Metal-mediated cyclization

A novel route to 2,3-dihydrothiophenes involved a titanocene-promoted carbene formation and subsequenct intramolecular cyclization onto a thiol ester <99SL1029>. Treatment of thioacetal 9 with the low-valent titanium complex 10 gave 2,3-dihydrothiophene 12 by intramolecular olefination of the thiol ester of titanium-carbene intermediate 11. Another metal-mediated cyclization onto the thiophene ring system involved the palladium-catalyzed cyclization of 1,6-diynes <99T485>. For example, treatment of thioether 1,6-diyne 13 with Pdlj in the presence of CO and Oj in methanol followed by treatment with base gave 14. 

Three prominent types of reactions fall in this classification cyclizations by condensation, metal-mediated cyclizations and nitrenoid insertion reactions. 

Nature found a direct path to perform this tandem fragmentation cyclization reaction in a stereospecific manner and under neutral conditions. Human creativity and luck aimed to uncover synthetic variants, which can compete efficiently with it. With the advent of mild, metal mediated cyclization reactions, the early idea of Grosheinz and Fisher [19a], who converted 6-deoxy-6-nitrohexoses to nitroinositols in a single step, matured to a general strategy of broad interest. 

With the variety of methods used, in conjunction with Wittig chemistry, for the formation of C-glycosides, it is helpful to compare the results of one method to another. Several reports have accomplished this. As shown in Scheme 7.1.8, Freeman, et al.,8 effected the cyclization of a Wittig-derived hydroxy olefin to the furanosyl C-glycoside shown. The reagents utilized in this report encompass both halogen and metal mediated cyclizations and provided the desired product in yields as high as 65%. 

Despite the now well-established geometric contributions to Bergman cyclization over the past 10 years, many fewer examples and much less is known about potential electronic contributions to the metal-mediated cyclization event. Although it is clear that the organometallic a-7t complexation mechanisms... 

Metal-mediated cyclizations have been applied to piperidine synthesis (Scheme 16). Ring closing metathesis catalyzed by Ru catalysts is used to prepare chiral piperidines <97TL677, 97AG(E)3036>. Similarly to the cyclization to 37 is Ti-(II)-mediated intramolecular cyclization of optically active enyne precursors for preparing chiral piperidines <97TL8351>. 

Metal-mediated cyclizations that rely on the initial complexation of an alkene or alkyne around a low oxidation state metal center are often sensitive to the presence of additional substituents (particularly electron-donating substituents), and relatively more stringent reaction conditions are often required for successful cychzation. This effect was noted in the Ni-catalyzed formal [4 -I- 4] cycloaddition reactions developed by Wender and Tebbe and is apparent when one compares the reported facility of Pd-catalyzed linear dimerization of 1,3-butadiene versus that of substituted 1,3-dienes. Similarly, the initial attempts at Pd-catalyzed cyclization of bisdiene 70a (Scheme 22) were rather disappointing. Using 0.05 equiv of [Pd(OAc)2/3 PhjP] (THF, 65 °C, 12 h), only a small... 

Transition-metal-mediated cyclization reactions play an increasing role in the synthesis of heterocycles, as shown by furan syntheses catalyzed by Pd, Cu, and Au. 

To the various synthetic apphcations mentioned already, the very usefiil metal-mediated cyclization reactions that lead to highly interesting polycycUc heterocycles... 

Because of these interesting biological activities and the scarcity of materials from their natural sources through isolation, great emphasis has been placed on synthetic approaches toward the efficient construction of tetrahydropyrans. These approaches include the Prins and related cyclization reactions, the hetero-Diels-Alder cyclizations, radical cyclizations, transition metal mediated cyclizations, as well as more traditional methods such as epoxide-mediated cyclizations and oxa-conjugate addition reactions. 

---