Acids heterocyclic cores

Fizeau interference fringes 130 flavellagic acid, heterocyclic cores 722 flexoelectricity... 

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. 

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 following syntheses demonstrate the application of resin-bound 3-hydroxy-2-methylidene propionic acids. Within only a few steps, a significant number of different linear and heterocyclic cores can be built up (Scheme 6.5) [22]. 

Another MW-assisted application of the Ugi-de-Boc cyclization sequence (vide supra) is the construction of the interesting N-containing heterocyclic core of a qui-noxalinone 48. When the reaction was performed at room temperature good yields were obtained but it took 36-48 h to complete [89]. Tempest et al. modified the procedure to reduce reaction times and to simplify the purification of the Ugi condensation products [75]. They did this by irradiating a mixture of F-Boc protected diamine with a slight excess of phenylglyoxylic acid 46, aldehyde, and isonitrile in MeOH in a monomode MW reactor for 10-20 min at 100 °C, initially obtaining intermediate 47 (Scheme 17.35). 

The heterocyclic core of martinelline and martinellic acid was prepared via the Povarov reaction between an aromatic imine derived from... 

S. Fujii, K. Ohta, T. Goto, H. Kagechika, Y. Endo, Acidic heterocycles as novel hydrophilic pharmacophore of androgen receptor ligands with a carborane core structme, Bioorg. Med. Chem., 2009, 17, 344-350. 

The synthesis of pyrido[2,3-d]pyrimidines has attracted considerable interest in heterocyclic chemistry. This ring system constitutes a deaza-analogue of the pyrazino[2,3-d]pyrimidine heterocychc core of fohc acid, analogues which can exhibit a wide range of biological properties as folate antagonists. Thus, the synthesis of this motif by MCR imder microwave-assisted conditions has the potential to rapidly introduce diversity into a biologically relevant scaffold. 

In 1996, Fu et al. reported the S3mthesis of the planar chiral heterocycles 64, formally DMAP fused with a ferrocene core [82]. While the original synthesis provided racemic 64a in only 2% overall yield requiring a subsequent resolution by preparative HPLC on a chiral stationary phase, a recently improved synthesis furnished the racemic complexes 64 in 32-40% yield over seven steps. A subsequent resolution with di-p-toluoyltartaric or dibenzoyltartaric acid gave access to the enantiomers with >99% ee (28 14% yield for each isomer in this step) [83]. 

---