Iminium ions, cyclisation

Lateral lithiation of 244 and intramolecular electrophilic substitution with iminium ions derived from the partly reduced phthalimide 247 in acidic solution leads to the polycyclic derivatives37 such as 248. The 4-Me compound cyclises with some regioselectivity favouring para to OMe. 

Three enantiomerically pure starting materials ensure remote stereochemical control Tandem iminium ion formation and vinyl silane cyclisation Part IV - Tandem Pericyclic Reactions Electrocyclic Formation of a Diene for Diels-Alder Reaction Tandem Ene Reactions Tandem [3,3]-Sigmatropic Rearrangements Tandem Aza-Diels-Alder and Aza-Ene Reactions... 

A protected version 99 of 98 is easily made and the tandem sequence works well. The unstable iminium ion 100 is formed in low concentrations but cyclises under the acidic conditions to form 101, the protected version of 96. 

It is initially puzzling that it is not necessary to hydrolyse the acetal before the Mannich reaction. Under the acidic conditions, the acetal is in equilibrium with the end ether and this is reactive enough to combine with the very electrophilic iminium ion 102. The stereochemistry of the product is determined in this cyclisation step and simply ensures that the two five-membered rings are cis fused. 

Even unactivated double bonds will cyclise onto reactive iminium salts as this synthesis of cis-4-hydroxy pipecolic acid 116 R = H shows. This is like a Prins reaction but involves an iminium ion instead of an aldehyde.18... 

Tandem iminium ion formation and vinyl silane cyclisation... 

Now comes the critical moment. Treatment of 141 with acid (camphor sulfonic acid is used, not because it is enantiomerically pure, but because it is convenient) opens the heterocyclic ring to give the unstable iminium ion that cyclises onto the vinyl silane 142 to give the (5-silyl cation 143 with retention of configuration at the alkene. The product 144 is formed in only moderate yield (52% from 141) but contains no trace of the F-isomer. 

Ni(COD)2/dppf catalyses the cyclisation of N-benzoyl aminals in the presence of a stoichiometric Lewis acid, forming isoindolinones in 43-76% yields. The reaction may occur via an iminium-ion intermediate formed by reaction of iV-benzoyl aminals with Lewis acid. Reaction of the iminium-ion intermediate with electron-rich Ni(0) leads to cyclisation products (Scheme 14.60). ... 

The cyclisation reactions of A-acyl iminium ions have yielded a wide range of distinct small molecule scalfolds (Scheme 1.6). Initially, peptide synthesis was used to connect a range of functionalised amino acid building blocks. Each of the resulting peptides, 18, was designed to contain a masked aldehyde, a suitably positioned secondary amide, and a pendant nucleophile. Treatment of the peptides with acid triggered the release of an aldehyde, the formation of an A-acyl iminium ion, and cyclisation to yield a final scalfold e.g. 19a-f). 

Scheme 1.6 Cyclisation of Af-acyl iminium ions in the synthesis of a range of small...

The cyclisation of the alkene onto the iminium salt must be concerted with the attack of the azide ion to some degree to account for the stereochemical control. Presumably the molecule folds as 127 and azide attacks at the back of the alkene through a transition state like 128. In these diagrams the OH group is drawn in the anomerically more stable axial conformation. 

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