Asymmetric Organocatalysis Introducing a Thiourea Catalyst for the Petasis Reaction

Asymmetric organocatalysis can be defined as enantioselective synthetic reactions that are catalyzed by small organic molecules. The term was introduced for what was long referred to as metal-free catalysis 6 . As opposed to transition metal complexes with organic ligands, of which many examples are given in Chaps. 5,9, 13, 14 and 16, the catalytic activity of organocatalysts resides in the low-molecular weight organic molecule, and no transition metal is required. To some extent,...

PdCatalyzed Tsuji Trost Coupling of Arylboronic Acids and Allylic Esters

Transition metal-catalyzed allylic substitution reactions with carbon nucleophiles are among the most important carbon-carbon bond formation methods in modern organic synthesis, because of their broad substrate scope under mild reaction conditions. In addition, they are applicable to enantioselective reactions, as well as exhibiting versatility towards the alkene functionality adjacent to the chiral centre for stereoselective derivatization. Tsuji-Trost allylic substitution, involving a...

Histamine Receptors as Biological Targets for Antiallergy Drugs

Histamine is a major chemical mediator in the pathogenesis of allergic disease. It is released, predominantly by mast cells, in response to cross-linking by allergens of specific immunoglobulin E antibodies bound to the cell membrane, as well as by some chemical stimuli. Activation by histamine of H1 receptors, present on various types of smooth muscle, endothelial cells and in the heart, causes many of the typical symptoms of allergic diseases. These include sneezing, swelling (due to plasma...

Ammonium Chloride an Effective Promoter of Catalytic Enantioselective Hydrogenation

The final improvement in the hydrogenation step was achieved before the large-scale process was set up, enabling production of 20,000 tons of sitagliptin by 2007 22 . In Scheme 4.3, 0.3 of ammonium chloride is indicated as the promoter of asymmetric hydrogenation. A positive effect of the inorganic salt was observed when the significant variability in the e.e. and yield was traced to the content of this salt in the various batches of the p-enamine amide 13 27 . In a separate experiment, a very...

Fexofenadine Hydrochloride

(a) Retrosynthetic analysis of fexofenadine, synthone approach (b) Alkines as synthetic equivalents for ketones, Hg(II) and Pt(II) promoted hydratation (c) ZnBr2-catalysed transposition of a-haloketones to terminal carboxylic acids mechanism (d) Oxazaborolidine-based catalysts for enantioselective reduction of ketones (e) Microbial oxidation of non-activated C-H bond biotransformation of terfenadine to fexofenadine with Cunninghamella blakesleeana and Absidia corymbifera (f) Bioisosteres...

Angiotensin AT1 Receptor a GProtein Coupled Receptor

Hypertension is the most prevalent disease in developed countries, with approximately one billion cases worldwide 2 . Various classes of antihypertensive agents have been introduced into therapy over the last 30-40 years. Yet hypertension remains an under-treated disease and a major health problem worldwide. Valsartan has become an outstanding representative of the angiotensin II type 1 (ATI) receptor antagonists, which are highly effective at reducing blood pressure and at the same time...

Rearrangement Catalysed by RhIbinap Complex

The enantioselective approach to ( )-menthol is outlined in Scheme 9.2 11 . It is a real challenge to our understanding of synthetic chemistry that such a simple short synthetic route, which starts from the achiral natural hydrocarbon isoprene, well known for its huge consumption by the rubber industry, can afford a chiral, cyclic alcohol with three stereogenic centres in defined absolute configurations and with high enantiopurity All the knowledge accumulated over the years at Takasago...

Crystallization Induced Asymmetric Transformation

Among chiral 1,4-BZDs, (6 Scheme 6.1), represents a particularly interesting structure, syntheses of single derivatives and libraries aimed at specific biological targets having been studied by various teams 15-17 . Synthetic and biological research in the field of 1,4-benzodiazepines were triggered in the early 1960s by the group of Sternbach at Hoffmann-La Roche Research Division, Nutley USA 18 . A synthetic approach to the racemic compound 6 was first reported by S. C. Bell et al. from the...

Strategy Based on Visual Imagery Starting from Natures Chiral Pool A Dali Like Presentation of Objects

The first synthetic approach to be considered in more detail was designed and largely completed by Hanessian et al. at the University of Montreal. The authors started from retrosynthetic analysis of the generic backbone structure 1 (Scheme 2.3) 21 . They noticed that compound II, when presented in its folded form IIA, visually overlaps better with the bicyclic lactam 2 Further retrosynthetic steps in this Scheme led to the logical synthetic equivalents 3-6, likely to be available in the...

CeCl3THF Solvate as a Promoter of the Grignard Reaction Phase Transfer Catalysis

The extraordinary effect of Ce(III) chloride on the Grignard reaction in step vi of the Scheme 11.1, giving significantly better yields of the tert-alcohol 17 than in the reaction performed in its absence, deserves analysis and comment. This step was studied in detail, and it was demonstrated that the use of properly activated Ce(III) chloride overcomes undesired reactions, such as enolization, reduction and condensation, competing with the formation of ferf-alcohols 33 . The activated Ce(III)...

Configurational Stability Racemization and Enantiomerization

Configurational or optical stability is crucial for any chiral compound intended as a drug substance. In view of the different behaviour of enantiomers in a chiral environment, which is regularly present in all compartments of the living organism, the requirement for optical stability is obvious. It is important to note that the chiral environment in biological fluids, either intra- or extracellularly, is generated by the presence of soluble chiral molecules. Insoluble, chiral biopolymers and...

Fine Tuning of the Chiral Ligand for the Rh Complex Hydrogenation of the Selected Substrate with Extreme

The intermediate structures of general formulae III, either racemic or in the optically pure form, are required on many routes to aliskiren (Scheme 2.7a). Synthetic pathways to optically pure derivatives have made use of a variety of different methods resolution of racemic acid III (X COOH) 22 , alkylation of Scheme 2.7 (a) From the key intermediates III to aliskiren (b) Enantioselective hydrog nation leading to 27 chiral auxiliary with bromobenzyl congener of III to give optically pure amide...

Biocatalytic Reduction with Ketoreductase KRED KetoREDuctase

In spite of these two relatively efficient reductions of the carbonyl group in 15, two research teams have jointly developed a biocatalytic process as an alternative approach, applicable to large scale production of the enantiopure intermediate 16 31 . Through synergistic efforts in process chemistry, molecular biology, bioinfor-matics and high throughput screening, a ketoreductase KRED (KetoREDuctase) with very high enantioselectivity, > 99.9 e.e., was developed. This biocatalytic process...

Natural Sources and First Technological Production of Menthol

World-wide production of ( )-menthol has reached 4,500 tons year, prompted by its use as an important ingredient in personal care products, perfumes and in the pharmaceutical industry. Being a natural product, until 1984, all ( )-menthol on the world market originated from the natural source, Mentha arvensis, and the restricted supply has maintained its high price. It is worth noting that natural sources (e.g., rose oil) provide a mixture of enantiomers containing up to 80 e.e. ( )-menthol 4 ....

Ring Closure Metathesis An Efficient Approach to Macrocyclic Nonnatural Natural Products

Ringclosing Meta Thesis

Contrary to azithromycin, 12-aza-epothilones 1 and 2 are not available from their natural congeners. Therefore, these target molecules must be approached by total synthesis, starting from small chiral building blocks. The key issue in their synthesis, Reagents and conditions i. NH20H A, -H20 ii. ArS02Cl A, then base Scheme 16.1 Synthetic route to the antibiotic azithromycin as in the synthesis of most macrocyclic natural and non-natural products is macro-cyclization. This process is not...

Leukotriene D4 Receptor LTD4 CysLT1 Receptor Antagonists

The design of montelukast was the result of structural development by several companies through various phases of complexity, from the first to the second generation of leukotriene D4 antagonists 2 . During research into mediators of allergy and asthma in the mid-twentieth century, slow reacting substance (SRS, a bronchial smooth muscle slow contracting substance) was identified by biologists as an important endogenous factor in the pathophysiology of human asthma, without any knowledge of its...

Asymmetric Ireland Claisen Rearrangement

Synthetic highlights on the pathway to the optimized leads 1-3 provide instructive examples of the intensive engagement of batch-wise synthetic chemistry at a relative early stage of lead optimization for future NDEs, as presented in Fig. 1.2. With the availability of an efficient method for the synthesis of enantiomerically pure (3S)-4, a multidisciplinary team at Merck Sharp and Dohme Research and o-js-n' n-soj F.3C > fV-CFa Reagents and conditions i. Mel, KjCO DMF ii. DIBAL-H,, THF, -10 C...

CuPromoted Catalytic Decarboxylative Biaryl Synthesis a Biomimetic Type Aerobic Decarboxylation

The stereogenic centre in valsartan has the S-configuration and is introduced with l-valine as the building block. However, the formation of the aryl-aryl bond represents the key step in the synthesis of many sartans. The biphenyl unit in valsartan 1 and other sartans is a common structural element, and proved to be essential for binding affinity to the receptor and for oral bioavailability. When the barrier for rotation around the central bond is high enough, axially chiral enantio-mers can be...

Stereoselective Reduction of Tetralone by Chiral Diphenyloxazaborolidine

There are numerous methods for asymmetric reduction of aryl-alkyl ketones 23, 24 . Stereoselective reduction of racemic ketones, substrates that already possess one stereogenic centre, is diastereoselective if one configuration prevails at the newly created stereogenic centre. Diastereoselectivity of reduction is controlled by the stereogenic centre already present, but it can be controlled twice when a chiral reducing agent is used. A favourable or matching situation appears when the chiral...

Action of Sertraline and Its Protein Target

The difference in biological properties between cis-and trans-diastereomers of 1, and in particular between (15,45)- and (1R,4R)-enantiomers of cis-1 is well documented, and enabled the selection of (15,45)-1 for further progression as a drug 5, 6 . Early comparison of the structure of the potent and chiral serotonin uptake inhibitor (15,45)-sertraline with that of the chiral conformer of (R)-fluoxetine indicated a close three-dimensional correspondence. This suggested that the conformer of...

Endogenous Glucoregulatory Peptide Hormones and Dipeptidyl Peptidase IV DPP4 Inhibitors

Glycaemic control is crucial in the therapy of type 2 diabetes mellitus. Physiologically, insulin, produced by the p-islet cells in the pancreas in response to an increase in blood glucose concentrations, facilitates the clearance of blood glucose, acting on specific insulin receptors to increase glucose uptake into the liver, muscle and fat cells and stimulating lipid metabolism. An important stimulus to this insulin production is provided by gastrointestinal hormones, such as gastrin,...

Highly Enantioselective Hydrogenation of Unprotected pEnamino Amides and the Use of Josiphos Ligands

In view of the extensive application in the life sciences of p-amino acids, as components of biologically active peptides and small molecule pharmaceuticals 15 , a great deal of research in organic synthesis has been focused on simple, practical and scalable methods for their preparation in an optically pure form 16, 17 . But, because of the obligatory use of N-acyl-p-enamines, on the one hand, and their fast equilibration into an E Z mixture, on the other, their asymmetric hydrogenation...

General Concept of Multicomponent Reactions

Multi-component reactions are highly variable, enabling the synthesis of a large number of products from only a few starting substances. Since MCRs are one-pot reactions and single-step conversions, they are, therefore, economical with resources and come close to what is defined as an ideal synthesis 34 . Despite this, the broad value of MCRs was not recognized until 1961, when I. Ugi described the most important variants of the four-component reactions 35 . This is a shame, because some...

RuII Catalyzed Enantioselective Hydrogen Transfer

Another method of enantioselective hydrogenation of 15 to 16 en route to montelukast was studied by Noyori et al. using Ru II -catalyzed asymmetric hydrogen transfer and formic acid as the source of hydrogen 26 . The catalytic complex 19 and the reductive process are presented in Scheme 11.6. Before considering the mechanism of this important variant of asymmetric hydrogen transfer, let us first look at earlier methods used in the field. Most of them were based on 2-propanol as the favourable...

Renin and the Mechanism of Action of Aliskiren

The target enzyme of aliskiren is renin EC 3.4.23.15 and the drug is the first direct inhibitor of this enzyme 2, 3 , in distinction to the older ACE inhibitors, which provide incomplete suppression of the renin-angiotensin-aldosterone system RAAS Fig. 2.1 . Renin is a protease, secreted by blood vessels in the juxtaglomerular apparatus of the kidney, under various physiological stimuli, including a decrease in renal perfusion pressure regulated by blood pressure , thus controlling filtration...

Development of NCL in Thiolactone Peptide Synthesis

As mentioned in the introduction to this chapter, the recent discovery of thiolactone peptides as potential antimicrobial agents, based on their ability to act as antagonists of natural auto-inducing peptides AIP , prompted the new synthetic achievements, which permitted the synthesis of these cyclic peptide inhibitors. Here, we discuss the most recent achievement in the synthesis of AIP mimics, based on an original linker for the Fmoc-based solid-phase methodology. Previous AIP syntheses...

Hydroboration of Ketones with Boranes from aPinenes and the Nonlinear Effect in Asymmetric Reactions

Montelukast has only one stereogenic centre but a complex assembly of functional groups. Various synthetic approaches have been claimed 13-16 and published 17-20 . In this and Sect. 11.4, we discuss selected and - from the synthetic chemistry point of view - most demanding steps, on the pathway to montelukast presented in Schemes 11.1, 11.7 and 11.9. Condensation of 2-methylquinolone 9 with dialdehyde 10 1.5 mol equiv , in the presence of acetic anhydride afforded, after elimination of...

ZnBr2Catalyzed Rearrangement of aHaloketones to Terminal Carboxylic Acids

Kawai et al. 27 have reported the synthesis of alkyne 7 after the stepwise formation of phenyl-2,2-dimethylacetic acid by double methylation of para-bromo-phenylacetic acid Scheme 10.4 . This seven-step route is characterized by a high average yield, but requires complete elimination of Hg ions and chromatographic purification of the ketone intermediate 11, which renders the whole process impractical for large-scale production of fexofenadine. Recently, a modification of this step has been...

Bioisosterism Silicon Switch of Fexofenadine to Sila Fexofenadine

Silicon switch of marketed drugs is a relatively new concept and consists of sila-substitution C Si exchange of existing drugs in the search for drug candidates that have improved biological properties providing a beneficial intellectual property IP status. It has been shown that silicone molecules can be accessed in a relative straightforward manner and can have a pharmacological or pharmacokinetic benefit over their carbon counterparts 47-49 . C Si bioisosterism has been considered repeatedly...

Catalytic Epimerization of the Trans to the Cis Isomer of Sertraline

Generally, racemization of chiral sec-amines can be represented as shown in Scheme 7.5. In these equilibria, both enantiomers interconvert via the prochiral intermediate, and are present in equal quantities, irrespective of the enantiomer that is in excess at the beginning of the process. When racemization of the wrong enantiomer is coupled with further conversion of the right one from the resulting mixture, this tandem transformation is named dynamic kinetic resolution see also concluding...

Catalytic Enantioselective Petasis Reaction

The enantioselective, organocatalytic variant of the Petasis reaction, developed by Takemoto and coworkers from the University of Kyoto, represents a breakthrough in the synthesis of enantiopure 1,2-dihydroquinolines. As mentioned before, this structural unit is present in many natural products and biologically active compounds, and therefore an effective and short synthetic route via the Petasis-type reaction to enantiopure compounds in this class is a major leap forwards. Screening of the new...

Desymmetrization of Oxabenzonorbornadiene Suzuki Coupling of Arylboronic Acids and Vinyl Halides

This section describes an original, multistep synthesis pathway to sertraline, as outlined in Scheme 7.8 28, 29 . This approach is based on the chiral dihydronaphthalene motif, represented by compound R -8. Generally, this motif is found in a number of biologically active molecules and therefore it is a chemically privileged structure in the sense of being a starting point for the identification of a lead compound for evaluation 30 . Reagents and conditions i. Ni COD 2 S -BINAP, DIBAL-H, THF,...

Absolute Configuration and Racemic Switch

All these studies of non-racemic fexofenadine were prompted by the development of an HPLC method for the chiral separation of fexofenadine enantiomers in human plasma 11, 12 . Based on these and additional studies on the pharmacokinetic 13 and enantioselective disposition of fexofenadine in the presence of verapamil 14 , it was proposed that the use of R- -fexofenadine only might provide a more predictable therapeutic effect and less drug-drug interactions 15 . A racemic switch, that is,...

Mitsunobu Reaction in the Ether Bond Formation

The general scheme of the Mitsunobu reaction in the synthesis of aryl-alkyl ethers reveals the complexity of the reacting system Scheme 3.4 . It illustrates the extremely low atom utilization or atom economy, usually expressed as the E-factor, of the process 30 . Quenching of 1 mol of water results in two large side-products, the hydrazodicarboxylic ester and triphenylphosphin-oxide. The Mitsunobu reaction requires two expensive reagents, a phosphine and a diazo ester. On the other hand, this...

Development of Native Chemical Ligation Chemoselectivity in Peptide Synthesis

On the basis of these methodologies that afforded proteins in high yield and good purity from unprotected building blocks, only one step remained to achieve the synthesis of large peptides with a natural amide bond at the ligation site. In 2004, Dawson et al. discovered an ingenious extension of the CL principle, and named it NCL 30 . This process is outlined in Scheme 12.2 23 . Simply mixing two peptide segments together that contain correctly designed and mutually reactive functional groups...

Montelukast Sodium

a Asymmetric hydrogenation of ketones with a-pinenes b Non-linear effect NLE in asymmetric reactions c Chiral Ru II complexes, catalysts for enantioselective hydrogen transfer d Biocatalytic reduction of ketones ketoreductase KRED KetoREDuctase scaled-up to a production batch of gt 200 kg e Remarkable effect of Ce III chloride on the Grignard reaction structure and mechanism f Replacement of the hydroxyl group for a thiol group high nucleophilicity of the soft Cs-salts of thioacids selective...

References

Federsel H-J 2008 Drug News Prosp 21 193-199 2. Gillespie P 2007 Am Drug Disc 2 14-17 3. Fischer J, Ganellin CR 2010 Analogue-based drug discovery II. Wiley-VCH, Weinheim 4. Brooks E, Brichacek M, Mc Grath N, Morton J, Batory L, Njardarson JT 2008 Compilation of the Njardarson Group, Cornell University 5. Sales figures from IMS Health 2004 6. Newman DJ, Cragg GM 2007 J Nat Prod 70 461-47 7. Laird T 2005 Org Proc Res Develop 9 1 8. Hoffmann T, Bishop C 2010 Drug Disc Today 15 260-264 9....

Structural Characteristics and Synthetic Approaches to Aliskiren

Aliskiren is representative of compounds with general structure I, varying in the nature of the aromatic substituents, the amide moiety, and alkyl groups, representing a novel carbon backbone with unique binding affinity to renin. R,, R2 methoxy, methoxyethoxy, etc. R4 methyl, isopropyl alkyl, aminolakyl, etc. R,, R2 methoxy, methoxyethoxy, etc. R4 methyl, isopropyl alkyl, aminolakyl, etc. While the structure-based design of aliskiren is straightforward, synthesis of this highly flexible...

Nonhydrolytic Anomalous Lactone Ring Opening

As stated in the introductory chapter, research towards a new drug entity NDE is a shuttle process, in which synthetic organic chemistry is often the initial step. As the research process advances, the targets and methods of synthetic organic chemistry are modified to deal with the increasing substance quantities required. According to standard terminology, compound 1 is a lead compound, and following the internal company documentation system, defined by a code number. Inventive synthetic...

Efficient Isocyanide Based Ugi Multicomponent Reactions

A final example is the one-step, three-component variant of the Ugi reaction Scheme 8.10 , according to which an important local anaesthetic agent, xylocaine 28 , was synthesized from formaldehyde, diethylamine and 2,6-dimethyl-pheny-lisocyanide 45 . Why are Ugi's MCRs so efficient The answer lies in the low activation energies of all the elementary steps, which are either equilibrium processes or irreversible steps. This concept of energetically preferred reactions is discussed in Chap. 15, in...

Simulated Moving Bed in the Commercial Production of Sertraline

The search for a cost-effective synthetic method for the production of 4S -tetralone 4, the intermediate on the pathway to sertraline, was shifted to technology that is still new to the pharmaceutical industry - continuous chromatographic separation of enantiomers based on a simulated moving bed SMB process 39, 40 . As an indication of the rapidly growing interest in SMB technology, over 1,700 papers and patents on the development and application of SMB technology are cited in electronic...

Stereoselective Approach to the Axially Chiral Biaryl System the Case of Vancomycin

As mentioned in the introduction, optically pure biaryl derivatives are present in a number of natural products of various origins and have a wide range of biological properties 43 . By far, the most important representative of biologically active compounds with axially chiral biaryl unit is vancomycin 7 , a clinically used glycopeptide antibiotic from Streptomyces orientalis 44 . Vancomycin is a broad spectrum antibacterial, which acts to inhibit the construction of the bacterial cell wall by...

Retrosynthetic Analysis of Fexofenadine

Fexofenadine serves as a good example of a target molecule TM that can be approached by retrosynthetic analysis, also known as the disconnection approach or the synthon approach. This methodology enables the organic chemist to design a synthetic route to the TM, starting from simple and readily available materials. It is important to note that the disconnection approach is an imaginary process, the reverse of an actual chemical reaction, which breaks a bond in the target molecule to yield the...

Thiolactone Peptides as Antibacterial Peptidomimetics

Biological target Thiolactone peptides are macrocyclic peptides that bind, on the surface of Staphylococcus aureus bacteria, to the accessory gene regulator C. This acts as a receptor for auto-inducing and quorum-sensing peptides produced by the bacteria and regulates the bacterial growth. Therapeutic profile In mimicking the quorum-sensing peptides, the thiolactone peptides act as antibacterials, naturally regulating the growth of the bacteria. Synthetic highlights This chapter describes the...