Ruthenium-catalyzed alkene-alkyne coupling: synthesis of the proposed structure of amphidinolide A.
The ruthenium-catalyzed alkene-alkyne coupling provides a powerful method for the synthesis of 1,4 dienes and a way to simplify synthetic strategy. The latter potential is explored in the context of a synthesis of the assigned structure of amphidinolide A, which also raises the question of the applicability of this reaction for macrocyclizations. Employing this reaction allows simplification of the target to three subunits corresponding to C-1 to C-6, C-7 to C-15, and C-16 to C-25. The C-7 to C-15 subunit involves introduction of chirality by an asymmetric dihydroxylation. The route to the C-16 to C-25 subunit introduces chirality by a Pd-catalyzed asymmetric allylic alkylation and an asymmetric epoxidation. Assembly of the three subunits employs the Ru-catalyzed addition inter- and intramolecularly. The synthesis culminated in the formation of the assigned structure and is identical to the synthetic samples prepared independently by two completely different routes. As noted by the other two groups, this structure appears to be a diastereomer of the natural product. Because this synthesis introduces all of the stereochemistry of the subunits by catalytic asymmetric processes, either enantiomer as well as diastereomers can be readily accessed to define the correct structure. Notably, the Ru-catalyzed macrocyclization to this macrolide proceeded in better yields than either a Pd-catalyzed cross-coupling or a Ru-catalyzed metathesis, macrocylization methods for the other two total synthesis.
Trost
Barry M
BM
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA. bmtrost@stanford.edu
Chisholm
John D
JD
Wrobleski
Stephen T
ST
Jung
Michael
M
D000475:Alkenes / Q000737:chemistry*; D000478:Alkylation; D000480:Alkynes / Q000737:chemistry*; D002384:Catalysis; D007783:Lactones / Q000138:chemical synthesis*; D018942:Macrolides; D010880:Piperidines / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry; D000097442:Amphidinolides
D000475:Alkenes; D000480:Alkynes; D007783:Lactones; D018942:Macrolides; D010880:Piperidines; D012428:Ruthenium; C469329:amphidinolide A; D000097442:Amphidinolides