Synthetic Highlights

Saxton reviews the isolation and synthesis of the aspidospermine alkaloids in Chapter 1, thereby updating the last review, which appeared in this series over 20 years ago. The chapter complements a contribution (also by Saxton) in Volume 50 that specifically focused on the synthetic highlights of this intensely studied aspect of indole alkaloid chemistry. 

Synthetic highlights A critical step in the synthesis of the compound involves non-hydrolytic anomalous lactone ring-opening by TMSl. To avoid racemization, the Mitsunobu reaction was applied in the formation of the ether bond. Optimization of the Mitsunobu reaction was finally achieved without loss of enantiomeric purity. 

In the next section, the synthetic highlights along the path to this lead structure and its analogues are described, in particular, non-hydrolytic, anomalous lactone ring opening, and stereo-uniform formation of the ether bond at the stereogenic centre through apphcation of the Mitsunobu or Williamson-type reaction. 

Synthetic highlights The Cu-promoted catalytic decarboxylative, biaryl synthesis of valsartan is an example of biomimetic, aerobic decarboxylation and enables C-C bond formation in aqueous solution. The chiral variant of biaryl synthesis is exemplified by the stereoselective approach to the axially chiral biaryl system present in vancomycin. 

Synthesis of valsartan represents one of the synthetic highlights on the basis of this methodology, and is outlined in Scheme 5.3 [41]. 

Synthetic highlights Racemization and enantiomerization are two consequences of configurational instability. Enantiomerically enriched 3-amino-1,4-BZDs have been generated via crystallization-induced asymmetric transformation. Enantiomerically pure target products have been obtained by asymmetric Ireland-Claisen rearrangement, highly enantioselective rearrangement of prochiral allylic esters to 1,2-disubstituted carboxylic acids and hydroboration of the terminal C=C bond, an efficient anti-Markovnikov hydratation process. 

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. 

Synthetic highlights A variety of pathways have been taken in the synthetic approach to sertraline. These include stereoselective reduction of ketones and imines under kinetic and thermodynamic control, using diastereoselective or enan-tioselective catalysts and reagents, desymmetrization of oxabenzonorbomadiene followed by the Suzuki coupling of arylboronic acids and vinyl halides and Pd-Catayzed (Tsuji-Trost) coupling of arylboronic acids and allylic esters. For the production of sertraline, the simulated moving bed (SMB), a cost-effective technology, has been introduced. 

Synthetic highlights The synthesis of 1,2-DQs exemplifies asymmetric organo-catalysis in which enantioselective synthetic reactions are catalyzed by small organic molecules. To generate 1,2-DQs, achiral thiourea and axially chiral biphenols are used as catalysts for the enantioselective Petasis reaction. This is an illustration of a multicomponent reaction (MCR), for which the general concept and examples are also described. 

Synthetic highlight Diastereoselective production of rac-menthol from its aromatic precursor is achieved by site-selective isopropylation and diastereoselective hydrogenation to the all-trans racemate. Enantioselective allylic amine-enamine-imine rearrangement of an acyclic diene-allylic amine, catalyzed by an Rh(I)-(—)-BINAP complex, affords (—)-menthol the process has been scaled-up to production of 1,000 tons/year. 

Synthetic highlights Although not feasible from a cost-benefit point of view, racemic switch to the R(+) enantiomer is discussed. Retrosynthetic analysis of the fexofenadine molecule is presented together with some inventive synthetic steps employed. These include ZnBr2-catalyzed transposition (rearrangement) of a-haloketones to terminal carboxylic acids and microbial oxidation of the non-activated C-H bond. The concept of bioisosterism is exemplified by the silicon switch of fexofenadine to sila-fexofenadine. 

Synthetic highlights This chapter describes the background for the development of modem peptide syntheses. This involves chemical ligation of unprotected peptides carried out with chaotropes. Using a transient thioester-linked intermediate, native chemical ligation (NCL) of two unprotected peptides is achieved. With Fmoc protecting groups and the use of Rink resin, chemoselectivity of peptide synthesis is feasible. The development of NCL, as applied to thiolactone peptide synthesis, is considered in detail. 

Synthetic highlights The initial step in the synthetic pathway to efavirenz involves the asymmetric addition of an alkyne anion to the ketone C=0 bond. The generation of chiral Li" aggregates elegantly determines the stereoselectivity of the reaction. Scale-up of aUcynylation is promoted by the use of EtaZn as a weak Lewis acid. 

Synthetic highlights The partial synthesis of paclitaxel was necessary to enhance the availability of the drug substance and avoid unsustainable use of yew trees. Many different synthetic routes have been reported and three inventive pathways for the enantioselective or site-selective approaches to various segments of the paclitaxel molecule are described. These are aU promoted by organometal catalytic complexes. Reactions presented include use of the intramolecular Heck reaction in the synthetic pathway to baccatine III the Sharpless reaction and the introduction of a trifunctional catalyst for biomimetic synthesis of chiral diols synthesis of the paclitaxel side-chain and use of a Zr-complex catalyst in the reductive N-deacylation of taxanes to primary amine, the key precursor of paclitaxel. 

Synthetic highlights Natural macrocycUc compounds have been subjected to both extensive and peripheral structural modifications in the search for new lead compounds. An example of the former is the antibiotic azithromycin, whereas 12-aza-epothilones must be approached by total synthesis. This total synthesis of epothilones involves ring closure metathesis using heteroleptic complexes as catalysts and has proved to be an efficient approach to non-natural, macrocyclic natural products . In one of the critical steps of this pathway to azathilones, creative site-selective diimide reduction of an allylic C=C bond was applied. 

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