Diastereoselective radical cyclization reactions: the synthesis of O-methylcorytenchirine

Abstract

Highly diastereoselective cyclization of radicals such as 4 provides a model for the synthesis of 8-substituted berbines. Thus the reaction of 6,7-dimethoxyisoquinoline 21 with the acid chloride 19 affords the key intermediate 22, which undergoes free radical cyclization on treatment with tributylstannane to give (±)-23 as the sole product. Reduction of 23 affords (±)-Omethylcorytenchirine 14. The carbamate 24 does not undergo radical cyclization when treated with tributylstannane, but the acetyl pyridine 33 affords the cyclized products 37 and 38 in reasonable yield and with good diastereoselectivity.

β-Phenylethylamines and the isoquinoline alkaloids

“…A synthesis of (±)-O-methylcorytenchirine has been achieved by the reaction of 6,7-dimethoxy-1-methyl-1,2-dihydroisoquinoline 94 with 2-bromo-4,5-dimethoxyphenylacetyl chloride 95 to give the amide 96, which readily underwent free radical cyclisation on treatment with tributyltin to racemic cis-8-oxo-Omethylcorytenchirine 97, which was reduced by lithium aluminium hydride to O-methylcorytenchirine 98. 58…”

Development of a cascade reaction to access complex tetrahydro-3,4'-biisoquinoline

“…THBIQs structural motifs are very scarce in the literature. Only one known example (5) was reported thus far by Bobbitt et al in 1965 (Scheme 1b). 8 Using very long reaction time (6 days), 5 was isolated as a byproduct in 24% yield from a Friedel-Crafts approach to tetrahydroisoquinolines.…”

“…3 However, unlike C-1-functionalized tetrahydroisoquinolines which are easily accessible, the synthesis of C-3-arylated tetrahydroisoquinolines without prefunctionalization is highly challenging. Methodologies such as the Bischler-Napieralski cyclization/reduction sequence, 4 radical cyclization approach, 5 and palladium-catalysed aryl-aryl coupling/reduction reactions 6 were mostly used. However, all of these methods require multi step synthesis.…”

“…Furthermore, NMR data were not reported for 5. Intrigued by this complex tetrahydro-3,4'-biisoquinoline (5) and its potential utility in one of our medicinal chemistry project, we thought that a cascade reaction sequence could be more suitable to access this structurally interesting THBIQs scaffold (Scheme 1c). 9 Herein, we introduce an unprecedented cascade approach under mild conditions and using simple achiral/chiral and readily accessible substrates for the synthesis of various substituted tetrahydro-3,4'biisoquinolines.…”