Synthesis of Conformationally Constrained Dipeptide Mimetics with Azabicyclo[4,3,0]nonanone and Azabicyclo[5,3,0]decanone Scaffolds

Article abstract of DOI:10.1021/acs.joc.0c00399

A general and efficient method for the synthesis of azabicyclo[4,3,0]nonanone and azabicyclo[5,3,0]decanone amino acid derivatives was developed with the palladium-catalyzed coupling of intermediates 9 and 10 with BocNH2 and Boc2NH and the following reduction of the C-C double bond by hydrogenation as the key steps. The exploration of the synthesis of C6-substituted dipeptide mimetics from 9 and 10 using Suzuki coupling as the key reaction has also been performed.

Full text of DOI:10.1021/acs.joc.0c00399

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Note
Synthesis of conformationally constrained dipeptide mimetics with
azabicyclo[4,3,0]nonanone and azabicyclo[5,3,0]decanone scaffolds
Wanlin Xi, Lei Du, Liping Zhang, and Haiying Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00399 • Publication Date (Web): 08 Jul 2020
Downloaded from pubs.acs.org on July 10, 2020
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The Journal of Organic Chemistry
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Synthesis of conformationally constrained dipeptide mimetics
with azabicyclo[4,3,0]nonanone and
azabicyclo[5,3,0]decanone scaffolds
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Wanlin Xi, Lei Du, Liping Zhang and Haiying Sun*
Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing 21009, China
Supporting Information Placeholder
ABSTRACT: A general and efficient method for the synthesis of azabicyclo[4,3,0]nonanone and azabicyclo[5,3,0]decanone amino
acids derivatives was developed with palladium catalyzed coupling of intermediates 9 and 10 with BocNH
following reduction of the C-C double bond by hydrogenation as the key steps. The exploration of the synthesis of C
2
and Boc
2
NH and the
6
substituted
dipeptide mimetics from 9 and 10 using Suzuki coupling as the key reaction has also been performed.
Natural peptides are valuable ligands for studying protein-
protein interactions, however their intrinsic drawbacks, such as
poor metabolic stability, poor cell permeability and unfavorable
bioavailability greatly limit their applications. To overcome these
drawbacks, many modification methods for natural peptides have
been developed. Among them, replacing a natural dipeptide
moiety with a conformationally constrained dipeptide mimetic is
an efficient strategy. Azabicyclo[X,Y,0]alkanone amino acid
derivatives and their analogues are well studied dipeptide
We firstly explored the synthesis of compounds 5 and 6, two
1
,2,6-8
well-known representatives in this series of compounds
. The
retro-synthetic analysis for the synthesis of these two compounds
is shown in Scheme 1. Because of the geometry control of the two
existing stereogenic centers, we envisioned that reduction of the
double bond in 7 and 8 by hydrogenation will give the all cis
isomers. Using hydrogenation to selectively obtain saturated cis
indolizidinone amino acids derivatives from unsaturated
9
intermediates has been reported previously . The Boc protected
1
,2
mimetics (1, Figure 1) . These dipeptide mimetics can restrict
the geometry of the peptide backbone and maintain the active
conformations of the peptides in binding to their target proteins,
therefore have been extensively used in many drug discovery
projects, such as thrombin inhibitors, stat3 inhibitors, CCK
receptor ligands, integrin receptor ligands, prostaglandin F2α
amine group in 7 and 8 can be introduced by coupling of BocNH
2
with bromides 9 and 10, respectively. Bromides 9 and 10 can be
prepared by bromination of the double bond in 11 and 12 and the
subsequent elimination of HBr, while 11 and 12 can be easily
synthesized from 13 and 14 through RCM reaction. Since
Grubbs’s group reported the synthesis of conformationally
restricted amino acids and peptides using olefin metathesis, this
method has been employed by several groups for the synthesis of
1
-5
(PGF2α) modulators, and Smac mimetics (Figure 1). Because
of their extensive applications, many synthetic methods for the
synthesis of this class of compounds and their analogues have
7
,8,14-16
dipeptide mimetics with azabicyclic core structures
.
1
,2,6-11
been reported
, and development of more general and
Scheme 1. Retro-synthetic analysis
efficient methods which can be used to expand the diversity of the
structure has always been actively pursued by organic chemists
n
n
n
N
12,13
and medicinal chemists
. In this note, we report a general and
6
N
3
N
efficient method for the synthesis of dipeptide mimetics with
BocHN
BocHN
Br
COOMe
COOMe
COOMe
O
O
O
azabicyclo[4,3,0]nonanone
scaffolds.
and
azabicyclo[5,3,0]decanone
5
, n = 1
7, n = 1
8, n = 2
9, n = 1
10, n = 2
6, n = 2
Figure 1 Examples of azabicyclo[X,Y,0]alkanone amino acids
n
and their applications in drug development
N
COOMe
n
N
COOMe
O
n
n
O
O
11, n = 1
12, n = 2
H2N
13, n = 1
14, n = 2
N
N
Ph
N
O
COOH
H
COOH
SH
O
The synthesis of key intermediates 9 and 10 is shown in
Scheme 2. Briefly, Boc protected amine 16 was prepared from N-
Boc-L-pyroglutamic acid methyl ester 15 in three steps according
to literature reported method as a mixture of two isomers
(cis:trans 3:1) . Removal of the Boc protecting group in 16 by
HCl in methanol yielded 17 as a salt with HCl. Amine 18 was
1
, n = 1-5
2, n = 1 or 2, ACE inhibitors
N
O
n
O
O
Ph
N
COOH
N
Ph
N
H
H
N
17
N
O
O
N
H
H
NH
O
N
Ph
O
H
Ph
3
, PGF2 modulator
4, n = 1-3, Smac mimetics
synthesized according to a reported method for the synthesis of
similar compounds with slight modifications . Briefly, addition
1
8
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The Journal of Organic Chemistry
Page 2 of 8
of but-3-en-1-yl magnesium bromide to the amide bond in 15
catalyst (entry 12), but comparing to that using Pd
2 3
(dba) as the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
broke the amide bond to yield a ketone. After removal of the Boc
protecting group in this ketone, the resulted imine formed by
intramolecular condensation of the amino group with the ketone
catalyst the yield was lower. Toluene is the most frequently used
1
9
solvent in the coupling of aryl halides with BocNH
2
, in order to
explore the influence of the solvent, we have tried the coupling
reactions in DMF (entry 13) and 1,4-dioxane (entry 14) and found
in these two solvents the yields were dramatically decreased,
indicating that toluene is indeed a more suitable solvent for this
reaction. We have also evaluated the influence of the temperature
to the reaction by running the coupling reaction at lower
temperature, the results indicated that with the decrease of the
temperature (entry 15 and 16), the yield was also decreased,
suggesting that running the reaction in toluene under refluxing
condition is necessary. Overall, through these reactions we have
successfully identified the optimal condition for this coupling as
showed in entry 8.
was reduced by NaBH
isomers with the desired cis isomer being the major product
cis:trans 1.5:1). The ratio of the two isomers was determined by
3
CN to provide 18 as a mixture of two
(
comparing the peaks of the methyl ester groups in the two isomers
1
in the H NMR spectrum. It was difficult to separate the two
isomers in 17 and 18 even with semi-preparative HPLC, however
in previous studies for the synthesis of bicyclic lactam scaffolds it
has been found that the trans isomer in 17 was much less active
than the cis isomer in the subsequent condensation and cyclization,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5,8
and could be removed in later steps , therefore the mixtures 17
and 18 were used directly in the following reactions.
Condensation of 17 and 18 with acrylic acid yielded two amides.
Ring closing metathesis of these amides under the catalyzation of
Table 1. Optimization of the condition for the coupling of 9
with BocNH
2
nd
Grubbs’ catalyst 2 generation provided two cyclized compounds.
Bromination of the double bond in these two compounds and the
following elimination of HBr were realized in one pot by treating
the two cyclized compounds with bromine and N,N-diisopropyl
ethyl amine subsequently to furnish key intermediates 9 and 10.
As predicted, both 9 and 10 were obtained as single isomers.
9
+
BocNH2
N
BocHN
COOMe
O
7
Entrya
Catalyst
Pd(OAc)2
Ligand
solvent
o
Yield
T ( C)
b
Scheme 2. Synthesis of key intermediates 9 and 10
(%)
NP
NP
53
a
1
2
3
4
5
6
7
8
9
t-Bu3P
XPhos
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
110
110
110
110
110
110
110
110
110
110
110
110
110
110
80
COOMe
COOMe
COOMe
O
N
N
N
Boc
15
Boc
16
H
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
17
t-BuXPhos
Xantphos
26
b
c
15
COOMe
or
17 18
9 or 10
N
Pd
Pd
Pd
Pd
Pd
Pd
2
2
2
2
2
2
(dba)
(dba)
(dba)
(dba)
(dba)
(dba)
3
3
3
3
3
3
t-Bu
3
P
NP
38
H
18
XPhos
t-BuXPhos
Xantphos
SPhos
31
Reagents and conditions: (a) 4 N HCl in 1,4-dioxane,
methanol, 95%; (b) i. but-3-en-1-ylmagnesium bromide, THF, -40
78
o
C, 2 hours; ii. 4 N HCl in 1,4-dioxane, methanol; iii. NaBH
3
CN,
62
methanol, 51% over three steps; (c) i. acrylic acid, EDC, HOBt,
1
0
JohnPhos
30
o
2 2
N,N-diisopropylethyl amine, CH Cl , 0 C to room temperature,
nd
11
12
13
14
15
Pd(dba)
2
t-Bu
3
P
NP
50
overnight; ii. Grubbs' catalyst 2 generation, toluene, reflux,
o
Pd(dba)2
Pd (dba)
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
overnight; iii. Br
2 2 2
, CH Cl , 0 C room temperature, 2 hours, then
o
N,N-diisopropylethylamine, 0 C to room temperature, overnight,
trace
25
2
2
2
2
3
4
4% for 9 and 38% for 10 over three steps.
Pd
Pd
Pd
(dba)
(dba)
(dba)
3
3
3
dioxane
toluene
toluene
The key step in our method is the coupling of intermediates 9
and 10 with BocNH . Palladium catalyzed C-N coupling reactions
2
50
1
6
60
34
of carbamates with aryl halides have been extensively studied,
therefore, we explored the optimum condition for the coupling of
2 3
a. In all of these reactions, Cs CO was used as the base.
b. NP means no desired product. All of the yields are isolated
yields by chromatography.
1
9
2
compound 9 with BocNH based on the reported methods . The
results were summarized in Table 1.
We then tried the reduction of the C-C double bonds in 7 by
hydrogenation (Scheme 3). Using 5% Pd-C as the catalyst, the
double bond in compound 7 was successfully reduced to give the
desired compound 5 as a single product. The structure of
2
We first tried the coupling reaction using Pd(OAc) as the
catalyst. It was found that the ligand has significant influence to
the reaction. When t-Bu P (entry 1) or XPhos (entry 2) was used
3
as the ligand, the reaction gave a complicated mixture without
detectable coupling product 7, but using t-BuXPhos (entry 3) or
Xantphos (entry 4) as the ligand, 7 was obtained in a yield of 53%
1
compound 5 was confirmed by comparing the H NMR of 5 with
6
the literature reported data . Using the optimized coupling
condition, BocNH was also successfully coupled to compound 10
2
or 26%, respectively. We then tried Pd
used catalyst in the coupling of aryl halides with carbamates. The
reaction was still not successful with t-Bu P (entry 5) as the ligand,
2 3
(dba) , another frequently
to give compound 8 in a yield of 72%, however, hydrogenation of
compound 8 under the catalysis of 5% Pd-C in methanol only
gave compound 6 with a yield of 29% together with a complicated
mixture of inseparable compounds. The structure of 6 was also
3
but when XPhos (entry 6) was used 7 was successfully produced
in a yield of 38%. The coupling was also successful with t-
BuXPhos (entry 7) as the ligand, however under this condition the
1
confirmed by comparing its H NMR data with the literature
7
1
reported data . We performed H NMR study for the mixture and
found the –NHBoc group is missing, suggesting that 8 can
isomerize to form an imino carbamate which is decomposed
during hydrogenation. This phenomenon was not noticed for
compound 7, maybe because 7 is more stable than its imino
isomer. Changing the reaction conditions by using different
solvents and catalysts failed to solve this problem. In order to
2
yield was only 31%, lower than that using Pd(OAc) (entry 3) as
the catalyst. The best yield was achieved when XantPhos was
used as the ligand (entry 8). Under this condition, 7 was obtained
in a yield of 78%. We have also tried using SPhos (entry 9) and
JohnPhos (entry 10) as ligands, but under these conditions the
yields were lower than that using XantPhos (entry 8) as the ligand.
2
With XantPhos as the ligand Pd(dba) can also be used as the
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prevent the isomerization, we synthesized compound 19 by
coupling of (Boc) NH with 10. This coupling produced 19 in a
products. The results were summarized in Scheme 5. Introduction
1
2
3
4
5
6
7
8
9
2
of a methyl or a nitrile group to the para position of the phenyl
ring in the boronic acid doesn’t influence the coupling reaction
(23d and 23e), but coupling reaction using o-tolylboronic acid or
m-tolylboronic acid gave a lower yield, maybe because of the
steric hindrance of the methyl group. The coupling reactions using
propylboronic acid (23g) and (2-methylprop-1-en-1-yl)boronic
acid (23f, 24b) also proceed successfully, indicating compounds 9
and 10 represent well compatible substrates for Suzuki coupling
reaction.
yield of 73%. The C-C double bond in 19 was successfully
reduced by hydrogenation, but the Boc protecting group was
partially cleaved to give a mixture of 6 and 20. Removal of the
Boc protecting group in 6 and 20 by treating the mixture with
trifluoroacetic acid furnished 21 as a single product.
Scheme 3. Synthesis of compounds 5, 6 and 21
a
7
5
Table 2. Optimization for Suzuki coupling reaction of 9 with
phenylboronic acid
b
c
complicated
mixture
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
10
10
8
6
+
N
e
9
+
B(OH)2
d
N
COOMe
O
(Boc)2N
COOMe
22a
O
19
Entry
Catalyst
Pd (dba)
Pd(dppf)Cl2
Solvent
1,4-dioxane
1,4-dioxane
1,4-dioxane
Yield (%)
1
2
3
4
2
3
42
51
63
86
f
N
N
X
COOMe
2
H N
COOMe
O
O
Pd(PPh
Pd(PPh
3
3
)
4
4
6
2
, X = NHBoc;
0, X = N(Boc)2
21
)
20% of water in
,4-dioxane
1
Reagents and conditions: (a) 5% Pd-C, H
2
(1 atm), methanol,
Scheme 4. Synthesis of compound 23a
room temperature, 2 hours, 90%; (b) tert-butyl carbamate,
Pd (dba) (5% mmol), Xantphos (10% mmol), Cs CO , toluene,
reflux, 72%; (c) 5% Pd-C, H (1 atm), methanol, room
temperature, 2 hours, 29%; (d) tert-butyl carbamate, Pd (dba) (5%
mmol), Xantphos (10% mmol), Cs CO , toluene, reflux, 73%; (e)
% Pd-C, H (1 atm), methanol, room temperature, 2 hours; (f)
trifluoroacetic acid, dichloromethane, room temperature, 1 hour,
2
3
2
3
a
N
22a
2
COOMe
O
2
3
23a
2
3
5
2
2
Reagents and conditions: (a) 5% Pd-C, H , MeOH, 30 minute,
85%
6
6% over two steps.
Scheme 5. Synthesis of C
6
substituted compounds
With intermediates 9 and 10 in hand, we then considered to
X
expend the structural diversity using these core structures.
Introduction of substituted group to α-iodo enones and β-bromo-
α,β-unsaturated indolizidinone amino acids derivatives by Suzuki
i, ii
23, X = -CH2-;
9 or 10
N
R
24, X = -(CH2)2-
COOMe
O
Reagents and conditions: i. boronic, Pd(PPh3)4, CsCO3, 1,4-dioxane:H2O 4:1, 100 oC, overnight;
9
,20
coupling reaction has been reported previously , therefore we
explored the introduction of various groups to C in the bicyclic
ii. 5% Pd-C, H2, methanol, 1 atm, overnight.
6
structures of 9 and 10 through Suzuki coupling reaction. These
coupling products can not only be used as dipeptide mimetics, but
may also be applied as intermediates for the synthesis of
derivatives of natural alkaloids with an azabicyclic scaffold, such
N
N
N
COOMe
COOMe
COOMe
O
O
O
23b
23c
23d
2
1
as pumiliotoxin analogues .
Boronic acid: o-tolylboronic acid Boronic acid: m-tolylboronic acid
Boronic acid: p-tolylboronic acid
Yield: 87% over two steps
Yield: 48% over two steps
Yield: 69% over two steps
Firstly we optimized the reaction conditions by exploring the
coupling of 9 with phenylboronic acid (Table 2). Three frequently
used palladium catalysts were employed in the reactions, and the
reactions were run in 1,4-dioxane, a solvent frequently used in
N
N
N
COOMe
COOMe
O
COOMe
O
O
NC
23e
23f
23g
Suzuki coupling reaction with Cs
indicated that Pd(PPh is more optimal than Pd
Pd(dppf)Cl . Because in Suzuki coupling reaction, adding water
2
CO
3
as the base. The results
Boronic acid: 4-cyanophenyl Boronic acid: (2-methylprop-1- Boronic acid: propylboronic acid
-boronic acid
en-1-yl)boronic acid
Yield: 64% over two steps
3
)
4
2
(dba) and
3
Yield: 82% over two steps
Yield: 70% over two steps
2
to enhance the solubility of boronic acid sometimes can improve
the yield, we tried running the reaction in a mixture of 1,4-
dioxane and water, and found the yield was indeed significantly
improved. Under this condition, the coupling product 22a was
obtained in a yield of 86%. We then tried the coupling of 1.1 g
N
N
COOMe
O
COOMe
O
24a
24b
Boronic acid: phenylboronic acid Boronic acid: (2-methylprop-1-
Yield: 73% over two steps
en-1-yl)boronic acid
(4.0 mmol) of 9 with 0.49 g (4.0 mmol) of phenylboronic acid
Yield: 67% over two steps
using the optimized condition and obtained 0.91 g of 22a with a
yield 84%, similar to that for the small scale reaction, thus
confirmed the effectiveness of the coupling condition.
In summary, we have developed a general and efficient method
for the synthesis of azabicyclo[4,3,0]nonanone and
azabicyclo[5,3,0]decanone amino acids derivatives. The key step
is palladium catalyzed coupling of easily synthesized
2
As expected, reduction of the C-C double bond in 22a gave 23a
as a single product (Scheme 4).
Using the optimized condition, we synthesized a series of C
6
bromoalkene containing intermediates 9 and 10 with BocNH or
substituted compounds by coupling of 9 and 10 with different
boronic acids and the following reduction of the resulted coupling
Boc NH. These two intermediates can also be used as the
2
substrates for Suzuki coupling reaction. Aryl, alkyl and alkenyl
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boronic acids can all couple successfully with 9 and 10, therefore
our method is highly applicable for the construction of compound
library of dipeptide mimetics with various substituted groups at C .
6
2 4
mL × 3). The combined organic layers were dried over Na SO
and then concentrated. The residue was purified by
chromatography using a mixture of ethyl acetate and hexane (1:3-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
:2, v/v) as the eluent to give 4.1 g of the condensation product as
EXPERIMENTAL SECTION
a pale yellow sticky liquid. The product was dissolved in 300 mL
nd
of anhydrous toluene. After adding 0.12 g of Grubbs catalyst 2
General Experimental Methods. Unless otherwise noted, all
chemicals were purchased from commercial suppliers and used
without further purification. Flash column chromatography was
carried out using commercially available 300-400 mesh silica gel
2
generation, the solution was refluxed for 24 hours under N . The
solvent was removed under reduced pressure and the residue was
purified by chromatography on silica gel using a mixture of ethyl
acetate and hexane (1:3-1:2, v/v) as the eluent to give 3.1 g of the
1
under pressure with ethyl acetate and hexane as the eluents. H
1
3
1
2 2
cyclized product. The product was dissolved in 100 mL of CH Cl
and C{ H} nuclear magnetic resonance (NMR) spectra were
recorded on a Bruker AV-300 (300 MHz) or AV-400 (400 MHz)
and then the solution was cooled to 0°C. 3.04 g of bromine (19.0
mmol) was added dropwise to this solution, then the solution was
allowed to warm to room temperature and stirred until TLC
indicated that all starting material has been consumed (about 3
hours). The solution was cooled to 0°C again, and then 5 mL of
N,N-diisopropylethylamine was added dropwise to this solution.
After the reaction mixture was stirred at room temperature
overnight, the solvent was removed under reduced pressure. The
residue was suspended in 30 mL of water and extracted with ethyl
acetate (50 mL × 3). The combined organic layers were dried over
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
NMR spectrometer. H and C NMR spectra are reported in parts
per million (ppm) downfield from an internal standard,
1
tetramethylsilane (0 ppm). H chemical shifts are reported with
3 2
CDCl (7.27 ppm) or CD HOD (3.31 ppm) as internal standards.
High resolution mass spectra (HRMS) were obtained on Agilent
Technologies 6520 Accurate-Mass Q-TOF LC/MS instruments.
Optical rotations were measured on a RUDOLPH AUTOPOL IV
automatic polarimeter. Infrared spectra analysis (IR) was
conducted on a SHIMADZU IRAffinity-1S fourier transform
infrared spectrophotometer.
2 4
Na SO and then concentrated. The residue was purified by
column chromatography on silica gel using a mixture of ethyl
acetate and hexane (1:3-1:2, v/v) as the eluent to provide 3.5 g of
Methyl (2S)-5-(but-3-3n-1-yl)pyrrolidine-2-carboxylate (18).
N-Boc-L-pyroglumatic acid methyl ester (7.3 g, 30 mmol) was
dissolved in 100 mL of dry THF. The solution was cooled to -40
25
compound 9 as a white solid. Yield 44 % over four steps. [α]D = -
1
7
1
7.6 (c = 0.50, MeOH); H NMR (300 MHz, CDCl
3
) δ 6.96 (m,
o
C and then 33 mL of but-3-en-1-ylmagnesium bromide solution
H), 4.56 (m, 1H), 3.91 (m, 1H), 3.73 (s, 3H), 2.60-1.80 (m, 6H);
(1 N in THF) was added dropwise at this temperature. After
1
3
1
C{ H} NMR (75 MHz, CDCl
7.9, 56.9, 52.2, 32.1, 31.3, 28.5; MS (ESI) m/z: [M + H] calcd
274.01, found 274.12; HRMS (ESI) m/z: [M +
H] calcd for C10 274.0079, found 274.0091; IR
(neat/KBr): 3434, 2953, 2923, 1744, 1655, 1601, 1438, 1368,
3
):  171.8, 158.2, 140.5, 118.5,
o
addition, the solution was stirred at -40 C for 2 hours and then
+
5
4
quenched with 30 mL of saturated NH Cl solution. After the
mixture was warmed to room temperature, the organic layer was
separated and the aqueous layer was extracted with ethyl acetate
for C10H13BrNO
3
+
H
13BrNO
3
2 4
(30 mL×3). The combined organic layers were dried over Na SO
-1
1335, 1178, 1101, 999, 827, 753, 634 cm .
and then concentrated. The residue was purified by
chromatography using a mixture of ethyl acetate and hexane (1:3-
1:2, v/v) as the eluent to give a ketone. The ketone was dissolved
in 50 mL of methanol. To this solution was added a solution of 4
N HCl in 1,4-dioxane (15 mL). The resulted solution was stirred
at room temperature overnight and then concentrated. The residue
was dissolved in 100 mL of methanol. To this solution was added
Methyl (3S,9aS)-6-bromo-5-oxo-2,3,5,8,9,9a-hexahydro-1H-
pyrrolo[1,2-a]azepine-3-carboxylate (10). Compound 10 was
prepared in the same procedure as 9 from amine 18 as a pale
yellow solid. From 9.15 g (49.9 mmol) of 18, 5.46 g of 10 was
2
5
obtained, yield 38 % over four steps. [α]D = - 44.3 (c = 0.60,
1
MeOH); H NMR (300 MHz, CDCl
3
) δ 6.91 (m, 1H), 4.59 (m,
5
.7 g of NaBH
3
CN (90 mmol) at room temperature with stirring.
1H), 3.89 (m, 1H), 3.75 (s, 3H), 2.58 (m, 1H), 2.37-2.16 (m, 3H),
13
1
The mixture was stirred at room temperature for 4 hours and then
concentrated. The residue was partitioned between 30 mL of
water and 100 mL of dichloromethane. The organic layer was
2.11-2.01 (m, 3H), 1.88 (m, 1H); C{ H} NMR (75 MHz, CDCl
3
)
δ 172.4, 162.9, 140.3, 118.5, 60.7, 58.0, 52.4, 35.2, 31.0, 28.1,
+
27.5; MS (ESI) m/z: [M + H] calcd for C11
H
15BrNO
3
288.03,
+
dried over Na
2
SO
4
and then concentrated. The residue was
found 288.22; HRMS (ESI) m/z: [M + H] calcd for C11
H
15BrNO
3
purified by chromatography using a mixture of ethyl acetate and
288.0235, found 288.0247; IR (neat/KBr): 3437, 2952, 1746,
-1
hexane (1:3-1:2, v/v) as the eluent to give amine 18 as a pale
1648, 1420, 1365, 1281, 1205, 1176, 820 cm .
1
yellow viscous liquid (2.8 g, 51% over three steps). H NMR (300
Methyl
(3S,8aR)-6-((tert-butoxycarbonyl)amino)-5-oxo-
3
MHz, CDCl ): δ 5.76 (m, 1H), 5.10-5.00 (m, 2H), 4.49 (m, 1H),
1
,2,3,5,8,8a-hexahydroindolizine-3-carboxylate (7). Bromide 9
3.80 (s, 1.8H, cis isomer), 3.78 (s, 1.2H, trans isomer), 3.68 (m,
(
0
0.1 g, 0.36 mmol), 127 mg of tert-butyl carbamate (1.08 mmol),
.18 g of Cs CO (0.56 mmol) and 4 mL of toluene were added
subsequently to a 25 mL round bottom flask. The flask was
flushed with nitrogen for three times, then 17 mg of Pd (dba) (5%
1
3
1
1H), 2.48 (m, 1H), 2.31-2.00 (m, 5H), 1.88-1.66 (m, 2H); C{ H}
NMR (75 MHz, CDCl ): δ 169.8, 169.6, 136.2, 136.1, 116.3,
16.2, 60.9, 59.2, 58.7, 53.5, 53.4, 31.1, 30.7, 30.5, 30.4, 29.9,
2
3
3
1
2
1
2
3
9.2, 28.3, 27.8; HRMS m/z: [M + H]+ calcd for C10
84.1338; found, 184.1334.
2
H18NO ,
mmol) and 21 mg of Xantphos (10% mmol) were added to the
flask. After flushing with nitrogen again, the mixture was refluxed
by heating with oil bath for 24 h before partitioned between 20
mL of EtOAc and 10 mL of brine. The organic layer was dried
over Na SO and then concentrated. The residue was purified by
2 4
chromatography using a mixture of ethyl acetate and hexane (1:3-
Methyl
(3S,8aR)-6-bromo-5-oxo-1,2,3,5,8,8a-
1
7
hexahydroindolizine-3-carboxylate (9). To a solution of 16 (8.0
g, 29.7 mmoL) in 50 mL of methanol was added 15 mL of a
solution of 4 N HCl in 1,4-dioxane. The solution was stirred at
room temperature overnight and then concentrated to give amine
1:2, v/v) as the eluent to give 88 mg of compound 7 as a white
2
5
1
1
7 as a salt with HCl. The salt was suspended in 50 mL of CH
To this mixture was added acrylic acid (2.2 g, 30 mmoL), EDC
5.8 g, 30 mmoL), HOBt mono hydrate (4.1 g, 30 mmoL) and 8
2
Cl
2
.
solid, yield 78%. [α]D = - 44.7 (c = 0.57, MeOH); H NMR (300
MHz, CDCl ) δ 7.21 (s, 1H), 6.82 (m, 1H), 4.56 (m, 1H), 3.82 (m,
3
(
1H), 3.75 (s, 3H), 2.61-2.11 (m, 5H), 1.80 (m, 1H), 1.46 (s,9H);
o
13
1
mL of (N,N-Diisopropylethylamine at 0 C. The solution was
allowed to warm to room temperature and stirred overnight. After
removal of the solvent by condensation, the residue was
suspended in 30 mL of water and extracted with ethyl acetate (50
3
C{ H} NMR (75 MHz, CDCl ) δ 172.1, 160.5, 153.0, 128.5,
113.8, 80.3, 57.6, 57.1, 52.5, 31.6, 29.0, 28.6, 28.3; MS (ESI) m/z:
+
[M + H] calcd for C H N O 311.15, found 311.22; HRMS
1
5
23
2
5
+
(ESI) m/z: [M + H] calcd for C H N O 311.1607, found
1
5
23
2
5
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Page 5 of 8
The Journal of Organic Chemistry
3
11.1613; IR (neat/KBr): 3400, 2955, 2929, 2870,1750, 1727,
2 4
The organic layer was dried over Na SO and then concentrated.
1
2
3
4
5
6
7
8
9
1667, 1637, 1515, 1448, 1369, 1202, 1160, 1078, 1046, 891, 839,
The residue was purified by chromatography using a mixture of
ethyl acetate and hexane (1:3-1:2, v/v) as the eluent to give 108
-1
7
71, 627 cm .
2
5
mg of compound 19 as a white solid, yield 73%. [α]D = -17.4 (c =
Methyl
(3S,6S,8aS)-6-((tert-butoxycarbonyl)amino)-5-
1
1
.00, MeOH); H NMR (300 MHz, CDCl
3
) δ 5.53 (m, 1H), 4.66
oxooctahydroindolizine-3-carboxylate (5). To a solution of 7 (80
mg, 0.26 mmol) in 15 mL of methanol was added 8.8 mg of 5%
Palladium on carbon. The mixture was stirred at room
(m, 1H), 4.24 (m, 1H), 3.73 (s, 3H), 3.50 (m, 1H), 3.04-2.75 (m,
2
H), 2.37-2.28 (m, 2H), 2.19-2.07 (m, 2H), 1.81 (m, 1H), 1.49 (s,
13
1
temperature under 1 atm of H
2
for 2 hours and then filtered
18H); C{ H} NMR (75 MHz, CDCl
137.4, 119.9, 82.8, 60.2, 55.3, 52.6, 50.4, 39.0, 32.8, 32.0, 28.0;
3
):  172.5, 171.8, 151.3,
through a pad of celite. The filtrate was concentrated under
vacuum and the residue was purified by chromatography using a
mixture of ethyl acetate and hexane (1:3-1:2, v/v) as the eluent to
+
MS (ESI) m/z: [M + H] calcd for C21
H
33
N
2
O
7
425.23, found
425.35; HRMS (ESI) m/z: [M + H] calcd for C21
25.2288, found 425.2296; IR (neat/KBr): 2978, 2923, 2851,
+
33 2 7
H N O
2
5
afford 72 mg of compound 5 as a white solid, yield 90%. [α]D = -
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
2
0
1744, 1705, 1647, 1439, 1369, 1284, 1203, 1176, 1116, 853 cm .
44.0 (c = 0.40, CHCl
3
); literature reported [α]D = -44.7 (c = 0.80,
6
1
13
CHCl
3
) ; the H NMR and C NMR data are consistent to the
Methyl (3S,6S,9aS)-6-amino-5-oxooctahydro-1H-pyrrolo[1,2-
a]azepine-3-carboxylate (21). To a solution of 19 (102 mg, 0.24
mmol) in 15 mL of methanol was added 9.2 mg of 5% palladium
on carbon. The mixture was stirred at room temperature under 1
6
literature reported data .
Methyl
(3S,9aS)-6-((tert-butoxycarbonyl)amino)-5-oxo-
2
,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate
2
atm of H for 2 hours and then filtered through a pad of celite. The
(8). Bromide 10 (0.1 g, 0.34 mmol), 122 mg of tert-butyl
filtrate was concentrated under vacuum and the residue was
dissolved in 3 mL of dichloromethane. After adding 2 mL of TFA,
the solution was stirred at room temperature for 1 hour. The
solvent was removed under reduced pressure and the residue was
purified by reverse phase semi-preparative HPLC. The gradient
ran from 80% A (water with 0.1% of TFA) and 20% B
carbamate (1.04 mmol), 0.17 g of Cs CO (0.52 mmol) and 4 mL
2
3
of toluene were added subsequently to a 25 mL round bottom
flask. The flask was flushed with nitrogen for three times, then 16
mg of Pd (dba) (5% mmol) and 20 mg of Xantphos (10% mmol)
2 3
were added to the flask. The mixture was refluxed for 24 h and
then partitioned between 20 mL of EtOAc and 10 mL of brine.
2 4
The organic layer was dried over Na SO and then concentrated.
(acetonitrile with 0.1% of TFA) to 40% A and 60% B in 30 min.
After removal of the solvent under reduced pressure, the residue
The residue was purified by chromatography using a mixture of
ethyl acetate and hexane (1:3-1:2, v/v) as the eluent to give 80 mg
was lyophilized to afford 58 mg of 21 (salt with TFA) as a white
2
5
2
5
powder, yield 66% over two steps. [α] = -39.9 (c = 0.40, MeOH);
D
of compound 8 as a white solid, yield 72%. [α]D = - 40.5 (c = 0.36,
1
1
H NMR (400 MHz, CDCl
3
) δ 4.75 (m, 1H), 4.12-4.06 (m, 2H),
MeOH); H NMR (300 MHz, CDCl
3
) δ 7.09 (s, 1H), 6.95 (m, 1H),
3
.77 (s, 3H), 2.99 (m, 1H), 2.75-2.61 (m, 5H), 2.38-2.07 (m, 3H),
4.65 (m, 1H), 3.87 (m, 1H), 3.78 (s, 3H), 2.65-2.36 (m, 2H), 2.27-
1
3
1
1
3
1
1.83 (m, 1H); C{ H} NMR (100 MHz, CDCl
3
) δ 172.4, 172.1,
1
.97 (m, 5H), 1.91 (m, 1H), 1.47 (s, 9H); C{ H} NMR (75 MHz,
6
0.3, 55.4, 52.6, 50.3, 38.9, 32.7, 31.9, 28.0, 18.3; MS (ESI) m/z:
CDCl
3
) δ 172.5, 164.5, 153.5, 129.3, 120.2, 79.9, 60.9, 58.7, 52.4,
+
+
[M + H] calcd for C11
H
19
N
2
O
3
227.14, found, 227.25; HRMS
(ESI) m/z: [M + H] calcd for C11 227.1396, found
227.1408; IR (neat/KBr): 3568, 3437, 3286, 2960,2924,
853,1739, 1645, 1605, 1454, 1365, 1278, 1207, 1184, 1132,
3
4.5, 31.6, 28.3, 27.9, 25.6; MS (ESI) m/z: [M + H] calcd for
+
+
19 2 3
H N O
C
16
H
25
N
2
O
5
325.18, found 325.30; HRMS (ESI) m/z: [M + H]
325.1763, found 325.1770; IR (neat/KBr):
3429, 2954, 2926, 2854,1744, 1648, 1437, 1367, 1205, 1177, 752,
25 2 5
calcd for C16H N O
2
-1
-1
1088, 1045, 1025, 721 cm .
700 cm .
Methyl
(3S,8aR)-5-oxo-6-phenyl-1,2,3,5,8,8a-
Methyl
(3S,6S,9aS)-6-((tert-butoxycarbonyl)amino)-5-
hexahydroindolizine-3-carboxylate (22a). Bromide 9 (0.1 g, 0.36
mmol), phenylboronic acid (38 mg, 0.36 mmol), Cs CO (0.24 g,
.73mmol), 1 mL of water and 4 mL of dioxane was added
subsequently into a 15 mL reaction tube. After the tube was
flushed with nitrogen for three times, Pd(PPh (21 mg, 5 mol%)
oxooctahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate (6). To a
solution of 8 (80 mg, 0.25 mmol) in 15 mL of methanol was
added 8.0 mg of 5% Palladium on carbon. The mixture was stirred
2
3
0
2
at room temperature under 1 atm of H for 0.5 hours and then
3 4
)
filtered through a pad of celite. The filtrate was concentrated
under vacuum and the residue was purified by chromatography
using a mixture of ethyl acetate and hexane (1:3-1:2, v/v) as the
eluent to afford 23 mg of compound 6 as a white solid, yield 29%.
was added before sealing the reaction tube with a cap. The
mixture was heated with heating mantle at 100°C with stirring for
1
2 hours, cooled to room temperature, and then partitioned
between 50 mL of EtOAc and 20 mL of brine. The organic layer
was dried over Na SO and then concentrated. The residue was
2
5
1
[
α] = - 54.5 (c = 0.20, MeOH); H NMR (300 MHz, CDCl
): 
.90 (m, 1H), 4.67 (m, 1H), 4.26 (m, 1H), 3.88 (m, 1H), 3.77 (s,
H), 2.33-2.22 (m, 3H), 2.09-2.03 (m, 3H), 1.85-1.77 (m, 3H),
D
3
2
4
5
3
1
1
2
3
purified by chromatography using a mixture of ethyl acetate and
hexane (1:3-1:2, v/v) as the eluent to give 85 mg of 22a as a white
1
3
1
.67 (m, 1H) , 1.45 (s, 9H); C{ H} NMR (75 MHz, CDCl
72.6, 171.6, 155.3, 79.5, 60.4, 59.2, 54.4, 52.4, 34.3, 32.9, 31.8,
8.4, 27.7, 27.6; HRMS m/z: [M + Na] calcd for C16
49.1739; found, 349.1732. IR (neat/KBr): 3416, 2924, 2856,
3
): 
2
5
1
solid, yield 86%. [α]D = - 89.2 (c = 0.55, MeOH); H NMR (300
MHz, CDCl ) δ 7.48-7.44 (m, 2H), 7.34-7.23 (m, 3H), 6.71 (m,
H), 4.59 (m, 1H), 3.90 (m, 1H), 3.73 (s, 3H), 2.68-2.45 (m, 2H),
+
3
26 2 5
H N O Na,
1
1
3
1
-1
3
2.25-2.06 (m, 3H),1.90 (m, 1H); C{ H} NMR (75 MHz, CDCl )
1747, 1709, 1646, 1448, 1431, 1368, 1203, 1169, 1061 cm . The
1
13
δ 172.8, 163.2, 136.5,136.1, 135.8, 128.5, 127.9, 127.7, 57.8, 56.8,
H NMR and C NMR are consistent to the literature reported
+
7
52.4, 32.0, 30.8, 28.6; MS (ESI) m/z: [M + H] calcd for
data . The optical rotation was not reported in that literature.
+
C
16
H
18NO
calcd for C16
3432, 2949, 2881, 1746, 1649, 1606, 1432, 1365, 1304, 1209,
3
272.13, found 272.22; HRMS (ESI) m/z: [M + H]
Methyl
,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate
19). Compound 10 (0.1 g, 0.34 mmol), 226 mg of di-tert-butyl
iminodicarboxylate (1.04 mmol), 0.17 g of Cs CO (0.52 mmol)
(3S,9aS)-6-(di(tert-butoxycarbonyl)amino)-5-oxo-
H
3
18NO 272.1287, found 272.1299; IR (neat/KBr):
2
(
-1
1
195, 1171, 987, 791, 698 cm .
2
3
Larger scale synthesis of 22a: To a 50 mL round bottom flask
and 4 mL of toluene were added subsequently to a 25 mL round
bottom flask. The flask was flushed with nitrogen for three times,
then 16 mg of Pd (dba) (5% mmol) and 20 mg of Xantphos (10%
2 3
mmol) were added to the flask. The mixture was refluxed for 24 h
and then partitioned between 20 mL of EtOAc and 10 mL of brine.
was added bromide 9 (1.1 g, 4.0 mmol), phenylboronic acid (0.49
g, 4.0 mmol), Cs CO (1.54 g, 8.0 mmol), 5 mL of water and 20
mL of dioxane subsequently. After the flask was flushed with
nitrogen for three times, Pd(PPh (230 mg, 0.2 mmol) was added.
2
3
3 4
)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 8
The mixture was heated with oil bath at 100°C and then stirred for
Methyl
(3S,6R,8aS)-6-(4-cyanophenyl)-5-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
12 hours. After cooled to room temperature, the mixture was
partitioned between 100 mL of EtOAc and 30 mL of brine. The
organic layer was dried over Na SO and then concentrated. The
2 4
residue was purified by chromatography using a mixture of ethyl
acetate and hexane (1:3-1:2, v/v) as the eluent to give 0.91 g of
oxooctahydroindolizine-3-carboxylate (23e). Compound 23e was
synthesized in the same procedure as 23a from 9. From 0.1 g of 9,
88 mg of 23e was obtained as a white solid, yield 82% over two
steps. [α]2 = 3.2 (c = 1.00, MeOH); H NMR (300 MHz, CDCl )
5
1
D
3
δ 7.63 (d, J = 9.00 Hz, 2H), 7.47 (d, J = 9.00 Hz, 2H), 4.56 (m,
1H), 3.97 (m, 1H), 3.77 (s, 3H), 3.67 (m, 1H), 2.29-1.88 (m, 7H),
2
2a as a white solid, yield 84%.
13
1
1
1
.66 (m, 1H); C{ H} NMR (75 MHz, CDCl
3
) δ 172.1, 170.6,
Methyl (3S,6R,8aS)-5-oxo-6-phenyloctahydroindolizine-3-
carboxylate (23a). To a solution of 22a (85 mg, 0.31 mmol) in 10
mL of methanol was added 8.5 mg of 5% palladium on carbon.
2
The mixture was stirred under 1 atm of H for 2 hours at room
temperature and then filtered through a pad of celite. The filtrate
was concentrated under vacuum and the residue was purified by
chromatography using a mixture of ethyl acetate and hexane (1:3-
47.8, 132.4, 129.3, 118.8, 110.7, 61.1, 58.5, 52.6, 45.7, 31.4,
30.3, 28.1, 24.2; MS (ESI) m/z: [M + H] calcd for C17H N O
19 2 3
99.14, found 299.20; HRMS (ESI) m/z: [M + H] calcd for
299.1396, found 299.1409; IR (neat/KBr): 3435,
953, 2228, 1745, 1685, 1642, 1439, 1142, 1111 cm .
+
+
2
17 19 2 3
C H N O
2
0
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-1
Methyl (3S,6R,8aS)-6-isobutyl-5-oxooctahydroindolizine-3-
carboxylate (23f). Compound 23f was synthesized in the same
1
:2, v/v) as the eluent to afford 77 mg of 23a as a white solid,
25
1
yield 90%. [α]D = -11.2 (c = 1.00, MeOH); H NMR (300 MHz,
procedure as 23a from 9. From 0.1 g of 9, 64 mg of 23f was
25
CDCl
3
) δ 7.32-7.19 (m, 5H), 4.52 (m, 1H), 3.86 (m, 1H), 3.76 (s,
obtained as a white solid, yield 70% over two steps. [α] = - 13.1
D
13
1
1
3
H), 3.63 (m, 1H), 2.22-1.76 (m, 8H); C{ H} NMR (75 MHz,
(c = 1.00, MeOH); H NMR (300 MHz, CDCl ) δ 4.43 (m, 1H),
3
CDCl
3
) δ 172.3, 171.5, 142.6, 128.6, 128.4, 126.7, 61.0, 58.4,
3.72 (s, 3H), 3.54 (m, 1H), 2.35 (m, 1H), 2.09-1.63 (m, 11H), 0.93
+
13
1
5
2.4, 45.8, 31.6, 30.7, 28.2, 24.3; MS (ESI) m/z: [M + H] calcd
(d, J = 6 Hz, 3H), 0.89 (d, J = 6 Hz, 3H); C{ H} NMR (75 MHz,
+
for C16
calcd for C16
H
20NO
3
274.14, found 274.25; HRMS (ESI) m/z: [M + H]
274.1443, found 274.1456; IR (neat/KBr):
CDCl ) δ 173.4, 172.7, 59.4, 58.0, 52.2, 40.6, 37.6, 31.8, 28.2,
3
+
H
18NO
3
25.5, 25.4, 23.4, 21.5; MS (ESI) m/z: [M + H] calcd for
+
3
1
412, 3061, 3029, 2952, 2865, 1744, 1684, 1619, 1496, 1451,
202, 1177, 796, 763, 702 cm .
C H NO 254.18, found 254.25; HRMS (ESI) m/z: [M + H]
1
4
24
3
-1
14 24 3
calcd for C H NO 254.1756, found 254.1760; IR (neat/KBr):
3
6
430, 2956, 2871, 1747, 1682, 1368, 1326, 1204, 1175, 1138, 722,
08 cm .
Methyl (3S,6R,8aS)-5-oxo-6-(o-tolyl)octahydroindolizine-3-
-1
carboxylate (23b). Compound 23b was synthesized in the same
procedure as 23a from 9. From 0.1 g of bromide 9, 49 mg of 23b
Methyl
(3S,6S,8aS)-5-oxo-6-propyloctahydroindolizine-3-
2
5
was obtained as a white solid, yield 48% over two steps. [α]D
carboxylate (23g). Compound 23g was synthesized in the same
procedure as 23a from 9. From 0.1 g of 9, 56 mg of 23g was
1
=8.9 (c =1.00, MeOH); H NMR (300 MHz, CDCl
3
) δ 7.34 (m,
2
5
1
3
H), 7.21-7.13 (m, 3H), 4.55 (m, 1H), 4.07 (m, 1H), 3.78 (s, 3H),
.65 (m, 1H), 2.31 (s, 3H), 2.25-2.06 (m, 4H), 2.01-1.71 (m, 4H);
obtained as a white solid, yield 64% over two steps. [α] = - 25.6
D
1
(c = 0.29, MeOH); H NMR (400 MHz, CDCl ) δ 4.46 (m, 1H),
3
1
3
1
C{ H} NMR (75 MHz, CDCl
3
) δ 172.6, 172.1, 140.7, 135.5,
3.72 (s, 3H), 3.55 (m, 1H), 2.36 (m, 1H), 2.14-1.95 (m, 4H), 1.89-
1
2
30.5, 128.0, 126.9, 126.2, 61.2, 58.6, 52.5, 41.9, 31.6, 28.8, 28.2,
1.70 (m, 4H), 1.63-1.34 (m, 4H), 0.92 (t, J = 8.00 Hz, 3H);
+
13
1
4.2, 19.4; MS (ESI) m/z: [M + H] calcd for C17
H
22NO
3
288.16,
3
C{ H} NMR (100 MHz, CDCl ) δ 173.7, 172.4, 59.8, 58.2, 52.2,
+
found 288.25; HRMS (ESI) m/z: [M + H] calcd for C17
88.1600, found 288.1608; IR (neat/KBr): 3437, 2952, 2860,
1748, 1633, 1493, 1458, 1437, 1362, 1202, 1179, 1095, 788, 758,
H
22NO
3
39.2, 34.2, 31.7, 28.2, 26.1, 25.2, 20.6, 14.0; MS (ESI) m/z: [M +
+
2
13 22 3
H] calcd for C H NO 240.16, found 240.20; HRMS (ESI) m/z:
+
[M + H] calcd for C H NO 240.1600, found 240.1606; IR
1
3
22
3
-
1
7
31 cm .
(neat/KBr): 3416, 2956, 2924, 2871,1747, 1639, 1364,1322, 1203,
-1
1
178, 1135 cm .
Methyl (3S,6R,8aS)-5-oxo-6-(m-tolyl)octahydroindolizine-3-
carboxylate (23c). Compound 23c was synthesized in the same
procedure as 23a from 9. From 0.1 g of bromide 9, 72 mg of 23c
Methyl (3S,6R,9aS)-5-oxo-6-phenyloctahydro-1H-pyrrolo[1,2-
a]azepine-3-carboxylate (24a). Compound 24a was synthesized
in the same procedure as 23a from 10. From 0.1 g of 10, 72 mg of
2
5
was obtained as a white solid, yield 69% over two steps. [α]D = -
1
25
4
.1 (c = 1.00, MeOH); H NMR (300 MHz, CDCl
3
) δ 7.23-6.99
24a was obtained as a white solid, yield 73% over two steps. [α]D
1
(
2
m, 4H), 4.53 (m, 1H), 3.84 (m, 1H), 3.76 (s, 3H), 3.63 (m, 1H),
= - 38.4 (c = 1.00, MeOH); H NMR (300 MHz, CDCl ) δ 7.39-
3
13
1
.33 (s, 3H), 2.21-1.75 (m, 8H); C{ H} NMR (75 MHz, CDCl
3
)
7.32 (m, 2H), 7.27 (m, 1H), 7.16-7.12 (m, 2H), 4.83 (m, 1H), 4.28
(m, 1H), 3.78 (s, 3H), 3.53 (m, 1H), 2.46 (m, 1H), 2.12-2.01 (m,
δ 172.2, 171.8, 142.4, 138.1, 129.2, 128.4, 127.4, 125.3, 61.0,
8.4, 52.4, 45.7, 31.6, 30.6, 28.2, 24.4, 21.4; MS (ESI) m/z: [M +
1
3
1
5
4H), 1.79-1.68 (m, 5H); C{ H} NMR (75 MHz, CDCl ) δ 175.9,
3
+
H] calcd for C17
H
22NO
3
288.16, found 288.25; HRMS (ESI) m/z:
M + H] calcd for C17 288.1600, found 288.1613; IR
neat/KBr): 3436, 2951, 2865, 1746, 1643, 1490, 1456, 1438,
172.4, 136.2, 129.0, 126.7, 126.6, 61.5, 58.7, 52.5, 51.1, 34.1,
+
+
[
(
H
22NO
3
32.9, 27.5, 26.4, 22.4; MS (ESI) m/z: [M + H] calcd for
+
C H NO 288.16, found 288.25; HRMS (ESI) m/z: [M + H]
1
7
22
3
-1
1
366, 1202, 1176, 785, 719, 704 cm .
17 22 3
calcd for C H NO 288.1600, found 288.1610; IR (neat/KBr):
3
1
432, 3028, 2932, 2860, 1746, 1632, 1497, 1434, 1370, 1203,
172, 741, 701 cm .
Methyl (3S,6R,8aS)-5-oxo-6-(p-tolyl)octahydroindolizine-3-
-1
carboxylate (23d). Compound 23d was synthesized in the same
procedure as 23a from 9. From 0.1 g of bromide 9, 90 mg of 23d
Methyl (3S,6R,9aS)-6-isobutyl-5-oxooctahydro-1H-pyrrolo[1,2-
a]azepine-3-carboxylate (24b). Compound 24b was synthesized
in the same procedure as 23f from 10. From 0.1 g of 10, 61 mg of
2
5
was obtained as a white solid, yield 87% over two steps. [α]D =
1
8.6 (c = 0.60, MeOH); H NMR (300 MHz, CDCl
3
) δ 7.20-7.09
2
4b was obtained as a white solid, yield 67% over two steps.
(
2
m, 4H), 4.54 (m, 1H), 3.87 (m, 1H), 3.76 (s, 3H), 3.64 (m, 1H),
2
5
1
1
3
1
[α]D = - 68.9 (c = 0.37, MeOH); H NMR (300 MHz, CDCl ) δ
.31 (s, 3H), 2.23-2.04 (m, 4H), 2.00-1.74 (m, 4H); C{ H}
) δ 172.4, 172.1, 139.3, 136.4, 129.3, 128.2,
1.2, 58.5, 52.5, 45.2, 31.6, 30.6, 28.2, 24.2, 21.0; MS (ESI) m/z:
3
4
1
.57 (m, 1H), 3.91 (m, 1H), 3.73 (s, 3H), 2.38 (m, 1H), 2.23 (m,
H), 2.09-1.96 (m, 3H), 1.86-1.73 (m, 4H), 1.70-1.59 (m, 3H),
NMR (75 MHz, CDCl
6
3
13
1
+
1.44 (m, 1H), 1.11 (m, 1H), 0.89-0.86 (m, 6H); C{ H} NMR (75
[
M + H] calcd for C17
H
22NO
3
288.16, found 288.25; HRMS (ESI)
288.1600, found 288.1611 IR
(neat/KBr): 3434, 2951, 2863, 1746, 1643, 1458, 1438, 1364,
+
MHz, CDCl ) δ 175.5, 173.3, 60.2, 58.7, 52.1, 42.6, 41.2, 34.7,
m/z: [M + H] calcd for C17
H
22NO
3
3
+
3
3.2, 30.0, 29.6, 27.7, 25.5, 22.8, 22.7; MS (ESI) m/z: [M + H]
-1
15 26 3
calcd for C H NO 268.19, found 268.25; HRMS (ESI) m/z: [M
1
202, 1174, 1089, 813, 782, 726 cm .
+
+
3
H] calcd for C15H26NO 268.1913, found 288.268.1922; IR
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(
neat/KBr): 3470, 2953, 2932, 2868, 1747, 1640, 1366, 1341,
6. Lobbart, H. G. and Lubell, W. D. Rigid dipeptide mimetics:
-1
1
2
3
4
5
6
7
8
9
1200, 1174 cm .
Efficient synthesis of enantiopure indolizidinone amino acids. J.
Org. Chem. 1996, 61, 9437-9446.
7
.
Beal, L. M.; Liu, B.; Chu, W. and Moeller, K. D. Anodic amide
oxidation/olefin metathesis strategies: Developing a unified
approach to the synthesis of bicyclic lactam peptidomimetics.
Tetrahedron, 2000, 56, 10113-10125.
ASSOCIATED CONTENT
Supporting Information
8
9
.
.
Duggan, H. M. E.; Hitchcock, P. B.; Young, D. W. Synthesis of
The Supporting Information is available free of charge on the
ACS Publications website.
5
/7-, 5/8- and 5/9-bicyclic lactam templates as constraints for
external betaturns. Org. Biomol. Chem. 2005, 3, 2287–2295.
Zhang, J.; Xiong, C.; Wang, W.; Ying J. and Hruby, V. J.
1
13
1
The original H NMR and C{ H} NMR spectra, IR spectra and
analytical HPLC for compounds 5, 6, 21 and 23a are provided as
Supporting Information.
Stereoselective
bromination-Suzuki
cross-coupling
of
dehydroamino acids to form novel reverse-turn peptidomimetics:
substituted unsaturated and saturated indolizidinone amino acids.
Org. Lett. 2002, 4 (23), 4029-4032.
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AUTHOR INFORMATION
Corresponding Author
1
1
1
0. Davies, D. E.; Doyle, P. M.; Farrant, R. D.; Hill, R. D.; H., Peter
B.; Sanderson, P. L. N.; Young, D. W. Synthesis of an external
beta-turn based on the GLDV motif of cell adhesion proteins.
Tetrahedron, 2005, 61 (1), 301-312.
1. Manzoni, L.; Arosio, D.; Belvisi, L.; Bracci, A.; Colombo, M.;
Invernizzi, D. and Scolstico, C. Functionalized azabicycloalkane
amino acids by nitrone 1,3-dipolar intramolecular cycloaddition.
J. Org, Chem. 2005, 70, 4124-4132.
2. Atmuri, N. D. P.; Reilley, D. J. and Lubell, W. D.
Peptidomimetic synthesis by way of diastereoselective
iodoacetoxylation and transannular amidation of 7-9-membered
lactams. Org. Lett. 2017, 19, 5066-5069.
*
E-mail: haiyings1969@cpu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from national natural science foundation of
China 81673288,81473079, the Program for Jiangsu Province
Innovative Research Team, the Program for Jiangsu Province
Innovative Personnel to Haiying Sun, the Program for Specially
Appointed Professor of Jiangsu Province to Haiying Sun, and the
Funding of Double First-rate Discipline Innovation Teams
13. Atmuri, N. D. P. and Lubell, W. D. Stereo- and regiochemical
transannular cyclization of a common hexahydro-1H-azonine to
afford three different indolizidinone dipeptide mimetics. J. Org,
Chem, 2020, 85, 1340-1351.
1
4. Miller, S. J. and Grubbs, R. H. Synthesis of conformationally
restricted amino acids and peptides employing olefin metathesis.
J. Am. Soc. Chem. 1995, 117, 5855-5856.
(CPU2018GY05 and CPU2018GF05) is acknowledged.
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