Solid-Phase Library Synthesis of Alkoxyprolines

Boldi, Armen M.; Dener, Jeffrey M.; Hopkins, Thutam P.

doi:10.1021/cc010007s

Cited by 20 publications

(9 citation statements)

References 20 publications

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“…Then, as reported by Boldi et al, we attempted the coupling of N -Fmoc-protected trans -4-hydroxyproline (Fmoc-Hyp) with the resin-bound amine. Several conditions were tested as follows: HOBt/DIC or HOBt/pyBOP/DIEA at different concentrations.…”

Section: Resultsmentioning

confidence: 99%

“…4 The hydroxyproline scaffold offers three points of attachment (the amine, the hydroxyl, and the carboxyl groups) making it a good candidate for library production. Several libraries 1,3,6 of hydroxyproline derivatives have been previously synthesized either in solution or on solid phase. However, these were primarily O-alkylated and/or N-acylated and the products often needed final purification.…”

Section: Introductionmentioning

confidence: 99%

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Solid-Phase Synthesis of a Library of Hydroxyproline Derivatives

Vergnon¹,

Pottorf²,

Player³

2003

J. Comb. Chem.

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The synthesis of a library of N-alkylated O-arylated hydroxyproline derivatives has been achieved on solid phase. The choice of O-protection and the optimization of the Mitsunobu reaction involving a secondary alcohol were key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-O-THP-hydroxyproline was accomplished readily. Subsequent deprotection of the Fmoc and reductive amination with different aldehydes resulted in the tertiary amine intermediate. The deprotection of the THP group by p-toluenesulfonic acid was followed by a Mitsunobu reaction with a series of phenols. Finally, the products were cleaved from the resin using trifluoroacetic acid to produce a 10 200 member library.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Solid-Phase Synthesis of a Library of Hydroxyproline Derivatives

Vergnon¹,

Pottorf²,

Player³

2003

J. Comb. Chem.

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“…[43] In this context, Boldi et al [44] have carried out a library of alkoxyprolines 91 using a nucleophile-cleavable solid support. Boc-hydroxyproline scaffolds 89 were coupled to the Marshall linker with DIC and catalytic DMAP.…”

Section: Scheme 322 the 'Marshall Linker' In The Synthesis Of Amidesmentioning

confidence: 99%

Nucleophile Cleavable Linker Units

Porcheddu

Giacomelli

2009

Linker Strategies in Solid‐Phase Organic Synthesis

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“…As part of a program to generate combinatorial libraries for drug discovery and lead optimization, we developed a synthesis of tetrahydroisoquinolines using a support-bound tyrosine ether that relies upon the Pictet−Spengler reaction (Scheme ). , Our choice of solid support, [4-(hydroxyphenyl)thiomethyl]polystyrene (Marshall resin, 6) , was based on our previous experience, whereby esters derived from 6 produced carboxamides after treatment of the carboxyl-supported esters with amines with concurrent liberation of the desired product from the resin. This resin is compatible with other reaction conditions such as acid-mediated deprotection and reductive amination …”

Section: Introductionmentioning

confidence: 95%

Solid-Phase Synthesis of 1,2,3,4-Tetrahydroisoquinoline Derivatives Employing Support-Bound Tyrosine Esters in the Pictet−Spengler Reaction

Kane

Kelly

et al. 2004

J. Comb. Chem.

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The solid-phase synthesis of 1,2,3,4-tetrahydroisoquinoline-3-carboxamides employing carboxyl-supported, o-alkylated tyrosine esters in a Pictet-Spengler reaction is described. Esterification of [4-(hydroxyphenyl)thiomethyl]polystyrene (Marshall resin) with ethers of N-BOC-L-tyrosine using diisopropylcarbodiimide (DIC) and 4-dimethylaminopyridine (4-DMAP) afforded the solid-supported ester derivatives. Removal of the BOC group with trifluoroacetic acid (TFA) afforded the carboxyl-supported tyrosine ester, which was then treated with paraformaldehyde and TFA to afford the desired solid-supported counterpart. Acylation of the secondary amine with arylsulfonyl chlorides followed by reaction with amines resulted in the formation of the desired 2-arylsulfonyl-7-alkoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamides. Alternatively, the support-bound tetrahydroisoquinoline-3-carboxylate derivatives could be treated with an aldehyde and a reducing agent to give the corresponding support-bound tertiary amine. Exposure of these resin-bound products to amines afforded the corresponding 2-alkyl-7-alkoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxamides after cleavage from the resin. Alternative routes to the desired chemotypes, as well optimization of the conditions for the Pictet-Spengler reaction and the conditions for the acylation and reductive amination of the support-bound secondary amines, are also described.

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Solid-Phase Library Synthesis of Alkoxyprolines

Cited by 20 publications

References 20 publications

Solid-Phase Synthesis of a Library of Hydroxyproline Derivatives

Solid-Phase Synthesis of a Library of Hydroxyproline Derivatives

Nucleophile Cleavable Linker Units

Solid-Phase Synthesis of 1,2,3,4-Tetrahydroisoquinoline Derivatives Employing Support-Bound Tyrosine Esters in the Pictet−Spengler Reaction

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