Signposts to Chiral Drugs

<p>1. Organic synthesis in drug discovery and development</p><p>1.      Introduction</p><p>2.      Synthetic organic chemistry in drug R&amp;D process</p><p>3.      New concepts in drug discovery process</p><p>         3.1.   The impact of natural products upon modern drug discovery</p><p>3.2.    Biology oriented and DNA-templated synthesis in drug discovery</p><p>         3.3.   Incorporation of genomics in drug discovery</p><p>4.      Conclusion</p><p>References</p><p>2. Aliskiren fumarate</p><p> </p><p>1.                 Introduction</p><p>2.            Renin and the mechanism of action of aliskiren</p><p>3.            Structural characteristics and synthetic approaches to aliskiren</p><p>3.1       Strategy based on visual imagery, starting from Nature’s chiral pool; a Dali-like presentation of objects </p><p>3.2 Fine-tuning of the chiral ligand for the Rh complex; hydrogenation of the selected substrate with extreme enantioselectivities</p><p>4.            Conclusion</p><p>References</p><p> </p><p>3. (R)-K-13675</p><p>3.1   Introduction</p><p>3.2   Peroxisome proliferator-activated receptor a (PPARa) agonists.</p><p>3.2.1 b-Phenylpropionic acids</p><p>3.2.2 a-Alkoxy-b-arylpropionic acids</p><p>3.2.3 a-Aryloxy-b-phenyl propionic acids.</p><p>3.2.4 Oxybenzoylglycine derivatives.</p><p>3.3 Non-hydrolytic anomalous lactone ring-opening</p><p>3.4 Mitsunobu reaction in the ether bond formation</p><p>3.5 Conclusion</p><p>References</p><p> </p><p>4. Sitagliptin phosphate monohydrate</p><p>4.1 Introduction</p><p>4.2 Endogenous glucoregulatory peptide hormones and dipeptidyl peptidase IV (DPP4) inhibitors </p><p>4.3 Synthesis with C-acyl mevalonate as the N-acylating agent</p><p>4.4   Highly enantioselective hydrogenation of unprotected b-enamino amides and the use of Josiphos-ligands</p><p>4.5 Ammonium chloride, an effective promoter of catalytic enantioselective hydrogenation</p><p>4.6 Conclusion </p><p>References</p><p> </p><p>5. Biaryl unit in valsartan and vancomycin  </p><p>5.1 Introduction</p><p>5.2   Angiotensin AT1 receptor, G-protein coupled receptors (GPCRs).</p><p>5.3 Cu-promoted catalytic decarboxylative biaryl synthesis, biomimetic type aerobic decarboxylation </p><p>5.4 Stereoselective approach to axially chiral biaryl system; the case of vancomycin</p><p>5.5 Conclusion</p><p>References</p><p> </p><p>6. 3-Amino-1,4-benzodiazepines </p><p>6.1 Introduction</p><p>6.2 3-Amino-1,4-benzodiazepine derivatives, g-secretase inhibitors</p><p>6.3 Configurational stability; racemization and enantiomerization</p><p>6.4 Crystallization induced asymmetric transformation</p><p>6.5 Asymmetric Ireland-Cleisen rearrangement</p><p>6.6 Hydroboration of the terminal C=C bond; anti-Markovnikov hydratation</p><p>6.7 Crystallization-induced asymmetric transformation in the synthesis of L-768,673</p><p>6.8 Conclusion</p><p>References</p><p> </p><p>7. Sertraline</p><p>7.1 Introduction</p><p>7.2 Synaptosomal serotonin uptake and its selective inhibitors (SSRI)</p><p>7.3 Action of sertraline and its protein target</p><p>7.4 General synthetic route</p><p>7.5 Stereoselective reduction of ketones and imines under kinetic and thermodynamic control</p><p>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</p><p>7.5.2 Kinetic resolution of racemic methylamine; hydrosylilation by (R,R)-(EBTHI)TiF₂ /PhSiH₃ catalytic system</p><p>7.5.3 Catalytic epimerization of the trans- to the cis-isomer of sertraline</p><p>7.5.4 Stereoselective reduction of tetralone by chiral diphenyloxazaborolidine</p><p>7.6. Desymmetrization of oxabenzonorbornadiene, Suzuki coupling of arylboronic acids and vinyl halides</p><p>7.7 Pd-Catalyzed (Tsuji-Trost) coupling of arylboronic acids and allylic esters</p><p>7.8 Simulated moving bed (SMB) in the commercial production of sertraline</p><p>7.9 Conclusion</p><p>References</p><p> </p><p>8. 1,2-Dihydroquinolines</p>8.1 Introduction<p><p>8.2       Glucocorticoid receptor (GCR)</p><p>8.3 Asymmetric organocatalysis; introducing a thiourea catalyst for Petasis   reaction</p><p>8.3.1 General consideration of the Petasis reaction</p><p>8.3.2 Catalytic,  enantioselective Petasis reaction</p><p>8.4 Multicomponent reactions (MCRs); general concept and examples</p><p>8.4.1 General concept of MCRs</p><p>8.4.2 Efficient, isocyanide-based Ugi MCRs</p><p>8.5 Conclusion</p><p>References</p><p> </p><p>9. (-)-Menthol</p><p>9.1 Introduction</p><p>9.2. Natural sources and first technological production of (-)-menthol</p>9.3   Enantioselective allylic amine-enamine-imine rearrangement, catalysed by Rh(I)-(-)-BINAP complex.<p><p>9.4 Production scale synthesis of both enantiomers</p><p>9.5 Conclusion</p><p>References</p><p> </p><p>10. Fexofenadine hydrochloride</p><p>10.1 Introduction</p><p>10.2 Histamine receptors as biological targets for antiallergy drugs</p><p>10.3 Absolute configuration and “racemic switch”</p><p>10.4 Retrosynthetic analysis of fexofenadine</p><p>10.4.1 ZnBr₂-Catalyzed rearrangement of a-haloketones to terminal carboxylic acids </p><p>10.4.2 Microbial oxidation of non-activated C-H bond.</p><p>10.4.3 Bioisosterism; silicon switch of fexofenadine to sila-fexofenadine</p>10.5 Conclusion<p><p>References</p><p> </p><p>11. Montelukast sodium</p><p>11.1 Introduction</p><p>11.2 Leukotriene D4 receptor (LTD₄), CysLT-1 receptor, antagonists</p><p>11.3 Hydroboration of ketones with boranes from ?-pinenes and the non-linear effect (NLE) in asymmetric reactions</p><p>11.4 Ru(II) catalyzed enantioselective hydrogen transfer</p><p>11.5 Biocatalytic reduction with ketoreductase KRED (KetoREDuctase)</p><p>11.6 CeCl₃-THF solvate as a promoter of the Grignard reaction; phase transfer catalysis</p><p>11.7 Conclusion</p><p>References</p><p> </p><p>12. Thiolactone peptides as antibacterial peptidomimetics</p><p>12.1. Introduction</p>12.2 Virulence and quorum sensing system of Staphylococcus aureus.<p><p>12.3 Development of chemical ligation (CL) in peptide synthesis</p><p>12.4  Development of native chemical ligation (NCL); chemoselectivity in peptide synthesis</p><p>12.5  Development of NCL  in thiolactone peptide synthesis</p><p>12.6 Conclusion</p><p>References</p><p> </p><p>13. Efavirenz</p><p>13.1 Introduction</p><p>13.2 HIV-1 reverse transcriptase (RT) inhibitors</p><p>13.2.1 Steric interactions at the active site</p><p>13.3 Asymmetric addition of alkyne anion to C=O bond with formation of chiral Li⁺ aggregates</p><p>13.3.1 Mechanism of the chirality transfer</p><p>13.3.2 Equilibration of lithium aggregates and the effect of their relative stability on enantioselectivity</p><p>13.4 Scale-up of alkynylation promoted by the use of Et₂Zn.  </p><p>13.5 Conclusion</p><p>References</p><p> </p><p>14. Paclitaxel</p><p>14.1 Introduction </p><p>14.2 Disturbed dynamics of cellular microtubules by binding to ß-tubulin</p><p>14.2  Three selected synthetic transformations on the pathway to paclitaxel</p><p>14.3 Three selected synthetic transformations on the pathway to paclitaxel</p><p>14.3.1 Intramolecular Heck reaction on the synthetic route to baccatin III</p><p>14.3.2 Trifunctional catalyst for biomimetic synthesis of chiral diols; synthesis of the paclitaxel side-chain</p><p>14.3.3 Zr-complex catalysis in the reductive N-deacylation of taxanes to the primary amine, the key precursor of paclitaxel</p><p>14.4 Conclusion</p><p>References</p><p> </p><p>15. Neoglycoconjugate </p><p>15.1 Introduction</p><p>15.2 Human a-1,3-fucosyltransferase (Fuc-T)</p><p>15.3 Click chemistry, energetically preferred reactions</p><p>15.4 Target-guided synthesis (TGS) or freeze-frame click chemistry</p><p>15.5 Application of click chemistry to the synthesis of nucleoconjugate 1</p><p>15.6 Conclusion</p><p>References</p><p> </p><p>16. 12-Aza epothilones</p><p>16.1 Introduction</p><p>16.2 Epothilones; mechanism of action and structure-activity relationships</p><p>16.3. Extensive versus peripheral structural modifications of natural products</p><p>16.4  Ring closure metathesis (RCM), an efficient  approach to mac rocyclic “non-natural natural-products”</p><p>16.5Diimide reduction of the allylic C=C bond</p><p>16.6Conclusion</p><p>References</p>