An effective means to synthesize indolizidinone amino acids has
been developed and furnishes all
possible stereoisomers of these conformationally rigid mimetics of
peptide secondary structures.
Inexpensive glutamic acid was employed as chiral educt in a
Claisen condensation/reductive
amination/lactam cyclization sequence that furnished stereoselectively
azabicyclo[3.4.0]alkane amino
acid 1. Enantiopure
(3S,6S,9S)- and
(3R,6R,9R)-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylic acids ((3S,6S,9S)- and
(3R,6R,9R)-1) were
respectively synthesized from l- and
d-N-(PhF)glutamates 2 (PhF = 9-(9-phenylfluorenyl)).
Slow addition of sodium
bis(trimethylsilyl)amide
to 2 provided good to excellent yields of β-keto esters
3, which were subsequently hydrolyzed and
decarboxylated to give symmetric
α,ω-bis[N-(PhF)amino]azelate
δ-ketones 5. Augmentation of
hydrogen pressure increased diastereoselectivity in reductive
aminations with 5 and afforded
5-alkylprolines 8 and 10. Lactam formation
on exposure of 10 to triethylamine and
N-protection
with di-tert-butyl dicarbonate gave methyl
2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate (12) which on C-terminal ester
hydrolysis with hydroxide ion gave enantiopure
[N-(BOC)amino]indolizidinone acid 1.
Alternatively, hydride addition to ketone 5a gave
symmetric
α,ω-bis[N-(PhF)amino]azelate
δ-alcohol 7a, which upon mesylation and intramolecular
SN2
displacement by the PhF amine gave specifically
cis-5-alkylproline 15 that was similarly
converted
to (3S,6S,9S)-1. In
addition, epimerization of the C-9 stereocenter of
(3S,6S,9S)-[N-(BOC)amino]indolizidinone methyl ester 12 with
NaN(SiMe3)2 and ester hydrolysis gave
(3S,6S,9R)-indolizidinone
amino acid (3S,6S,9R)-1.
By providing efficient methodology for synthesizing all of the
possible
stereoisomers of enantiopure indolizidinone amino acid 1,
our route is specifically designed to
enhance the general use of these peptide mimetics in the exploration of
conformation−activity
relationships of various biologically active peptides.
With the emergence of drug-resistant strains and the cumulative toxicities associated with current therapies, demand remains for new inhibitors of HIV-1 replication. The inhibition of HIV-1 entry is an attractive, yet underexploited therapeutic approach with implications for salvage and preexposure prophylactic regimens, as well as topical microbicides. Using the combination of a field-derived bioactive conformation template to perform virtual screening and iterative bioisosteric replacements, coupled with in silico predictions of absorption, distribution, metabolism, and excretion, we have identified new leads for HIV-1 entry inhibitors.
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