmetric Catalysis, John Wiley & Sons, New

York, 2007 p. 383.

Chiral Compounds 29

90 P. Kocovsky, A.V.Malkov in P.I. Dalko (ed.):Enantioselective

Organocatalysis, Wiley-VCH, Weinheim 2007, p. 255.

91 T. Marcelli, J.H. van Maarseveen, H. Hiemstra, Angew. Chem.

Int. Ed. 45 (2006) 7496.

92 F. Xu, E. Corley, M. Zacuto, D.A. Conlon, B. Pipik,

G. Humphrey, J. Murry, D. Tschaen, J. Org. Chem. 75,

(2010) 1343.

93 D. Kampen, C.M. Reisinger, B. List, Topics in Current Chem-

istry 291 (2010) 395.

94 T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 348 (2006)

999.

95 K. Maruoka (ed.): Asymmetric Phase Transfer Catalysis,

Wiley-VCH, Weinheim 2008.

96 T. Ooi, K. Maruoka, Angew. Chem. Int. Ed. 46 (2007) 4222.

97 S.E.Denmark,N.D.Gould, L.M.Wolf, J.Org. Chem. 76 (2011)

4260 and 4337.

98 M. Ikunaka, K. Maruoka in H.U. Blaser, H.-J. Federsel (eds.):

Asymmetric Catalysis on Industrial Scale II, Wiley-VCH,

Weinheim 2010, p. 151.

99 A. Mastracchio, A.A. Warkentin, A.M. Walji, D.W.C.

MacMillan, Proc. Natl. Acad. Sci. USA 107 (2010) 20648.

100 D. Enders, T. Balensiefer, O. Niemeier, M. Christmann in P.I.

Dalko (ed.): Enantioselective Organocatalysis, Wiley-VCH,

Weinheim 2007, p. 331.

101 W.M. McGarrigle, V.K. Agarwal in E.N. Jacobsen, H. Yama-

moto, A. Pfaltz (eds.): Comprehensive Asymmetric Catalysis,

Springer, Berlin 1999, p. 357.

102 A. Armstrong E.N. Jacobsen, H. Yamamoto, A. Pfaltz (eds.):

Comprehensive Asymmetric Catalysis, Springer, Berlin 1999,

p. 403.

103 D.J. Ager, K. Anderson, E. Oblinger, Y. Shi, J. VanderRoest,

Org. Process. Res. Devel. 11 (2007) 44.

104 F. Cozzia, Adv. Synth. Catal. 348 (2006) 1367.

105 Y. Arakawa, M. Wiesner, H. Wennemers, Adv. Synth. Catal.

353 (2011) 1201.

106 A. Dondoni, A. Massi, Angew. Chem. Int. Ed. 47 (2008) 4638.

107 L.Albrecht, H. Jiang,K.A. Jørgensen,Angew.Chem. Int. Ed. 50

(2011) 8492.

108 S. Zhou, S. Fleischer, K. Junge, M. Beller, Angew. Chem. Int.

Ed. 50 (2011) 5120 and references therein.

109 T. Matsuda, R. Yamanaka, K. Nakamura, Tetrahedron: Asym-

metry 20 (2009) 513.

110 F. Hollmann, I.W.C.E. Arends, D. Holtmann, Green Chem. 13

(2011) 2285.

111 M.T. Reetz, Angew. Chem. Int. Ed. 50 (2011) 138.

112 Daicel Corporation: Chiral Technologies, http://www.daicel-

chiral.com/en/contents/chiralscreen/oh/index.html (accessed

March 5, 2012).

113 Codexis Inc., http://www.codexis.com/screening_tools_kits

(accessed March 5, 2012).

114 J. Liang, E. Mundorff, R. Voladri, S. Jenne, L. Gilson, A.

Conway, A. Krebber, J. Wong, G. Huisman, S. Truesdell, J.

Lalonde, Org. Process. Res. Devel. 14 (2010) 188.

115 C.S. Shultz, S.W. Krska, Acc. Chem. Res. 40 (2007) 1320.

116 D. Steinhuebel, Y. Sun, K.Matsumura, N. Sayo, T. Saito, J. Am.

Chem. Soc. 131 (2009) 11316.

117 C.K. Savile, J.M. Janey, E.C.Mundorff, J.C.Moore, S. Tam,W.

R. Jarvis, J.C. Colbeck, A. Krebber, F.J. Fleitz, J. Brands, P.N.

Devine, G.W. Huisman, G.J. Hughes, Science 329 (2010) 305.

118 F.G. Mutti, J. Sattler, K. Tauber, W. Kroutil,Chem. Cat. Chem.

3 (2011) 109.

30 Chiral Compounds