A New Synthesis of (±)-Celacinnine by Means of Non-spermoidine-based Methodology

+)-Celacinninewas synthesized r e l y i n g on the novel methodology which features n u c l e o p h i l i c r i n g opening o f 2-substituted 5,6-dihydro-4H-1,3oxazine as a carboxamide synthon and requires n e i t h e r spermidine n o r amino a c i d condensation process f o r the lactam framework.Celacinnine (1) was i s o l a t e d from Maytenus serrata by Kupchan and co-workers1 and belongs t o the p l a n t a l k a l o i d derived from spermidine which i s an important c o n s t i t u e n t of every l i v i n g c e l l as spermine does so.'Because o f the notable b i o l o g i c a l a c t i v i t y shown by members of these polyamine an a c t i v e e f f o r t has been made on the t o t a l synthesis o f these n a t u r a l ~r o d u c t s .~ As f a r as 1 i s concerned, three representative routes t o 1 have proven t o be f e r t i l e so far, t h a t highl i g h t 1 ) s e l e c t i v e N-alkylation o f spermidine and subsequent macrocyclization between amino-and t e t r a b u t y l a m n i u m carboxylate-groups promoted by c a t e c h ~l b o r a n e , ~2) successive r i n g expansion through a transamidation process i n v o l v i n g a m i n ~l a c t a m , ~ and 3) stepwise manipulation o f spermidine framework and f i n a l intramolecular aminolysis o f aminoester system f a c i l i t a t e d by boron-template, 7respectively.Recent e f f o r t i n our laboratory t o u t i l i z e 2-methyl-5,6-dihydro-4H-l,3-oxazine (2) as a potent secondary carboxamide b u i l d i n g blocka has prompted us t o apply such idea t o the t o t a l synthesis of 1i n order t o t e s t the f e a s i b i l i t y o f t h i s strateqy (Scheme 1) i n the synthesis of polyamine lactam family.Retrosynthetic design based on the strategy i s o u t l i n e d i n Scheme 2. This, i f successful, would become an unprecedented method o f polyamine lactam synthesis which requires n e i t h e r spermi-Scheme 1 Me$SiNa-McOH DMF