Enantioselective Synthesis of the Novel Chiral Sulfoxide Derivative as a Glycogen Synthase Kinase 3.BETA. Inhibitor

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder manifested by cognitive and memory deterioration, progressive impairment of the activities involved in daily living, and behavioral disturbances. Glycogen synthase kinase 3b (GSK3b) inhibitors are thought to be attractive agents for the treatment of AD.1,2) Recently we reported a novel GSK-3b inhibitor ( Fig. 1) and this compound significantly reduced tau phosphorylation in a mouse model. 3)Compound (S)-1 initially was obtained by the resolution of racemic-1 using chiral high performance liquid chromatography (HPLC). Although separation by HPLC was a sufficient method for the preparation of small quantities of (S)-1, large scale production was expected to be problematic for this compound. Thus, we investigated asymmetric synthesis routes for (S)-1. Among the various methods of asymmetric oxidation for sulfides, 4) the method using a chiral titanium complex derived from a Sharpless reagent reported by Kagan and colleagues 5) is attractive. Our colleagues have previously applied this methodology to the synthesis of optically active lansoprazole.6) Therefore, we embarked upon optimizing reaction conditions for preparing (S)-1 from prochiral sulfides 2 (Chart 1). Results and DiscussionThe starting material, methyl sulfide 2 was prepared by the 6-step protocol previously reported.3) Spectroscopic data and X-ray crystal structures confirmed the configuration of (S)- 1.3) First, we attempted conditions similar to those used for the synthesis of chiral lansoprazole, 6) which used a stoichiometric amount of Ti(O-i-Pr) 4 , (ϩ)-diethyl tartrate (DET) as ligand, cumene hydroperoxide (CHP) as oxidant, and toluene or dichloromethane as solvent, in the presence of water. Because of the difficulty in separating the sulfoxide 1 and sulfone 3, we used substoichiometric CHP (0.83 eq) relative to sulfide. The condition using toluene as solvent resulted in production of undesired enantiomer with low enantiomeric excess (Table 1, entry 1). We assumed the low enantioselectivity was caused by low solubility of sulfide 2 in toluene. Therefore, we used dichloromethane as solvent and reaction proceeded in a homogenous solution to show improved enantiomeric excess of 66% ee (entry 2). From this result, we used dichloromethane in further investigations. Since (ϩ)-DET resulted in the conversion of sulfide 2 to the undesired (R)-1, we changed the ligand to (Ϫ)-DET. It is known that the amount of water significantly affects the selectivity of this reaction. 5) Although combination of Ti(O-i-Pr) 4 /H 2 O (1 : 1) is effective in enantioselective oxidation, 7) 0.5 eq of water ensured a good enantiomeric excess for this particular substrate (entries 3-5). Lower temperature was preferred in terms of selectivity and afforded good enantiomeric excess (entries 6-8). However, the reaction rate tended to be slow at low temperatures and reaction was not completed within 24 h at Ϫ40°C (entries 9, 10). Enantioselectivity was not affected by the use of molecular sieves (entry 11).7) Other ligands suc...

Cognitive Enhancers (Nootropics). Part 2: Drugs Interacting with Enzymes. Update 2014

“…Takeda (Osaka) presented very potent GSK-3␤ inhibitors with 1,3,4-oxadiazole structures with IC 50 values of 2 nM [464][465][466]. The chiral sulfoxide MMBO (Fig.…”