Studies in stereoselective synthesis via reissert compound chemistry

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Virginia Tech


Isoquinoline alkaloids have long been known for their biological activity. Many of the isoquinoline alkaloids have been made as racemic mixtures. The present investigation was aimed at developing methodology for the asymmetric synthesis of some isoquinoline alkaloids through Reissert compound chemistry.

The stereochemistry of lepidine and isoquinoline Reissert compounds has not been reported. To better understand the stereochemistry of these compounds, selected Reissert compounds were synthesized and subsequently studied by proton NMR. The two types of isomerism studied were amide isomerism and aryl / carbonyl rotation. In at least some cases, both amide isomers and restricted aryl / carbonyl rotamers were observed. For other cases only the restricted aryl / carbonyl rotamers were observed. The presence of ortho substituents on the aroyl moiety was found to greatly increase the chance amide isomerism on the NMR time scale.

(-)-Menthy] chloroformate, (+)-menthy] chloroformate, and (-)-menthoxyacety] chloride have been utilized as chiral acyl auxiliaries to induce the stereochemistry at C,, resulting in diastereomeric isoquinoline Reissert compounds.

By reaction of a mixture of the diastereomeric Reissert anions of 2-(1)-(mentho1 ,x2-ydichyadrroisboqouinnayldolni)tr-il e (110) with pivaldehyde we were able to form the resulting diastereomeric carbonates of 1-isoquinolyl-t-butyl carbinyl menthyl carbonate (120) in a 77:23 ratio by NMR [82 : 18 ratio by HPLC). After obtaining the major diastereomer of the carbonate in pure form, hydrolysis yielded the enantiomerically pure (S)-(-)-1-isoquinoy] t-buty] carbinol (121).

The proton NMR spectra of the diastereomeric Reissert compounds led to elucidation of the stereochemistry. The diastereomeric ratios were determined for both 110 and 2-(1)-methoxyacetyl- 1 ,2-dihydroisoquinaldonitrile (125). Amide isomerism was observable in the case of 110 but not in the case of 125. Aromatic solvent induced shift (ASIS) studies of the compound 125 showed the s-trans amide to be predominant. The reaction of the diastereomeric Reissert anion of 110 with CS, and partial conversion with pivaldehyde allowed us to determine that the Reissert anion equilibrates.

Reaction of the anion of 125 with pivaldehyde gave 1-isoquinolyl t-butyl carbinyl menthyl acetate (127) in quantitative yield and 0 % de. However, the diastereomers are easily separated using simple silica gel column chromatography.