Accessing the Expanded Chiral Pool using ChirBase Molecular Database
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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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Chirality u 3mrs fr chirbase u 3mrs fr

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


Contents

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


Chirality u 3mrs fr chirbase u 3mrs fr

  • Introduction

    • Advantages of chiral chromatography

    • Comparison of chiral methods

    • Industrial examples

  • ChirBase: overview and statistics

  • ChirBase chiral pool: chemoinformatic applications


Introduction chiral chromatography

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


Introduction chiral chromatography1

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


Comparison of chiral methods

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


Example resolution via crystallization chiral hplc

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


Example asymmetric synthesis chiral hplc

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.


Example enzymatic resolution chiral hplc

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.


Example racemic synthesis at early stage development glaxosmithkline

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


Example industrial process pfizer sertraline

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)


Chirality u 3mrs fr chirbase u 3mrs fr

  • 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

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 overview1

ChirBase database overview

Multiple

criteria

result

forms

Searchable

Chemical

structures

Detailed experimental conditions and results

Full reference


Chirbase database overview2

Query assistant

and dialog boxes

to help novice users

to build

advanced queries

ChirBase database overview


Chirbase statistics release july 2005

Chirbase statisticsRelease July-2005


Existing databases of commercially available chiral chemicals

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

Distribution of ChirBase compounds by chemical class

Large choice

of optically pure

chiral precursors


Molecular weight distribution

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)


Drug like property statistics in chirbase

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


Drug like distribution in chirbase

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)


Lead like distribution in chirbase

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)


Structural diversity of chirbase compounds comparison with aldrich catalogue

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

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)


Chirality u 3mrs fr chirbase u 3mrs fr

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

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


Chirality u 3mrs fr chirbase u 3mrs fr

  • 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

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)  


Constructing diverse chiral combinatorial libraries from chirbase chiral pool1

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


Combinatorial amide library contains a diverse source of new chiral leads

Combinatorial amide library contains a diverse source of new chiral leads


Extending the list of small chiral starting blocks accessible in chirbase

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


Chirality u 3mrs fr chirbase u 3mrs fr

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


New extended chirbase chiral pool represents a rich source of small starting materials

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


Synthesis from chirbase chiral pool a virtual case study

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


Synthesis from chirbase chiral pool a virtual case study1

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


Synthesis from chirbase chiral pool a virtual case study2

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


Synthesis from chirbase chiral pool a virtual case study3

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

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


Synthesis of r dexecadotril and s ecadotril a new procedure suggested from chirbase chiral pool

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)


Conclusion

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


Conclusion1

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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