More than 10 years ago we have synthesized FmocThr(Bu-t)OH,
Fmoc-Ser(Bu-t)OH
and FmocTyr(Bu-t)OH on multigram scale exactly according to procedures
described by Meienhofer J. et al.
References for the related papers may be found in Sheppard/Atherton
FmocSPPS mannual in the 'Practical Approach' IRL Press series or their
earlier review in The Peptides Vol.9 (Academic Press).
As far as I remember, the synthetic steps were as follows:
Thr ----->Z-Thr-OH -----> Z-Thr-OBzl-pNO2---->Z-Thr(Bu-t)-OBzl-pNO2---->
-->Thr(Bu-t)-OH ----->FmocThr(Bu-t)-OH
Tert-butylation of the above particular intermediate using
isobutylene/sulfuric acid proceeded rather efficiently (and this was not
the case with many other amino acid derivatives we tried to tert-butylate
from time to time over the years!).
Although the above approach may seem too laborious at the first glance,
but it is reliable and definitely worth trying. All intermediates are nice
crystalline substances and very often this is a serious advantage in
synthetic chemistry:-)).
Of course, the direct tert-butylation of Fmoc-Thr-OMe looks very
straightforward... but - at the first glance only as well.
In my humble opinion, TBTA - BF3.Et2O reagent you rely upon is effectively
a mild source of tert-Bu cation and I strongly suspect it to cause
mono/di-alkylation of fluorene aromatics at positions 2 and 7.
The circumstances of this may be truly dramatic from preparative point of
view: the precious allo-Thr will be 'delocalized' as 2,7-di-t-Bu-Fmoc-,
(S)-2-t-Bu-Fmoc-, (R)-2-t-Bu-Fmoc- (monoalkylation of fluorene will induce
chirality at the 9th position) and, finally, Fmoc derivatives.
Oily stuff --->preparative HPLC and so far, and so on...
Quantitative 2,7-di-tert-butylation of fluorenes was described to proceed
under very mild conditions (2.6-di-tertbutyl-p-cresol+Lewis acid) see eg
Kajigaeshi S. et al, Synthesis 1984 n.4, 335-337; Bull.Chem.Soc.Jpn. 1986,
59(1), 97-103.
Hope this information will help.
Regards
Igor Rodionov
Laboratory Of Peptide Chemistry
Branch of Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry
Pushchino, Moscow Region
142292, Russian Federation
E-mail: <rodionov@fibkh.serpukhov.su> or <Igor_Rodionov@iname.com>
Fax: (0967)-79-05-27
Phones: (0967) 73 54 42; private: (0967) 73 58 26