A new protecting group and linker for uridine ureido nitrogen

Article abstract of DOI:10.1016/j.tet.2012.03.121

(2,6-Dichloro-4-methoxyphenyl)(2,4,6-trichlorophenyl) methoxymethyl chloride [1, monomethoxydiph-enylmethoxylmethyl chloroide (MDPM-Cl)] shows a significant relative stability and 1 reacts with uridine ureido nitrogen in the presence of DBU to form the corresponding protected uridine 8 in 95% yield. The MDPM-protected uridines are stable to a wide variety of conditions utilized for the synthesis of analogs of capuramycin and muraymycins. Significantly, the MDPM protecting group can conveniently be deprotected by using 30% TFA in CH ₂Cl₂. In addition, polymer-bound MDPM-Cl 23 is useful for immobilization of uridine derivatives.

Full text of DOI:10.1016/j.tet.2012.03.121

Tetrahedron 68 (2012) 4797e4804
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new protecting group and linker for uridine ureido nitrogen
*
Yong Wang, Michio Kurosu
Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881Madison, 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:
(2,6-Dichloro-4-methoxyphenyl)(2,4,6-trichlorophenyl) methoxymethyl chloride [1, monomethoxydiph-
enylmethoxylmethyl chloroide (MDPM-Cl)] shows a significant relative stability and 1 reacts with uridine
ureido nitrogen in the presence of DBU to form the corresponding protected uridine 8 in 95% yield. The
MDPM-protected uridines are stable to a wide variety of conditions utilized for the synthesis of analogs of
capuramycin and muraymycins. Significantly, the MDPM protecting group can conveniently be deprotected
by using 30% TFA in CH2Cl2. In addition, polymer-bound MDPM-Cl 23 is useful for immobilization of uridine
derivatives.
Received 15 February 2012
Received in revised form 28 March 2012
Accepted 30 March 2012
Available online 9 April 2012
Keywords:
Ureido nitrogen
Uridine
Ó 2012 Elsevier Ltd. All rights reserved.
Monomethoxydiphenylmethoxylmethyl
group
Polymer-bound linker
1. Introduction
In our ongoing program of development of drug leads for MDR
Mycobacterium tuberculosis, we have synthesized analogs of mur-
Uridine is an essential biological compound for multiple bio-
synthetic processes and found in all cells.1 To date, a large number
of uridine-containing natural products that show significant bi-
ological activities have been isolated.2 Uridine-containing antibi-
otics, such as liposidomycin, caprazamycin, muraymycins, and
capuramycin have been of increasing interest to the development
of new antibacterial agents for MDR-bacterial infections.3
aymycins A1 and capuramycin.4 Protection of the uridine ureido
nitrogen was indispensable to achieve the synthesis of a wide range
of uridine-containing molecules. Benzyloxymethyl (BOM) group
has been utilized as a convenient protecting group for the uridine
ureido nitrogen (P1).5 However, we and other groups observed that
BOM deprotection of uridine derivatives under hydrogenation
conditions often resulted in poor yield with over-reduction prod-
uct(s).6 In general, hydrogenolytic deprotection is the only method
to remove the BOM group of the uridine ureido nitrogen.
We have sought an alternative methoxymethyl-type protecting
group for the uridine ureido nitrogen that (1) is stable to reaction
conditions for the syntheses of a wide range of muraymycin and
capuramycin analogs, but (2) can be cleaved with mild and volatile
acids. In this paper we report our studies of (2,6-dichloro-4-
methoxyphenyl)(2,4,6-trichlorophenyl) methoxymethyl chloride
* Corresponding author. E-mail address: mkurosu@uthsc.edu (M. Kurosu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.121

4798
Y. Wang, M. Kurosu / Tetrahedron 68 (2012) 4797e4804
[1, monomethoxydiphenylmethoxylmethyl chloroide (MDPM-Cl)
for the protection of the uridine ureido nitrogen and application of
1 to the polymer-bound MDPM-Cl for synthesis of analogs on
polymer-support.
can be stored for several months without loss of purity. The uridine
ureido nitrogen was efficiently protected with 1 in the presence of
DBU in DMF to afford 8 in 95% yield (Table 1). The MDPM group of 8
exhibited excellent stability against a variety of Brønsted and Lewis
acids such as 20% TFA, 10% TMSOTf, 10% HCl, 30% HF, 80% AcOH, 30%
TsOH, La(OTf)3, BF3$OEt2, and TiCl4 at rt. The MDPM-protected uri-
dine 8 also showed stability under basic conditions; 8 was intact
under NH4OH (40% in aq MeOH), LiOH (10% in aq THF/MeOH), and
DBU (10% in toluene) at rt for over 24 h. Selected examples are
summarized in Table 1. Moreover, the MDPM protecting group of 8
was stable to the reduction conditions, such as Al(Hg), nBu3SnH/
AIBN, and Raney Ni. The MDPM-protected uridine 8 was stable to
NBS, and was photolytically stable (200e350 nm for over 6 h). The
MDPM protecting group of 8 was not cleaved by hydrogenation
conditions using PdeC or Pd black even at 100 psi. The MDPM group
could not be cleaved by using the standard conditions for the
deprotection of PMB (p-methoxybenzyl) ether groups, however,
could be deprotected with 30% TFA in CH2Cl2 to afford uridine (7).
The (2,4-dichloro-4-methoxyphenyl)(2,4,6-trichlorophenyl)methyl
cation generated by the treatment of 8 with 30% TFA is a sterically
hindered species and stabilized by the electron-withdrawing Cl
atoms, being efficiently reacted with the trifluoroacetate ion to af-
2. Results and discussion
We have previously reported utilities of rac-5a and optically pure
5a for protections of alcohols, amines, and carboxylic acids, and as
a chiral derivatizing agent.7 (2,6-Dichloro-4-methoxyphenyl)(2,4-
dichlorophenyl)methanol (5a) could efficiently be synthesized via
a FriedeleCrafts reaction followed by LiBH4 reduction. Similarly,
a
large quantity of (2,6-dichloro-4-methoxyphenyl)(2,4,6-
trichlorophenyl) methanol (5b) could be synthesized efficiently.
Stability tests of 5a and 5b against a wide variety of Lewis and
Brønsted acids revealed that 5b exhibited longer half-life in the
acidic conditions summarized in Table 1; 5a was converted to the
corresponding TFA ester in 30 min when exposed to 30% TFA in
CH2Cl2 at rt, on the other hand, 5b required more than 1 h to form its
TFA ester under the same reaction conditions. In addition, we have
recognized that rac-5a forms diastereomers in NMR spectra when
reacted with chiral substrates. However, 5b has not formed notice-
able diastereomers in NMR spectra. In addition, generated di-
astereomers have not been separated via HPLC.8 Because of the
reasons stated above, we decided to utilize 5b for further in-
ford
(2,4-trichloro-4-methoxyphenyl)(2,4,6-trichlorophenyl)
methyl 2,2,2-trifluoroacetate (9) in quantitative yield. The treat-
ment of 9 with NH3/MeOH of 7 gave rise to the parent alcohol 5b in
quantitative yield (Scheme 2). Thus, the MDPM-Cl 1 can be regen-
erated through the chemical steps illustrated in Scheme 1.
vestigation. As illustrated in Scheme
1
(2,6-dichloro-4-
methoxyphenyl)(2,4,6-trichlorophenyl) methanol (5b) could be
converted to the corresponding MDPM-Cl 1. The alcohol 5b was first
transformed to the (alkoxymethyl)methyl sulfide 6 in 98% yield,
which was then subjected to a Cl-displacement reaction with SO2Cl2
to yield 1 in greater than 95% yield.9 MDPM-Cl 1 was stable at rt and
In order to demonstrate robustness of MDPM group as a pro-
tecting group for the uridine ureido nitrogen, the MDPM-protected
uridine 8 was transformed to awide range of uridine derivatives that
can be utilized for the syntheses of analogs of muraymycins and
capuramycin.4d Selected examples are summarized in Table 2. Ketal
formations of 10 or 8 under acidic conditions provided the corre-
sponding 2,3-protected derivatives in good to high yields (entries 1
and 5). The primary TBS and TIPS group of 11a or 13 could be
deprotected selectively with 50% HF in CH3CN to furnish 12 and 8,
respectively, without cleavage of the MDPM group (entries 2 and 4).
The trityl group of 11b was selectively removed by using BF3$OEt2 in
the presence of TolSH without affecting the MDPM group (entry 3).
Selective hydrogenolytic deprotection of the benzyl group of 15 was
carried out via 10% PdeC in iPrOH-water to furnish 13 without over-
reduction of the uracil double bond (entry 6). Olefination of the
carbonodithioate 16 was achieved by using nBu3SnH and AIBN in
toluene at refluxing temperature to provide 20,30-didehydro-20,30-
dideoxy derivative 17 in a reasonable yield (entry 7). Hydrogenation
of the double bond of 17 was also achieved under a standard hy-
drogenation condition with 10% PdeC within 1 h to provide the
MDPM-protected uridine-20,30-dideoxy derivative 18 in high yield
(entry 8). Thus, it was experimentally proved that MDPM group is
a robust protecting group for the uridine ureido nitrogen to syn-
thesize a wide range of uridine derivatives.
We havepreviously developed a novel esterlinker 27, whoseesters
are stableagainstBrønsted and Lewis acids, Brønsted bases and awide
variety of nucleophiles.7c If the uridine ureido nitrogen can be
immobilized onto polymer-resin, systematic syntheses of capur-
amycin and muraymycin analogs would be dramatically enhanced. As
summarized in Scheme 3, the (2,6-dichloro-4-hydroxyphenyl) (2,4,6-
trichlorophenyl) methanone (20)10 could efficiently be linked with
hydroxymethylpolystyrene (PS) (w2 mmol/g) via a Mitsunobu re-
action.11 The carbonyl group of 21 was reduced by LiBH4 in THF to
afford the PS-alcohol 22. Available alcohol-linkers on the polymer
surface were determined to be 1.8e2.0 mmol/g by coupling of the
Table 1
Protection of the uridine ureido nitrogen with 1 and its relativities against repre-
sentative reagents
Conditionsa
8 (t1/2
>6 h
)
Conditionsa
8 (t1/2)
20% TFA
CH2Cl2
10% TMSOTf
CH2Cl2
10% HCl
McCN
10% HCl
1,4-Dixoane
30% HF
DBU
Toluene
Al(Hg)
1,4-Dioxane
Raney Ni
1,4-Dioxane
nBu3SnH, AIBN
Toluene, reflux
NBS
>24 h
>12 h
>12 h
>6 h
>2 h
>6 h
>6 h
>12 h
>12 h
>12 h
>12 h
>12 h
>4 h
>6 h
MeCN
80% AcOH
THF
hv
MeCN
H2/PdeC, 1 atom
MeOH
H2/PdeC, 100 psi
MeOH
H2/PdeC, 50 psi
MeOH
H2/PdeC, 100 psi
MeOH
H2/Pd black
MeOH
30% TsOH
1,4-Dioxane
La(OTf)3
THF
10% BF3eOEt2
CH2Cl2
10% TiCL4
CH2Cl2
DDQ
>6 h
>12 hb
>12 hb
>12 hb
>12 hb
linkers with Fmoc-b-Ala-OH and subsequent release of Fmoc chro-
>12 h
CH2Cl2ewater
mophore and elemental analyses of the Cl atoms for 22. According to
the procedure summarized in Scheme 1, the PS-alcohol was trans-
formed to the PS-MDPM-Cl 23, whose available chloromethoxygroup
a
Reaction was carried out at rt.
The uracil double bond of 8 was reduced.
b

Y. Wang, M. Kurosu / Tetrahedron 68 (2012) 4797e4804
4799
Scheme 1. Syntheses of monomethoxydiphenylmethoxylmethyl chloroides 1.
Scheme 2. Deprotection of MDPM group.
Table 2
Functionalizations of MDPM-protected uridines
Entry
Starting material
Conditions
Product
Yielda (%)
1
75 (95)b for 10a
90 (98)b for 10b
2
50% HF/CH3CN, rt, 1 h
80
3
BF3eOEt2 (3 equiv), TolSH/CH2Cl2, rt, 1 h
90
(continued on next page)

4800
Y. Wang, M. Kurosu / Tetrahedron 68 (2012) 4797e4804
Table 2 (continued )
Entry
Starting material
Conditions
Product
Yielda (%)
4
50% HF/CH3CN, rt, 12 h
88
5
90
6
H2 (1 atom)/10% PdeC
95c
iPrOH-water, 2 h
7
nBuSnH, AIBN/toluene, reflux, 2 h
75
8
H2 (1 atom)/10% PdeC
95c
MeOH, 2 h
a
Product was isolated by SiO2 chromatography or PTLC.
Yield based on recovering starting material.
No over-reduction was observed.
b
c
was determined to be 1.5e1.8 mmol/g by its elemental analysis. Uri-
dine (7) and 2,3-isopropylidene uridine 24 could be loaded onto the
linker resin in 6 h via a twofold excess of 7 or 24 and DBU in DMF. The
loaded uridine or 2,3-isopropyliden uridine were cleaved with 30%
TFA in CH2Cl2 in 3 h to afford uridine (7) in greater than 85% yields.
as BOM group has been widely utilized in organic syntheses, a new
protecting group 1 and linker resin 23 described here will be
valuable assets to protect not only for ureido nitrogens, but also for
primary, secondary, and phenolic alcohols, and carboxylic acids.12 It
is worth mentioning that immobilization of the uridine ureido ni-
trogen on polymer-support is not possible with previously reported
linker resins. Utility of 1 and 23 in generation of optimized libraries
of uridine-containing antibiotics in solution or on polymer-support
will be reported elsewhere.
3. Conclusion
In conclusion, we have developed a new protecting group, (2,6-
dichloro-4-methoxyphenyl)(2,4,6-dichlorophenyl) methoxymethyl
chloride (1) for the uridine ureido nitrogen. MDMP protecting
group has significant advantages over BOM protecting group for the
syntheses of muraymycin and capuramycin analogs systematically
in that MDMP group (1) is stable to a wide variety of acids, (2) is
also stable to hydrogenation conditions, and (3) can efficiently be
deprotected by solvolytic cleavage with TFA (at 30% concentrations)
at rt within 2 h without the addition of a cation scavenger.11 Sim-
ilarly, the MDMP resin 23 has been developed to immobilize uri-
dine and a uridine derivative. In this article we have demonstrated
robustness of the MDMP group in uridine derivatives and utility of
the linker resin 23 with a limited number of molecules. Moreover,
4. Experimental section
4.1. General
All glasswares were oven dried, assembled hot, and cooled un-
der a stream of nitrogen before use. Reactions with air sensitive
materials were carried out by standard syringe techniques. Com-
mercially available reagents were used as received without further
purification. Thin layer chromatography was performed using
0.25 mm silica gel 60 plates visualizing at 254 nm, or stained with
anisaldehyde solution by heating with a hot-air gun. Specified

Y. Wang, M. Kurosu / Tetrahedron 68 (2012) 4797e4804
4801
vacuo. Purification by silica gel chromatography (hexanes/
EtOAc¼5/1) gave rac-5b (368 mg, 95%). 1H NMR (CDCl3, 400 MHz)
7.31 (s, 2H), 6.85 (s, 2H), 6.69 (d, J¼10 Hz, 1H), 3.79 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 159.23, 135.91, 135.04, 133.92, 129.57, 127.85,
115.55, 72.82, 55.88; IR (film): 3476, 1457, 1431, 1309 cmꢁ1; HRMS
(EI) m/z¼384.9123 calcd for C14H12Cl5O2 [MþH]; found: 384.9116.
4.4. (2,6-Dichloro-4-methoxyphenyl)-(2,4,6-trichlorophenyl)
methoxymethyl methyl sulfide (6)
To a stirred suspension of NaH (31 mg, 60% in oil, 0.47 mmol) in
THF (0.4 mL) rac-5b (100 mg, 0.26 mmol) in THF (0.3 mL) was
added at 0 ꢀC. After 30 min, chloromethyl methyl sulfide (0.044 mL,
0.52 mmol) was added. Reaction mixture was stirred at 0 ꢀC for 3 h,
and quenched by satd aq NH4Cl. The aqueous layer was extracted
with Et2O, and the combined extract was washed with brine, dried
over Na2SO4, and evaporated in vacuo. Purification by silica gel
chromatography (hexanes/EtOAc¼10/1) gave 6 (114 mg, 98%). 1H
NMR (CDCl3, 400 MHz) 7.31 (s, 2H), 6.86 (s, 2H), 6.68 (s, 1H), 4.72 (q,
J¼11.6 Hz, 2H), 3.79 (s, 3H), 2.19 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
159.26, 136.77, 133.95, 132.79, 129.57, 125.47, 115.53, 75.67, 74.29,
55.70, 14.88; IR (film): 3469, 1544, 1368, 1351 cmꢁ1; HRMS (EI) m/
z¼446.8977 calcd for C16H13Cl5O2SNa ([MþNa]þ); found: 446.8985.
4.5. (2,6-Dichloro-4-methoxyphenyl)(2,4,6-trichlorophenyl)-
methoxy methyl chloride (1)
To a stirred solutionof6 (447 mg,1.0mmol) inCH2Cl2 (2.5mL) was
added sulfuryl chloride (0.08 mL, 1.0 mmol) at rt. The reaction mix-
ture was stirred for 1 h and all volatiles were evaporated to provide
the cure product, which was solidified by addition of hexanes (2 mL).
The white solid was washed with hexanes twice to afford 1 (418 mg,
96%). 1H NMR (CDCl3, 400 MHz) 7.33 (s, 2H), 6.88 (s, 2H), 6.77 (s, 1H),
5.57 (q, J¼6.4 Hz, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3)
Scheme 3. The linker 23 for immobilizations of uridine derivatives.
products were purified by flash column chromatography using
silica gel 60. IR absorptions were performed on NaCl plates. 1H NMR
spectral data were recorded on 500 or 400 MHz NMR spectrometer.
The residual solvent signal was utilized as an internal reference
CDCl3 (7.26). 13C NMR spectral data were recorded at 125, 100 MHz
instruments. The residual solvent signal was utilized as an internal
d
159.56, 136.83, 136.63, 134.40, 131.73, 129.68, 124.31, 115.62, 80.11,
55.75; IR (film): 3473, 1445, 1309 cmꢁ1; Anal. Calcd C15H10Cl6O2: C,
41.42; H, 2.32; Cl, 48.91. Found: C, 41.81; H, 2.41; Cl, 48.97.
reference CDCl3 (77.23). For all NMR spectra,
d values are given in
parts per million and J values in hertz.
4.6. 3-[(2,6-Dichloro-4-methoxyphenyl)(2,4,6-trichlorophenyl)
methoxymethyl]-1-(3,4-dihydroxy-5-hydroxymethyl tetrahyd-
rofuran-2-yl)-1H-pyrimidine-2,4-dione (8)
4.2. (2,6-Dichloro-4-methoxyphenyl)(2,4,6-trichlorophenyl)
methanone (4b)
To a stirred solution of uridine (7, 1.83 g, 7.5 mmol) in DMF
(15 mL) at 0 ꢀC DBU (1.5 mL, 10.0 mmol) and 1 (2.18 g, 5.0 mmol)
were added. After 1 h, MeOH (2 mL) was added, and the reaction
mixture was partitioned between EtOAc and water. The aqueous
layer was extracted with EtOAc, and the combined extract was
washed with brine, dried over Na2SO4, and evaporated in vacuo.
Purification by silica gel chromatography (DCM/MeOH¼15/1)
afforded 8 (2.70 g, 84%). 1H NMR (CDCl3, 400 MHz) 7.67 (d, J¼6.8 Hz,
1H), 7.30 (d, J¼3.6 Hz, 2H), 6.83 (d, J¼4.8 Hz, 2H), 6.57 (s, 1H), 5.77
(d, J¼8.4 Hz, 1H), 5.59 (m, 3H), 4.32 (m, 2H), 4.24 (s, 1H), 3.97 (d,
J¼12.0 Hz, 1H), 3.90 (s, 1H), 3.83 (m, 1H), 3.78 (s, 3H), 3.05 (s, 1H),
Anhydrous AlCl3 (450 mg, 3.4 mmol) was added to PhNO2 (10 mL).
The reaction mixture was cooled to 0 ꢀC, and 2,4,6-trichlorobenzoyl
chloride (0.53 mL, 3.4 mmol) and 3,5-dichloroanisole (500 mg,
2.82 mmol) were added. The reaction mixture was stirred at rt for
24 h, then it was diluted with Et2O (10 mL) at 0 ꢀC and quenched by
1 N NaOH (w3 mL). The mixture was stirred vigorously until pre-
cipitate was formed. Filter and wash the precipitate with DCM. The
organic layer was dried over Na2SO4 and concentrated to give the
crude product. Purification by silica gel chromatography (hexanes/
EtOAc¼20/1) provided 4b (867 mg, 80%). 1H NMR (CDCl3, 500 MHz)
7.36 (s, 2H), 6.88 (s, 2H), 3.85 (s, 3H); 13C NMR (125 MHz, CDCl3)
2.20 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 162.94, 159.36, 151.86,
d
194.25,163.33,141.89,138.12,136.31,129.29,127.78,117.65, 57.03; IR
140.07, 136.64, 134.06, 132.46, 129.49, 125.15, 115.49, 101.61, 93.18,
85.71, 77.85, 74.79, 70.39, 69.14, 61.69, 55.73, 36.61, 31.51; IR (film):
3435, 1719, 1665, 1440, 1081 cmꢁ1; HRMS (EI) m/z¼640.9819 calcd
for C24H22Cl5N2O8 [MþH]; found: 640.9825.
(film): 1633, 1557, 1388, 1341 cmꢁ1; HRMS (EI) m/z¼382.8967 calcd
for C14H8Cl5O2 (MHþ); found: 382.8975.
4.3. (2,6-Dichloro-4-methoxyphenyl)-(2,4,6-trichloro-phenyl)
methanol (rac-5b)
4.7. 1-[5-(tert-Butyldimethylsilanyloxymethyl)-3,4-dihydroxy-
tetrahydrofuran-2-yl]-3-[(2,6-dichloro-4-methoxyphenyl)(2,4,6
-trichlorophenyl)methoxymethyl]-1H-pyrimidine-2,4-dione
(10a)
A stirred solution of 4b (385 mg, 1 mmol) in THF (2 mL) was
added LiBH4 (2 mL, 2.0 M in THF) dropwise at 0 ꢀC. After 12 h at rt,
the reaction mixture was quenched by satd aq NH4Cl (4 mL) at 0 ꢀC.
The water phase was extracted with Et2O. The combined extract
was washed with brine, dried over Na2SO4, and evaporated in
To a stirred solution of 8 (64 mg, 0.1 mmol) in CH2Cl2 (0.5 mL)
were added imidazole (14 mg, 0.2 mmol) and TBSCl (18 mg,

4802
Y. Wang, M. Kurosu / Tetrahedron 68 (2012) 4797e4804
0.12 mmol). After 4 h, the reaction mixture was quenched with
water and extracted with EtOAc. The combined extract was dried
over Na2SO4, evaporated in vacuo. Purified by silica gel chroma-
tography (hexanes/EtOAc¼5/1) provide 10a (62 mg, 82%). 1H NMR
mixture was stirred at rt and protected from light with an alumi-
num foil for 15 min. The reaction mixture was quenched with Et3N
(50 mL), and extracted with CH2Cl2. The organic extract was washed
with 10% Na2S2O3, and satd aq NaHCO3, and dried over Na2SO4.
(CDCl3, 400 MHz)
d
7.89 (d, J¼8.4 Hz, 1H), 7.28 (s, 2H), 6.81 (s, 2H),
Purified by silica gel chromatography (hexanes/EtOAc¼10/1)
6.56 (s, 1H), 5.76 (t, J¼4.0 Hz, 1H), 5.72 (d, J¼8.4 Hz, 1H), 5.55 (s, 1H),
4.18 (br s, 3H), 4.12 (m, 1H), 3.96 (d, J¼11.6 Hz, 1H), 3.79 (d,
J¼11.6 Hz, 1H), 3.75 (s, 3H), 3.13 (br s, 1H), 0.90 (s, 9H), 0.13 (s, 6H);
afforded 11a (63 mg, 75%). 1H NMR (500 MHz, CDCl3)
d 7.69 (d,
J¼8.5 Hz, 1H), 7.29 (d, J¼3.5 Hz, 2H), 6.82 (d, J¼3.5 Hz, 2H), 6.59 (d,
J¼8.5 Hz, 1H), 5.94 (d, J¼4.0 Hz, 1H), 5.72 (d, J¼8.0 Hz, 1H), 5.59 (m,
2H), 4.73 (m, 1H), 4.65 (m, 1H), 4.29 (d, J¼2.5 Hz, 1H), 3.93 (d,
J¼11.5 Hz, 1H), 3.79 (d, J¼11.5 Hz, 1H), 3.77 (s, 3H), 1.77 (m, 2H), 1.67
(m, 2H), 1.57 (m, 4H), 1.40 (m, 2H); 13C NMR (125 MHz, CDCl3)
13C NMR (100 MHz, CDCl3)
d 162.80, 159.33, 152.24, 138.47, 136.65,
134.03, 132.48, 129.47, 125.22, 115.47, 101.46, 91.72, 85.99, 77.93,
76.44, 70.51, 69.17, 62.29, 55.69, 36.57, 31.6, ꢁ5.48, ꢁ5.56; ½a D20
þ28
ꢂ
(c 2.5 in CHCl3); IR (film): 3420, 1701, 1659, 1439, 1255, 1088 cmꢁ1
;
d 162.53, 159.24, 151.44, 141.79, 136.70, 133.94, 132.58, 129.47,
HRMS (EI) m/z¼755.0684 calcd for C30H36Cl5N2O8Si [MþH]; found:
125.18, 115.50, 114.94, 102.13, 97.64, 87.33, 83.16, 79.85, 78.03,
69.25, 63.28, 55.68, 37.17, 34.89, 25.89, 24.91, 23.95, 23.63, 18.33,
755.0681.
ꢁ5.40, ꢁ5.45; Yield:75%. ½a D20
þ19 (c 2.0 in CHCl3); IR (film): 1726,
ꢂ
4.8. 3-[(2,6-Dichloro-4-methoxy-phenyl)(2,4,6-trichlorophenyl)
methoxymethyl]-1-(3,4-dihydroxy-5-trityloxymethyl tetrahydr-
ofuran-2-yl)-1H-pyrimidine-2,4-dione (10b)
1703, 1656, 1442, 1261, 1088 cmꢁ1;. HRMS (EI) m/z¼835.1310 calcd
for C36H44Cl5N2O8Si [MþH]; found: 835.1316.
4.12. 3-[(2,6-Dichloro-4-methoxyphenyl)-(2,4,6-trichloro phe-
nyl)methoxymethyl]-1-(2-cyclohexyl-6-trityloxymethyltetrahy-
drofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrimidine-2,4-dione (11b)
To a stirred solution of 8 (128 mg, 0.2 mmol) in pyridine (0.7 mL)
were added trityl chloride (67 mg, 0.24 mmol) and DMAP (2 mg).
The reaction mixture was stirred at 60 ꢀC for 4 h and cooled to rt.
All volatiles were removed. The partition between EtOAc and water
was conducted. EtOAc phase was washed with 1 N HCl and brine.
The organic phase was dried over Na2SO4 and concentrated in
vacuo. Purification by silica gel chromatography (hexanes/EtOAc¼6/
Procedure, see Section 4.11. Yield: 90%.1H NMR (400 MHz, CDCl3)
d
7.50 (dd, J¼4.0 Hz, 1H), 7.39 (d, J¼7.6 Hz, 7H), 7.29 (m, 9H), 6.82 (d,
J¼3.2 Hz, 2H), 6.54 (d, J¼8.4 Hz, 1H), 5.85 (d, J¼3.2 Hz, 1H), 5.55 (t,
J¼11.6 Hz, 1H), 5.46 (t, J¼10.0 Hz, 1H), 5.36 (br s, 1H), 4.78 (d, J¼6.4,
2H), 4.35 (s, 1H), 3.75 (s, 3H), 3.40 (br s, 2H), 1.74 (m, 2H), 1.59 (m,
1) gave the 10b (155 mg, 88%). 1H NMR (500 MHz, CDCl3)
d 7.71 (t,
J¼8.5 Hz, 1H), 7.31 (d, J¼7.5 Hz, 6H), 7.25 (m, 6H), 7.22 (m, 5H), 6.74
(s, 2H), 6.47 (s, 1H), 5.64 (s, 1H), 5.51 (m, 2H), 5.39 (d, J¼7.0 Hz, 1H),
4.27 (br s, 1H), 4.14 (br s, 2H), 4.10 (br s, 1H), 3.65 (d, J¼4.5 Hz, 3H),
3.42 (d, J¼11.0 Hz, 1H), 3.33 (m, 1H), 2.94 (br s, 1H); 13C NMR
2H),1.25 (m, 6H); 13C NMR (100 MHz, CDCl3)
d 162.60,159.33,152.07,
143.19, 138.02, 136.48, 134.15, 132.76, 129.50, 128.69, 128.09, 127.48,
125.28, 115.51, 101.66, 97.63, 91.91, 87.56, 84.51, 77.80, 76.19, 70.51,
69.19, 62.42, 55.71, 37.15, 34.60, 25.04, 23.55; ½a D20
þ17 (c 2.3 in
ꢂ
(125 MHz, CDCl3)
d
162.70, 159.35, 152.09, 143.18, 138.42, 136.68,
CHCl3); IR (film): 1736,1719,1674,1444,1231,1075 cmꢁ1; HRMS (EI)
m/z¼963.1540 calcd for C49H44Cl5N2O8 [MþH]; found: 963.1544.
134.05, 132.56, 129.51, 128.64, 128.09, 127.48, 125.25, 115.50, 101.65,
91.90, 87.56, 84.51, 77.86, 76.19, 70.61, 69.17, 62.40, 55.71, 25.64;
½
a 2D0
ꢂ
þ23 (c 1.5 in CHCl3); IR (film): 3425, 1718, 1669, 1446,
4.13. 3-[(2,6-Dichloro-4-methoxy-phenyl)-(2,4,6-trichloro-
phenyl)-methoxymethyl]-1-(2-cyclohexyl-6-hydroxymethyl-
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-1H-pyrimidine-2,4-
dione (12)
1096 cmꢁ1; HRMS (EI) m/z¼883.0914 calcd for C43H36Cl5N2O8
[MþH]; found: 883.0916.
4.9. 3-[(2,6-Dichloro-4-methoxy-phenyl)(2,4,6-trichloro-phe-
nyl)methoxymethyl]-1-(3,4-dihydroxy-5-triisopropylsilanylo-
xymethyltetrahydrofuran-2-yl)-1H-pyrimidine-2,4-dione (13)
To a stirred solution of 11b (35 mg, 0.04 mmol) in CH2Cl2
(0.4 mL) at 0 ꢀC were added TolSH (14 mg, 0.12 mmol) and BF3$Et2O
(100 mL). After 1 h at rt, the reaction was quenched with satd aq
The same procedure for the synthesis of 10a was applied, but
NaHCO3. The aqueous layer was extracted with CH2Cl2 three times.
The combined organic extract was dried over Na2SO4, and con-
centrated in vacuo. The crude product was purified by silica gel
chromatography (hexanes/EtOAc¼4/1) to provide 12 (26 mg, 90%).
TIPSCl was used. Yield: 90%. 1H NMR (500 MHz, CDCl3)
d 7.90 (q,
J¼8.0 Hz, 1H) 7.30 (s, 2H), 6.83 (d, J¼1.5 Hz, 2H), 6.57 (s, 1H), 5.74 (m,
2H), 5.57 (m, 2H), 4.32 (br s,1H), 4.19 (m, 2H), 4.06 (d, J¼12.5 Hz, 1H),
3.77 (s, 3H), 2.92(brs,1H),1.16 (m, 3H),1.08 (d, J¼6.5 Hz, 9H); 13C NMR
1H NMR (400 MHz, CDCl3)
d
7.32 (s, 1H), 7.30 (d, J¼5.2 Hz, 2H), 6.83
(125 MHz, CDCl3)
d
162.68, 159.35, 152.37, 138.26, 136.69, 134.05,
(d, J¼6.4 Hz, 2H), 6.58 (s, 1H), 5.77 (dd, J¼8.0 Hz, 1H), 5.57 (s, 2H),
5.47 (dd, J¼5.6 Hz, 1H), 5.00 (d, J¼2.8 Hz, 1H), 4.93(dd, J¼3.6 Hz,
1H), 4.28 (d, J¼2.8 Hz, 1H), 3.88 (d, J¼8.0 Hz, 1H), 3.79 (d, J¼8.0 Hz,
1H), 3.77 (s, 3H), 2.50 (br s, 1H), 1.67 (m, 2H), 1.64 (m, 2H), 1.59 (m,
132.58,129.50,125.25,115.50,101.48, 92.01, 86.31, 77.95, 76.64, 70.59,
69.17, 62.55, 55.72, 25.65, 18.02, 11.85, ꢁ3.58; ½a D20
þ27 (c 5.5 in
ꢂ
CHCl3); IR (film): 3422, 1700, 1657, 1441,1243, 1093 cmꢁ1; HRMS (EI)
m/z¼797.1153 calcd for C33H42Cl5N2O8Si [MþH]; found: 797.1159.
4H), 1.41 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 162.56, 159.27,
151.34, 141.88, 136.70, 133.96, 132.55, 129.46, 125.17, 115.52, 115.04,
102.16, 97.66, 87.43, 83.15, 79.88, 78.00, 69.26, 62.86, 55.70, 37.12,
4.10. General procedure of desilylations
34.66, 24.92, 23.98, 23.54; ½a D20
þ17 (c 1.0 in CHCl3); IR (film): 3464,
ꢂ
To a stirred solution of 13 (26 mg, 0.03 mmol) in MeCN (0.5 mL)
at rt was added 50% HF (100 mL). After 5 h, the reaction mixture was
quenched by aq NaHCO3. The organic layer was washed with brine,
and then dried over Na2SO4. Purification by silica gel chromatog-
raphy (hexanes/EtOAc¼4/1) gave the product 8 (19 mg, 88%).
1743, 1710, 1665, 1456, 1222 cmꢁ1; HRMS (EI) m/z¼721.0445 calcd
for C30H30Cl5N2O8 [MþH]; found: 721.0450.
4.14. Acetonization of 8
To a stirred solution of 8 (64 mg, 0.1 mmol) in acetone (0.6 mL)
4.11. Cyclohexylidenation of 10a
at 0 ꢀC were added PTSA (2 mg) and 2,2-dimethoxypropane (15
mL,
0.12 mmol). The mixture was stirred for 4 h at the same tempera-
ture and concentrated in vacuo. Purification by silica gel chroma-
tography (hexanes/EtOAc¼4/1) afford 14 (59 mg, 87%). 1H NMR
To a stirred solution of 10a (75.6 mg, 0.1 mmol) in MeCN
(0.5 mL) were added dipent-4-enyl acetal (30 mg, 0.12 mmol), NBS
(47 mg, 0.26 mmol), and BF3eOEt2 (0.01 mmol). The reaction
(400 MHz, CDCl3)
d
7.33 (s, 1H), 7.30 (d, J¼5.6 Hz, 2H), 6.83 (d,

Y. Wang, M. Kurosu / Tetrahedron 68 (2012) 4797e4804
4803
J¼6.0 Hz, 2H), 6.58 (s,1H), 5.76 (d, J¼8.0 Hz,1H), 5.55 (br s, 2H), 5.47
(dd, J¼5.6 Hz, 1H), 5.02 (d, J¼2.0 Hz, 1H), 4.94 (d, J¼5.6 Hz, 1H), 4.28
(d, J¼2.8 Hz, 1H), 3.90 (dd, J¼4.8 Hz, 1H), 3.89 (s, 1H), 3.88 (s, 3H),
2.52 (br s, 1H), 1.57 (s, 3H), 1.35 (s, 3H); 13C NMR (100 MHz, CDCl3)
chromatography (hexanes/EtOAc¼10/1) gave 16 (26 mg, 71%). 1H
NMR (400 MHz, CDCl3)
d
7.78 (m, 1H), 7.31 (d, J¼2.0 Hz, 2H), 6.88
(br s, 1H), 6.75 (d, J¼4.8 Hz, 2H), 6.23 (d, J¼9.2 Hz, 1H), 5.81 (m, 1H),
5.69 (m, 1H), 5.61 (m, 2H), 4.88 (br s, 1H), 3.87 (m, 1H), 3.78 (m, 1H),
3.69 (s, 1H), 3.68 (s, 3H), 0.90 (s, 9H), 0.17 (d, J¼12.0 Hz, 6H); 13C
d
162.55, 159.28, 151.35, 141.74, 136.69, 133.97, 132.53, 129.46,
125.18, 115.46, 114.24, 102.13, 97.58, 87.30, 83.67, 80.34, 78.03,
NMR (100 MHz, CDCl3) d 163.10, 159.26, 139.28, 136.78, 133.94,
69.24, 62.84, 55.70, 27.25, 25.25; ½a D20
ꢂ
þ17 (c 1.5 in CHCl3); IR (film):
132.83, 129.42, 126.83, 125.24, 115.43, 101.80, 90.59, 87.41, 77.80,
3462, 1740, 1713, 1666, 1448, 1221 cmꢁ1; HRMS (EI) m/z¼681.0132
calcd for C27H26Cl5N2O8 [MþH]; found: 681.0138.
69.21, 64.14, 55.68, 25.92, 18.52, ꢁ5.36, ꢁ5.50; ½a D20
þ20 (c 1.5 in
ꢂ
CHCl3); IR (film): 1705, 1658, 1443, 1255, 1079 cmꢁ1; HRMS (EI) m/
z¼721.0629 calcd for C30H34Cl5N2O6Si [MþH]; found: 721.0623.
4.15. 1-(6-Benzyloxymethyl-2,2-dimethyl-tetrahydro-furo
[3,4-d][1,3]dioxol-4-yl)-3-[(2,6-dichloro-4-methoxy-phenyl)-
(2,4,6-trichloro-phenyl)methoxymethyl]-1H-pyrimidine-2,4-
dione (15)
4.19. 1-[5-(tert-Butyl-dimethylsilanyloxymethyl)-tetrahydrofu
ran-2-yl]-3-[(2,6-dichloro-4-methoxyphenyl)(2,4,6-trichloro-
phenyl)methoxymethyl]-1H-pyrimidine-2,4-dione (18)
The procedure described for 15 was applied. Yield: 95%. 1H NMR
To a stirred suspension of NaH (5 mg, 60% in oil, 0.125 mmol) in
DMF (0.5 mL) at 0 ꢀC was added 14 (78 mg, 0.1 mmol) in DMF
(400 MHz, CDCl3)
d
7.70 (m, 1H), 7.29 (d, J¼2.0 Hz, 2H), 6.77 (d,
(0.5 mL). After 5 min BnBr (36 mL, 0.3 mmol) was added. After 3 h,
J¼4.8 Hz, 2H), 6.21 (d, J¼9.2 Hz, 1H), 5.85 (m, 1H), 5.78 (m, 1H), 5.63
(m, 1H), 4.80 (br s, 1H), 3.82 (m, 1H), 3.71 (m, 1H), 3.68 (s, 1H), 3.66
(s, 3H), 2.15 (m, 2H), 1.85 (m, 2H), 0.90 (s, 9H), 0.17 (d, J¼12.0 Hz,
the reaction mixture was quenched with H2O, and extracted with
EtOAc. The organic phase was washed with brine, dried over
Na2SO4, and evaporated in vacuo to give the crude product. This
was used for the study of debenzylation.
6H); 13C NMR (100 MHz, CDCl3)
d 163.11, 159.22, 139.25, 136.79,
133.96, 132.85, 125.21, 115.40, 101.87, 90.64, 87.39, 77.82, 69.19,
64.11, 55.66, 28.01, 25.95, 21.33, 18.55, ꢁ5.35, ꢁ5.51; ½a D20
þ21 (c 1.3
ꢂ
in CHCl3); IR (film): 1707, 1650, 1440, 1245, 1083 cmꢁ1; HRMS (EI)
m/z¼723.0785 calcd for C30H36Cl5N2O6Si [MþH]; found: 723.0789.
4.16. General procedure of hydrogenation
i
To a solution of 15 (76 mg, 0.1 mmol) in PrOH/H2O (2/1, 3 mL)
was added 10% Pd/C (10 mg) under N2. H2 was introduced by using
a balloon. After 2 h, Pd/C was filtered with a Celite pad. The filtrate
was concentrated in vacuo. Purification by silica gel chromatogra-
phy (hexanes/EtOAc¼4/1) afforded 14 (65 mg, 95%). Physical data
for 14, see Section 4.14.
4.20. Polymer-supported (2,6-dichloro-4-methoxyphenyl)(2,4,6
-trichlorophenyl)methanone 21
Hydromethylstyrene resin 19 (purchased from Aldrich, 1.0 g,
w2 mmol) was washed with THF. Compound 19 was suspended in
THF (20 mL) and TPP (5.24 g, 20 mmol), DIAD (3.93 mL, 20 mmol),
and 20 (1.11 g, 3 mmol) were added. The reaction mixture was
gently stirred for 12 h. The polymer-resins were filtered, and
thoroughly washed with THF/H2O (4/1), THF, EtOAc, and hexanes,
and dried dried under high vacuum to give 21 (1.75 g).
4.17. O,O0-((2R,3S,4S,5R)-2-(((tert-Butyldimethylsilyl)oxy)me-
thyl)-5-(3-(((2,6-dichloro-4-methoxyphenyl)(2,4,6-trichlor-
ophenyl)methoxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-
1(2H)-yl)tetrahydrofuran-3,4-diyl) S,S0-dimethyl
dicarbonodithioate (16)
4.21. Polymer-supported (2,6-dichloro-4-methoxyphenyl)(2,4,6
-trichlorophenyl)methanol 22
To a stirred solution of 10a (160 mg, 0.21 mmol) in DMSO
(0.3 mL) was added 5 N NaOH (0.2 mL). After 20 min, CS2 (0.2 mL)
was added. After an additional 30 min, MeI (0.3 mL) was added.
Then the reaction mixture was stirred for 2 h, and quenched by satd
aq NH4Cl, and extracted with EtOAc. The combined organic extract
was washed with brine, dried over Na2SO4, concentrated in vacuo.
Purification by silica gel chromatography (hexanes/EtOAc¼10/1)
To a gently stirred polymer-resin 21 (1.75 g) in THF (8 mL) was
added LiBH4 (10 mL, 2.0 M inTHF) at 0 ꢀC. After 12 h at rt, the reaction
mixture was quenched with H2O (5 mL). The polymer-resins were
thoroughly washed with THF/1% HCl (4/1), THF, EtOAc, and hexanes,
and dried under high vacuum to afford the polymer-resin 22 (1.66 g).
gave 15 (135 mg, 69%). 1H NMR (400 MHz, CDCl3)
d
7.88 (d, J¼8.0 Hz,
1H), 7.28 (d, J¼11.6 Hz, 2H), 6.82 (d, J¼9.2 Hz, 2H), 6.60 (t, J¼7.6 Hz,
1H), 6.55 (d, J¼9.2 Hz, 1H), 6.25 (t, J¼5.2 Hz, 1H), 6.05 (m, 1H), 5.77
(t, J¼6.8 Hz, 1H), 5.60 (m, 2H), 4.45 (s, 1H), 4.03 (dd, J¼27.2 Hz, 2H),
3.76 (s, 3H), 2.59 (s, 3H), 2.52 (d, J¼15.2 Hz, 3H); 0.95 (s, 9H), 0.19 (d,
4.22. Polymer-supported MDPM-Cl 23
To a suspension of 22 (0.44 g) in THF (10 mL) was added
NaHMDS (0.6 mL, 1.0 M in THF, 0.6 mmol). After 30 min, chlor-
omethyl methyl sulfide (0.09 mL, 1.3 mmol) was added. After 8 h,
the polymer was thoroughly washed with THF/H2O (4/1), THF,
EtOAc, and hexanes, and dried in vacuo to give the polymer-
supported methyl sulfide (464 mg). This was suspended in CH2Cl2
(2 mL) and sulfuryl chloride (0.17 mL, 4.1 mmol) was added. After
5 h, the polymer-resins were washed thoroughly with CH2Cl2, and
dried under high vacuum to afford 23. Anal. Found Cl 232 mg/g.
J¼12.0 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 214.70, 162.61, 159.23,
151.29, 138.36, 136.69, 134.58, 133.93, 132.88, 129.38, 125.23, 115.53,
102.83, 85.97, 84.37, 80.01, 78.77, 77.81, 69.47, 63.35, 55.69, 26.01,
19.11, 18.40, ꢁ5.25, ꢁ5.59; ½a D20
þ23 (c 2.5 in CHCl3); IR (film): 1711,
ꢂ
1648, 1446, 1259, 1079 cmꢁ1; HRMS (EI) m/z¼956.9699 calcd for
C34H39Cl5N2O8S4SiNa ([MþNa]þ); found: 956.9702.
4.18. 1-[5-(tert-Butyl-dimethylsilanyloxymethyl)-2,5-
dihydrofuran-2-yl]-3-[(2,6-dichloro-4-methoxyphenyl)(2,4,6-
trichloro-phenyl)methoxymethyl]-1H-pyrimidine-2,4-dione
(17)
4.23. Loading uridine on PS-MDPM-Cl resin 23
To a suspension of PS-MDPM-Cl 23 (800 mg) in DMF (1 mL)
To a stirred solution of 15 (47 mg, 0.05 mmol) in toluene (0.5 mL)
were added AIBN (4 mg) and nBu3SnH (0.07 mL, 0.25 mmol) at
100 ꢀC. After 30 min, the reaction mixture was cooled to rt and all
volatiles were evaporated in vacuo. Purification by silica gel
were added DBU (30 mL, 0.2 mmol) and uridine (49 mg, 0.2 mmol).
After 3 h, the polymer-resins were thoroughly washed with THF/
H2O (4/1), THF, EtOAc, and hexanes, and then dried under high
vacuum to afford 25 (55 mg).

4804
Y. Wang, M. Kurosu / Tetrahedron 68 (2012) 4797e4804
2. (a) Bryskier, A.; Dini, A. C. Agents: Antibacter. Antifung. 2005, 377e398; (b)
4.24. Loading 24 on PS-MDPM-Cl resin 23
Timothy, D. H.; Lloyd, A. J.; Roper, D. I. Infect. Disorders: Drug Targets 2006, 6,
85e106.
The procedure was same as described in Section 4.23.
3. (a) Reddy, V. M.; Einck, L.; Nacy, C. A. Antimicrob. Agents Chemother. 2008, 52,
719e721; (b) Ichikawa, S. Chem. Pharm. Bull. 2008, 56, 1059e1072; (c) Dini,
C. Curr. Top. Med. Chem. 2005, 5, 1221e1236; (d) Dini, C.; Drochon, N.; Fe-
teanu, S.; Guillot, J. C.; Peixoto, C.; Aszodi, J. Bioorg. Med. Chem. Lett. 2001, 11,
529e531.
4.25. Cleavage of linker
4. (a) Kurosu, M.; Li, K.; Crick, D. C. Org. Lett. 2009, 11, 2393e2397; (b) Kurosu, M.;
Li, K. J. Org. Chem. 2008, 73, 9767e9771; (c) Kurosu, M.; Biswas, K.; Crick, D. C.
Org. Lett. 2007, 9, 1141e1145; (d) Kurosu, M.; Narayanasamy, P.; Crick, D. C.
Heterocycles 2007, 72, 339e352; (e) Kurosu, M.; Mahapatra, S.; Narayanasamy,
P.; Crick, D. C. Tetrahedron Lett. 2007, 48, 799e803.
5. (a) Hanessian, S.; Kloss, J.; Sugawara, T. J. Am. Chem. Soc. 1986, 108, 2758e2759;
(b) Goff, D. A.; Harris, R. N.; Bottaro, J. C.; Bedford, C. D. J. Org. Chem. 1986, 51,
4711e4714; (c) Connor, D. S.; Klein, G. W.; Taylor, G. N.; Boeckman, R. K.;
Medwid, J. B. Org. Synth. 1972, 52, C10eC19.
The resin 25 was washed with CH2Cl2, and added 30% TFA in
CH2Cl2 (2 mL). After 4 h at rt, the polymer-resins were washed
thoroughly with CH2Cl2. The filtrate was concentrated in vacuo.
Purification by silica gel chromatography (CHCl3/MeOH¼10/1)
furnished uridine (7) (19 mg, 90%). The resin 26 was cleaved via the
same procedure to afford 7 (21 mg, 85%).
6. Spork, A. P.; Wiegmann, D.; Granitzka, M.; Stalke, D.; Ducho, C. J. Org. Chem.
2011, 76, 10083e10098.
Acknowledgements
7. (a) Kurosu, M.; Li, K. Org. Lett. 2009, 11, 911e914; (b) Kurosu, M.; Li, K. Synthesis
2009, 21, 3633e3641; (c) Kurosu, M.; Biswas, K.; Crick, D. C. Org. Lett. 2007, 9,
1141e1144; (d) Kurosu, M.; Biswas, K.; Narayanasamy, P.; Crick, D. C. Synthesis
2007, 16, 2513e2516.
The authors thank the National Institutes of Health (NIAID grant
AI084411-02) and The University of Tennessee for generous fi-
nancial supports. NMR data were obtained on instruments sup-
ported by the NIH Shared Instrumentation Grant.
8. The esters and carbamates synthesized with 5b showed single isomers in their
1H NMRs and single peaks in their HPLC chromatography analyses.
ꢀ
ꢁ
9. Goomez, C.; Macia, B.; Lillo, V. J.; Yus, M. Tetrahedron 2006, 62, 9832e9839.
10. (2,6-Dichloro-4-hydroxyphenyl) (2,4,6-trichlorophenyl) methanone (20) was
synthesized by demethylation of 4b with HBr in AcOH.
References and notes
11. Mitsunobu, O. Synthesis 1981, 29, 1e28.
12. The BOM group has been utilized to protect alcohols and carboxylic acids. We
realized that 1 and 23 could protect or immobilize primary alcohols, phenolic
alcohols, and carboxylic acids.
1. (a) Yamamoto, T.; Koyama, H.; Kurajoh, M.; Shoji, T.; Tsutsumi, Z.; Moriwaki, Y.
Clin. Chim. Acta 2011, 412, 1712e1724; (b) Guillemette, C.; Levesque, E.; Harvey,
M.; Bellemare, J.; Menard, V. Drug Metab. Rev. 2010, 42, 24e44.