Synthesis of 10,11-Didehydro Cinchona Alkaloids and Key Derivatives

A series of 10,11-didehydro Cinchona alkaloids containing an ethynyl group at C(3) were prepared efficiently in two steps from the naturally occurring Cinchona alkaloids (Scheme 1). 10,11-Didehydroquinine (4c) and 10,11-didehydroquinidine (4a) belong to a significantly new class of semi-natural Cinchona alkaloids. They are more polar and basic than the natural compounds and serve as versatile building blocks for further functionalization; they were transformed into the corresponding 11-halo and 11-pseudohalo derivatives and (Z)-vinyl halides (Schemes 2 and 3). The conformation of the alkaloids was elucidated by NOE and X-ray crystal diffraction analysis of 4a (Fig.), and the cytostatic activity of selected didehydroquinidine derivatives was evaluated (Table 5).