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Issue 37, 2013
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Novel synthesis of various orthogonally protected Cα-methyllysine analogues and biological evaluation of a Vapreotide analogue containing (S)-α-methyllysine

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Abstract

Prochiral malonic diesters containing a quaternary carbon center have been successfully transformed into a diverse set of tBoc-Fmoc-α2,2-methyllysine-OH analogues through chiral malonic half-ester intermediates obtained via enzymatic (Pig Liver Esterase, PLE) hydrolysis. The variety of chiral half-ester intermediates, which vary from 1 to 6 methylene units in the side chain, are achieved in moderate to high optical purity and in good yields. The PLE hydrolysis of malonic diesters with various side chain lengths appears to obey the Jones's PLE model according to the stereochemical configurations of the resulting chiral half-esters. The established synthetic strategy allows the construction of both enantiomers of α2,2-methyllysine analogues, and a (S)-β2,2-methyllysine analogue from a common synthon by straightforward manipulation of protecting groups. Two different straightforward and cost effective synthetic strategies are described for the synthesis of α2,2-methyllysine analogues. The described strategies should find significant usefulness in preparing novel peptide libraries with unnatural lysine analogues. A Vapreotide analogue incorporating (S)-α2,2-methyllysine was prepared. However, the Vapreotide analogue with (S)-α-methyl-α-lysine is found to lose its specific binding to somatostatin receptor subtype 2 (SSTR2).

Graphical abstract: Novel synthesis of various orthogonally protected Cα-methyllysine analogues and biological evaluation of a Vapreotide analogue containing (S)-α-methyllysine

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Publication details

The article was received on 20 Jun 2013, accepted on 05 Aug 2013 and first published on 05 Aug 2013


Article type: Paper
DOI: 10.1039/C3OB41282B
Org. Biomol. Chem., 2013,11, 6307-6319

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    Novel synthesis of various orthogonally protected Cα-methyllysine analogues and biological evaluation of a Vapreotide analogue containing (S)-α-methyllysine

    S. Banerjee, W. J. Wiggins, J. L. Geoghegan, C. T. Anthony, E. A. Woltering and D. S. Masterson, Org. Biomol. Chem., 2013, 11, 6307
    DOI: 10.1039/C3OB41282B

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