A reliable Pd-mediated hydrogenolytic deprotection of BOM group of uridine ureido nitrogen

Article abstract of DOI:10.1016/j.tetlet.2012.05.035

The benzyloxymethyl (BOM) group has been utilized widely in syntheses of a variety of natural and non-natural products. The BOM group is also one of few choices to protect uridine ureido nitrogen. However, hydrogenolytic cleavage of the BOM group of uridine derivatives has been unreliably performed via heterogeneous conditions using Pd catalysts. One of the undesirable by-products formed by Pd-mediated hydrogenation conditions is the over-reduced product in which the C5-C6 double bond of the uracil moiety was saturated. To date, we have generated a wide range of uridine-containing antibacterial agents, where the BOM group has been utilized in their syntheses. In screening of deprotection conditions of the BOM group of uridine ureido nitrogen under Pd-mediated hydrogenation conditions, we realized that the addition of water to the ⁱPrOH-based hydrogenation conditions can suppress the formation of over-reduced uridine derivatives and the addition of HCO₂H (0.5%) dramatically improve the reaction rate. An optimized hydrogenation condition described here can be applicable to the BOM-deprotections of a wide range of uridine derivatives.

Full text of DOI:10.1016/j.tetlet.2012.05.035

Tetrahedron Letters 53 (2012) 3758–3762
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A reliable Pd-mediated hydrogenolytic deprotection of BOM group
of uridine ureido nitrogen
⇑
Bilal A. Aleiwi, Michio Kurosu
Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison, Memphis, TN 38163, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The benzyloxymethyl (BOM) group has been utilized widely in syntheses of a variety of natural and non-
natural products. The BOM group is also one of few choices to protect uridine ureido nitrogen. However,
hydrogenolytic cleavage of the BOM group of uridine derivatives has been unreliably performed via het-
erogeneous conditions using Pd catalysts. One of the undesirable by-products formed by Pd-mediated
hydrogenation conditions is the over-reduced product in which the C5–C6 double bond of the uracil
moiety was saturated. To date, we have generated a wide range of uridine-containing antibacterial
agents, where the BOM group has been utilized in their syntheses. In screening of deprotection conditions
of the BOM group of uridine ureido nitrogen under Pd-mediated hydrogenation conditions, we realized
Received 11 April 2012
Revised 1 May 2012
Accepted 4 May 2012
Available online 12 May 2012
Keywords:
Ureido nitrogen
Uridine
Benzyloxymethyl (BOM) group
Hydrogenolytic cleavage
Pd–C
i
that the addition of water to the PrOH-based hydrogenation conditions can suppress the formation of
over-reduced uridine derivatives and the addition of HCO2H (0.5%) dramatically improve the reaction
rate. An optimized hydrogenation condition described here can be applicable to the BOM-deprotections
of a wide range of uridine derivatives.
MraY inhibitors
Ó 2012 Elsevier Ltd. All rights reserved.
Introduction
NH2
O
HO
MeO
Me
To date, a large number of uridine-containing natural products
that show significant biological activities have been isolated from
the culture of Streptomyces spp.1
O
O
Me
O
R
O
O
H
N
H
H
N
H
N
NH
O
N
N
H
HO
Me
N
Uridine-containing antibiotics such as the muraymycins and
capuramycin have gained great interest in the development of
new antibacterial agents for multidrug (MDR)-bacterial infec-
tions.2 In our ongoing program of discovery of new MraY
(catalyzing the biosynthesis of lipid I from UDP-N-acyl-Mur-penta-
peptide) inhibitors for MDR-resistant Mycobacterium tuberculosis,3
we have generated a 200-membered library molecules based on
the core structures of muraymycins and capuramycin (Fig. 1). In
their syntheses we utilized the benzyloxymethyl (BOM) group as
a convenient protecting group for the uridine ureido nitrogen of
the uracil moiety.4
However, we encountered that success of deprotection of the
BOM group of the uridine derivatives vary depending on the
structure and physico-chemical properties of uridine derivatives.
Chemical structures of representative key intermediates are shown
in Figure 2. Various hydrogenation conditions for the deprotection
of BOM protecting group have been reported in literatures using
Pd catalysts in alcoholic solvents.5 Recently, Ducho and co-workers
reported that in hydrogenolytic deprotection of the BOM group of
HO
O
O
NH
Me
O
N
H
NH
HO OH
OH
N
O
R =
H2N
O
8
Muraymycin A1
NH
O
O
H
N
HN
OH
O
O
H
O
NH2
O
HO
NH
O
N
O
H
MeO
OH
Capuramycin
Figure 1. Muraymycin A1 and capuramycin.
the uridine derivative the over-reduction of the C5–C6 double bond
of the uracil moiety could be minimized (ꢀ5%) by using Pd-black in
MeOH in the presence of nBuNH2.6 However, in our studies addition
⇑
Corresponding author. Tel.: +1 901 448 1045; fax: +1 901 448 6940.
E-mail address: mkurosu@uthsc.edu (M. Kurosu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.035

B. A. Aleiwi, M. Kurosu / Tetrahedron Letters 53 (2012) 3758–3762
3759
O
(entry 4). Significant solvent effect on the BOM deprotection with
10% Pd–C was observed. Reaction rate in EtOH or EtOAc or PrOH
was much slower than that in MeOH (entries 5–7). However, the
O
i
5
5
BOM
H2N
BOM
R4
O
N
N
O
R3
6
H
N
H
1
N
6
N
N
2/11 selectivity ratio was significantly improved in the reaction
R5
O
O
O
O
H
i
i
H
in EtOAc or PrOH. It was found that the reaction in PrOH–H2O
(10/1) yielded the desired product 2 in 25% yield (>95% yield based
on recovering 1) after 6 h without contamination of 11 (entry 8).
The conversion of 2 from 1 was slightly improved under medium
pressure conditions (50 psi) (entry 9). In order to accelerate the
Pd–C mediated hydrogenolytic cleavage of the BOM group of 1 in
iPrOH–H2O (10/1), the effect of additives was investigated. All at-
tempts with water tolerate Lewis acids such CeCl3Á7H2O and
La(OTf)3 and gave rise to the formation of the by-product 11 (data
not shown in Table 1). The addition of HCO2NH4 to the reaction
mixture did not noticeably improve the reaction rate, and resulted
in the formation of 2 and 11 (80/20 ratio) in 90% yield after 12 h
(entry 10). It was found that the addition of (CF3)2CHOH was very
effective in the selective BOM-deprotection of 1; under these con-
ditions 1 could be converted into 2 in 90% yield after 12 h (entry
11). Addition of AcOH (0.5%) was also effective in the selective
deprotection of the BOM-group of 1 (entry 12), but the reaction
was not completed in 6 h. The Pd–C catalyzed hydrogenation in
iPrOH2O (10/1) was dramatically accelerated by addition of HCO2H
(0.5%); the reaction was completed within 6 h to afford 2 in quan-
titative yield (entry 13). It was realized that under the conditions of
entry 13, hydrogenolytic cleavage of the BOM group of 1 was com-
pleted even in 2 h (entry 14). The reaction rate was increased un-
der a medium pressure condition (50 psi) to yield 2 without
contamination of the by-product 11 (entry 15).
R1 = H, OH, Me
R2 = H, OH, Me
R3 = H, CONH2
R4 = glycoside
R5 = acyl, peptide
R2 R1
R2
R1
Figure 2. Representative structures of the key intermediates for the syntheses of
MraY inhibitors.
of primary amines to suppress the over-reduction of the uracil dou-
ble bond during deprotections of the BOM group resulted in gener-
ation of the desired product in capricious yields with significant
amounts of the over-reduced product(s).7
In order to identify versatile hydrogenolytic deprotection condi-
tions of the BOM group of uridine derivatives that do not produce
the by-products (vide supra), we have screened hydrogenation
conditions by varying Pd sources in a wide range of solvent sys-
tems. Herein, we report a simple but reliable hydrogenolytic con-
dition that remove the BOM and Bn groups of uridine derivatives
without affecting the C5–C6 double bond of the uracil moiety.
Results and discussion
We have screened hydrogenolytic BOM-deprotection condi-
tions with Pd–C, Pd black, Pd(OH)2, and PtO2 that convert 1 to 2
without contamination of the over-reduced product 11. A series
of hydrogenation conditions examined are summarized in Table
1. Hydrogenation of 1 with 10% Pd–C in MeOH provided a mixture
of 1 and 2 with predominantly 2 (entry 1). The same reaction with
Pd-black or Pd(OH)2 in MeOH resulted in the formation of a large
amount of the over-reduced product 11 (entries 2 and 3). PtO2-
Catalyzed hydrogenation reaction in MeOH gave 11 exclusively
In order to obtain more insight into the optimized deprotection
conditions (H2 (1 atm), 10% Pd–C/iPrOH–H2O (10/1), HCO2H (0.5%))
for the BOM-protecting group using 1, we have applied these
conditions to a wide variety of the BOM-protected uridine deriva-
tives. Selected examples are summarized in Table 2. Simultaneous
deprotections of the BOM and Bn groups of 1b and 1c using the
conditions utilized in entries 1–3 in Table 1 resulted in the forma-
tion of the desired products 6b and 6c in very poor yields (0–20%)
Table 1
Screening of conditions for hydrogenolytic cleavage of the BOM group of 1
O
O
O
5
BOM
NH
NH
N
6
HO
HO
H2
catalyst
conditions
HO
N
N
N
O
O
O
O
+
O
O
O
O
O
O
O
O
H3C
CH3
H3C
CH3
11
H3C
CH3
1
2
Entry
Catalyst
Conditions
Time (h)
Ratio (2/11)
Yield (%)
1
2
3
4
5
6
7
8
10% Pd/C
Pd black
Pd(OH)2
PtO2
MeOHa
MeOHa
MeOHa
MeOHa
EtOHa
6
6
6
6
6
6
6
6
20/80
10/90
5/95
0/100
30/70
95/5
>95
>95
>95
>95
50
<10
25
25
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
EtOAca
iPrOHa
95/5
iPrOH–H2O (10/1)a
100/0
100/0
80/20
100/0
100/0
100/0
100/0
100/0
9
iPrOH–H2O (10/1) 50 psi
6
30–40
90
90
10
11
12
13
14
15
iPrOH–H2O (10/1)a HCO2NH4 (0.5%)
iPrOH–H2O (10/1)a (CF3)2CHOH (0.5%)
iPrOH–H2O (10/1)a AcOH (0.5%)
12
12
6
6
2
90
iPrOH–H2O (10/1)a HCO2H (0.5%)
iPrOH–H2O (10/1)a HCO2H (0.5%)
iPrOH–H2O (10/1) HCO2H (0.5%) 50 psi
>99
>99
>99
0.5
a
The reaction was conducted at 1 atm H2 pressure.

Table 2
Hydrogenolytic cleavage of the BOM group of uridine derivatives
O
O
O
O
BOM
H2N
BOM
H2N
R4
O
N
R4
O
N
NH
NH
O
R3
O
H
N
H
R3
H
N
H
N
H2 (1 atm), 10% Pd-C
N
N
N
N
N
R5
O
O
or
O
O
R5
O
O
or
O
O
H
H
H
H
iPrOH-H2O (10/1)
HCO2H (0.5%)
R1 = Bn, Me, Ac
R2 = Me, Bn
R1 = H, Me, Ac
R2 = H, Me
R2O
OR1
R2O OR1
R2O
OR1
R2O OR1
R1, R2 = acetonide
R3 = H, CONH2
R4 = glycoside
R1, R2 = acetonide
R3 = H, CONH2
R4 = glycoside
3
5
and
1, 2 and 4
6, 7 and 9
8 and 10
R
= Cbz, Boc
R
= H, Boc
Entry
Starting material
Product
Reaction time (h)
Yield (%)
Entry
Starting material
Product
Reaction time (h)
Yield (%)
O
O
OAc
OAc
OAc
OAc
O
O
BOM
O
O
N
NH
O
AcO
AcO
AcO
H2N
BOM
H2N
AcO
N
NH
O
HO
HO
N
N
O
O
O
O
O
N
O
N
O
O
O
O
1
12
>99
7
3
97
MeO OBn
MeO
OH
6b
O
O
1b
O
O
Me
Me
Me Me
4a
9a
O
O
OCbz
O
OH
OAc
O
O
O
BOM
O
NH
N
AcO
AcO
AcO
AcO
H2N
H2N
BOM
NH
O
N
HO
HO
N
N
O
O
O
O
O
O
O
O
O
N
N
O
O
2
12
95
8
12
95
BnO
HO OMe
OMe
1c
O
O
O
O
6c
Me
Me
Me
Me
4b
9b
O
O
O
O
H2N
HO
H2N
H2N
H2N
HO
BOM
BOM
NH
O
N
NH
N
O
O
O
O
O
AcO
HO
O
O
N
N
N
N
O
O
O
O
O
O
O
O
3
3
>99
9
3
97
AcO OAc
AcO OAc
MeO
MeO OAc
O
O
O
O
OAc
2a
7a
Me
4c
Me
Me
Me
9c
O
O
O
O
H2N
HO
H2N
HO
BOM
H2N
H2N
BOM
NH
O
N
N
NH
O
O
O
O
O
O
CbzO
HO
O
O
N
N
N
N
O
O
O
O
O
O
O
4
3
>99
10
12
97
AcO
AcO
OAc
OAc
O
O
O
O
O
O
O
O
Me
2b
Me
Me
Me
7b
Me Me
Me
9d
Me
4d

B. A. Aleiwi, M. Kurosu / Tetrahedron Letters 53 (2012) 3758–3762
3761
with the formation of a large amount of the over-reduced products
in which the uracil moiety was saturated with H2. On the contrary,
simultaneous hydrogenolytic cleavages of the BOM and Bn groups
of 1b and 1c using the optimized conditions (H2 (1 atm), 10% Pd–
C/iPrOH–H2O (10/1), HCO2H (0.5%)) gave rise to the corresponding
products 6b and 6c in quantitative yield (entries 1 and 2 in Table
2). Deprotections of the molecules, 2a and 2b, possessing the
a-
hydroxyamide functional group furnished the desired products
7a and 7b, respectively in quantitative yield within 3 h. Signifi-
cantly, the 1,3-diamino derivatives 3a and 3b could be converted
into the corresponding BOM-deprotected diamines 8a and 8b,
respectively, after a basic work-up to remove the HCO2H salts.
On the other hand, hydrogenolytic deprotection of the BOM and
Cbz groups of 3a with 10% Pd/C in MeOH resulted in an incomplete
reaction mixture containing the BOM protected-8a in 90% yield
even after prolonged reaction time. We observed that reaction rate
of the BOM-deprotection is very slow the BOM-protected uridines
possessing free-amine in molecules. Thus, BOM-deprotection was
not observed for 3a with 10% Pd/C in MeOH due to the fact that
Cbz deprotection occurred prior to the BOM deprotection to form
the free amine. However, a deactivation mechanism of the Pd cat-
alyst by the complexation with the free amine is diminished in the
Pd-mediated hydrogenation reactions by using a water containing
solvent. Hydrogenolytic cleavage of the BOM group of the manno-
sides 4a using the optimized condition gave rise to 9a in 97% yield.
In general, deprotections of the O-Cbz group require relatively long
hydrogenation time even with the conditions of 10% Pd–C or Pd-
black in MeOH in the presence of AcOH at 100 psi.8 The optimized
conditions utilized in Table 2 could convert 4a to 9b in 95% yield
within 12 h without contamination of the over-reduced product.
Similarly, the BOM group of the riboside 4c and the BOM and O-
Cbz groups of 4d could be efficiently deprotected to furnish 9c
and 9d in high yield. The BOM- and N-Cbz-groups of the amino-
ribosyl uridine 5a were deprotected via the optimized hydrogeno-
i
lytic cleavage conditions (10% Pd–C in PrOH–H2O (10/1) in the
presence of HCO2H (0.5%)) to provide 10a in 97% within 3 h. In
our screening of hydrogenation conditions with Pd species for
the simultaneous deprotections of 5a, the only conditions demon-
strated in Table 2 provided the desired product 10a in high yield
without affecting the uracil double bond.
In summary, we have demonstrated hydrogenolytic cleavage
reactions of the BOM group of a series of complex uridine deriva-
i
tives with simple hydrogenation conditions (10% Pd–C in PrOH–
H2O (10/1) in the presence of HCO2H (0.5%) at 1 atm H2 pressure).9
Under these conditions, the BOM-protected uridines were cleanly
converted into the corresponding deprotected uridines without
formation of the by-products where the uracil C5–C6-double bond
was saturated. Unlike the reported conditions to suppress the gen-
eration of the over-reduced uracil products by using amines,10 the
components in the hydrogenation conditions reported here can
readily be removed after the reaction by filtration followed by sim-
ple evaporation of all volatiles. Thus, an optimized hydrogenation
condition reported here has a beneficial effect in systematic depro-
tections of the BOM group to generate
a series of uridine
derivatives. As we have demonstrated deprotections of the Bn, N-
Cbz, and O-Cbz groups during the BOM-deprotection reactions,
the hydrogenation conditions summarized in Table 2 should be
applicable to debenzylations of a wide range of compounds pos-
sessing multiple benzyl groups in a single molecule.
Acknowledgments
The authors thank the National Institutes of Health (NIAID
Grant AI084411-02) and The University of Tennessee for generous
financial supports. NMR data were obtained on instruments
supported by the NIH Shared Instrumentation Grant.

3762
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1997, 62, 1368–1375; (b) Fraser, A. S.; Kawasaki, A. M.; Jung, M. E.; Muthiah, M.
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9. General procedure for BOM deprotections: To a stirred solution of the BOM
protected uridine derivative (1 equiv) in iPrOH:H2O (10:1) and HCO2H (0.5%)
was added 10% Pd–C (10%) under N2. H2 gas was introduced to the reaction
mixture using a double-folded balloon. Upon completion, the reaction mixture
was filtered through a Celite pad and washed with EtOAc (or MeOH). All
volatiles were evaporated in vacuo. When the HCO2H-amine salt was
generated, the crude mixture was dissolved in CHCl3 and washed with aq.
NaHCO3. The combined organic extracts were dried over Na2SO4 and
evaporated in vacuo. Purification by silica gel chromatography afforded the
desired compound (yields are given in Tables 1 and 2).
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10. Reported amine additives for controlled-hydrogenation conditions with Pd
species have relatively high boiling point.
4. Synthesis of uridine-containing natural products using the BOM-protecting
group, see: (a) Ichikawa, S.; Shuto, S.; Minakawa, N.; Matsuda, A. J. Org. Chem.