Conformationally constrained analogues of diacylglycerol. 24. Asymmetric synthesis of a chiral (R)-DAG-lactone template as a versatile precursor for highly functionalized DAG-lactones.
[structure: see text] Commercially available 2-methylenepropane-1,3-diol was converted to chiral epoxide (R)-2 via Sharpless asymmetric epoxidation in >96% ee. Regiospecific epoxide ring opening and reduction of the intermediate alkyne set the stage for a one-pot lactonization to give (R)-6, a convenient precursor for all functionalized chiral DAG-lactones used as potent PK-C ligands. The synthesis of the most potent DAG-lactones known to date, (Z)-10 and (E)-10, served to confirm PK-C's exclusive preference for the (R)-stereochemistry in this class of compounds.
Kang
Ji-Hye
JH
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
Siddiqui
Maqbool A
MA
Sigano
Dina M
DM
Krajewski
Krzysztof
K
Lewin
Nancy E
NE
Pu
Yongmei
Y
Blumberg
Peter M
PM
Lee
Jeewoo
J
Marquez
Victor E
VE
D001665:Binding Sites; D002384:Catalysis; D004075:Diglycerides / Q000737:chemistry*; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis*; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D011493:Protein Kinase C / Q000378:metabolism*; D013237:Stereoisomerism
C011439:1,2-diacylglycerol; D004075:Diglycerides; D004852:Epoxy Compounds; D007783:Lactones; D008024:Ligands; D011493:Protein Kinase C