Total Synthesis of Aquayamycin

Article abstract of DOI:10.1002/chem.201604697

An efficient and practical total synthesis of aquayamycin has been accomplished. The highly oxidized and stereochemically complex tetracyclic ring system was constructed using three key reactions: 1) highly diastereoselective 1,2-addition of C-glycosyl naphthyllithium to a cyclic ketone, 2) indium-mediated site-selective allylation-rearrangement sequence of naphthoquinone, and 3) diastereoselective intramolecular pinacol coupling. This synthetic strategy offers a novel and efficient pathway to prepare aquayamycin-type angucycline antibiotics.

Full text of DOI:10.1002/chem.201604697

A Journal of
Accepted Article
Title: Total Synthesis of Aquayamycin
Authors: Shunichi Kusumi, Harunobu Nakayama, Takumi Kobayashi,
Hajime Kuriki, Yuka Matsumoto, Daisuke Takahashi, and
Kazunobu Toshima
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To be cited as: Chem. Eur. J. 10.1002/chem.201604697
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10.1002/chem.201604697
Chemistry - A European Journal
COMMUNICATION
Total Synthesis of Aquayamycin
Shunichi Kusumi, Harunobu Nakayama, Takumi Kobayashi, Hajime Kuriki, Yuka Matsumoto, Daisuke
Takahashi and Kazunobu Toshima*
Dedicated to Professor K. C. Nicolaou on the occasion of his 70th birthday
Abstract: An efficient and practical total synthesis of aquayamycin
has been accomplished. The highly oxidized and stereochemically
complex tetracyclic ring system was constructed using three key
reactions: 1) highly diastereoselective 1,2-addition of C-glycosyl
naphthyllithium to a cyclic ketone, 2) indium-mediated site-selective
allylation-rearrangement sequence of naphthoquinone, and 3)
diastereoselective intramolecular pinacol coupling. This synthetic
two groups have achieved the total synthesis of 1 and related
compounds.[11-13]
strategy offers
a
novel and efficient pathway to prepare
aquayamycin-type angucycline antibiotics.
In the past 50 years, more than 100 types of angucycline
antibiotics have been reported and represent an important class
of microbial antibiotics.[1] They exhibit a broad spectrum of
biological activity, such as antifungal, antitumor, and enzyme
inhibitory activity, and their unique angular tetracyclic core
skeleton (benz[a]anthraquinone) have attracted many synthetic
organic chemists. Some angucyclines, including landomycin A[2]
and vineomycin B2,[3] have been synthesized in a regio- and
stereoselective manner by several different methods,[1,4] such as
Diels-Alder reaction, Friedel-Crafts reaction, nucleophilic
addition, Hauser annulation, and free-radical annulation. Despite
the synthetic strategies developed, there are still remaining
challenges with regard to the synthesis of aquayamycin-type
angucyclines.
Among angucycline antibiotics, aquayamycin (1) and
aquayamycin-type angucyclines constitute the largest class;
more than 30 types of compounds, such as vineomycin A1,[5] PI-
080,[6] urdamycins,[7] and saquayamycins,[8] have been isolated
(Figure 1). The most structurally basic compound 1 was isolated
in 1967 by Umezawa et al. from culture broth of Streptomyces
misawanensis. It is active against Gram-positive bacteria,
Ehrlich ascites carcinoma, and Yoshida rat sarcoma cells.[9]
Figure 1. Chemical structures of representative aquayamycin-type
angucycline antibiotics. L-Rho = L-rhodinose, L-Acu = L-aculose, D-Oliv = D-
olivose.
Suzuki et al. achieved the total synthesis of 1 in 2000.[11]
Their strategy involves Hauser annulation of C-glycosylphthalide
3 and cyclohexanone 4 to construct the BCD-ring system, and
intramolecular pinacol coupling reaction of ketoaldehyde 2 to
form the A-ring with an angular cis-diol (Scheme 1A). The
research group of Zhu reported the total synthesis of the related
compound, derhodinosylurdamycin A, in 2015, using modified
Suzuki's strategy to construct the aglycon moiety.[12] This
strategy enabled construction of the unstable AB-ring system in
a highly stereoselective manner during a late stage of the
synthesis. However, preparation of the key intermediates 3 and
4 required 24 and 23 steps, respectively, from commercially
available starting materials 5-7. In addition, a total of 60 steps
were required for the total synthesis of 1 (see Supporting
Information for a summary). Thus, development of a new
approach to the total synthesis of 1 that involves fewer steps is
needed for investigations such as SAR study and drug discovery
is highly desirable.
Structurally,
its
features
include
a
C-glycosylated
benz[a]anthraquinone skeleton and two hydroxyl groups at the
ring junction (C-4a and C-12b positions).[10] Compared with other
angucycline antibiotics, the main difficulty in the synthesis of
aquayamycin-type angucycline antibiotics is construction of the
highly oxidized and stereochemically complex AB-ring system,
which possesses an angular cis-diol. In addition, this system
decomposes easily under acidic, basic, and photo-irradiation
conditions.[10] Therefore, although it possesses important
biological activities and an interesting chemical structure, only
The present report describes a novel synthetic approach for
1 that has 16 fewer steps than the previously reported synthesis
and has three major features: 1) highly diastereoselective 1,2-
addition of easily prepared C-glycosyl naphthyllithium and a
cyclic ketone to connect the CD-ring and A-ring, 2) indium-
[*] S. Kusumi, H. Nakayama, T. Kobayashi, H. Kuriki, Y. Matsumoto, Prof.
Dr. D. Takahashi, Prof. Dr. K. Toshima
Department of Applied Chemistry, Faculty of Science and Technology,
Keio University
3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan)
E-mail: toshima@applc.keio.ac.jp
mediated
site-selective
allylation
rearrangement
of
naphthoquinone, and 3) diastereoselective intramolecular
pinacol coupling for constructing the B-ring.
A retrosynthetic analysis is shown in Scheme 1B. The B-ring
Supporting information for this article is given via a link at the end of
the document.
moiety was constructed from the known intermediate 8[11a] during
a
late stage by intramolecular diastereoselective pinacol
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10.1002/chem.201604697
Chemistry - A European Journal
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coupling of ketoaldehyde 9. Diastereoselectivity was expected to
be obtained by approach of the vanadium complex from the
convex face of 9. Compound 9 would be prepared by two-
carbon elongation of the naphthalene 11 by indium-mediated
Highly functionalized 13 would be prepared from commercially
available D-(-)-quinic acid as a chiral source.
The synthesis of bromonaphthyl C-glycoside 12 is outlined in
Scheme 2. After optimizing conditions for C-glycosylation,
Sc(OTf)3-catalyzed C-glycosylation[15] of D-olivosyl acetate 14
and naphthol 15[16] proceeded smoothly to produce C-glycoside
16 in high yield with excellent -stereoselectivity (80% yield, :
= 1:>99). The phenolic hydroxyl group of 16 was benzylated,
and the resulting naphthalene was oxidized using CAN to give
naphthoquinone 17 in high yield. Regioselective bromination,
followed by sodium dithionite reduction and subsequent
methylation using Me2SO4 and K2CO3,[17] afforded 12 in good
yield.
allylation-rearrangement[14]
of
the
corresponding
naphthoquinone 10. The connection of the CD-ring and A-ring
would be achieved via diastereoselective 1,2-addition of
naphthyllithium species, derived from bromonaphthalene 12, to
an appropriately functionalized cyclic ketone 13. Calculations
indicated that the -face of 13 was more crowded than the -
face, due to the bulkiness of the TBS group on the adjacent axial
hydroxyl group (the most stable conformation of 13 was
calculated using B3LYP/6-31G*; see Supporting Information).
Scheme 2. Synthesis of bromonaphthyl C-glycoside 12. Reagents and
conditions: a) Sc(OTf)3, Drierite®, DCE, -30 to -10 ºC, 80%; b) BnBr, NaH,
DMF, 0 ºC, 97%; c) CAN, MeCN-H2O, 0 ºC, 96%; d) Br2, CHCl3, -60 ºC; then
Et3N, -60 ºC, e) aq. Na2S2O4, NaHCO3, CH2Cl2-Et2O, RT; f) Me2SO4, K2CO3,
acetone, reflux, 80% (3 steps). CAN = cerium(IV) ammonium nitrate, DCE =
1,2-dichloroethane, DMF = N,N-dimethylformamide.
Scheme 3. Synthesis of cyclic ketone 13. Reagents and conditions: a) NaBH4,
EtOH, RT; b) TsCl, Et3N, Me3N·HCl, MeCN, 0 ºC; c) DBU, benzene, RT, 90%
(3 steps); d) LiAlH4, THF, RT, quant.; e) AllylBr, NaH, DMF, 0 ºC, 93%; f) BnBr,
KH, DMF, 0 ºC, 99%; g) 1 N aq. HCl, dioxane, 50 ºC, 95%; h) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 ºC, 90%; i) AZADOL®, PhI(OAc)2, CH2Cl2-phosphate buffer
(pH 7), RT, 98%. DBU
= 1,8-diazabicyclo[5.4.0]undec-7-ene, THF =
tetrahydrofuran, AZADOL® = 2-hydroxy-2-azaadamantane.
Next, the highly functionalized cyclic ketone 13 was
synthesized (Scheme 3). The lactone 19,[18] derived from D-(-)-
Scheme 1. Comparison of retrosynthetic analyses of aquayamycin (1).
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10.1002/chem.201604697
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quinic acid (18), was reduced by NaBH4 to afford triol 20.
Tosylation of the primary alcohol, followed by intramolecular
substitution using DBU as base and reduction of the resulting
epoxide 21 using LiAlH4, gave diol 22. Protecting group
manipulations of 22 (1. allylation of the secondary alcohol; 2.
benzylation of the tertiary alcohol; 3. deprotection of the
cyclohexylidene acetal; 4. selective silylation of the secondary
alcohol) and AZADO-mediated oxidation[19] of the remaining
secondary alcohol gave cyclic ketone 13 in high yield.
the resulting naphthoquinone 10 was added to a solution of
allylindium species, which was prepared in situ from indium,
sodium iodide, and allylbromide,[14] to form the allylated quinone
25. Then, one-pot rearrangement-methylation of 25 was
conducted using NaH and MeOTs to afford 26 in 76% yield in 2
steps.[21,22] Next, allylnaphthalene 26 was converted into
ketoaldehyde 9 by removal of the TBS group, followed by Dess-
Martin oxidation and mild oxidative cleavage using OsO4, NaIO4,
and 2,6-lutidine.[23] Next, intramolecular pinacol coupling of
ketoaldehyde 9 was examined utilizing a Pedersen modified
procedure.[24] Results showed that the desired diol 27 was
obtained successfully in high yield as a single diastereomer.
Compound 27 was converted into the known bis-acetonide to
confirm the stereochemistry.[25,26] The high stereoselectivity
observed in this reaction was due to reaction of the aldehyde
from the convex face of 9, along with the expected chelation of
the 1,2-diol with a vanadium(II) complex.[24] Finally, mesylation of
the secondary alcohol of 27, followed by removal of the
acetonide group and Swern oxidation, afforded the known
intermediate 8 in high yield.
With the key fragments prepared, connecting the A-ring and
CD-ring was investigated (Scheme 4). Bromonaphthalene 12
was lithiated with nBuLi, followed by addition of the cyclic ketone
13 to the resulting naphthyllithium. Reaction proceeded
smoothly to afford 11 in good yield with excellent
diastereoselectivity
(99:1).
Efforts
to
determine
the
stereochemistry of 11 at this stage failed, therefore,
stereochemistry of the tertiary alcohol at C-12b position
(aquayamycin-based numbering) was confirmed after the
pinacol coupling reaction (vide infra), and the desired
diastereomer was found to be obtained as expected. Next, 11
was converted into 24 by 4-step protecting group manipulations
(1. desilylation; 2. acetonide protection; 3. deallylation;[20] 4.
silylation) in each nearly quantitative yield.
Intermediate 8 was converted into aquayamycin (1) by a
modified procedure (Scheme 5).[11a] Deprotection of all benzyl
ethers of 8 over 5% Pd/C catalyst,[27,28] and the resulting hexa-ol
was mono-benzylated using Cs2CO3 to afford 28. Compound 28
was oxidized with CAN to afford the naphthoquinone 29. Finally,
hydrogenolysis of 29 and subsequent elimination of the
mesylate under mild conditions afforded aquayamycin (1) in
63% yield over three steps. Synthetic 1 was identical in all
respects with the natural product (see Supporting Information).
The next challenge was construction of the B-ring moiety.
Initially, introduction of an allyl group at the C-6a position
(aquayamycin-based numbering) in 24 was examined by
halogenation or metalation, but these attempts failed. However,
after extensive effort, introduction of allyl group was achieved via
the naphthoquinone 10. Thus, after treatment of 24 with CAN,
Scheme 4. Synthesis of the known intermediate 8. Reagents and conditions: a) nBuLi, THF, -78 ºC; then 13 (2.0 eq.), -78 ºC to RT, 85% (dr 99:1); b) TBAF, THF,
RT, 98%; c) 2-methoxypropene, p-TsOH·H2O, benzene, RT, 97%; d) Pd(PPh3)4, DMBA, dioxane-H2O (3:1), 50 ºC, quant.; e) TBSOTf, 2,6-lutidine, CH2Cl2, 0 ºC,
97%; f) CAN, NaHCO3, MeCN-H2O, 0 ºC, 95%; g) In, NaI, AllylBr, DMF, -40 to 0 ºC; h) NaH, MeOTs, DMF, 0 ºC to RT, 76% (2 steps), i) TBAF, THF, RT, quant.; j)
Dess-Martin periodinane, NaHCO3, CH2Cl2, RT, 93%; k) OsO4, NaIO4, 2,6-lutidine, dioxane-H2O (4:1), RT, 85%; l) VCl3(thf)3, Zn, DMF, CH2Cl2, RT, 95%; m) MsCl,
DMAP, CH2Cl2-pyridine (2:5), RT, 94%; n) 5% aq. H2SO4-dioxane (1:4), 80 ºC, 96%; o) (COCl)2, DMSO, Et3N, CH2Cl2, -50 to 0 ºC, 94%. TBAF =
tetrabutylammonium fluoride, DMBA = dimethylbarbituric acid, DMAP = N,N-dimethyl-4-amino pyridine, DMSO = dimethylsulfoxide.
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Matsuda, T. Sawa, H. Nakagawa, M. Hamada, T. Takeuchi, H.
Umezawa, J. Antibiot. 1985, 38, 1171.
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Scheme 5. Completion of total synthesis of 1. Reagents and conditions: a) H2,
5% Pd/C, EtOAc-MeOH (1:1), RT; b) BnBr, Cs2CO3, DMF, 0 ºC to RT, 89% (2
steps); c) CAN, MeCN-H2O, 0 ºC; d) H2, 5% Pd/C, EtOAc-MeOH (1:1), RT; e)
DIPEA, dioxane, RT, 63% (3 steps). DIPEA = N,N-diisopropylethylamine.
[13] For the synthetic studies of aquayamycin and its core structure, see: a)
S. Vila-Gisbert, A. Urbano, M. C. Carreño, Chem. Commun. 2013, 49,
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In summary, a highly efficient and practical synthetic route of
aquayamycin (1) was developed. This novel synthesis features
[14] D. Pan, S. K. Mal, G. K. Kar, J. K. Ray, Tetrahedron 2002, 58, 2847.
[15] A. Ben, T. Yamauchi, T. Matsumoto, K. Suzuki, Synlett 2004, 225.
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Trans. 1 1975, 1339; b) F. Peng, B. Fan, Z. Shao, X. Pu, P. Li, H.
Zhang, Synthesis 2008, 3043.
construction of the complex AB-ring system in
stereoselective and step-economical manner,
a
highly
utilizing
diastereoselective 1,2-addition of C-glycosyl naphthyllithium to a
cyclic ketone, indium-mediated site-selective allylation-
rearrangement, and diastereoselective intramolecular pinacol
coupling. This synthetic strategy offers an efficient path to
aquayamycin-type angucycline antibiotics. Synthetic studies of
other aquayamycin-type angucycline antibiotics, such as
vineomycin A1, are now in progress.
[17] Y. Zhang, X. Wang, M. Sunkara, Q. Ye, L. V. Ponomereva, Q.-B. She,
A. J. Morris, J. S. Thorson, Org. Lett. 2013, 15, 5566.
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[19] a) M. Shibuya, Y. Sasano, M. Tomizawa, T. Hamada, M. Kozawa, N.
Nagahama, Y. Iwabuchi, Synthesis 2011, 3418; b) M. Shibuya, M.
Tomizawa, I. Suzuki, Y. Iwabuchi, J. Am. Chem. Soc. 2006, 128, 8412.
[20] H. Tsukamoto, Y. Kondo, Synlett 2003, 1061.
Acknowledgements
[21] This reaction proceeded via 1,2-allylation mechanism followed by 1,2-
carbon migration, which is different from the more common procedure
(reduction, O-allylation and Claisen rearrangement).[22]
We sincerely thank Prof. Dr. Yoshiaki Takahashi at the Institute
of Microbial Chemistry (BIKAKEN) for providing the valuable
NMR data for aquayamycin. This research was supported in part
by the MEXT-supported Program for the Strategic Research
Foundation at Private Universities, 2012-2016, and JSPS
KAKENHI Grant Numbers JP16H01161 in Middle Molecular
Strategy.
[22] For the examples of the introduction of the allyl group via Claisen
rearrangement, see: a) Q. Chen, Y. Zhong, G. A. O'Doherty, Chem.
Commun. 2013, 49, 6806; b) Q. Chen, M. Mulzer, P. Shi, P. J. Beuning,
G. W. Coates, G. A. O'Doherty, Org. Lett. 2011, 13, 6592.
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Konradi, S. F. Pedersen, J. Am. Chem. Soc. 1989, 111, 8014.
[25] The diol of 27 was protected by acetonide group to afford known bis-
acetonide 30.[26] The structure of 30 was found to be identical with the
reported data.
Keywords: natural products • total synthesis • antitumor
antibiotics • angucycline antibiotics • aquayamycin
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Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Shunichi Kusumi, Harunobu Nakayama,
Takumi Kobayashi, Hajime Kuriki, Yuka
Matsumoto, Daisuke Takahashi and
Kazunobu Toshima*
Page No. – Page No.
Total Synthesis of Aquayamycin
Efficient and practical total synthesis of aquayamycin has been accomplished.
The complex tetracyclic ring system was constructed by highly diastereoselective
1,2-addition, indium-mediated site-selective allylation-rearrangement, and
diastereoselective intramolecular pinacol coupling.
This article is protected by copyright. All rights reserved.