Main description:

Highlighting 15 selected chiral structures, which represent candidate or marketed drugs, and their chemical syntheses, the authors acquaint the reader with the fascinating achievements of synthetic and medicinal chemistry.

The book starts with an introduction treating the discovery and development of a new drug entity. Each of the 15 subsequent chapters presents one of the target structures and begins with a description of its biological profile as well as any known molecular mechanisms of action, underlining the importance of its structural and stereochemical features. This section is followed by detailed discussions of synthetic approaches to the chiral target structure, highlighting creative ideas, the scaling-up of laboratory methods and their replacement by efficient modern technologies for large-scale production. Nearly 60 synthetic reactions, most of them stereoselective, catalytic or biocatalytic, as well as chiral separating methodologies are included in the book.

Vitomir Sunjic and Michael J. Parnham provide an invaluable source of information for scientists in academia and the pharmaceutical industry who are actively engaged in the interdisciplinary development of new drugs, as well as for advanced students in chemistry and related fields.

Contents:

1. Organic synthesis in drug discovery and development

1. Introduction

2. Synthetic organic chemistry in drug R&D process

3. New concepts in drug discovery process

3.1. The impact of natural products upon modern drug discovery

3.2. Biology oriented and DNA-templated synthesis in drug discovery

3.3. Incorporation of genomics in drug discovery

4. Conclusion

References

2. Aliskiren fumarate

1. Introduction

2. Renin and the mechanism of action of aliskiren

3. Structural characteristics and synthetic approaches to aliskiren

3.1 Strategy based on visual imagery, starting from Nature's chiral pool; a Dali-like presentation of objects

3.2 Fine-tuning of the chiral ligand for the Rh complex; hydrogenation of the selected substrate with extreme enantioselectivities

4. Conclusion

References

3. (R)-K-13675

3.1 Introduction

3.2 Peroxisome proliferator-activated receptor a (PPARa) agonists.

3.2.1 b-Phenylpropionic acids

3.2.2 a-Alkoxy-b-arylpropionic acids

3.2.3 a-Aryloxy-b-phenyl propionic acids.

3.2.4 Oxybenzoylglycine derivatives.

3.3 Non-hydrolytic anomalous lactone ring-opening

3.4 Mitsunobu reaction in the ether bond formation

3.5 Conclusion

References

4. Sitagliptin phosphate monohydrate

4.1 Introduction

4.2 Endogenous glucoregulatory peptide hormones and dipeptidyl peptidase IV (DPP4) inhibitors

4.3 Synthesis with C-acyl mevalonate as the N-acylating agent

4.4 Highly enantioselective hydrogenation of unprotected b-enamino amides and the use of Josiphos-ligands

4.5 Ammonium chloride, an effective promoter of catalytic enantioselective hydrogenation

4.6 Conclusion

References

5. Biaryl unit in valsartan and vancomycin

5.1 Introduction

5.2 Angiotensin AT1 receptor, G-protein coupled receptors (GPCRs).

5.3 Cu-promoted catalytic decarboxylative biaryl synthesis, biomimetic type aerobic decarboxylation

5.4 Stereoselective approach to axially chiral biaryl system; the case of vancomycin

5.5 Conclusion

References

6. 3-Amino-1,4-benzodiazepines

6.1 Introduction

6.2 3-Amino-1,4-benzodiazepine derivatives, g-secretase inhibitors

6.3 Configurational stability; racemization and enantiomerization

6.4 Crystallization induced asymmetric transformation

6.5 Asymmetric Ireland-Cleisen rearrangement

6.6 Hydroboration of the terminal C=C bond; anti-Markovnikov hydratation

6.7 Crystallization-induced asymmetric transformation in the synthesis of L-768,673

6.8 Conclusion

References

7. Sertraline

7.1 Introduction

7.2 Synaptosomal serotonin uptake and its selective inhibitors (SSRI)

7.3 Action of sertraline and its protein target

7.4 General synthetic route

7.5 Stereoselective reduction of ketones and imines under kinetic and thermodynamic control

7.5.1 Diastereoselectivity of hydrogenation of rac-tetralone-methylimine; the old (MeNH2/TiCl4/toluene) method is improved by using MeNH2/EtOH-Pd/CaCO3, 60-65 oC in a telescoped process

7.5.2 Kinetic resolution of racemic methylamine; hydrosylilation by (R,R)-(EBTHI)TiF2 /PhSiH3 catalytic system

7.5.3 Catalytic epimerization of the trans- to the cis-isomer of sertraline

7.5.4 Stereoselective reduction of tetralone by chiral diphenyloxazaborolidine

7.6. Desymmetrization of oxabenzonorbornadiene, Suzuki coupling of arylboronic acids and vinyl halides

7.7 Pd-Catalyzed (Tsuji-Trost) coupling of arylboronic acids and allylic esters

7.8 Simulated moving bed (SMB) in the commercial production of sertraline

7.9 Conclusion

References

8. 1,2-Dihydroquinolines

8.1 Introduction

8.2 Glucocorticoid receptor (GCR)

8.3 Asymmetric organocatalysis; introducing a thiourea catalyst for Petasis reaction

8.3.1 General consideration of the Petasis reaction

8.3.2 Catalytic, enantioselective Petasis reaction

8.4 Multicomponent reactions (MCRs); general concept and examples

8.4.1 General concept of MCRs

8.4.2 Efficient, isocyanide-based Ugi MCRs

8.5 Conclusion

References

9. (-)-Menthol

9.1 Introduction

9.2. Natural sources and first technological production of (-)-menthol

9.3 Enantioselective allylic amine-enamine-imine rearrangement, catalysed by Rh(I)-(-)-BINAP complex.

9.4 Production scale synthesis of both enantiomers

9.5 Conclusion

References

10. Fexofenadine hydrochloride

10.1 Introduction

10.2 Histamine receptors as biological targets for antiallergy drugs

10.3 Absolute configuration and "racemic switch"

10.4 Retrosynthetic analysis of fexofenadine

10.4.1 ZnBr2-Catalyzed rearrangement of a-haloketones to terminal carboxylic acids

10.4.2 Microbial oxidation of non-activated C-H bond.

10.4.3 Bioisosterism; silicon switch of fexofenadine to sila-fexofenadine

10.5 Conclusion

References

11. Montelukast sodium

11.1 Introduction

11.2 Leukotriene D4 receptor (LTD4), CysLT-1 receptor, antagonists

11.3 Hydroboration of ketones with boranes from ?-pinenes and the non-linear effect (NLE) in asymmetric reactions

11.4 Ru(II) catalyzed enantioselective hydrogen transfer

11.5 Biocatalytic reduction with ketoreductase KRED (KetoREDuctase)

11.6 CeCl3-THF solvate as a promoter of the Grignard reaction; phase transfer catalysis

11.7 Conclusion

References

12. Thiolactone peptides as antibacterial peptidomimetics

12.1. Introduction

12.2 Virulence and quorum sensing system of Staphylococcus aureus.

12.3 Development of chemical ligation (CL) in peptide synthesis

12.4 Development of native chemical ligation (NCL); chemoselectivity in peptide synthesis

12.5 Development of NCL in thiolactone peptide synthesis

12.6 Conclusion

References

13. Efavirenz

13.1 Introduction

13.2 HIV-1 reverse transcriptase (RT) inhibitors

13.2.1 Steric interactions at the active site

13.3 Asymmetric addition of alkyne anion to C=O bond with formation of chiral Li+ aggregates

13.3.1 Mechanism of the chirality transfer

13.3.2 Equilibration of lithium aggregates and the effect of their relative stability on enantioselectivity

13.4 Scale-up of alkynylation promoted by the use of Et2Zn.

13.5 Conclusion

References

14. Paclitaxel

14.1 Introduction

14.2 Disturbed dynamics of cellular microtubules by binding to ss-tubulin

14.2 Three selected synthetic transformations on the pathway to paclitaxel

14.3 Three selected synthetic transformations on the pathway to paclitaxel

14.3.1 Intramolecular Heck reaction on the synthetic route to baccatin III

14.3.2 Trifunctional catalyst for biomimetic synthesis of chiral diols; synthesis of the paclitaxel side-chain

14.3.3 Zr-complex catalysis in the reductive N-deacylation of taxanes to the primary amine, the key precursor of paclitaxel

14.4 Conclusion

References

15. Neoglycoconjugate

15.1 Introduction

15.2 Human a-1,3-fucosyltransferase (Fuc-T)

15.3 Click chemistry, energetically preferred reactions

15.4 Target-guided synthesis (TGS) or freeze-frame click chemistry

15.5 Application of click chemistry to the synthesis of nucleoconjugate 1

15.6 Conclusion

References

16. 12-Aza epothilones

16.1 Introduction

16.2 Epothilones; mechanism of action and structure-activity relationships

16.3. Extensive versus peripheral structural modifications of natural products

16.4 Ring closure metathesis (RCM), an efficient approach to mac rocyclic "non-natural natural-products"

16.5Diimide reduction of the allylic C=C bond

16.6Conclusion

References