Total synthesis and biological evaluation of pacidamycin D and its 3′-hydroxy analogue

Article abstract of DOI:10.1021/jo202159q

Full details of the total synthesis of pacidamycin D (4) and its 3′-hydroxy analogue 32 are described. The chemically labile Z-oxyacyl enamide moiety is the most challenging chemical structure found in uridylpeptide natural products. Key elements of our approach to the synthesis of 4 include the efficient and stereocontrolled construction of the Z-oxyvinyl halides 6 and 7 and their copper-catalyzed cross-coupling with the tetrapeptide carboxamide 5, a thermally unstable compound containing a number of potentially reactive functional groups. This synthetic route also allowed us to easily prepare 3′-hydroxy analogue 32. The assemblage by cross-coupling of the Z-oxyvinyl halide 6 and the carboxamide 5 at a late stage of the synthesis provided ready access to a range of uridylpeptide antibiotics and their analogues, despite their inherent labile nature with potential epimerization, simply by altering the tetrapeptide moiety.

Full text of DOI:10.1021/jo202159q

Article
pubs.acs.org/joc
Total Synthesis and Biological Evaluation of Pacidamycin D and
Its 3′-Hydroxy Analogue
Kazuya Okamoto,† Masahiro Sakagami,† Fei Feng,‡ Hiroko Togame,† Hiroshi Takemoto,†
Satoshi Ichikawa,*,§ and Akira Matsuda§
†Shionogi Innovation Center for Drug Discovery, Shionogi & Co., Ltd., Kita-21 Nishi-11, Kita-ku, Sapporo 001-0021, Japan
‡Faculty of Advanced Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, 001-0021, Japan
§Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
S
* Supporting Information
ABSTRACT: Full details of the total synthesis of pacidamycin
D (4) and its 3′-hydroxy analogue 32 are described. The
chemically labile Z-oxyacyl enamide moiety is the most
challenging chemical structure found in uridylpeptide natural
products. Key elements of our approach to the synthesis of 4
include the efficient and stereocontrolled construction of the
Z-oxyvinyl halides 6 and 7 and their copper-catalyzed cross-
coupling with the tetrapeptide carboxamide 5, a thermally
unstable compound containing a number of potentially reactive functional groups. This synthetic route also allowed us to easily
prepare 3′-hydroxy analogue 32. The assemblage by cross-coupling of the Z-oxyvinyl halide 6 and the carboxamide 5 at a late
stage of the synthesis provided ready access to a range of uridylpeptide antibiotics and their analogues, despite their inherent
labile nature with potential epimerization, simply by altering the tetrapeptide moiety.
transferase (MraY) catalyzes the first step of the lipid-linked cycle
of the reactions, where UDP-MurNAc-pentapeptide is attacked by
the undecaprenol monophosphate in the bacterial cell membrane
providing lipid I.14−17 Lipid I anchored to the cell membrane is
further glycosylated by N-acetylglucosamine to afford lipid II.
Therefore, the MraY is an essential enzyme in bacteria, and 1 is a
strong inhibitor of MraY (IC50 = 0.05 μg/mL).18,19 Because of
their structural and biological similarities, it has been suggested
that 2−4 may share the same mode of action as 1. Consequently,
uridylpeptide antibiotics, with a novel mode of action, are expected
to be good candidates as antibacterial agents against P. aeruginosa.
Intrigued by the promising biological activity, structure−activity
relationship studies have been conducted by several groups.20−27
However, no total synthesis of 1−4 has yet been accomplished.
Uridylpeptide antibiotics share a common structural feature.
Namely, they consist of a 3′-deoxyuridine with a Z-enamide
structure at the 4′,5′-positions, a tetrapeptide moiety containing a
nonproteinogenic amino acid, and α,β-diaminobutyric acid, a urea
linkage connecting two amino acids at the C-terminus. The α,
β-diaminobutyric acid plays a pivotal role connecting the
N-terminal amino acid, the ureadipeptide, and the 3′-deoxyuridine
moieties (Figure 1). The potential difficulty in the total synthesis
of this class of natural products may be the chemically labile
Z-oxyacyl enamide moiety, which is a particularly challenging
chemical structure. The analogues possessing the enamide
functionality have been prepared only by a chemogenetic approach
INTRODUCTION
■
Bacterial pathogens inevitably develop severe resistance to
every new antibacterial drug launched. Multi-drug-resistant
Pseudomonas aeruginosa is one of the most problematic bacteria
because of the limited number of effective drugs in the clinic. A
class of uridylpeptide antibiotics (Figure 1, 1−4) has shown
potent and selective antibacterial activity against strains of
P. aeruginosa.1,2 This class contains mureidomycins,3−6 napsamy-
cins,7 pacidamycins,8−11 and recently identified sansanmy-
cins.12,13 Among the class of uridylpeptide antibiotics, the
mureidomycins (1), isolated from Streptomyces flavidoviridens
SANK 60486, showed the most potent antibacterial activity
against strains of Pseudomonas with minimum inhibitory
concentrations (MICs) ranging from 0.1 to 3.12 μg/mL in
vitro, also protecting mice against P. aeruginosa infection.3−6
The pacidamycins (4) were isolated from the fermentation
broth of the Streptomyces coeruleorubiduns strain and possess a
Trp residue at the C-terminus. They also exhibit anti-P.
aeruginosa activity with MICs ranging from 1.5 to 12.5
μg/mL.8−11 The mode of action was well studied for 1, and
they interfere the bacterial cell wall biosynthesis in a different
manner to β-lactams and vancomycin. Peptidoglycan biosyn-
thesis consists of three stages, including the formation of uridine
diphosphate N-acetylmuraminylpentapeptide (UDP-MurNAc-
pentapeptide) in cytoplasm, the membrane-anchored synthesis
of lipid I and lipid II, a precursor to the peptide glycan, and
polymerization of the resulting lipid II by transpeptidation and
transglycosidation (Figure 2). The second and the third stages are
involved in a lipid cycle, and phospho-MurNAc-pentapeptide
Received: October 20, 2011
Published: December 22, 2011
© 2011 American Chemical Society
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Figure 1. Structure of uridylpeptide natural products.
Figure 2. Biosynthesis of peptidoglycan precursor.
combining genetics and organic synthesis28 and by biosynthesis,29
owing to recent elucidation of biosynthetic pathway of uridylpeptide
antibiotics.30,31 The acyl enamide structure can be synthesized by
addition of amides to alkynes,32 acylation of imines,33 Curtius
rearrangement of α,β-unsaturated acyl azides,34 condensation
of carbonyl derivatives with amines,35 oxidative amidation of
alkenes,36 oxidative decarboxylation−elimination of N-acyl-
α-amino acids,37 reductive amidation of ketones,38 aza-Wittig
reaction of acyl azides with aldehydes,39 isomerization of
N-allylamides,40 and cross-coupling of amides with vinyl halides.41
The methods applicable to the synthesis of uridylpeptide
antibiotics 1-4 are quite limited among them. Recently we
accomplished the first total synthesis of 4.42 Herein we describe
the full details of the total synthesis of 4 and its 3′-hydroxy
analogue 32. Our retrosynthetic approach to 4 includes two key
reactions, which are an efficient and stereocontrolled construc-
tion of the Z-oxyvinyl iodides 6 and 7, and their copper-
catalyzed cross-coupling with the tetrapeptide carboxamide 5
(Scheme 1). Taking the chemical lability in consideration, we
planned to construct the Z-oxyacyl enamide moiety in the late
stage of the synthesis. The tetrapeptide 5 contains a number of
potentially reactive functional groups and renders selective
synthetic modification difficult. The challenge of our synthetic
approach is whether the C−N cross-coupling proceeds with 5,
and if so, whether the selective reaction at the N-unsubstituted
carboxamide moiety proceeds in the presence of several
potential reactive sites, including the primary amide, the
carbamate, and the urea groups. The pacidamycins as well as
the other congeners described in Figure 1 are 3′-deoxyuridine
derivatives. Owing to the intriguing biological activity of the
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After deprotection of the Boc group of 8, the liberated amine 9
was condensed with 10 in the presence of i-Pr2NEt in DMF to
give the tripeptide 11. N−O bond cleavage of 11 was achieved
by catalytic hydrogenation to give the secondary amine 12 in
quantitative yield over three steps. The amine 12 was further
reacted with the Pfp ester of the N-Boc-L-Ala 13 to afford the
tetrapeptide carboxylic acid 14. Conversion of the carboxyl
group of 14 to the carboxamide was then investigated. First,
amidation of a mixed anhydride prepared from 14 by either
EtO2CCl or N,N′-carbonyldiimidazole with 28% aq ammonia
was conducted. However, the desired 5 was obtained in mode-
rate isolated yields of 5 (47−50%). The amidation was next
focused on the use of peptide coupling reagents. Treatment of
14 with EDCI and HOBt in THF followed by NH3 in dioxane
at rt. gave a complex mixture of products. Optimization of the
reaction conditions led us to find the conditions employing
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hex-
afluorophosphate (HATU), NH4Cl, N-methylmorpholine
(NMM) in DMF to give 5 in 82% yield.
Scheme 1. Retrosynthetic Analysis of Pacidamycin D (4)
As for the uridine derivatives, the coupling partners of 5, the
synthetic study began with the preparation of oxyvinyl halides
7a and 7b, which are more accessible than that of the 3′-
deoxyuridine derivative (Scheme 3). We first applied the method
corresponding ribo-type, we decided to prepare an analogue
such as 32 (Scheme 6) in addition to 4. Accordingly, our first
plan for the synthesis of 4 was the first construction of a
ribo-type analogue followed by removal of the allylic 3′-hydroxyl
group at the uridine moiety by Barton deoxygenation after the
cross-coupling reaction.
Scheme 3. Preparation of Ribo-Type Vinyl Halides
RESULTS AND DISCUSSION
■
By using the known carboxylic acid 829 and the pentafluor-
ophenyl (Pfp) ester of the unsymmetrical urea 10,43 the tetra-
peptide carboxamide 5 was prepared as shown in Scheme 2.
Scheme 2. Preparation of Tetrapeptide Carboxamide 5
developed by Tanaka, et al.44 The exo-olefin derivative of the
uridine 1545,46 was reacted with PhSCl generated from PhSH
and NCS, and the resulting 4′-chloro-5′-phenylthio intermedi-
ate was treated with DBU to eliminate the hydrogen
chloride47,48 and provide the desired Z-phenylthio derivative
16. The geometry of the olefin was confirmed by a 500 MHz
NOE experiment in CDCl3, where the correlation to H-3′ was
observed upon irradiation at H-5′ (7.8%). The desired 16 was
obtained stereoselectively; however, the yield was low (22%).
Protection of the N-3 position of the uracil moiety improved
the yield of the phenylthiolation. Namely, benzyloxymethyl
(BOM) protection of 15 (BOMCl, DBU, DMF, rt, quant)
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followed by the same addition−elimination sequence on 17
gave in 84% yield 18, which was identical to that obtained from
the BOM protection of the N-3 position of 16. Substitution of
the phenylthio group with the tributylstannyl group by a radical
reaction (Bu3SnH, AIBN, i-Pr2NEt, toluene, 83%) gave the
Z-stannyl olefin 19 selectively. The observed formation of only
the Z-isomer 19 from 18 was based on the conformational
preference of the intermediate C4′-radical as proposed in
Tanaka’s study.44 Halogenation of 19 with NBS or I2 cleanly
provided the corresponding Z-vinyl bromide 7a (93%) or
Z-vinyl iodide 7b (92%), respectively, with retention of the
olefin geometry.49
Table 1. Direct Iodination of 23
temp
(°C)
isolated yield
(%, 6/26/27)
ratio
entry
solvent
(6/26/27)
1
2
3
4
5
6
THF
0
26/14/31
28/10/39
34/12/10
42/10/16
53/9/25
44/9/30
36/13/51
37/20/43
61/21/18
62/15/23
61/10/29
53/11/36
CH2CI2
MeCN
MeCN
MeCN
MeCN
rt
rt
0
−20
−40
(6/26/27 = 36/13/51). The geometry of the desired Z-olefin 6
was confirmed by a 500 MHz NOE experiment in CDCl3,
where the correlation to H-3′ was observed upon irradiation at
H-5′ (4.8%). The observed decrease of the selectivity could be
attributed to the absence of a substituted hydroxyl group at the
3′-position. The effect of the solvent was then investigated to
improve the selectivity. Little improvement was observed for
the reaction in CH2Cl2 (entry 2). On the other hand, when
MeCN, a polar and Lewis basic solvent, was used, the desired
Z-vinyl iodide 6 was obtained as the major product (entries 3−6).
The reaction at the lower temperature improved not only the
total chemical yield (87%) but also the Z/E selectivity with a
ratio of 61/10, and the desired 6 was obtained in 53% isolated
yield (entry 5). Since the direct iodination of the Z-exo-olefin
23 was successful in obtaining 6, this procedure was applied to
the preparation of 7b from 17 (Scheme 3). In this case, the
iodination by IDCT afforded 7b as the sole product in 79%
yield. The observed stereochemical outcome could be
rationalized as described in Scheme 5, that is the reaction of
The Z-vinyl iodide of the 3′-deoxyuridine derivative 6 was
prepared as described in Scheme 4. After protecting group
Scheme 4. Preparation of 3′-Deoxyvinyl Iodide 6
Scheme 5. Proposed Stereoselectivity in the Direct
Iodination
manipulation of the known 3′-deoxyuridine derivative 2050
(BOMCl, DBU, DMF, 83%, aq AcOH, 60 °C, 85%), the
primary alcohol of 21 was converted to the iodo group
(I2, PPh3, imidazole, THF, 99%). Elimination of HI from 22
was promoted by DBU to afford the exo-olefin 23 in 93% yield.
In a manner similar to the synthesis of 18, the exo-olefin 23 was
reacted with PhSCl. Although the Z-phenylthio derivative 24
was produced, 24 was not isolated in a pure form. The sub-
sequent conversion of the phenylthio group of 24 to the tri-
butylstannyl group did not proceed well, and the corresponding
25 was obtained in only 3% yield over two steps. In order to
overcome these limitations, extensive efforts were investigated
to obtain the desired Z-vinyl iodide 6. Finally, the use of
iodoniumdicollidinium triflate (IDCT)51,52 in THF appeared
to be the most promising. Thus, when the exo-olefin 23 was
treated with 1.0 equiv of IDCT in THF for 30 min at 0 °C
(Table 1, entry 1), the desired Z-vinyl iodide 6 was obtained in
26% yield. The undesired E-vinyl iodide 26 (14%) and endo-
vinyl iodide 27 (31%) were also obtained, although these were
easily separable using silica gel column chromatography. As a
result, the combined isolate chemical yield of the products was
77% with the endo-vinyl iodide 27 being the major prod-
uct albeit slightly Z-selective in terms of the olefin geometry
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Table 2. Optimization of Cross-Coupling To Form the Enamide 30a
23 with IDCT presumably forms the 5′-iodo-4′-oxonium
intermediate 28 and the elimination of proton provides the
vinyl iodides. The elimination proceeded via a transition state
where the C-5′−H-5′ σ-bond overlapped with the π-orbital
of the O-4′−C-4′ double bond. This being the case, four con-
formers are possible in the transition state of the elimination,
namely confs-1-4. Since the steric repulsion between the iodo
group and the substituents at the C-3′ position (the hydrogen
atom and the R group) is increased in conf-2 and conf-4, it is
expected that conf-1 and conf-3 are more energetically stable,
and therefore the ensuing elimination would provide the
Z-vinyl iodide. The difference in the conformational energies
would be larger by increasing the size of the R group, resulting
in high stereoselectivity as observed in the iodination of 17.
Presumably the coordination of MeCN to 28 affects the stereo-
selectivity of the elimination step although the precise reaction
mechanism is not clear from the current study.
(entries 6 and 7). Next, the coupling of the iodide 7b with a
variety of amide derivatives of amino acids was undertaken,53
and the results are summarized in Table 3. Generally, all the
amides 29b−g reacted smoothly with the iodide 7b under
the conditions optimized in Table 2, and the corresponding
Table 3. Cu-Catalyzed Cross-Coupling with a Variety of
Carboxamides
Once the Z-exo-vinyl halides 6, 7a, and 7b were obtained, the
key copper-catalyzed cross-coupling reaction41 to form the
oxyenamide structure was examined with 7 and benzamide
(29a, 1.2 equiv) as a model study (Table 2). The metal catalyst
was preliminarily tested with either Pd or Cu, which are widely
used for C−N couplings. The reaction of both the bromide
7a and the iodide 7b with benzamide (29a) catalyzed by
Pd(OAc)2 in the presence of Xantphos or cataCXium and
Cs2CO3 in 1,4-dioxane did not provide the enamide 30a at all,
and the reduced product 17 was obtained (entries 1−3).41a,c
On the other hand, the use of a copper catalyst was promising.41d,e
Namely, when CuI was used as the catalyst (0.2 equiv) of the
coupling reaction of the iodide 7b in the presence of N,N′-
dimethylethylenediamine as the ligand (0.4 equiv), the Z-enamide
30a was obtained in 89% yield without any isomerization of the
olefin geometry (entry 5). No improvement was achieved by
limited screening of the ligands briefly tested in this study
a
b
2.5 equiv of Cs2CO3 was used. 2.0 equiv of the amide, 0.5 equiv of
Cul, 1.0 equiv of the ligand, and 1.5 equiv of Cs2CO3 were used.
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Z-enamide derivatives 30b−g were obtained in good yield (77%
quant). No epimerization at the α-position of the carboxamide
moiety under these conditions (entries 4−6), an important
characteristic for the final coupling with the tetrapeptide 5,
which contains four α-protons to the carbonyls.
Then, the coupling of 7b with the tetrapeptide 5 was
investigated (Scheme 6 and Table 4). The iodide 7b was
react with the t-Bu ester at the C-terminus to form cyclic
compounds 34 and 35. In order to prevent the approach of the
nitrogen atom to the t-Bu ester, the size of the ligand
coordinating to the copper atom was increased, namely by
choosing specific ligands B-D (Table 4). Consistent with this
hypothesis, the use of the ligands B-D resulted in increased
yields (entries 2−4, 16−32%). Their stereochemistry did not
influence the chemical yield (entry 3 vs 4). The improved 86%
yield of 31 can be attributed to increased catalyst loading
(0.8 equiv), which indicates that the catalyst coordinates to the
highly functionalized tetrapeptide carboxamide 5, thereby
resulting in reduced catalytic activity. However, the copper-
catalyzed cross-coupling is still effective in forming the Z-oxy-
acyl enamide moiety, which is chemically labile and the most
challenging chemical structure in the molecule to construct,
using the tetrapeptide carboxamide 5. Of note is the highly
selective reaction at the N-unsubstituted carboxamide moiety
despite the presence of several potential reactive sites, including
the primary amide, the carbamate, and the urea groups. An
alternative approach to prepare 31 from the intermediate 30g
would be by sequential coupling (Scheme 6). Deprotection of
Table 4. Optimization of Cross-Coupling of 5 and 7b
Scheme 6. Synthesis of the 3′-Hydroxypacidamycin D (32)
reacted with the tetrapeptide 5 under the optimized conditions
(0.2 equiv of CuI, 0.4 equiv of MeNHCH2CH2NHMe,
Cs2CO3, THF, 70 °C, entry 1). However, a large amount of
the iodide remained unreacted, and only a trace amount of the
desired 31a was obtained. Although not fully confirmed, cyclic
products such as 34 and 35, the structures of which are shown
in Figure 3, were obtained from the reaction mixture as indicated
Figure 3. Structure of byproduct in cross-coupling of 5 and 7b.
by MS analysis. In general, the copper-mediated C−N cross-
coupling proceeds through initial formation of the nitrogen−
copper complex followed by an oxidative insertion into the
halide and reductive elimination.41f It is presumed that if the
oxidative insertion was slow, the nitrogen atom activated by
formation of the carboxamide−copper(I) complex 36 would
the Boc group of 30g was achieved by TFA in CH2Cl2 at 0 °C,
and the liberated amine 33 was coupled with the urea−
dipeptide 10 (HATU and NMM in CH2Cl2, 95%) to give
31b. Deprotection of the protecting groups in 31a (BCl3,55
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CH2Cl2, −78 °C, then 3HF·NEt3, 25% over two steps) pro-
vided 3′-hydroxyl pacidamycin D (32), a ribonucleoside analogue.
Although unsuccessful, preliminary model studies toward the
total synthesis of 4 were first conducted using a selective
deoxygenation of the allylic 3′-hydroxyl group on the cyclic
thiocarbonate 38 (Scheme 7). Thus, the TBS groups of 30g
The MraY inhibitory59,60 and antibacterial activity61 of 4 and
32 was evaluated. Synthetic pacidamycin D (4) potently
inhibited MraY using cell-free biochemical assay with an IC50
value of 22 nM. 3′-Hydroxypacidamycin D (32) also exhibited
good MraY inhibitory activity (IC50 = 42 nM). The anti-
bacterial activity of 4 and 32 was then evaluated against a range
of P. aeruginosa strains (Table 5). Pacidamycin D (4) exhibited
Scheme 7. Attempt of Deoxygenation of 38
Table 5. Antibacterial Activity of 4 and 32
MIC (μg/mL)
strain
4
32
P. aeruginosa PAO1
64
16
16
16
32
16
16
8
P. aeruginosa ATCC 25619
P. aeruginosa SR 27156
P. aeruginosa YY165(ΔmexB)
antibacterial activity with an MIC value of 64 μg/mL for
P. aeruginosa PAO1, 16 μg/mL for P. aeruginosa ATCC 25619,
16 μg/mL for P. aeruginosa SR 27156, and 16 μg/mL for
P. aeruginosa YY165(ΔmexB), respectively. Slightly better
antibacterial activity was observed for 32 with an MIC value of
32 μg/mL for P. aeruginosa PAO1, 16 μg/mL for P. aeruginosa
ATCC 25619, 16 μg/mL for P. aeruginosa SR 27156, and 8 μg/mL
for P. aeruginosa YY165(ΔmexB), respectively. These data sug-
gest that introducing the hydroxyl group at the 3′-position of
the uridine moiety is tolerated for both MraY inhibition and
antibacterial activity.
CONCLUSION
■
were removed (TBAF, THF, 99%), and the resulting diol 37
was reacted with O-phenyl chlorothionoformate in MeCN56 to
afford the cyclic thiocarbonate 38 in 75% yield. However,
exposure of 38 to either Bu3SnH and AIBN57 in toluene at
reflux or Bu3SnH and V-7058 in CH2Cl2 at room temperature
led to a complex mixture of products such as 40 and 41, and
the desired deoxygenated compound 39 was not isolated.
Ultimately, the total synthesis of 4 was pursued with the
3′-deoxyvinyl iodide 6 (Scheme 8). The iodide 6 and the
In summary, the details of total synthesis of pacidamycin D
has been described. The assemblage by Cu(I)-catalyzed cross-
coupling of the Z-oxyvinyl halide 6 and the tetrapeptide 5 at a
late stage of the synthesis allowed ready access to a range of
uridylpeptide antibiotics and their analogues, despite their
inherent labile nature with potential epimerization, simply by
altering the tetrapeptide moiety, which could be obtained by
conventional solid-phase parallel synthesis. Both 4 and 32
exhibit potent MraY inhibitory and antibacterial activity against
P. aeruginosa. Moreover, introducing the hydroxyl group at the
3′-position of the uridine moiety was tolerated in both the MraY
biochemical inhibition and whole-cell antibacterial activity, which
is advantageous from a medicinal chemical point of view because
the 3′-hydroxyl analogue is synthetically more accessible.
Scheme 8. Total Synthesis of Pacidamycin D (4)
EXPERIMENTAL SECTION
■
Experimental procedure and characterization data for compounds
4−6, 7b, 12, 14, 17, 21−23, 31a, and 42 are described in ref 42.
3-(Benzyloxymethyl)-1-[(Z)-2,3-di-O-(tert-butyldimethylsilyl)-
4,5-dehydro-5-phenylthio-β-D-ribo-pentofuranosyl]uracil
(18). A solution of NCS (457 mg, 3.43 mmol) in CH2Cl2 (20 mL) was
treated with benzenethiol (309 μL, 3.01 mmol) at 0 °C under N2 for
30 min. Compound 17 (788 mg, 1.37 mmol) was added to the
mixture, which was stirred at 0 °C for further 30 min. 1,5-
Diazabicyclo[4.3.0]non-5-ene (337 μL, 2.74 mmol) was added to
the mixture, which was refluxed for 2 h. The reaction mixture was
diluted with saturated aqueous NaHCO3, and extracted with EtOAc.
The combined organic layers were washed with saturated aqueous
NaCl, dried over Na2SO4, filtrated, and concentrated in vacuo. The
residue was purified by silica gel column chromatography (10 ×
2.6 cm, 10−12% EtOAc/hexane) to give 18 (788 mg, 84%) as a pale
tetrapeptide 5 were coupled using the optimized conditions
(0.8 equiv of CuI, 1.6 equiv of ligand C, Cs2CO3, THF, 70 °C,
69%) to afford the fully protected pacidamycin D (42). Finally,
deprotection of the BOM, Cbz and t-Bu groups (BCl3, CH2Cl2,
−78 °C) and the TBS group (5HF·NEt3, 30% over two steps)
successfully afforded 4 as the TFA salts. The analytical data for
the synthetic compound were in good agreement with those
reported for the natural material.11
yellow oil: [α]23 +35.0 (c 1.01, CHCl3); 1H NMR (CDCl3, 500
D
MHz) δ 7.37−7.17 (m, 10H), 7.06 (d, 1H, J = 8.1 Hz), 6.21 (d, 1H,
J = 5.6 Hz), 5.80 (d, 1H, J = 8.1 Hz), 5.50 (d, 1H, J = 9.8 Hz), 5.46
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(d, 1H, J = 9.8 Hz), 5.44 (d, 1H, J = 0.5 Hz), 4.68 (s, 2H), 4.46 (d, 1H,
J = 4.2 Hz), 4.28 (dd, 1H, J = 4.2, 5.6 Hz), 0.94 (s, 9H), 0.87 (s, 9H),
0.14 (s, 3H), 0.14 (s, 3H), 0.06 (s, 3H), 0.02 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 162.4, 157.2, 150.9, 138.1, 137.9, 136.3, 129.2,
128.4, 128.4, 127.8, 126.7, 126.3, 103.1, 94.9, 91.1, 75.3, 72.3, 72.3,
70.5, 25.9, 25.8, 18.3, 18.1, 4.2, 4.3, 4.5, 4.8 (C27); ESIMS-LR m/z 683
[(M + H)+]; ESIMS-HR calcd for C35H51N2O6SSi2 683.3001, found
683.2999; IR (ATR) νmax 2956, 2932, 2888, 2859, 1725, 1681, 1585,
1454, 1409, 1353, 1315, 1255, 1220, 1167, 1093, 1026, 948, 910, 861,
837, 810, 779, 739, 694 cm−1.
in vacuo to give the crude title compound as a white foam. This
compound was used to the next reaction without further purification.
(2S,3S)-3-[(S)-2-(Benzyloxycarbonylamino)-N-methylpropa-
namido]-2-(tert-butoxycarbonylamino)butanamide (29g). A
solution of crude 42 (1.97 mmol), NH4Cl (1.05 g, 19.7 mmol),
and HATU (1.50 g, 3.94 mmol) in DMF (10 mL) was added by
N-methylmorpholine (3.03 mL, 27.6 mmol) at 0 °C under N2, and the
mixture was stirred at 0 °C for 30 min. The reaction mixture was
diluted with H2O and extracted with EtOAc. The combined organic
layers were washed with 0.2 N aqueous HCl and brine, dried over
Na2SO4, filtrated, and concentrated in vacuo. The residue was purified
by silica gel column chromatography (2.6 × 15 cm, 0−5% MeOH/
3-(Benzyloxymethyl)-1-[(Z)-2,3-di-O-(tert-butyldimethylsil-
yl)-4,5-dehydro-5-tributylstannyl-β-D-ribo-pentofuranosyl]-
uracil (19). A solution of 18 (390 mg, 0.57 mmol) in toluene (8 mL)
was added by n-Bu3SnH (457 μL, 1.71 mmol), AIBN (47 mg, 0.29 mmol),
and Hunig’s base (299 μL, 1.71 mmol) at room temperature under N2.
The mixture was refluxed for 6 h. The solvent was removed, and the
residue was purified by silica gel column chromatography (2.6 ×
15 cm, 5−20% EtOAc/hexane) to give 19 (409 mg, 83%) as a colorless
CHCl3) to give 29g (673 mg, 78% for two steps) as a white solid:
1
[α]23 −2.8 (c 0.62, CHCl3); H NMR (CDCl3, 500 MHz) δ: 7.39−
D
7.29 (m, 5H), 6.67 (br s, 1H), 5.70 (d, 1H, J = 8.0 Hz), 5.56 (d, 1H,
J = 7.1 Hz), 5.43 (br s, 1H), 5.11 (d, 1H, J = 12.2 Hz), 5.08 (d, 1H, J =
12.2 Hz), 4.67−4.61 (m, 1H), 4.56−4.48 (m, 1H), 4.46−4.39
(m, 1H), 2.97 (s, 3H), 1.43 (s, 9H), 1.39 (d, 3H, J = 6.6 Hz), 1.19 (d, 3H,
J = 6.4 Hz); 13C NMR (CDCl3, 125 MHz) δ: 173.8, 172.3, 155.8,
155.6, 136.6, 128.6, 128.3, 128.2, 80.1, 66.9, 57.1, 53.6, 47.7, 31.0, 28.4,
18.3, 12.3 (C17); FABMS-LR m/z 437.873 [(M + H)+]; FABMS-HR
calcd for C21H33N4O6 437.2400, found 437.2394; IR (ATR) νmax 2954,
2931, 2887, 2859, 2126, 1725, 1679, 1452, 1408, 1351, 1256, 1221,
1189, 1166, 1096, 1023, 944, 910, 837, 810, 778, 737, 698 cm−1.
Typical Procedure for the Cu-Catalyzed Cross-Coupling
Compound 30a (Table 2, Entry 5). Vinyl iodide 7b (70 mg,
0.1 mmol), benzamide (14.5 mg, 0.120 mmol), copper(I) iodide
(3.81 mg, 0.020 mmol), and cesium carbonate (48.9 mg, 0.150 mmol)
were added to a dried test tube under N2. Tetrahydrofuran (1 mL) and
N,N′-dimethylethane-1,2-diamine (3.53 mg, 0.040 mmol) were added
to the mixture. The mixture was evacuated and backfilled with N2
three times and stirred at 70 °C for 7 h. The reaction mixture was
cooled to room temperature and diluted with EtOAc. The precipitates
were filtered off through Celite pad, and the filtrate was concentrated
in vacuo. The residue was purified by silica gel column chromato-
graphy (2 × 7.5 cm, 15−35% EtOAc/hexane) to give 30a (61.7 m g,
oil: [α]23 +31.8 (c 0.62, CHCl3); 1H NMR (CDCl3, 500 MHz)
D
δ 7.39−7.25 (m, 5H), 7.09 (d, 1H, J = 8.1 Hz), 6.10 (d, 1H, J = 4.9 Hz),
5.79 (d, 1H, J = 8.1 Hz), 5.51 (d, 1H, J = 9.7 Hz), 5.47 (d, 1H, J =
9.7 Hz), 4.79 (d, 1H, J = 0.7 Hz), 4.70 (s, 2H), 4.28 (d, 1H, J =
4.0 Hz), 4.07 (dd, 1H, J = 4.0, 4.9 Hz), 1.53−1.43 (m, 6H), 1.34−1.24
(m, 6H), 0.94−0.88 (m, 6H), 0.92 (s, 9H), 0.87 (t, 9H, J = 7.3 Hz),
0.86 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 164.9, 162.4, 150.8, 137.8, 137.4, 128.3,
127.7, 102.4, 94.9, 89.4, 75.7, 72.5, 72.2, 70.3, 29.1, 27.2, 25.8, 25.6, 18.3,
18.0, 13.7, 10.1, −4.4, −4.5, −4.7, −4.9; ESIMS-LR m/z 865 [(M + H)+];
ESIMS-HR calcd for C41H73N2O6Si2Sn 865.4024, found 865.4022; IR
(ATR) νmax 2955, 2928, 2857, 1722, 1681, 1453, 1352, 1253, 1168, 1073,
1057, 957, 898, 869, 837, 806, 778, 734, 696, 648 cm−1.
3-(Benzyloxymethyl)-1-[(Z)-2,3-di-O-(tert-butyldimethylsil-
yl)-4,5-dehydro-5-bromo-β-D-ribo-pentofuranosyl]uracil (7a).
A solution of 19 (70 mg, 0.081 mmol) in THF (2 mL) was treated
with NBS (22 mg, 0.122 mmol) at room temperature under N2 for
2 h. The reaction mixture was diluted with saturated aqueous NaHCO3
and extracted with CHCl3. The combined organic layers were dried over
Na2SO4, filtrated, and concentrated in vacuo. The residue was purified
by silica gel column chromatography (2 × 7.5 cm, 10−20% EtOAc/
89%) as a white solid: [α]23 −19.0 (c 0.52, CHCl3); 1H NMR
D
(CDCl3, 500 MHz) δ 7.84−7.78 (m, 2H), 7.62 (d, 1H, J = 10.0 Hz),
7.55−7.24 (m, 7H), 7.14 (d, 1H, J = 8.1 Hz), 6.60 (d, 1H, J = 10.3
Hz), 6.31 (d, 1H, J = 7.1 Hz), 5.86 (d, 1H, J = 8.1 Hz), 5.51 (d, 1H,
J = 9.7 Hz), 5.47 (d, 1H, J = 9.7 Hz), 4.69 (s, 2H), 4.50 (d, 1H, J =
4.2 Hz), 4.31 (dd, 1H, J = 7.1, 4.2 Hz), 0.93 (s, 9H), 0.85 (s, 9H), 0.15
(s, 3H), 0.14 (s, 3H), 0.05 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 163.9, 162.3, 151.2, 141.8, 138.4, 137.8, 133.3, 132.3,
128.9, 128.5, 127.9, 127.8, 127.3, 103.4, 101.7, 90.1, 75.3, 72.3, 71.2,
70.5, 25.9, 25.7, 18.3, 18.1, −4.0, −4.3, −4.4, −4.9 (C28); ESIMS-LR
m/z 694 [(M + H)+]; ESIMS-HR calcd for C36H52N3O7Si2 694.3338,
found 694.3342; IR (ATR) νmax 3322, 2930, 2887, 2858, 1721, 1674,
1581, 1517, 1486, 1454, 1409, 1357, 1253, 1180, 1155, 1092, 1042,
hexane) to give 7a (49 mg, 93%) as a pale yellow oil: [α]23 +0.7
D
(c 1.00, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 7.38−7.25 (m, 5H),
7.11 (d, 1H, J = 8.3 Hz), 6.27 (d, 1H, J = 6.4 Hz), 5.85 (d, 1H, J = 8.3
Hz), 5.50 (d, 1H, J = 9.8 Hz), 5.47 (d, 1H, J = 9.8 Hz), 5.36 (s, 1H),
4.69 (s, 2H), 4.43 (d, 1H, J = 4.2 Hz), 4.28 (dd, 1H, J = 4.2, 6.4 Hz),
0.92 (s, 9H), 0.84 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.04 (s, 3H),
−0.01 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 162.3, 156.4, 150.9,
138.1, 137.9, 128.4, 127.8, 127.8, 103.3, 90.8, 80.3, 75.5, 72.3, 72.2,
70.5, 25.8, 25.7, 18.3, 18.1, −4.4, −4.5, −4.9; ESIMS-LR m/z 653
[(M + H)+]; ESIMS-HR calcd for C29H46BrN2O6Si2 653.2072,
found 653.2074; IR (ATR) νmax 2954, 2930, 2887, 2858, 1723,
1679, 1639, 1452, 1408, 1351, 1310, 1254, 1218, 1167, 1098, 1028,
945, 908, 836, 810, 777, 735, 698, 674 cm−1.
948, 833, 810, 777, 695 cm−1.
1
Data for 30b: colorless oil; [α]23 −19.8 (c 1.01, CHCl3); H
D
NMR (CDCl3, 300 MHz) δ 7.93 (d, 1H, J = 7.6 Hz), 7.43−7.22
(m, 5H), 7.10 (d, 1H, J = 8.1 Hz), 6.32 (d, 1H, J = 10.2 Hz), 6.27 (d,
1H, J = 7.1 Hz), 5.82 (d, 1H, J = 8.1 Hz), 5.51 (d, 1H, J = 9.6 Hz),
5.44 (d, 1H, J = 9.6 Hz), 5.21 (br s, 1H), 4.68 (s, 2H), 4.40 (d, 1H, J =
4.0 Hz), 4.24−4.11 (m, 1H), 3.86 (d, 1H, J = 4.5 Hz), 3.84 (d, 1H, J =
4.5 Hz), 1.40 (s, 1H), 0.90 (s, 1H), 0.83 (s, 1H), 0.11 (s, 1H), 0.09
(s, 1H), 0.02 (s, 1H), −0.06 (s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 166.6, 162.2, 156.2, 151.2, 141.5, 138.4, 137.7, 128.4, 127.9, 127.8,
103.3, 100.6, 89.6, 80.5, 75.4, 72.2, 71.1, 70.4, 44.3, 28.3, 25.8, 25.7,
18.2, 18.0, −4.1, −4.4, −4.4, −5.0 (C28); ESIMS-LR m/z 747 [(M + H)+];
ESIMS-HR calcd for C36H59N4O9Si2 747.3815, found 747.3815; IR
(ATR) νmax 3321, 2932, 2860, 1670, 1527, 1456, 1365, 1255, 1216,
3-(Benzyloxymethyl)-1-[(Z)-2,3-di-O-(tert-butyldimethylsil-
yl)-4,5-dehydro-5-iodo-β-D-ribo-pentofuranosyl]uracil (7b). A
solution of 19 (1.09 g, 1.26 mmol) in THF (20 mL) was treated with
I2 (480 mg, 1.89 mmol) at room temperature under N2 for 1 h. The
reaction mixture was diluted with 10% aqueous Na2S2O3 and extracted
with EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4, filtrated, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (4.6 × 13 cm, 5−20%
EtOAc/hexane) to give 7b (810 mg, 92%) as a pale yellow oil. Charac-
terization data may be found in ref 42.
(2S,3S)-3-[(S)-2-(Benzyloxycarbonylamino)-N-methylpropa-
namido]-2-(tert-butoxycarbonylamino)butanoic Acid. A solu-
tion of (2S,3S)-3-amino-2-(tert-butoxycarbonylamino)butanoic acid
(458 mg, 1.97 mmol), Z-L-Ala-OSu (821 mg, 2.56 mmol), and Hunig’s
base (517 μL, 2.96 mmol) in CH2Cl2 (10 mL) was stirred at room
temperature for 3 h. The reaction mixture was diluted with 0.5 N
aqueous HCl and extracted with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4, filtrated, and concentrated
1165, 1099, 1075, 1047, 948, 901, 836, 778, 734, 700 cm−1.
1
Data for 30c: colorless oil; [α]23 −15.3 (c 1.00, CHCl3); H
D
NMR (CDCl3, 300 MHz) δ 7.84 (d, 1H, J = 8.2 Hz), 7.45−7.08
(m, 10H), 7.02 (d, 1H, J = 8.1 Hz), 6.32 (d, 1H, J = 10.4 Hz), 6.22 (d,
1H, J = 6.7 Hz), 5.78 (d, 1H, J = 8.1 Hz), 5.47 (d, 1H, J = 9.4 Hz), 5.39
(d, 1H, J = 9.4 Hz), 5.09 (s, 2H), 4.64 (s, 2H), 4.38 (d, 1H, J = 3.7 Hz),
4.13 (dd, 1H, J = 3.7, 6.7 Hz), 4.00 (dd, 1H, J = 5.9, 16.8 Hz), 3.89
1374
dx.doi.org/10.1021/jo202159q | J. Org. Chem. 2012, 77, 1367−1377

The Journal of Organic Chemistry
Article
(dd, 1H, J = 5.2, 16.8 Hz), 0.89 (s, 9H), 0.81 (s, 9H), 0.10 (s, 3H),
0.08 (s, 3H), 0.01 (s, 3H), −0.09 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 166.1, 162.1, 156.7, 151.1, 141.6, 138.4, 137.7, 136.1,
128.7, 128.5, 128.4, 128.1, 127.9, 127.8, 103.3, 100.6, 89.9, 75.4, 72.2,
71.1, 70.4, 67.4, 44.5, 25.8, 25.7, 18.2, 18.0, −4.1, −4.4, −4.4, −5.0
(C31); ESIMS-LR m/z 781 [(M + H)+]; ESIMS-HR calcd for
C39H57N4O9Si2 781.3659, found 781.3658; IR (ATR) νmax 3318, 2932,
2859, 1721, 1670, 1524, 1456, 1358, 1255, 1215, 1173, 1098, 1074,
The mixture was stirred at 0 °C for 6 h. The reaction mixture was
diluted with saturated aqueous NaHCO3 and extracted with EtOAc.
The combined organic layers were washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, filtrated, and concentrated in
vacuo to give crude 33 (45 mg, 0.074 mmol) as a brown oil. This
compound was used to the next reaction without further purification:
1H NMR (CDCl3, 500 MHz) δ 8.86 (d, 1H, J = 11.0 Hz), 7.37−7.25
(m, 10H), 7.10 (d, 1H, J = 8.2 Hz), 6.27 (d, 1H, J = 10.8 Hz), 6.18
(d, 1H, J = 6.8 Hz), 5.82 (d, 1H, J = 8.2 Hz), 5.68 (d, 1H, J = 7.6 Hz),
5.52 (d, 1H, J = 15.6 Hz), 5.47 (d, 1H, J = 15.6 Hz), 5.10−5.07
(m, 4H), 4.70−4.66 (m, 2H), 4.68 (s, 2H), 4.62−4.57 (m, 1H), 4.41
(d, 1H, J = 4.2 Hz), 4.33−4.23 (m, 2H), 3.54 (d, 1H, J = 4.9 Hz), 2.92
(s, 3H), 1.34 (d, 3H, J = 7.3 Hz), 1.31 (d, 3H, J = 6.6 Hz), 0.91 (s, 9H),
0.83 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.03 (s, 3H), −0.03 (s, 3H).
Compound 31b. A solution of 33 (45 mg, 0.074 mmol) and
10 (21.8 mg, 0.058 mmol) in CH2Cl2 (1 mL) was added to HATU
(27.6 mg, 0.073 mmol) and N-methylmorpholine (16 μL, 0.145 mmol) at
room temperature under N2 for 3 h. The reaction mixture was diluted
with H2O and extracted with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4, filtrated, and concentrated
in vacuo. The residue was purified by silica gel column chromato-
graphy (2 × 7.5 cm, 0−5% MeOH/CHCl3) to give 31b (58 mg, 64%
over 2 steps) as a white solid: [α]23D −2.8 (c 0.53, CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 7.57−7.40 (m, 1H), 7.40−7.18 (m, 11H), 7.07
(d, 1H, J = 8.3 Hz), 7.06 (t, 1H, J = 7.6 Hz), 6.99 (t, 1H, J = 7.5 Hz),
6.95 (s, 1H), 6.18 (d, 1H, J = 9.3 Hz), 6.10 (d, 1H, J = 5.6 Hz), 5.76
(d, 1H, J = 8.3 Hz), 5.45 (d, 1H, J = 9.4 Hz), 5.40 (d, 1H, J = 9.4 Hz),
5.09 (d, 1H, J = 14.4 Hz), 5.05 (d, 1H, J = 14.4 Hz), 4.73−4.59
(m, 3H), 4.65 (s, 2H), 4.59−4.45 (m, 2H), 4.36 (d, 1H, J = 3.9 Hz), 4.32−
4.23 (m, 1H), 3.27−2.73 (m, 2H), 2.62 (s, 3H), 1.39−1.15 (m, 18H),
0.87 (s, 9H), 0.82 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H), 0.01 (s, 3H),
−0.07 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 175.0, 174.8, 173.3,
172.6, 166.4, 162.4, 157.2, 155.9, 150.8, 142.6, 139.2, 137.8, 137.7,
136.5, 135.9, 128.6, 128.4, 128.2, 127.9, 127.8, 124.0, 121.8, 119.0,
118.7, 111.5, 109.2, 102.8, 100.4, 91.4, 82.3, 75.1, 72.2, 71.3, 70.3, 66.9,
57.9, 53.8, 51.2, 49.5, 47.6, 30.2, 29.8, 28.0, 25.8, 25.7, 19.0, 18.5, 18.2,
18.0, 13.9, −4.2, −4.4, −4.5, −5.0 (C54); ESIMS-LR m/z 1266 [(M +
H)+]; ESIMS-HR calcd for C64H92N9O14Si2 1266.6297, found
1266.6290; IR (ATR) νmax 3347, 2932, 2857, 2165, 2051, 1981,
1722, 1675, 1531, 1454, 1411, 1355, 1253, 1157, 1095, 1028, 948, 902,
838, 779, 740, 697 cm−1.
3′-Hydroxypacidamycin D (32). From 31a. A solution of 31a
(30 mg, 0.024 mmol) in CH2Cl2 (2 mL) was treated with 1 M BCl3 in
CH2Cl2 (243 μL, 0.243 mmol) at −78 °C for 1 h and then, −40 °C for
1 h under N2. After MeOH and saturated aqueous NaHCO3 were
added at −78 °C, the resulting mixture was stirred at 0 °C for further
5 min. The mixture was extracted with CHCl3, and the combined
organic layers were dried over Na2SO4, and filtrated. Ethane-1,2-dithiol
(10.2 μL, 0.122 mmol) was added to the filtrate, and the mixture was
concentrated in vacuo. A solution of the resulting residue in CH2Cl2/
MeCN (1:1, 4 mL) was treated with triethylamine trihydrofluoride
(119 μL, 0.730 mmol) at room temperature under N2 for 96 h. The
volatiles were removed in vacuo, and the residue was purified by
ODS column chromatography (1.1 × 30 cm, 0−40% MeCN/H2O
containing 0.1% TFA) to give 32 as a TFA salt (5.1 mg, 25% over
2 steps) after lyophilization as a white foam.
From 31b. A solution of 31b (26 mg, 0.021 mmol) in CH2Cl2
(2 mL) was treated with 1 M BCl3 in CH2Cl2 (411 μL, 0.411 mmol) at
−78 to −40 °C for 2 h and then, at 0 °C for 2 h under N2. After
MeOH and saturated aqueous NaHCO3 were added at −78 °C, the
resulting mixture was stirred at 0 °C for further 5 min. The mixture
was extracted with CHCl3, and the combined organic layers were dried
over Na2SO4, and filtrated. Ethane-1,2-dithiol (8.6 μL, 0.103 mmol)
was added to the filtrate, and the mixture was concentrated in vacuo. A
solution of the resulting residue in CH2Cl2/MeCN (1:1, 4 mL) was
treated with triethylamine trihydrofluoride (0.10 mL, 0.616 mmol) at
room temperature under N2 for 96 h. The volatiles were removed
in vacuo, and the residue was purified by ODS column chromato-
graphy (1.1 × 30 cm, 0−30% MeCN/H2O containing 0.1% TFA) to give
32 (4.5 mg, 26% over two steps) after lyophilization as a white foam:
1045, 948, 900, 836, 779, 737, 699 cm−1.
1
Data for 30d: colorless oil; [α]23 −27.0 (c 1.02, CHCl3); H
D
NMR (CDCl3, 500 MHz) δ 8.86 (d, 1H, J = 10.8 Hz), 7.38−7.26
(m, 5H), 7.12 (d, 1H, J = 8.1 Hz), 6.35 (d, 1H, J = 10.8 Hz), 6.28
(d, 1H, J = 6.9 Hz), 5.84 (d, 1H, J = 8.1 Hz), 5.51 (d, 1H, J = 9.6 Hz),
5.47 (d, 1H, J = 9.6 Hz), 4.69 (s, 2H), 4.43 (d, 1H, J = 4.2 Hz), 4.26
(dd, 1H, J = 4.2, 6.9 Hz), 3.44 (d, 1H, J = 17.8 Hz), 3.39 (d, 1H, J =
17.8 Hz), 0.91 (s, 9H), 0.84 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.04
(s, 3H), −0.04 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 169.7, 162.2,
151.0, 141.4, 138.3, 137.8, 128.3, 127.7, 127.6, 103.1, 100.5, 89.9, 75.4,
72.1, 71.1, 70.4, 44.5, 25.8, 25.6, 18.1, 17.9, −4.2, −4.5, −4.5, −5.1
(C25); ESIMS-LR m/z 647 [(M + H)+]; ESIMS-HR calcd for
C31H51N4O7Si2 647.3291, found 647.3281; IR (ATR) νmax 3322, 2931,
2858, 1721, 1670, 1512, 1454, 1409, 1354, 1253, 1181, 1095, 1042,
944, 898, 832, 776, 738, 698 cm−1.
Data for 30e: white foam; [α]23D −14.6 (c 0.80, CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 7.92−7.65 (m, 1H), 7.41−7.24 (m, 5H), 7.12
(d, 1H, J = 8.2 Hz), 6.31 (d, 1H, J = 10.2 Hz), 6.28 (d, 1H, J =
6.4 Hz), 5.85 (d, 1H, J = 8.2 Hz), 5.51 (d, 1H, J = 9.7 Hz), 5.47 (d, 1H,
J = 9.7 Hz), 4.94−4.77 (m, 1H), 4.69 (s, 2H), 4.42 (d, 1H, J = 4.1 Hz),
4.29−4.09 (m, 2H), 1.39 (s, 9H), 1.38 (d, 3H, J = 6.4 Hz), 0.91
(s, 9H), 0.84 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H), 0.03 (s, 3H), −0.03
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ 169.4, 162.2, 155.7, 151.0,
141.6, 138.0, 137.7, 128.3, 127.7, 127.7, 103.2, 100.7, 89.7, 80.7, 75.5,
72.1, 71.0, 70.4, 50.0, 28.2, 25.7, 25.6, 18.1, 17.9, 17.6, −4.3, −4.5,
−4.5, −5.1 (C29); ESIMS-LR m/z 761 [(M + H)+]; ESIMS-HR calcd
for C37H61N4O9Si2 761.3972, found 761.3969; IR (ATR) νmax 3323,
2933, 2859, 2289, 2051, 1721, 1673, 1498, 1454, 1356, 1253, 1162,
1095, 1048, 945, 892, 835, 777, 698 cm−1.
Data for 30f: white foam; [α]23D −24.5 (c 0.23, CHCl3); 1H NMR
(CDCl3, 500 MHz) δ 7.40−7.25 (m, 5H), 7.08 (d, 1H, J = 8.1 Hz),
6.30 (d, 1H, J = 10.3 Hz), 6.28 (d, 1H, J = 6.4 Hz), 5.83 (d, 1H, J =
8.1 Hz), 5.52 (d, 1H, J = 9.6 Hz), 5.47 (d, 1H, J = 9.6 Hz), 4.69 (s, 2H),
4.40 (d, 1H, J = 4.2 Hz), 4.31−4.09 (m, 2H), 1.40 (s, 9H), 1.37 (d,
3H, J = 7.1 Hz), 0.90 (s, 9H), 0.83 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H),
0.03 (s, 3H), −0.05 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 169.6,
162.1, 155.6, 151.0, 141.3, 138.1, 137.7, 128.3, 127.7, 127.7, 103.2,
100.7, 89.5, 80.4, 75.5, 72.1, 71.0, 70.3, 49.9, 28.3, 25.7, 25.6, 18.1,
17.9, 14.2, −4.2, −4.5, −4.6, −5.1 (C29); ESIMS-LR m/z 761 [(M +
H)+]; ESIMS-HR calcd for C37H61N4O9Si2 761.3972, found 761.3968;
IR (ATR) νmax 3318, 2932, 2859, 2288, 2051, 1717, 1670, 1497, 1454,
1360, 1253, 1162, 1096, 1047, 947, 891, 834, 777, 698 cm−1.
1
Data for 30g: white solid; [α]23 +1.2 (c 1.01, CHCl3); H NMR
D
(CDCl3, 500 MHz) δ 8.12 (br s, 1H), 7.41−7.23 (m, 10H), 7.13
(d, 1H, J = 8.0 Hz), 6.27 (d, 1H, J = 10.0 Hz), 6.21 (d, 1H, J = 6.1 Hz),
5.81 (d, 1H, J = 8.0 Hz), 5.77 (d, 1H, J = 7.1 Hz), 5.63 (d, 1H, J =
8.1 Hz), 5.48 (d, 1H, J = 9.8 Hz), 5.43 (d, 1H, J = 9.8 Hz), 5.12
(d, 1H, J = 12.2 Hz), 5.04 (d, 1H, J = 12.2 Hz), 4.67 (s, 2H), 4.64−
4.51 (m, 2H), 4.40 (d, 1H, J = 4.2 Hz), 4.34−4.29 (m, 1H), 4.28−4.23
(m, 1H), 2.90 (s, 3H), 1.39 (s, 9H), 1.33 (d, 3H, J = 6.6 Hz), 1.24
(d, 3H, J = 7.6 Hz), 0.90 (s, 9H), 0.83 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H),
0.03 (s, 3H), −0.03 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 174.0,
173.0, 167.0, 162.3, 155.6, 155.5, 151.0, 142.1, 138.4, 137.9, 136.6,
128.6, 128.4, 128.2, 127.8, 103.1, 100.3, 90.6 80.3, 75.4, 72.2, 71.1,
70.4, 66.9, 58.5, 53.1, 47.6, 30.7, 28.3, 25.8, 25.7, 18.6, 18.2, 18.0, 13.3,
−4.2, −4.4, −4.5, −5.0 (C40); ESIMS-LR m/z 1009 [(M + H)+];
ESIMS-HR calcd for C50H77N6O12Si2 1009.5133, found 1009.5130; IR
(ATR) νmax 3696, 3664, 3308, 2933, 2859, 2288, 2051, 1981, 1720,
1678, 1498, 1453, 1411, 1354, 1253, 1163, 1095, 1049, 1033, 946, 902,
836, 778, 737, 697 cm−1.
Compound 33. A solution of 30g (74.3 mg, 0.074 mmol) in
CH2Cl2 (2.4 mL) was treated with TFA (0.3 mL, 3.89 mmol) at 0 °C.
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The Journal of Organic Chemistry
Article
[α]23D −13.6 (c 0.11, H2O); 1H NMR (D2O, 500 MHz) δ 7.69 (d, 1H,
J = 7.8 Hz), 7.54 (dd, 1H, J = 3.4, 8.1 Hz), 7.52 (d, 1H, J =
8.1 Hz), 7.28 (s, 1H), 7.26 (dd, 1H, J = 7.8, 8.1 Hz), 7.18 (t, 1H, J =
7.8 Hz), 6.19 (s, 1H), 6.11 (d, 1H, J = 5.4 Hz), 5.88 (d, 1H, J =
8.1 Hz), 4.89 (dq, 1H, J = 5.9, 7.6 Hz), 4.74 (d, 1H, J = 5.9 Hz), 4.59−
4.50 (m, 3H), 4.29 (q, 1H, J = 6.9 Hz), 4.13 (q, 1H, J = 7.2 Hz), 3.33
(dd, 1H, J = 4.9, 14.7 Hz), 3.23 (ddd, 1H, J = 3.4, 7.5, 14.7 Hz), 2.87
(d, 3H, J = 2.7 Hz), 1.33 (d, 2H, J = 7.2 Hz), 1.25 (d, 3H, J = 7.6 Hz),
1.17 (d, 3H, J = 6.9 Hz); 13C NMR (D2O, 100 MHz) δ 183.2, 179.3,
173.6, 170.8, 168.8, 161.5, 154.3, 147.1, 144.7, 139.0, 130.1, 127.1,
124.6, 122.0, 121.7, 114.6, 113.3, 105.7, 102.1, 93.7, 75.3, 71.3, 59.5,
58.3, 53.5, 52.7, 50.2, 32.3, 31.1, 19.6, 18.2, 15.6; ESIMS-LR m/z 728
[(M + H)+]; ESIMS-HR calcd for C32H42N9O11 728.2998, found
728.2996; IR (ATR) νmax 3294, 1655, 1546, 1459, 1388, 1261, 1186,
1134, 801, 747, 722 cm−1.
2% dimethyl sulfoxide in order to increase the solubility of the
compounds.
Antibacterial Activity Evaluation. P. aeruginosa PAO1,
P. aeruginosa ATCC 25619, P. aeruginosa SR 27156, and P. aeruginosa
YY165(ΔmexB) were clinical isolates collected from hospitals of Japan
and kindly provided by Shionogi & Co., Ltd. (Osaka, Japan). MICs
were determined by a microdilution broth method as recommended
by the NCCLS (National Committee for Clinical Laboratory
Standards, 2000, National Committee for Clinical Laboratory
Standards, Wayne, PA) with cation-adjusted Mueller−Hinton broth
(CA-MHB). Serial 2-fold dilutions of each compound were made in
appropriate broth, and the plates were inoculated with 5 × 104 CFU of
each strain in a volume of 0.1 mL Plates were incubated at 35 °C for
20 h, and then MICs were scored.
ASSOCIATED CONTENT
Compound 37. A solution of 30g (281 mg, 0.278 mmol) in
THF (3 mL) was treated with 1 M TBAF solution in THF (835 μL,
0.835 mmol) at 0 °C under N2 for 30 min. The volatiles were removed
in vacuo, and the residue was purified by silica gel column chro-
■
S
* Supporting Information
1
NMR data for H NMR and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
matography (2.6 × 10 cm, 0−10% MeOH/CHCl3) to give 37
1
(217 mg, 99%) as a white solid: [α]23 −1.8 (c 1.01, CHCl3); H
D
NMR (CDCl3, 500 MHz) δ 8.67 (d, 1H, J = 9.3 Hz), 7.42−7.18 (m,
10H), 6.92−6.92 (m, 1H), 6.34 (d, 1H, J = 9.8 Hz), 6.23 (br s, 1H),
5.99 (br s, 1H), 5.75 (br s, 1H), 5.64 (d, 1H, J = 7.3 Hz), 5.50 (d, 1H,
J = 9.7 Hz), 5.45 (d, 1H, J = 9.7 Hz), 5.08 (d, 1H, J = 12.2 Hz), 5.03
(d, 1H, J = 12.2 Hz), 4.70 (d, 1H, J = 12.0 Hz), 4.66 (d, 1H, J = 12.0
Hz), 4.60−4.51 (m, 1H), 4.51−4.31 (m, 3H), 3.87−3.87 (m, 1H),
2.98 (s, 3H), 1.39 (s, 9H), 1.20 (d, 3H, J = 4.6 Hz), 1.16 (d, 3H, J =
6.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 174.4, 167.5, 161.9, 155.8,
155.6, 151.4, 141.9, 137.6, 137.5, 136.4, 128.5, 128.4, 128.1, 128.1,
127.9, 127.8, 103.6, 103.1, 100.3, 80.5, 74.2, 72.4, 70.4, 68.9, 66.8, 57.8,
51.4, 47.3, 30.5, 28.3, 18.1, 14.0 (C32); ESIMS-LR m/z 781 [(M +
H)+]; ESIMS-HR calcd for C38H49N6O12 781.3403, found 781.3406;
IR (ATR) νmax 3297, 2981, 1716, 1659, 1525, 1454, 1414, 1363, 1230,
1164, 1051, 809, 774, 738, 698 cm−1.
AUTHOR INFORMATION
Corresponding Author
*Phone: (+81) 11-706-3229. Fax: (+81) 11-706-4980. E-mail:
ichikawa@pharm.hokudai.ac.jp.
■
ACKNOWLEDGMENTS
■
We thank Mr. Kouichi Uotani (Medicinal Research Labo-
ratories, Shionogi & Co., Ltd.) for evaluating the antibacterial
activities and Ms. Fumiyo Takahashi (Shionogi Innovation
Center for Drug Discovery, Shionogi & Co., Ltd.) for
evaluating MraY inhibitory activity of the synthesized
analogues.
Compound 38. A solution of 37 (60 mg, 0.077 mmol) and DMAP
(23.5 mg, 0.192 mmol) in MeCN (1 mL) was treated with O-phenyl
chlorothionocarbonate (19.9 mg, 0.115 mmol) at 0 °C under N2. The
mixture was stirred at room temperature for 2 h. The reaction mixture
was diluted with saturated aqueous NH4Cl and extracted with EtOAc.
The combined organic layers were washed with saturated aqueous
NaHCO3 and brine, dried over Na2SO4, filtrated, and concentrated in
vacuo. The residue was purified by silica gel column chromatography
(2 × 7.5 cm, 50−100% EtOAc/Hexane) to give 38 (48 mg, 75%) as a
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NOTE ADDED AFTER ASAP PUBLICATION
■
The version of this paper published on the web on January 18,
2012 contained errors in Table 5, the Conclusion, and the char-
acterization of compounds 7b, 32, and 37 in the Experimental
Section. The corrected version was reposted on January 23,
2012.
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1377
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