Diastereoselective Tandem 6-exoCarbolithiation Intramolecular Ring Opening in (−)-8-Aminomenthol-Derived Perhydrobenzoxazines. A New Synthesis of Enantiopure 4-Substituted Tetrahydro Isoquinolines and 2-Azabenzonorbornanes

Abstract

Aryllithiums prepared by bromine-lithium interchange in chiral 2-(o-bromophenyl)-substituted perhydro-1,3-benzoxazines participate in the intramolecular 6-exo carbolithiation reaction with unactivated double bonds attached to the nitrogen substituent of the heterocycle. When the reaction time is extended or no TMEDA is used, the cyclized lithium intermediates react intramolecularly with the N,O-acetal system leading to 2-azabenzonorbornane derivatives. The reactions are highly stereoselective and constitute a high-yielding synthesis of enantiopure 4-substituted tetrahydroisoquinolines or 7-substituted 2-azabenzonorbornanes.

Stereocontrolled synthesis of vicinally functionalized piperidines by nucleophilic β-addition of alkyllithiums to α-aryl substituted piperidine enecarbamates

“…5b,26,27 This is supported by NBO analysis of 18a/b (Figure 5) where C–Li bonding is not pronounced (see the Supporting Information for a full reaction coordinate/transition state analysis). In contrast, for the C2-methyl intermediate 19 , a highly covalent C2–Li bond was computed.…”

Inter- and intramolecular enantioselective carbolithiation reactions

“…The 6- exo cyclization of an aryllithium intermediate is also possible, but generally the alkene has to be substituted with a stabilizing group for the resulting organolithium to favor the cyclization, as has been shown before for alkyllithium derivatives (Scheme 12) [44]. This type of reaction has been used, for instance, for the diastereoselective synthesis of enantiomerically pure isoquinoline rings [34,37], but just a few examples of the enantioselective variant have been reported so far. Thus, as shown on Scheme 18, the cyclization of the aryllithium generated from 49a does not occur on the unsubstituted alkene, whereas the introduction of an amide group favors a fast cyclization at low temperature, and pyrroloisoquinoline 50b is isolated in good yield.…”

From Berbines to Protopines: Regiocontrolled Hofmann Elimination/Hydroboration/Oxidation of N‐Substituted Berbinium Salts

“…In order to avoid this competitive process a minor modification of the standard PCC oxidation procedure, using sodium acetate and molecular sieves, [15] allowed us to obtain the corresponding protopine derivatives 7a,b in good yields.…”