The Synthesis of (±)-Oxyisocyclointegrin

Article abstract of DOI:10.1002/ejoc.201801751

The total synthesis of oxyisocyclointegrin is described. The key steps in the synthesis included a Tsuji–Trost allyl migration to exclusively afford the corresponding monoallylated 1,3-diketone and a photochemical initiated oxidative cyclization to forge the oxepine core.

Full text of DOI:10.1002/ejoc.201801751

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Accepted Article
Title: The Synthesis of (±)-Oxyisocyclointegrin
Authors: Robert J Smith, Rebekah Bower, Scott A Ferguson, Rhonda
Rosengren, Greg M Cook, and Bill C. Hawkins
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801751
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10.1002/ejoc.201801751
European Journal of Organic Chemistry
COMMUNICATION
The Synthesis of (±)-Oxyisocyclointegrin
Robert J. Smith,[a] Rebekah L. Bower,[b] Scott A. Ferguson,[c] Rhonda J. Rosengren,[b] Greg M. Cook[c]
and Bill C. Hawkins*[a]
Abstract: The total synthesis of oxyisocyclointegrin is described. The
key steps in the synthesis included a Tsuji-Trost allyl migration to
exclusively afford the corresponding monoallylated 1,3-diketone and
a photochemical initiated oxidative cyclization to forge the oxepine
core.
Introduction
The wood of the moraceae family, which includes the mulberry
and fig tree, is a rich source of phenol and flavone-derived natural
products. Most notable is a series of prenylated flavones and
several oxidised derivatives with a common tricyclic or tetracyclic
core.[1] One of the most studied subsets of these natural products
are the morusins (morusin (1), cyclomorusin (2), neocyclomorusin
(3), Figure 1). Investigations into the biological activity of these
compounds have discovered a wealth of potential medical
applications, with activity including anti-cancer (neocyclomorusin,
morusin,
(neocyclomorusin, morusin), inhibition of platelet aggregation
(neocyclomorusin) and radical scavenging ability
cyclomorusin)
and
antibacterial
properties
(neocyclomorusin).[2] Among the first reported compounds from
this family of structurally related molecules are integrin (4) and
oxyisocyclointegrin (5).[3] It is not clear if oxyisocyclointergrin (5)
exists as a racemate or as a single stereoisomer as no optical
rotation data has been reported. To the best of our knowledge no
biological activity data for either 4 or 5 has been reported in the
literature. Given the promising biological activity associated with
other structurally similar members of this natural product family
(vide supra), a robust and facile entry into these natural products
would be of great interest. Herein we report the first total synthesis
of the natural products integrin (4) and oxyisocyclointegrin (5) as
well as preliminary biological data indicating both compounds
possess moderate to weak antibacterial and anticancer properties.
Figure 1. Representative natural products from the morusin family.
Results and Discussion
Unsurprisingly, retrosynthetic analysis of oxyisocyclointegrin (5)
revealed integrin (4) to be a direct precursor, which could be
converted to the natural product by an oxidative cyclization
strategy (Scheme 1). Preparation of the natural product integrin
could be performed by cross metathesis of the 3-allylflavone 6.
Synthesis of this key intermediate necessitates the preparation of
the 2-allyl-1,3-diketone 7. We propose that a Tsuji-Trost type allyl
migration of the 1-(phenyl-(2-O-allyl)-1,3-diketone (8) would
provide a concise method to access this substrate, whilst avoiding
the potential for over alkylation of the 1,3-diketone.[4]
[a]
R. J. Smith, Dr. B. C. Hawkins
Department of Chemistry
University of Otago
Dunedin, New Zealand
bhawkins@chemistry.otago.ac.nz
https://blogs.otago.ac.nz/hawkinsgroup/
Dr. R. L. Bower, Prof. R. J. Rosengren
Department of Pharmacology
University of Otago
[b]
[c]
Dunedin, New Zealand
Dr. S. A. Ferguson, Prof. G. M. Cook
Department of Microbiology and Immunology
University of Otago
Dunedin, New Zealand
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801751
European Journal of Organic Chemistry
COMMUNICATION
Scheme 1. Retrosynthetic analysis of oxyisocyclointegrin
In a forward synthetic sense, the synthesis began with the known
ketone 12, which was prepared from the commercially available
2,4,6-trihydroxyacetophenone following literature procedures
(Scheme 2).[5] Standard Claisen condensation protocols failed to
deliver significant quantities of the corresponding 1,3-diketone.
Recently, soft enolization of ketones followed by acylation using
acylbenzotriazoles has been shown to be an effective way of
generating 1,3-diketones.[6] Pleasingly, treatment of 12 and the
acylbenzotriazole 13 with magnesium bromide diethyletherate
and diisopropyl ethyl amine smoothly provided the electron rich
diketone 14 in a 65% yield.[6] With this substrate in hand we turned
our attention to the Tsuji-Trost type allyl migration, exposure of
the ketone 14 to Pd(PPh3)4 and potassium carbonate in methanol
resulted in exclusive formation of the mono α-allyl 1,3-diketone 15
in a 69% yield.[7] Subsequent treatment of 15 with 10% H2SO4 in
AcOH provided the 3-allylflavone 16 in an excellent yield.
Selective demethylation was achieved upon careful treatment of
the tetramethylether 16 with three equivalents of BBr3 providing
the desired mono-methylether flavone 17 in a 73% yield (Scheme
2). Flavone 17 was found to readily undergo palladium-mediated
intramolecular oxidative cyclization,[8] to afford the vinylpyran 19,
a synthetic analog of cyclomorusin (2), in a 51% yield.
Scheme 2. Construction of the flavone core
Cross metathesis of flavone 17 with 2-methyl-2-butene using
Grubb’s second-generation catalyst was met with failure,
presumably due to the free phenol functional groups interacting
with the catalyst. Acetylation of 17 under standard reaction
conditions provided the triacetate derivative 18 in good yield. The
acetate derivative 18 proved to be more amenable to cross-
metathesis, affording the desired 3-prenylflavone 20 in a modest
57% yield (Scheme 3). The low yield was the result of the
formation of by-products, including the alternate cross metathesis
product 21. Methanolysis of 20 provided the natural product
integrin (4) in a 76% yield.
We proposed that cyclization of integrin (4) to form
oxyisocyclointegrin (5) would be possible through an oxidative
cyclization reaction. After extensive screening,[9] it was found that
irradiation of integrin (4) in the presence of oxygen, with a high
pressure mercury lamp for 7 hours, provided a mixture of
oxyisocyclointegrin and its hydroperoxide (1:4 ratio, respectively
1
determined by H NMR).[10] The crude residue was then treated
with sodium borohydride in methanol to provide the natural
product oxyisocyclointegrin (5) in 84% yield over 2 steps. The
synthetic material was spectroscopically equivalent to that
reported for the isolated natural product.[3]
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10.1002/ejoc.201801751
European Journal of Organic Chemistry
COMMUNICATION
focusing on the synthesis of related natural products is underway
and will be reported in due course.
Experimental Section
Method: Antimicrobial susceptibility testing was performed by
measuring the minimum inhibitory concentration (MIC) by broth
microdilution. S. aureus ATCC 6538 was grown overnight (16 h)
at 37°C with shaking at 200 rpm in Cation Adjusted Mueller Hinton
II Broth (CAMHB) (BD BBL™). The following day a cell
suspension was prepared by diluting the overnight culture to an
optical density (OD600) of 0.003 in CAMHB. A 96 well polystyrene
plate was then set up to contain a 2-fold dilution series of each
compound in 50 μL CAMHB. The cell suspension (50 μL) was
then added to the diluted compounds yielding an OD600 (final) of
0.0015 in 100 μL (final) to ensure that the cell concentration was
adjusted to approximately 5 x 105 CFU/ml. Media, compound-free
(untreated), and DMSO vehicle controls were also included. The
plates were then incubated for 24 h at 37°C with shaking at 200
rpm. The MIC was reported as the lowest concentration of the test
compound for which no growth occurred. Experiments were
performed with biological replicates.
Scheme 3. The synthesis of isoxycyclointegrin (5)
Keywords: flavone • natural product • total synthesis • oxepine•
antibacterial
Vinylpyran 19, integrin (4) and oxyisocyclointegrin (5) were found
to possess moderate to weak activity against Staphylococcus
aureus (Table 1). Oxyisocyclointegrin (5) possessed weak activity
against prostate cancer cells (LnCap).
[1]
[2]
E. H. Hakim, S. A. Achmad, L. D. Juliawaty, L. Makmur, Y. M. Syah, N.
Aimi, M. Kitajima, H. Takayama, E. L. Ghisalberti, J. Nat. Med. 2006, 60,
161-184.
Table 1. Antibacterial activity
a) J. Xue, R. Li, X. Zhao, C. Ma, X. Lv, L. Liu, P. Liu, Chem. Biol. Interact.
2018, 283, 59-74; b) Y.-R. Liao, P.-C. Kuo, W.-J. Tsai, G.-J. Huang, K.-
H. Lee, T.-S. Wu, Bioorg. Med. Chem. Lett. 2017, 27, 309-313; c) F. Oke-
Altuntas, G. D. W. F. Kapche, J. L. Nantchouang Ouete, I. Demirtas, M.
B. Koc, B. T. Ngadjui, Med. Chem. Res. 2016, 25, 2250-2257; d) A. T.
Mbaveng, L. P. Sandjo, S. B. Tankeo, A. R. Ndifor, A. Pantaleon, B. T.
Nagdjui, V. Kuete, SpringerPlus 2015, 4, 823; e) N. T. Dat, P. T. X. Binh,
L. T. P. Quynh, C. Van Minh, H. T. Huong, J. J. Lee, Fitoterapia 2010,
81, 1224-1227; f) H. Y. Sohn, K. H. Son, C. S. Kwon, G. S. Kwon, S. S.
Kang, Phytomedicine 2004, 11, 666-672.
S. aureus ATCC
6538
LnCap
IC50 (M)
Compound[a]
MIC (g/mL)
Vinylpyran 19
16-32
32-64
128
60
60
16
Integrin (4)
Oxyisocyclointegrin (5)
Penicillin G (control)
[3]
[4]
A. D. Pendse, R. Pendse, A. V. R. Rao, K. Venkataraman, Indian J.
Chem., Sect. B 1976, 14B, 69-72.
0.03125
B. E. Swaney, S. Gai, M. R. Clark, B. C. Hawkins, Chemistry – An Asian
Journal, 0.
[5]
[6]
[7]
[8]
[9]
R. C. R. Wootton, University of Salford 2000.
Conclusions
D. Lim, Fang, G. Zhou, D. M. Coltart, Org. Lett. 2007, 9, 4139-4142.
B. E. Swaney, S. Gai, M. R. Clark, B. C. Hawkins, Chem. Asian. J.
N. Ayyagari, J. D. Belani, Synlett 2014, 25, 2350-2354.
See supporting information.
In conclusion, we have reported the first total synthesis of integrin
and oxyisocyclointegrin, these compounds were found to possess
moderate antibacterial activity against S. aureus. Future work
[10] T. Nomura, T. Fukai, S. Yamada, M. Katayanagi, Chem. Pharm. Bull
1978, 26, 1431-1436.
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Total Synthesis*
Robert J. Smith, Rebekah L. Bower,
Scott A. Ferguson, Rhonda J.
Rosengren, Greg M. Cook and Bill C.
Hawkins*
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The Synthesis of (±)-
Oxyisocyclointegrin
The total synthesis of the oxepine-fused flavone natural product oxyisocyclointegrin
is described. The synthesis was achieved in 7 steps and an overall yield of 15%,
oxyisocyclointegrin was found to possess moderate antibacterial and modest
cytotoxicity.
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