Improved synthesis of capuramycin and its analogues

Article abstract of DOI:10.1002/chem.201302389

Capuramycin and its congeners are considered to be important lead molecules for the development of a new drug for multidrug-resistant (MDR) Mycobacterium tuberculosis infections. Extensive structure-activity relationship studies of capuramycin to improve the efficacy have been limited because of difficulties in selectively chemically modifying the desired position(s) of the natural product with biologically interesting functional groups. We have developed efficient syntheses of capuramycin and its analogues by using new protecting groups, derived from the chiral (chloro-4-methoxyphenyl)(chlorophenyl)methanols, for the uridine ureido nitrogen and primary alcohol. The chiral nonracemic (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanol derivative is a useful reagent to resolve rac-3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin- 2-one, the (S)-configuration isomer of which plays a significant role in improving the mycobactericidal activity of capuramycin. Battling TB: Capuramycin and its congeners (see scheme) are considered to be important lead molecules for the development of a new drug for multidrug-resistant Mycobacterium tuberculosis infections. Efficient synthesis of capuramycin and its analogues by using new protecting groups for the uridine ureido nitrogen and primary alcohol was accomplished. Copyright

Full text of DOI:10.1002/chem.201302389

FULL PAPER
DOI: 10.1002/chem.201302389
Improved Synthesis of Capuramycin and Its Analogues
Yong Wang, Shajila Siricilla, Bilal A. Aleiwi, and Michio Kurosu*[a]
Abstract: Capuramycin and its conge-
ners are considered to be important
lead molecules for the development of
logically interesting functional groups.
We have developed efficient syntheses
of capuramycin and its analogues by
using new protecting groups, derived
G
E
E
G
for
a
new drug for multidrug-resistant
(MDR) Mycobacterium tuberculosis in-
fections. Extensive structure–activity
relationship studies of capuramycin to
improve the efficacy have been limited
because of difficulties in selectively
chemically modifying the desired posi-
tion(s) of the natural product with bio-
from the chiral (chloro-4-methACTHNGUETRNNUoG xy-
Keywords: capuramycin · drug de-
sign · mycobacterium tuberculosis ·
peptidoglycan biosynthesis · pro-
tecting groups · total synthesis
Introduction
nation TB chemotherapy, and 4) do not interfere with the
ability of HAART to treat HIV patients who are co-infected
with Mtb.
The emergence of multidrug-resistant (MDR) strains of My-
cobacterium tuberculosis (Mtb) seriously threatens tubercu-
losis (TB) control and prevention efforts.[1] Moreover, HIV–
AIDS patients are susceptible to TB infection[2] and there
are significant problems associated with treatment of AIDS
and Mtb co-infected patients. Rifampicin and isoniazid [a
key component of the directly observed treatment, short-
course (DOTS) therapy] induce the cytochrome P450 3A4
enzyme in the liver, which shows significant interaction with
protease inhibitors for HIV infection.[3] In addition, rifampi-
cin strongly interacts with non-nucleoside reverse transcrip-
tase inhibitors. Thus, clinicians avoid starting highly active
antiretroviral therapy (HAART), which consists of three or
more highly potent reverse transcriptase inhibitors and pro-
tease inhibitors, until the TB infection has been cleared.[4]
Thus, there is significant need and interest in developing
new TB drugs. However, over the last 40 years, only beda-
quiline (Sirturo), an ATP synthase inhibitor, has been ap-
proved for the treatment of MDR-Mtb infections as a mon-
otherapeutic agent, in 2012.[5] The ultimate goal of the de-
velopment of treatments for MDR-Mtb strains is to find
novel antibacterial agents that 1) interfere with unexploited
bacterial molecular targets, 2) can shorten a TB drug regi-
men (one- to three-month regimen), 3) can apply to combi-
Since peptidoglycan (PG) is an essential bacterial cell-
wall polymer, the machinery for PG biosynthesis provides a
unique and selective target for antibiotic action. However,
only a few enzymes in PG biosynthesis, such as the penicil-
lin-binding proteins (PBPs), have been extensively studied.[6]
Thus, the enzymes associated with the early PG biosynthesis
enzymes [MurA, B, C, D, E, and F, MraY (phospho-Mur-
NAcpentapeptide translocase or translocase I), and MurG]
are considered to be a source of unexploited drug targets.[7]
Our interest in unexploited molecular targets related to PG
biosynthesis is MraY,[8] which catalyzes the transformation
of UDP-N-acylmuramyl-l-alanyl-g-d-glutamyl-meso-diami-
nopimelyl-d-alanyl-d-alanine (the Park nucleotide) into pre-
nylpyrophosphoryl-N-acylmuramyl-l-Ala-g-d-glu-meso-
DAP-d-Ala-d-Ala (lipid I).[9] MraY is inhibited by nucleo-
side-based complex natural products, such as muraymy-
cins,[10] liposidomycin,[11] caprazamycin,[12] pacidamycin,[13]
capuramycin,[14] and other related natural products.[15] Ca-
puramycin (1) and its analogues have exhibited significant
mycobacterial growth inhibitory activities in vitro and in
vivo (Figure 1) and very low toxicity in mice.[16] Moreover,
capuramycin killed Mtb much faster than other first-line TB
drugs (>90% of the bacilli were killed within 48 h), and
thus could dramatically reduce the timeframe for effective
antiTB chemotherapy. Therefore, capuramycin and its con-
geners are considered to be important lead molecules for
the development of a new drug for MDR-Mtb infections.
Since the discovery of capuramycin as a specific spectrum
antimycobacterial agent, extensive structure–activity rela-
tionship (SAR) studies of capuramycins have been limited
because of difficulties in modifying the complex natural
product at the desired position(s) with a wide range of func-
[a] Dr. Y. Wang, S. Siricilla, Dr. B. A. Aleiwi, Prof. M. Kurosu
Department of Pharmaceutical Sciences, College of Pharmacy
University of Tennessee Health Science Center
881 Madison, Memphis, TN 38163-0001 (USA)
Fax : (+1)901-448-6940
E-mail: mkurosu@uthsc.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302389.
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cleavage of the benzyloxy-
methyl (BOM) group of the
uridine ureido nitrogen under
heterogeneous conditions often
yields the over-reduced prod-
ꢀ
uct in which the C5 C6 double
bond of the uracil moiety is sa-
turated.[19] Recently, we identi-
fied a new capuramycin ana-
logue, UT-01309 (2), contain-
ing (S)-3-amino-1,4-benzodia-
zepine-2-one [(S)-13], which
Figure 1. Structures of capuramycin (1) and UT-01309 (2).
showed improved antimyco-
tional groups. Accordingly, it is essential to establish a con-
cise and convergent synthesis of capuramycin that is amena-
ble to the synthesis of analogues for SAR studies. The first
total synthesis of capuramycin was reported in 1994 by
Knapp et al. Their synthesis requires 22 linear steps from
diisopropylidene-d-glucofuranose, and relatively lengthy
synthesis of the manno-pyranuronate glycosyl donor.[17] We
have developed a concise synthesis of capuramycin in which
the intact molecule can be synthesized in 15 steps from the
known intermediate 3 (Scheme 1).[18] Although each step in
our previously reported capuramycin synthesis is a high-
yielding conversion when applied on a small to medium
scale, several steps are not ideal for the synthesis of a large
amount of capuramycin and its analogues for in vivo studies
by using rodents.
bacterial activity (2.5 vs. 12.0 mgmLꢀ1 for 1 against M. tuber-
culosis).[20] Significantly, UT-01309 (2) is active against drug-
resistant M. tuberculosis and did not exhibit cytotoxicity
against Vero monkey kidney cells and HepG2 human hepa-
toblastoma cells, even at 250 mgmLꢀ1 concentrations (see
below). Thus, we are very interested in in vivo evaluation of
2 in comparison with capuramycin (1) and related mole-
cules. Herein, we report the improved synthesis of capura-
mycin (1) and its analogue UT-01309 (2) through use of
1) novel protecting groups for the uridine ureido nitrogen
and primary alcohol, and 2) the chiral carbonate reagent for
the resolution of rac-3-amino-1,4-benzodiazepine-2-one (13).
Results and Discussion
a-Mannosylation of 5 with the thioglycoside 6 requires di-
luted conditions (0.05m) and long reaction times (12–16 h).
Selective deacetylation at the 6’’-position of 7a has to be
stopped at around 30–70% conversion to avoid the over-re-
actions and the recovered starting material is recycled to
perform the same reaction multiple times. Hydrogenolytic
Our synthetic strategy to improve the syntheses of capura-
mycin (1) and capuramycin analogue UT-01309 (2) is illus-
trated in Scheme 2. We have developed new protecting
groups, (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)-
methyl [monomethoxytetrachlorodiphenylmethyl (MTPM)]
and (2,6-dichloro-4-methoxy-
phenyl)(2,4,6-O-di
ACHUTGTNRNEUGpN henACHTUNGTRENNUNGyl-
AHCTUNGTRENGNmUN ethyl trichloroacetimidateo-
phenyl)methoxymethyl [mono-
methoxydiphenylmethoxyl-
methyl (MDPM)] for primary
alcohols and ureido nitrogen
atoms, respectively.[21] These
protecting groups showed sig-
nificant relative stability under
a wide variety of conditions
utilized for the syntheses of
natural and unnatural products.
However, the MTPM and
MDPM protecting groups can
be conveniently removed by
using 30% trifluoroacetic acid
(TFA) in CH2Cl2. The use of
these protecting groups for the
uridine ureido nitrogen (3-po-
sition) and the primary alcohol
(6’’-position) will significantly
improve the synthesis of capur-
Scheme 1. Previously reported syntheses of capuramycin (1; Tol=tolyl).
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Capuramycin and Its Analogues
FULL PAPER
Scheme 2. Improved synthetic strategy for capuramycin analogues.
amycin analogues (Scheme 2). (S)-3-Amino-1,4-benzodiaze-
pin-2-one [(S)-13] is an important functional group to im-
prove antimycobacterial activity of capuramycin analogues.
methylation conditions to yield the desired monomethoxy
derivative in 60% yield.[23] Selective chloroacetylation of the
primary alcohol of the diol was performed with
For our SAR studies of capuramycin analogues, it is de
sir-
ClCH2CO2H,
1-ethyl-3-(3-dimethylaminopropyl)carboACHTUNGTRENNUNGdi-
A
ACHTUNGTRENiNUNG mide (EDCI), NaHCO3, and glyceroacetonide–Oxyma (17)
amino acids that are not commercially available. We expect-
ed that the optically pure carbonate (S)-14, derived from un-
symmetrical
in 5% H2O/CH3CN to give rise to 18 in 98% yield.[24] The
regiochemistry of 18 was unequivocally determined by ex-
1
(2,6-dichloro-4-methoxyphenyl)(2,4-di
G
tensive H NMR decoupling studies and 2D NOESY experi-
A
E
ments.[25] Although the ordinal esterification conditions
[e.g., ClCH2CO2H, N,N-dicyclohexylcarbodiimide (DCC), 4-
dimethylaminopyridine (DMAP) in CH2Cl2 or ClCH2COCl,
pyridine in CH2Cl2) provided a mixture of 18 and the over-
reaction products, we did not observe the formation of the
secondary alcohol ester under the conditions applied to the
synthesis of 18. Acetylation of the secondary alcohol of 18,
followed by removal of the chloroacetyl group with thiourea
in MeOH, afforded 19 in 95% overall yield.[26] The primary
alcohol in 19 was oxidized under Pfitzner–Moffatt condi-
tions (DCC, Cl2CHCO2H, DMSO/CH2Cl2) to provide the
corresponding aldehyde 20, which was utilized without puri-
fication.[27] We have extensively studied cyanohydrin forma-
tion reactions of the uridylaldehyde derivatives by using tri-
methylsilyl cyanide (TMSCN).[28] In all cases, Lewis acid
promoted trimethylsilyl cyanation reactions of the uridylal-
dehydes furnished a mixture of the TMS-protected cyanohy-
drins, favoring the undesired (R)-configuration products
(e.g., 21), in low yields. Lewis base catalyzed trimethylsilyl
cyanation reactions (e.g., Ph3PO, N-methylmorpholine N-
the carbamates through convenient chromatography and be
readily removed under mild conditions.[22]
Synthesis of (2S)-uridylhydroxyacetonitrile 10 and mannosyl
donor imidate 11: MDPM and MTPM groups have signifi-
cant advantages over other ordinal protecting groups for the
syntheses of capuramycin analogues in that these new pro-
tecting groups 1) are stable in the presence of a wide variety
of acids, 2) are not susceptible to hydrogenation under
standard conditions, and 3) can be removed efficiently by
solvolytic cleavage with 30% TFA at room temperature
within 2 h without addition of a cation scavenger.[21] We syn-
thesized over 10 g of MDPMCl (16) and MTPM-imidate
(22) by following established procedures.[21] The uridine
ureido nitrogen was protected with MDPMCl (16) in the
presence of 1,8-diazabicyclo
afford the MDPM-protected uridine
(Scheme 3). Selective alkylation of 9 at the secondary alco-
hol (3’-position) was achieved by using SnCl2-mediated
ACHTUNGTRENNUNG
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M. Kurosu et al.
Scheme 3. Syntheses of the glycosyl donor 10 and acceptor 11.
oxide (NMO), 1,4-diazabicyclo
[2.2.2]octane (DABCO), cin-
(BzCN) in DMSO/H2O afforded a 2:1 mixture of 10 and 21
in 95% yield from 19.[30] Because water-catalyzed hydrocya-
nation with BzCN is operationally simple and results in
high-yielding conversion, we decided to scale-up the conver-
sion of 19 to 10 under these conditions and the undesired
stereochemistry of 21 was inverted by a modified Mitsunobu
reaction [diisopropyl azodicarboxylate (DIAD), triphenyl-
phosphine (TPP), ClCH2CO2H, pyridine (1:1:1:1)]. The
chloroacetyl group in the ester was selectively removed with
thiourea in MeOH. Thus, we could achieve the synthesis of
the mannosyl acceptor 10 in 7 steps from uridine (15) with
34% overall yield without the inversion process (21!10) or
in 9 steps with 45% overall yield including the Mitsunobu
reaction, followed by deprotection.
chona alkaloids) did not provide the products due to the
fact that the uridylaldehydes were not stable in the presence
of Lewis and Brønsted bases. In previous studies, we have
observed that the Ti-mediated conditions gave the desired
(S)-configuration cyanohydrin as the major product with sat-
isfactory yield.[18] Similarly, TMSCN addition to 20 with [Ti-
ACHTUNGTRENNUNG(OiPr)4] (10 mol%) in CH2Cl2/H2O (1%) provided a mix-
ture of 10 and 21 in 90% yield with a 10/21 ratio of 1.5–
2.0:1 after desilylation.[29] In our recent studies, we found
that the trimethylsilyl cyanation reaction of 20 with 1,3-
bis[2-(dimethylamino)ethyl]thiourea also gave a mixture of
10 and 21 with comparable selectivity and yield to the reac-
tion with [Ti
ACHTUNGTRENNUNG(OiPr)4] in CH2Cl2/H2O (1%). Moreover, we
observed that hydrocyanation of 20 with benzoyl cyanide
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Capuramycin and Its Analogues
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The mannosyl donor 11 was synthesized in 4 steps from
a-benzyl glycoside 22 (Scheme 3). The primary acetate in 22
was selectively removed with [{tBu2SnCl(OH)}2][31] and the
generated alcohol was protected with MTPM-imidate 23 in
the presence of trimethylsilyl trifluoromethanesulfonate
(TMSOTf), to afford 24 in 93% overall yield.[21] Hydrogeno-
lytic cleavage of the anomeric benzyl ether, followed by the
imidate-formation reaction, provided 11 in 95% overall
yield.[32]
tion of the diastereomers formed by amide-forming reac-
tions with optically active amino acids, and only a few re-
ports have demonstrated the resolution of (ꢁ)-13 with readi-
ly cleavable chiral agents. Sherrill et al. reported the resolu-
tion of 13 by use of the para-nitrophenyl carbonate of (R)-
a-methyl benzyl alcohol. In their procedure, the carbamate
auxiliary was cleaved with HBr (gas) in CH2Cl2 and the gen-
erated byproduct, (1-bromoethyl)benzene, needed to be re-
moved by recrystallization.[38]
We envisioned the resolution of (ꢁ)-13 with the chiral car-
bonate (S)-14, which was originally developed as a new
chiral derivatizing agent for determination of the absolute
configuration of amino acids (Scheme 5).[21c] Carbamate for-
mation between (ꢁ)-13 and (S)-14 was achieved by using
iPr2NEt in a mixture of acetone and H2O (3:1). Gratifyingly,
the generated diastereomers could be purified by silica gel
column chromatography to afford 28 and 29 in 98% yield
(approximately 49% each). As shown in Figure 2, we have
reported that the absolute configuration of a wide range of
amino acids can be determined by only analyzing the carba-
mate nitrogen protons of (S)-14 and (R)-14 derivatives in
1H NMR spectra. In all cases, the nitrogen protons of carba-
mates derived from l-amino acids and (S)-14 were shifted
downfield relative to those obtained with l-amino acid–(R)-
Mannosylation of cyanohydrin 10 with 11: In our previous
capuramycin synthesis, we searched for an effective promot-
er to catalyze the mannosylation of 5 with thioglycoside 6
(Scheme 1). We found that a-selective mannosylation of 5
with 6 was achieved through the combination of N-iodosuc-
cinimide (NIS) and AgBF4 in CH2Cl2 (at 0.05m concentra-
tions; Scheme 4).[18,33] Interestingly, the NIS/AgBF4-promot-
ed mannosylation of 5 provided the orthoester 25 within
15 min, which underwent the rearrangement within 16 h to
afford 7a exclusively in 90% yield. Orthoester 25 could be
1
distinguished from 7a in the H NMR spectrum of the crude
reaction mixture; 25 showed a characteristic chemical shift
of d=1.78 ppm (CH3).[34] All triflate ion associated gly
N
ACHTUNGTNERsNUNG yl-
ACHTUNGTRENNUNGaACHTUNGTRENNUNG
1
acid (TfOH) or N-bromosuccinimide (NBS)/TfOH] yielded
a mixture of a- and b-mannosides.[35] Under the NIS/AgBF4
promoted conditions, mannosylation of the MDPM-protect-
ed compound 10 with the thioglycoside 26 did not provide
the desired product 12. The acceptor 10 was stable under
the NIS/AgBF4 conditions, whereas thioglycoside 26 was
completely consumed to form complex mixtures. Although
mannosylation of 10 with a-mannopyranose 2,3,4,6-tetraace-
tate 1-(2,2,2-trichloroethanimidate) (27) did not provide the
desired product 7b, TMSOTf- and BF3·OEt2-catalyzed man-
nosylation of 10 with the imidate 11 did provide the desired
product 12 in 45 and 75% yield, respectively. It is worth
noting that the mannosylation with 11 could be achieved at
high concentrations in short reaction times compared to the
mannosylation of 5 with 6 under the NIS/AgBF4 conditions.
We confirmed that mannosylation of 10 with 11 was repro-
ducible at any concentration between 0.1–0.5m and could be
applied to a gram-scale synthesis of 12.
14 derivatives.[22] In H NMR spectra, the chemical shifts of
29 should be identical to those of the antipode of 29 (ent-29)
(Figure 2). Thus, the DdACHTNUTGRNEUNG
(S–R) value of the Na protons of 28
and ent-29 should determine the absolute stereochemistry of
28. The Dd(Na28–Na29) value was +0.03 and thus the abso-
lute stereochemistry of 28 was assigned to be the l-configu-
ration (S for 3-amino-1,4-benzodiazepine-2-one) as shown in
Scheme 5. The diastereomeric excesses (de values) of puri-
fied 28 and 29 were determined by HPLC to be >99.0%.
Removal of the carbamate auxiliaries of 28 and 29 was ach-
ieved by use of 20% TFA in CH2Cl2, to afford (S)-13 and
(R)-13 in >95% yield. The chiral auxiliary was recovered as
the racemic trifluoroacetate 30 in quantitative yield. The ab-
solute configurations of (S)-13 and (R)-13 were unequivocal-
ly confirmed by the comparison of optical rotations with the
reported values for (S)-13 and (R)-13.[37c]
Syntheses of capuramycin and UT-01309 (2): We have previ-
ously reported the synthesis of capuramycin (1) from 7 in 7
steps (Scheme 1).[18] The use of MDPM and MPTM protect-
ing groups for the uridine ureido nitrogen and primary alco-
hol could, however, significantly improve the synthesis of 8.
As summarized in Scheme 6, capuramycin (1) and UT-01309
(2) were synthesized in 6 steps from 12. The improved
method required purifications by chromatography for only
three of the total number of synthetic steps (Scheme 6). The
cyano group in 12 was hydrated by using InCl3–aldoxime in
toluene, furnishing the corresponding primary amide.[39]
Without further purification, the primary amide was subject-
ed to simultaneous removal of the MDPM and MPTM
groups with TFA (30%) in CH2Cl2, to afford 8 in >95%
overall yield for the two steps. We could achieve the synthe-
sis of over 1 g of 8 through the new protecting-group strat-
Resolution of racemic 3-amino-1,4-benzodiazepine-2-one:
We have previously identified that in vitro antimycobacterial
activity of capuramycin (1) was improved by the replace-
ment of the (S)-3-aminoazepan-2-one moiety of 1 with (S)-
3-amino-1,4-benzodiazepine-2-one [(S)-13] (see above). To
synthesize sufficient quantities of UT-01309 (2) for in vivo
studies, it was desirable to establish an efficient resolution
method for racemic 3-amino-1,4-benzodiazepine-2-one [(ꢁ)-
13]. Due to the fact that 3-amino-1,4-benzodiazepine-2-ones
are important building blocks[36] for the development of sev-
eral therapeutic areas (e.g., to combat the respiratory syncy-
tial virus), resolution methods for racemic 3-amino-1,4-ben-
zodiazepine-2-one [(ꢁ)-13] have been reported by several
groups.[37] However, most reported protocols provide separa-
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M. Kurosu et al.
Scheme 4. Mannosylation of the cyanohydrins.
egy summarized in Schemes 3, 4, 5, and 6. The conversions
of 8 to capuramycin (1) and UT-01309 (2) were carried out
through the previously reported procedures except for the
amide-forming reactions.[18] Oxidation–elimination reactions
of 8 by using SO3·pyridine in a biphasic solvent system
(DMSO/Et3N, 3:1) provided the a,b-unsaturated aldehyde
31.[40] Aldehyde 31 was then oxidized to the corresponding
carboxylic acid (32) by Pinnick oxidation (NaClO2, 2-
methyl-2-butene).[41] The resulting crude carboxylic acid was
coupled with (S)-aminocaprolactam (33) by using an amide
forming reaction in water media [glyceroACTHNUGTRENNUaG cetoACHUTTGNRENnNUNG ide–Oxyma
(17), EDCI, NaHCO3 in H2O] to yield 33 in 80–85% overall
yield from 8.[42] In our previous synthesis of 1, 1-hydroxy-7-
azabezotriazole (HOAt) was used as the peptide-coupling
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Capuramycin and Its Analogues
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Scheme 5. Resolution of rac-3-amino-1,4-benzodiazepine-2-one.
Mycobacterium spp. The IC50
value of 2 against Mtb MraY
was 5.5 nm (1: IC50 =18 nm
against Mtb MraY). UT-01309
(2) did not exhibit growth in-
hibitory activity against
a
series of Gram-positive and
-negative bacteria, including S.
aureus, E. faecalis, E. coli, K.
pneumonia, and P. aeruginosa,
even at 400 mgmLꢀ1 concentra-
tions. UT-01309 (2) showed
bactericidal activities specific
to Mycobacterium spp. UT-
01309 (2) killed M. tuberculo-
sis (H37Rv) completely at
2.5 mgmLꢀ1
concentrations,
Figure 2. Absolute configurations of 28 and 29.
whereas capuramycin required
12.0 mgmLꢀ1. UT-01309 (2)
additive to couple the segments 32 and 33. HOAt and some
other byproducts generated under the coupling-reaction
conditions [EDCI, HOAt, N-methylmorpholine (NMM) in
DMF] were difficult to separate from the desired product by
standard column chromatography. In contrast, in the
showed a minimum inhibitory concentration (MIC) of
6.5 mgmLꢀ1 against M. smegmatis. Significantly, UT-01309
(2) is active against drug-resistant M. tuberculosis (e.g., M.
tuberculosis H37Rv INHr and M. tuberculosis H37Rv
RFPr), and did not exhibit cytotoxicity against Vero
monkey kidney cells and HepG2 human hepatoblastoma
cells, even at 250 mgmLꢀ1 concentrations.
glyceroACHTUNGTRENNUNGacetoACHTUNGTRENNUNGnide–Oxyma (17)/EDCI-mediated coupling re-
action, simple basic and acidic aqueous workup procedures
could remove all reagents utilized in the reactions, to afford
the coupling product 34 in high yield with excellent purity.
Saponification of 34 by using LiOH in THF/H2O provided
capuramycin (1) in greater than 95% yield. Similarly, UT-
01309 (2) was synthesized by the same process, but by using
(S)-13 instead of 33 (Scheme 6). The purities of synthetic
products 1 and 2 were determined to be >99% by reverse-
phase HPLC analyses.
Conclusion
We present an improved synthesis of capuramycin (1) and
its analogue UT-01309 (2), a promising investigational drug
lead for MDR-Mycobacterium tuberculosis infections.
MDPM and MPTM protecting groups for the uridine ureido
nitrogen atom and primary alcohol improved the overall ef-
ficiency of the syntheses of 1 and 2. The synthetic scheme
reported herein enables us to synthesize gram quantities of
the key intermediate 8 for the synthesis of a series of capur-
amycin analogues; 8 could be synthesized in 9 steps from ur-
idine (15) in 32% overall yield. In addition, we have demon-
The in vitro biological evaluation of UT-01309 (2): UT-
01309 (2) was identified by cell-based assays of a small opti-
mized library of capuramycin analogues. The in vitro biolog-
ical activities of 2 synthesized herein were evaluated against
Mtb MraY (IC50 values) and a series of bacteria including
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M. Kurosu et al.
Scheme 6. Synthesis of capuramycin and UT-01309 (2).
strated efficient resolution of racemic 3-amino-1,4-benzodia-
zepine-2-one [(ꢁ)-13] with the chiral carbonate (S)-14 to
yield (S)-13, an important building block to improve the in
vitro biological activity of capuramycin. We will evaluate
UT-01309 (2) in vivo by using an infected-mouse model and
study the toxicity and pharmacokinetics and pharmacody-
namics (PK/PD) profile of 2; these data will be reported
elsewhere.
500 MHz instruments. 13C NMR spectral data were obtained by using 100
and 125 MHz instruments.
(2,6-Dichloro-4-methoxyphenyl)(2,4,6-trichlorophenyl)methoxy
methyl
chloride (16): (2,6-Dichloro-4-methoxyphenyl)(2,4,6-trichlorophenyl)me-
thoxymethyl methyl sulfide was synthesized according to the previously
reported procedure.[7a] Sulfuryl chloride (2.0 mL, 25.0 mmol) was added
to a stirred solution of (2,6-dichloro-4-methoxyphenyl)(2,4,6-trichloro-
phenyl)methoxymethyl methyl sulfide (11.18 g, 25.0 mmol) in CH2Cl2
(63.0 mL) at RT. The reaction mixture was stirred for 1 h and all volatile
compounds were evaporated to provide the crude product as an oil that
was pure enough for the next reaction (10.45 g, 96%). 1H NMR
(400 MHz, CDCl3): d=7.33 (s, 2H), 6.88 (s, 2H), 6.77 (s, 1H), 5.57 (q,
J=6.4 Hz, 2H), 3.80 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
159.6, 136.8, 136.6, 134.4, 131.7, 129.7, 124.3, 115.6, 80.1, 55.8 ppm; IR:
n˜ =3473, 1445, 1309 cmꢀ1; elemental analysis calcd (%) for C15H10Cl6O2:
C 41.42, H 2.32, Cl 48.91; found: C 41.81, H 2.41, Cl 48.97.
Experimental Section
General: All reagents and solvents were of commercial grade and were
used as received, without further purification, unless otherwise noted.
Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled from
sodium benzophenone ketyl under an argon atmosphere prior to use. Di-
chloromethane (CH2Cl2), acetonitrile (CH3CN), benzene, toluene, and
triethylamine (Et3N) were distilled from calcium hydride under an argon
atmosphere. Flash column chromatography was performed with What-
man silica gel (Purasil 60 ꢁ, 230–400 Mesh). Analytical thin-layer chro-
matography was performed with 0.25 mm coated commercial silica gel
plates (EMD, Silica Gel 60F254) visualizing at 254 nm, or developed with
ceric ammonium molybdate or anisaldehyde solutions by heating on a
hot plate. 1H NMR spectral data were obtained by using 400 and
3-[(2,6-Dichloro-4-methoxyphenyl)(2,4,6-trichlorophenyl)methoxymeth-
yl]-1-(3,4-dihydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-1H-pyrimi-
dine-2,4-dione (9): DBU (9.0 mL, 60.0 mmol) and 16 (13.08 g, 30.0 mmol)
were added to a stirred solution of uridine (10.98 g, 45.0 mmol) in DMF
(120 mL) at 08C. After 1 h at 08C, the reaction was quenched by addition
of MeOH (24 mL). All volatiles were evaporated in vacuo and the crude
product was purified by silica gel column chromatography with CHCl3/
MeOH (95:5) to afford 9 as an oil (17.62 g, 95%). Rf =0.3 (10% MeOH/
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.67 (d, J=6.8 Hz, 1H), 7.30
(d, J=3.6 Hz, 2H), 6.83 (d, J=4.8 Hz, 2H), 6.57 (s, 1H), 5.77 (d, J=
8.4 Hz, 1H), 5.59 (m, 3H), 4.32 (m, 2H), 4.24 (s, 1H), 3.97 (d, J=
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Capuramycin and Its Analogues
FULL PAPER
12.0 Hz, 1H), 3.90 (s, 1H), 3.83 (m, 1H), 3.78 (s, 3H), 3.05 (s, 1H),
2.20 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=162.9, 159.4, 151.9,
140.1, 136.7, 134.1, 132.5, 129.5, 125.2, 115.5, 101.6, 93.2, 85.7, 77.9, 74.8,
70.4, 69.1, 61.7, 55.7, 36.6, 31.5 ppm; IR: n˜ =3435, 1719, 1665, 1440,
1081 cmꢀ1; HRMS (ESI+): m/z calcd for C24H22Cl5N2O8: 640.9819; found:
640.9825.
Data for 21: Rf =0.45 (60% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3): d=7.31 (d, J=5.5 Hz, 2H), 6.83 (s, 2H), 6.55 (m, 1H), 5.81 (dd,
J=4.5 Hz, 1H), 5.69 (m, 1H), 5.57 (m, 2H), 5.42 (m, 1H), 4.77 (m, 1H),
4.71 (brs, 1H), 4.49 (brs, 1H), 4.33 (m, 2H), 3.77 (s, 3H), 3.45 (s, 3H),
2.19 (s, 3H); 13C NMR (100 MHz, CDCl3): d=169.9, 162.7, 159.4, 151.4,
140.0, 136.7, 134.1, 132.3, 129.5, 125.1, 117.3, 115.5, 102.7, 83.6, 81.1, 77.9,
73.5, 61.4, 59.4, 55.7, 42.4, 23.4 ppm; IR: n˜ =3378, 1755, 1724, 1676, 1463,
1238 cmꢀ1; HRMS (ESI+): m/z calcd for C28H24Cl5N3NaO9: 745.9823;
found: 745.9826.
Synthesis of 18: SnCl2 (1.91 g, 10.0 mmol) was added to a stirred solution
of 9 (12.8 g, 20.0 mmol) in DMF (300 mL). The reaction mixture was
heated to 508C followed by addition of CH2N2 (150 mL, 60.0 mmol, 0.4m
in Et2O). After 1 h, all volatile compounds were evaporated in vacuo.
The selectivity ratio and yield of the monomethyl ethers were deter-
mined, by 1H NMR analyses of the crude mixture, to be a 3:2 ratio in
favor of the desired product. The crude product was dissolved in 5%
H2O/MeCN (1.0 mL). Glyceroacetonide–Oxyma (17; 6.7 g, 30.0 mmol),
EDCI (5.7 g, 30.0 mmol), chloroacetatic acid (3.72 g, 40.0 mmol), and
NaHCO3 (10.1 g, 120.0 mmol) were added to the reaction mixture. After
3 h, the reaction was quenched with aqueous NaHCO3. The aqueous
layer was extracted twice with EtOAc. The combined organic extracts
were dried over Na2SO4 and concentrated in vacuo to yield the desired
ester 18 as a colorless liquid (8.6 g, 59% over the two steps). Rf =0.3
(30% hexanes/EtOAc); 1H NMR (500 MHz, CDCl3): d=7.29 (d, J=
7.5 Hz, 1H), 7.20 (s, 2H), 6.76, (s, 2H), 6.50 (s, 1H), 5.71 (d, J=7.5 Hz,
1H), 5.48 (m, 3H), 4.45 (m, 1H), 4.34 (m, 2H), 4.15 (m, 1H), 4.04 (m,
2H), 3.96 (m, 1H), 3.71 (s, 3H), 3.42 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=166.9, 162.7, 159.3, 151.2, 140.3, 136.7, 134.0, 132.6, 129.5,
125.3, 115.5, 102.1, 79.7, 78.9, 77.8, 72.7, 69.2, 65.0, 58.9, 55.7, 40.6 ppm;
IR: n˜ =3442, 1711, 1660, 1445, 1309, 1070 cmꢀ1; HRMS (ESI+): m/z calcd
for C27H24C6N2NaO9: 754.9481; found: 754.9484.
Synthesis of 10 through
a Mitsunobu reaction: DIAD (22.0 mg,
0.10 mmol) was added to a stirred solution of 21 (72.0 mg, 0.10 mmol),
ClCH2COOH (10.0 mg, 0.10 mmol), Ph3P (26.0 mg, 0.10 mmol), and pyri-
dine (8.0 mL, 0.10 mmol) in toluene (1 mL). After 4 h at RT, all volatile
compounds were removed in vacuo and the crude ester was purified by
silica gel column chromatography. Thiourea (38.0 mg, 0.50 mmol) was
added to a stirred solution of the ester in MeOH (2 mL), and the reac-
tion mixture was heated to 508C. After 4 h at 508C, the reaction was
cooled to RT and MeOH was evaporated in vacuo. The residue was puri-
fied by silica gel column chromatography with hexanes/EtOAc (1:1) to
give 10 as a colorless oil (68.0 mg, 90%). This reaction was also per-
formed for 1.5 g (2.01 mmol) of 21.
Synthesis of 26: [{tBu2SnCl(OH)}2] (0.58 g, 1.0 mmol) was added to a stir-
red solution of 6 (9.0 g, 20.0 mmol) in MeOH (200 mL). Upon comple-
tion, the reaction mixture was concentrated in vacuo and filtered through
a silica gel plug and concentrated to yield the free alcohol in quantitative
yield. Imidate 23[7b] (11.9 g, 24.0 mmol) and then TMSOTf (1.0 mL,
12.0 mmol) were added to the free alcohol in CH2Cl2 (400 mL) at 08C.
After 2 h at 08C, the reaction mixture was quenched with saturated aque-
ous NaHCO3. The aqueous layer was extracted twice with CH2Cl2 and
the combined organic extracts were washed with brine, dried over
Na2SO4, and evaporated. Purification of the crude material by silica gel
column chromatography afforded 26 as a colorless liquid (13.7 g, 92%
Synthesis of 19: Ester 18 was dissolved in pyridine/Ac2O (2:1, 200 mL)
and stirred at RT. Upon completion, all volatile compounds were evapo-
rated in vacuo to afford the desired acetate. The crude material was dis-
solved in MeOH (200 mL) and thiourea (3.8 g, 50.0 mmol) was added to
the mixture. The reaction mixture was stirred at 508C for 4 h and cooled
to RT. All volatile compounds were evaporated in vacuo. Purification by
silica gel column chromatography with hexanes/EtOAc (1:1) yielded the
desired product 19 as an oil (7.8 g, 95% over the two steps). Rf =0.4
(30% hexanes/EtOAc); 1H NMR (500 MHz, CDCl3): d=7.48 (d, J=
7.5 Hz, 1H), 7.30 (s, 2H), 6.83 (s, 2H), 6.57 (s, 1H), 5.77 (d, J=7.5 Hz,
1H), 5.66 (s, 1H), 5.57 (brs, 2H), 5.44 (brs, 1H), 4.18 (brs, 1H), 4.11
(brs, 1H), 4.00 (d, J=11.5 Hz, 1H), 3.80 (s, 1H), 3.77 (s, 3H), 3.41 (s,
3H), 2.25 (brs, 1H), 2.16 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
170.5, 162.6, 159.3, 151.4, 140.3, 136.7, 134.0, 132.6, 129.5, 125.3, 115.5,
102.3, 91.4, 83.0, 80.9, 77.8, 70.1, 69.2, 61.3, 59.0, 55.7, 20.8 ppm; IR: n˜ =
3445, 1719, 1665, 1440, 1302, 1081 cmꢀ1; HRMS (ESI+): m/z calcd for
C27H25Cl5N2NaO9: 720.9871; found: 720.9875.
1
over the two steps). Rf =0.5 (30% EtOAc/hexanes); H NMR (500 MHz,
CDCl3): d=7.83 (dd, J=8.5 Hz, J=25.5 Hz, 1H), 7.37 (m, 2H), 7.18 (dd,
J=7.5 Hz, J=15.0 Hz, 1H), 7.00 (d, J=8.0 Hz, 2H), 6.83 (d, J=5.5 Hz,
2H), 6.21 (s, 0.5H), 6.15 (s, 0.5H), 5.47 (s, 1H), 5.31 (m, 3H), 4.59 (m,
1H), 3.78 (d, J=6.5 Hz, 3H), 3.64 (m, 1H), 3.57 (d, J=9.5 Hz, 1H), 2.32
(s, 3H), 2.07 (s, 3H), 2.00 (s, 3H), 1.97 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=169.9, 159.5, 137.5, 137.2, 136.4, 133.4, 132.7, 132.4, 131.7,
131.6, 129.9, 129.8, 129.0, 126.1, 125.5, 125.0, 115.2, 86.0, 76.1, 71.2, 70.4,
69.7, 69.4, 68.2, 67.1, 55.7, 25.7 ppm; IR: n˜ =3050, 1742, 1613, 1481 cmꢀ1
;
HRMS (ESI+): m/z calcd for C33H32Cl4NaO9S: 769.0389; found:
769.0387.
Synthesis of 24: [{tBu2SnCl(OH)}2] (0.87 g, 1.5 mmol) was added to a stir-
red solution of 22 (13.2 g, 30.0 mmol) in MeOH (300 mL). Upon comple-
tion, the reaction mixture was concentrated in vacuo, filtered through a
silica gel plug and concentrated to yield the free alcohol in 100% yield.
TMSOTf (1.0 mL, 6.0 mmol) was added dropwise to a stirred solution of
the primary alcohol (12.0 g, 30.0 mmol) and imidate 23[7b] (16.3 g,
33.0 mmol) in CH2Cl2 (300 mL) at 08C. After being stirred for 2 h, the re-
action mixture was quenched with saturated aqueous NaHCO3. The
aqueous layer was extracted twice with CH2Cl2 and the combined organic
extracts were washed with brine and dried over Na2SO4. The evaporation
of all volatile compounds in vacuo gave the crude product, which was pu-
rified by silica gel column chromatography to afford 24 as a colorless
liquid (21.9 g, 98%). Rf =0.5 (30% EtOAc/hexanes); 1H NMR
(500 MHz, CDCl3): d=7.91 (m, 1H), 7.27 (m, 7H), 6.85 (s, 2H), 6.23 (d,
J=6.5 Hz, 1H), 5.36 (m, 2H), 5.27 (s, 1H), 5.22 (m, 1H), 4.85 (d, J=
7.5 Hz, 1H), 4.71 (m, 1H), 4.52 (d, J=11.5 Hz, 1H), 4.06 (m, 1H), 3.80
(s, 3H), 3.63 (m, 2H), 2.13 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=170.1, 170.0, 169.9, 169.7, 159.5, 137.4, 137.2,
136.4, 133.5, 132.5, 131.6, 129.1, 128.5, 128.2, 126.1, 125.6, 125.1, 115.2,
96.4, 96.0, 76.9, 70.4, 69.7, 69.3, 69.0, 68.4, 67.6, 66.9, 60.4, 55.7, 20.8 ppm;
Synthesis of 10: DCC (4.0 g, 20.0 mmol) and dichloroacetic acid (1.02 g,
8.0 mmol) were added to a stirred solution of 19 (5.75 g, 8.0 mmol) in
CH2Cl2/DMSO (1:1, 80 mL) at 08C. After 1 h at 08C, the reaction mix-
ture was diluted with CH2Cl2 (60 mL) and washed with aqueous
NaHCO3. The combined organic extracts were dried over Na2SO4 and
concentrated in vacuo to give the crude aldehyde, which was used direct-
ly in the next step after passing through a SiO2 pad. BzCN (1.58 g,
12.0 mmol) was added to a stirred solution of the crude aldehyde in
DMSO/H2O (4:1, 80 mL). After being stirred for 12 h at RT, aqueous
NaHCO3 was added, followed by EtOAc. The aqueous layer was extract-
ed twice with EtOAc. The combined organic extracts were dried over
Na2SO4 and concentrated. The resulting crude material was purified by
silica gel column chromatography with EtOAc/hexanes (2:3) to give 10
(3.7 g, 63%) and 21 (1.88 g, 32%).
Data for 10: Rf =0.4 (60% EtOAc/hexanes); 1H NMR (500 MHz,
CDCl3): d=7.31 (d, J=7.5 Hz, 2H), 6.84 (d, J=10.0 Hz, 2H), 6.56 (s,
1H), 5.83 (dd, J=5.5, 6.0 Hz, 1H), 5.58 (m, 1H), 5.40 (brs, 1H), 5.34
(brs, 1H), 5.23 (brs, 1H), 4.67 (d, J=11.0 Hz, 1H), 4.55 (brs, 1H), 4.35
(s, 1H), 3.77 (s, 3H), 3.40 (s, 3H), 2.18 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=170.2, 162.2, 159.4, 151.7, 142.2, 136.7, 134.2, 132.3, 129.6,
124.9, 117.2, 115.6, 103.1, 95.1, 84.2, 78.5, 70.4, 69.3, 61.7, 59.3, 55.8, 43.1,
21.9 ppm; IR: n˜ =3378, 1755, 1724, 1676, 1463, 1238 cmꢀ1; HRMS (ESI+
): m/z calcd for C28H24Cl5N3NaO9: 745.9823; found: 745.9826.
IR: n˜ =3055, 1744, 1615, 1484 cmꢀ1 HRMS (ESI+): m/z calcd for
;
C33H32Cl4NaO10: 753.0618; found: 753.0615.
Synthesis of 11: Pd/C (4.5 g, 10 wt%) was added to a stirred solution of
24 (10.8 g, 15.0 mmol) in MeOH (600 mL) under N2. H2 gas was intro-
duced through a double-folded balloon and the reaction mixture was stir-
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M. Kurosu et al.
red for 4 h under H2. Upon completion, the solution was filtered through
Celite and eluted with EtOAc. The organic solvent was evaporated to
form the crude product, which was used directly without further purifica-
tion. The crude product was dissolved in dry CH2Cl2, followed by the ad-
dition of CCl3CN (15.0 mL) and DBU (0.45 mL). The mixture was stirred
for 2 h. Upon completion, all volatile compounds were evaporated in
vacuo. Purification by silica gel column chromatography afforded the de-
sired product 11 as a colorless oil (11.2 g, 95%). Rf =0.7 (30% EtOAc/
hexanes); 1H NMR (500 MHz, CDCl3): d=8.71 (s, 1H), 7.87 (dd, J=7.5,
10.0 Hz, 1H), 7.26 (m, 2H), 6.83 (s, 2H), 6.26 (d, J=8.5 Hz, 1H), 6.19 (s,
1H), 5.44 (m, 3H), 4.23 (m, 1H), 3.78 (s, 3H), 3.74 (m, 1H), 3.64 (m,
1H), 2.18 (s, 1.5H), 2.16 (s, 1.5H), 2.01 (s, 3H), 1.97 (s, 1.5H), 1.94 ppm
(s, 1.5H); 13C NMR (100 MHz, CDCl3): d=169.9, 169.8, 169.4, 159.7,
159.5, 137.3, 136.4, 133.4, 132.3, 131.6, 131.4, 129.0, 128.8, 126.1, 125.8,
125.4, 125.0, 115.2, 94.6, 94.3, 90.6, 76.5, 75.8, 72.8, 71.8, 69.0, 68.2, 68.0,
al was partitioned between EtOAc (5 mL) and HCl (1 n, 5 mL). The
water phase was extracted twice with EtOAc. The combined organic ex-
tracts were dried over Na2SO4 and concentrated in vacuo. Purification by
silica gel column chromatography (hexanes/acetone, 1:3) afforded the de-
sired diastereomers 28 and 29 as an amorphous solid (31.0 mg each, 98%
total yield). This reaction was performed with 1 g of rac-13 to provide 28
(1.24 g).
Data for 28: Rf =0.34 (95% CHCl3/MeOH); [a]2D0 = +77 (c=0.2 in
MeOH); 1H NMR (400 MHz, CD3OD): d=7.52 (m, 5H), 7.45 (m, 2H),
7.36 (m, 4H), 7.20 (m, 3H), 6.91 (s, 2H), 6.71 (m, 1H), 5.38 (d, J=
8.8 Hz, 1H), 3.82 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=168.6,
168.2, 160.0, 154.9, 138.6, 137.4, 134.5, 133.6, 132.4, 131.6, 130.9, 130.1,
129.9, 128.5, 127.9, 126.7, 125.1, 124.5, 121.6, 115.5, 71.9, 69.5, 56.0 ppm;
IR: n˜ =3441, 1936, 1711, 1413, 1354, 1222, 1150 cmꢀ1; HRMS (ESI+): m/z
calcd for C30H21Cl4N3NaO4: 652.0154; found: 652.0150; HPLC: retention
time, 8.5 min (de>99%).
Data for 29: Rf =0.30 (95% CHCl3/MeOH); [a]2D0 = +181 (c=0.2 in
MeOH); 1H NMR (400 MHz, CD3OD): d=7.48 (d, J=16.8 Hz, 1H),
7.46 (m, 4H), 7.40 (m, 1H), 7.38 (m, 5H), 7.20 (m, 2H), 7.12 (m, 1H),
6.86 (s, 2H), 6.82 (m, 1H), 5.35 (d, J=8.0 Hz, 1H), 3.78 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=170.6, 168.1, 159.7, 154.7, 138.4, 137.2,
134.4, 133.4, 132.2, 131.5, 130.7, 129.9, 129.7, 128.3, 127.7, 126.4, 124.8,
124.3, 121.3, 115.3, 71.7, 69.0, 55.7 ppm; IR: n˜ =3441, 1936, 1711, 1413,
1354, 1222, 1150 cmꢀ1; HRMS (ESI+): m/z calcd for C30H21Cl4N3NaO4:
652.0154; found: 652.0151; HPLC: retention time, 8.0 min (de>99%).
67.1, 66.0, 55.8, 55.6, 20.7 ppm; IR: n˜ =3050, 1755, 1680, 1622, 1480 cmꢀ1
;
HRMS (ESI+): m/z calcd for C28H26Cl7NNaO10
: 805.9245; found:
805.9249.
Synthesis of 12: Molecular sieves (MS; 3 ꢁ, 10.0 g) were added to a stir-
red solution of 10 (2.90 g, 4.0 mmol) and 11 (6.26 g, 8.0 mmol) in dry
CH2Cl2 (50 mL). The reaction was stirred for 30 min at RT. The reaction
mixture was cooled to ꢀ58C, followed by dropwise addition of BF3·OEt2
(1.48 mL, 12.0 mmol). After being stirred for 3 h at ꢀ58C, the reaction
was quenched with aqueous NaHCO3. The reaction mixture was passed
through a SiO2 pad and eluted with CH2Cl2. The organic layer was sepa-
rated and dried over Na2SO4 and concentrated in vacuo. Purification by
silica gel column chromatography afforded 12 as an oil (4.04 g, 75%).
Rf =0.45 (60% EtOAc/hexanes); 1H NMR (500 MHz,CDCl3): d=7.98
(dd, J=21, 7.0 Hz, 1H), 7.30 (s, 4H), 7.25 (s, 1H), 6.84 (s, 4H), 6.56 (s,
1H), 6.27 (s, 0.5H), 6.17 (s, 0.5H), 5.94 (d, J=7.5 Hz, 1H), 5.88 (m, 1H),
5.58 (m, 3H), 5.39 (brs, 1H), 5.25 (d, J=10.5 Hz, 1H), 5.22 (s, 1H), 5.00
(d, J=20.5 Hz, 1H), 4.60 (m, 1H), 4.38 (s, 1H), 4.19 (m, 1H), 3.82 (m,
1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.66 (m, 1H), 3.45 (s, 3H), 2.20 (s, 3H),
2.18 (s, 1.5H), 2.16 (s, 1.5H), 2.11 (s, 1.5H), 2.06 (s, 1.5H), 2.02 (s, 3H),
1.97 (s, 1.5H), 1.96 ppm (s, 1.5H); 13C NMR (100 MHz, CDCl3): d=
169.6, 162.3, 159.6, 149.8, 137.1, 136.9, 135.8, 134.4, 133.9, 133.0, 131.7,
131.1, 129.7, 129.3, 126.3, 125.1, 124.3, 115.4, 114.7, 103.8, 95.9, 89.7, 89.3,
80.9, 80.1, 73.1, 72.1, 71.8, 68.9, 68.1, 65.7, 63.5, 59.2, 55.8, 29.7, 20.6 ppm;
IR: n˜ =3338, 2921, 2250, 1737, 1669, 1465, 1221 cmꢀ1; HRMS (ESI+): m/z
calcd for C54H48Cl9N3NaO18: 1367.9968; found: 1367.9975.
(S)-3-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one [(S)-13]:
Carbamate 28 (30.0 mg, 0.05 mmol) was dissolved in TFA/CH2Cl2 (1:4,
2 mL) under N2. After 1 h at RT, the reaction mixture was concentrated
in vacuo. The residue was partitioned between aqueous NaHCO3 and
CHCl3/MeOH (10:1). The aqueous layer was back extracted with CHCl3/
MeOH (10:1). The combined organic extracts were dried over Na2SO4
and concentrated in vacuo. Purification of the crude material by silica gel
column chromatography afforded the desired product (S)-13 as an amor-
phous solid (12.0 mg, 95%) and the byproduct ester 30 as an oil
(24.0 mg, 100%).
Data for (S)-13: [a]D20 =ꢀ220 (c=0.2 in CH2Cl2); 1H NMR (400 MHz,
[D6]DMSO): d=10.74 (brs, 1H), 7.64 (m, 1H), 7.50 (m, 5H), 7.33 (m,
2H), 7.25 (m, 1H), 4.29 (s, 1H), 2.60 ppm (brs, 2H); 13C NMR
(100 MHz, [D6]DMSO): d=170.5, 164.7, 138.8, 138.6, 131.6, 130.1, 129.3,
128.2, 126.6, 122.8, 121.2, 70.4 ppm; IR: n˜ =3389, 2935, 1688, 1519, 1251,
1081 cmꢀ1; HRMS (ESI+): m/z calcd for C15H13N3NaO: 274.0956; found:
274.0958.
Synthesis of 8: InCl3 (0.4 g, 1.8 mmol) and acetaldoxime (0.67 mL,
10.8 mmol) was added to a stirred solution of 12 (2.42 g, 1.8 mmol) in tol-
uene (180 mL). The reaction mixture was heated at 708C for 4 h. Upon
completion, the reaction was cooled to RT and all volatile compounds
were evaporated. The crude material was passed through a short SiO2
pad. The amide was dissolved in TFA/CH2Cl2 (1:2, 75 mL) and stirring
was continued for 1 h at RT. The reaction mixture was concentrated in
vacuo. The crude product was purified by silica gel column chromatogra-
phy to afford 8 as an amorphous solid (1.1 g, 96% over the two steps).
Rf =0.3 (95% CHCl3/MeOH); [a]2D0 = +75 (c=0.4 in MeOH); 1H NMR
(500 MHz, CD3OD): d=7.83 (d, J=8.0 Hz, 1H), 5.98 (d, J=1.5 Hz, 1H),
5.91 (d, J=8.5 Hz, 1H), 5.52 (s, 1H), 5.40 (t, J=5.0 Hz, 1H), 5.28 (m,
2H), 5.01 (s, 1H), 4.49 (d, J=3.0 Hz, 1H), 4.40 (m, 1H), 4.20 (t, J=
4.0 Hz, 1H), 3.91, (brs, 1H), 3.61 (m, 3H), 3.40 (s, 3H), 2.13 (s, 6H), 2.04
(s, 3H), 2.00 ppm (s, 3H); 13C NMR (100 MHz, CD3OD): d=172.8,
172.0, 171.7, 171.6, 166.3, 152.2, 142.1, 103.9, 98.2, 89.4, 83.8, 79.4, 76.7,
75.2, 73.9, 71.1, 70.5, 67.2, 62.0, 59.4, 20.8, 20.6 ppm; IR: n˜ =3413, 1710,
Data for 30: Rf =0.6 (95% hexanes/EtOAc); 1H NMR (500 MHz,
CDCl3): d=7.70 (s, 1H), 7.46 (s, 1H), 7.25 (s, 2H), 6.94 (s, 2H),
3.83 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=172.0, 160.5, 136.8,
135.8, 134.7, 130.9, 126.9, 122.1, 115.6, 74.3, 55.9 ppm; IR: n˜ =1721, 1438,
1410, 1325 cm-1; HRMS (ESI+): m/z calcd for C16H9Cl4F3NaO3:
470.9126; found: 470.9124.
Synthesis of 35: A solution of SO3·pyridine (0.252 g, 1.60 mmol) in dry
DMSO (5 mL) was added to a vigorously stirred solution of alcohol 8
(0.20 g, 0.32 mmol) in dry DMSO (10 mL) and dry Et3N (5 mL) at 208C
under N2. After 1 h at RT, the reaction mixture was quenched with water
(0.1 mL). The DMSO and all volatile compounds were removed by evap-
oration in vacuo to give the crude aldehyde 31, which was used without
purification in the next step.
A solution of NaH2PO4 (11.0 mg,
0.10 mmol) and NaClO2 (9.0 mg 0.10 mmol) in H2O (0.8 mL) was added
to a vigorously stirred solution of crude aldehyde 31 in tBuOH (0.8 mL)
and 2-methyl-2-butene (0.60 mL) at RT. After 1 h at RT, the reaction
mixture was extracted with EtOAc, then CHCl3/MeOH (10:1). The com-
bined organic extracts were dried over Na2SO4 and concentrated in
vacuo to give the crude acid 32. EDCI (90.0 mg, 0.48 mmol), glyceroace-
tonide–Oxyma (17, 0.114 g, 0.48 mmol), and NaHCO3 (0.102 g,
1.20 mmol) were sequentially added to a stirred solution of the crude
acid 32 (55.0 mg, 96.0 mmol) and (S)-13 (48.0 mg, 192.0 mmol) in DMF/
H2O (2:1, 3 mL). After 4 h at RT, all volatile compounds were evaporat-
ed and the resulting slurry was partitioned between EtOAc and aqueous
NaHCO3. The aqueous layer was extracted three times with EtOAc. The
combined organic extracts were dried over Na2SO4 and concentrated in
1680, 1223, 1066 cmꢀ1; HRMS (ESI+): m/z calcd for C25H33N3NaO16
:
654.1753; found: 654.1746.
(2-Oxo-5-phenyl-2,3-dihydro-1H-benzo[e]ACTHNUTRGNEU[GN 1,4]diazepin-3-yl)carbamic
acid (2,6-dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methyl ester (28,
29): Racemic 3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one
[(ꢁ)-13] was synthesized by following the reported procedure.[14] (S)-(2,6-
Dichloro-4-methoxyphenyl)(2,4-dichlorophenylmethyl-N-succinimidyl
carbonate [(S)-14; 58.0 mg, 0.20 mmol] and iPr2NEt (70.0 mL, 0.40 mmol)
were added to a stirred solution of (ꢁ)-13 (25.0 mg, 0.10 mmol) in ace-
tone/H2O (3:1, 3 mL) at RT. Upon completion after 4 h, the reaction
mixture was concentrated in vacuo to remove acetone. The crude materi-
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Capuramycin and Its Analogues
FULL PAPER
vacuo to give the crude product, which was purified by silica gel column
chromatography, to afford 35 as an amorphous solid (66.7 mg, 85% from
8). [a]2D0 = +99 (c=0.2 in MeOH); 1H NMR (500 MHz, CD3OD): d=
7.91 (s, 1H), 7.86 (m, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.53 (m, 2H), 7.43 (m,
2H), 7.31 (m, 2H), 7.22 (m, 1H), 5.98 (s, 2H), 5.96 (s, 1H), 5.50 (s, 1H),
5.41 (s, 1H), 5.09 (m, 1H), 4.97 (m, 1H), 4.74 (m, 2H), 4.37 (s, 1H), 4.18
(m, 1H), 3.89 (m, 2H), 3.76 (m, 2H), 3.44 (s, 1H), 3.41 (s, 3H), 2.14 (s,
3H), 2.11 (s, 3H), 2.05 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
172.3, 171.6, 169.3, 166.1, 152.1, 141.5, 140.1, 133.4, 132.1, 131.8, 130.9,
129.4, 128.7, 124.7, 122.5, 104.0, 98.1, 88.7, 82.3, 82.9, 79.5, 76.7, 75.9, 73.5,
71.8, 70.9, 70.4, 65.1, 62.2, 59.5, 20.6 ppm; IR: n˜ =3389, 2935, 1688, 1519,
1251, 1081 cmꢀ1; HRMS (ESI+): m/z calcd for C38H38N6NaO15: 841.2293;
found: 841.2296.
Acknowledgements
The National Institutes of Health is greatly acknowledged for financial
support of this work (AI084411). We also thank the University of Ten-
nessee for generous financial support. NMR data were obtained on in-
struments supported by the NIH Shared Instrumentation Grant.
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Synthesis of UT-01309 (2): LiOH (0.08 mL, 1m in H2O) was added to a
stirred solution of 34 (13.0 mg, 16.0 mmol) in THF/H2O (10:1, 0.4 mL) at
08C. After being stirred for 1 h at 08C, the reaction mixture was
quenched with THF/AcOH (10:1, 0.08 mL). All volatile compounds were
evaporated in vacuo. Purification by silica gel PTLC (MeOH/CHCl3, 1:2)
afforded 2 as an amorphous solid (10.60 mg, 95%). Rf =0.4 (70% CHCl3/
MeOH); [a]2D0 = +85 (c=0.1 in MeOH); 1H NMR (500 MHz, CD3OD):
d=7.88 (d, J=8.5 Hz, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.41 (m, 3H), 7.33
(m, 2H), 7.22 (m, 3H), 6.00 (d, J=4.0 Hz, 1H), 5.81 (d, J=3.0, 1H), 5.64
(d, J=8.5 Hz, 1H), 5.33 (s, 1H), 5.19 (d, J=6.0 Hz, 1H), 4.67 (s, 1H),
4.43 (d, J=6.5 Hz, 1H), 4.35 (d, J=5.5 Hz, 1H), 4.30 (m, 1H), 3.89 (t,
J=5.5 Hz, 1H), 3.74 (t, J=4.0 Hz, 1H), 3.40 ppm (s, 3H); 13C NMR
(100 MHz, CD3OD): d=179.1, 173.8, 166.3, 164.9, 152.3, 142.0, 140.0,
133.6, 132.2, 131.9, 131.0, 129.4, 128.6, 124.8, 122.7, 102.7, 100.7, 91.1,
83.6, 80.0, 76.3, 75.8, 74.1, 72.7, 71.5, 70.6, 68.3, 62.8, 58.4 ppm; IR: n˜ =
3411, 2933, 1696, 1515, 1279 cmꢀ1
;
HRMS (ESI+): m/z calcd for
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C32H32N6NaO12: 715.1976; found: 715.1972.
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Synthesis of 34: EDCI (90.0 mg, 0.48 mmol), glyceroacetonide–Oxyma
(17, 0.114 g, 0.48 mmol), and NaHCO3 (0.102 g, 1.20 mmol) was sequen-
tially added to a stirred solution of the acid 32 (55.0 mg, 96.0 mmol) and
33 (31.0 mg, 192.0 mmol) in H2O (1.0 mL). After being stirred for 4 h at
RT, all volatile compounds were evaporated and the resulting slurry was
partitioned between EtOAc and aqueous NaHCO3. The aqueous layer
was extracted three times with EtOAc. The combined organic extracts
were dried over Na2SO4 and concentrated in vacuo to give the crude
product. For data collection, a portion was purified by silica gel column
chromatography to afford 34 as an amorphous solid (57.0 mg, 85% from
8). [a]2D0 = +103 (c=0.3 in CHCl3); 1H NMR (500 MHz, CDCl3): d=9.72
(brs, 1H), 7.96 (d, J=6.8 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.39 (brs,
1H), 7.20 (brs, 1H), 6.23 (brs, 1H), 6.05 (d, J=3.2 Hz, 1H), 5.80 (s, 1H),
5.69 (t, J=3.6 Hz, 1H), 5.49 (s, 1H), 5.29 (m, 2H), 4.61 (dd, J=7.2,
10.8 Hz, 1H), 4.55 (s, 1H), 4.39 (d, J=5.6 Hz,1H), 4.01 (s, 1H), 3.30 (s,
2H), 3.25 (s, 3H), 2.11 (s, 6H), 2.06 (s, 3H), 1.86 (m, 2H), 1.60 (m, 3H),
1.40 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=176.1, 170.3, 170.2,
170.12, 170.08, 169.03, 169.00, 163.5, 159.1, 150.8, 144.5, 140.6, 104.1,
103.8, 98.0, 82.0, 73.3, 65.2, 63.1, 59.1, 52.0, 42.4, 31.6, 28.8, 20.95, 20.88,
20.83 ppm; IR: n˜ =3379, 2930, 1691, 1509, 1250, 1070 cmꢀ1; HRMS (ESI+
): m/z calcd for C29H8N5NaO15: 718.2178; found: 718.2186.
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Synthesis of capuramycin (1): LiOH (0.08 mL, 1m in H2O) was added to
a stirred solution of 34 (11.0 mg, 16.0 mmol) in THF/H2O (10:1, 0.4 mL)
at 08C. After being stirred for 1 h at 08C, the reaction mixture was
quenched with THF/AcOH (10:1, 0.08 mL). All volatile compounds were
evaporated in vacuo. Purification by silica gel PTLC (MeOH/CHCl3, 1:2)
afforded the desired product 1 as an amorphous solid (8.60 mg, 95%).
Rf =0.4 (70% CHCl3/MeOH); [a]2D0 = +98 (c=0.1 in H2O); 1H NMR
(400 MHz, CD3OD): d=7.71 (d, J=8.0 Hz, 1H), 5.97 (s, 1H), 5.82 (d,
J=8.0 Hz, 1H), 5.73 (s, 1H), 5.35 (s, 1H), 4.59 (d, J=11.2 Hz, 2H), 4.47
(s, 1H), 4.44 (d, J=4.8 Hz, 1H), 4.34 (s, 1H), 4.15 (s, 1H), 3.71 (t, J=
4.8 Hz, 1H), 3.26 (s, 3H), 1.97 (m, 6H), 1.32 ppm (m, 2H). 13C NMR
(100 MHz, D2O): d=176.3, 173.0, 166.1, 161.4, 151.2, 141.5, 141.0, 109.4,
101.8, 99.3, 90.1, 81.6, 78.1, 75.5, 71.9, 64.7, 61.7, 57.8, 52.2, 41.4, 30.3,
27.3 ppm; IR: n˜ =3411, 2933, 1696, 1515, 1279 cmꢀ1; HRMS (ESI+): m/z
calcd for C23H31N5NaO12: 592.1867; found: 592.1864.
Chem. Eur. J. 2013, 00, 0 – 0
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Received: June 21, 2013
Published online: && &&, 0000
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Capuramycin and Its Analogues
FULL PAPER
Battling TB: Capuramycin and its con-
geners (see scheme) are considered to
be important lead molecules for the
development of a new drug for multi-
drug-resistant Mycobacterium tubercu-
losis infections. Efficient synthesis of
capuramycin and its analogues by
using new protecting groups for the
uridine ureido nitrogen and primary
alcohol was accomplished.
Total Synthesis
Y. Wang, S. Siricilla, B. A. Aleiwi,
M. Kurosu* ................... &&&& — &&&&
Improved Synthesis of Capuramycin
and Its Analogues
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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