β-amino amides from β-lactams: Application to the formal synthesis of a peptide-deformylase inhibitor

Article abstract of DOI:10.1055/s-2006-951499

A facile and a practical synthesis of peptide-deformylase inhibitor 1 is described using an acid-catalyzed aminolysis of β-lactam 12 with pyrrolidine 6 as the key transformation. In addition, simplified conditions for the conversion of a β-hydroxy acid to

Full text of DOI:10.1055/s-2006-951499

LETTER
3179
b-Amino Amides from b-Lactams: Application to the Formal Synthesis of a
Peptide-Deformylase Inhibitor
b-Amino
A
mide
s
f
i
rom
b
-
n
Lactam
s
glong Jiang, Kapa Prasad,* Mahavir Prashad, Joel Slade, Oljan Repič, Thomas J. Blacklock
Process Research & Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA
E-mail: Prasad.kapa@novartis.com
Received 16 June 2006
outset was to exclude the intermediacy of b-amino acids
Abstract: A facile and a practical synthesis of peptide-deformylase
as it adds an additional step that requires the use of activa-
tion methodology needed for the formation of the peptidic
bond from the carboxylic acid.
inhibitor 1 is described using an acid-catalyzed aminolysis of b-lac-
tam 12 with pyrrolidine 6 as the key transformation. In addition,
simplified conditions for the conversion of a b-hydroxy acid to a b-
lactam are reported.
Instead, the N-oxygenated b-lactams in the present study
are activated enough to facilitate direct aminolysis as re-
ported earlier by Jin and Kim5 using 10 equivalents of
40% methylamine solution. These results were encourag-
ing enough to start our work but not yet practical as the
amine component was used in large excess.
Key Words: b-amino amides, b-lactams, peptide-deformylase in-
hibitor
Compound 1 is an extremely potent inhibitor of peptide
deformylase (PDF)1 in vitro while showing good antibac-
terial activity in vivo. It is active against pathogenic bac-
terial strains that have acquired resistance to other
antibacterial agents. The PDF inhibitors of this class have
the potential to be developed into an antibacterial agent
with the ability to eradicate many bacterial respiratory in-
fections.
The b-lactam 12 was made in a high yield starting from 9
as shown in Scheme 3. Condensation of 9 with benzy-
loxyamine·HCl salt in water in the presence of 1-[3-(di-
methylamino)propyl]-3-ethylcarbodiimide hydrochloride
(EDCI) gave 10 in quantitative yield.6
Conversion of 10 to mesylate 11 was accomplished in py-
ridine, and the product was isolated in >98% yield as a
solid by quenching the reaction mixture with aqueous
HCl. Finally, the b-lactam formation from 11 was accom-
plished by using potassium carbonate, tetrabutylammoni-
um bromide in THF and heating the reaction mixture at
40 °C for 6 hours.7 Pure product 12 was isolated after
filtration and evaporation of the solvent and extraction
with ethyl acetate and water.
Me
OHC
F
O
N
O
–O
N+
O–
N
N
H
Mg2+
Initial studies on the aminolysis (see Table 1) of 12 with
1.2 equivalents of 6 were disappointing. In neat methanol
and 8% aqueous methanol the product formation was neg-
ligible. However, when a concentrated 40% aqueous
methanol was used desired 13 was produced in 80% yield
along with a by-product. The yield was dramatically im-
proved to >96% by using 2-ethylhexanoic acid as the cat-
alyst, and the preferred solvent was THF.
2
1
Figure 1
Initial quantities of 1 that were needed for studies were
made1,2 utilizing a Michael addition of O-benzylhydroxyl-
amine to compound 2 as the key step to generate the ste-
reogenic center in the b-amino amide portion of the
molecule (Scheme 1). This addition gave a mixture of dia-
stereoisomers 3 in a 4:1 ratio. The desired isomer 4 was
isolated in pure state as tosic acid salt by crystallization.
As we needed a more expeditious synthesis to make larger
quantity of 1, we investigated the concept of arriving at
b-amino amides from b-lactams (Scheme 2), and this led
to a practical preparation of 1.
Having accomplished the preparation of b-amino amide
13 in high yield, the only step remaining for formal com-
pletion of the synthesis of 1 was the formylation. This was
carried out in a straightforward manner using formic acid–
acetic anhydride mixture in isopropyl acetate while main-
taining the temperature at –7 °C. Product 7 was isolated as
a crystalline solid in 80% overall yield starting from 11,
and its identity was confirmed by comparison with an au-
thentic sample.
The use of b-lactams in the preparation of b-amino acids
and their subsequent conversion to b-amino amides is
well documented in the literature.3,4 Our strategy from the
In conclusion, a highly efficient synthesis of 1 was de-
scribed using aminolysis of a b-lactam intermediate as the
key step. The stereochemical integrity of all chiral centers
was preserved through out the synthesis, and the prepara-
tion of b-lactam itself was carried out in a highly practical
manner from 9.
SYNLETT 2006, No. 18, pp 3179–3181
0
3
.1
1
.2
0
0
6
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951499; Art ID: S14506ST
© Georg Thieme Verlag Stuttgart · New York

3180
X. Jiang et al.
LETTER
O
O
O
O
O
O
HCl·H2N
O
O
Me
TsOH·HN
N
Me
N
TsOH
Me
N
O
O
HN
O
O
4
2
3
1.
Na2CO3
2. LiOH, H2O2
NH
Me
O
HN
N
O
O
Me
OH
OHC
F
HCO2H
Ac2O
Me
OH
F
OHC
O
6
N
O
O
N
·HN
HN
O
O
N
N
N
H
N
H
7
O
O
O
5
CO(NH2)2/H2O2
Me
OHC
F
Pd/C
NH4HCO2
O
N
O
O
1
N+
N
N
NaOH
MgCl2
H
O–
8
Scheme 1
Scheme 2
R
R
O
H
N
O
O
N
O
N(R)2
Table 1 Aminolysis of 12 with 6
Entry Solvent
Additive
None
Temp (°C)
Time (h)
13 (%)
Impurity (%) Unreacted 12 (%)
a
a
1
2
3
4
5
6
7
8
9
MeOH (25 mL)
65
3
3
–
–
>95
>95
2
a
H2O (2 mL)
H2O (2 mL)
None
70
–
MeOH (5 mL)
Toluene
83
17
4
80
18
a
reflux
reflux
reflux
72
–
>95
>90
10
a
1 equiv TMSCl
1 equiv 2-EHA
3
–
3
70
>96
15
20
<2
5
THF
0.5 equiv 2-EHA
7
<2
80
THF
0.5 equiv HCl (6 N)
0.5 equiv 2-EHA
68
4
Isopropyl acetate
72
8
90
8
2
a Not detected.
Synlett 2006, No. 18, 3179–3181 © Thieme Stuttgart · New York

LETTER
b-Amino Amides from b-Lactams
3181
O
NH2
O
O
O
ONa
Me
Me
N
H
EDCI
H2O
MeSO2Cl/
pyridine
>98%
HO
HO
9
10
>98%
O
O
N
Me
O
O
H
S
O
Me
11
K2CO3
Bu4N+Br–
THF
F
Me
O
H
N
N
N
H
F
O
N
H
6
O
N
O
O
Me
N
O
N
N
THF
2-ethylhexanoic acid
H
13
12
HCO2H/Ac2O
80% over three steps
isopropyl acetate
7
Scheme 3
(m, 5 H), 8.52 (s, 1 H). 13C (CDCl3): d = 13.78, 22.47, 28.02,
29.10, 37.23, 43.98, 70.21, 78.43, 128.66, 128.87, 129.31,
135.03, 170.06; [a]D25 +5.901 (c 1.06, MeOH).
References and Notes
(1) (a) Lopez, S.; Wu, C.; Blais, J.; Hackbarth, C.; Gomez, M.;
Kubo, A.; Jain, R.; Sundaram, A.; Alvarez, S.; Bracken, K.;
Dean, K.; Weidmann, B.; Patel, D.; Trias, J.; White, R.;
Yuan, Z. 44th Annual Interscience Conference on Microbial
Agents and Chemotherapy; Washington, D.C., 2004;
October 20 – November 2, Poster No. F1959. (b) Patel, D.
V.; Yuan, Z.; Jain, R. K.; Garcia Alvarez, S.; Jacobs, J. WO
2002102790, 2002. (c) Jones, R. N.; Sader, H. S.; Fritsche,
T. R. Diagn. Microbiol. Infect. Dis. 2005, 51, 139.
(2) Slade, J.; Parker, D. J.; Girgis, M.; Mueller, M.; Vivelo, J.;
Liu, H.; Bajwa, J. S.; Chen, G.-P.; Carosi, J.; Lee, P.;
Chaudhary, A.; Wambser, D.; Prasad, K.; Bracken, K.;
Dean, K.; Boehnke, H.; Repič, O.; Blacklock, T. J. Org.
Process Res. Dev. 2006, 10, 78.
Compound 12: 1H NMR (CDCl3): d = 0.87 (t, J = 7.14 Hz, 3
H), 1.27–1.29 (m, 4 H), 1.43–1.48 (m, 1 H), 1.65–1.67 (m, 1
H), 2.81–2.83 (m, 1 H), 2.90 (dd, J = 2.46, 3.88 Hz, 1 H),
3.34 (dd, J = 2.46, 4.89 Hz, 1 H), 4.93 (s, 2 H), 7.35–7.39 (m,
5 H). 13C NMR (CDCl3): d = 13.85, 22.42, 28.49, 29.25,
45.11, 51.46, 77.94, 128.32, 128.69, 129.85, 135.31, 166.99;
[a]D25 +24.63 (c 1.02, MeOH).
Compound 13: 1H NMR (CDCl3): d = 0.78 (t, J = 6.90 Hz, 3
H), 0.82–0.90 (m, 1 H), 1.08–1.28 (m, 4 H), 1.31–1.38 (m, 1
H), 1.51–1.68 (m, 1 H), 1.69–1.73 (m, 1 H), 1.82–2.10 (m, 2
H), 2.32–2.42 (m, 1 H), 2.86–3.05 (m, 2 H), 3.20–3.31 (m, 1
H), 3.42–3.56 (m, 2 H), 4.68 (s, 2 H), 4.72–4.76 (m, 1 H),
7.20–7.42 (m, 6 H), 8.10–8.20 (m, 2 H), 9.75 (s, 1 H). 13
C
(3) Xu, Y.; Miller, M. J. J. Org. Chem. 1998, 63, 4314.
(4) Jin, Y.; Kim, D. H. Bioorg. Med. Chem. Lett. 1998, 8, 3515.
(5) Jin, Y.; Kim, D. H. Synlett 1998, 1189.
(CDCl3): d = 13.91, 22.79, 24.33, 24.95, 29.60, 31.03, 42.36,
47.54, 53.83, 60.40, 75.85, 114.45, 114.50, 124.63, 124.89,
127.98, 128.45, 135.35, 135.69, 137.61, 147.72, 147.75,
154.58, 157.90, 169.53, 176.32; [a]D25 –74.43 (c 1.01,
MeOH).
(6) Spectral data on new compounds are as follows.
Compound 10: 1H NMR (CDCl3): d = 0.85 (t, J = 4.12 Hz,
3 H), 1.18–1.26 (m, 5 H), 1.50–1.53 (m, 1 H), 2.10–2.23 (m,
1 H), 3.56–3.57 (s, 1 H), 3.60–3.62 (m, 2 H), 4.81–4.88 (m,
2 H), 7.31–7.37 (m, 5 H), 9.47 (s, 1 H). 13C NMR (CDCl3):
d = 14.29, 23.01, 28.41, 29.73, 46.88, 63.96, 79.02, 128.70,
128.99, 129.60, 135.70, 173.56; [a]D25 +0.556 (c 1.05,
MeOH).
(7) (a) In the literature, acetone in combination with potassium
carbonate was typically used for the formation of these type
of b-lactams, see ref. 7b. For practical reasons we preferred
THF as the solvent and this necessitated the use of a phase-
transfer catalyst. (b) Floyd, D. M.; Fritz, A. W.; Pluscec, J.;
Weaver, E. R.; Cimarusti, C. M. J. Org. Chem. 1982, 47,
5160.
Compound 11: 1H NMR (CDCl3): d = 0.87 (t, J = 6.78 Hz, 3
H), 1.30–1.40 (m, 5 H), 1.58–1.60 (m, 1 H), 2.41–2.43 (m, 1
H), 2.97 (s, 3 H), 4.26–4.28 (m, 2 H), 4.93 (s, 2 H), 7.30–7.40
Synlett 2006, No. 18, 3179–3181 © Thieme Stuttgart · New York