Enzyme Inhibitors. XIX. The Synthesis of Some l-Hydroxy-2-hydroxymethyl-4-(6-substituted-9-purinyl)cyclohexanes as Nucleoside Analogs

Howard J. Schaeffer, Robert Vince

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14 Scopus citations

Abstract

The syntheses of some 1-hydroxy-2-hydroxymethyl-4-(6-substituted-9-purinyl)cyclohexanes were accomplished by the following procedure. Diethyl 4,4-ethylenedioxypimelate on Dieckmann cyclization gave 2-carbethoxy-4,4-ethylenedioxycyclohexanone. Catalytic hydrogenation of the ketone followed by LiAlH4 reduction of the ester gave 2-hydroxymethyl-4,4-ethylenedioxycyclohexanol which after several additional reactions was separated into trans- and cis-3-acetoxymethyl-4-acetoxycyclohexanes (5a and 5b). Hydrogenation of the ketone group of 5a and 5b gave the alcohols which were converted into tosylates. Displacement of the tosylate with azide followed by catalytic hydrogenation of the azides gave the amines. The major product from 5a was 1α-amino-3α-hydroxymethyl-4β-hydroxycyclohexane, whereas 5b gave nearly an equal mixture of 1α- and 1β- amino-3α-hydroxymethyl-4α-hydroxycyclohexanes. The stereochemistry of these trisubstituted cyclohexanes was deduced from nmr studies. Finally two of these amines were converted into some lβ-hydroxy-2α-hydroxymethyl-4α-(6-substituted-9-purinyl)cyclohexanes and 1α-hydroxy-2α-hydroxymethyl-4α-(6-amino-9-purinyl)-cyclohexane. These compounds were not potent inhibitors of adenosine deaminase, possibly because they are repelled by the hydrophobic region of this enzyme.

Original languageEnglish (US)
Pages (from-to)15-20
Number of pages6
JournalJournal of Medicinal Chemistry
Volume11
Issue number1
DOIs
StatePublished - Jan 1 1968
Externally publishedYes

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