Novel total synthesis of anserinone A and B

Article abstract of DOI:10.1080/00397911.2016.1255755

Anserinones A and B are natural products that have been shown to have potential anticancer, antifungal, and antibacterial properties. This work entails the novel synthesis of these natural products.

Full text of DOI:10.1080/00397911.2016.1255755

Novel Total Synthesis of Anserinone A and B
Jonathan Whisenant1, Daniel Vinson1, Michael Blanco1, Carson Hughes1, Samuel David1
1Department of Chemistry, University of Texas of the Permian Basin, Odessa, TX, USA
Corresponding author Samuel David E-mail: david_s@utpb.edu
Abstract
Anserinones A and B are natural products that have been shown to have potential
anticancer, antifungal and antibacterial properties. This work entails the novel synthesis
of these natural products.
Graphical Abstract
KEYWORDS: antifungal agents, antitumor agents, antibiotics, natural products, total
synthesis
INTRODUCTION
Increasingly persistent resistance against antibacterial and antifungal drugs currently
available necessitates a search for alternative compounds.[1] Anserinone A and B (Figure
1)[2,3,4,5] are unique natural products in that they have potential antifungal, antibacterial as
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well as antitumour activity and were produced in deep water and terrestrial fungi that are
phylogenetically distant.
These benzoquinones were discovered in 1997 in a subculture of an isolate of Podospora
anserina (Cesati) Niessl (Lasiosphaeriaceae), obtained from mouse dung.[2] Surprisingly,
in 2004 these natural products were also isolated from a deep-water marine-derived salt
water culture of P. corylophylum, P. cf corylophylum and Penicillium sp., obtained from
a deep water transect between the mouth of the Rewa river and Matuka in Fiji.[4]
Both anserinones showed micromolar inhibition against fungi and bacteria.[2] In
centrepoint inoculation disk assays, both compounds showed cytotoxic inhibition (1
µmole/disk) against Sordaria fimicola, Ascobolus furfuraceus, B. subtilis and S. aureus.
In addition, both anserinones A and B displayed moderate cytotoxicity in the NCI’s 60
human tumour cell line panel with average GI50 values of 9.1 µmolar (1.9 µg/mL) and 21
µmolar (4.4 µg/mL) for anseriones A and B, respectively.[2] Additionally, both
anserinones showed micromolar or sub-micromolar cytotoxicity against a range of
murine and human cancer cell lines.[4] In disk diffusion assays, at 95 µg (457
nmole)/disk, anserinone A showed significant inhibition against murine lymphocytic
leukaemia and colon adenocarcinoma cell lines. At 174 µg (828 nmole)/disk,),
anserinone B showed significant inhibition against murine lymphocytic leukaemia and
colon adenocarcinoma, as well against human colon tumour, lung non-small cell
carcinoma and lymphocytic leukaemia cell lines. In addition, anserinone B showed
selective inhibition of murine leukaemia cells over murine solid tumour cells.[4] The
above results were confirmed with a sulforhodamine B assay (using the MDA-MB-435
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cell line), which gave cytotoxic dose response curves with IC50 ≤ 19 nmolar (≤ 4µg/mL)
for both anserinone A and B.[4]
These natural products are substituted 1,4-benzoquinones that are polyketides (secondary
metabolites from moulds and fungi).[6] Some of these compounds have been shown to
have both antifugal/antibiotic and antitumour properties.[7] Substituted 1,4-benzophenone
natural products or drugs are usually synthesised by one of three methods: either by
substituting a preformed 1,4-benzoquinone ring or by adding substituents to the skeleton,
followed by cyclisation and oxidation to the 1,4-benzoquinone.[7] Examples of the first
method include using Suzuki coupling[8] and a double Diels-Alder reaction.[9] The
second method uses a wide variety of approaches, including thermolysis,[10] electrocyclic
ring closure,[11,28] and photolysis.[11,12] In the third method, a phenyl ring is appropriately
substituted (having at least one oxygen attached to the ring, e.g. phenol, methoxy group,
etc.) and is then oxidised to 1,4-benzoquinone.[7]
DISCUSSION
Our parallel synthesis approach (Scheme 1) follows the third method, involving the
construction of a common intermediate, a 1,2,3,5-tetra substituted phenyl ring (with
stereochemistry installed) from commercially available 1-bromo-3,5-dimethoxybenzene.
This common intermediate could then undergo either a single oxidation to make
anserinone B or a double oxidation to make anserinone A.
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We started the synthesis (Scheme 2) with R-propylene oxide and the above mentioned
commercially available substituted bromoarene to make alcohol 1 via a metal-halogen
exchange reaction.[13] Since the ring methyl group in the common intermediate (5) was
intended to be accessed via an aldehyde intermediate (3), the alcohol on the side chain
was benzylated (2) in order to prevent the subsequent formation of the lactol (see Scheme
2). This was followed by installation of the aldehyde (3) via a Vilsmeier-Heck
formylation.[14] In the next reaction, the electron rich ring facilitated the reduction of the
aldehyde to the methyl group (4) using BH3·S(CH3)2.[15] In an earlier attempt, the
aldehyde was successfully installed using an acetyl protecting group for the side chain
alcohol, but the subsequent reduction of this aldehyde to a methyl group using
[15]
NaBH4/BF3·OEt[14] or BH3·S(CH3)2
resulted in very poor yields (15-25%), with the
diol in Scheme 2 being one of the major products. Next, 4 was debenzylated with
lithium/naphthalene[16] to afford the common intermediate 5. This was followed by
attempts to carry out a one-pot double oxidation of 5 to 8 using various oxidants[17] that
were shown to oxidise either a ring similar to the one in consideration or a side chain
alcohol. In the event, our efforts resulted in only a single oxidation (exclusively of the
ring or the side chain alcohol) or multiple products or very poor yields (data not shown).
Therefore stepwise oxidations were carried out; first the side chain alcohol was oxidised
using pyridinium chlorochromate (7)[18] and then the ring was oxidsed[19] to give the first
target, anserinone A (8). The ring in 5 was similarly oxidised to anserinone B (6).
Characterisation data were identical to literature[2] values (see supporting information).
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This study is the first published total synthesis of anserinone A and B and should help
facilitate more detailed evaluation of the medicinal properties of these compounds.
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra. This material can be found via the
‘‘Supplementary Content’’ section of this article’s webpage.
ACKNOWLEDGMENTS
We would like to thank Brant Kedrowski from the University of Wisconsin Oshkosh for
help in some early experiments. Thanks is also due to James Vyvyan from Western
Washington University. This work is supported by the Robert A. Welch Foundation
grant, AW-0013.
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This manuscript has not been published elsewhere and it has not been submitted
simultaneously for publication elsewhere.
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Scheme 1. Retrosynthetic analysis
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Scheme 2. Anserinone A and B synthetic scheme
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Figure 1. Natural Product Targets
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