Signposts to Chiral Drugs, 2011 Organic Synthesis in Action

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.

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