A new and convergent synthesis for 2,5-diamino-tetrahydropyrimidones

Article abstract of DOI:10.1016/S0040-4039(03)00226-0

AN1057A/B has shown potent activity against MRSA. A novel and concise route to the synthesis of its heterocycle core 2,5-diamino-5,6-dihydro-1H-pyrimidine-4-one is described. This methodology allows the synthesis of an array of analogs with different amin

Full text of DOI:10.1016/S0040-4039(03)00226-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2601–2604
A new and convergent synthesis for
2,5-diamino-tetrahydropyrimidones
Lianhong Xu,* Lijun Zhang, Clifford M. Bryant and Choung U. Kim
Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA
Received 18 December 2002; revised 21 January 2003; accepted 21 January 2003
Abstract—AN1057A/B has shown potent activity against MRSA. A novel and concise route to the synthesis of its heterocycle
core 2,5-diamino-5,6-dihydro-1H-pyrimidine-4-one is described. This methodology allows the synthesis of an array of analogs
with different amine substitutions at the 2-position. © 2003 Elsevier Science Ltd. All rights reserved.
TAN-1057A/B, isolated a few years ago from Flexibac-
ter in Japan, exists as a mixture of tautomers 1a and 1b
(Fig. 1). This unique dipeptide antibiotic has exhibited
potent in vitro and in vivo activity against Gram-posi-
tive bacteria, especially against methicillin resistant
Staphylococcus aureus (MRSA).1 During the course of
our investigation of the structure–activity relationship
(SAR) of TAN-1057A/B analogs, we were interested in
Figure 1.
modification of the urieo-substitutions at the 2-
position.
Two independent total syntheses of TAN-1057A/B
have been reported to date.2 Some preliminary investi-
gation at the 2-position was published by the Williams
group.3 Recently, an approach to TAN-1057A/B hete-
rocycle was also disclosed.4 Unfortunately, these exist-
ing approaches of building the heterocyclic core
preclude an extensive investigation at the 2-position. In
this communication we report a new strategy that
allows for the convenient synthesis of novel TAN-
1057A/B analogs with a variety of alterations at 2-
position.
In order to introduce a variety of amine substitutions at
Scheme 1.
2-position, it was necessary to develop a new and
efficient pathway for the synthesis of 2,5-diamino-5,6-
dihydro-1H-pyrimidine-4-one (4). As shown in Scheme
1, we envisioned that once the heterocyclic core was
Based on the knowledge that guanidine are generated
built, the desired analogs 2 could be constructed by
via reaction of amines with acyl-S-methylisothioureas,5
coupling of diazoketone 3 and dihydropyrimidone 4
we reasoned if acyl-S-methylisothiourea 5 could be
with the known strategy disclosed by the de Meijere
obtained, treatment of 5 with requisite primary and
group.2b
secondary amines should provide an efficient and con-
vergent way to access a variety of structurally diverse
* Corresponding author. E-mail: lianhong xu@gilead.com
acyl guanidines 4 (Scheme 2).
–
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00226-0

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L. Xu et al. / Tetrahedron Letters 44 (2003) 2601–2604
in Scheme 4. Upon treatment with amines, the diacyl
isothiourea 8 was smoothly converted to the desired
cyclic guanidine 9 in fair to excellent yields.8 Examples
that demonstrate this transformation with a variety of
amines are listed in Table 1.
As depicted in Table 1, both primary and secondary
amines gave good yield (entries a, d and g). Hydroxy-
amine and morpholine (entries b and c) also provided
product with good yield. When the amine salt was used
for the reaction, organic base (iPr2NEt) was added.
However, neither pre-generated amide salt nor its silyl-
ated imidate reacted with 8 (entry h).
Scheme 2.
With 2-amino heterocyclic compound 9 in hand, it was
further converted to TAN-1057A/B analog. TAN-1057
analogs with 2-alkylamines 2b–e were thus obtained
following the procedures displayed in Scheme 5, repre-
sented by 2e. The Cbz-group was removed by
hydrogenolysis, and the resulting amine 10e was cou-
pled with diazoketone 3 in the presence of AgClO4 to
afford compound 11e. We found that AgClO4 was a
better catalyst than PhCOOAg used by the de Meijere
group for the coupling reaction. AgClO4 had much
wider tolerance of substrates and provided more consis-
tent yield. In addition, purification of the final product
is easier. Final deprotections of coupled product 11e,
removal of Boc with acid followed by hydrogenolysis of
Cbz-groups afforded the desired 2e.
Scheme 3.
It was envisioned that 5 could be formed from N-pro-
tected N-methyldehydroalanine methyl ester 66 and S-
methylisothiourea
7
by Michael addition and
subsequent cyclization analogous to the known method
for the preparation of 2-S-methylthio-5,6-dihydro-1H-
pyrimidine-4-one.7 As illustrated in Scheme 3, reaction
of dehydroalanine 6 with isothiourea 7 in the presence
of base (K2CO3) afforded heterocyclic compound 5 as a
white solid in 70% yield. The reaction proceeded under
mild condition and was amenable to a large scale
preparation. During the process of preparing dihydro-
pyrimidone 4, we came to realize that 4 decomposed
readily in the presence of strong nucleophiles or under
strongly basic conditions, especially at elevated temper-
atures. The sensitivity of heterocycle 4 required the
identification of mild reaction conditions for any follow
up transformations. Unfortunately, treatment of
monoacyl isothiourea 5i with amines under mild condi-
tions failed to provide any desired dihydro-pyrimidone
product 4 (Scheme 3). In order to facilitate the smooth
conversion, the isothioureas 5 were activated with
either a Cbz- or a Boc- function to provide 8 as shown
Syntheses of TAN-1057 analogs with 2-carboxy amines
2f–g are outlined in Scheme 6. It was observed9 that the
triacylated guanidines were highly reactive toward
nucleophiles. In order to introduce an acylamino at
2-position, Boc-group of 9f and 9g was first removed to
afford 12f and 12g, respectively. Compound 12f was
converted to 2-acylaminoguanidine 13f by treating with
EDC and HOBt. Treatment of 12g with CDI in the
presence of triethylamine yielded 2-urieo 13g. Follow-
ing the established procedure, deprotection of the Cbz-
group, coupling the resulting amine with diazoketone 3,
followed by removal of the Cbz-group on the side chain
provided TAN-1057A/B analogs 2f–g.
In summary, we have demonstrated an efficient and
convergent route to construct the heterocyclic core of
TAN-1057A/B by first forming 2-thio-tetrahydro-
pyrimidone through Michael addition and subsequent
cyclization, followed by elaboration at the 2-position
Scheme 4.

L. Xu et al. / Tetrahedron Letters 44 (2003) 2601–2604
Table 1. Conversion of isothiourea 8 to guanidine 9
2603
Scheme 5.
with various amines. A variety of TAN analogs were
thus prepared. This route enables us to quickly evaluate
analogs and establish SAR in this region. The biologi-
cal activity of these series of analogs will be reported
soon.
Acknowledgements
We thank Dr. Ke-Yu Wang for performing NMR studies
on the key intermediates and compound, and Dr. Dean
Boojamra for his assistance in manuscript preparation.

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L. Xu et al. / Tetrahedron Letters 44 (2003) 2601–2604
Scheme 6.
References
K2CO3 (1.52 g, 11 mmol) followed by isothiourea 7 (1.46
g, 10.5 mmol). After stirring at room temperature for 30 h,
the mixture was diluted with EtOAc, and filtered. The
filtrate was evaporated and the resulting crude product
was purified by flash chromatography to give 5 (1.86 g,
68%) as a white solid. A solution of 5 (274 mg, 1 mmol) in
CH3CN (8 mL) was added K2CO3 (277 mg, 2.0 mmol),
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mixture was stirred at room temperature for 2 h before
MeNH2/CH3OH (2.0 M, 1.5 mL, 3 mmol) was added.
After stirring at room temperature for 1.5 h, the mixture
was filtered, and evaporated to dryness. The crude product
was purified on silica gel to afford 9a (290 mg, 74%) as a
white foam.
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