First Total Syntheses of Tetracenomycins C and X

Article abstract of DOI:10.1002/anie.201707099

The first total syntheses of tetracenomycins C and X were achieved, featuring 1) preparation of a hexasubstituted naphthonitrile oxide by successive benzyne cycloadditions and an oxidative ring-opening reaction; 2) a novel ortho-quinone mono-acetal as the A-ring unit; 3) construction of three contiguous stereogenic centers by an asymmetric benzoin cyclization, an isoxazole oxidation, and a stereoselective reduction.

Full text of DOI:10.1002/anie.201707099

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Accepted Article
Title: First Total Syntheses of Tetracenomycins C and X
Authors: Shogo Sato, Keiichiro Sakata, Yoshimitsu Hashimoto, Hiroshi
Takikawa, and Keisuke Suzuki
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707099
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10.1002/anie.201707099
Angewandte Chemie International Edition
COMMUNICATION
First Total Syntheses of Tetracenomycins C and X
Shogo Sato, Keiichiro Sakata, Yoshimitsu Hashimoto, Hiroshi Takikawa, and Keisuke Suzuki*
In memory of the late Professor Osamu Yonemitsu
Abstract: The first total syntheses of tetracenomycins C and X have
been achieved, featuring 1) preparation of hexasubstituted
aromatization, 2) the regiocontrolled installation of substituents
on the tetracyclic core, and 3) the stereocontrolled construction
of the angular cis-diol.
a
naphthonitrile oxide by successive benzyne cycloadditions and an
oxidative ring-opening reaction; 2) a novel ortho-quinone mono-
acetal as the A-ring unit; 3) construction of three contiguous
stereogenic centers by an asymmetric benzoin cyclization, an
isoxazole oxidation, and a stereoselective reduction.
Herein, we describe the first total syntheses of 1 and 2 through
an isoxazole-based polyketide assembling strategy,[5] including a
two-step protocol for an isoxazole oxidation to construct the
characteristic tetracyclic core with the angular cis-diol moiety.[6]
Our retrosynthetic analysis is shown in Scheme 1. The C4-
alcohol is retrosynthetically oxidized to ketone 4, aiming for a
regio- and stereoselective hydride reduction at the final stage.
The AB-ring system in 4 has a functional symmetry by the
presence of two common 2-hydroxy-1,3-diketo structures
(marked in blue and pink). We assumed that the upper functional
array could be generated by a hydroxylation of isoxazole 5,[6]
while the lower one could be constructed by an asymmetric
benzoin cyclization of ketoaldehyde 6. [7]
We report the first total syntheses of stereogenic members of the
tetracenomycin (TCM)-class antibiotics: TCMs C (1) and X (2),
isolated as Actinomycetes metabolites, which exhibit broad
activity against Gram-positive bacteria and cytotoxic activity
against L1210 leukemia cells (Figure 1).[ 1 ] Their structures
feature a densely oxygenated tetracycle with a characteristic AB-
ring system bearing three contiguous stereogenic centers.[ 2 ]
Biosynthetic studies by Hutchinson[3] revealed that the three
stereogenic centers in the A-ring emerge from an oxygenase-
mediated threefold hydroxylation of a fully-aromatized congener,
TCM A2 (3), providing a general model for the biogenesis of this
class of type-II polyketide metabolites.
Further disconnection of isoxazole 6 by assuming 1,3-dipolar
Me OH
O
O
N
O
OR
O
O
OH
OH
MeO2C
MeO
12a
4a
4
OMe
OMe
OH
OH
OH
O
R
Me OH
O
B
O
A
Me OH
O
OH
O
O
4
1
MeO2C
MeO
MeO2C
isoxzazole
oxidation
D
C
OMe MeO
OMe
OH
OH
O
O
O
Me OR
OR
N
O
MeO2C
MeO
tetracenomycin C (1): R = H
tetracenomycin X (2): R = Me
tetracenomycin A2 (3)
OMe
OR
4a
4
OMe
OR
OR
O
RO
OH
asymmetric
benzoin
O
O
5
Figure 1. Structures of tetracenomycins C (1), X (2) and A2 (3).
6
The important biological activities as well as the uniquely
complex molecular architecture of TCMs have attracted
considerable attention of synthetic community. However, despite
more than 30 years have passed since the initial isolation report,
the fully-aromatized congeners such as 3 have been the only
O–
OR
+
N
Me OR
MeO2C
MeO
C
CHO
CHO
OMe
O
OMe
]
members that were successfully synthesized.[ 4 The total
OMe
RO OR
7
A
8
syntheses of the stereogenic members had remained
unachieved, which may have been due to formidable challenges
that are posed by the stereochemical and functional complexity.
We identified three synthetic challenges, 1) the potential
chemical instability of synthetic intermediates due to dehydrative
oxidative
ring opening
?
Me OR
Me OR
NOH
O
MeO2C
MeO
MeO2C
MeO
O
OMe
OMe
9
10
[*]
S. Sato, K. Sakata, Dr. Y. Hashimoto,[+] Dr. H. Takikawa,[$]
Prof. Dr. K. Suzuki
Department of Chemistry, Tokyo Institute of Technology
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
E-mail: ksuzuki@chem.titech.ac.jp
Present address: Showa Pharmaceutical University
3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543 (Japan)
Present address: Graduate School of Pharmaceutical Sciences,
Kyoto University
OR
OR
Me
O
MeO2C
MeO
I
I
MeO
OTBS
OMe
[+]
[$]
TsO
OTs
[4+2]
[2+2]
C (13: R = Bn)
12
B
11
Yoshida, Sakyo-ku, Kyoto 606-8501 (Japan)
Scheme 1. Retrosynthetic analysis.
Supporting information is given via a link at the end of the document.
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10.1002/anie.201707099
Angewandte Chemie International Edition
COMMUNICATION
cycloaddition and dehydrogenation suggested naphthonitrile
oxide 7 and ortho-quinone mono-acetal 8 as precursors.[ 8 ]
Concerning the preparation of nitrile oxide 7 having six different
substituents on its naphthalene core, conventional retrosynthetic
analysis would suggest dialdehyde A, in which two formyl
groups need to be discriminated as respective progenitors to the
nitrile oxide and the acetal moiety in 7. To overcome this issue,
we recently developed a viable approach via oxidative ring
opening of cyclobutenone oximes,[9] which allowed us to set
oxime 9 as a precursor. Further disconnection of 9, via the key
Furthermore, we established a one-pot protocol to perform the
two successive benzyne cycloadditions (Scheme 3),[15] giving
the bis-cycloadduct 15 in 44% yield, slightly higher than the
stepwise protocol (vide supra, 41% yield in 2 steps). Bis-
cycloadduct 15 was subjected to reductive aromatization (TiCl4,
Zn, THF, RT, 1 h) [16] followed by hydrolysis of the silyl acetal (aq.
HF, MeCN, 0 °C, 1 h), giving benzocyclobutenone 16 in 78%
yield. At this stage, the structure was unambiguously re-
confirmed by X-ray diffraction analysis.[17] Ketone 16 was then
converted to oxime 17 (NH2OH·HCl, pyridine, MeOH, 60 °C, 18
h) in 88% yield as a single isomer, whose E/Z configuration was
not assigned. Pleasingly, the key oxidative ring opening[9] of
oxime 17 proceeded nicely, via chloronitroso compound D, by
treatment with NCS (2.4 equiv.) and Et3N (2.4 equiv.) in a solvent
tricycle 10, suggested
a
three-component assembly by
exploiting dual cycloadditions of 1,4-benzdiyne equivalent B.[10]
Two relevant benzyne species would be sequentially generated
from bis(tosyloxy)diiodobenzene C, reacting with two different
arynophiles: [2+2] cycloaddition[11] with ketene silyl acetal (KSA)
11 and [4+2] cycloaddition with trisubstituted furan 12.[12] Based
on this analysis, we started the synthetic venture, and its
successful implementation is described in the following.
mixture [MeOH, CH2Cl2 (v/v
=
2/1),
0
°C,
1
h], giving
naphthonitrile oxide 18 as a white solid in 73% yield.[18]
OBn
Me OBn
O
OMe
OTBS
The synthesis started with the generation of a benzyne species
from bis-tosylate 13 (n-BuLi, THF, –95 °C, 10 min), which
underwent the regioselective [2+2] cycloaddition to premixed
KSA 11 (–95 → –20 °C, 1 h), giving benzocyclobutene 14 in
I
I
MeO2C
MeO
a
b,c
see text
and ref. 15
TsO
OTs
OMe
13
15
]
73% yield (Scheme 2).[ 13 The next step was the [4+2]
cycloaddition of iodo-tosylate 14 with furan 12[12] (n-BuLi, THF, –
78 °C, 4 h), which gave two products. Pleasingly, careful
structural analysis revealed these products to be stereoisomeric
bis-cycloadducts 15 (d.r. = 1:1) due to the lack of facial
selectivity relative to the stereogenic centers in 14, but both
were composed of single regioisomers as later proven by X-ray
diffraction analysis (see 16, Scheme 3). This rigorous
regioselectivity could be rationalized by the primary orbital
interaction as shown in Scheme 2a, which is notable in view of
the potential conflict due to steric clash.[14]
Me OBn
Me OBn
NOH
OMe
O
MeO2C
MeO
MeO2C
MeO
d
OMe
16 (X-ray)
17
Me OBn
+ O–
N
OBn
N
O
MeO2C
MeO
C
e
Cl
OMe
OMe
OMe
18
D
OBn
OBn
Scheme 3. Synthesis of naphthonitrile oxide 18. a) 11 (1.1 equiv), n-BuLi,
THF, –95 → –20 °C, 2 h, then 12 (1.5 equiv), n-BuLi, –78 °C, 20 min (44 %); b)
TiCl4, Zn, THF, RT, 1 h; c) aq. HF, MeCN, 0 °C, 1 h (78%, 2 steps); d) NH2OHꢀ
HCl, pyridine, MeOH, 60 °C, 18 h (88%); e) NCS, Et3N, MeOH, CH2Cl2, 0 °C,
1 h (73%). NCS = N-chlorosuccinimide.
OMe
OTBS
I
I
MeO
OTBS
OMe
I
a
+
TsO
OTs
TsO
OMe
13
11
14
Me OBn
O
OMe
Having the requisite naphthonitrile oxide 18 in hand, the
construction of the tetracyclic skeleton was examined (Scheme
4). Upon reaction of nitrile oxide 18 with the known ortho-
quinone mono-acetal 19[19] (PhCl, RT, 60 h), regioselective 1,3-
dipolar cycloaddition proceeded smoothly to give isoxazoline 20
as a single product in 79% yield. After dehydrogenation of 20
(NiO2, CH2Cl2, 0 °C, 30 min),[20] chemoselective hydrolysis of the
benzylic acetal under acidic conditions (2 M H2SO4, THF, RT, 3
h) gave ketoaldehyde 21 in 95% yield, ready for the key benzoin
cyclization.
The initial attempt at the benzoin cyclization was treatment of
ketoaldehyde 21 with a combination of achiral triazolium salt
23a[21] (30 mol%) and Et3N (30 mol%). Although the desired α-
ketol 22 was obtained, the yield was moderate (46%), and a
considerable amount of ketoaldehyde 21 was recovered (20%).
In spite of extensive investigations, we were not able to find
suitable conditions to drive this reaction to full conversion.
MeO2C
MeO
b
OTBS
OMe
15
a)
OBn
Me
O
Me
OMe
OTBS
MeO2C
MeO
MeO2C
O
MeO
OMe
HOMO LUMO
12
12
Scheme 2. Dual benzyne cycloadditions. a) 11 (1.1 equiv), n-BuLi (1.1 equiv),
THF, –95 → –20 °C, 1 h, (73%); b) 12 (1.5 equiv), n-BuLi (1.25 equiv), THF, –
78 °C,
4 h (56%). Bn = benzyl, Ts = p-toluenesulfonyl, TBS = tert-
butyldimethylsilyl.
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10.1002/anie.201707099
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COMMUNICATION
O–
Me OBn
N
H
O
H
+
N
hydrolysis (2 M H2SO4, THF, RT, 3 h) gave ketoaldehyde 25 in
80% yield in 2 steps, ready for the crucial benzoin cyclization.
Me OBn
MeO2C
MeO
C
MeO2C
MeO
a
OMe
OMe
OMe
O
MeO
MeO
OMe
a)
O
N
OMe
OBn
N
OBn N
O
18
20
RN
NR
b,c
OMe
OMe
4a
OMe
O
retro-benzoin
OH
OMe
OMe
MeO
O
O
Me OBn
N
O
O
OMe
MeO2C
MeO
21
22
MeO OMe
OMe
OMe
19
b)
c)
O
N
OBn N
O
OBn
N
O
RN
NR
MeO
O
21
OMe
OMe
OMe
O
O
d
OH
O
O
O
O
O
O
–
Me
OBn
N
O
O
BF4
N
+
MeO2C
MeO
N
C6F5
N
O
OMe
O
OMe
O
OMe
O
OMe
OMe
OMe
O
O
O
O
O
O
O
OH
23a
22
24a
unstable
(see text)
24b
isolable
Scheme 4. Synthesis of α-ketol 22. a) 19 (1.8 equiv), PhCl, RT, 60 h (79%); b)
NiO2, CH2Cl2, 0 °C, 30 min (82%); c) 2 M H2SO4, THF, RT, 3 h (95%); d) 23a
(30 mol%), Et3N (30 mol%), THF, RT, 3 h [46% (20% recovery of 21)].
24c
unremovable
at the final stage
24d
Scheme 5. Problem and solution for the benzoin cyclization.
Through the trials and errors, we noticed the presence of a retro-
benzoin reaction as an origin of the problem (Scheme 5a),[22]
and ascribed the unfavorable equilibrium to the high steric
congestion of the α-ketol product 22 around its C4a angular
position. We came up with the idea of lowering the steric
demand by replacing the dimethyl acetal with a cyclic acetal
(Scheme 5b),[23] and thus prepared four ortho-quinone mono-
acetals 24a–d with different cyclic acetal moieties (Scheme 5c).
Extensive experimentation concluded that only 24d[24] gave us
the opportunity to complete the total synthesis as will be
discussed later. Beforehand, it would be appropriate briefly to
note the negative aspects of the other three acetals 24a–c. First,
ethylene acetal 24a was unstable itself, easily undergoing
dimerization.[25] By contrast, propylene acetal 24b was stable
enough for isolation, suggesting that cyclic acetals having six-
membered ring or larger would be suitable for practical use.
ortho-Xylylene acetal 24c attracted our attention, which we
hoped to be removable by acidic hydrolysis or hydrogenolysis.[26]
Although not detailed due to space limitations, ortho-quinone
mono-acetal 24c turned out to be indeed a great substrate,
allowing the transformations until the last synthetic intermediate
immediately before the target 1. Unfortunately, all attempts at the
final deprotection failed.
O
Me OBn N
MeO2C
MeO
a–c
O
OMe
18
+
O
O
OMe
O
O
O
O
25
24d
Me OBn N
O
MeO2C
MeO
–
BF4
d
N +
N C6F5
N
OMe
OH
O
O
O
R
R = H (23a)
= i-Pr (23b)
26
Scheme 6. Synthesis of α-ketol 26. a) 18 + 24d (1.8 equiv), PhCl, 50 °C, 3.5 h
(76%); b) NiO2, CH2Cl2, 0 °C, 1 h (82%); c) 2 M H2SO4, THF, RT, 3 h (97%); d)
23a or 23b (15 mol%), Et3N (15 mol%), THF, RT, 3 h (89% with 23a; 87%,
>99% ee with 23b).
However,
we
now
pleasingly
report
that
2,3-
dimethylnaphthalene-α,α’-diyl (DMN) acetal 24d worked nicely
]
for all steps, including the final oxidative deprotection,[ 27
Pleasingly, upon treatment with achiral triazolium salt 23a (15
mol%) and Et3N (15 mol%) (THF, RT, 3 h), the benzoin
cyclization of 25 proceeded smoothly to completion, affording α-
ketol 26 in 89% yield. Thus, the use of a cyclic acetal realized
full conversion of the benzoin cyclization. Furthermore,
screening of chiral triazolium salts identified Rovis’ triazolium salt
enabling the total synthesis as follows. Scheme 6 shows the
synthesis of α-ketol 26 having the DMN acetal moiety.
Ketoaldehyde 25, the direct precursor of 26, was prepared by
using the same protocol as above (vide supra, 18+19 → 20 →
21): Reaction of DMN-acetal 24d[28] (1.8 equiv) with nitrile oxide
18 (PhCl, 50 °C, 3.5 h) afforded the corresponding isoxazoline in
76% yield. Dehydrogenation (NiO2, CH2Cl2, 0 °C, 1 h) and
29
]
23b[
as the best catalyst precursor, allowing the
enantioselective cyclization of 25 to give α-ketol 26 [(R)-
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10.1002/anie.201707099
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COMMUNICATION
configuration][ 30 ] in high yield and perfect enantioselectivity
(87%, >99% ee). [31]
cyanoborohydride as
a
reductant under acidic conditions.
Pleasingly, the chemo- and stereoselective reduction was
achieved under carefully optimized conditions with two key
requirements: 1) the use of CH2Cl2 as a solvent, and 2) the use
of minimal amounts of acid. Treatment of ketone 30a with
NaBH3CN in CH2Cl2 and AcOH (v/v = 30:1, 0.02 M, 0 °C, 2 h)
afforded β-alcohol 31 as a major product (78% yield, β:α =
4.2:1). The minor C4-epimer was separable by column
chromatography (diol-modified SiO2, hexane/EtOAc = 7/3→1/1),
and in turn recycled by oxidation to ketone 30a.[37]
Scheme 7 shows the successful route to the target 1 from α-
ketol 26, which called for another subtle selection of the
protecting group for the C4a-OH.[32] Among various protecting
groups tested, the [D7]benzyl group[33] (Bn*) provided us with the
desired stability for the further transformations as discussed
below. The tert-hydroxy group in 26 was protected by a Bn*
group (Bn*Br, NaH, DMF, –20 → 0 °C, 1 h). N-Methylation
–
(Me3O+ BF4 , MS4A, CH2Cl2, RT, 14 h) followed by precipitation
(Et2O/EtOAc = 9/1) gave isoxazolium salt 27 in excellent yield.
Upon treatment of 27 with NaOCl (acetone, –40 °C, 10 min)
The final step was hydrogenolytic removal of two benzyl groups
using PdCl2 (H2, AcOH, H2O, MeOH, RT, 1 h), and the
purification by column chromatography (diol-modified SiO2,
hexane/EtOAc = 1/1→1/4) gave the target 1 in 70% yield, which
showed physical data (1H-, 13C NMR, IR, HRMS) identical in all
respects to those reported for the natural product, including the
34
]
under carefully controlled conditions (pH 8.9),[
the
hydroxylation proceeded smoothly to give the desired alcohol
29a in 66% yield as a single diastereomer.
Liberation of the C4 carbonyl group proved to be a challenge, as
it failed either by acid hydrolysis or by hydrogenolysis.
Pleasingly, an oxidative protocol proved effective, and treatment
of 29a with DDQ (2,6-di-tert-butylpyridine, CH2Cl2, 80 °C, 6 h)
gave ketone 30a in 78% yield. At this step, the Bn* protecting
group played a key role; serious degradation was observed for
the alcohol 29b having a non-deuterated benzyl group under the
same conditions, primarily due to the undesired oxidation at the
benzylic position.[35] We chose the Bn*-protecting group in hope
of its increased robustness toward oxidation by kinetic isotope
effect,[36] which indeed gave a positive result (vide supra).
With tetraketone 30a in hand, the remaining tasks toward the
total synthesis were: 1) the reduction of the C4 carbonyl group,
and 2) the deprotection of two benzyl groups. Since ketone 30a
24
optical rotation in sign and magnitude, [[α]D +22.2 (c 1.00, 1,4-
dioxane), lit. [α]D24 +22 (c 1, 1,4-dioxane)].[1]
Furthermore, after methylation of the C12a alcohol in 29a (MeI,
NaH), the same sequence of final conversion stated above gave
tetracenomycin
X (2), which also exhibited physical data
20
consistent with the reported data for the natural product [[α]D
+105 (c 0.290, MeOH), lit. [α]D20 +108.4 (c 0.66, MeOH)].[38]
In summary, the first asymmetric total syntheses of
tetracenomycins C (1) and X (2) have been achieved. The
synthetic route is efficient, and thus allows the synthesis of
various congeners with potential biological activities. Further
work along these lines is in progress.
was
base-labile,
we
decided
to
employ
sodium
–
BF4
Me
Me OBn N
O
Me OBn N+
O
Me OBn O
O
OH
MeO2C
MeO2C
MeO
MeO2C
MeO
a,b
c
12a
4a
4
MeO
OMe
OMe
OMe
OH
O
O
R
O
R
O
O
O
O
O
O
O
O
26
27 (R = Bn*)
28 (R = H)
29a (R = Bn*)
29b (R = Bn)
Me OH
O
O
O
Me OBn O
O
Me OBn O
O
OH
OH
OH
MeO2C
MeO
MeO2C
MeO
MeO2C
MeO
f
e
d
4
4
OMe
OMe
OMe
OH
OH
O
O
O
O
OH
O
R
R
(+)-tetracenomycin C (1)
31 (R = Bn*)
30a (R = Bn*)
30b (R = Bn)
Me
Me
Me
Me OH
O
O
O
Me OBn O
O
Me OBn O
O
O
O
O
MeO2C
MeO
MeO2C
MeO
MeO2C
MeO
j
i
g,h
OMe
OMe
OMe
OH
OH
O
O
O
OH
O
O
Bn*
Bn*
(+)-tetracenomycin X (2)
33
32
Scheme 7. Endgame. a) Bn*Br, NaH, DMF, –20 ꢁ 0 °C, 1 h (94%); b) Me3O+BF4–, MS4A, CH2Cl2, RT, 14 h (97%); c) aq. NaOCl (pH 8.9), acetone, –40 °C, 10
min (66%); d) DDQ, 2,6-di-tert-butylpyridine, 1,2-dichloroethane, 80 °C, 6 h (30a: 78% from 29a, 30b: 35% from 29b); e) NaBH3CN, AcOH, CH2Cl2, 0 °C, 2 h
(78%, d.r. 4.2:1); f) H2 (balloon), PdCl2, AcOH, H2O, MeOH, RT, 1 h (70%); g) MeI, NaH, DMF, 0 °C, 30 min (90%); h) DDQ, 2,6-di-tert-butylpyridine, 1,2-
dichloroethane, 80 °C, 4.5 h (75%); i) NaBH3CN, AcOH, CH2Cl2, 0 °C, 3 h (83%, d.r. 4.9:1); j) H2 (balloon), PdCl2, AcOH, H2O, MeOH, RT, 3 h (76%). DDQ = 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone, Bn* = [D7]benzyl.
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10.1002/anie.201707099
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COMMUNICATION
Acknowledgments
min. Further stirring for 20 min gave bis-cycloadducts 15 as a mixture
of two diastereomers (1:1, Rf 0.67, 0.60, hexane/EtOAc = 1/1) in 44%
combined yield.
This work was supported by Grant-in-Aid from Japan Society
for the Promotion of Science (JSPS) (Grant Nos. JP23000006,
JP16H06351, JP26105715, and JP26750363). We are grateful
to Ms. Sachiyo Kubo for X-ray analyses.
[16] M. A. Meador, H. Hart, J. Org. Chem. 1989, 54, 2336–2341.
[17] CCDC 1543805 (16) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Keywords: antibiotics • total synthesis • benzyne • nitrile oxide
• isoxazole
Cambridge
www.ccdc.cam.ac.uk/data_request/cif.
[18] Nitrile oxide 18 could be stored at –18 °C for at least one month.
Crystallographic
Data
Centre
via
[19] T.-C. Kao, G. J. Chuang, C.-C. Liao, Angew. Chem. Int. Ed. 2008, 47,
7325–7327, and the references cited therein.
[1]
1) W. Weber, H. Zähner, J. Siebers, K. Schröder, A. Zeeck, Arch.
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of total synthesis. The absolute stereochemistry of 1 was established
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H. Takikawa, S. Sato, R. Seki, K. Suzuki, Chem. Lett. 2017, 46, 998–
1000.
analysis using
a chiral stationary phase, which allowed good
separation of the racemic sample of 26; see Supporting Information.
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product under the same conditions.
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[15] Experimental procedure: Bis-tosylate 13 was treated with n-BuLi (1.1
equiv) in the presence of KSA 11 (1.1 equiv) (THF, –95 → –20 °C, 2
h). TLC-control showed that the starting material was consumed, and
mono-cycloadduct 14 (Rf 0.73, hexane/EtOAc = 1/1) was formed.
Furan 12 (1.5 equiv) was added to the reaction mixture, which was
chilled to –78 °C, and n-BuLi (1.25 equiv) was slowly added over 5
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gave ketone 30a in 81% yield gave ketone 30a in 81% yield.
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This article is protected by copyright. All rights reserved.

10.1002/anie.201707099
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Shogo Sato, Keiichiro Sakata, Dr.
Yoshimitsu Hashimoto, Dr. Hiroshi
Takikawa and Prof. Dr. Keisuke Suzuki*
Page No. – Page No.
First Total Syntheses of
Tetracenomycins C and X
The first total syntheses of tetracenomycins C and X have been achieved, featuring
1) preparation of a hexasubstituted naphthonitrile oxide by successive benzyne
cycloadditions and an oxidative ring-opening reaction; 2) a novel ortho-quinone
mono-acetal as the A-ring unit; 3) construction of three contiguous stereogenic
centers by an asymmetric benzoin cyclization, an isoxazole oxidation, and a
stereoselective reduction.
This article is protected by copyright. All rights reserved.