The efficient synthesis of pharmacologically active molecules remains a primary goal of the synthetic organic chemist. Organometallic based synthetic methods have been responsible for some of the most important developments in this area during the past two decades. It is with the aim of developing new transition metal catalyzed synthetic methods that the present work proposes to initiate a program to systematically examine and develop a transition metal catalyzed carbometalation/anion capture sequence for use in the synthesis of medicinally active, structurally complex molecules.
The specific aims of the proposed project period are: (1) to systematically investigate the scope and generality of this transition metal catalyzed carbometalation/anion capture sequence; these studies include a thorough investigation of the mechanistic details of the factors controlling the chemo-, regio-, and stereo- selectivity of this chemistry; (2) the application of this process to the development of concise syntheses of pharmacologically important and structurally complex molecules which can readily adapted to the synthesis of analogues possessing increased biological activity and/or stability. This is demonstrated in the efforts towards the synthesis of three biologically active molecules: (a) the potent antitumor antibiotic Neocarzinostatin Chromophore A; (b) 1alpha-Hydroxyvitamin D3, a direct precursor to the hormonally active form of Vitamin D3, 1alpha,25-Dihydroxyvitamin D3 (calcitriol); and, (c) 'the complex polycyclic quinone (+/-)-Pleurotin.The utility of this carbometalation/anion capture sequence in the construction of analogues is demonstrated by studies which seek to explore more thoroughly the relationship between the unique structure and biological activity of Neocarzinostatin Chromophore A. Using this carbometalation/anion capture sequence, construction of analogues possessing the salient features of Neocarzinostatin Chromophore A is expected to be easily accomplished, allowing considerable data to be gathered.The ultimate significance of this research in the health related fields lies in the potentially powerful new synthetic methods developed and the insights gained during the course of the studies outlined in this proposal; it is hoped these advances will eventually lead to the efficient production of therapeutically important molecules and their analogues.
| Arkin, I T; Adams, P D; Brunger, A T et al. (1997) Structure of the transmembrane cysteine residues in phospholamban. J Membr Biol 155:199-206 |
