Signposts to Chiral Drugs
Organic Synthesis in Action
(Sprache: Englisch)
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...
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Produktinformationen zu „Signposts to Chiral Drugs “
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.
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.
Klappentext zu „Signposts to Chiral Drugs “
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.
Inhaltsverzeichnis zu „Signposts to Chiral Drugs “
1. Organic synthesis in drug discovery and development1. 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
... mehr
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-Dihydroquinolines8.1 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 (-)-menthol9.3 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-fexofenadine10.5 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. Introduction12.2 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
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-Dihydroquinolines8.1 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 (-)-menthol9.3 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-fexofenadine10.5 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. Introduction12.2 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
... weniger
Bibliographische Angaben
- Autoren: Michael Parnham , Vitomir Sunjic
- 2011, 2011, 252 Seiten, Masse: 16 x 24,1 cm, Gebunden, Englisch
- Verlag: Springer Basel AG
- ISBN-10: 3034801246
- ISBN-13: 9783034801249
- Erscheinungsdatum: 12.05.2011
Sprache:
Englisch
Rezension zu „Signposts to Chiral Drugs “
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)
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