Synthesis of Benzylic Functionalised Ether Linked Series
The OHOH compounds originated from a potent lead produced during a Pfizer biosynthesis experiment. Laboratory re-synthesis is fairly lengthy at six steps from a common intermediate.
The synthesis starts with the acid catalyzed protection of Tris to give 1 followed by oxidative cleavage to the ketone 2. The appropriate Grignard reagent is then prepared and reacted with 2 to give 3. This then needs to be de-protected, and subsequently re-protected to leave the desired secondary alcohol group free, compound 5. Compound 5 is then coupled to the core with sodium hydride to give the protected OHOH 7. Acid de-protection (HCl) gives the final OHOH compound 8.
ELN link for the synthesis of the phenyl, 3,4-difluoro and N-dimethylaniline.
Attempts to use the unprotected triol, 4, directly in the substitution step were unsuccessful, with a number of unstable side-products produced.
These compounds are synthesised through the mono-substitution of a symmetric diol onto the chlorotriazolopyrazine core. Protecting groups are not required for successful results. There are two options for the synthesis of the diol: 1) Reaction of a phenylacetic acid ethyl ester with diethylcarbonate in the presence of NaH (see Ed Tse's EGT 374) or 2) catalytic arylation of diethyl malonate. Both result in a diester which is reduced with lithium aluminum hydride to the intended diol.