A facile construction of the 3,6-diamino-1,2,3,4-tetrahydropyridine-4-one scaffold: synthesis of N-3 to carbon replacement analog of TAN-1057A/B

Article abstract of DOI:10.1016/j.tetlet.2007.03.008

A facile construction of the 3,6-diamino-1,2,3,4-tetrahydropyridine-4-one class of compounds is described. Compound 2, a carbon analog at the N-3 position of TAN-1057A/B, was synthesized using this approach.

Full text of DOI:10.1016/j.tetlet.2007.03.008

Tetrahedron Letters 48 (2007) 3273–3275
A facile construction of the
3,6-diamino-1,2,3,4-tetrahydropyridine-4-one scaffold: synthesis
of N-3 to carbon replacement analog of TAN-1057A/B
Lijun Zhang, Choung U. Kim and Lianhong Xu*
Department of Medicinal Chemistry, Gilead Sciences, Inc., 342 Lakeside Drive, Foster City, CA 94404, USA
Received 7 February 2007; revised 23 February 2007; accepted 1 March 2007
Available online 4 March 2007
Abstract—A facile construction of the 3,6-diamino-1,2,3,4-tetrahydropyridine-4-one class of compounds is described. Compound 2,
a carbon analog at the N-3 position of TAN-1057A/B, was synthesized using this approach.
Ó 2007 Elsevier Ltd. All rights reserved.
TAN-1057A/B (1) (Fig. 1), isolated from bacteria Flexi-
bacter by Takeda Chemical Co. in 1993, is a dipeptide
antibiotic with potent activity against methicillin-resis-
tant Staphylococcus aureus (MRSA).1 TAN-1057A/B
consists of b-homoarginine and a distinctive heterocyclic
amidinourea derivative of 2,3-diaminoproprionic acid.
Its potent anti-infective activity and intriguing structural
feature attracted attention from scientists around the
world. Several total and/or core unit syntheses2 and a
few SAR studies have been published.3 However, the
NH
CH3
N
*
NH
O
H2N
N
1
5
H
3
O
NH2
1 TAN-1057A/B
O
N
N
NH2
H
Hydrolysis
NH
O
NH
CH3
N
O
*
N
H
N
NH2
H2N
N
H
H
O
NH2
unique
2,5-diamino-5,6-1H-dihydropyrimidine-4-one
OH
ring is rather sensitive toward hydrolysis, which occurs
in both acidic and basic media. TAN-1057A/B gradually
loses its antibacterial activity in basic aqueous solution
due to the hydrolysis of the acetyl amidine and opening
of the heterocyclic ring (Scheme 1).1 It was envisioned
that replacement of N-3 of the original hydrolytically la-
bile 2,5-diamino-5,6-1H-dihydropyrimidine-4-one with
a carbon, to produce a 3,6-diamino-1,2,3,4-tetrahydro-
pyridine-4-one, would stabilize the ring system toward
Scheme 1.
hydrolysis and maintain minimal structural disturbance.
Furthermore, we and others discovered that replace-
ment of the 2-ureido moiety in TAN-1057A/B with 2-
acetylamino provided a more potent analog.4 Therefore
compound 2, the acetylamino N-3 to carbon replace-
ment analog of TAN-1057A/B (Scheme 2), was targeted
in our effort to discover novel antibacterial agents.
NH
CH3
The synthesis of 2 can be realized through the coupling
of diazoketone 3 and heterocycle core 4 (Scheme 2), uti-
lizing a similar strategy used in the total synthesis of
TAN-1057A/B and its analogs.2b Heterocycle core 4 is
the key intermediate for synthesis of 2. We envisaged
that core 4, 3,6-diamino-1,2,3,4-tetrahydropyridine-4-
one, could be obtained from heterocycle 5 via decarbox-
ylation. Through the extensive literature mining, we
were very surprised to find that both tetrahydropyridone
4 and 5 are novel heterocycles: neither has been reported
N
*
H2N
N
NH O
1
5
H
3
O
NH2
O
N
N
NH2
H
1a TAN-1057A *S
1b TAN-1057B *R
Figure 1. Structure of TAN-1057A/B.
*
Corresponding author. Tel.: +1 650 522 5828; fax: +1 650 522
5899; e-mail: lianhong.xu@gilead.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.008

3274
L. Zhang et al. / Tetrahedron Letters 48 (2007) 3273–3275
rectly acetylating amidine 9, the acetyl group was in-
NH
Me
N
stalled at the imidate stage regio-specifically. In
addition, in order to obtain amine 4 in a more conver-
gent manner under mild conditions, a benzyl ester was
chosen instead of ethyl. As outlined in Scheme 4, to test
our hypothesis, acetyl imidate 14 was prepared from
cyanoacetic acid 11. Acid 11 was converted to its benzyl
ester 12.6 Acetyl imidate 14 was then prepared by con-
version of nitrile 12 to imidate 13, followed by acetyla-
tion. Coupling of imidate 14 with amine 8 proceeded
smoothly to afford acetyl amidine 15. As expected, when
deactivated amidine 15 was treated with sodium acetate
in ethanol, formation of pyrimidone 10b was not ob-
served. Unfortunately, under this condition, starting
material 15 stayed untouched, the desired Dieckmann-
type cyclization product carbocyclic 16 could not be de-
tected. A variety of conditions, including basic (e.g.,
NaOEt, NaOAc, TEA) and acidic (e.g., AcOH) reaction
media, failed to realize the desired cyclization to provide
16. It has been shown that the combination of anhy-
drous magnesium chloride and triethylamine is a useful
base system for chealating activation of malonate-type
compounds,7 and this condition was tested to direct
the desired cyclization. When imidate 15 was treated
with magnesium bromide diethyl etherate and triethyl-
amine in acetonitrile at room temperature for 16 h, the
desired cyclic product 16 was isolated in a good yield.8
Concomitant removal of both benzyl and Cbz- groups
by hydrogenation yielded amine 17. Decarboxylation
with 10% trifluoroacetic acid in water at room tempera-
ture proceeded uneventfully to give amine 4. Compound
*
H2N
NH
N
NH
O
H
NH2
O
2
O
N
Me
H
Me
HN
O
N2
NH
NHR
+
CbzHN
N
Cbz
NHCbz
Cbz
O
3
4 (R=Ac)
Me
N
NH
NHR
CO2Et
O
5
Scheme 2.
to date. In this Letter, we would like to report the new
methodology we developed for an efficient construction
of these types of heterocycles.
The most straightforward strategy for the construction
of tetrahydropyridone 5 would be based on a Dieck-
mann-type cyclization of appropriately functionalized
ester 9 (Scheme 3). Compound 9 was prepared through
coupling of amino ester 82b with imidate 7, which was
obtained from cyanoacetate 6 by known procedures.5
However, when amidine 9 was treated with sodium ace-
tate in ethanol, cyclization only occurred via attack of
amidine nitrogen to give compound 10a (yield: ꢀ30%).
Effort to force the desired cyclization under various con-
ditions was unsuccessful. Compound 10a was subjected
to a series of basic conditions in an effort to achieve a
ring opening and closure sequence to generate the tar-
geted heterocycle 5. Unfortunately, all attempts toward
this end were fruitless.
CbzCl
TEA
CN
CN
EtOH
HCl
NH
O
EtO
O
Ph
CO2H
11
CO2CH2Ph
12
DMAP
13
O
It is obvious that the undesired cyclization is due to the
superior reactivity of amidine nitrogen over the a-car-
bon of the ester. To prevent this undesired cyclization,
the reactivity of amidine nitrogen needs to be reduced.
The amidine was deactivated with an acetyl group which
is also present in target molecule 2. To avoid generation
of a mixture of regioisomers at amidine nitrogen by di-
8
Ac2O, Py
N
O
NaOAc, EtOH
88%
60% from 12
EtO
O
Ph
14
O
Me
O
N
MgBr2-Et2O, TEA
N
Cbz
NH
O
Ph
MeCN
82%
Cbz
N
O
OMe
15
Me
NH2
CN
NH
O
EtOH, HCl
8
CO2Me
EtO
OEt
Me
CO2Et
6
Me
N
7
HN
NH
O
Cbz
NH O
H2, Pd/C
Me
N
Me
N
NR
NH
O
N
H
OH
O
N
MeOH
96%
CO2Et
H
Cbz
NH
Cbz
O
O
OCH2Ph
17
O
NHR
CO2Et
16
O
OMe
9
5
Me
N
NaOAc
EtOH
Me
(R=H)
1) 3, AgClO4,TEA, DMF
HN
O
10% TFA/H2O
Cbz
NH
NH
O
2
2) H2, PdCl2, Pd/C, MeOH
68%
CO2Et
40 oC
95%
O
N
R
N
10a R=H
H
10b R=Ac
4
Scheme 3.
Scheme 4.

L. Zhang et al. / Tetrahedron Letters 48 (2007) 3273–3275
3275
4 was coupled with side chain 3,3 then de-protected to
provide target compound 2 following the known
procedures.9
Xu, L.; Kim, C. U. Tetrahedron Lett. 2003, 44, 5871; (e)
Lin, P.; Ganesan, A. Synthesis 2000, 14, 2127.
3. (a) Brands, M.; Endermann, R.; Gahlmann, R.; Kruger, J.;
Raddatz, S. Bioorg. Med. Chem. Lett. 2003, 13, 241; (b)
Brands, M.; Grande, Y. C.; Endermann, R.; Gahlmann, R.;
Kruger, J.; Raddatz, S. Bioorg. Med. Chem. Lett. 2003, 13,
2641; (c) Brands, M.; Endermann, R.; Gahlmann, R.;
Kruger, J.; Raddatz, S.; Stoltefub, J.; Belov, V. N.;
Nizamov, S.; Sokolov, V. V.; Meijere, A. D. J. Med.
Chem. 2002, 45, 4246.
In summary, we developed a new methodology for the
construction of 3,6-diamino-1,2,3,4-tetrahydropyridine-
4-one, which is also suitable for the preparation of other
amino tetrahydropyridine-4-ones. Compound 2, a novel
carbon analog at the N-3 position of TAN-1057A/B,
was synthesized using this facile approach for the tetra-
hydropyridone scaffold. Studies indicated that the het-
erocycle core of 2 was stable to hydrolysis in both
acidic and basic media, in which TAN-1057 A/B experi-
enced decomposition. Its biological data will be reported
in a future publication.
4. Williams, R.; Yuan, C.; Lee, V.; Chamberland, S. J.
Antibiot. 1998, 51, 189.
5. Lounasmaa, M.; Hanhien, P. Heterocycles 1996, 43, 1981.
6. Kim, S.; Lee, J. I.; Kim, Y. C. J. Org. Chem. 1985, 50, 560.
7. (a) Rathke, M. W.; Cowan, P. J. J. Org. Chem. 1985, 50,
2622; (b) Rathke, M. W.; Nowak, M. A. Synth. Commun.
1985, 15, 1039; (c) Clay, R. J.; Collom, T. A.; Karrick, G.
L.; Wemple, J. Synthesis 1993, 290.
8. Experimental procedures for tetrahydropyridone 16: To a
solution of 15 (1.3 g, 2.69 mmol) in acetonitrile (20 ml) was
added MgBr2–Et2O (2.1 g, 8.1 mmol), followed by a slow
addition of triethylamine (1.1 g, 10.9 mmol). The reaction
mixture was stirred at room temperature for 16 h, and
evaporated to a small volume. The residue was partitioned
between ethyl acetate and 0.2 N HCl. The organic phase
was washed with water and NaHCO3, dried over MgSO4,
filtered, and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel (eluted
with 1:1 hexane/ethyl acetate) to give compound 16 as a
colorless solid (0.7 g, 57.7%). 1H NMR (CDCl3) d 12.95 (br
s, 1H), 10.05 (br s, 1H), 7.3–7.6 (m, 10H), 5.1–5.5 (m, 4H),
5.0/4.75 (m, 1H), 3.8 (m, 2H), 3.0 (s, 3H), 2.3 (s, 3H). MS
(M+Na)+: 474.3.
Acknowledgments
We thank Dr. Ke-Yu Wang for performing NMR stud-
ies on the key intermediates and final compounds, and
Drs. Randy Vivian and Christopher Lee for their assis-
tance in preparation of this manuscript.
References and notes
1. (a) Katayama, N.; Fukusumi, S.; Funabashi, Y.; Iwahi, T.;
Ono, H. J. Antibiot. 1993, 46, 606; (b) Funabashi, Y.;
Tsubotani, S.; Koyama, K.; Katayama, N.; Harada, S.
Tetrahedron 1993, 49, 13.
2. (a) Yuan, C.; Williams, R. J. Am. Chem. Soc. 1997, 119,
11777; (b) Sokolov, V. V.; Kozhushkov, S. I.; Nikolskaya,
S.; Belov, V. N.; Es-Sayed, M.; Meijere, A. D. Eur. J. Org.
Chem. 1998, 777; (c) Xu, L.; Zhang, L.; Bryant, C. M.;
Kim, C. U. Tetrahedron Lett. 2003, 44, 2601; (d) Zhang, L.;
9. Spectra data for compound 2 (diastereomeric mixture ꢀ1:2):
1H NMR (DMSO-d6) d 10.87/10.76 (d, J = 8 Hz, 0.35H, s,
0.65H), 8.7/8.6 (s, 1H), 8.05 (br s, 2H), 7.9 (m, 1H), 7.3 (br
s, 3H), 4.95/4.75 (m, 1H), 4.65/4.42 (s, 0.65H; m, 0.35H),
3.4–3.7 (m, 3H), 3.1 (m, 2H), 2.8/2.65 (s, 3H), 2.5–2.8 (m,
2H), 2.05 (s, 3H), 1.6 (m, 4H). MS (M+1)+: 354.2.