DOI: 10.1595/147106709X474226 Novel Chiral Chemistries Japan 2009 PGMs RETAIN THEIR PIVOTAL ROLE IN ASYMMETRIC CATALYSIS

Reviewed by David J. Ager DSM, PMB 150, 9650 Strickland Road, Suite 103, Raleigh, NC 27615, U.S.A.; E-mail: [email protected]

The third Novel Chiral Chemistries Japan simultaneous use of bio- and chemocatalysis to (NCCJapan) Conference and Exhibition was held enable dynamic kinetic resolutions (DKR) to be in Tokyo on 18th and 19th April 2009 (1). The sec- carried out. The initial work was performed with ond meeting had been held in 2007 (2) and the first secondary alcohols. The readily available enzyme, in 2006. All meetings in the series have followed a Candida antarctica lipase B (CALB) (Novozym® similar format, with keynote addresses and sup- 435), which is derived from a yeast, is used to acy- porting lectures, although this time there were late one of a secondary alcohol. A some dual presentations in which two speakers catalyst then racemises the unreacted from the same company gave complementary talks enantiomer. Initially the Shvo catalyst, 1, was used on slightly different topics within a single time slot. but the racemisation is slow and requires heating to Professor Takao Ikariya (Tokyo Institute of give acceptable reaction rates. Use of the Technology, Japan) and his team, in particular monomeric ruthenium catalyst 2 provides faster Kyoko Suzuki, must be congratulated for the reactions, even at ambient temperatures. excellent job they did to ensure that the conference ran smoothly. As in previous meetings, Professor Ph O O Ph Ikariya put together an exciting mix of speakers H from both academia and industry across the world. Ph Ph Ph Ph There were around 130 attendees, with the major- Ph H Ph ity being from Japan. Ru Ru OC During the coffee and lunch breaks there was 1 CO OC CO an exhibition by companies with products mainly associated with chiral chemistry. The exhibitors Ph Ph ranged from companies that provide biocatalysts and chemical catalysts including ligands, to chro- Ph Ph matography, chemistry services and instrument Ph Ru Cl manufacturers. OC 2 CO Keynote Presentations The opening keynote address was given by CALB provides the (R)-acetate, while a spe- Professor Yoshiji Takemoto (Kyoto University, cially treated subtilisin Carlsberg enzyme gives the Japan) on asymmetric catalysis with multifunction- (S)-product ester. With 1,3-dihydroxy com- al ureas. The reactions described included pounds, the selectivity of the enzyme ensures high asymmetric versions of the Michael and Mannich selectivity for the (R,R)-diacetoxy product. reactions, hydrazination and the aza-Henry reac- However, due to the slow racemisation rates with tion with 1,3-dicarbonyl compounds, as well as the Shvo catalyst system, significant amounts of Petasis-type additions to quinolines and conjugate meso-products were formed with 1,4- and 1,5-diols. additions to enones. Use of the faster catalyst 2 alleviates this problem. The second keynote address was given by Analogous uses of the concept have been Professor Jan-Erling Bäckvall (Stockholm Univer- employed for the DKR of chlorohydrins, amines sity, Sweden). This lecture covered his work on the and allenic alcohols.

Platinum Metals Rev., 2009, 53, (4), 203–208 203 The third keynote address was given by OMe Professor Hisashi Yamamoto (University of Chicago, U.S.A.) on the uses of Brønsted acids in organic synthesis. The emphasis of the talk was on the use of triflimide, (CF3SO2)2NH, as a superacid H2N that can regenerate itself during a Mukaiyama aldol OMe reaction. The use of the tris(trimethylsilyl)silyl (TTMS) group as a ‘super silyl’ group also makes H2N the enol ether more reactive. 4 (S)-DAIPEN Asymmetric Catalysis In addition to these keynote addresses there for the reduction of α,β- and γ,δ-enoic acids for were fifteen other presentations. Topics included pharmaceutical applications, such as in the the uses of biocatalysis, transition metal catalysis preparation of an intermediate for Solvay’s and the synthesis of target molecules, among SONU 20250180. α,β-Enoic acids can also be others. In line with the emphasis of this publica- reduced by an iridium or rhodium catalyst with tion, those talks relating to the use of platinum Me-BoPhozTM, 5, as the chiral ligand or by a group metals (pgms) have been highlighted. rhodium–Xyl-PhanePhos, 6, system. Fred Hancock (Johnson Matthey Catalysis and Chiral Technologies, U.K.) gave an overview of some case histories in which Johnson Matthey had P(xyl)2 N looked for an appropriate catalyst to perform an PPh 2 PPh2 asymmetric transformation. He described the Fe P(xyl)2 advantages of chemocatalytic and enzymatic meth- ods for the reduction of carbonyl compounds for 5 (R)-Me-BoPhozTM 6 (R)-Xyl-PhanePhos a number of example systems. The reduction of aryl ketones can be achieved in high yield and with high enantioselectivity by the system RuCl2[(R)- André de Vries and David Ager (DSM, The P-Phos][(S)-DAIPEN], 3a and 4, in a manner anal- Netherlands and U.S.A., respectively) gave a joint ogous to the method developed by Noyori (3). The presentation. de Vries described the advantages of use of this system with xyl-P-Phos, 3b, was illus- performing asymmetric of unsatu- trated for a pharmaceutical application as part of rated carbon–carbon multiple bonds with a the synthesis of Nycomed’s imidazo[1,2-a]pyridine rhodium catalyst using the MonoPhosTM family of BYK-311319. The P-Phos family of ligands can ligands, 7 (4). The method can be automated, also be used in the catalyst system [RuCl2(P- which allows for rapid screening of products. Phos)(DMF)n] (DMF = N,N-dimethylformamide), R4 OMe 3 R5 R3 a Ar = Ph ((R)-P-Phos) N b Ar = xyl ((R)-xyl-P-Phos) O P NR1R2 MeO PAr2 O

MeO PAr2 R5 R3 N R4 TM OMe 7 MonoPhos family of ligands

Platinum Metals Rev., 2009, 53, (4) 204 Higher reaction rates and enantioselectivities can 1 be observed when two different monodentate lig- R SO2 X = Cl R2 ands are used at the same time. This has resulted Ph N R1 = aryl or alkyl in an economical process for the preparation of 2 Ru Ar–R = cymene, part of Novartis’ renin inhibitor, Aliskiren. The mesitylene or TM phosphoramidite MonoPhos ligands are also Ph N X hexamethylbenzene H2 useful for the reduction of carbonyl groups, 10 including β-keto esters, with ruthenium as the metal. Iridium systems with phosphoramidites can Ian Lennon (Chiral Quest, Inc, U.K.) described be used to prepare phenylalanines by asymmetric the chemistry and uses of a number of ligand sys- , and also provide high selectivity in tems developed by Chiral Quest. C3-TunePhos, 11, the reduction of imines. Ager discussed enzymatic provides excellent enantioselectivity for the reduc- methods to prepare cyanohydrins with high enan- tion of β-keto esters. The analogue C3*-TunePhos, tioselectivity, and the development of the 12, extends this to ketones and α-keto esters as industrial production of DSM’s PharmaPLETM, a well as retaining its selectivity with β-keto esters. recombinant pig liver esterase that can be used in TangPhos, 13, has proven to be a useful ligand in pharmaceutical applications. the rhodium-catalysed reduction of dehydroamino Professor Andreas Pfaltz (University of Basel, acids, itaconates and enamides. The latter class of Switzerland) continued the asymmetric hydro- compounds can now be accessed from oximes by genation theme with his iridium-catalysed a rhodium-on-carbon-catalysed hydrogenation in asymmetric reduction of unfunctionalised alkenes the presence of acetic anhydride. The analogue of in the presence of P,N-ligands. In addition to the TangPhos, DuanPhos, 14, provides excellent well-established system 8, which can be used with stereoselectivity for the reduction of function- a wide variety of alkene substitution patterns, the alised aryl alkyl ketones, while BINAPINE, 15, phosphinooxazolines, 9, have also proven useful, provides access to β-amino esters. particularly with trisubstituted alkenes. For this Christophe Le Ret (Umicore AG & Co KG, class of reductions, it is particularly important to Germany) described a different aspect of asym- use a non-nucleophilic counterion for the metal, metric hydrogenation: the formation of such as tetra[3,5-bis(trifluoromethyl)phenyl]borate metal–ligand complexes and the influence of the (BArF). metal precursor. For rhodium, an example ligand was MandyPhosTM, 16. For the asymmetric reduction of (Z)-acetamidocinnamic acid methyl

ester, with Rh(nbd)2 (nbd = 2,5-norbornadiene) O O as the metal source, in situ formation of the cata- lyst or the use of the P,N-complex gave a slower PAr2 N PAr2 N hydrogenation rate than the P,P-complex system. 8 R 9 Ph With ruthenium, it was found that the use of 2 3 Ar = Ph or o-Tol bis(η5-2,4-dimethylpentadienyl)ruthenium(II), 17, was superior for complex formation with Kunihiko Murata (Kanto Chemical Co, Inc, MandyPhosTM and other ferrocene-based ligands. Japan) described the development of the rutheni- Wataru Kuriyama (Takasago International um-based asymmetric transfer hydrogenation Corp, Japan) described the synthesis of chiral alco- catalyst 10 for the reduction of ketones, which hols by the catalytic reduction of esters. The system removes the need for a chiral phosphine ligand. is based on a ruthenium–diamine complex, 18. For The diamine provides the asymmetry. This catalyst high enantioselectivity, the stereogenic centre has can also be used to carry out asymmetric Henry to be present in the substrate, as it is in α-alkyl, β- and Michael reactions. amino, β-alkoxy, β-hydroxy and α-hydroxy esters.

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

12 C3*-TunePhos H H O O PPh 2 PAr2 P H P PPh 2 PAr2 t-But t-But O O Bu Bu

13 TangPhos

11 C3-TunePhos Ar = Ph, 4-MePh, t 3,5-di- BuPh, 3,5-diMePh or 4-MeO-3,5-di-tBuPh H H H H

P P P P t-ButBu t-ButBu 15 BINAPINE t-ButBu tBu-Bu 14 DuanPhos

NMe2

Ph Ph H2 Ph P H N Ph Fe Ru PPh2 Ru Ph PH N Ph Ph H Ph 2 PhPhBH3 Me2N PPh2 18 16 MandyPhos 17

The key to success was performing the reactions in David Chaplin (Dr Reddy’s Laboratories Ltd, the absence of base. U.K.) described asymmetric hydroformylation Professor Ken Tanaka (Tokyo University of reactions. Linear products are most commonly Agriculture and Technology, Japan) presented on formed from an achiral hydroformylation reaction, rhodium-catalysed [2 + 2 + 2] cycloadditions for but the product aldehydes can be substrates for a the preparation of axial chiral aromatic compounds. wide variety of reactions. For an asymmetric The products can be biaryl systems or others with version of the reaction, regioselectivity as well as hindered rotation, such as benzamides. The ligands enantioselectivity must be considered, as the used for the reactions are BINAP, 19, and deriva- branched aldehyde is usually the required product ® tives, such as H8-BINAP, 20, and SEGPHOS , 21. because it generates the stereogenic centre. This

O

O PPh2 PPh2 PPh2

PPh22 PPh2 O PPh2

O ® 19 BINAP 20 H8-BINAP 21 SEGPHOS

Platinum Metals Rev., 2009, 53, (4) 206 problem can be exacerbated if the alkene is not terminal. A screening exercise showed that the DiazaPhos-SPE diazaphospholane ligand system, NMe2 22, was the best to prepare a bistetrahydrofuran R2P Fe P 1 R P Fe PR 2 with good diastereoselectivity in the presence of a 2 rhodium-based catalyst, Scheme I. 23 Kephos 24 Fengphos O O Ph Ph Fe N N H H O O P PR2 1 N N R O Fe Fe P P P NMe N N 2 H R1 PR2 O O H H N N 25 Chenphos 26 Jospophos Ph Ph O O as L-proline with an aldehyde and an alkene under 22 Bis(R,R,S)-DiazaPhos-SPE hydroformylation conditions provides 1,3-diols with good enantioselectivity. The self-assembly Hans-Ulrich Blaser and Garrett Hoge (Solvias concept has been extended to chiral ligands in AG, Switzerland) gave a joint presentation. Blaser which the phosphorus moiety provides the asym- described the extensive Solvias ligand families, metry, such as 3-DMPICon, 28, and 3-BIPICon, 29. mainly based on the ferrocene skeleton. New lig- As with the reductions using DSM MonoPhosTM, ands that have been prepared and are currently the use of monodentate ligands allows for syner- being evaluated are Kephos, 23, Fengphos, 24, gistic effects when two different ligands are used Chenphos, 25, and Jospophos, 26. Hoge explained in asymmetric hydrogenations. how Solvias performs ligand screenings and illus- Yongkui Sun (Merck & Co, Inc, U.S.A.) trated the methodology with a number of practical described some case studies on the use of asym- examples including the reduction of acrylic acids metric hydrogenations for drug synthesis at and ketones. Merck. The final step in the synthesis of Professor Bernhard Breit (Albert-Ludwigs- sitagliptin, 30, is an to Universität Freiburg, Germany) uses the concept give the β-amino amide. The use of a ferrocene of self-assembly to prepare bisphosphine ligands ligand has been superseded by the use of a by dimerisation of monophosphines, such as 6- ruthenium–DM-SEGPHOS® (SEGPHOS® with diphenylphosphinyl-2(1H)-pyridinone (6-DPPon), P(xyl)2 groups in place of PPh2) catalyst, with the 27. The dimeric ligand can be used to achieve high β-keto amide in the presence of ammonium ratios of linear products in the hydroformylation salicylate as the amine donor. Examples of enzy- of terminal alkenes. Use of an organocatalyst such matic reactions, such as ketone reductions,

Scheme I HO H Hydroformylation reaction to prepare O (i) Rh(CO)1. Rh(CO)2(acac),2(acac), DiazaPhos-SPE Ligand a bistetrahydrofuran O OH CO/H2CO/ H2 O O in the presence of a 2. THF,(ii) HCl THF, HCl H rhodium-based catalyst system with endo:exo = 10:1 DiazaPhos-SPE α:β = 8:1 ligand

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

P NH2 O N N Ph2P N O NH H N F N O 27 6-DPPon 28 3-DMPICon 30 Sitagliptin CF3

in particular the use of pgm-based systems with phosphine ligands. As in the previous meetings, R there was a good balance between the discovery of new methods and the industrial application of O existing techniques. This conference series P O deserves to continue to grow and prosper and Professor Ikariya hinted that the next one might NH R have the title Novel Chiral Chemistries Asia. I wish him well with this endeavour and look forward to O 29 3-BIPICon (R = H) another excellent meeting. transaminations and the formation of cyanohy- drins were also given. References Professor Mikiko Sodeoka (RIKEN Advanced 1 Novel Chiral Chemistries Japan 2009 (NCCJapan) Science Institute, Japan) described asymmetric Conference Programme: http://www.takasago- i.co.jp/news/2009/NCCJ2009_Program.pdf reactions of metal enolates primarily based on the (Accessed on 27th July 2009) use of , with DM-SEGPHOS® as the 2 D. J. Ager, Platinum Metals Rev., 2007, 51, (4), 172 chiral ligand. A wide range of reactions give high 3 R. Noyori, Angew. Chem. Int. Ed., 2002, 41, (12), 2008 enantioselectivities including Michael, aldol, 4 D. J. Ager, A. H. M. de Vries and J. G. de Vries, α Platinum Metals Rev., 2006, 50, (2), 54 Mannich and -fluorination reactions. For the last 5 CPhI Japan: http://www.cphijapan.com/eng/ class of reactions, use of N-fluorobenzenesulfon- (Accessed on 27th July 2009) amide, (PhSO2)2NF, (NFSI) as the fluorinating agent provides the best selectivity. The Reviewer David Ager has a Ph.D. (University of Concluding Remarks Cambridge), and was a post-doctoral As with the other meetings in this series, worker at the University of Southampton. He worked at Liverpool NCCJapan 2009 was held just before CPhI Japan and Toledo (U.S.A.) universities; (5), allowing participants to attend both. There was NutraSweet Company’s research and development group (as a Monsanto sufficient time between lectures and at the banquet Fellow), NSC Technologies, and Great to allow for interaction between the participants, Lakes Fine Chemicals (as a Fellow) responsible for developing new exhibitors and speakers. As noted above, a wide synthetic methodology. David was then variety of methodology was covered, much associ- a consultant on chiral and process chemistry. In 2002 he joined DSM as the Competence Manager for homogeneous catalysis. In ated with the use of transition metal catalysis, and January 2006 he became a Principal Scientist.

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