"divakaramenon venugopal" <dvenug@nybc.org>
References: <4.2.2.20000208123235.00a4f9e0@server.nybc.org>
Subject: Re: Side chain modification
Date: Tue, 15 Feb 2000 22:40:40 +0300
Organization: Branch of IBCh
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Dear Dr. Venugopal,
I would like to draw your attention to another serious problem
associated with activation of the side chain carboxyls of internal Glu
or Asp. A variable portion of activated species will form ubiquitous
5-membered cycles (pGlu and aspartimide(Asu), respectively) before they
meet any amino group, which depends upon sequence and coupling technique
employed. (Note, that CDI (carbonyldiimidazol) promotes quantitative
cyclization of internal Glu -->pGlu - Khan,S.A. and Erickson,B.W.
Synthesis and regioselective hydrolysis of peptides containing an
internal residue of pyroglutamic acid. J.Am.Chem.Soc.,
1984,106(3),798-799).
Once formed, acyl-pGlu (or Asu) will slowly react with amines and water.
Unfortunately, regioselectivity of these reactions is either poor or
"wrong".
The only way to avoid imide formation completely is to protect backbone
nitrogen of Glu with Hmb, Tmob, Dmob, etc. Otherwise, one should at
least exclude strong activation methods mediated by 'overactivated'
species (O-acylurea in case of DCC+additive, HOAt esters, etc) to keep
the above complications at minimum.
I recommend to try one of 'Sakakibara reagents' CF3C(O)OX (X=PFP, Nsu,
Np, etc.) in presence of equivalent of pyridine or any other R3N in DMF.
In our experience, CF3C(O)OPFP[*] (available from Aldrich) appeared to
be a reagent of choice for converting various D,E-containing dipeptides
into the PFP esters. Only traces of by-products were detectable in case
of CF3C(O)OPFP while using of DCC-HOPFP, F-complex (=DCC*3HOPFP), or
dipentafluorophenylcarbonate with the same peptides resulted in
intractable mixtures of products.
I believe this approach should be helpful in your case. (I see no
reasons why it shouldn't work.)
[*] Green M., Berman J. Preparation of pentafluorophenyl esters of Fmoc
protected amino acids with pentafluorophenyl trifluoroacetate.-
Tetrahedron Lett, 1990, v.31(41), pp.5851-2.
Regards
Igor
------------------------------------------------
Igor L. Rodionov
Laboratory of Peptide Chemistry
Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry
Science Avenue 6
Pushchino, Moscow Region
142292, Russian Federation
E-mail: rodionov@fibkh.serpukhov.su
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