Polymer-supported Petasis Borono-Mannich Reactions

Polymer-supported Petasis Borono-Mannich Reactions 

Klopfenstein and co-workers outlined a solid-phase route to the synthesis of peptide mimetics using the Petasis borono-Mannich reaction [57]. In this study, a Wang resin supported Fmoc-protected amino acid 57 (attached via an ester linkage) was first reductively aminated to give a secondary amine 58, which was then reacted with 

The poor de of each final product 60 presumably reflects a non-stereoselective Petasis borono-Mannich step. Although few examples were given, die authors allude to the utility of the process in a high-throughput fashion, using 96-well reaction blocks, for the creation of peptide mimetics. 

The boronic acid component can also be attached directly to the resin, as shown by Hansen and co-workers [33], A Wang-resin supported arylboronic acid (66) was coupled with either glyoxylic acid or salicylaldehyde and secondary amines (Equation 11). Products were obtained in high purities but low yields (as for 67), a factor that may be due in part to the electron-deficient nature of the supported arylboronic acid. 

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Polymer-supported Petasis Borono-Mannich Reactions... 

Scheme 7.13 Application of polymer-supported amines in the Petasis borono-Mannich reaction.

Finn also showed the formation of 2H-chromenes under the same reaction conditions, using alkenylboronic acids and morpholine in dioxane at 90 °C. A more convenient route to the 2H-chromenes was then developed using a catalytic amount of dibenzylamine in the presence of alkenylboronic adds and salicylaldehyde (42, Scheme 7.11) [30]. Chromenes 43 were reported to arise from the initial Petasis borono-Mannich adducts 44 via an add promoted intramolecular S 2 attack of the ortho-hydroxyl group onto the protonated allylic amine of intermediate 45. A more likely mechanism involves elimination from 45 to intermediate 46, followed by 6n-electrocychzation to the product The reaction is tolerant of various functional groups and substitution patterns on the salicylaldehyde, and could also be promoted using a polymer-supported base, such as Merrifield resin-supported dibenzylamine (40-50 mol%) [30]. 

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