Enantioselective Synthesis of Tetrahydroisoquinolines which have a Quaternary centre at C-1

Abstract

<p> The reactions of methyllithium and phenyllithium with the iminium chloride, [(2R,3S)-2,3-dihydroxy-3-(6,7 -dimethoxy-3,4-dihydroisoquinolin-1-yl)]propionate hydrochloride, 34 as a means of preparing enantiomerically pure compounds are described. These reactions afford a single product in high yield. The nmr spectra of the products, 1-(1 ,2,3-trihydroxy-3,3-dimethylpropyl)-1 ,2,3,4-tetrahydro-6,7 -dimethoxy-1- methylisoquinoline 54 and 1-( 1,2,3-trihydroxy-3,3-diphenylpropyl)-1,2,3,4-tetrahydro-6,7- dimethoxy-1-phenylisoquinoline 62, are discussed and an explanation is given to account for the diastereoselectivity of the reaction. By this method, enantiomerically pure compounds bearing a quaternary centre at C-1 of the tetrahydroisoquinoline system may be prepared. Oxidative degradation of the hydroxylated side chain of compound 62 has led to the preparation of several other new compounds. </p> <p> The usefulness of the t-butoxycarbonyl group as a selective protecting group for nitrogen in the preparation of 2-t-butyloxycarbonyl-1,2,3,4-tetrahydro-1-(1,2,3- trihydroxy-3,3-dimethylpropyl)-6,7-dimethoxy-1-methylisoquinoline 59 is described. It has advantages over the ethoxycarbonyl group in that it not only selectively protects the amino group but also is easy to remove by short treatment with trifluoroacetic acid and water at room temperature. Treatment of 59 with sodium periodate afforded the aldehyde, 1-formyl-2-t-butyloxycarbonyl-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline, 60. An attempted oxidation of the aldehyde 60 to the acid is also described. </p> <p> A review of recent methods of inducing chirality at C-1 of the tetrahydroisoquinoline system is given in the Introduction. </p>