A short synthetic route to (+)-austamide, (+)-deoxyisoaustamide, and (+)-hydratoaustamide from a common precursor by a novel palladium-mediated indole --> dihydroindoloazocine cyclization.
The first synthesis of (+)-austamide (1), (+)-deoxyisoaustamide (2), and (+)-hydratoaustamide (10) by a very direct route is described (Scheme 1). Starting from tryptophan methyl ester (3) intermediate 5 is generated in two steps in >98% overall yield. The key step in the synthesis is a novel cyclization of 5 involving organopalladium intermediates which gives the dihydroazocine 6. From this key intermediate the target structures are accessible in just a few steps as shown in Scheme 1. The remarkable conversion of 5 --> 6 can be rationalized by the mechanistic pathway shown in Scheme 2 that involves a multistep sequence which includes palladation, cyclization, and rearrangement.
Baran
Phil S
PS
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Corey
E J
EJ
D001392:Azocines / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis*; D010165:Palladium / Q000737:chemistry*; D013237:Stereoisomerism; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry
D001392:Azocines; D007211:Indoles; C463619:austamide; C463620:deoxyisoaustamide; C463621:hydratoaustamide; D010165:Palladium; C028129:tryptophan methyl ester; D014364:Tryptophan