Abstract
A concise and high-yielding double aza-Michael reaction is presented as an atom-efficient method to access chiral 2-substituted 4-piperidone building blocks from divinyl ketones. The piperidones were further converted into analogues of donepezil, an acetylcholinesterase inhibiting drug used in the treatment of Alzheimer’s disease. The donepezil analogues were obtained as inseparable diastereomeric mixtures with resolved stereochemistry in position 2 of the piperidine ring. Biological evaluation of the acetylcholinesterase inhibition by these analogues provides a new insight into structure–activity relationship studies with regard to donepezil’s piperidine moiety toward stereochemical enhancement.
Highlights
The piperidine ring is an important scaffold in pharmaceutical research and a ubiquitous structural motif which is present in several natural products.[1,2] In general, the 1,4-disubstitution pattern on the piperidine ring prevails among drug prototypes due to more accessible synthetic routes and limited stereochemical complications
Our approach toward the synthesis of donepezil analogues 4 (Scheme 1) involves the use of chirally resolved 2-substituted 1-S-α-phenylethyl-4-piperidones 2 that are further converted into aldehyde intermediates 3
The first step toward the synthesis of divinyl ketones 7 was the reaction of suitable vinyl aldehydes 5 with vinylmagnesium bromide under standard Grignard conditions (Scheme 2)
Summary
The piperidine ring is an important scaffold in pharmaceutical research and a ubiquitous structural motif which is present in several natural products.[1,2] In general, the 1,4-disubstitution pattern on the piperidine ring prevails among drug prototypes due to more accessible synthetic routes and limited stereochemical complications. By modifying the reported synthesis of donepezil,[28] diastereomeric methyl- and phenyl-substituted 4-piperidones building blocks 2a + c and 2′a + c were subjected to a Wittig reaction using [(Ph3)PCH2OCH3]Cl and lithium diisopropylamide (LDA),[29] to generate the corresponding methoxymethylene derivatives 9a− d + 9′a−d in good to high yields (Table 3). Mixture of 2S-methyl-substituted aldehydes 3 + 3′a and 2Rmethyl-substituted aldehydes 3 + 3′b was subjected to the aldol condensation reaction (Table 5, entries 1 and 2), not trivially separable methylene products were obtained and their diastereomeric ratios could be determined by analysis of the signals for the olefinic protons in the crude 1H NMR spectra. Substituent in position 4 in relation to the stereochemistry of the substituent in position 2 (i.e., syn- or anti- conformation) significantly influences the overall inhibitory activity of the diastereomeric mixtures
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