Signposts to Chiral Drugs: Organic Synthesis in Action

ISBN-13: 9783034807708 / Angielski / Miękka / 2014 / 232 str.

Vitomir Sunjic;Michael J Parnham

Opis

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.

Recenzje

From the reviews:

"In this timely book, Sunjic and Parnham provide an exciting selection of major achievements in drug development and unfold 15 intriguing success stories of aliskiren, vancomycin, paclitaxel, menthol, efavirenz, and others from the perspective of a medicinal chemist. ... This book will be most appealing to undergraduate and graduate students with an interest in synthesis and stereochemistry ... . it should be considered an instructive teaching supplement that underscores the general significance and impact of creative synthetic chemistry and stimulates further discussion in the classroom." (Christian Wolf, Journal of the American Chemical Society, September, 2011)

"The subject of the book are chiral drugs. ... Each chapter can be read separately and consists of an abstract, introduction, the main part with the synthetic approach to a certain drug, conclusion and references. ... References are relevant and up-to date. A long list of abbreviations and acronyms is provided at the beginning ... . The book will be very useful to synthetic organic and medicinal chemists in innovative pharmaceutical companies and to scientists and ambitious students of chemistry and pharmacy." (Branka Zorc, Acta Pharmaceutica, Vol. 61, 2011)

"This ... volume will be of interest to those working in synthetic organic chemistry, particularly in the medicinal chemistry area, and having as their aim the discovery of new drug entities for the pharmaceutical industries. ... there is also a useful summary of synthetic methods and concepts that are developed in the individual chapters, together with a useful index. The standard of presentation is very high, with many clearly presented reaction schemes, and each chapter has a comprehensive list of references to the specific area." (D. W. Allen, Inflammopharmacology, Vol. 19, 2011)

Spis treści

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