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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
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
• Introduction
  – Advantages of chiral chromatography
  – Comparison of chiral methods
  – Industrial examples
• ChirBase: overview and statistics
• ChirBase chiral pool: chemoinformatic
  applications
               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 blocks or
    synthons
    -stereochemical diversity for CombiChem
           Introduction: Chiral chromatography


• Advantages of chromatography
  – Availability of all the enantiomers of a given
    chiral compound
  – Speed up early development works: fast access to
    milligrams of both enantiomers (100% pure)
  - Production: multi-kilogram scale can be readily
    obtained (industrial simulated moving-bed)
  - Undesired enantiomer can be racemized and
    recycled to obtain 100% of the targeted
   enantiomer
               Comparison of chiral methods(*)




                                                            Chiral chromatography
                                                              can compete with
                                                                other strategies




(*) Conference presented At ChemWeek Innovation in Technologies (September 10,
     2002) by Thomas Archibald (VP Research and Innovation Rhodia Chirex)
        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
O                         crystallization using 1S Camphorsulfonic
                          acid (benzenesulfonyl)hydrazone or chiral
    N
                          dipalladium complexes ( yield 77-86 %, ee
        P                 > 96%).
N
                      •   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
              Example: Asymmetric synthesis / Chiral HPLC




          O        O
                            •   O. Fujimura (J. Am. Chem.
                                Soc., 1998, 120, 10032-10039)
                       O        reported on the
                                enantioselective aldol
                                condensation using several
                                Platinium BINAP catalysts (ee
                                from 46% to 88%)
               O            •   In sup. mat. the
O       O                       chromatograms on
                                CHIRALPAK AD column are
                                reported as ee determination
Ph PhO                          proof. Rt: 11.3 / 22.9 min. and
    P                           8 / 23 min. respectively
     Pt                     •   Obviously preparative CHIRAL
          O
    P                           HPLC is a short way to have
Ph Ph                           the two enantiomers in hands
                                for further applications.
    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-
              O
                      lactones.
       O          •   In the experimental part, the ee
                      determination is reported on
                      CHIRALCEL OD with Rt (R): 14.1
                      and Rt (S): 23 min.
O
                  •   Obviously preparative CHIRAL
                      HPLC is a short way to have
                      the two enantiomers in hands
                      for further applications.
        Example: Racemic synthesis at early stage
                 development (GlaxoSmithKline )
               When chromatography is the quickest route

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
                                                           N

                  F                                    N
                                Preparative                               F
                      F         Chiral HPLC                                   F
              N   F
    O             O                                                  N    F
                      O                                    O              O
                                                                              O
                          O   (Chiralcel OJ)
                                                                                  O

                                                     (S)-enantiomer was isolated


 • In 2004: Preclinical, asymmetric synthesis for commercial
   process (US Patent 6825188 Nov 2004)
  Example: Industrial process (Pfizer Sertraline)

                When chromatography is the most economical route

                    O                                       O
                               Chiral Chromatography
                                        SMB                                         N
                                                                       MeNH2/EtOH
                                                                 (S)
   Cheap                                                                                 (S)
Rac-Tetralone
                          Cl                                       Cl
                    Cl                                      Cl
                                                                                          Cl
                                                             O                      Cl

                                                                                         Pd/CaCO3
  Low cost                               Racemization             (R)                    H2/EtOH
   racemic
  synthesis              AlCl3           (R) Is recycled
                                                                       Cl           N    (S)
                                                             Cl
                O                                                                              Sertraline
                                                                                         (S)
                                          No superior asymmetric synthesis
                                          process yet found (Quallich G.J.,
                                          Chirality 17:S120-S126, 2005)
                                   Cl                                                     Cl
                            Cl                                                      Cl
• 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
                   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
ChirBase database overview


                     Multiple
                     criteria
                      result
                      forms


                    Searchable
                     Chemical
                    structures


                     Detailed
                   experimental
                  conditions and
                      results



                   Full reference
                       ChirBase database overview

   Query assistant
  and dialog boxes
to help novice users
      to build
 advanced queries
                                 Chirbase statistics
                                 Release July-2005

    Chiral           112,154                83,000
  separations        ( total )           ( commercial )


 Unique chiral        32,451                64,902
 compounds       chiral compounds         enantiomers

                      30,800                61,600
   Resolved
                 chiral compounds         enantiomers

  Available by        28,000                56,000
  preparative
chromatography   chiral compounds         enantiomers
                         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
          Distribution of ChirBase compounds by
                                   chemical class
        cyanohydrins     186
      oxazolidinones      436
  beta-hydroxy acids       567
         halohydrins       586
                                                                  Large choice
              epoxys           838
                                                                 of optically pure
             lactones           1014
                                                                 chiral precursors
 alpha-hydroxy acids             1256
  amines prim. (NH2)                 1415
  beta-amino alcohol                  1644
            lactames                        2251
      acides (COOH)                                2974
       ketones (C=0)                                  3620
         amino acids                                      3715
amines tert (N-RR'R'')                                       4349
  amines sec (NH-R)                                                           7573
  amides (C=O-NH2)                                                              7958
       esters (COOR)                                                                   9948
             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




                        Lipinski rule
                        MW <= 500




        Chirbase                                      Aldrich catalogue
28,000 chiral compounds                            15,000 chiral compounds

         * screening assistant » software available from ICOA UMR CNRS 6005
         Université d’Orléans (France)
Drug-Like property statistics in ChirBase




        Lipinski rule
        H-acceptor <= 10                        Lipinski rule
                                                H-donor <= 5




             Lipinski rule
             LogP <= 5
                                For most compounds,
                             Lipinski’s rules are satisfied
                    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
        Only one green property is not satisfied       - logP ≤ 7
                                                       - H donors ≤ 5
      Drug-Like                                        - rotatable bonds ≤ 15
                                                       - no reactive functions (eliminate false
                                                       positives)
             No unsatisfied property                   - 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


        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)
               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:
     Lead-Like                           - molecular weight ≤ 400 g.mol-1
                                         - logP ≤ 4.2
                                         - H acceptors ≤ 9
                                         - rotatable bonds ≤ 10
                                         - smallest set of smallest rings ≤ 4




        50% of ChirBase compounds can be
considered as lead-like (Compounds with a score <=1)
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
               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 =                               Aldrich + ChirBase =
                            ChirBase                                           ChirBase
      48,000 compounds                                   45,000 compounds
                              80%                                                86%



                                                          Chiral
         Aldrich
                                                          Aldrich
        precursor
                                                           35%
           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)
           Vizualisation of Aldrich and ChirBase chemical space
        (Principal component analysis of molecular descriptors)


                                      Aldrich / chiral
Aldrich / precursors




                       ChirBase
                                                            ChirBase
                                                             covers
                                                            a larger
                                                         chemical space
                     Diverse ChirBase building blocks that are readily
                            available by chiral liquid chromatography
                 O           O
                                                                                                                                      O
                     N
                                 O                        O                       O
                                                                                                                                                                                             H
         O                                        O
                                                                                                      O                                                      O
     O                                        O                                                                       O
                     O               O                            O                                                                            O
                                                                                                                                                                                     O
                                                              O           O                           N           O       O                                              O           O
                                                                                                                                                   O
                                                                                                                              O                         Cl
                                     Cl                                                                                   N
 O                                                                                                N                                                                      O                           O
         N                                                        O                                                                        O                                         N
                         O       O                                                        N                                                                  O
                                                                                                                                                                                                 O
                                                          N                                                                                                                              N
Cl                                                                                                        N                                                                  O
             O                                                            O                                                                             O
                                          N           O                                                       N                                    O
                                                                                                                                                                     N
                                                                                          O                                                                                  N       N
                                                                                                      O
 O
                                                              O                                                                                    Cl
                                     N                                                                    O
                             O                        O                                                                                                                          N
                                                                                                                                                                                         O
                                                                                                                                                         O       H
             O                                                                                                                         O
                                                                      O                                                                                                                  O
                                                                                                                                                                                                     O
                                                                                  O           O
                                                  N                   S                                                           O
             O                   O                                        N                                                                                                                  N
                                                                                                  O                       O                        O                     N

                         N                    O           O           O
                                                                                                                              O                                                      O
             N                                        O                                                                                                                  O
                                          O                                   O                   N
     N
                     O                                                O                                                               Cl                         O
                             N                                                                                O
O                                                                                     O
                                                                                                                                                                                                 O
• 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
      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                     H

                                            N
                                                H

                                    O


                                        O


                                                                N       N
                        Amine     Jchem reactor
                        library                         O
                                                                    O



                                                            O               Amide
                                                                            library
Chirbase                                            H
                        Acide                       O
                        library         N

                                            O




    (*) Chemaxon Ltd (www.chemaxon.com)
     Constructing diverse chiral combinatorial libraries
                             from ChirBase chiral pool


1415 chiral               2974 chiral                                    1502 amides
                                                                      Multiple asymmetric
  amines                    acides
   R-NH2       +           R’-COOH
                                                                             centers
                                                                          R-CONH-R’
                                                     Combined in
                                                   sequential mode
                                                   Amine1 + Acide1     New amide library
                                                   Amine2 + Acide2



                 Diversity creation
      172                                          284           Stereochemical
  frameworks                                   frameworks
                 Amines
                                                                 diversity in
                                      Acides                     CombiChem
   868 new
 frameworks


               Amides
                Combinatorial amide library contains a diverse
                                   source of new chiral leads
    F                                                       O
                                N
                                                N
            O              O                    N       N

                                                                N
                     O
                                                            O   N
                               O
                                                                        O
                                                            O   O
                                                O
            N                           N
                                            N
                                                                                N
        O                   O                   O                   N
                N                                                               O
                                   O        O
                                                                        N
                            O       +               N
                                   N
O                                                                           O
                                   O
                                                                    N
           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:

  O            O                    O                         O                  O
                                                                                 S
      O            N            N         N               O       N          N       O


esters       amides             urea                     carbamates       sulphonamides



                                                                        Hydrolysis can release
                                                                      new chiral small molecules




                      Amine     Acide         Alcohol
                      library   library        library
                                                                             Extended chiral pool
                   New small chiral molecule                                 potentially available
                          libraries                                              in ChirBase
        New chiral building blocks can be obtained by
        combined chiral chromatography and reaction

 • Cleavage of protected and derivatized compounds
   provided a library of 19,692 new chiral materials
   accessible by chiral chromatography

60000
                                                             48,000 chiral compounds

50000                                               Total



40000
                                                               96,000 enantiomers
        ChirBase chiral
30000        pool

                              extended chiral
                                   pool
20000

                          +                     =
10000                                                       Reflect the full potential
                                                            of ChirBase chiral pool

   0
            New extended ChirBase chiral pool represents a rich
                             source of small starting materials
                O                        N
                                                                                                                                              O
                                                                     O
                                                             O                               Si                                                       O
                                             N                                                            N   O
                N                    N
O                                                                                                                             N
                                                                                                      N                                           N
                                                                         N
    O                        O                                                               N                                            O
                                             O
        N                                                                    O
                                                         O                                            N                                           N
                        O                                                                                             N
                                                                                                                                  N
                    O                                                            N                            O
                                                                 N
                                                 O                                                                    O
                                                                                                  N
            N                    N
                                                                                                                          N
O
                            Cl           O                   H                                                                        N
                                                                                                      O
                                                     O               S       O
                                                                                                          N                           O       N
    N
                                                                                     O                                    O
                        N                            O                       N                                    O
                                                                                         N
                                     O                       O                   O                O   O                   N

                                             O                                                            O
        O           O                                                O                                            O                       O
                                                                                                              O
        O           F                                                                             N
                                     N                   N                           O
                                                                                                                          N
                                        Synthesis from ChirBase chiral pool:
                                                        a virtual case study
O                               Both enantiomers are desired:
    S   O                       •       (R)-enantiomer (dexecadotril): intestinal
                    O
            N                           antisecretatory agent
                O
                                •       (S)-enantiomer (ecadotril): cardiovascular
                                        activity


                               O

                                    S     O

                                              OH
                                                   +              O
                                                       H2 N
                                                              O


                                        TARGET



                Challenge: synthesis of the chiral mercaptoacyl
                             precursor of the drug
                                     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                                 O
                                                                                                 O
         – Chemical resolution of racemic starting                                          S
         materials                                                                                   OH



                                                                                                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
                            Synthesis from ChirBase chiral pool:
                                            a virtual case study

    – Enzymatic resolution                                      O

                                                                    S    O

                                                                             OH



                                                                        Target

 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
                          Synthesis from ChirBase chiral pool:
                                          a virtual case study
•   Similarity search in Chirbase




            Fragment similarity search to find small precursors
           ChirBase chiral pool approach to synthesis of optically
                              active targets : a virtual case study
13 precursors found in ChirBase as:
   O

                     O   O                         O
       S                                   S
                                                              O                     O
                                                                      S
                                               O
                                                O
                         S
                                                              S
       O                                   O
                         Si
                                                                                    S



 Chiralcel OD       Chiralpak AD   Chiralcel OC            Chiralcel OJ           Chiralcel OJ
           S
                                                                          O
                                               O

                                                                  S           O
                                   S                   O
           O




                                       Separated on Chiralcel OJ chiral column
   Chiralcel OD
                                          Most interesting precursors
            Synthesis of (R)-dexecadotril and (S)-ecadotril: a new
                 procedure suggested from ChirBase chiral pool
                          O                                                        O
                                                    O   O

                  S           O                                  - Deprotection        S     O
                                        acylation   S       O - Peptide coupling                         O
                                                                                                 N
                                                                                                     O
                          (R)

        O
                                                                                           (R) Enantiomer
S           O
                       Prep-Chiral                                                          (dexecadotril)
                       HPLC -OJ

    Racemate
                          (S)                                                      O

                              O                     O   O                              S     O
                                                                  - Deprotection
                                                                  - Peptide coupling                     O
                                      acylation                                                  N
                   S              O                 S        O
                                                                                                     O


                                                                                             (S) Enantiomer
                                                                                              (ecadotril)
                                                     Conclusion
                                                       Chirbase Chiral Pool
  Discovery syntheses         Early-stage              expands the scope of
                                 drug                  the discovery route's
                              development                     toolbox



De novo enantiopure chiral
         building                                  Racemates are diverse, cheap and
  blocks or intermediate                                  readily available
  materials not available
                                Focus on
                                 delivery
                                 timeline
                                                 Potential route
                                                 to any chiral       Well-established
                                                 building block      technology
Multitude of sophisticated
   chiral technologies



                             diversity-driven   Short-time supply
 Specific         Costs of                      of the first grams         Low risk
knowledge          failure                       of enantiomers             costs
                                  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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