Total Synthesis of Actinorhodin

Article abstract of DOI:10.1002/anie.201814172

The enantioselective total synthesis of actinorhodin (1) is described. The synthesis features 1) dual benzyne reactions en route to the monomer, 2) the trans-selective installation of the side chain, and 3) a regioselective oxidative dimerization.

Full text of DOI:10.1002/anie.201814172

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Accepted Article
Title: First Total Synthesis of Actinorhodin
Authors: Mamiko Ninomiya, Yoshio Ando, Fumitaka Kudo, Ken
Ohmori, and Keisuke Suzuki
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201814172
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10.1002/anie.201814172
Angewandte Chemie International Edition
COMMUNICATION
First Total Synthesis of Actinorhodin
Mamiko Ninomiya, Yoshio Ando, Fumitaka Kudo, Ken Ohmori,* and Keisuke Suzuki*
Dedicated to Professor Dr. Axel Zeeck
products,[15] we embarked on the total synthesis of 1, keeping in
Abstract: The enantioselective first total synthesis of actinorhodin
(1) is described, featuring (1) dual benzyne reactions en route to the
monomer, (2) trans-selective installation of the side chain, and (3)
the regioselective oxidative dimerization.
mind three synthetic issues shown in a retrosynthetic fashion in
Figure 2. Issue 1 is the regiocontrol of the dimerization, a challenge,
given the high symmetry around the reaction sites. Assuming a
solution resorting to a directing-effect of free phenols,[9a,16] the
second task is to install multiple oxy-functions in a discriminating
fashion, so that the free phenols are at our disposal at the
dimerization stage. The third issue is rigorous stereocontrol in both
enantio- and diastereomeric senses in the preparation of the
monomer. However, seemingly-simple stereocontrol of the 1,3-
trans-relationship has not been established:[17] The often-used
strategy is acid-mediated equilibration (Figure 2b),[10,11a,b,d–k,12a,b,d–
Actinorhodin (1) is
a red pigment isolated in 1947 from
Streptomyces coelicolor A3(2) by Brockmann et al.[1] and
historically the oldest pyranonaphthoquinone antibiotic (Figure
1).[2] As a representative type-II polyketide metabolite,[3] the
structure of 1 appears in many books.[4] Surprisingly, however, no
NMR data of 1 has been recorded, presumably due to its extreme
insolubility (vide infra). Thus, the structure of 1, including the
relative and absolute stereochemistries, was assigned on the
chemical bases by Brockmann and Zeeck,[5,6] and the position of
the biaryl bond was determined by the biosynthetic study by
Floss.[6h]
g]
which only gives imperfect cis/trans-ratio, inevitably requiring
isomer separation.
a)
Issue 2
selectively protected
monomer unit
O
O
HO
HO
Issue 3
stereocontrol
enantio-
HO2C
At first glance, the structure of 1 appears to be a dimer of
nanaomycin A,[7] a representative monomer of this class. In reality,
however, there are two significant distinctions, (1) the monomeric
unit is enantiomeric (n.B., ent-nanaomycin A is also a natural
product),[8] and (2) additional hydroxy groups at C6 and C6’ are
present, conforming to binaphthazarin.
OH
O
O
diastereo-
O
CO2H
Issue 1
site-selective coupling
OH
O
b) acid-mediated isomerization
H+
O
OH
O
OH O
H+
H+
O
HO
6’
O
O
O
O
O
OH
O
HO
R
OH
O
OH
OH
O
O
O
O
OH
O
O
O
O
cis-isomer
(disfavored)
trans-isomer
(favored)
OH
O
HO
6
OH
6
O
OH
O
nanaomycin A
actinorhodin (1)
Figure 2. Synthetic challenges to 1 and acid isomerization of monomer.
O
O
O
HO
O
OH
O
OH
O
O
Herein, we describe the first enantioselective total synthesis of 1,
based on the retrosynthetic analysis shown in Scheme 1. The H
NMR data of 1, not previously reported due to its extreme
insolubility, is now recorded.
O
O
1
HO
O
O
O
OH
γ-actinorhodin
O
O
kalafungin
O
site-selective
dimerization
O
O
HO
HO
Figure 1. Pyranonaphthoquinones.
OH
O
HO2C
OH
O
8
O
O
8
8’
O
CO2H
CO2H
While numerous syntheses of the related monomers have been
reported,[9–12] the dimer synthesis is far more challenging,[13] and
the only example of the completed synthesis has been the recent
report on the total synthesis of a kalafungin-related, more oxidized
dimer, g-actinorhodin by Brückner.[14]
×2
OR
O
A
1
OH
O
[O]
asymmetric reduction
OH
OH
OH
OH
O
O
In connection with our synthetic interest in dimeric natural
CO2H
OH
OR
D
CO2Me
C
B
OR
OR
stereoselective substitution
[*]
Ms. Mamiko Ninomiya, Dr. Yoshio Ando, Prof. Dr. Fumitaka Kudo,
Prof. Dr. Ken Ohmori, Prof. Dr. Keisuke Suzuki
[4+2]
OH
OH
OBn
OH
Department of Chemistry, Tokyo Institute of Technology
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
Fax: (+81) 3-5734-2788
TsO
I
OTf
SiMe3
O
O
CO2Me
F
G
1,4-benzdiyne
E
OR
CO2Me
2
E-mail: ksuzuki@chem.titech.ac.jp; kohmori@chem.titech.ac.jp
acyl-alkylation
dual benzyne reactions
Supporting information\ is available on the WWW under
http://dx.doi.org/10.1002/anie.2014 xxxxxx.
Scheme 1. Retrosynthetic analysis
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10.1002/anie.201814172
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COMMUNICATION
The dimer 1 can be disconnected into the two identical monomers
A. The hope was that the unprotected phenols would allow the site-
selective oxidative coupling of A at C8–C8’;[9a,16] we had a good
experience with this approach in another project.[15a] Naphthazarin
A would in turn be derived from naphthalenediol derivative B by
adjusting the oxidation state. Here again, regioselective
manipulations would hopefully be possible by selective protection
of the phenolic functions. The side chain in B would be installed by
using lactol C as the precursor, and the Lewis acid-mediated
activation followed by attack of p-nucleophile would allow the
desired trans-selective reaction under kinetic control.[18] The
stereocenter in alcohol D would be established by enantioselective
reduction of ketone E. Finally, naphthyl ketoester E, a penta-
substituted benzene, would be assembled by dual benzyne
reactions.[19] Bis-sulfonate 2 would work as a 1,4-benzdiyne
equivalent[20] to allow stepwise generations of two benzyne species,
reacting with furan (F) and methyl acetoacetate (G), respectively.
The two different functional arrays, iodo–tosylate[21] and silyl–
triflate,[22] in 2 would allow chemoselective generation of two
different benzyne species.
ensuing attack of the benzene anion on the ketone moiety leads to
the oxy-anion substituted benzocyclobutene K,[27] which undergoes
a ring opening by a retro-aldolization, providing ketoester 10.[28]
OBn
TsO
I
OTf
OBn
SiMe3
OTf
a)
2
7
O
OBn
SiMe3
b)
O
O
8
9
O
CO2Me
O
O
(10 equiv)
10
OMe
(2.5 equiv)
OBn
OTf
OBn
OBn
O–
O
δ–
O
O
O
O
δ+
SiMe3
CO2Me
[4+2]
J
K
OMe
With this plan in mind, our synthetic study began with preparation
of the 1,4-benzdiyne equivalent 2 from pyrogallol (3) (Scheme 2).
Following a literature procedure with slight modification,[23] the
central hydroxy group in 3 was selectively benzylated, giving ether
4 in 46% yield. Iodination of 4 with NIS in the presence of a
catalytic amount of TfOH with careful control of the temperature
gave diiodide 5 in 90% yield.[24] Conversion of 5 into silyl triflate 2
was executed by a one-pot procedure: silylation of the phenols in 5
with (Me3Si)2NH followed by the retro-Brook rearrangement[25] of
H by treatment with nBuLi at –95 °C gave phenoxide I, which was
immediately trapped by Tf2O. After quenching by addition of
Et2NH to consume the unreacted Tf2O, the resulting phenol 6 was
tosylated to give 2 in 79% yield in 4 steps.
Scheme 3. Dual benzyne reactions. a) nBuLi (1.2 equiv), THF, –78 °C, 6 h
(91%). b) KF (3.0 equiv), 18-crown-6 (3.0 equiv), toluene, THF (0.02 M), 18 h
(53%).
Next, the asymmetric reduction of ketone 10 was attempted (Table
1). Although ketone 10 was a racemic mixture, we chose a reagent-
controlled approach, assuming that the pre-existing stereogenic
centers are far enough from the reaction site, and would not affect,
if any, the asymmetric induction process.
As the first attempt, Noyori reduction[29] was examined, which only
gave partial recovery of the starting material 10 (entry 1). By
contrast, the catalytic CBS reduction[30] produced many
unidentified byproducts, which we ascribed to the competing
hydroboration of the C=C bond in 10.
OH
OBn
OBn
HO
OH
HO
OH
Me3SiO
I
OSiMe3
I
This notion led us to an idea of using equimolar amounts of the
CBS reagent and BH3. The hope was that pre-coordinated complex
L[30b] would be responsible only for the carbonyl reduction, not
affecting the olefin. Thus, to a chilled (–78 °C) THF solution of
ketoester 10 and CBS reagent (2.0 equiv) was carefully added
BH3·THF (2.0 equiv); further stirring at –50 °C for 22 h gave lactol
11 in 69% yield and diol 12 in 24% yield.[31]
d)
c)
a)
X
X
3
H
4: X = H
5: X = I
b)
OBn
OBn
OBn
TsO
OTf
SiMe3
HO
I
OTf
SiMe3
Me3SiO
I
OLi
e)
f)
I
SiMe3
Table 1. Asymmetric reduction of ketone 10.
I
6
2
OBn
OBn
(R)
1
see table
Scheme 2. Synthesis of 1,4-benzdiyne equivalent. a) BnBr (1.0 equiv), K2CO3
(1.0 equiv), acetone, 18 h (46%). b) NIS (3.0 equiv), TfOH (0.2 equiv), CH2Cl2,
–78 ® –60 °C, 3 h (90%). c) (Me3Si)2NH (3.0 equiv), THF, 3 h. d) nBuLi (1.0
equiv), THF, –95 °C, 10 min. e) Tf2O (1.1 equiv); Et2NH (0.2 equiv). f) TsCl
(1.5 equiv), K2CO3 (2.0 equiv), DMF, –95 °C ® RT, 13 h (79% for 4 steps). Bn
= benzyl, NIS = N-iodosuccinimide, TfOH = trifluoromethanesulfonic acid, Tf2O
= trifluoromethanesulfonic anhydride, Ts = p-toluenesulfonyl, DMF = N, N-
dimethylformamide.
O
O
O
O
CO2Me
OH
10
11
(mixture of 4 diastereomers)
Entry
1
Conditions
Results
Ru cat. (0.01 equiv), HCOOH (31 equiv), NEt3
(26 equiv), RT, 36 h
50% recovery of 10*
2
3
CBS reagent (0.1 equiv), BH3·THF (2.0 equiv),
messy
THF (0.1 M), –78 °C→RT, 5 h
CBS reagent (2.0 equiv), BH3·THF (2.0 equiv),
THF (0.1 M), –78→ –50 °C, 22 h
11: 69%, 12: 24%
With 1,4-benzdiyne equivalent 2 in hand, we embarked on the
synthetic endeavor, starting with the first benzyne generation in the
presence of furan (7) as the arynophile (Scheme 3). Treatment of 2
with nBuLi at –78 °C in the presence of an excess amount of 7
allowed the benzyne generation and [4+2] cycloaddition, giving
cycloadduct 8 in 91% yield. It should be noted that, without any
obvious reasons, cycloadduct 8 was potentially explosive when
condensed to a neat solid, and should be kept as a solution in
organic solvent. The second benzyne species was generated from 8
in the presence of methyl acetoacetate (9), using KF and 18-crown-
6 (THF, 18 h, room temperature) – in which diluted conditions
(0.02 M) were critical – giving keto ester 10 in 53% yield.[26] The
regioselectivity is derived from the benzyloxy group as in J. An
*The unrecovered materials were an intractable mixture of unknown compounds.
Ph
OBn
Ph
H
H
Ph
Ph
1
OH
OH
Ru
Cl
H2N
O
O
NTs
Ph
O
N+
N
B
B
Ph
H3B– Me
Me
12
(inseparable)
CBS reagent
Ru cat.
L
Pleasingly, the stereochemical analysis on 11, although not easy,
provided two positive conclusions:
(1) Perfect facial selection (>99% selectivity)
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10.1002/anie.201814172
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COMMUNICATION
Scheme 5. Synthesis of dimerization precursor. a) allyltrimethylsilane (10.0
equiv), Me3SiOTf (1.0 equiv), CH2Cl2, –78 °C, 15 min (76%, >99% ee). b)
PhI(OCOCF3)2 (2.5 equiv), H2O, 1,4-dioxane, acetone, 0 °C, 3 h; Na2S2O4 aq.
c) (MeO)2SO2 (1.2 equiv), K2CO3 (1.5 equiv), acetone, reflux, 5.5 h.
(2) (R)-Configuration of the C1 stereogenic center
As the product 11 was an inseparable diastereomeric mixture by
the pre-existing stereogenic centers and the configurational
inhomogeneity of the lactol moiety, the analysis was done as
follows: Lactol 11 was reduced to diol 12 (LiAlH4, THF, 2 h),
which was assayed by HPLC on the chiral stationary phase,
establishing >99% ee for each diastereomer. Mono-silylation of
diol 12 gave diastereomeric silyl ethers 13a and 13b, which were
separated (Scheme 4). Each isomer was subjected to modified
Mosher analysis, after conversion into (+)- and (–)-MTPA esters
(See Supporting Information).[32]
The stage was set for the dimerization of naphthol 16 with a free
C9-hydroxy group (Scheme 6). To our delight, exposure of 16 to
Laatsch’s conditions (Ag2O, Et3N) [9a] smoothly gave quinoid 18 as
a dark navy-blue solid, which was reduced with Zn to give
colorless pyranonaphthol 19 in excellent yield. The regioselectivity
of dimerization at C8–C8’ was evidenced by extensive 2D NMR
analysis of 19. Protection of the resulting phenols by methyl groups
gave dimer 20 in quantitative yield.
OBn
OBn
R = (+)-MTPA
R = (–)-MTPA
1
1
*
TBDPSCl
imidazole
*
OH
OH
OR
MeO
O
O
OH OBn
9
DMF
OTBDPS
O
OBn
*
a)
O
12
13
O
O
less polar (13a): 41%
more polar (13b): 45%
R = H;
separable
BnO
O
OMe
16
18
OMe
MeO
Scheme 4. Modified Mosher analysis of 13. TBDPS = tert-butyldiphenylsilyl
OR OBn
b)
O
8
8’
O
Once correct stereochemistry was confirmed, we moved on to the
introduction of the side chain into lactol 11 (Scheme 5). To a
chilled solution of 11 and allyltrimethylsilane in CH2Cl2 at –78 °C
was added TMSOTf, where the substitution by an allyl group
(OH→CH2CH=CH2) and aromatization proceeded simultaneously,
giving pyranonaphthol 14 as a single diastereomer.[18] The trans
relationship of the two substituents, methyl and allyl, was
established by NOE analysis. The stereochemical outcome could
be explained by considering the allylic strain in oxonium species
M, in which the diastereotopic faces are well discriminated.[33]
Two additional notes: (1) Opening of the 1,4-epoxide in 11
proceeded regioselectively, as rationalized by the directing effect
of benzyloxy group,[34] (2) The ee of 14 was assessed to be >99%
by HPLC analysis on chiral stationary phase,[35] an additional data
BnO RO
OMe
19: R = H
20: R = Me
c)
Scheme 6. Oxidative dimerization. a) Ag2O (1.8 equiv), Et3N (0.64 equiv),
CH2Cl2, RT, 2 h. b) Zn (4.0 equiv), AcOH, CHCl3, RT, 1 h (96% for 2 steps). c)
(MeO)2SO2, NaH, DMF, 0 °C, 1.5 h (quant).
Scheme 7 shows the endgame of the synthesis. The terminal olefins
in dimer 20 were cleaved by Lemieux–Johnson oxidation,[40]
giving the corresponding dialdehyde 21, which was oxidized to
dicarboxylic acid 22,[41] and further converted to diester 23 for the
ease of handling. After removal of the benzyl groups by
hydrogenolysis, the resulting naphthol 24 was oxidized with CAN,
giving binaphthazarin 25. The methyl protecting groups for the
phenols in 25 were removed by exposure to MgI2·OEt2 (50 equiv,
Et2O, MeCN, room temperature),[42] providing binaphthazarin 26
as a purple red solid. No isomerization into the cis-stereoisomer
was observed under these conditions. Saponification of 26 with
LiOH·H2O, and acidification by DOWEX® (H+ form) gave the
final product 1.
for the perfect selectivity in the CBS-reduction, 10®11, vide supra.
[36]
Oxidation of 14 with PhI(OCOCF3)2
in aq. 1,4-dioxane in the
dark[37] followed by treatment of the resulting p-quinone with
aqueous Na2S2O4 gave air-sensitive hydroquinone 15, which,
without purification, was immediately treated with (MeO)2SO2 and
K2CO3, giving the dimerization precursor 16 in 58% overall yield
(3 steps). At this stage, a small amount of the corresponding
dimethyl ether 17 was obtained (13% yield).[38] Preferential
methylation at the C6 hydroxy group was a desired outcome, as
expected by its higher reactivity in comparison to the C9 hydroxy
group that has a hydrogen bonding with proximal benzyloxy
group.[39]
MeO
OMe OBn
OMe OBn
a)
O
O
O
R
BnO MeO
OMe
OMe
20
21: R = CHO
b)
c)
22: R = COOH
23: R = COOMe
OBn
OBn
MeO
MeO
a)
O
O
b)
OMe OH
O
d)
e)
O
O
OH
O
O
11
14
OH
HO MeO
OMe
OMe
OH OBn
OR OBn
9
24
O
RO
RO
c)
O
O
MeO
OR
OR
O
g)
6
O
O
actinorhodin (1)
O
O
OH
OMe
15
O
16: R = H (58%, 3 steps)
17: R = Me (13%, 3 steps)
OMe
O
25: R = Me
26: R = H
Ha
H
H
Ha
OBn
f)
Nu–
H
NOE
Ha
OR
Dowex®
(H+)
O
H
O
Hb
LiOH
H
OH
14
M
Nu–
I
II
III
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10.1002/anie.201814172
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COMMUNICATION
Scheme 7. Endgame. a) OsO4 (0.1 equiv), NaIO4 (8.0 equiv), 2,6-lutidine (4.0
equiv), 1,4-dioxane, H2O (96%). b) NaClO2 (6.0 equiv), NaH2PO4·2H2O (10
equiv), 2-methyl-2-butene (50 equiv), THF, tBuOH, H2O, 1 h. c) TMSCHN2 (10
equiv), MeOH, toluene, 15 min (87% for 2 steps). d) H2, 10% Pd/C, benzene,
MeOH, 1.5 h (84%). e) Ce(NH4)2(NO3)6 (10 equiv), H2O, 1,4-dioxane, MeCN,
0 °C, 3 h (92%). f) MgI2·OEt2, Et2O, MeCN (62%). g) LiOH·H2O, THF, H2O (ca.
92%). TMS = trimethylsilyl.
Further efforts to synthesize other dimeric pyranonaphthoquinone
antibiotics are currently underway in our laboratory.
Acknowledgements
The reaction mixture showed impressive color change. Upon
treatment of 26 with the base, the color quickly changed from
purple red to blue, which turned into purple red upon acidification
(see I→II→III in Scheme 7). Such pH-chromic behavior is
characteristic to naphthazarin derivatives.[43]
We thank Prof. Axel Zeeck for kindly sending a copy of
dissertation of Dr. Bernd Krone. We are grateful to Prof. Gregory
L. Challis (Univ. Warwick) for kindly providing the spore of
Streptomyces coelicolor A3(2), and to Prof. Gaku Fukuhara,
Tokyo-Tech, for CD spectra measurement. This work was
supported by JSPS KAKENHI Grants JP23000006 and
JP16H06351, and Takeda Science Foundation.
The crude material of 1 contained small amounts of impurities
(assessed by 1H NMR). Reprecipitation from 1,4-dioxane gave
pure 1 as a purple red solid, which became further insoluble. It
should be noted that the solubility of 1 to various solvents was
1
extremely poor.[1] The peaks in H NMR spectrum of pure 1 were
Keywords: actinorhodin · natural product · pigments ·
weaker in magnitude than the satellite peaks of the solvent (THF-
d8) (Figure 3a). Since, in the 1H NMR spectrum of synthetic 1,
unidentified impurities come from distilled THF-d8 were included
(Figure 3b), the 1H NMR spectrum of blank THF-d8 was subtracted
from the 1H NMR spectrum of synthetic 1, giving a clear spectrum
as shown in Figure 3c.
pyranonaphthoquinone · total synthesis
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Figure 3. 1H NMR spectra (600 MHz, THF-d8, 13.2–1.4 ppm); a) synthetic 1,
b) blank THF-d8, c) differential spectrum of synthetic 1 (a–b).
As the 1H NMR spectra of the natural product had not been
reported, we conducted the fermentation of Streptomyces
coelicolor A3(2) in our lab and isolated an authentic sample of 1
according to the literature procedure.[44] Upon direct comparison,
1
the H NMR spectra of the synthetic and authentic specimen fully
coincided. Due to the low solubility of 1 in various solvents,
comparison of the CD spectra was done after conversion into
diester 26 (Figure 4). The CD curve of synthetic 26 was
superimposable with that of 26 derived from the natural sample,
giving an independent validation of the absolute configuration of
1.[45]
CD (26 from natural actinorhodin)
CD (Synthetic 26)
4
3
4
3
2
2
[11] Enantioselective total synthesis of nanaomycins by employing chiral pools: a) K.
Tatsuta, K. Akimoto, M. Annaka, Y. Ohno, M. Kinoshita, J. Antibiot. 1985, 38, 680–
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Fernandes, S. V. Mulay, V. P. Chavan, Tetrahedron: Asymmmetry 2013, 24, 1548–
1555; h) N. P. S. Hassan, B. J. Naysmith, J. Sperry, M. A. Brimble, Tetrahedron 2015,
71, 7137–7143. For the approaches employing Sharpless dihydroxylation: i) R. A.
Fernandes, R. Brückner, Synlett 2005, 56, 1281–1285; j) M. Mahlau, R. A. Fernandes,
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Eur. J. Org. Chem. 2017, 2512–2539. Very recently, direct control of the trans-
substituted pyran in the synthesis of (–)-nanaomycin A has been reported, where,
1
1
e
e
0
0
-1
-2
-1
-2
250
350
450
550
650
750
250
350
450
550
650
750
l
/ nm
l
/ nm
Figure 4. CD spectra of actinorhodin dimethyl ester (in CHCl3): synthetic
sample 26 (left) and sample derived from natural actinorhodin (right).
In summary, the first enantioselective total synthesis of
actinorhodin (1) has been achieved, featuring use of benzdiyne
equivalent as a precursor for the pyranonaphthoquinone structure.
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M. Ninomiya, Y. Ando, F. Kudo, K.
stepwise
benzyne formation
CBS reduction
HO
Ohmori,* K. Suzuki*
site-selective
dimerization
O
O
HO
HO
OR
OH OR
OH
O
OH
Page No. – Page No.
O
O
O
O
O
O
CO2Me
First Total Synthesis of Actinorhodin
diastereoselective
substitution
OH
OR’
1,4-benzdiyne
OH
O
actinorhodin
The first total synthesis of representative pyranonaphthoquinone dimer,
actinorhodin, has been accomplished, featuring 1) a sequential benzyne formation
to construct multi-substituted naphthalene, 2) a robust control of the configuration
on the pyran-ring, and 3) a site-selective dimerization of pyranonaphthalene unit.
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