Diverging Rh(I)-catalyzed carbocylization strategy to prepare a library of unique cyclic ethers.
A library of 90 carboxamide-containing oxepines and pyrans was synthesized. A dual-branching strategy was used where a common intermediate, an allenyl-hydroxy ester, was either allylated or propargylated then subjected to rhodium(I)-catalyzed carbocyclization reaction conditions to afford an oxepine- or triene-containing pyran, respectively. The oxepines were selectively reduced to afford two functionally unique scaffolds using complementary hydrogenation conditions. Diversification of the oxepines and pyrans involved conversion of the methyl carboxylate group to a carboxamide via either a microwave-assisted amidation using polymer-bound carbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) or a NaCN-catalyzed aminolysis. The scope of a rarely used carbonyl-yne reaction was expanded to the preparation of 10 new allenyl-hydroxy esters using microwave irradiation. Finally, a cell-based diversity analysis using BCUT (Burden (B) CAS (C) Pearlman at the University of Texas (UT)) metrics calculations and two-dimensional fingerprint similarity approaches shows that when compared to the 100,000 Pittsburgh Molecular Library Screening Center (PMLSC) compound database and PubChem the new compound library occupies a unique chemical space.
Mao
Shuli
S
University of Pittsburgh Center for Chemical Methodologies & Library Development and Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Probst
Donald
D
Werner
Stefan
S
Chen
Jianzhong
J
Xie
Xiangqun
X
Brummond
Kay M
KM
D002384:Catalysis; D003500:Cyclization; D004987:Ethers / Q000737:chemistry*; D012211:Rhenium / Q000737:chemistry*
D004987:Ethers; D012211:Rhenium