The application of enantiopure sulfinimines towards the asymmetric synthesis of tetrahydroisoquinolines and tetrahydronaphthyridines

Enantiopure tetrahydroisoquinolines (THIQ's) and tetrahydronaphthyridines represent a large class of naturally occurring alkaloids which possess a broad range of biological activities. The usual methods for the synthesis of these compounds involve an intramolecular electrophilic aromatic cyclization step to form the nitrogen containing ring of the isoquinoline; i.e. Bischler-Napieralski, Pictet-Spengler, Pomeranz Fritch reactions. Although these methods have been successfully exploited for the synthesis of various isoquinolines, the success of these methods is greatly enhanced when the aromatic ring is exceedingly electron rich which may not always be present in the target molecule. Also, these procedures require relatively harsh reaction conditions and suffer from unreliable regio- and stereoselectivity as well as side reactions involving reactive nitrilium ion intermediates.;An alternative method for the synthesis of tetrahydroisoquinolines was discovered that involves the addition of laterally lithiated species to enantiopure sulfinimines (N-sulfinyl imines) to afford sulfinamides which are then cyclized to form enantiopure THIQ's in just a few steps. This new methodology was applied towards the asymmetric synthesis of xylopinine as well as cis- and trans-6,8-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline. It was found that the nitrile directing group sufficiently lowered the pKa of the o-alkyl group and allowed for deprotonation with amine bases. The diastereoselectivity of the addition product (sulfinamide) could easily be determined by integration of the p-Tolyl methyl protons from the 1H NMR spectra.;The concise asymmetric synthesis of a tetrahydronaphthyridine alkaloid, (−)-normalindine was successfully completed in eight total steps from the addition of the laterally metallated 3-cyano-4-methylpyridine to N-[(1E)-(1-(4-methoxybenzyl)-3-{2[(4-methoxybenzyl)oxy] ethyl}-1H-indol-2-yl)methylene]-4-methylbenzenesulfinamide with an overall yield of 8.8%. The methodology developed in the synthesis of (−)-normalindine could be used towards the synthesis of other electron deficient THIQ and tetrahydronaphthyridines.;The asymmetric synthesis of a 1,2,3-tetrahydroisoquinolin-4-ols was also explored. The addition of a laterally lithiated dithiane o-benzoic acid methyl ester to an enantiopure sulfinimine provided the corresponding isoquinolone directly in excellent yield and high enantioselectivity. Further modification via a palladium catalyzed Fukuyama-Liebeskind-Negishi coupling of a thioimidate with alkyl zinc reagents was exploited to introduce substituents to the C-1 position of the isoquinoline.