Steric effects on the isomer equilibrium of amides
N-terminal to proline can be explored with
5-alkylprolines having bulky 5-position substituents. Enantiopure
5-tert-butylprolines were thus
synthesized from glutamic acid via an acylation/diastereoselective
reductive amination sequence.
Double deprotonation of γ-methyl
N-(PhF)glutamate (2) with
LiN(SiMe3)2 and C-acylation
with
pivaloyl chloride provided β-keto ester 3, which upon
γ-ester hydrolysis and decarboxylation gave
δ-oxo-α-[N-(PhF)amino]heptanoic acid
(4). Syntheses of (2S,5R)- and
(2R,5S)-N-(BOC)-5-tert-butylprolines ((2S,5R)-1 and
(2R,5S)-1) were accomplished by
catalytic hydrogenation of their
respective (2S)- and (2R)-methyl
δ-oxo-α-[N-(PhF)amino]heptanoates
((2S)-5a and (2R)-5a)
in
methanol with di-tert-butyl dicarbonate followed by
chromatography and ester hydrolysis with
potassium trimethylsilanolate. The 5-tert-butylproline
cis-diastereomers were proven to be of >99%
enantiomeric purity after their conversion to diastereomeric
α-methylbenzylamides 10. Good
diastereoselectivity in favor of the trans-diastereomer was
observed when
(2S,5S)-5-tert-butylproline
was synthesized from
(2S)-δ-oxo-α-[N-(PhF)amino]heptanoate
((2S)-4) by solvolysis of the PhF
group
in trifluoroacetic acid and subsequent reduction of
5-tert-butyl-Δ5-dehydroproline (11)
with
tetramethylammonium triacetoxyborohydride; however, imino acid
11 was shown to be configurationally labile and racemized under acidic conditions.
5-tert-Butyl-Δ5-dehydroproline
N‘-methylamide 15 was configurationally stable in acid, yet
preliminary attempts to reduce 15 favored
cis-diastereomer 16. Alternatively,
enantiopure trans-diastereomer,
(2R,5R)-methyl N-(BOC)-5-tert-butylprolinate (9) was prepared by
epimerization of (2S,5R)-9. In
summary, this synthetic
methodology now provides access to all four enantiopure
5-tert-butylproline isomers from inexpensive
l- and d-glutamate as chiral
educts
