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Accessing the Expanded Chiral Pool using ChirBase Molecular Database Prof. Christian Roussel Mixed Research Unit of Chirotechnology Marseille (France). http://chirality.u-3mrs.fr http://chirbase.u-3mrs.fr. Contents. Introduction Advantages of chiral chromatography - comparison of

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  1. Accessing the Expanded Chiral Pool using ChirBase Molecular Database Prof. Christian RousselMixed Research Unit of ChirotechnologyMarseille (France) http://chirality.u-3mrs.fr http://chirbase.u-3mrs.fr

  2. Contents • Introduction • Advantages of chiral chromatography - comparison of • chiral methods - industrial examples • ChirBase: overview and statistics • – existing databases of chiral chemicals – compound • distributions - drug-like and lead-like distributions - • compound diversity studies • ChirBase chiral pool: chemoinformatic applications • building chiral combinatorial libraries- extending current • ChirBase chiral pool - approach to the virtual • synthesis of optically active targets – searching • precursors of chiral commercial drugs

  3. Introduction • Advantages of chiral chromatography • Comparison of chiral methods • Industrial examples • ChirBase: overview and statistics • ChirBase chiral pool: chemoinformatic applications

  4. Introduction: Chiral chromatography • Chiral analytical chromatography is a well established method for ee determination. • Reciprocally each reported ee determination is a source of information on molecular structures which could be readily separated on a given chiral stationary phase. • Thus chiral preparative chromatography, which takes advantage of all the reported chiral separations is a potential source of -molecular diversity in chiral building blocksorsynthons -stereochemical diversity for CombiChem

  5. Introduction: Chiral chromatography • Advantages of chromatography • Availability ofall the enantiomersof a given chiral compound • Speed upearly development works: fast accesstomilligrams of both enantiomers(100% pure) • Production:multi-kilogram scalecan be readily obtained (industrial simulated moving-bed) • Undesiredenantiomer can beracemizedandrecycledto obtain 100% of the targeted enantiomer

  6. Comparison of chiral methods(*) (*) Conference presented At ChemWeek Innovation in Technologies (September 10, 2002) by Thomas Archibald (VP Research and Innovation Rhodia Chirex) Chiral chromatography can compete with other strategies

  7. Example: Resolution via crystallization / Chiral HPLC • S. Virgil et coll. ( J. Org. Chem., 1998, 63, 2597-2600, Tetrahedron Asymmetry, 1999, 10, 25-29) reported the resolution of quinazolone atropisomers via crystallization using 1S Camphorsulfonic acid (benzenesulfonyl)hydrazone or chiral dipalladium complexes ( yield 77-86 %, ee > 96%). • The same authors reported the ee determination of the process using CHIRALCEL OD (98:2 Hexane / 2-PrOH, 0.5ml/min.)(S)-(+): 17.8 min. / R-(-): 32.4 min. • Obviously preparative CHIRAL HPLC is an alternative to the laborious and costly crystallization process

  8. Example: Asymmetric synthesis / Chiral HPLC • O. Fujimura (J. Am. Chem. Soc., 1998, 120, 10032-10039) reported on the enantioselective aldol condensation using several Platinium BINAP catalysts (ee from 46% to 88%) • In sup. mat. the chromatograms on CHIRALPAK AD column are reported as ee determination proof. Rt: 11.3 / 22.9 min. and 8 / 23 min. respectively • Obviously preparative CHIRAL HPLC is a short way to have the two enantiomers in hands for further applications.

  9. Example: Enzymatic resolution / Chiral HPLC • S. Nelson et coll., J. Org. Chem., 2000, 65, 1227-1230 reported on a sequential acyl halide-aldehyde cyclocondensation and enzymatic resolution as a route to enantiomerically enriched beta-lactones. • In the experimental part, the ee determination is reported on CHIRALCEL OD with Rt (R): 14.1 and Rt (S): 23 min. • Obviously preparative CHIRAL HPLC is a short way to have the two enantiomers in hands for further applications.

  10. Example: Racemic synthesis at early stage development (GlaxoSmithKline ) When chromatography is the quickest route • In 2004: Preclinical, asymmetric synthesis for commercial process (US Patent 6825188 Nov 2004) SB 273,005 – Vitronectin receptor antagonists (for Osteoporosis) at GlaxoSmithKline: • in 2001: early stage development, racemic synthesis and separation of the enantiomers by Chiral HPLC Preparative Chiral HPLC (Chiralcel OJ) (S)-enantiomer was isolated

  11. Example: Industrial process (Pfizer Sertraline) When chromatography is the most economical route Chiral Chromatography SMB MeNH2/EtOH (S) Cheap Rac-Tetralone (S) Pd/CaCO3 H2/EtOH Racemization (R) Low cost racemic synthesis AlCl3 (R) Is recycled (S) Sertraline No superior asymmetric synthesis process yet found (Quallich G.J., Chirality 17:S120-S126, 2005) (S)

  12. Introduction • ChirBase: overview and statistics • Existing databases of chiral chemicals • Compound distributions • Drug-like and lead-like distributions • Compound diversity studies • ChirBase chiral pool: chemoinformatic applications

  13. ChirBase database overview • Launched in 1989, provides today a voluminous collection of chiral separations by HPLC • Search on molecule structures and conditions • Adds over 10,000 new chiral separations annually and complete partial data • Provides a research tool that enables the application of chiral chromatography to a wide range of end-users and topics from preclinical to production

  14. ChirBase database overview Multiple criteria result forms Searchable Chemical structures Detailed experimental conditions and results Full reference

  15. Query assistant and dialog boxes to help novice users to build advanced queries ChirBase database overview

  16. Chirbase statisticsRelease July-2005

  17. Existing databases of commercially available chiral chemicals Available as one enantiomer (internet search): • Bark Information Services (www.chiraldata.com) • Launched in 2004 a database of over 1500 chiral chemicals available from worldwide suppliers • Fluka • More than 1500 chiral building blocks • More than 600 Boc or Fmoc protected chiral building blocks • Chiron (University of Montreal, Prof. Hanessian) • Computer program for selection of precursors or starting materials • In version 5 (2005), 2617 chiral precursors (1800 synthetic, 817 commercial) • Sigma-Aldrich • 5,000 chiral products (according to www.sigmaaldrich.com) ChirBase provides 28,000 chiral compounds available as both enantiomers

  18. Distribution of ChirBase compounds by chemical class Large choice of optically pure chiral precursors

  19. Molecular weight distribution (*) Molecular weight profile of ChirBase compounds is comparable with other commercial libraries. Lipinski’s rule (MW<=500) is satisfied for 95% of the compounds 250-275 325-360 Lipinskirule MW <= 500 Chirbase 28,000 chiral compounds Aldrich catalogue 15,000 chiral compounds * screening assistant » software available from ICOA UMR CNRS 6005 Université d’Orléans (France)

  20. Drug-Like property statistics in ChirBase Lipinski rule H-acceptor <= 10 Lipinski rule H-donor <= 5 For most compounds, Lipinski’s rules are satisfied Lipinski rule LogP <= 5

  21. Drug-Like distribution in ChirBase Using the « screening assistant » software(*) *, drug-like compounds were filtered by considering the following properties: -100 ≤ molecular weight ≤ 800 g.mol-1 - logP ≤ 7 - H donors ≤ 5 - rotatable bonds ≤ 15 - no reactive functions (eliminate false positives) - halogen atoms ≤ 7 - alkyl chains ≤ -(CH2)6CH3 - no perfluorinated chains: -CF2CF2CF3 - rings ≤ 6 - no big size ring with more than 7 members - at least one N or O atom Only one green property is not satisfied Drug-Like No unsatisfied property 70% of ChirBase compounds can be considered as drug-like (Compounds with a score <=1) * screening assistant » software available from ICOA UMR CNRS 6005 Université d’Orléans (France)

  22. Lead-Like distribution in ChirBase • Lead-like compounds are: • Small molecules • Potential starting material of drugs • They were filtered by considering the previous drug-like properties including the following corrections: • -molecular weight ≤ 400 g.mol-1 • - logP ≤ 4.2 • - H acceptors ≤ 9 • - rotatable bonds ≤ 10 • - smallest set of smallest rings ≤ 4 Lead-Like 50% of ChirBase compounds can be considered as lead-like (Compounds with a score <=1)

  23. Structural diversity of ChirBase compounds: comparison with Aldrich catalogue ChirBase diversity was compared with two files: • Aldrich precursor database • built from 20,000 chiral or achiral precursors (imported from Aldrich Web site) • Aldrich chiral database • Built from the full catalogue database (150,000 organic compounds, chiral + achiral) • From this database, we could extract 15,000 chiral compounds

  24. Structural diversity of ChirBase compared to Aldrich catalogue (precursor database) - Aldrich databases were merged with ChirBase using the « screening assistant » software - Diversity of the databases was estimated from a cluster analysis (using chemical descriptors and structural fragments) Diversity contribution of ChirBase when merged with Aldrich databases Aldrich + ChirBase = 48,000 compounds Aldrich + ChirBase = 45,000 compounds ChirBase 80% ChirBase 86% Chiral Aldrich 35% Aldrich precursor 40% 15-20% of each Aldrich database have features not represented in ChirBase * screening assistant » software available from ICOA UMR CNRS 6005 Université d’Orléans (France)

  25. Vizualisation of Aldrich and ChirBase chemical space (Principal component analysis of molecular descriptors) Aldrich / chiral Aldrich / precursors ChirBase ChirBase covers a larger chemical space

  26. Diverse ChirBase building blocks that are readily available by chiral liquid chromatography

  27. Introduction • ChirBase overview and statistics • ChirBase chiral pool: chemoinformatic applications • Building chiral combinatorial libraries • Extending current ChirBase chiral pool • Approach to the virtual synthesis of optically active targets • Searching precursors of chiral commercial drugs

  28. Constructing diverse chiral combinatorial libraries from ChirBase chiral pool • Jchem reactor module (*) was used to produce from ChirBase virtual reactions and create new chiral compounds Amine library Amide library Jchem reactor Chirbase Acide library (*) Chemaxon Ltd (www.chemaxon.com)  

  29. Constructing diverse chiral combinatorial libraries from ChirBase chiral pool 1502 amides Multiple asymmetric centers R-CONH-R’ 1415 chiral amines R-NH2 2974 chiral acides R’-COOH + Combined in sequential mode Amine1 + Acide1 Amine2 + Acide2 New amide library Stereochemical diversity in CombiChem 172 frameworks 284 frameworks 868 new frameworks

  30. Combinatorial amide library contains a diverse source of new chiral leads

  31. Extending the list of small chiral starting blocks accessible in ChirBase ChirBase contains a number of molecules that can be readily chemically cleaved. Examples are: esters amides urea carbamates sulphonamides Hydrolysis can release new chiral small molecules Amine library Acide library Alcohol library Extended chiral pool potentially available in ChirBase New small chiral molecule libraries

  32. New chiral building blocks can be obtained by combined chiral chromatography and reaction • Cleavage of protected and derivatized compounds provided a library of19,692 new chiral materialsaccessible by chiral chromatography 48,000 chiral compounds 96,000 enantiomers + = Reflect the full potential of ChirBase chiral pool

  33. New extended ChirBase chiral pool represents a rich source of small starting materials

  34. Synthesis from ChirBase chiral pool: a virtual case study Both enantiomers are desired: • (R)-enantiomer(dexecadotril): intestinal antisecretatory agent • (S)-enantiomer(ecadotril):cardiovascular activity TARGET Challenge: synthesis of the chiral mercaptoacyl precursor of the drug

  35. Synthesis from ChirBase chiral pool: a virtual case study • According to a review (*), chiral process still needs to be improved. • Different approaches have been studied: • Chiral pool 5 steps expensive from unnatural (R)-phenylalanine • Chemical resolution of racemic starting materials Target low yields (10 to 35%) (*) Thierry Monteil, Denis Danvy, Miryam Sihel, Richard Leroux and Jean-Christophe Plaquevent Mini Reviews in Medicinal Chemistry, 2002, 2, 209-217

  36. Target Synthesis from ChirBase chiral pool: a virtual case study • Enzymatic resolution high ee but: access to only one enantiomer / low yields • Asymmetric synthesis Synthesis through chiral chromatography was not evaluated difficult to use on a large scale / low yields / low ee

  37. Synthesis from ChirBase chiral pool: a virtual case study • Similarity search in Chirbase Fragment similarity search to find small precursors

  38. ChirBase chiral pool approach to synthesis of optically active targets : a virtual case study 13precursorsfound in ChirBase as: Chiralcel OD Chiralpak AD Chiralcel OC Chiralcel OJ Chiralcel OJ Separated on Chiralcel OJ chiral column Chiralcel OD Most interesting precursors

  39. Synthesis of (R)-dexecadotril and (S)-ecadotril: a new procedure suggested from ChirBase chiral pool - Deprotection - Peptide coupling acylation (R) Prep-Chiral HPLC -OJ (R) Enantiomer (dexecadotril) Racemate (S) - Deprotection - Peptide coupling acylation (S) Enantiomer (ecadotril)

  40. Conclusion Early-stage drug development Chirbase Chiral Pool expands the scope of the discovery route's toolbox Discovery syntheses De novo enantiopure chiral building blocks or intermediate materials not available Racemates are diverse, cheap and readily available Focus on delivery timeline Potential route to any chiral building block Well-established technology Multitude of sophisticated chiral technologies Short-time supply of the first grams of enantiomers diversity-driven Specific knowledge Costs of failure Low risk costs

  41. Conclusion It is important today to develop this way of thinking about chiral chromatography in discovery labs and stimulate chemists to take advantage of these readily available chiral materials in their retrosynthetic schemes or CombiChem (Stereochemical diversity or ligand screening). The cpds are available by chiral chromatography. The CHIRBASE molecular files in ISIS-format can be exported to any Computer Assisted Synthesis Software or Properties Evaluation Software

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