Remodelling of the natural product fumagillol employing a reaction discovery approach.
In the search for new biologically active molecules, diversity-oriented synthetic strategies break through the limitation of traditional library synthesis by sampling new chemical space. Many natural products can be regarded as intriguing starting points for diversity-oriented synthesis, wherein stereochemically rich core structures may be reorganized into chemotypes that are distinctly different from the parent structure. Ideally, to be suited to library applications, such transformations should be general and involve few steps. With this objective in mind, the highly oxygenated natural product fumagillol has been successfully remodelled in several ways using a reaction-discovery-based approach. In reactions with amines, excellent regiocontrol in a bis-epoxide opening/cyclization sequence can be obtained by size-dependent interaction of an appropriate catalyst with the parent molecule, forming either perhydroisoindole or perhydroisoquinoline products. Perhydroisoindoles can be further remodelled by cascade processes to afford either morpholinone or bridged 4,1-benzoxazepine-containing structures.
Department of Chemistry, Center for Chemical Methodology and Library Development, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, USA.
Bradley R
BR
Balthaser
Meghan C
MC
Maloney
Aaron B
AB
Beeler
John A
JA
Porco
John K
JK
Snyder
D000588:Amines / Q000737:chemistry; D003500:Cyclization; D003510:Cyclohexanes / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D012717:Sesquiterpenes / Q000737:chemistry*
D000588:Amines; D003510:Cyclohexanes; D012717:Sesquiterpenes; C057299:fumagillol