Methods, processes, and compositions for improved preparation of hu308 and hu433

A method of enantioselectively preparing a compound of formula 8:

• the method comprising:
• providing a first reactant of formula 12,
• performing a first allylic oxidation comprising compound 12, SeO2, and peroxide to yield a compound of formula 13:
• performing a protection reaction comprising compound 13, acid chloride, dichloromethane (DCM), and a first base to yield a compound of formula 14:
• performing a second allylic oxidation comprising compound 14, CrO3, tert-butyl hydroperoxide (TBHP), a first solvent to yield a compound of formula 15:
• performing a reduction reaction comprising compound 15, sodium borohydride (NaBH4) and ethanol to yield a compound of formula 16:
• performing an acid-catalyzed coupling reaction comprising compound 16, an acid, DCM, and a compound of formula 2:
• to yield a first mixture comprising a compound of formula 6:
• and a compound of formula 17:
• performing a coupling reaction comprising the first mixture, Boc-alanine, N,N′-dicyclohexylcarbodiimide (DCC), and 4-dimethylaminopyridine (DMAP) to yield a second mixture comprising a compound of formula 10:
• and a compound of formula 11:
• purifying the second mixture to yield enantiomerically purified compound 10;
• performing a hydrolysis reaction comprising enantiomerically purified compound 10, a third base and a third solvent, to yield enantiomerically purified compound 6;
• performing a methylation reaction comprising enantiomerically purified compound 6, dimethyl sulfate (Me2SO4), potassium carbonate (K2CO3) and acetone to yield an enantiomerically purified compound of formula 7:
• performing a deprotection reaction comprising enantiomerically purified compound 7, a second base and a second solvent to yield the enantiomerically purified compound 8;
• and
• isolating the enantiomerically purified compound 8.