Synthesis of the first fluorinated cantharidin analogues

Norcantharidin Analogues: Synthesis, Anticancer Activity and Protein Phosphatase 1 and 2A Inhibition

“…[4] Several groups, including our own, have reported SAR studies of compounds 1 and 2 in order to ascertain the key inhibitory features of these molecules. [16][17][18][19][20][32][33][34][35][36][37] Evaluation of norcantharidin derivatives as PP inhibitors showed that analogues containing a C5=C6 lost some potency, although a few compounds exhibited some selectivity between PP1 and PP2A. [33,35] The C7ÀO bridgehead is involved in a key hydrogen bonding interaction with the protein phosphatase, consequently, modifications to this moiety are detrimental to the PP inhibition.…”

Synthesis and Diels–Alder reactions of α-fluoro- and α-trifluoromethylacrylonitriles

“…cyclohexene derivatives [40,41]. This type of reactions has been shown to be of particular interest in syntheses of fluorinated analogues of biologically active compounds such as cantharidin, endothall [42] and D-homosteroids [43]. Previously, we found that simple vinyl fluorides such as a-or b-fluorostyrenes are weak dienophiles which only react with very active dienes like diphenylisobenzofuran [44,45] or some fluorinated cyclohexa-2,4-dienones [46].…”

Fluorinated Furan‐2(5H)‐ones: Reactivity and Stereoselectivity in Diels–Alder Reactions

“…[25] On the other hand, it has already been observed that the reactions of other α-fluoro-α,β-unsaturated carbonyl compounds with cyclopentadiene, [6][7][8] other 1,3-dienes [11] and particularly with furans led preferably to exo isomers. [5,18] However, a 98 % endo selectivity has recently been reported for the reaction between diphenylisobenzofuran and 2-fluoro-5-(hydroxymethyl)but-2-en-4-olide in acetonitrile at 170°C for 6 hours. [26] In contrast, the reactions of 3,4-difluoro-5-methyl-(2) and 5-(3-bromopropyl)-3,4-difluorofuran-2(5H)-one (3) with the same diene on heating in toluene at 130°C in a sealed tube were complete after 2 days.…”

“…[11,17] Recently, we used the Diels-Alder reactions between 2-fluoro-and 2,3-difluoromaleic anhydrides and furan to synthesize fluorinated analogues of the protein phosphatase inhibitor cantharidin. [18] Unfortunately, the anhydride moieties in the products appeared to be very easily hydrolysed to afford dicarboxylic acids exhibiting low bioactivity. With a lactone ring replacing the anhydride the hydrolytic stability of the [4+2] cycloadducts might be increased.…”