Design and synthesis of 6-amino-5-oxo-1,2,3,5-tetrahydro-3-indolizinecarboxylic acids as β-sheet peptidomimetics

Article abstract of DOI:10.1016/S0040-4039(02)02447-4

6-Amino-5-oxo-1,2,3,5-tetrahydro-3-indolizinecarboxylic acid was designed as a novel scaffold that can effectively mimic the extended conformation of a peptide. The key reaction in the synthesis of the scaffold involved a [3+2]-cycloaddition of a dicarbon

Full text of DOI:10.1016/S0040-4039(02)02447-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9663–9666
Design and synthesis of
6-amino-5-oxo-1,2,3,5-tetrahydro-3-indolizinecarboxylic acids as
b-sheet peptidomimetics
Xiaojun Zhang,* Aaron C. Schmitt and Carl P. Decicco
Discovery Chemistry, Bristol-Myers Squibb, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA
Received 23 September 2002; accepted 21 October 2002
Abstract—6-Amino-5-oxo-1,2,3,5-tetrahydro-3-indolizinecarboxylic acid was designed as a novel scaffold that can effectively
mimic the extended conformation of a peptide. The key reaction in the synthesis of the scaffold involved a [3+2]-cycloaddition of
a dicarbonyl stabilized isomu¨nchnone intermediate. Its effectiveness as a b-sheet mimetic was demonstrated by the preparation of
a potent HCV NS3 protease inhibitor. © 2002 Elsevier Science Ltd. All rights reserved.
One challenging aspect of medicinal chemistry is the
design of highly potent, target selective, and metaboli-
cally stable peptidomimetics. An important step in this
effort is the development of molecular scaffolds induc-
ing conformational constraints.1,2 Within this field, b-
sheet and reverse-turn templates are of special interest
because a large number of small peptides having regula-
tory roles adopt either extended or turn conformations.
While many bicyclic scaffolds have been designed and
synthesized to mimic the turn conformations,3–6 bicyclic
b-sheet mimetics are scarce. We report herein a design
and synthesis of 6-amino-5-oxo-1,2,3,5-tetrahydro-3-
indolizinecarboxylic acid (3, Fig. 1) as a novel scaffold
that can effectively mimic the extended conformation of
peptides.20
A recent Hepatitis C virus (HCV) NS3 serine protease
program prompted us to design a molecular scaffold to
replace a hexapeptide lead. Based on the assumption
that proteases typically bind their substrate in an
extended conformation, we looked for b-sheet scaffolds
that have been reported. Among them, pyridones 1 and
pyrazinones 2 have been successfully employed against
a wide variety of protease targets, e.g. elastase,7
thrombin,8,9 and interleukin-1b-converting enzyme.10,11
It was postulated and subsequently confirmed by X-ray
crystal structures that the CO and NH off the ring
could form a pair of b-sheet H-bonds with the enzyme
backbone.12,13 However, neither 1 nor 2 worked well
against HCV NS3. We reasoned that by a constraint
using a bicyclic pyridone as in compound 3, a more
Figure 1. From monocyclic heterocycles to bicyclic pyridones as a conformational constraint.
* Corresponding author. Fax: (302)-467-6850; e-mail: xiaojun.zhang@bms.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02447-4

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X. Zhang et al. / Tetrahedron Letters 43 (2002) 9663–9666
rigid conformation could be generated, which in turn
should produce a more potent compound. This letter
reports the synthesis of derivatives of 3 (Scheme 1).
pyridone 14 was prepared in similar yields following the
same chemistry.
This synthetic sequence is versatile in terms of functional
group tolerance, as demonstrated by the preparation of
a heavily functionalized pyridone 20 (Scheme 2). Mono-
methylation of 15 was performed in high yield with
MeOTf. Carbonylation of 16 with benzyl chloroformate
was achieved stereospecifically to give 17.18,19 Deprotec-
tion of the Boc group in 17 gave precursor 18. Following
the same chemistry described above, compound 18 was
converted to a Boc-protected amino bicyclic pyridone 19.
Hydrogenolysis of 19 and a second Curtius reaction
afforded a differentially protected diaminopyridone 20.
Our synthesis took advantage of a recent elegant report
by Padwa et al. on the synthesis of 8-acetyl-6-hydroxyl
indolizinecarboxylic ester 4 by a [3+2]-cycloaddition of
a phenylsulfonyl stabilized isomu¨nchnone intermedi-
ate.14,15 In principal, the hydroxy of 4 could be trans-
formed to an amino group by a palladium-catalyzed
amination reaction of its triflate. In consideration of the
strongly basic conditions typically found for this transfor-
mation, we opted to prepare the 6-carboxyl analog 5
through a dicarbonyl stabilized isomu¨nchnone intermedi-
ate (e.g. 10 in Scheme 1). The carboxylate 5 could be
readily converted to the protected amino analog 6 by a
Curtius rearrangement.
Compounds 6, 14 and 20 can be further modified through
the amino and carboxyl groups (Scheme 3). For example,
deprotection of 14 and 20, followed by reaction with
m-toluenesulfonyl chloride gave sulfonamides 21 and 23.
Saponification of 21 and coupling of the free acid with
NH2CH(Et)B(C10H16O2)·HCl afforded a potent HCV
NS3 protease inhibitor with IC50=0.12 mM in the
enzymatic assay. On the other hand, hydrogenation of
23 and reaction of the corresponding free amine with
isocyanates gave rise to ureas 24 in high yields.
The lithium salt of 7 reacted with t-butyl diazomalonyl
chloride 816 to give diazo imide 9 in 90% yield. Rh2(OAc)4
(2–5% mol) catalyzed decomposition of 9 to isomu¨nch-
none intermediate 10, followed by in situ trapping with
methyl vinyl ketone gave tricyclic compound 11 as a
mixture of three diastereomers in high yield. Although
each diastereomer was isolated and characterized, the
stereochemistry had no significance for the preparation
of the target molecules because the two newly formed
chiral centers would be converted to sp2 carbons. Treat-
ment of 11 with a catalytic amount of PTSA in CH2Cl2
cleaved one of the ether bonds to give a mixture of two
diastereomeric alcohols 12 in 74% yield. Dehydration of
12 to 5 was effected with POCl3 in pyridine. Burgess
reagent17 was also effective for dehydration of 12, but
POCl3/pyridine is more convenient to use. Deprotection
of the t-butyl ester in 5 to its acid, followed by a Curtius
rearrangement of the acyl azide, gave Boc-protected
amino bicyclic pyridone 6 in good yields.21 Starting from
a phenylpropyl substituted pyroglutamate 13, bicyclic
In summary, we have designed 6-amino-5-oxo-1,2,3,5-tet-
rahydro-3-indolizinecarboxylic acid as a novel molecular
scaffold that can mimic the extended conformation of a
peptide. The key reaction in the synthesis of the scaffold
involved a [3+2]-cycloaddition of a dicarbonyl stabilized
isomu¨nchnone intermediate. The synthetic sequence is
versatile, giving highly functionalized templates that can
be further elaborated. Furthermore, we demonstrated
that by incorporation of the correct side chains into the
scaffold, a potent non-peptidic HCV NS3 serine protease
inhibitor could be obtained.
Scheme 1. Reagents and conditions: (a) LHMDS, THF, −78°C, 90%; (b) Rh2(OAc)4, benzene, 90°C; (c) PTSA, CH2Cl2, 75% for
two steps; (d) POCl3, pyridine, 65%; (e) (1) TFA, CH2Cl2, (2) EtOCOCl, Et3N, THF, −5°C, NaN3, (3) toluene, t-BuOH, 90°C,
60%.

X. Zhang et al. / Tetrahedron Letters 43 (2002) 9663–9666
9665
Scheme 2. Reagents and conditions: (a) KHMDS, toluene, −78°C, MeOTf, >90%; (b) LHMDS, THF, −78°C, BnOCOCl, 92%; (c)
TFA, CH2Cl2, 90%; (d) LHMDS, THF, −78°C, then 8, 89%; (e) Rh2(OAc)4, methyl vinyl ketone, benzene, 90°C; (f) PTSA,
CH2Cl2, 50°C, 70% for two steps; (g) POCl3, pyridine, 55%; (h) (1) TFA, CH2Cl2, (2) EtOCOCl, Et3N, THF, −5°C, NaN3, (3)
toluene, t-BuOH, 90°C, 60%. (i) (1) Pd/C, H2, MeOH, (2) EtOCOCl, Et3N, THF, −5°C, NaN3, (3) toluene, BnOH, 90°C, 80%.
Scheme 3. Reagents and conditions: (a) TFA, CH2Cl2; (b) m-toluenesulfonyl chloride, pyridine, Et3N, 65%; (c) LiOH, THF/H2O;
(d) NH2CH(Et)B(C10H16O2)·HCl, DIEA, PyAOP, DMF, 60%; (e) Pd/C, H2, MeOH; (f) RNCO, CH2Cl2, Et3N, 80–90%.
Acknowledgements
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We thank Professor David Evans of Harvard Univer-
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X. Zhang et al. / Tetrahedron Letters 43 (2002) 9663–9666
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5.52 mmol) in benzene (40 mL) was added methyl vinyl
ketone (1.3 mL, 15.4 mmol) and [Rh(OAc2)]2 (3 mg). The
reaction was heated to 90°C for 6 h. p-TsOH (130 mg,
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to 50°C overnight. Flash chromatography gave product
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1.81 mmol) and let stir for 40 min at −20°C. The reaction
was allowed to warm to −5°C and NaN3 (268 mg, 4.12
mmol) in water (1.2 mL) was added and allowed to stir
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acetate, washed with brine, dried with MgSO4 and con-
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1
product 6 (340 mg, 60%). H NMR (300 MHz, CDCl3) l
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