Synthetic study of the angular tetracyclic core skeleton of landmycine a via Masamune-Bergman cyclization

Article abstract of DOI:10.1055/s-0031-1290937

We describe the synthesis, via Masamune-Bergman cyclization, of an angucycline derivative involving a quinone in the B ring and a nonaromatic hydroxylated C ring. The naphthoquinone was synthesized via the copper-catalyzed Ullmann reaction of the dihalo a

Full text of DOI:10.1055/s-0031-1290937

LETTER
▌1327
lSetyternthetic Study of the Angular Tetracyclic Core Skeleton of Landmycine A via
Masamune–Bergman Cyclization
Synthetic Study of the Angular Tetracyclic Core Skeleton of Landmycine A
Sho Yamaguchi,a Hiroshi Tanaka,*a Ryo Yamada,b Susumu Kawauchi,b Takashi Takahashi*a
a
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro,
Tokyo 152-8552, Japan
Fax +81(3)57342884; E-mail: thiroshi@apc.titech.ac.jp
b
Department of Organic and Polymer Materials, Graduate School of Science and Engineering, Tokyo Institute of Technology 2-12-1-E4-6,
Ookayama, Meguro, Tokyo 152-8552, Japan
E-mail: skawauchi@polymer.titech.ac.jp
Received: 13.02.2012; Accepted after revision: 13.03.2012
Abstract: We describe the synthesis, via Masamune–Bergman cy-
O
HO
O
O
clization, of an angucycline derivative involving a quinone in the B
ring and a nonaromatic hydroxylated C ring. The naphthoquinone
was synthesized via the copper-catalyzed Ullmann reaction of the
dihalo aryl moiety, and the subsequent oxidation of a corresponding
hydroquinone. The aryl dihalide was prepared by the dihalogena-
tion of the 1,4-diradical generated during the Masamune–Bergman
cyclization of the 1,2- dialkynylbenzene under neutral conditions.
This methodology suggests a new route for the construction of nat-
ural products containing an anthraquinone skeleton.
O
HO
O
OH
O
O
O
O
H
OH
2
HO
landomycin A (1)
OH
O
Key words: aglycon, deoxyoligosaccharide, quinone, NHK cou-
pling, Ullmann coupling
OH
OH
O
O
OH
Landomycin A (1, Figure 1)1 and TAN-1085 (2)2 are an-
gucycline antibiotics3 possessing an angular tetracyclic
aglycon (A–D ring) and deoxyglycosides. The aglycons
involve a quinone in the B ring and a nonaromatic hydrox-
ylated C ring. The unique aglycons serve as attractive syn-
thetic targets because the nonaromatic C ring readily
undergoes aromatization via β-elimination of the hydroxy
group.4 Suzuki et al. reported on the synthesis of TAN-
1085 involving the preparation of its aglycon via pinacol
coupling between the two hydroxy groups on the C
ring.4e–g Roush et al. reported the synthesis of the pro-
posed landomycin aglycon based on Dötz annulation and
intramolecular Michael addition.4d Recently, Yu et al.
successfully achieved the total synthesis of landomycin A,
in which the aglycon was prepared via a modified Roush’s
method.4i On the other hand, Grissom et al. have been re-
ported on a unique approach for the synthesis of quinone
derivatives by the Masamune–Bergman cyclization, in
which the generated p-benzene biradicals were oxidized
with TEMPO to quinone derivatives.5
O
OH
HO
TAN-1085 (2)
Figure 1 The structure of landomycin A (1) and TAN-1085 (2)
synthetic precursor. The aryl dihalide 4 would be convert-
ed to quinone 3 via the copper-catalyzed Ullmann reaction
of a dihalo aryl moiety using methanol as an oxygen
source with a subsequent oxidation of the corresponding
hydroquinone 3. Although the substitution of methanol
proceeds under strong basic conditions, the likelihood of
β-elimination seemed to be significantly lower because of
its installation prior to the establishment of the anthraqui-
none skeleton. The aryl dihalide 4 could be obtained from
a highly strained 1,2-dialkynylbenzene derivative 7,
which underwent the Masamune–Bergman cyclization
under neutral conditions to provide the 1,4-diradical 5 fol-
lowed by dihalogenation.6–8 Transition-state analysis of
the Masamune–Bergman cyclization of the 1,2-dialkynyl-
benzene derivative 7 to biradical 5 based on DFT calcula-
tion at the ωB97XD/6-31G* level by Gaussian 099
indicated that the activation energy of the cyclization
would be 26.9 kJ/mol.
Herein, we report on a new approach for the synthesis of
anglucycline 3 via Masamune–Bergman cyclization.
The strategy for the synthesis of anglucycline 3 via the
Masamune–Bergman cyclization is shown in Scheme 1.
In our retrosynthetic plan, we set up aryl dihalide 4 as a
These results suggested that the ten-membered 1,2-
dialkynylbenzene derivative would undergo the
Masamune–Bergman cyclization under mild heating.10
The ten-membered 1,2-dialkynylbenzene derivative 7 can
be prepared by the intramolecular Nozaki–Hiyama–Kishi
SYNLETT 2012, 23, 1327–1330
Advanced online publication: 14.05.2012
DOI: 10.1055/s-0031-1290937; Art ID: ST-2012-U0130-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1328
S. Yamaguchi et al.
LETTER
Scheme 1 Strategy for the synthesis of quinone 3
(NHK) cyclization of the precursor 8, which possesses tected primary alcohol 12 by the reduction of the aldehyde
both the iodoacetylene and aldehyde moieties.
to a primay alcohol, followed by protection of the primary
alcohol in a 77% yield in two steps. Treatment of phenyl-
acetylene 12 and bromide 9 with PdCl2(PPh3)2 and CuI
provided the biaryl alkyne 13 in a 66% yield. Conversion
of the aldehyde moiety 13 to an acetylene unit was accom-
plished using the Ohira–Bestmann reagent 14,13 followed
by deprotection of the TBS group by TBAF. Finally, the
iodination of the acetylene moiety, followed by the oxida-
tion of primary alcohol, efficiently afforded the intramo-
lecular NHK cyclization precursor 8.
The synthesis of intramolecular NHK cyclization precur-
sor 7 is shown in Scheme 2.11 Treatment of 2-bromobenz-
aldehyde (9) and trimethylsilylacetylene with a catalytic
amount of PdCl2(PPh3)2 and CuI, under Sonogashira cou-
pling conditions, provided phenylacetylene 10 in 88%
yield. Next, the Wittig reaction with MeOCH2PPh3Cl pro-
vided a methylvinyl ester. Subsequent deprotection of the
TMS group and hydrolysis of the vinyl ester afforded the
homobenzyl aldehyde 11 in a 65% yield in three steps.12
Then the aldehyde moiety was converted to the TBS-pro-
O
TMS
O
O
a) n-BuLi, THF
MeOCH2PPh3Cl
TMS
Br
PdCl2(PPh3)2
CuI, Et2NH
DMF
b) K2CO3, MeOH
c) 4 M HCl, THF
reflux
9
10
11
80 °C, 88%
3 steps 65%
1) NaBH4, EtOH
2) TBSCl, imdazole
2 steps 77%
O
O
O
OMe
P
1)
OMe
O
N2
14
OTBS
OTBS
Br
9
K2CO3, MeOH
92%
PdCl2(PPh3)2
2) TBAF, 99%
CuI, Et2NH
DMF, 80 °C
66%
13
12
I
OH
O
1) I2, morpholine
toluene, 90%
2) Dess–Martin
periodinane
CH2Cl2, 94%
15
8
Scheme 2 Synthesis of the NHK cyclization precursor 8
Synlett 2012, 23, 1327–1330
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthetic Study of the Angular Tetracyclic Core Skeleton of Landmycine A
1329
Intramolecular NHK cyclization also was examined (Ta- When CBr4 was used as the bromine source,15 the desired
ble 1).14 Treatment of the precursor 8 with 9.0 equivalents product 4a was obtained in only a 37% yield over two
of CrCl2 and 0.64 equivalents of NiCl2 provided the ten- steps (Table 1, entry 1), and when I2 and NIS were used as
membered-ring 1,2-dialkynylbenzene derivative 7. How- the iodine source, the desired product 4b was obtained in
ever, precursor 7 was unstable at ambient conditions, so a trace amount due to decomposition (Table 1, entries 2
the residue was used for the next reaction and without pu- and 3). However, when 1,2-diiodoethane was used as the
rification. The introduction of halogen (Br or I), following iodine source, the diiodo aryl compound 4b was provided
the Masamune–Bergman cyclization, was examined. in a satisfactory yield of 52% (Table 1, entry 4).16,17
Table 1 Intramolecular NHK Cyclization and Introduction of Halogen, following the Masamune–Bergman Cyclization
OH
OH
X
I
O
CrCl2, NiCl2
reagent
THF
10 min, r.t.
MeCN
60 °C, 1 h
X
7
4a: X = Br
4b: X = I
8
Entry
X
Reagent
Product
Yield (2 steps, %)
1
2
3
4
Br
I
CBr4
I2
4a
4b
4b
4b
37
dec.
trace
52
NIS
ICH2CH2I
The conversion of aryl dihalides 4a and 4b into dime- do aryl compound 4b was converted into the desired prod-
thoxy aryl compound 16 in a copper-catalyzed Ullmann uct 4b in a 77% yield (Table 2, entry 3). Interestingly, no
reaction was examined (Table 2).18 First, using NaOMe, aromatized byproduct was caused by β-elimination. Final-
2,6-lutidine, and CuI with the dibromo aryl compound 4a ly, the synthesis of quinone 3, as shown in Scheme 3, was
resulted in decomposition of the product (Table 2, entry accomplished when the dimethoxy aryl compound 16,
1).19 Treatment with KOt-Bu, 1,10-phenanthroline, and which was synthesized via the copper-catalyzed Ullmann
CuI under microwave irradiation (300 W, 150 °C) mainly reaction of diiodo aryl compound 4b, was treated with 2.2
provided the undesired monosubstituted product (Table 2, equivalents of CAN to afford quinone 3 in a 75% yield.21
entry 2).20 However, under the same conditions, the diio-
Table 2 Ullmann Reaction with Methanol and CuI
Entry
Substrate
Reagents
Yield (%)
1a
2b
3b
4a
4a
4b
2,6-lutidine, Na
dec.
trace
77
1,10-phenanthroline, KOt-Bu
1,10-phenanthroline, KOt-Bu
a Conditions: reflux, 24 h.
b Conditions: microwave irradiation 300 W, 150 °C, 1 h.
X
OH
OMe OH
O
O
OH
CAN
MeCN
H2O
Table 2
r.t., 10 min
75%
X
OMe
16
4a: X = Br
4b: X = I
3
Scheme 3 Synthesis of quinone 3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1327–1330

1330
S. Yamaguchi et al.
LETTER
Kawauchi, S.; Sugiyama, H.; Takahashi, T. Chem. Commun.
2010, 46, 5942.
In conclusion, we have achieved the synthesis of the
angucycline aglycon core involving a quinone in the B
ring and a nonaromatic hydroxylated C ring via the
Masamune–Bergman cyclization from a 1,2-dialkynyl-
benzene derivative precursor. This synthetic method sug-
gests a new synthetic route for the construction of natural
products containing naphthoquinone skeletons. The syn-
thesis of the more complex oxy-functionalized aromatic
derivatives is in progress and will be reported in due time.
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Acknowledgment
This work was financially supported by JSPS Research Fellowship
for Young Scientists (DC2). We also thank Professor John Nielsen
for his help to prepare the manuscript.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmorinftIangoimnuSpinorttfoIangiStupor
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1H NMR (400 MHz, CDCl3): δ = 8.40 (m, 1 H), 8.26–8.20
(m, 2 H), 7.64–7.56 (m, 2 H), 7.36–7.32 (m, 3 H), 5.46 (t, 1
H, J = 2.9 Hz), 3.15 (dd, 1 H, J = 2.9, 15.4 Hz), 3.10 (dd, 1
H, J = 2.9, 15.4 Hz). 13C NMR (100 MHz, CDCl3): δ = 140.8,
139.0, 136.8, 135.40, 135.16, 134.66, 134.33, 133.9, 132.9,
132.7, 131.6, 130.2, 129.3, 129.1, 129.0, 128.7, 128.4,
127.6, 127.1, 126.0, 108.5, 102.4, 74.6, 49.4, 37.4. IR (neat):
3437, 3019, 1722, 1216, 1045, 753, 667 cm–1. HRMS (ESI-
TOF): m/z calcd [M + H]+: 498.9056; found: 498.9035.
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H), 8.14 (m, 1 H), 7.82–7.74 (m, 2 H), 7.44–7.35 (m, 3 H),
5.30 (t, 1 H, J = 4.8 Hz), 3.23 (dd, 1 H, J = 4.8, 15.5 Hz), 3.11
(dd, 1 H, J = 4.8, 15.5 Hz). 13C NMR (100 MHz, CDCl3): δ
= 185.5, 185.1, 139.8, 138.6, 135.8, 134.0, 133.8, 132.9,
131.8, 130.8, 130.6, 129.3, 127.9, 127.2, 126.9, 126.0, 61.5,
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HRMS (ESI-TOF): m/z calcd [M + H]+ 277.0865; found:
277.0860.
Synlett 2012, 23, 1327–1330
© Georg Thieme Verlag Stuttgart · New York

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