Target preparation convergent synthesis

Romagnoli et al. have reported a convergent synthesis of a class of microtubule targeting agents where they aj lied the Suzuki-Miyaura reaction to highly substituted 5-bromothiazoles. With various aryl boronic acid, highly substituted thiazole derivatives were prepared and evaluated for their anti-proliferative activity against a panel of human tumor cell lines. 

Our strategy for target preparation was a standard "northern-southern hemisphere convergent synthesis (2,12), as shown in Scheme I. 

I I The angiotensin 11 antagonist irbesartan (E, cf p. 280), a widely used antihypertensive dmg, is obtained in a convergent synthesis Two building blocks B and C are prepared from the educts X and Y and combined (d) to afford the target molecule E ... 

A synthetically powerful method, an approach based on cycloaddition chemistry, allows one to assemble the pyridine ring in one step. Not only is this method efficient, atom economy, but also its convergency allows for the preparation for highly substituted systems in which one can, in principle, control all five positions on the pyridine ring. A versatile example of this methodology is the Boger reaction. It has been applied to the synthesis of a very diverse set of targets. 

Scheme 14.12 shows another example of the stepwise synthesis of azacalix[n] pyrazines that has been reported by Zhao and Wang [48]. Reaction of 2,6-bis (methylamino)pyrazine 38 and 2,6-dichloropyrazine 37 produced trimer 39 effectively. Attempted convergent macrocyclic cross coupling reaction of 39 with 38 failed to afford the targeted azacahx[4]pyrazine. Instead, a linear tetramer 40 was produced in 47 % yield along with the recovery of 31 % yield of reactant 39. Catalyzed by Pd2(dba)3, moderate yields of azacalix[4]pyrazine (21 %) and its macrocychc octamer, namely, azacalix[8]pyrazine (31 %) were achieved from 40 when the reaction was carried out in 1,4-dioxane in the presence of DavePhos as a ligand and CS2CO3 as a base (Scheme 14.12). Following the same strategy, the same authors reported very recently the preparation of azacalix[3n]pyrazine[n] pyridines (n = l, 2) when the linear trimer 39 was reacted with 2,6-bis (methylamino)pyridine [49].

---