Solid-phase intramolecular N-acyliminium Pictet-Spengler reactions as crossroads to scaffold diversity

The Journal of Organic Chemistry
Thomas E Nielsen, Morten Meldal

Abstract

A novel solid-phase intramolecular Pictet-Spengler reaction is presented. The approach utilizes masked aldehyde building blocks protected as their N-Boc-1,3-oxazinanes for the clean generation of solid-supported aldehydes. When exposed to simple acidic treatment, the aldehyde functionality is rapidly released and becomes susceptible to nucleophilic attack from an amide nitrogen of the peptide backbone, which results in the formation of a highly reactive cyclic N-acyliminium ion. Subsequently, a quantitative and highly stereoselective Pictet-Spengler reaction takes place by attack of the indole from a neighboring tryptophan, thus appending two new N-fused rings to the indole moiety. Extension of this intramolecular reaction to substituted indoles, and other reactive heterocycles, such as furane and thiophenes, provides a convenient and rapid access to a range of pharmacologically interesting tri- and tetracyclic scaffolds. Finally, the reaction products may conveniently be released from the solid support (PEGA) by cleavage of the base-labile linker (HMBA).

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Citations

Dec 18, 2012·ACS Combinatorial Science·Agustina La VeniaViktor Krchňák
May 12, 2017·Chemical Reviews·Peng Wu, Thomas E Nielsen
May 12, 2006·Organic & Biomolecular Chemistry·Giovanna ZinzallaSteven V Ley
Dec 15, 2007·Angewandte Chemie·Thomas E Nielsen, Stuart L Schreiber
Sep 29, 2009·Chemistry : a European Journal·Wolfram WilkHerbert Waldmann
Mar 13, 2010·Biopolymers·Sebastian T Le QuementThomas E Nielsen
Aug 11, 2011·Angewandte Chemie·Joachim StöckigtHerbert Waldmann
Jan 22, 2020·Angewandte Chemie·Connor J ThomsonDarren J Dixon
Apr 16, 2015·Chemical Science·Tristan E RosePatrick G Harran
May 8, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Vanesa Giménez-Navarro, Viktor Krchňák
Oct 5, 2011·Organic & Biomolecular Chemistry·Mark DowAdam Nelson
Oct 27, 2010·Organic & Biomolecular Chemistry·Ekaterina ShinkevichKourosch Abbaspour Tehrani
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May 3, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Peng ZhangSai Wen
Jul 9, 2009·Organic Letters·Christian Bukovec, Uli Kazmaier
May 29, 2009·Journal of Combinatorial Chemistry·Daniel Blanco-AniaFloris P J T Rutjes

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