Heterocyclic Cores

The site of dihydroxylation in heterocycles depends on the nature of the heteroaromatic system (Scheme 9.31) usually, electron-rich heterocycles like thiophene are readily biooxidized but give conformationally labile products, vhich may undergo concomitant sulfoxidation [241]. Electron deficient systems are not accepted only pyridone derivatives give corresponding cis-diols [242]. Such a differentiated behavior is also observed for benzo-fused compounds biotransformation of benzo[b] thiophene gives dihydroxylation at the heterocyclic core as major product, while quinoline and other electron-poor systems are oxidized at the homoaromatic core, predominantly [243,244]. 

This schematic overview of NHC ligands found in the literature shows that most are based on five-membered heterocyclic cores. The most common are listed in Section 1.1.3. 

Microwave-assisted Sonogashira protocols have also been used for the decoration or functionalization of various heterocyclic core structures. Some recent examples involving pyrazines [47], pyrimidines [66], and thiophenes [42] are shown in Scheme 6.32. 

The Friedlander reaction is the acid- or base-catalyzed condensation of an ortho-acylaniline with an enolizable aldehyde or ketone. Henichart and coworkers have described microwave-assisted Friedlander reactions for the synthesis of indoli-zino[l,2-b]quinolincs, which constitute the heterocyclic core of camptothecin-type antitumor agents (Scheme 6.238) [421], The process involved the condensation of ortho-aminobenzaldehydcs (or imines) with tetrahydroindolizinediones to form the quinoline structures. Employing 1.25 equivalents of the aldehyde or imine component in acetic acid as solvent provided the desired target compounds in 57-91% yield within 15 min. These transformations were carried out under open-vessel conditions at the reflux temperature of the acetic acid solvent. 

Similarly to the above section, no additional specific nuclear magnetic resonance (NMR) data have been published since CHEC(1984) and CHEC-II(1996) <1996CHEC-II(8)249> NMR data for new substituted compounds are routinely reported. Several X-ray structures of bioactive molecules possessing this heterocyclic core have been reported C1999BML1979, 1999JME779>. 

Synthesis of the heterocyclic core possessing a fully saturated six-membered ring can be achieved using a catalytic hydrogenation (see Section 11.10.4.5.5). The six-membered ring can also be formed starting from the appropriate... 

Similarly, we were able to modify the initial synthetic route to prepare additional arrays of compounds with different heterocyclic cores (Scheme 2.82). 

Tempest P, Ma V, Kelly MG, Jones W, Huhne C (2001) MCC/SNAr methodology. Part 1 Novel access to a range of heterocyclic cores. Tetrahedron Lett 42 4963 968... 

With the fully functionalized heterocyclic core completed, synthetic attention next focused on introduction of the 3,5-dihydroxyheptanoic acid side-chain. This required initial conversion of the ethyl ester of 35 to the corresponding aldehyde through a two-step reduction/oxidation sequence. In that event, a low-temperature DIBAL reduction of 35 provided primary alcohol 36, which was then oxidized to aldehyde 37 with TRAP. Subsequent installation of the carbon backbone of the side-chain was accomplished using a Wittig olefination reaction with stabilized phosphonium ylide 38 resulting in exclusive formation of the desired -olefin 39. The synthesis of phosphonium ylide 38 will be examined in Scheme 12.5 (Konoike and Araki, 1994). 

Pitavastatin (3) was launched in 2003 and is currently marketed in Japan under the trade name Livalo . Like rosuvastatin and fluvastatin, pitavastatin is a completely synthetic HMG-CoA reductase inhibitor that was developed by Kowa, Nissan Chemical, and Sankyo (Sorbera et al., 1998). Multiple syntheses of pitavastatin have been reported and an exhaustive review of these efforts is beyond the scope of this text (Hiyama et al., 1995a, b Minami and Hiyama, 1992 Miyachi et al., 1993 Takahashi et al., 1993, 1995 Takano et al., 1993). Instead, we will focus our discussion on two related and innovative synthetic approaches that differ strategically from the routes we have previously examined for rosuvastatin and fluvastatin. These routes to pitavastatin employed palladium-mediated coupling reactions to install the 3,5-dihydroxyheptanoic acid side-chain. This key retrosynthetic disconnection is highlighted in Scheme 12.6, in which a suitable functionalized side-chain (52 or 53) is attached to the heterocyclic core of pitavastatin (51) through palladium-mediated coupling. 

The Heck reaction of a 2-bromoindole derivative was used to introduce a three-carbon chain onto the heterocyclic core en route to indoloquinolizidine alkaloids (6.58.).ss... 

It is assumed that the heterocyclic core structure is responsible for the appropriate orientation of the aromatic rings in space and finally for binding to the enzyme. A wide variety of heterocycles can serve as templates, i.e. pyrrole, thiazole, oxazole furane, furanone, imidazole, isoxazole, pyrimidine and thiophene, but at the moment pyrazole and cylopentenone seem to be the most appropriate for achieving COX-2 specificity. For optimal activity, one aromatic ring must be substituted with a methylsulfonyl or a sulfonamide substituent in the para position. Substitution at position 4 of one of the aromatic systems with a sulfonamide or a methylsulfonyl group is essential for COX inhibition. Replacement of the methylsulfonyl group by a sulfonamide group reduces COX-2 selectivity but improves oral bioavailability. 

Structural variants of porphyrins obtained by heterocyclic core modification, macrocyclic ring expansion, alteration of structural topology, and incorporation of tailor-made substituents constitute an area of considerable interest. Potentially rich families of conjugated heteroporphyrins with well-defined structures provide an opportunity for implementation in applications in the field of chemistry, biology, and material science. This chapter reports on the synthesis and structural modifications of a number of heteroporphyrins. 

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