Solid-phase synthesis of pyrroloisoquinolines via the intramolecular N-acyliminium Pictet - Spengler reaction

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In the present investigation, solid-phase routes toward 1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-ones via the intramolecular N-acyliminium Pictet - Spengler reaction are established. Peptide aldehydes generated from their parent N-Boc 1,3-oxazines by acidic reaction conditions undergo intramolecular condensation reactions with the amide N of a solid-supported peptide backbone, thus forming a 1:1 epimeric mixture of a cyclic 5-hydroxylactam, which in turn is in equilibrium with the corresponding intermediate N-acyliminium ion. Provided appropriate acidic reaction conditions, a second ring may be appended via Pictet-Spengler cyclization from the aromatic ring of a neighboring phenylalanine derivative in the peptide sequence. The aromatic substitution pattern of the nucleophilic benzene ring of the phenylalanine derivative and the nature of the acidic reaction media are critically important for the course of the reaction, and both Lewis and Brønsted acids may be employed to effect the cyclization process. This intramolecular reaction is under strict control of stereoselectivity, and only a single stereoisomer is detected in the crude products. A range of mono-, di-, and trisubstituted phenylalanines with diverse sets of electron-donating and electron-withdrawing substituents, pyrene, and naphthalenes have successfully been brought within the scope of the reaction, thus providing a unique scaffold for combinatorial library synthesis.

TidsskriftJournal of Combinatorial Chemistry
Udgave nummer4
Sider (fra-til)599-610
Antal sider12
StatusUdgivet - jul. 2005
Eksternt udgivetJa

ID: 326847152