The third Novel Chiral Chemistries Japan(NCCJapan) Conference and Exhibition was heldin Tokyo on 18th and 19th April 2009 (1). The sec-ond meeting had been held in 2007 (2) and the firstin 2006. All meetings in the series have followed asimilar format, with keynote addresses and sup-porting lectures, although this time there weresome dual presentations in which two speakersfrom the same company gave complementary talkson slightly different topics within a single time slot.Professor Takao Ikariya (Tokyo Institute ofTechnology, Japan) and his team, in particularKyoko Suzuki, must be congratulated for theexcellent job they did to ensure that the conferenceran smoothly. As in previous meetings, ProfessorIkariya put together an exciting mix of speakersfrom both academia and industry across the world.There were around 130 attendees, with the major-ity being from Japan.

During the coffee and lunch breaks there wasan exhibition by companies with products mainlyassociated with chiral chemistry. The exhibitorsranged from companies that provide biocatalystsand chemical catalysts including ligands, to chro-matography, chemistry services and instrumentmanufacturers.

Keynote PresentationsThe opening keynote address was given by

Professor Yoshiji Takemoto (Kyoto University,Japan) on asymmetric catalysis with multifunction-al ureas. The reactions described includedasymmetric versions of the Michael and Mannichreactions, hydrazination and the aza-Henry reac-tion with 1,3-dicarbonyl compounds, as well asPetasis-type additions to quinolines and conjugateadditions to enones.

The second keynote address was given byProfessor Jan-Erling Bäckvall (Stockholm Univer-sity, Sweden). This lecture covered his work on the

simultaneous use of bio- and chemocatalysis toenable dynamic kinetic resolutions (DKR) to becarried out. The initial work was performed withsecondary alcohols. The readily available enzyme,Candida antarctica lipase B (CALB) (Novozym®

435), which is derived from a yeast, is used to acy-late one enantiomer of a secondary alcohol. Aruthenium catalyst then racemises the unreactedenantiomer. Initially the Shvo catalyst, 1, was usedbut the racemisation is slow and requires heating togive acceptable reaction rates. Use of themonomeric ruthenium catalyst 2 provides fasterreactions, even at ambient temperatures.

CALB provides the (R)-acetate, while a spe-cially treated subtilisin Carlsberg enzyme gives the(S)-product ester. With 1,3-dihydroxy com-pounds, the selectivity of the enzyme ensures highselectivity for the (R,R)-diacetoxy product.However, due to the slow racemisation rates withthe Shvo catalyst system, significant amounts ofmeso-products were formed with 1,4- and 1,5-diols.Use of the faster catalyst 2 alleviates this problem.Analogous uses of the concept have beenemployed for the DKR of chlorohydrins, aminesand allenic alcohols.

203Platinum Metals Rev., 2009, 53, (4), 203–208

Novel Chiral Chemistries Japan 2009PGMs RETAIN THEIR PIVOTAL ROLE IN ASYMMETRIC CATALYSIS

Reviewed by David J. AgerDSM, PMB 150, 9650 Strickland Road, Suite 103, Raleigh, NC 27615, U.S.A.; E-mail: david.ager@DSM.com

DOI: 10.1595/147106709X474226

RuH

Ru

OH

O

Ph

Ph

Ph

Ph

Ph

PhPh

Ph

OCCOCO OC1

RuCl

Ph

Ph

Ph

Ph

Ph

OCCO2

The third keynote address was given byProfessor Hisashi Yamamoto (University ofChicago, U.S.A.) on the uses of Brønsted acids inorganic synthesis. The emphasis of the talk was onthe use of triflimide, (CF3SO2)2NH, as a superacidthat can regenerate itself during a Mukaiyama aldolreaction. The use of the tris(trimethylsilyl)silyl(TTMS) group as a ‘super silyl’ group also makesthe enol ether more reactive.

Asymmetric CatalysisIn addition to these keynote addresses there

were fifteen other presentations. Topics includedthe uses of biocatalysis, transition metal catalysisand the synthesis of target molecules, among others. In line with the emphasis of this publica-tion, those talks relating to the use of platinumgroup metals (pgms) have been highlighted.

Fred Hancock (Johnson Matthey Catalysis andChiral Technologies, U.K.) gave an overview ofsome case histories in which Johnson Matthey hadlooked for an appropriate catalyst to perform anasymmetric transformation. He described theadvantages of chemocatalytic and enzymatic meth-ods for the reduction of carbonyl compounds fora number of example systems. The reduction ofaryl ketones can be achieved in high yield and withhigh enantioselectivity by the system RuCl2[(R)-P-Phos][(S)-DAIPEN], 3a and 4, in a manner anal-ogous to the method developed by Noyori (3). Theuse of this system with xyl-P-Phos, 3b, was illus-trated for a pharmaceutical application as part ofthe synthesis of Nycomed’s imidazo[1,2-a]pyridineBYK-311319. The P-Phos family of ligands canalso be used in the catalyst system [RuCl2(P-Phos)(DMF)n] (DMF = N,N-dimethylformamide),

for the reduction of α,β- and γ,δ-enoic acids forpharmaceutical applications, such as in the preparation of an intermediate for Solvay’sSONU 20250180. α,β-Enoic acids can also bereduced by an iridium or rhodium catalyst withMe-BoPhozTM, 5, as the chiral ligand or by arhodium–Xyl-PhanePhos, 6, system.

André de Vries and David Ager (DSM, TheNetherlands and U.S.A., respectively) gave a jointpresentation. de Vries described the advantages ofperforming asymmetric hydrogenations of unsatu-rated carbon–carbon multiple bonds with arhodium catalyst using the MonoPhosTM family ofligands, 7 (4). The method can be automated,which allows for rapid screening of products.

Platinum Metals Rev., 2009, 53, (4) 204

N

N

OMe

MeO

MeO

OMe

PAr2

PAr2

3

a Ar = Ph ((R)-P-Phos)

b Ar = xyl ((R)-xyl-P-Phos)

H2N

H2NOMe

OMe

4 (S)-DAIPEN

Fe

N

PPh2 PPh2

5 (R)-Me-BoPhozTM

P(xyl)2

P(xyl)2

6 (R)-Xyl-PhanePhos

R4

R4

R3

O

O

R3

R5

R5

P NR1R

2

7 MonoPhosTM

family of ligands

Higher reaction rates and enantioselectivities canbe observed when two different monodentate lig-ands are used at the same time. This has resultedin an economical process for the preparation ofpart of Novartis’ renin inhibitor, Aliskiren. Thephosphoramidite MonoPhosTM ligands are alsouseful for the reduction of carbonyl groups,including β-keto esters, with ruthenium as themetal. Iridium systems with phosphoramidites canbe used to prepare phenylalanines by asymmetrichydrogenation, and also provide high selectivity inthe reduction of imines. Ager discussed enzymaticmethods to prepare cyanohydrins with high enan-tioselectivity, and the development of theindustrial production of DSM’s PharmaPLETM, arecombinant pig liver esterase that can be used inpharmaceutical applications.

Professor Andreas Pfaltz (University of Basel,Switzerland) continued the asymmetric hydro-genation theme with his iridium-catalysedasymmetric reduction of unfunctionalised alkenesin the presence of P,N-ligands. In addition to thewell-established system 8, which can be used witha wide variety of alkene substitution patterns, thephosphinooxazolines, 9, have also proven useful,particularly with trisubstituted alkenes. For thisclass of reductions, it is particularly important touse a non-nucleophilic counterion for the metal,such as tetra[3,5-bis(trifluoromethyl)phenyl]borate(BArF).

Kunihiko Murata (Kanto Chemical Co, Inc,Japan) described the development of the rutheni-um-based asymmetric transfer hydrogenationcatalyst 10 for the reduction of ketones, whichremoves the need for a chiral phosphine ligand.The diamine provides the asymmetry. This catalystcan also be used to carry out asymmetric Henryand Michael reactions.

Ian Lennon (Chiral Quest, Inc, U.K.) describedthe chemistry and uses of a number of ligand sys-tems developed by Chiral Quest. C3-TunePhos, 11,provides excellent enantioselectivity for the reduc-tion of β-keto esters. The analogue C3*-TunePhos,12, extends this to ketones and α-keto esters aswell as retaining its selectivity with β-keto esters.TangPhos, 13, has proven to be a useful ligand inthe rhodium-catalysed reduction of dehydroaminoacids, itaconates and enamides. The latter class ofcompounds can now be accessed from oximes bya rhodium-on-carbon-catalysed hydrogenation inthe presence of acetic anhydride. The analogue ofTangPhos, DuanPhos, 14, provides excellentstereoselectivity for the reduction of function-alised aryl alkyl ketones, while BINAPINE, 15,provides access to β-amino esters.

Christophe Le Ret (Umicore AG & Co KG,Germany) described a different aspect of asym-metric hydrogenation: the formation ofmetal–ligand complexes and the influence of themetal precursor. For rhodium, an example ligandwas MandyPhosTM, 16. For the asymmetricreduction of (Z)-acetamidocinnamic acid methylester, with Rh(nbd)2 (nbd = 2,5-norbornadiene)as the metal source, in situ formation of the cata-lyst or the use of the P,N-complex gave a slowerhydrogenation rate than the P,P-complex system.With ruthenium, it was found that the use ofbis(η5-2,4-dimethylpentadienyl)ruthenium(II), 17,was superior for complex formation withMandyPhosTM and other ferrocene-based ligands.

Wataru Kuriyama (Takasago InternationalCorp, Japan) described the synthesis of chiral alco-hols by the catalytic reduction of esters. The systemis based on a ruthenium–diamine complex, 18. Forhigh enantioselectivity, the stereogenic centre hasto be present in the substrate, as it is in α-alkyl, β-amino, β-alkoxy, β-hydroxy and α-hydroxy esters.

Platinum Metals Rev., 2009, 53, (4) 205

PAr2 N

O

R2

N

O

PAr2

Ph3

8 9

Ar = Ph or o-Tol

NH2

N

Ru

Ph

Ph X

R1SO2

R2

10

X = Cl

R1

= aryl or alkyl

Ar–R2

= cymene,

mesitylene or

hexamethylbenzene

The key to success was performing the reactions inthe absence of base.

Professor Ken Tanaka (Tokyo University ofAgriculture and Technology, Japan) presented onrhodium-catalysed [2 + 2 + 2] cycloadditions forthe preparation of axial chiral aromatic compounds.The products can be biaryl systems or others withhindered rotation, such as benzamides. The ligandsused for the reactions are BINAP, 19, and deriva-tives, such as H8-BINAP, 20, and SEGPHOS®, 21.

David Chaplin (Dr Reddy’s Laboratories Ltd,U.K.) described asymmetric hydroformylationreactions. Linear products are most commonlyformed from an achiral hydroformylation reaction,but the product aldehydes can be substrates for awide variety of reactions. For an asymmetric version of the reaction, regioselectivity as well asenantioselectivity must be considered, as thebranched aldehyde is usually the required productbecause it generates the stereogenic centre. This

Platinum Metals Rev., 2009, 53, (4) 206

PPh2

PPh2

O

O

PAr2

PAr2

O

O

P P

H

t-Bu

H

t-Bu

P P

t-Bu t-Bu

HH

P P

t-Bu t-Bu

HH

11 C3-TunePhos

12 C3*-TunePhos

13 TangPhos

15 BINAPINE

H

tBu

tBu

tBu

14 DuanPhos

tBu

tBu

tBu

Ar = Ph, 4-MePh,

3,5-di-tBuPh, 3,5-diMePh

or 4-MeO-3,5-di-tBuPh

16 MandyPhos 17

Me2N

Fe PPh2

Ph

PPh2

Ph

NMe2

Ru

NH2

H2

N

Ru

Ph

Ph

P

P

Ph Ph

PhPh

H

H

BH3 18

Ph

Ph

PPh2

PPh2

PPh2

PPh2

O

O

O

O

PPh2

PPh2

19 BINAP 20 H8-BINAP 21 SEGPHOS®

PPh2

PPh2

PPh2

PPh2

PPh2

PPh2

problem can be exacerbated if the alkene is notterminal. A screening exercise showed that theDiazaPhos-SPE diazaphospholane ligand system,22, was the best to prepare a bistetrahydrofuranwith good diastereoselectivity in the presence of arhodium-based catalyst, Scheme I.

Hans-Ulrich Blaser and Garrett Hoge (SolviasAG, Switzerland) gave a joint presentation. Blaserdescribed the extensive Solvias ligand families,mainly based on the ferrocene skeleton. New lig-ands that have been prepared and are currentlybeing evaluated are Kephos, 23, Fengphos, 24,Chenphos, 25, and Jospophos, 26. Hoge explainedhow Solvias performs ligand screenings and illus-trated the methodology with a number of practicalexamples including the reduction of acrylic acidsand ketones.

Professor Bernhard Breit (Albert-Ludwigs-Universität Freiburg, Germany) uses the conceptof self-assembly to prepare bisphosphine ligandsby dimerisation of monophosphines, such as 6-diphenylphosphinyl-2(1H)-pyridinone (6-DPPon),27. The dimeric ligand can be used to achieve highratios of linear products in the hydroformylationof terminal alkenes. Use of an organocatalyst such

as L-proline with an aldehyde and an alkene underhydroformylation conditions provides 1,3-diolswith good enantioselectivity. The self-assemblyconcept has been extended to chiral ligands inwhich the phosphorus moiety provides the asym-metry, such as 3-DMPICon, 28, and 3-BIPICon, 29.As with the reductions using DSM MonoPhosTM,the use of monodentate ligands allows for syner-gistic effects when two different ligands are usedin asymmetric hydrogenations.

Yongkui Sun (Merck & Co, Inc, U.S.A.)described some case studies on the use of asym-metric hydrogenations for drug synthesis atMerck. The final step in the synthesis ofsitagliptin, 30, is an asymmetric hydrogenation togive the β-amino amide. The use of a ferroceneligand has been superseded by the use of a ruthenium–DM-SEGPHOS® (SEGPHOS® withP(xyl)2 groups in place of PPh2) catalyst, with theβ-keto amide in the presence of ammonium salicylate as the amine donor. Examples of enzy-matic reactions, such as ketone reductions,

Platinum Metals Rev., 2009, 53, (4) 207

OH

O

O

OO

H

H

HO

1. Rh(CO)2(acac), Ligand

CO/H2

2. THF, HCl

(i) Rh(CO)2(acac), DiazaPhos-SPE

CO/ H2

(ii) THF, HCl

endo:exo = 10:1

α:β = 8:1

N

NP

O

O

N

NP

O

O

NH

O

Ph

O

HN

Ph

O

NH

Ph

HN

O

Ph

22 Bis(R,R,S)-DiazaPhos-SPE

Scheme IHydroformylationreaction to preparea bistetrahydrofuranin the presence of arhodium-basedcatalyst system withDiazaPhos-SPEligand

23 Kephos24 Fengphos

25 Chenphos 26 Jospophos

R2P Fe P

R2P Fe PR1

2

NMe2

PR2

Fe

PR2

P

R1

H

OFe

Fe

P

R1

NMe2

transaminations and the formation of cyanohy-drins were also given.

Professor Mikiko Sodeoka (RIKEN AdvancedScience Institute, Japan) described asymmetricreactions of metal enolates primarily based on theuse of palladium, with DM-SEGPHOS® as thechiral ligand. A wide range of reactions give highenantioselectivities including Michael, aldol,Mannich and α-fluorination reactions. For the lastclass of reactions, use of N-fluorobenzenesulfon-amide, (PhSO2)2NF, (NFSI) as the fluorinatingagent provides the best selectivity.

Concluding RemarksAs with the other meetings in this series,

NCCJapan 2009 was held just before CPhI Japan(5), allowing participants to attend both. There wassufficient time between lectures and at the banquetto allow for interaction between the participants,exhibitors and speakers. As noted above, a widevariety of methodology was covered, much associ-ated with the use of transition metal catalysis, and

in particular the use of pgm-based systems withphosphine ligands. As in the previous meetings,there was a good balance between the discovery ofnew methods and the industrial application ofexisting techniques. This conference seriesdeserves to continue to grow and prosper andProfessor Ikariya hinted that the next one mighthave the title Novel Chiral Chemistries Asia. I wishhim well with this endeavour and look forward toanother excellent meeting.

Platinum Metals Rev., 2009, 53, (4) 208

NH

Ph2P O

NH

O

P

NH

O

O

OP

R

R

27 6-DPPon

28 3-DMPICon

29 3-BIPICon (R = H)

F

F

FNH2

N

O

NN

N

30 Sitagliptin CF3

References1 Novel Chiral Chemistries Japan 2009 (NCCJapan)

Conference Programme: http://www.takasago-i.co.jp/news/2009/NCCJ2009_Program.pdf(Accessed on 27th July 2009)

2 D. J. Ager, Platinum Metals Rev., 2007, 51, (4), 1723 R. Noyori, Angew. Chem. Int. Ed., 2002, 41, (12), 20084 D. J. Ager, A. H. M. de Vries and J. G. de Vries,

Platinum Metals Rev., 2006, 50, (2), 545 CPhI Japan: http://www.cphijapan.com/eng/

(Accessed on 27th July 2009)

The ReviewerDavid Ager has a Ph.D. (University ofCambridge), and was a post-doctoralworker at the University ofSouthampton. He worked at Liverpooland Toledo (U.S.A.) universities;NutraSweet Company’s research anddevelopment group (as a MonsantoFellow), NSC Technologies, and GreatLakes Fine Chemicals (as a Fellow)responsible for developing newsynthetic methodology. David was then

a consultant on chiral and process chemistry. In 2002 he joinedDSM as the Competence Manager for homogeneous catalysis. InJanuary 2006 he became a Principal Scientist.