Synthesis and antitumor activities of aquayamycin and analogues of derhodinosylurdamycin A

Article abstract of DOI:10.1039/C9OB00121B

Total syntheses of aquayamycin (3) and a number of analogues of angucycline antitumor antibiotic derhodinosylurdamycin A bearing various 2-deoxy sugar subunits (4-7) have been achieved. These molecules (3-7) were synthesized based on a convergent strategy for the synthesis of derhodinosylurdamycin A (2) previously reported from our group. In particular, our recently developed mild cationic gold-catalyzed glycosylation with S-but-3-ynyl thioglycoside donors was employed for the synthesis of analogues (6 and 7) bearing disaccharide subunits containing α-l-olivoside and α-l-olioside moiety, respectively. Aquayamycin (3), analogues (4-7), and our previously synthesized derhodinosylurdamycin A (2) were then submitted to the Development Therapeutics Program of the National Cancer Institute of National Institutes of Health for the NCI-60 Human Tumor Cell Lines Screening using standard protocols. It was found that derhodinosylurdamycin A (2), aquayamycin (3), and three other analogues (5-7) bearing sugar subunits did not show significant antiproliferative activity against those cancer cell lines. Interestingly, analogue (4) bearing no sugar subunit demonstrates good potential for growth inhibition and cytotoxic activity against a variety of human cancer cell lines.

Full text of DOI:10.1039/C9OB00121B

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DOI: 10.1039/C9OB00121B
Organic & Biomolecular Chemistry
PAPER
Synthesis and antitumor activities of aquayamycin and analogues
of derhodinosylurdamycin A†
Padam P. Acharya, Hem Raj Khatri, Sandip Janda, and Jianglong Zhu*
Received 00th January 20xx,
Accepted 00th January 20xx
Total syntheses of aquayamycin (3) and a number of analogues of angucycline antitumor antibiotic derhodinosylurdamycin
A bearing various 2-deoxy sugar subunits (4-7) have been achieved. These molecules (3-7) were synthesized based on a
convergent strategy for the synthesis of derhodinosylurdamycin A (2) previously reported from our group. In particular, our
recently developed mild cationic gold-catalyzed glycosylation with S-but-3-ynyl thioglycoside donors was employed for the
synthesis of analogues (6 and 7) bearing disaccharide subunits containing α-L-olivoside and α-L-olioside moiety, respectively.
Aquayamycin (3), analogues (4-7), and our previously synthesized derhodinosylurdamycin A (2) were then submitted to the
Development Therapeutics Program of the National Cancer Institute of National Institutes of Health for the NCI-60 Human
Tumor Cell Lines Screening using standard protocols. It was found that derhodinosylurdamycin A (2), aquayamycin (3), and
three other analogues (5-7) bearing sugar subunits did not show significant antiproliferative activity against those cancer
cell lines. Interestingly, analogue (4) bearing no sugar subunit demonstrates good potential for growth inhibition and
cytotoxic activity against a variety of human cancer cell lines.
DOI: 10.1039/x0xx00000x
www.rsc.org/
numerous synthetic studies have been reported toward the urdamycin
family antibiotics including aquayamycin (urdamycinone A)
Introduction
1
8
19-23
tetracyclic core structure as well as urdamycinone B
and related
Angucycline antibiotics are a class of bioactive natural products
containing an angularly assembled tetracyclic ring frame and diverse
sugar subunits, and they exhibit a wide range of biological activities
such as antimicrobial, antifungal, antitumor, enzyme inhibiting, and
24-25
structures.
However, due to the highly labile nature of the
26
aquayamycin core system, thus far only two groups have
independently accomplished the total synthesis of aquayamycin (3).
In 2000, Suzuki and co-workers reported the first total synthesis of
platelet aggregation inhibiting activities.1 The urdamycins (cf. 1
and 2, Fig. 1) are a subclass of angucyclines first isolated in 1986 and,
structurally, they are related to an early isolated molecule,
-4
5-9
27-29
30-
aquayamycin.
Their key strategy involves a Hauser annulation
31
of β-C-glycosylated 3-(benzenesulfonyl)phthalide and a complex
cyclohexanone followed by an intramolecular pinacol coupling to
construct the tetracyclic angular aglycon. Recently in 2016, Toshima
1
0
aquayamycin (3). Aquayamycin was also known as urdamycinone
A and it contains a C-glycosylated benz[a]anthraquinone core and a
cis-diol at the ring junction (3). Other known aquayamycin-type
26
and co-workers reported the second synthesis of aquayamycin and
1
0
key steps include: 1) a diastereoselective 1,2-addition of C-glycosyl
naphthyllithium to a cyclic ketone derived from D-(-)-quinic acid; 2)
an indium-mediated site-selective allylation-rearrangement; and 3) a
diastereoselective intramolecular pinacol coupling. This synthetic
route was relatively shorter and may be more practical to access
aquayamycin-type angucycline antibiotics.
1
1
12
1
angucycline antibiotics include saquayamycins, vineomycin A ,
1
3
and PI-080. Among urdamycin family antiobiotics, urdamycin A
and derhodinosylurdamycin A share the same 2-deoxy trisaccharide
subunit consisting of two D-olivoses and one L-rhodinose C-linked to
5
the tetracyclic core (Fig. 1). Structurally, urdamycin A (1) was
identical to a previously isolated molecule Kerriamycin B, while
derhodinosylurdamycin A (2)
The urdamycins were reported to be active against Gram-positive
bacteria and murine L1210 leukemia stem cells. For instance,
urdamycin A and derhodinosylurdamycin A possess significant
anticancer activity against L1210 Leukemia stem cells with an IC50
value of 0.55 and 0.75 μg/ml, respectively. In addition, aquayamycin
While there has not been a total synthesis of urdamycin A reported
thus far, in 2015 our group accomplished the first and only total
1
4-15
16
was the same as Kerriamycin C.
32
synthesis of derhodinosylurdamycin A (2). As shown in Scheme 1,
the synthesis was achieved by employing a modified strategy based
27-29
on Suzuki’s work
and the strategy was specifically designed in
order to facilitate the preparation of derhodinosylurdamycin A
analogues bearing different sugar subunits for structure and activity
relationship (SAR) studies. In brief, Hauser annulation of
(3) was found to inhibit tyrosine hydroxylase and is active against
Gram-positive bacteria, Ehrlich ascites carcinoma, and Yoshida rat
28
cyanophthalide 8 and known complex enone 9 followed by pinacol
1
7
sarcoma cells.
coupling and necessary functional group manipulations afforded
tetracyclic aryliodide 10 (confirmed by single-crystal X-ray
crystallographic analysis). Next, Stille coupling of glycal stannane 11
The complex structures and interesting biological properties of the
urdamycins have drawn a great deal of attention. Since their isolation,
3
3-
with tetracyclic aryliodide 10 followed by stereoselective reduction
3
4
of the resulting enol ether and desilylation provided β-C-
Department of Chemistry and Biochemistry and School of Green Chemistry and
Engineering, The University of Toledo, Toledo, OH, 43606, USA. Email:
Jianglong.Zhu@utoledo.edu
arylglycoside 12. Stereoselective α-glycosylation between
disaccharide donor 13 and acceptor 12 gave derhodinosylurdamycin
A (2).
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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DOI: 10.1039/C9OB00121B
Organic & Biomolecular Chemistry
PAPER
OH
O
O
HO
O
O
O
X
O
O
O
urdamycin A (1) X =
Y =
OH
OH
O
O
O
HO
HO
O
O
Y
HO
O
O
OH
derhodinosylurdamycin A (2) X = OH,
previously synthesized by the Zhu group32
)
Y =
HO
(
HO
O
HO
aquayamycin (urdamycinone A) (3) X = OH, Y = HO
O
HO
(
previously synthesized by Suzuki27-29 and Toshima26
)
O
O
HO
OH
analogue (4) X = OH, Y = H
analogue (6) X = OH, Y =
O
HO
O
HO
HO
O
O
analogue (5) X = OH, Y =
analogue (7) X = OH, Y =
OH
HO
Fig. 1 Urdamycin A, derhodinosylurdamycin A, aquayamycin, and related molecules.
Previously, limited structure and activity relationship (SAR) amenable to the preparation of analogues of derhodinosylurdamycin
studies of urdamycin family antitumor antibiotics were reported based A, we decided to carry out the synthesis and explore the structure and
on the derivatization of limited amounts of isolated naturally activity relationship of by varying the structures of the 2-deoxy sugar
occurring molecules.14 Since the actual mode of action of the subunits. Herein, we wish to report the synthesis of aquayamycin (3)
urdamycins is not exactly known, it would be appealing to chemically and several analogues of derhodinosylurdamycin A (cf. 4-7, Fig. 1) as
prepare these molecules as well as their analogues for biological well as their antitumor activities.
studies. With the successful development of a convergent strategy
derhodinosylurdamycin A (2)
O
OAc
O
BnO
BnO
O
13
previously reported
in reference 32
O
OTBDPS
O
MeO
HO
O
OBn
O
O
BnO
O
MeO
HO
OBn
OBn TBSO
O
9
SnBu3
O
O
OH
OMs
11
BnO
HO
OH
OH
I
I
CN
OBn
BnO MeO
BnO MeO
12
8
10
this work
this work
aquayamycin (3) and
analogues (6 and 7)
analogues (4 and 5)
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Scheme 1 Our strategies for the synthesis of derhodinosylurdamycin A (2), aquayamycin (3), and analogues (4-7)._
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converted to aquayamycin (3) in 68% yield fDoOlloI:w10in.1g03o9u/Cr 9pOreBv0i0o1u2s1lBy
reported three-step sequence: 1) cerium(IV) ammonium nitrate
(CAN)-mediated oxidation of 15 to the corresponding quinone; 2)
quick Pd/C-catalyzed hydrogenolysis to remove the phenolic benzyl
ether and concomitant reduction of the quinone to hydroquinone
followed by oxidation of the hydroquinone back to quinone via
exposure to the air; 3) N,N-diisopropylethylamine-mediated
elimination of the mesylate. Similarly, analogue (4) was prepared
from known tetracyclic aryliodide (10) in five steps: 1) selective
mesylation of the secondary alcohol of 10 to give 16; 2) Pd/C-
catalyzed global hydrogenolysis of 16 for removal of aryl iodide and
benzyl ethers to produce 17 (62% yield in two steps); 3) selective
protection of the phenol as its benzyl ether 18 (70% yield); 4) CAN
oxidation of 18 to the corresponding quinone; 5) Pd/C-catalyzed
hydrogenolysis to remove the phenolic benzyl ether and concomitant
reduction of the quinone to hydroquinone followed by air-mediated
oxidation of the hydroquinone back to quinone and subsequent
spontaneous elimination (66% over 2 steps).
Results and discussion
Chemistry
In general, our syntheses of aquayamycin (3) and analogues (4-7)
follow our previously reported strategy for the synthesis of
derhodinosylurdamycin A (2). The highly functionalized building
blocks, including tetracyclic aryliodide (10) and partially protected β-
C-arylglycoside (12), were prepared in good quantities from
commercially available starting substrates following previously
3
2
disclosed strategies and procedures. As shown in Scheme 2, global
3
2
debenzylation of known β-C-arylglycoside 12 via palladium on
carbon-catalyzed global hydrogenolysis afforded desired product 14
which upon selective protection of the phenol provided key
intermediate 15 (79% yield over 2 steps). Next, compound 15 was
O
HO
o
MeO
OR
1. CAN, CH3CN, 0 C,
O
HO
2
. H , Pd/C, EtOAc/MeOH
O
OH
2
RT, then air
O
OH
RO
HO
O
OH
OMs
HO
HO
3. iPr NEt, dioxane, 40 C,
o
OR' OMe
2
68% for 3 steps
OH O
1
2 R = R' = Bn
4 R = R' = H
Pd/C, H (40 psi)
EtOAc/MeOH, RT
2
aquayamycin (urdamycinone A) ( )
3
1
Cs CO , BnBr,
2
3
DMF, RT, 79%
for 2 steps
15 R = H, R' = Bn
O
MeO
HO
O
o
1
. CAN, CH CN/CH Cl , 0 C,
MeO
HO
3
2
2
O
OR
OH
O
O
2. H , Pd/C, EtOAc/MeOH
Cs CO , BnBr,
DMF, RT,
2
HO
OH
OH
2
3
RT, then air
OH
OY
OH
OMs
X
70%
66% for 2 steps
R'O MeO
BnO MeO
HO
18
MsCl, DMAP,
pyridine, RT
10 R = R' = Bn, X = I, Y = H,
analogue (4)
1
6 R = R' = Bn, X = I, Y = Ms
7 R = R' = X = H, Y = Ms
Pd/C, H , RT
EtOAc/MeOH,
2
1
62% for 2 steps
Scheme 2 Synthesis of aquayamycin (3) and analogue (4).
hydroquinone back to quinone; 4) N,N-diisopropylethylamine-
The synthesis of analogue (5) commenced with the preparation of mediated elimination of the mesylate (69% over 3 steps).
D-fucal stannane 19 which was obtained from 3,4-di-O-tert-
3
5
36
butyldimethylsilyl-D-fucal in four steps: 1) lithiation of the C1 of
In order to prepare analogues (6) and (7) bearing 2-deoxy
glycal followed by stannylation; 2) global silyl ether deprotection to disaccharide subunit, we chose to utilize our recently developed mild
the diol; 3) regioselective silylation of the hydroxyl group at C3; and cationic gold(I)-catalyzed glycosylation methodology employing S-
3
7
4
) benzylation of the remaining C4-hydroxyl group. Next, Stille but-3-ynyl thioglycoside donors. In the event, cationic (4-
coupling of D-fucal stannane 19 with tetracyclic aryliodide 10 which CF Ph) PAuOTf-catalyzed glycosylation between readily available
3
3
3
6
provided C-arylated D-fucal 20 in 70% yield (Scheme 3). Mesylation L-olivose-derived S-but-3-ynyl thioglycoside donor 24 and β-C-
of the secondary alcohol of 20 followed by stereoselective reduction arylglycoside 12 acceptor afforded corresponding disaccharide in
3
6
of the enol ether moiety and concomitant acid-mediated desilylation 91% yield as a mixture of inseparable α/β anomers (α/β, 2/1). The
afforded β-C-arylglycoside 22 (70% yield over two steps). Likewise, inseparable α/β anomers were then subjected to global debenzylation
analogue (5) was prepared from 22 in five steps: 1) removal of all by Pd/C-catalyzed hydrogenolysis. Once all benzyl ethers were
three benzyl ethers of 22 by Pd/C-catalyzed global hydrogenolysis removed, α/β anomers can be separated and the α-disaccharide was
and subsequent selective protection of the phenol as its benzyl ether obtained in 36% yield after purification. The α-anomer was then
2
3 (65% yield over two steps); 2) CAN oxidation of 23 to the subjected to selective benzylation of the phenol to provide desired
corresponding quinone; 3) Pd/C-cataylzed hydrogenation to remove product 26 in 63% yield (21% yield over three steps). Next,
the phenolic benzyl ether and concomitant reduction of the quinone to intermediate 26 was converted to analogue (6) following
hydroquinone followed by air-mediated oxidation of the aforementioned strategy: 1) CAN oxidation of 26 to the corresponding
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ARTICLE
Journal Name
quinone; 2) Pd/C-cataylzed hydrogenation to remove the phenolic quinone followed by spontaneous elimination of the mVieewsyAlratitcele(O8n4li%ne
benzyl ether and concomitant reduction of the quinone to overall). Similarly, cationic
(4-CF D3 POhI:) 13 0P.A10u3O9/TCf9-OcaBt0a0ly1z2e1Bd
hydroquinone; 3) air-mediated oxidation of the hydroquinone back to glycosylation between readily available L-oliose-derived S-but-3-
O
O
MeO
1
0, Pd(PPh ) Cl ,
BnO
TBSO
3 2
o
2
MeO
HO
NaBH CN,
HCl, EtOH,
HO
OBn
3
OBn
BnO
HO
toluene, 100 C,
O
BnO
O
OH
OMs
O
OH
OR
SnBu3 70% TBSO
RT, 70% for
2 steps
1
9
BnO MeO 22
BnO MeO
2
0 R = H
MsCl, DMAP,
pyridine, RT
1. Pd/C, MeOH/EtOAc(1/1),
H (40 psi), RT, 89%
2
21 R = Ms
2
. Cs CO , BnBr, DMF, RT
2
3
65%
o
1
. CAN, CH CN, 0 C,
3
O
O
O
MeO
HO
2
. H , Pd/C, EtOAc/MeOH
2
OH
HO
OH
OH
HO
HO
RT, then air
HO
HO
O
OH
O
i
o
3
. Pr NEt, dioxane, 40 C,
2
OMs
69% for 3 steps
BnO MeO
HO
O
23
analogue (5)
Scheme 3 Synthesis of analogue (5) bearing β-C-aryl D-olioside moiety.
disaccharide was separated from its β-anomer and obtained in 56%
ynyl thioglycoside donor 2536 and β-C-arylglycoside 12 acceptor yield after purification. The α-anomer was then subjected to selective
afforded corresponding disaccharide in 84% yield as a mixture of benzylation of the phenol to provide desired product 27 in 57% yield
inseparable α/β anomers. Upon global debenzylation of this mixture (27% yield over three steps). Likewise, intermediate 27 was converted
of inseparable α/β anomers by Pd/C-catalyzed hydrogenolysis, the α- to analogue (7) following aforementioned two-step sequence (75%
overall).
O
O
MeO
HO
OH
MeO
HO
OBn
1
. (4-CF Ph) PAuCl, AgOTf, CH Cl , RT,
3 3 2 2
glycosyl donor 24 or 25;
O
OH
OMs
O
OH
HO
BnO
HO
O
OMs
2. Pd/C, H (40 psi), EtOAc/MeOH, RT
2
OBn OMe
OBn OMe
3. Cs CO , BnBr, DMF, RT
2
3
O
X
12
OH
Y
2
2
6 X = OH, Y = H (21% over 3 steps)
7 X = H, Y = OH (27% over 3 steps)
o
1
. CAN, CH CN, 0 C;
3
2
. H , Pd/C, EtOAc/MeOH
2
S
RT, then air
O
O
HO
OH
O
24
BnO
OBn
O
OH
HO
O
S
OH O
O
O
X
25
OH
OBn
Y
BnO
analogue (6) X = OH, Y = H (84% overall)
analogue (7) X = H, Y = OH (75% overall)
Scheme 4 Synthesis of analogues (6 and7).
Biological studies
quinonoid
structures may
significantly
influence
their
oxidative/reductive properties. In general, the cytotoxicity of
quinonoid molecules are attributed to two major mechanisms: 1)
promoting oxidative stress; and 2) deactivation of cellular
nucleophiles via alkylation/nucleophilic addition. For instance, β-
lapachone, a recently naturally occurring ortho-naphthoquinone and a
novel drug for cancer treatment, has been known to induce apoptosis
Quinonoid molecules, especially naphthoquinones, demonstrate
excellent efficiency in cancer chemotherapeutic treatment. They are
well-known as oxidizing or dehydrogenating agents which undergo
reduction very easily. In addition, quinones are electrophiles which
can be attacked by a variety of nucleophiles. The presence of an
electron-withdrawing group or electron-donating substitution on the
3
8
4
| J. Name., 2012, 00, 1-3
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ARTICLE
in various human cancer cell lines by inhibiting DNA topoisomerase
View Article Online
DOI: 10.1039/C9OB00121B
3
9
I and II. Recently, it was also found that the anticancer activity of β-
4
0
lapachone may be due to its inhibition of allosteric 5-lipoxygenase.
In addition, β-lapachone and structurally related ortho-
naphthoquinone, rhinacanthone, were also extensively investigated
a
4
1
4
2-44
in SAR studies
for their cytotoxicity against cancer cell lines.
With newly synthesized aquayamycin (3), analogues (4-7) and
previously prepared derhodinosylurdamycin A (2) in hand, we
decided to evaluate their antiproliferative activities against various
cancer cell lines. After careful consideration, we submitted these
molecules to the Development Therapeutics Program of the National
Cancer Institute of National Institutes of Health for the NCI-60
Human Tumor Cell Lines Screening using standard protocols. These
known 60-cell panel contains a variety of human cell lines of leukemia,
non-small cell lung cancer, colon cancer, CNS cancer, melanoma,
ovarian cancer, renal cancer, prostate cancer, and breast cancer, would
be ideal for in vitro assay of our synthesized molecules.
Initially, six compounds 2-7 were evaluated for their
antiproliferative activities against 60 human cancer cell lines at 10 µM
concentration. The growth percent for selected cancer cells in the
presence of each of these six molecules at 10 µM concentration are
shown in Table 1 and also illustrated using by dynamic heat map
presentation. The growth percent for all 60 cancer cells in the presence
of each of these six molecules at 10 µM concentration are provided in
the Supporting Information. Despite that it was known that
derhodinosylurdamycin A (2) is active against L1210 Leukemia stem
1
4
cells and aquayamycin (3) is active against Ehrlich ascites
1
7
carcinoma and Yoshida rat sarcoma cells, to our surprise, in this
NCI-60 Human Tumor Cell Lines Screening none of
derhodinosylurdamycin A (2), aquayamycin (3), and analogues 5-7
bearing various 2-deoxy sugar subunits showed significant
antiproliferative activities against these 60 human cancer cell lines.
Gratifyingly, analogue 4 demonstrated potent growth inhibition
against a broad range of human cancer cell lines, especially for some
colon, melanoma, ovarian, renal, prostate, and breast cancer cell lines.
Despite numerous previous reports indicating that sugar play critical
4
5-46
roles in the bioactivity of their carrier molecules,
the biological
Table 1
Selected Results showing antiproliferative activity of
studies herein indicated that sugars do not help improve the anticancer
activity of these aquayamycin-type of angucycline antibiotics.
compounds 2-7 in the NCI-60 human tumor cell lines screening at 10
µM.
Next, due to its promise analogue (4) was advanced to next level
and subjected to five dose testing at 10 nM, 100 nM, 1 μM, 10 μM,
and 100 μM. The GI50 values are provided in Table 2 and also
illustrated using by dynamic heat map presentation. The
comprehensive list of GI50, TGI, and LC50 values of analogue (4) as
well as dose response curves and mean graphs for all 60 cell lines are
provided in the Supporting Information. As shown in Table 2, the
GI50 values of analogue (4) range from approximately 0.23 μM to 18
μM against all the 60 human cancer cell lines. It was found that
analogue (4) was most active against colon cancer cell COLO 205
(
GI50 0.229 μM), Leukemia cell CCRF-CEM (GI50 0.342 μM),
Melanoma MALME-3M (GI50 0.492 μM), Renal cancer cell ACHN
GI50 0.5 μM), and breast cancer cell MCF7 (GI50 0.257 μM). In
(
general, analogue (4) was found not very active against CNS cancer
cell lines, some of the non-small cell lung cancer cell lines and ovarian
cancer cell lines. Overall, analogue (4) showed good potential for
growth inhibition and cytotoxic activity against a variety of human
cancer cell lines.
Table 2 GI50 values of MTS assay on survival of NCI-60 human tumor
cell lines treated with analogue A (4) at 10 nM, 100 nM, 1 μM, 10 μM,
and 100 μM.
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1
Proton and carbon nuclear magnetic resonance spectra ( H NMR
View Article Online
and 13C NMR) were recorded on either BruDkOeIr: 1600.1003(9H/C9NOMB0R0-16201B0
1
1
3
MHz; C NMR 150 MHz) at ambient temperature with CDCl
CD OD as the solvent unless otherwise stated. Chemical shifts are
reported in parts per million relative to residual protic solvent internal
3
or
3
1
13
1
13
standard CDCl
3 3
( H, δ 7.26; C, δ 77.36), CD OD ( H, δ 3.31; C δ
1
4
9.15). Data for H NMR are reported as follows: chemical shift,
integration, multiplicity (app = apparent, par obsc = partially obscure,
ovrlp = overlapping, s = singlet, d = doublet, dd = doublet of doublet,
t = triplet, q = quartet, m = multiplet) and coupling constants in Hertz.
1
3
All C NMR spectra were recorded with complete proton decoupling.
High resolution mass spectrometry (HRMS) was performed on a TOF
mass spectrometer. Optical rotations were measured with Autopol-IV
digital polarimeter; concentrations are expressed as g/100 mL. All
reagents and chemicals were purchased from Acros Organics, Sigma
Aldrich, Fisher Scientific, Alfa Aesar, and Strem Chemicals and used
without further purification. THF, methylene chloride, toluene, and
diethyl ether were purified by passing through two packed columns of
neutral alumina (Innovative Technology). Anhydrous DMF and
benzene were purchased from Acros Organics and Sigma-Aldrich and
used without further drying. All reactions were carried out in oven-
dried glassware under an argon atmosphere unless otherwise noted.
Analytical thin layer chromatography was performed using 0.25 mm
silica gel 60-F plates. Flash column chromatography was performed
using 200-400 mesh silica gel (Scientific Absorbents, Inc.). Yields
refer to chromatographically and spectroscopically pure materials,
unless otherwise stated.
Despite that the cytotoxic mechanism for these aquayamycin-type
molecules (2-7) is not clear, it may be due to the electrophilic property
of the 2-vinylnaphthoquinone moiety. In principle, protein or cellular
nucleophiles may add to the 2-vinylnaphthoquinone moiety via
Michael-type addition and, therefore, get deactivated. This relatively
reactive 2-vinylnaphthoquinone moiety may also be responsible to the
labile nature of these molecules. In addition, analogue (4) lacking the
sugar subunit contains less polar hydroxyl groups and may be more
lipophilic than derhodinosylurdamycin A (2), aquayamycin (3), and
other anlogues (5-7). The more potent cytotoxicity of analogue (4)
discovered according to our experiments is also in agreement with
Aquayamycin (3). To a solution of partially protected β-C-
3
2
arylglycoside 12 (30 mg, 0.034 mmol) in 1.4 mL of mixed solvents
EtOAc/MeOH, 1/1, v/v), 10% palladium on carbon (36.2 mg, 0.034
(
mmol) was added. After being evacuated and filled with hydrogen
five times, the reaction mixture was stirred at room temperature under
positive hydrogen pressure (40 psi) for 32 h. The reaction mixture was
then diluted with CH Cl /MeOH (10/1, v/v), filtered through celite,
2 2
and concentrated to afford crude compound 14 (20.8 mg, quantitative)
previous report that increase of the lipophilicity of organic molecules
improved their cytotoxicity.41
which was used directly in the next step without purification. A
solution of compound 14 (20.8 mg, 0.034 mmol) in 0.74 mL DMF
º
was cooled at 0 C. To this solution was added Cs
2
CO
3
(13.3 mg, 0.041
mmol) followed by addition of 37 µL stock solution of benzyl
bromide in DMF (0.051 mmol, 1.5 eq.) (Note: the stock solution was
Conclusions
In conclusion, we have described the total syntheses of aquayamycin prepared by adding 40 µL of benzyl bromide in 200 µL DMF). The
3) and a number of analogues of angucycline antitumor antibiotic reaction mixture was stirred at room temperature for 5 h before being
derhodinosylurdamycin A bearing various 2-deoxy sugar subunits (4- quenched with a pinch of solid ammonium chloride. DMF was
). These molecules were prepared from commercially available removed by air flow and the residue was purified by using preparative
starting substrates in approximately 30 linear steps following a TLC in CH Cl /MeOH (10/1, v/v) to afford 18.9 mg (79% yield) of
(
7
2
2
convergent strategy previously reported for the synthesis of compound 15. Next, A solution of 15 (14.6 mg, 0.021 mmol) in 1.3
º
derhodinosylurdamycin A from our group. It is worth noting that the mL of acetonitrile was cooled at 0 C and 83 µL of stock solution of
α-L-olivoside and α-L-olioside moiety in analogues C and D were cerium ammonium nitrate in water (0.0624 mmol, 3 eq.) was added
installed by using our recently developed mild cationic gold-catalyzed (Note: the stock solution was prepared by adding 174 mg of cerium
glycosylation using S-but-3-ynyl thioglycoside donors. Upon NCI-60 ammonium nitrate in 400 µL water). The reaction mixture was stirred
º
Human Tumor Cell Lines Screening by the Development at 0 C for 35 min before being diluted with 4 mL ethyl acetate. 0.5
Therapeutics Program of the National Cancer Institute of National mL of ice cooled saturated NaHCO
Institutes of Health, it was found that none of aquayamycin, analogues mixture was stirred for 2 minutes. The organic layer was separated
A-D, and our previously synthesized derhodinosylurdamycin A and passed through a small pad of Na SO , concentrated under reduce
3
was added and the resulting
2
4
bearing diverse 2-deoxy sugar subunits demonstrated significant pressure, and kept in vacuum for 10 minutes. This crude material was
antiproliferative activity against those cancer cell lines. Interestingly, dissolved in 0.26 mL of mixed solvents (EtOAc/MeOH, 1:1, v/v) and
analogues (4) bearing no sugar subunit demonstrates good potential 10% palladium on carbon (4.4 mg, 0.0042 mmol) was added. The
for growth inhibition and cytotoxic activity against most of the 60 mixture was evacuated and filled with hydrogen for three times. After
human cancer cell lines, except CNS cancer cells, some of the non- being stirring at room temperature under positive hydrogen pressure
small cell lung cancer cells and ovarian cancer cell lines.
for 30 min, the reaction mixture was diluted with methanol, filtered
through celite, and concentrated under reduced pressure. The resulting
crude compound was dissolved in 0.8 mL of 1,4-dioxane and N,N-
diisopropylethylamine (7.3 µL, 0.042 mmol) was added. After being
stirred at 40 C for 1 h, the reaction mixture was cooled down. Dioxane
was removed by air flow and the residue was purified by preparative
Experimental
Chemistry
º
TLC in CH
2
Cl
2
/MeOH (10/1, v/v) to furnish 6.9 mg of aquayamycin
Methods and materials
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 12
O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Journal Name
ARTICLE
2
3
º
(
3) as dark red solid (68% yield for 3 steps). [훼]D = 119.8 (c = 0.1, methanol, filtered through celite, and concentrated uVinedweArrticreledOuncliende
CH
3
OH); FT-IR (thin film): 3367, 2963, 2921, 2852, 1723, 1637, pressure. The residue was purified byDOpI:re1p0a.1r0a3t9iv/Ce9OTBL0C0121iBn
CH Cl /MeOH (20/1, v/v) to furnish 6.2 mg of analogue A (4) as dark
-1 1
1
563, 1260, 1055, 650 cm ; H NMR (600 MHz,CD
J=7.9 Hz, 1 H), 7.59 (d, J=7.7 Hz, 1 H), 6.87 (d, J=9.7 Hz, 1 H), 6.40 red solid (66 % yield for 2 steps).
d, J=9.7 Hz, 1 H), 4.90 (br. s., 1 H), 3.69 (ddd, J=11.2, 8.8, 5.0 Hz, 1 FT-IR (thin film): 3369, 2976, 2930, 1725, 1635, 1456, 1086, 1045,
3
OD)  7.86 (d,
2
2
2
3
º
[훼]
D = -48.0 (c = 0.1, CH
OH);
3
(
-
1 1
H), 3.42 - 3.46 (m, 1 H), 3.03 (t, J=9.0 Hz, 1 H), 2.82 (d, J=12.8 Hz, 696 cm ; H NMR (600 MHz, CD
H), 2.66 (dd, J=12.9, 2.1 Hz, 1 H), 2.37 - 2.46 (m, 1 H), 2.01 - 2.06 H), 7.58 (dd, J=7.5, 1.1 Hz, 1 H), 7.31 (dd, J=8.4, 0.9 Hz, 1 H), 6.87
m, 2 H), 1.37 (d, J=6.2 Hz, 4 H), 1.24 (s, 3 H) ppm; 13C NMR (150 (d, J=9.9 Hz, 1 H), 6.41 (d, J=9.7 Hz, 1 H), 2.84 (d, J=12.8 Hz, 1 H),
MHz, CD
OD)  206.94, 190.43, 183.60, 158.92, 145.91, 140.48, 2.67 (dd, J=12.9, 2.3 Hz, 1 H), 2.03 - 2.05 (m, 2 H), 1.24 (s, 3 H) ppm;
3
OD)  7.71 (dd, J=8.3, 7.5 Hz, 1
1
(
3
1
3
1
7
39.89, 139.31, 134.29, 132.24, 120.03, 118.12, 115.44, 82.09, 78.80,
3
C NMR (150 MHz, CD OD)  206.96, 189.47, 183.73, 162.69,
8.64, 77.76, 77.67, 73.57, 72.49, 53.25, 44.73, 41.11, 30.17, 18.61 146.35, 140.37, 139.90, 138.00, 133.59, 125.29, 120.07, 118.22,
ppm; ESI-HRMS [M+Na] calculated for C25H26NaO10 509.1424, 115.95, 82.10, 78.67, 77.72, 53.24, 44.72, 30.16 ppm; ESI-HRMS
[M+Na] calculated for C19
Glycal stannane (19). To a flame-dried round-bottomed flask
.162 mmol) in 0.8 mL anhydrous pyridine, methanesulfonyl chloride containing potassium tert-butoxide (2.4 g, 21.2 mmol) in 15 mL dry
19 µL, 0.243 mmol) and 4-dimethylaminopyridine (2 mg, 0.0162 THF (dried with n-BuLi using 1,10-phenanthroline as an indicator)
+
+
found 509.1438.
7
H16NaO 379.0794, found 379.0796.
3
2
Mesylate (18). To a solution of tetracyclic aryliodide 10 (115 mg,
0
(
º
mmol) were added. The resulting mixture was stirred at room cooled at -78 C, was added 22 mL of 1.6 M n-BuLi (35.4 mmol). To
temperature for 24 h before pyridine was removed by air flow. The this mixture was added a solution of 3,4-di-O-tert-butyldimethylsilyl-
3
5
reaction mixture was diluted with CH
2 2
Cl , washed sequentially with D-fucal (4.23 g, 11.8 mmol) in 8.5 mL dry THF and the resulting
º
saturated CuSO solution, water, and brine. The organic layer was mixture was stirred at -78 C for 1 h. 9.5 mL of tri-n-butyltin chloride
4
separated, dried over sodium sulfate, filtered, and concentrated under (35.4 mmol) was then added, and the resulting mixture was warmed
reduce pressure to produce crude compound 16 which was directly to room temperature and stirred for 1 h. The reaction mixture was
used in the next step. To a solution of 16 in 2 mL of EtOAc/MeOH quenched with saturated NaHCO
3
and extracted with ethyl acetate.
(4/1, v/v), 10% palladium on carbon (172 mg, 0.162 mmol) was The combined organic fractions were washed with water and brine,
added. After the reaction mixture was evacuated and filled with dried over sodium sulfate, and concentrated under reduce pressure.
hydrogen for three times, it was stirred at room temperature under The residue was then passed through a small pad of silica using
positive hydrogen pressure for 13 days. The reaction mixture was hexanes as the eluent, and the organic fractions were concentrated to
2 2
diluted with CH Cl /MeOH (10:1, v/v), filtered through celite, and afford crude glycal stannane which was used directly in the next step.
concentrated under reduce pressure. The residue was purified by using To a solution of this crude glycal stannane in 39 mL THF cooled at 0
º
preparative TLC in CH
2 2
Cl /MeOH (15/1, v/v) to afford 48.8 mg (62% C was added 35.4 mL of 1.0 M tetra-n-butyl ammonium fluoride
yield for 2 steps) of desired compound 17. To a solution of compound (35.4 mmol) and the resulting mixture was stirred at room temperature
º
1
7 (48.8 mg, 0.101 mmol) in 2.2 mL DMF cooled at 0 C was added for 10 h. Saturated aqueous NaHCO
Cs CO (40 mg, 0.122 mmol). After the addition of benzyl bromide was removed under reduce pressure. The aqueous layer was extracted
18 µL, 0.152 mmol), the resulting mixture was stirred at room with ethyl acetate and combined organic extracts were washed
temperature for 6 h. The reaction mixture was quenched with a pinch sequentially with water and brine, dried over sodium sulfate, and
of solid NaHCO and DMF was removed by air flow. The residue was concentrated. The crude residue was purified by silica gel flash
purified via preparative TLC (hexanes/ethyl acetate, 1/1, v/v) to give column chromatography (hexanes/ethyl acetate, 10/1 to 4/1, with 1%
3
solution was added and THF
2
3
(
3
2
3
º
4
0
1
7
0.5 mg (70% yield) of the desired mesylate 18. [훼]D = -75.0 (c = Et
.1, CHCl
); FT-IR (thin film): 3445, 2972, 2861, 1720, 1572, 1326, of this diol (1.13 g, 2.69 mmol) in 2.7 mL DMF were added Et
167, 1053, 926, 697 cm ; H NMR (600 MHz, CD
.65 (m, 1 H), 7.57 - 7.60 (m, 2 H), 7.39 - 7.44 (m, 3 H), 7.32 - 7.36
3
N) to provide 2.13 g (43% yield for 2 steps) of diol. To a solution
3
N (1.87
3
-1
1
mL, 13.5 mmol) and tert-butyldimethylsilyl chloride (0.44 g, 2.96
mmol). The resulting mixture was stirred at room temperature for 10
h before being quenched with water. The mixture was extracted with
ethyl acetate, and combined organic extracts were washed with water
and brine, dried over sodium sulfate, and concentrated under reduce
pressure. The crude residue was purified by silica gel flash
3
OD)  7.63 -
(
m, 1 H), 7.11 (d, J=7.3 Hz, 1 H), 5.21 - 5.26 (m, 2 H), 5.03 (dd, J=5.8,
1
3
2
1
1
1
6
.4 Hz, 1 H), 3.77 (s, 3 H), 3.69 - 3.74 (m, 1 H), 3.68 (s, 3 H), 3.51 -
.58 (m, 1 H), 3.18 (s, 3 H), 2.76 (d, J=12.7 Hz, 1 H), 2.56 (dd, J=12.7,
.9 Hz, 1 H), 1.98 (dd, J=14.9, 2.9 Hz, 1 H), 1.88 (d, J=14.7 Hz, 1 H),
OD)  207.23, 156.29,
52.24, 151.19, 138.41, 131.73, 129.52, 128.99, 128.90, 127.72,
23.00, 122.56, 116.46, 110.27, 82.08, 79.14, 79.05, 76.07, 72.46,
1
3
chromatography (hexanes/ethyl acetate, 10/1, with 1% Et N) to afford
.16 (s, 3 H) ppm; C NMR (150 MHz, CD
3
3
1
.33 g (93% yield) of glycal stannane 3-O-TBS ether. To a solution
of this glycal stannane 3-O-TBS ether (1.33 g, 2.49 mmol) in 8.3 mL
º
DMF cooled at 0 C was added sodium hydride (0.2 g, 4.98 mmol) and
3.32, 62.05, 51.46, 42.98, 38.31, 31.04, 30.47 ppm; ESI-HRMS
o
+
the mixture was stirred at 0 C for 45 minutes. Benzyl bromide (0.36
[M+Na] calculated for C29
H
32NaO10S 595.1614, found 595.1637.
mL, 2.99 mmol) was then added and the resulting mixture was
warmed up to room temperature and stirred for 30 h before being
quenched with water. The aqueous mixture was extracted with ethyl
acetate and combined organic extracts were washed with water, dried
over sodium sulfate, filtered, and concentrated in vacuo. Purification
on silica gel flash column chromatography (hexanes/dichloromethane
Analogue (4). A solution of mesylate 18 (15 mg, 0.026 mmol) in
.0 mL of CH CN/CH Cl (5/1, v/v) was cooled to 0 C. 104 µL of
3 2 2
º
2
stock solution of cerium ammonium nitrate in water (0.079 mmol, 3
eq.) was added (Note: the stock solution was prepared by adding 174
mg of cerium ammonium nitrate in 400 µL water). The reaction
º
mixture was stirred at 0 C for 1 h before being diluted with 2 mL ethyl
=
3
40/1, with 1% Et N) provided 1.1 g (71% yield) of corresponding
acetate. 0.5 mL of ice cooled saturated NaHCO
resulting mixture was stirred for 5 minutes. The organic layer was glycal stannane (19).
separated and passed through a small pad of Na SO
, concentrated film): 3071, 2953, 2925, 2856, 2674, 2559, 1677, 1288, 1072, 702
under reduce pressure, and kept in vacuum for 10 minutes. This crude cm ; H NMR (600 MHz, CDCl
material was dissolved in 0.34 mL of mixed solvents (EtOAc/MeOH, (m, 2 H), 7.23 - 7.26 (m, 1 H), 4.97 (d, J=12.1 Hz, 1 H), 4.66 (dd,
:1, v/v) and 10% palladium on carbon (28 mg, 0.0262 mmol) was J=2.8, 1.3 Hz, 1 H), 4.61 (d, J=11.9 Hz, 1 H), 4.46 - 4.51 (m, 1 H),
3
was added and the
2
3
º
[훼]
D = -60.7 (c = 0.1, CHCl
); FT-IR (thin
3
2
4
-1 1
3
)  7.36 - 7.40 (m, 2 H), 7.29 - 7.33
1
added. The mixture was evacuated and filled with hydrogen for three 3.99 - 4.05 (m, 1 H), 3.51 (dt, J=3.7, 2.0 Hz, 1 H), 1.48 - 1.55 (m, 6
times. After being stirring at room temperature under positive H), 1.31 (dq, J=14.8, 7.4 Hz, 6 H), 1.23 (d, J=6.8 Hz, 3 H), 0.86 - 0.94
1
3
3
hydrogen pressure for 1.5 h, the reaction mixture was diluted with (m, 24 H), 0.11 (d, J=4.2 Hz, 6 H) ppm; C NMR (150 MHz, CDCl )
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 8 of 12
ARTICLE
Journal Name

163.09, 139.66, 128.39, 128.02, 127.50, 113.71, 76.05, 73.34, 73.00, DMF was removed by air flow and the residue was purViiefiwedArtbicyleuOsnilninge
9.27, 27.55, 26.27, 18.60, 16.79, 14.07, 10.02, -4.02, -4.32 ppm; preparative TLC in CH Cl /MeOH (10/1, vD/Ov)I: t1o0.1f0u3r9n/iCsh9O2B10.7012m1Bg
2
2
2
+
23
º
ESI-HRMS [M+H] Calculated for C31
25.3113.
H
57
O
3
SiSn 625.3099, found (65% yield) of the desired mesylate (23). [훼]D = -100.0 (c = 0.1,
6
CHCl ); FT-IR (thin film): 3407, 2934, 2978, 1716, 1331, 1166,
3
-
1 1
2
-Deoxy β-C-glycoside (22). Glycal stannane 19 (1.32 g, 2.11 1041, 905, 530 cm ; H NMR (600 MHz, CDCl )  7.85 (d, J=8.8
3
32
3 2 2
mmol), aryl iodide 10 (0.50 g, 0.70 mmol) and Pd(PPh ) Cl (0.1 g, Hz, 1 H), 7.67 (d, J=8.8 Hz, 1 H), 7.38 - 7.48 (m, 5 H), 5.23 (s, 1 H),
0
.141 mmol) were taken into a flame dried flask, evacuated, and filled 5.08 - 5.14 (m, 2 H), 4.78 - 4.84 (m, 2 H), 4.13 - 4.18 (m, 2 H), 3.97
with argon. 7 mL of degassed dry toluene was added to the flask and (d, J=19.4 Hz, 1 H), 3.77 - 3.83 (m, 1 H), 3.74 - 3.76 (m, 6 H), 3.63 -
º
the resulting mixtures was stirred at 100 C for 8 h. The reaction 3.67 (m, 1 H), 3.56 (d, J=6.8 Hz, 1 H), 3.39 (dd, J=19.8, 5.9 Hz, 1 H),
mixture was cooled to room temperature and directly subjected to 3.16 (s, 3 H), 2.77 - 2.83 (m, 2 H), 2.29 (d, J=7.9 Hz, 1 H), 2.09 - 2.14
purification via silica gel flash column chromatography (m, 1 H), 2.00 - 2.06 (m, 2 H), 1.83 (dd, J=14.7, 2.0 Hz, 1 H), 1.71 (q,
1
3
(
hexanes/ethyl acetate = 10/1, 2% Et
yield) of the C1-arylated glycal 20. To a solution of C1-arylated glycal
0 (424 mg, 0.463 mmol) in 2.3 mL pyridine were added
3
N) to affording 452 mg (70% J=12.7 Hz, 1 H), 1.34 (d, J=6.4 Hz, 3 H), 1.23 (s, 3 H) ppm; C NMR
150 MHz, CDCl )  206.11, 150.70, 150.57, 150.52, 137.75, 133.89,
30.31, 128.97, 128.62, 128.53, 126.66, 125.23, 123.93, 121.42,
(
3
2
1
1
6
methanesulfonyl chloride (54 µL, 0.70 mmol) and 4-
dimethylaminopyridine (5.6 mg, 0.046 mmol). After the resulting
mixture was stirred at room temperature for 36 h, pyridine was
removed by air flow. The residue was diluted with CH
sequentially with aqueous saturated CuSO solution, water, and brine.
The organic solution was dried over sodium sulfate, filtered, and
concentrated under reduce pressure to produce the crude mesylate 21
which was used directly in the next step. The mesylate 21 was
dissolved in 8.8 mL ethanol and a pinch of bromocresol green was
added as an indicator. To the mixture was added sodium
cyanoborohydride (0.056 g, 0.89 mmol) followed by addition of 0.5
M HCl in methanol (3.6 mL, 1.8 mmol). The resulting reaction
mixture was stirred at room temperature for 15 minutes. A second
batch of sodium cyanoborohydride (0.056 g, 0.886 mmol) and 0.5 M
HCl in methanol (3.6 mL, 1.772 mmol) were added, and the reaction
mixture was stirred at room temperature for 30 h before being
19.98, 80.01, 78.53, 77.72, 77.08, 75.06, 74.83, 72.91, 71.20, 70.37,
3.32, 61.84, 50.44, 41.85, 39.07, 36.09, 30.70, 29.85, 17.66 ppm;
+
ESI-HRMS [M+Na] calculated for C35
H
42NaO13S 725.2244, found
2 2
Cl , washed
7
25.2236.
4
Analogue (5). A solution of mesylate 23 (17 mg, 0.024 mmol) in
.5 mL of acetonitrile was cooled at 0 C. 96 µL of stock solution of
cerium ammonium nitrate in water (0.073 mmol, 3 eq.) was added
Note: the stock solution was prepared by adding 174 mg of cerium
ammonium nitrate in 400 µL water). The reaction mixture was stirred
º
1
(
º
at 0 C for 35 min before being diluted with 2 mL ethyl acetate. 0.5
mL of ice cooled saturated NaHCO
mixture was stirred for 5 minutes. The organic layer was separated
and passed through a small pad of Na SO , concentrated under reduce
3
was added and the resulting
2
4
pressure, and kept in vacuum for 10 minutes. This crude material was
dissolved in 0.3 mL of mixed solvents (EtOAc/MeOH, 1:1, v/v) and
0% palladium on carbon (5.1 mg, 0.0048 mmol) was added. The
mixture was evacuated and filled with hydrogen for three times. After
being stirring at room temperature under positive hydrogen pressure
for 1 h, the reaction mixture was diluted with methanol, filtered
through celite, and concentrated under reduced pressure. This residue
1
3
quenched with saturated NaHCO solution. The aqueous mixture was
extracted with ethyl acetate and combined organic extracts were
washed with water, dried over sodium sulfate, filtered, and
concentrated under reduce pressure. Purification on silica gel flash
column chromatography (toluene/ethyl acetate = 20:1 to 5:1)
furnished 310 mg (70% yield for 2 steps) of 2-deoxy β-C-glycoside
was dissolved in 0.93 mL of dioxane and N,N-diisopropylethylamine
º
(
8.5 µL, 0.048 mmol) was added. After being stirred at 40 C for 1 h,
2
3
º
(
2
22). [훼]D = -26.0 (c = 0.1, CHCl
883, 1682, 1453, 1326, 1027, 698 cm ; H NMR (600 MHz, MHz, flow and the crude material was purified by preparative TLC in
CDCl )  7.88 (d, J=8.8 Hz, 1 H), 7.74 (d, J=8.8 Hz, 1 H), 7.31 - 7.50 CH
Cl /MeOH (10/1, v/v) to furnish 8.1 mg of analogue B (5) as dark
3
); FT-IR (thin film): 3407, 2934, the reaction mixture was cooled down. Dioxane was removed by air
-1 1
3
2
2
2
3
º
(
4
m, 15 H), 5.04 - 5.09 (m, 2 H), 5.02 (s, 1 H), 4.81 - 4.92 (m, 3 H), red solid (69% yield for 3 steps). [훼]D = 42.3 (c = 0.1, CH OH); FT-
3
.68 - 4.72 (m, 2 H), 4.41 (d, J=9.5 Hz, 1 H), 4.34 (s, 1 H), 3.96 (d, IR (thin film): 3384, 2961, 2923, 2853, 1725, 1637, 1284, 1259,
J=19.6 Hz, 1 H), 3.84 (s, 3 H), 3.80 (d, J=3.5 Hz, 1 H), 3.72 (s, 3 H),
.57 (d, J=6.6 Hz, 1 H), 3.54 (d, J=3.1 Hz, 1 H), 3.38 (dd, J=19.8, 5.9
-1 1
1
3
080, 652 cm ; H NMR (600 MHz, CD OD)  7.99 (d, J=7.7 Hz, 1
3
H), 7.59 (d, J=7.9 Hz, 1 H), 6.87 (d, J=9.7 Hz, 1 H), 6.40 (d, J=9.7
Hz, 1 H), 4.84 - 4.87 (m, 1 H), 3.86 - 3.90 (m, 1 H), 3.70 - 3.75 (m, 1
H), 3.61 (d, J=2.8 Hz, 1 H), 2.82 (d, J=12.8 Hz, 1 H), 2.66 (dd, J=13.0,
Hz, 1 H), 3.18 (dd, J=13.4, 2.9 Hz, 1 H), 3.13 (s, 3 H), 2.75 (d, J=13.4
Hz, 1 H), 2.15 (dd, J=14.9, 2.9 Hz, 1 H), 1.90 - 2.00 (m, 2 H), 1.81 -
1
1
3
.88 (m, 2 H), 1.38 (d, J=6.4 Hz, 3 H), 1.32 (s, 3 H) ppm; C NMR
2
.4 Hz, 1 H), 2.06 - 2.10 (m, 1 H), 2.02 - 2.05 (m, 2 H), 1.61 (q, J=11.9
150 MHz, CDCl )  205.48, 150.72, 150.59, 150.52, 138.77, 137.86, Hz, 1 H), 1.33 (d, J=6.4 Hz, 3 H), 1.24 (s, 3 H) ppm; C NMR (150
1
3
(
3
1
1
1
6
37.06, 134.04, 130.29, 129.03, 128.96, 128.88, 128.76, 128.73,
28.57, 128.41, 128.33, 128.18, 127.27, 125.56, 123.86, 121.72,
19.87, 81.52, 80.98, 79.55, 78.72, 78.48, 76.30, 75.40, 72.57, 70.78,
MHz, CD
1
7
3
OD)  206.94, 189.88, 183.63, 158.77, 146.24, 140.48,
39.88, 139.67, 134.93, 132.16, 120.02, 118.22, 115.36, 82.10, 78.65,
7.71, 76.11, 72.76, 71.84, 71.10, 53.26, 44.73, 35.35, 30.17, 17.71
5.02, 63.55, 61.76, 44.69, 43.38, 38.87, 37.29, 30.39, 25.74, 18.34
+
ppm; ESI-HRMS [M+Na] calculated for C25H26NaO10 509.1424,
found 509.1424.
S-But-3-ynyl 3,4-di-O-benzyl-L-olivoside donor (24). To S-but-3-
ynyl 3,4-di-O-acetyl-L-olivoside (150 mg, 0.50 mmol) was added
+
ppm; ESI-HRMS [M+Na] calculated for C49
found 905.3214.
H
54NaO13S 905.3183,
Mesylate (23). To a solution of 2-deoxy β-C-glycoside 22 (50 mg,
.057 mmol) in 1.6 mL of mixed solvents (EtOAc/MeOH, 1/1, v/v)
37
0
1
3
.1 mL of 7.0 N NH in MeOH and the resulting mixture was stirred
was added 10% palladium on carbon (60 mg, 0.057 mmol). The
reaction mixture was evacuated and filled with hydrogen for five
times and then stirred at room temperature under positive hydrogen
pressure (40 psi) for 50 h. The reaction mixture was then diluted with
at room temperature for 6 h. Solvent was removed under reduced
pressure and the residue was azeotroped with toluene to produce crude
diol. This diol was dissolved in 1.7 mL DMF and cooled at 0 C. NaH
º
(
60% in mineral oil, 60 mg, 1.5 mmol) was added and the reaction
CH
2
Cl
2
/MeOH (10/1, v/v), filtered through celite, and concentrated.
Cl /MeOH, 10/1,
º
mixture was stirred for 45 min at 0 C. Next, benzyl bromide (0.15 mL,
.25 mmol) was added and the resulting mixture was stirred for 12 h
The residue was purified via preparative TLC (CH
2
2
1
v/v) to afford 31 mg (89% yield) of desired product. To a solution of
at room temperature before being quenched with water. The aqueous
mixture was extracted with ethyl acetate and combined organic
extracts were washed with water, dried over sodium sulfate, filtered,
and concentrated in vacuo. Purification on flash column
º
this product (29.1 mg, 0.0476 mmol) in 1 mL DMF cooled at 0 C were
added Cs
.071 mmol). The reaction mixture was stirred at room temperature
for 5 h and then quenched with a pinch of solid ammonium chloride.
2 3
CO (18.6 mg, 0.0571 mmol) and benzyl bromide (8.5 µL,
0
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 12
O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Journal Name
ARTICLE
chromatography (hexanes/ethyl acetate, 10/1, v/v) provided 189 mg 95.16, 82.07, 79.25, 79.17, 79.08, 79.03, 78.08, 77.89,Vi7ew6.A6r6tic,le7O6n.1lin0e,
of corresponding S-but-3-ynyl 3,4-di-O-benzyl-L-olivoside donor 73.10, 69.44, 69.34, 63.60, 62.05, 51.52, 43.D0O4,I:3190..13093,93/C8.93O1B,03071.2918B,
2
3
+
º
(
24) (96% yield for 2 steps). [훼]D = -82.3 (c = 0.3, CHCl
3
); FT-IR 30.97, 30.49, 18.81, 18.24 ppm; ESI-HRMS [M+Na] calculated for
-
(
1
thin film): 3289, 3029, 2929, 2858, 1496, 1453, 1091, 734, 697 cm
)  7.29 - 7.40 (ovrlp, 10 H, α and β),
.41 (d, J=5.5 Hz, 1 H, H α), 4.98 (ovrlp, 1 H, α and β), 4.57 - 4.73
ovrlp, 3 H, α and β and 1H, H β ), 4.13 (dq, J=9.4, 6.2 Hz, 1 H, H
α), 3.91 (ddd, J=11.6, 8.6, 4.8 Hz, 1 H, H α), 3.66 (ddd, J=11.2, 8.6,
.1 Hz, 1 H, H β), 3.39 (dq, J=9.3, 6.1 Hz, 1 H, H β), 3.17 (ovrlp, 1
H, H α and H β), 2.91 - 2.97 (m, 1 H, β), 2.77 - 2.86 (m, 2 H, α), 2.67
2.73 (m, 1 H, β), 2.47 - 2.64 (ovrlp, 2 H, α and β), 2.41 (ddd, J=12.7,
.1, 1.7 Hz, 1 H, H β), 2.31 - 2.36 (m, 1 H, H α), 2.02 - 2.09 (ovrlp,
H, α and β and 1 H, H α), 1.71 - 1.79 (q, 1 H, H β), 1.37 (d, J=6.1
41
C H52NaO16S 855.2874, found 855.2869.
1
Analogue (6). To a solution of mesylate 26 (10 mg, 0.012 mmol)
;
H NMR (600 MHz, CDCl
3
º
1
in 0.76 mL acetonitrile cooled at 0 C was added 48 µL of stock
solution of cerium ammonium nitrate in water (0.036 mmol, 3 eq.)
was added (Note: the stock solution was prepared by adding 174 mg
of cerium ammonium nitrate in 400 µL water). The reaction mixture
5
(
3
5
3
1
5
5
º
4
4
was stirred at 0 C for 30 min before being diluted with 2 mL ethyl
acetate. 0.5 mL of ice cooled saturated NaHCO
resulting mixture was stirred for 5 minutes. The organic layer was
separated and passed through a small pad of Na SO , concentrated
3
was added and the
-
5
1
2
2
2
2
2
4
6
6
13
under reduce pressure, and kept in vacuum for 10 minutes. This crude
material was dissolved in 0.15 mL of mixed solvents (EtOAc/MeOH,
:1, v/v) and 10% palladium on carbon (2.6 mg, 0.0024 mmol) was
added. The mixture was evacuated and filled with hydrogen for three
times. After being stirring at room temperature under positive
hydrogen pressure for 1 h, the reaction mixture was diluted with
methanol, filtered through celite, and concentrated under reduced
pressure. The residue was purified through preparative TLC in
Hz, 3 H, C – CH
3
β), 1.33 (d, J=6.2 Hz, 3 H, C – CH
3
α) ppm; C
NMR (150 MHz, CDCl
3
)  138.72, 138.64, 138.60, 138.47, 128.69,
1
1
1
7
2
28.66, 128.64, 128.61, 128.33, 128.21, 128.00, 127.95, 127.94,
27.90, 84.61, 83.65, 82.86, 80.73, 80.56, 79.88, 75.90, 75.61, 75.41,
2.04, 71.72, 69.75, 69.72, 67.93, 37.38, 36.30, 30.13, 29.96, 20.69,
+
0.16, 18.66, 18.31 ppm; ESI-HRMS [M+Na] calculated for
C
24
H
28NaO
3
S 419.1657, found 419.1667.
Mesylate (26). A mixture of S-but-3-ynyl 3,4-di-O-benzyl-L-
olivoside donor 24 (33.6 mg, 0.085 mmol) and partially protected β-
CH
red solid (84% yield for 2 steps). [훼]D = 99.3
with 2 mL benzene and kept in high vacuum for 30 minutes. To this IR (thin film): 3380, 2958, 2921, 2854, 1725, 1636, 1260, 1055, 476
2 2
Cl /MeOH (10/1, v/v) to afford 6.2 mg of analogue C (6) as dark
2
3
3
2
º
3
(c = 0.1, CH OH); FT-
C-arylglycoside acceptor 12 (50 mg, 0.057 mmol) was azeotroped
-1 1
mixture were sequentially added 23 mg of freshly activated 4 Ǻ cm ; H NMR (600 MHz, CD
molecular sieves, silver triflate (1.5 mg, 0.0057 mmol) and a freshly (d, J=7.9 Hz, 1 H), 6.87 (d, J=9.7 Hz, 1 H), 6.40 (d, J=9.7 Hz, 1 H),
prepared solution of gold catalyst in dry CH Cl
(prepared by 5.04 (d, J=3.1 Hz, 1 H), 4.85 - 4.87 (m, 1 H), 3.91 - 3.97 (m, 1 H),
dissolving 2.0 mg (0.0028 mmol) of chloro[tris(para- 3.85 (ddd, J=11.6, 9.0, 5.0 Hz, 1 H), 3.73 - 3.79 (m, 1 H), 3.45 - 3.51
trifluoromethylphenyl)phosphine]gold(I) in 0.56 mL CH Cl
). The (m, 1 H), 3.11 - 3.18 (m, 1 H), 2.96 (t, J=9.3 Hz, 1 H), 2.82 (d, J=12.8
resulting mixture was stirred at room temperature for 1 h before being Hz, 1 H), 2.67 (dd, J=13.0, 2.6 Hz, 1 H), 2.56 (ddd, J=12.7, 4.8, 1.7
quenched with a pinch of solid NaHCO
. The reaction mixture was Hz, 1 H), 1.95 - 2.08 (m, 3 H), 1.61 - 1.67 (m, 1 H), 1.38 (d, J=6.1 Hz,
diluted with CH Cl2, filtered through small pad of Na
concentrated under vacuo, and purified using preparative TLC CD
3
OD)  7.86 (d, J=7.9 Hz, 1 H), 7.58
2
2
2
2
3
1
3
2
2 4
SO ,
3 H), 1.27 (d, J=6.1 Hz, 3 H), 1.24 (s, 3 H) ppm; C NMR (150 MHz,
OD)  206.91, 189.82, 183.58, 158.75, 146.29, 140.46, 139.89,
hexanes/ethyl acetate, 2/1, v/v, with 1% MeOH) to afford 61.5 mg 139.13, 134.37, 132.26, 120.02, 118.19, 115.43, 95.33, 82.09, 79.00,
91% yield) of desired disaccharide as a mixture of inseparable 78.64, 77.83, 77.79, 77.68, 76.65, 72.32, 69.42, 69.39, 53.26, 44.72,
3
(
(
+
anomers (α/β, 2/1). To a mixture of these anomers (50 mg, 0.042 39.40, 37.55, 30.76, 30.17, 18.79, 18.16 ppm; ESI-HRMS [M+Na]
mmol) dissolved in 1.6 mL of EtOAc/MeOH (1/1, v/v) was added calculated for C31 36NaO13 639.2054, found 639.2084.
0% palladium on carbon (45 mg, 0.042 mmol). The resulting mixture S-but-3-ynyl 3,4-di-O-benzyl-L-olioside donor (25). To S-but-3-
was evacuated and filled with hydrogen for five times and stirred at ynyl 3,4-di-O-acetyl-L-olioside (120 mg, 0.40 mmol) was added
room temperature under positive hydrogen pressure (40 psi) for 40 h. 0.86 mL of 7.0 N NH in MeOH and the resulting mixture was stirred
The reaction mixture was diluted with CH Cl /MeOH (10/1, v/v), at room temperature for 12 h. Solvent was removed under reduced
filtered through celite, concentrated, and purified via preparative TLC pressure and the residue was azeotroped with toluene to produce crude
H
1
3
7
3
2
2
º
(CH
2 2
Cl /MeOH, 10/1, v/v) to give 11.2 mg (36% yield) of desired α- diol. This diol was dissolved in 1.3 mL DMF and cooled at 0 C. NaH
disaccharide. To a solution of this α-disaccharide (15.5 mg, 0.021 (60% in mineral oil, 48 mg, 1.2 mmol) was added and the reaction
º
º
mmol) in 0.45 mL DMF cooled at 0 C was added Cs
2 3
CO (8.2 mg, mixture was stirred for 45 min at 0 C. Next, benzyl bromide (0.12 mL,
0
.025 mmol) followed by addition of 22 µL stock solution of benzyl 1.0 mmol) was added and the resulting mixture was stirred for 12 h at
bromide in DMF (0.031 mmol, 1.5 eq.) (Note: the stock solution was room temperature before being quenched with water. The aqueous
prepared by adding 40 µL of benzyl bromide in 200 µL DMF). The mixture was extracted with ethyl acetate and combined organic
reaction mixture was stirred at room temperature for 7 h and quenched extracts were washed with water, dried over sodium sulfate, filtered,
with a pinch of solid ammonium chloride. DMF was removed by air and concentrated in vacuo. Purification on flash column
flow and the residue was purified by using preparative TLC in chromatography (hexanes/ethyl acetate, 10/1, v/v) provided 139 mg
CH
desired mesylate (26). [훼]D = -69.3 (c = 0.1, CHCl
film): 3391, 2923, 2856, 1721, 1330, 1041, 973, 908, 529 cm ; H film): 3291, 3030, 2931, 1496, 1454, 1362, 1059, 733, 697 cm ; H
NMR (600 MHz, CD
2 2
Cl /MeOH (10/1, v/v) to furnish 11.1 mg (63% yield) of the of corresponding S-but-3-ynyl 3,4-di-O-benzyl-L-olioside donor (25)
2
3
22
º
º
); FT-IR (thin (88% yield for 2 steps). [훼]D = -76.5 (c = 0.3, CHCl
); FT-IR (thin
3
3
-1
1
-1 1
3
OD)  7.88 (d, J=8.8 Hz, 1 H), 7.62 (d, J=8.8 NMR (600 MHz, CDCl )  7.29 - 7.45 (ovrlp, 10 H, α and β), 5.55
3
1
Hz, 1 H), 7.47 - 7.50 (m, 2 H), 7.41 - 7.45 (m, 2 H), 7.35 - 7.39 (m, 1 (d, J=5.7 Hz, 1 H, H α), 4.97 - 5.04 (ovrlp, 1 H, α and β), 4.70 - 4.77
1
H), 5.04 - 5.08 (m, 2 H), 4.99 (d, J=3.1 Hz, 1 H), 4.89 - 4.92 (m, 2 H), (ovrlp, 1 H, α and β), 4.54 - 4.69 (ovrlp, 2 H, α and β and 1H, H β),
5
3
3
3
(
.90 - 3.95 (m, 1 H), 3.82 - 3.87 (m, 2 H), 3.79 (s, 3 H), 3.77 (s, 3 H), 4.17 (q, J=6.5 Hz, 1 H, H α), 3.88 (ddd, J=12.2, 4.4, 2.5 Hz, 1 H, H
4
3
.56 - 3.66 (m, 2 H), 3.27 - 3.30 (m, 1 H), 3.18 - 3.21 (m, 3 H), 3.13 α), 3.64 (s, 1 H, H α), 3.60 (ddd, J=11.6, 4.6, 2.6 Hz, 1 H, H β), 3.55
t, J=9.0 Hz, 1 H), 2.97 (t, J=9.2 Hz, 1 H), 2.80 (d, J=12.7 Hz, 1 H), - 3.58 (m, 1 H, H β), 3.41 - 3.48 (m, 1 H, H β), 2.96 (ddd, J=13.3,
4
5
2
2
.59 (dd, J=12.7, 2.8 Hz, 1 H), 2.22 (dd, J=12.6, 3.6 Hz, 1 H), 1.93 - 8.5, 6.6 Hz, 1 H, β), 2.77 - 2.86 (ovrlp, 1 H, α and β), 2.66 - 2.74 (m,
2
.04 (m, 3 H), 1.55 - 1.65 (m, 2 H), 1.31 (d, J=6.1 Hz, 3 H), 1.28 (d, 1 H,α), 2.50 - 2.62 (ovrlp, 2 H, α and β and 1 H, H α ), 2.21 (q, J=11.8
1
3
2
2
J=6.2 Hz, 3 H), 1.20 (s, 3 H) ppm; C NMR (150 MHz, CD
2
1
3
OD)  Hz, 1 H, H β), 2.07 - 2.14 (m, 1 H, H β), 2.04 - 2.06 (ovrlp, 1 H, α
2
6
07.17, 151.68, 151.52, 151.37, 138.92, 134.78, 131.26, 129.72, and β), 2.01 - 2.04 (m, 1 H, H α), 1.25 (d, J=6.4 Hz, 3 H, C – CH
3
29.67, 129.66, 129.25, 128.92, 126.15, 124.59, 123.52, 120.45, β), 1.22 (d, J=6.4 Hz, 3 H, C – CH
6
13
3
α) ppm; C NMR (150 MHz,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 10 of 12
ARTICLE
Journal Name
CDCl
3
)  138.86, 138.77, 138.38, 128.52, 128.49, 128.43, 128.42, under reduce pressure, and kept in vacuum for 10 minuVteiesw. TArhticislecOrnulidnee
1
1
7
3
28.39, 128.35, 128.24, 128.21, 128.16, 127.70, 127.66, 127.59, material was dissolved in 0.23 mL of mixed sDoOlvI:e1n0t.s10(E39tO/CA9Oc/BM00e1O2H1B,
27.47, 127.36, 127.31, 82.95, 82.77, 81.15, 80.13, 78.87, 75.91, 1:1, v/v) and 10% palladium on carbon (3.9 mg, 0.0037 mmol) was
5.01, 74.47, 74.46, 74.25, 70.48 , 70.19, 69.37, 69.27, 67.20, 32.05, added. The mixture was evacuated and filled with hydrogen for three
0.93, 29.95, 29.44, 20.42, 19.93, 17.65, 17.21 ppm; ESI-HRMS times. After being stirring at room temperature under positive
+
[
M+Na] calculated for C24
H
28NaO
3
S 419.1657, found 419.1655.
hydrogen pressure for 1 h, the reaction mixture was diluted with
Mesylate (27). A mixture of S-but-3-ynyl 3,4-di-O-benzyl-L- methanol, filtered through celite, and concentrated under reduced
olioside donor 25 (33.6 mg, 0.085 mmol) and partially protected β-C- pressure. The residue was purified through preparative TLC in
3
2
arylglycoside acceptor 12 (50 mg, 0.057 mmol) was azeotroped with CH
2
2 2
Cl /MeOH (10/1, v/v) to afford 8.4 mg of analogue D (7) as dark
2
3
º
mL benzene and kept in high vacuum for 30 minutes. To this red solid (75% yield for 2 steps). [훼]D = 41.3 (c = 0.1, CH OH); FT-
3
mixture were sequentially added 23 mg of freshly activated 4 Ǻ IR (thin film): 3389, 2974, 2927, 1723, 1637, 1436, 1284, 1082,
-
1 1
molecular sieves, silver triflate (1.5 mg, 0.0057 mmol) and a freshly 1056, 598 cm ; H NMR (600 MHz, CD OD)  7.85 (d, J=7.7 Hz, 1
3
prepared solution of gold catalyst in dry CH
dissolving 2.0 mg (0.0028 mmol) of chloro[tris(para- Hz, 1 H), 5.07 (d, J=3.3 Hz, 1 H), 4.85 (s, 1 H), 4.21 (q, J=6.5 Hz, 1
trifluoromethylphenyl)phosphine]gold(I) in 0.56 mL CH Cl ). The H), 4.01 - 4.05 (m, 1 H), 3.72 - 3.79 (m, 1 H), 3.55 - 3.57 (m, 1 H),
resulting mixture was stirred at room temperature for 1.5 h before 3.45 - 3.51 (m, 1 H), 3.10 - 3.16 (m, 1 H), 2.80 - 2.88 (m, 1 H), 2.67
being quenched with a pinch of solid NaHCO . The reaction mixture (dd, J=12.9, 2.7 Hz, 1 H), 2.55 (ddd, J=12.7, 4.8, 1.7 Hz, 1 H), 2.00 -
was diluted with CH Cl2, filtered through small pad of Na SO
2.08 (m, 2 H), 1.93 (td, J=12.5, 3.9 Hz, 1 H), 1.68 (dd, J=12.7, 5 Hz,
concentrated under vacuo, and purified using preparative TLC 1 H), 1.38 (d, J=6.1 Hz, 3 H), 1.23 - 1.25 (m, 7 H) ppm; C NMR
2 2
Cl (prepared by H), 7.57 (d, J=7.9 Hz, 1 H), 6.87 (d, J=9.9 Hz, 1 H), 6.40 (d, J=9.7
2
2
3
2
2
4
,
1
3
(
(
hexanes/ethyl acetate, 2/1, v/v, with 1% MeOH) to afford 56.6 mg
84% yield) of desired disaccharide as a mixture of inseparable
(
150 MHz, CD
3
OD)  206.91, 189.82, 183.57, 158.74, 146.29,
1
9
6
40.45, 139.88, 139.14, 134.35, 132.23, 120.03, 118.19, 115.41,
5.50, 82.08, 78.62, 77.76, 77.69, 77.50, 76.70, 72.43, 72.32, 67.75,
6.70, 53.26, 44.71, 37.49, 33.48, 30.18, 18.81, 17.18 ppm; ESI-
HRMS [M+Na] calculated for C31
anomers (α/β, 2/1). To a mixture of these anomers (50 mg, 0.042
mmol) dissolved in 1.6 mL of EtOAc/MeOH (1/1, v/v) was added
1
was evacuated and filled with hydrogen for five times and stirred at
room temperature under positive hydrogen pressure (40 psi) for 66 h.
0% palladium on carbon (45 mg, 0.042 mmol). The resulting mixture
+
H
36NaO13 639.2054, found
6
39.2068.
The reaction mixture was diluted with CH
filtered through celite, concentrated, and purified via preparative TLC
CH Cl /MeOH, 10/1, v/v) to give 17.4 mg (56% yield) of desired α-
disaccharide. To a solution of this α-disaccharide (17.3 mg, 0.023
2 2
Cl /MeOH (10/1, v/v),
Biological studies
Synthetic aquayamycin (3), analogues (4-7) and previously
prepared derhodinosylurdamycin A (2) were submitted to the
Development Therapeutics Program of the National Cancer
Institute of National Institutes of Health for the NCI-60 Human
Tumor Cell Lines Screening using standard protocols. These
known 60-cell panel contains a variety of human cell lines of
leukemia, non-small cell lung cancer, colon cancer, CNS cancer,
melanoma, ovarian cancer, renal cancer, prostate cancer, and
breast cancer. Detailed data are provided in the Supporting
Information.
(
2
2
º
2 3
mmol) in 0.5 mL DMF cooled at 0 C was added Cs CO (9.1 mg,
0
.028 mmol) followed by addition of 25 µL stock solution of benzyl
bromide in DMF (0.031 mmol, 1.5 eq.) (Note: the stock solution was
prepared by adding 40 µL of benzyl bromide in 200 µL DMF). The
reaction mixture was stirred at room temperature for 5 h and quenched
with a pinch of solid ammonium chloride. DMF was removed by air
flow and the residue was purified by using preparative TLC in
CH
mesylate (27) (α only). [훼]D = -89.7 (c = 0.1, CHCl
film): 3393, 2976, 2938, 1718, 1329, 1167, 1040, 699, 639, 529 cm
2 2
Cl /MeOH (10/1, v/v) to furnish 11 mg (57% yield) of the desired
2
3
º
3
); FT-IR (thin
-
1
1
Conflicts of interest
;
3
H NMR (600 MHz, CD OD)  7.87 (d, J=9.0 Hz, 1 H), 7.61 (d,
J=8.8 Hz, 1 H), 7.47 (d, J=7.2 Hz, 2 H), 7.40 - 7.45 (m, 2 H), 7.37 (d,
J=7.3 Hz, 1 H), 5.05 (dd, J=16.0, 4.2 Hz, 3 H), 4.90 (d, J=4.6 Hz, 2
H), 4.20 (d, J=6.8 Hz, 1 H), 4.04 (dd, J=12.1, 1.8 Hz, 1 H), 3.84 (d,
J=19.1 Hz, 1 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.63 - 3.66 (m, 1 H), 3.55
There are no conflicts of interest to declare.
Acknowledgements
-
3.61 (m, 2 H), 3.27 - 3.30 (m, 1 H), 3.19 (s, 3 H), 3.10 - 3.15 (m, 1
H), 2.79 (d, J=12.7 Hz, 1 H), 2.59 (dd, J=12.7, 2.8 Hz, 1 H), 2.23 (dd, We are very grateful to The University of Toledo for supporting this
J=12.38, 3.6 Hz, 1 H), 2.00 - 2.04 (m, 1 H), 1.92 - 1.96 (m, 1 H), 1.91 research. This work is also supported in part by a grant from National
(
1
d, J=3.7 Hz, 1 H), 1.67 (dd, J=12.7, 5.0 Hz, 1 H), 1.57 (q, J=12.5 Hz, Science Foundation (CHE-1213352). We thank the Development
H), 1.30 (d, J=6.1 Hz, 3 H), 1.25 (d, J=6.6 Hz, 3 H), 1.18 (s, 3 H) Therapeutics Program of the National Cancer Institute of National
1
3
ppm; C NMR (150 MHz, CD
3
OD)  207.15, 151.65, 151.50, Institutes of Health for evaluating our synthetic molecules for their
1
1
,
51.35, 138.87, 134.77, 131.22, 129.66, 129.64, 129.25, 128.90 , anticancer activity using the NCI-60 Human Tumor Cell Lines Screen.
26.16 , 124.58 , 123.51 , 120.44 , 95.34 , 82.04 , 79.25, 79.13 , 79.06 We also thank Ms. Myoung Soo Choi, Mr. Hee Bum Lee, and Mr.
77.84 , 77.77, 76.69, 76.08 , 73.06, 72.40 , 71.52 , 67.67, 66.70 , Christopher Lopez for experimental assistance.
6
1
3.60 , 62.07 , 51.50 , 43.01, 38.32 , 37.94, 33.47, 30.96 , 30.49,
+
8.82, 17.26 ppm; ESI-HRMS [M+Na]
52NaO16S 855.2874, found 855.2867.
Analogue (7). To a solution of mesylate 27 (15.2 mg, 0.0183
calculated for
41
C H
Notes and references
º
1
2
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0 | J. Name., 2012, 00, 1-3
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1
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Organic & Biomolecular Chemistry
Page 12 of 12
View Article Online
DOI: 10.1039/C9OB00121B
Synthesis and antitumor activities of aquayamycin and analogues of
derhodinosylurdamycin A†
Padam P. Acharya, Hem Raj Khatri, Sandip Janda, and Jianglong Zhu*
An analogue without the sugar moiety of natural derhodinosylurdamycin A is better.
O
HO
O
derhodinosylurdamycin A (2) X =
O
O
O
O
HO
OH
OH
O
HO
HO
O
X
O
HO
HO
aquayamycin (urdamycinone A) (3) X =
OH
analogue (4) X = H (active agaisnt a wide range of human cancer
cell lines, GI50 values range 0.23 - 18.3 M)