Abstract:The synthetic investigation of biologically active natural compounds serves two main purposes: (i) the total synthesis of alkaloids and their analogues; (ii) modification of the structures for producing more selective, more effective, or less toxic derivatives. In the chemistry of dimeric Vinca alkaloids enormous efforts have been directed towards synthesizing new derivatives of the antitumor agents vinblastine and vincristine so as to obtain novel compounds with improved therapeutic properties.

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The first direct synthesis of (+)-lysergic acid (2a) suitable for scale-up has been achieved by the following reaction sequence. Bromoketones 4d or 4g were allowed to react with amine 5 followed by deprotection, and the resulting diketone 6c was transformed into the unsaturated ketone (+/-)-7 by the LiBr/Et(3)N system. Resolution afforded (+)-7, which was further transformed by Schöllkopf's method into the mixture of esters 2e and 2f. Upon hydrolysis the latter mixture afforded (+)-2a. The peptide part of alpha-ergocryptine (1) was prepared according to the Sandoz method; the stereoefficiency, however, has been significantly improved by applying a new resolution method and recycling the undesired enantiomer. Coupling the peptide part with lysergic acid afforded 1. Having synthetic (+)-7 in hand, we can claim the total synthesis of all the alkaloids which were prepared earlier from (+)-7 that had been obtained through degradation of natural lysergic acid.