Signposts to Chiral Drugs (eBook)

1. Organic synthesis in drug discovery and development1.      Introduction2.      Synthetic organic chemistry in drug R&D process3.      New concepts in drug discovery process         3.1.   The impact of natural products upon modern drug discovery3.2.    Biology oriented and DNA-templated synthesis in drug discovery         3.3.   Incorporation of genomics in drug discovery4.      ConclusionReferences2. Aliskiren fumarate 1.                 Introduction2.            Renin and the mechanism of action of aliskiren3.            Structural characteristics and synthetic approaches to aliskiren3.1       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 enantioselectivities4.            ConclusionReferences 3. (R)-K-136753.1   Introduction3.2   Peroxisome proliferator-activated receptor a (PPARa) agonists.3.2.1 b-Phenylpropionic acids3.2.2 a-Alkoxy-b-arylpropionic acids3.2.3 a-Aryloxy-b-phenyl propionic acids.3.2.4 Oxybenzoylglycine derivatives.3.3 Non-hydrolytic anomalous lactone ring-opening3.4 Mitsunobu reaction in the ether bond formation3.5 ConclusionReferences 4. Sitagliptin phosphate monohydrate4.1 Introduction4.2 Endogenous glucoregulatory peptide hormones and dipeptidyl peptidase IV (DPP4) inhibitors 4.3 Synthesis with C-acyl mevalonate as the N-acylating agent4.4   Highly enantioselective hydrogenation of unprotected b-enamino amides and the use of Josiphos-ligands4.5 Ammonium chloride, an effective promoter of catalytic enantioselective hydrogenation4.6 Conclusion References 5. Biaryl unit in valsartan and vancomycin  5.1 Introduction5.2   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 vancomycin5.5 ConclusionReferences 6. 3-Amino-1,4-benzodiazepines 6.1 Introduction6.2 3-Amino-1,4-benzodiazepine derivatives, g-secretase inhibitors6.3 Configurational stability; racemization and enantiomerization6.4 Crystallization induced asymmetric transformation6.5 Asymmetric Ireland-Cleisen rearrangement6.6 Hydroboration of the terminal C=C bond; anti-Markovnikov hydratation6.7 Crystallization-induced asymmetric transformation in the synthesis of L-768,6736.8 ConclusionReferences 7. Sertraline7.1 Introduction7.2 Synaptosomal serotonin uptake and its selective inhibitors (SSRI)7.3 Action of sertraline and its protein target7.4 General synthetic route7.5 Stereoselective reduction of ketones and imines under kinetic and thermodynamic control7.5.1 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 process7.5.2 Kinetic resolution of racemic methylamine; hydrosylilation by (R,R)-(EBTHI)TiF2 /PhSiH3 catalytic system7.5.3 Catalytic epimerization of the trans- to the cis-isomer of sertraline7.5.4 Stereoselective reduction of tetralone by chiral diphenyloxazaborolidine7.6. Desymmetrization of oxabenzonorbornadiene, Suzuki coupling of arylboronic acids and vinyl halides7.7 Pd-Catalyzed (Tsuji-Trost) coupling of arylboronic acids and allylic esters7.8 Simulated moving bed (SMB) in the commercial production of sertraline7.9 ConclusionReferences 8. 1,2-Dihydroquinolines8.1 Introduction8.2       Glucocorticoid receptor (GCR)8.3 Asymmetric organocatalysis; introducing a thiourea catalyst for Petasis   reaction8.3.1 General consideration of the Petasis reaction8.3.2 Catalytic,  enantioselective Petasis reaction8.4 Multicomponent reactions (MCRs); general concept and examples8.4.1 General concept of MCRs8.4.2 Efficient, isocyanide-based Ugi MCRs8.5 ConclusionReferences 9. (-)-Menthol9.1 Introduction9.2. 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 enantiomers9.5 ConclusionReferences 10. Fexofenadine hydrochloride10.1 Introduction10.2 Histamine receptors as biological targets for antiallergy drugs10.3 Absolute configuration and “racemic switch”10.4 Retrosynthetic analysis of fexofenadine10.4.1 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 ConclusionReferences 11. Montelukast sodium11.1 Introduction11.2 Leukotriene D4 receptor (LTD4), CysLT-1 receptor, antagonists11.3 Hydroboration of ketones with boranes from ?-pinenes and the non-linear effect (NLE) in asymmetric reactions11.4 Ru(II) catalyzed enantioselective hydrogen transfer11.5 Biocatalytic reduction with ketoreductase KRED (KetoREDuctase)11.6 CeCl3-THF solvate as a promoter of the Grignard reaction; phase transfer catalysis11.7 ConclusionReferences 12. Thiolactone peptides as antibacterial peptidomimetics12.1. Introduction12.2 Virulence and quorum sensing system of Staphylococcus aureus.12.3 Development of chemical ligation (CL) in peptide synthesis12.4  Development of native chemical ligation (NCL); chemoselectivity in peptide synthesis12.5  Development of NCL  in thiolactone peptide synthesis12.6 ConclusionReferences 13. Efavirenz13.1 Introduction13.2 HIV-1 reverse transcriptase (RT) inhibitors13.2.1 Steric interactions at the active site13.3 Asymmetric addition of alkyne anion to C=O bond with formation of chiral Li+ aggregates13.3.1 Mechanism of the chirality transfer13.3.2 Equilibration of lithium aggregates and the effect of their relative stability on enantioselectivity13.4 Scale-up of alkynylation promoted by the use of Et2Zn.  13.5 ConclusionReferences 14. Paclitaxel14.1 Introduction 14.2 Disturbed dynamics of cellular microtubules by binding to ß-tubulin14.2  Three selected synthetic transformations on the pathway to paclitaxel14.3 Three selected synthetic transformations on the pathway to paclitaxel14.3.1 Intramolecular Heck reaction on the synthetic route to baccatin III14.3.2 Trifunctional catalyst for biomimetic synthesis of chiral diols; synthesis of the paclitaxel side-chain14.3.3 Zr-complex catalysis in the reductive N-deacylation of taxanes to the primary amine, the key precursor of paclitaxel14.4 ConclusionReferences 15. Neoglycoconjugate 15.1 Introduction15.2 Human a-1,3-fucosyltransferase (Fuc-T)15.3 Click chemistry, energetically preferred reactions15.4 Target-guided synthesis (TGS) or freeze-frame click chemistry15.5 Application of click chemistry to the synthesis of nucleoconjugate 115.6 ConclusionReferences 16. 12-Aza epothilones16.1 Introduction16.2 Epothilones; mechanism of action and structure-activity relationships16.3. Extensive versus peripheral structural modifications of natural products16.4  Ring closure metathesis (RCM), an efficient  approach to mac rocyclic “non-natural natural-products”16.5Diimide reduction of the allylic C=C bond16.6ConclusionReferences