An efficient approach to asymmetric synthesis of dipeptide β-turn mimetics: Indolizidinone amino acids

Article abstract of DOI:10.1016/S0040-4039(01)00409-9

Azabicyclo[X.Y.0] alkane amino acids are rigid dipeptide β-turn mimetics with great potential applications for drug discovery. The lack of efficient methods to synthesize these compounds is a major bottleneck in this field. Herein we report an efficient a

Full text of DOI:10.1016/S0040-4039(01)00409-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3159–3161
An efficient approach to asymmetric synthesis of dipeptide b-turn
mimetics: indolizidinone amino acids
Wei Wang, Chiyi Xiong and Victor J. Hruby*
Department of Chemistry, University of Arizona, Tucson, AZ 85721, USA
Received 16 January 2001; revised 2 March 2001; accepted 5 March 2001
Abstract—Azabicyclo[X.Y.0] alkane amino acids are rigid dipeptide b-turn mimetics with great potential applications for drug
discovery. The lack of efficient methods to synthesize these compounds is a major bottleneck in this field. Herein we report an
efficient approach to the enantiopure synthesis of (3S,6S,9S) and (3R,6R,9R) methyl 2-oxo-3-[N-(Boc/Cbz)amino]-1-azabicy-
clo[4.3.0]nonane-9-carboxylates 1. In this approach, the key intermediates 5a and 5b with different stereochemical configurations
were efficiently constructed from the same precursor in high stereoselectivity via asymmetric hydrogenations using (S,S) or (R,R)
Et-DUPHOS, Rh(I)-based catalysts. The process, starting from inexpensive diethyl 1,3-acetonedicarboxylate 2, can allow for the
practical synthesis of this class of compounds. © 2001 Elsevier Science Ltd. All rights reserved.
One of the active peptide mimetic fields is the so-called
‘rigid dipeptide b-turn mimetics’ that have been pro-
posed to mimic or induce b-turn secondary structural
features for peptides and proteins that are thought to
play important roles in molecular recognition and bio-
logical activity.1,2 Several peptide mimetic systems have
been designed to try and mimic different types of
reverse-turns.1,2 Azabicyclo[X.Y.0]-alkane amino acids
are particularly attractive because of their ability to
serve as conformationally fixed surrogates of peptide
turn secondary structures (Fig. 1).1,2 It has been demon-
strated that incorporation of some of these scaffolds
into biologically active peptides has led to peptide
mimetic ligands with enhanced activities and metabolic
stabilities.1–3 As part of our a-MSH (melanocyte stimu-
lating hormones) program, we have identified the core
a-MSH peptides. This has created a need for efficient
synthetic approaches toward such molecules. The syn-
thesis of these molecules is very challenging because of
many chiral centers. Though many methods have been
developed for the synthesis of these compounds,1a,b
most of these approaches require relatively long syn-
thetic sequences, limiting practical syntheses. Here we
report an efficient approach to synthesis of enantiopure
indolizidinone-type 6,5-fused bicyclic lactams 1.
Our group has been long interested in the design and
synthesis of novel unnatural amino acids and peptide
mimetics.2,5 Recently we have developed a convenient
method for the synthesis of (2S,6S)-diaminopimelic
acid (DAP) and meso-(2S,6R)-diaminopimelic acid
(meso-DAP), and aryl-substituted phenylalanine and
tryptophan amino acids using asymmetric hydrogena-
tion of didehydroamino acids with Burk’s catalyst,
Rh(I)(COD)-(S,S) or (R,R) Et-DUPHOS in high
stereoselectivity (>95% ee). Herein we have employed
these methods to synthesize the key intermediates 5-
(1,3-dioxolane)-2,8-bis[N-benzyloxycarbonylamino]no-
nane-1,9-dioic acid dimethyl esters (5), which can be
useful precursors of indolizidinone-type 6,5-fused
bicyclic lactams 1 (Scheme 1).
sequence of a-MSH peptides His-(D/L) Phe-Arg-Trp
and found a b-turn which includes the Phe and Arg
residues.4 We propose that azabicyclo[X.Y.0]-alkane
amino acids may be useful to mimic the b-turn in
R4
R3
6
5
R1: H, Boc or Cbz
8
3
N
R1HN
9
R2: H or Me
1
COOR2
R3, R4: alkyl, aryl
O
Figure 1. Indolizidinone amino acids 1.
The synthesis started from commercially available
diethyl 1,3-acetonedicarboxylate (2) (Scheme 1). The
functional carbonyl group in 2 was protected as a ketal
by refluxing a mixture of 2 and ethylene glycol in the
presence of catalytic amounts of BF3·OEt2 in benzene.6
Keywords: amino acids; b-turn mimetics; asymmetric hydrogenation.
* Corresponding author. Tel.: (520) 621-6332; fax: (520) 621-8407;
e-mail: hruby@u.arizona.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00409-9

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W. Wang et al. / Tetrahedron Letters 42 (2001) 3159–3161
O
O
O
O
O
O
O
b
a
OCH3
NHCbz
H3CO
O
O
O
O
NHCbz
OEt OEt
OEt OEt
4
2
3
H
N
O
O
O
O
e
c
OCH3
4
H3CO
BocHN
CbzHN
COOMe
COOMe
O
CbzHN
NHCbz
5a
1a
H
O
O
O
O
d
e
OCH3
NHCbz
H3CO
CbzHN
4
N
5b
O
1b
H
N
O
f
1a
COOMe
COOMe
N
Boc
6a
BocHN
MeO
COOMe
O
O
BocHN
1c
H
O
f
N
N
Cbz
MeO
CbzHN
1b
CbzHN
COOMe
1d
6b
Scheme 1. Synthesis of indolizidinone amino acid 1. (a) HO(CH2)2OH, BF3·OEt2, benzene, reflux, 24 h, 76%; (b) (i) DIBAL,
−78°C, toluene, 70 min, ca. 70%, (ii) (MeO)2P(O)CH(NHCbz)COOCH3, DBU, CH2Cl2, rt, 4 h, 72%; (c) Rh (I) (COD) (S,S)
Et-DUPHOS, H2 (70 psi), 24 h, MeOH, 97%; (d) Rh (I) (COD) (R,R) Et-DUPHOS, H2 (70 psi), 24 h, MeOH, 95%;(e) (i) 10%
Pd/C, H2 (70 psi), MeOH/conc. HCl (1/4), 24 h, (ii) NaHCO3, 1,4-dioxane, H2O, 3–4 h, then (Boc)2O or Cbz-Cl, 3 h, 71–74%;
(f) NaN(SiMe3)2, THF, −50°C, 1 h, then −20°C, 1 h, 70–74%.
The product 3 was obtained after work-up with high
purity without further purification. The diethyl ester 3
was reduced to a dialdehyde using DIBAL (diisobutyl-
aluminum hydride) in anhydrous toluene at −78°C for
about 70 min. Approximately a 70% yield of the desired
product was obtained as determined by 1H NMR of the
crude product mixture, with ca. 15% monoreduction
product and 15% unreacted starting materials. Without
purification of the crude product, the resulting mixture
was subjected to the subsequent reaction (Scheme 1).
Therefore, ketal hydrolysis and reductive amination
followed by lactamization was accomplished in a mix-
ture of methanol and concentrated hydrochloric acid
(volume ratio 4/1) in the presence of 10% Pd/C under
70 psi of hydrogen for 24 h.12,13 Without purification of
the crude product, the free amino group was protected
with Boc (t-butoxycarbonyl) or Cbz (benzoxycarbonyl).
In fact, because of the incomplete lactamization reac-
tion under acidic conditions, the reaction mixture was
stirred for 3–4 h under basic conditions (pH 8–9) to
render the lactamization complete followed by addition
of (Boc)2O or Cbz-Cl.13 The final product 1a or 1b was
separated in 74 and 71% yields, respectively. Only one
diastereomer (3S,6S,9S) 1a or (3R,6R,9R) 1b was iso-
lated in each case. In contrast, previous literature
results gave two isomers, (3S,6S,9S) 1a or (3R,6R,9R)
1b as the major products and (3S,6R,9S) or (3R,6S,9R)
as the minor products.13 Compounds 6a and 6b were
also obtained in 8–12% yields due to incomplete lac-
tamization, respectively.13 The optical rotation [h]2D1−
The didehydroamino acid dimethyl ester
4 was
obtained as the major product via the Horner–Emmons
olefination7 of the mixture with the phosphonate
(MeO)2P(O)CH(NHCbz)COOMe and DBU (1,8-diaza-
bicyclo[5.4.0]undec-7-ene) as the base, in 72% yield.
The ratio of (2Z,7Z) and (2E,7Z) was determined to be
1
95:5 by H NMR.8 Asymmetric hydrogenation of the
mixture of the didehydroamino acids 4 using Burk’s
catalysts Rh (I) (COD) (S,S)-Et-DuPHOS or (R,R)-Et-
DuPHOS afforded 5a and 5b in 97 and 95% yields,
respectively, after column purification.8–10 The two new
absolute configurations were assigned as 2S,7S in 5a
and 2R,7R in 5b based on the selectivity of the (S,S)-
Et-DuPHOS and (R,R)-Et-DuPHOS ligands, respec-
tively.11 The key intermediates 5a and 5b then
underwent deprotection, reductive amination, cycliza-
tion, and protection to provide the final molecules 1
(Scheme 1). We adapted a literature one-pot process of
deprotection, reductive amination, and cyclization.
1
17.4 (c 0.96, CHCl3)], H and 13C NMR of (3S,6S,9S)
1a was the same as reported in the literature13 [h]D20−
17.6 (c 1.0, CHCl3)]. This result indicated that a >95%
ee was achieved in the asymmetric hydrogenation reac-
tions.8 The epimerization of the C-9 center in 1a or 1b
with NaN(SiMe3)3 in THF at −50°C for 1 h, then
−20°C for 1 h, afforded the 9R or 9S diastereomer 1c
or 1d as the major product in 70–74% yield following
the literature procedure.13

W. Wang et al. / Tetrahedron Letters 42 (2001) 3159–3161
3161
In conclusion, we have developed an efficient approach
to the synthesis of enantiopure indolizidinone amino
acids 1. In this approach, the key intermediates 5a and
5b, with different stereochemical configurations, were
efficiently constructed from the same precursor via
asymmetric hydrogenations using Burk’s Rh(I)-based
catalysts with different chrial ligands (S,S) or (R,R)
Et-DUPHOS in high stereoselectivity. This method can
be further exploited for the synthesis of alkyl-substi-
tuted indolizidinone amino acids 1 (Fig. 1).14 The incor-
poration of these molecules into biologically active
a-MSH peptides and the study of structure–activity
relationships are in progress.
3594–3600; (c) Haubner, R.; Schmitt, W.; Holzemann,
G.; Goodman, S. L.; Jonczyk, A.; Kessler, H. J. Am.
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Acknowledgements
This work was supported by US Public Health Service
(DK 17420) and the National Institute of Drug Abuse
(DA 13449). We also thank Professor Dominic V.
McGrath for using his group’s polarimeter. The views
are those of the authors and not necessarily the
USPHS.
9. For a recent review in the applications of asymmetric
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10. Compound 5a: [h]2D4 −11.8 (c1.01, CHCl3); 1H NMR
(CDCl3) l 1.59–1.69 (m, 6H), 1.88–1.93 (m, 2H), 3.74 (s,
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