A synthetic approach to chrysophaentin F

Article abstract of DOI:10.1039/C9CC01666J

The chrysophaentins are a newly discovered natural product family displaying promising anti-infective activity. Herein we describe an approach to chrysophaentin F that uses an array of metal catalysed coupling reactions (Cu, Ni, Pd, W, Mo) to form key bonds.

Full text of DOI:10.1039/C9CC01666J

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Vendeville, R. Matters, A. Chen, G. J. Tizzard, M. E. Light and C. L. L. Chai, Chem. Commun., 2019, DOI:
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DOI: 10.1039/C9CC01666J
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A Synthetic Approach to Chrysophaentin F.
Jean-Baptiste Vendeville,a,b Rebecca F. Matters,a Anqi Chen,b Mark E. Light,a Graham J.
Tizzard,a Christina L. L. Chai,b,c* and David C. Harrowven.a*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
OH
O
HO
Cl
X
X
The chrysophaentins are a newly discovered natural product
family displaying promising anti-infective activity. Herein we
describe an approach to chrysophaentin F that uses an array of
metal catalysed coupling reactions (Cu, Ni, Pd, W, Mo) to form
key bonds.
B
HO
Cl
OH
HO
B
C
OH
C
OH
Cl
Cl
HO
HO
HO
O
D
A
D
A
HO
O
OH
X'
HO
X'
The chrysophaentins were discovered by Bewley et al. in the
methanoic extract of Chrysophaeum taylori alga during a
screening study to identify promising new anti-infectives.1 Eight
closely related bioactives macrocycles were identified in the
extract, named chrysophaentins A-H (1-5, 8-10), which were
subsequently joined by the linear chrysophaentins E2 (6) and E3
(7) (Figure 1).2 From a structural perspective they define a new
class of marine natural products, the bis-diarylbutenes. Their
core resembles that of the bis-bibenzyl family of natural
products,3,4 but with two additional carbon centres and
unsaturation in each of the chains linking the diaryl ether units.
In assays against Staphylococcus aureus (SA), methicillin-
resistant SA (MRSA) and multidrug-resistant SA (MDR-SA),
chrysophaentins A (1), F (8) and H (10) were found to have
useful potency, with minimum inhibitory concentrations
(MIC50) in the range of 0.8-9.5 μg/mL.1 By contrast, the acyclic
chrysophaentin E 5, and those with a bromide on arene A or
arene C (2-4 and 9), showed greatly reduced activity.
Chrysophaentin A (1) was also found to inhibit the bacterial cell
division protein FtsZ, a popular target in antimicrobial drug
discovery programmes.5
Chrysophaentins A-D
1, X = Cl, X' = Cl
2, X = Cl, X' = Br
3, X = Br, X' = Cl
4, X = Br, X' = Br
Chrysophaentin E-E3
5, X = Cl, X' = Cl
6, X = Br, X' = Cl
7, X = Br, X' = Br
X
Chan-Lam-Evans
coupling
Ring Closing
OH
Alkyne Metathesis
X
C
O
OH
OH
Hydrozirconation
and chlorination
B
C
O
OH
OH
HO
B
Cl
Cl
OH
HO
X
X
D
A
HO
O
X"
D
OH
A
HO
O
X'
OH
Pd-catalysed
sp-sp3 coupling
Chrysophaentins F-H
X
Ni-catalysed
8, X = Cl, X' = Cl, X" = H
9, X = Br, X' = Cl, X" = H
10, X = Cl, X' = Cl, X" = Br
sp-sp3 coupling
11, X = H
8, X = Cl
Figure 1 The chrysophaentins and our approach to their total synthesis
gaining access to the macrocyclic core.2,4-6 Herein we describe
our work on the development of a general synthetic approach
to the natural product family, exemplified by syntheses of the
dehalogentated core 11 and, tentatively, of chrysophaentin F
(8) in impure form. Our approach, summarized in Figure 1, has
both divergent and convergent phases and uses an array of
metal catalyzed reactions (Cu, Ni, Pd, W and Mo) to construct
key bonds.
To test the validity of our approach, we first targeted the
chrysophaentin F-H core 11 lacking all halogen substituents.
Our synthesis began with the preparation of benzo-1,3-dioxane
15 and phenol 16 using standard protocols (Scheme 1).7-9 Their
union to diaryl ether 18 was then achieved using a Chan-Lam-
Evans coupling procedure.10 After examining a range of
catalysts, solvents and reaction conditions, we found that it was
best to employ Cu(OTf)2 with 4Å molecular sieves in ethanol
under an oxygen atmosphere. In that way diaryl ether 18 could
be formed reliably in 76% yield. Sequential hydrolysis of the
From a synthetic perspective the chrysophaentins have proven
to be elusive targets. To date, all of the approaches described
have sought to make one of the symmetrical chrysophaentins
using a cyclodimerization strategy, yet none has succeeded in
a. Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ (UK).
b. Institute of Chemical and Engineering Sciences, Agency for Science, Technology
and Research (A*STAR), 8 Biomedical Grove, Neuros, #07-01, Singapore, 138665
c. Department of Pharmacy, National University of Singapore, 18 Science Drive 4,
Singapore 117543.
Electronic Supplementary Information (ESI) available: experimental accounts with
spectral details and copies of NMR spectra are available as supplementary
information. See DOI: 10.1039/x0xx00000x
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acetal to phenol 17; protection as benzyl ether 19 and
conversion of the benzylic alcohol to the corresponding
chloride,11 gave the pivotal diaryl ether 20 in high overall yield.
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DOI: 10.1039/C9CC01666J
Scheme 1 Synthesis of the pivotal diaryl ether 20
At this juncture our synthesis entered a divergent phase where
diaryl ether 20 was advanced to both the B-O-C and A-O-D
subunits, 26 and 28 respectively (Scheme 2). Thus, using a Pd-
catalysed procedure developed by Buchwald et al.12 diaryl ether
20 was coupled with TMS-acetylene and 1-hexyne respectively,
to afford alkynes 21 and 22 in excellent yield. The esters in each
of these products were then reduced with LiAlH4 to facilitate
their conversion to halides 25 and 26.11 Alas, attempts to effect
the coupling of benzyl bromide 25 and 1-hexyne using the
aforementioned Buchwald procedure also induced alkyne to
allene isomerisation.12 However, by switching to a nickel
catalyzed coupling reaction developed by Gau et al.,13 it was
successfully coupled with hexynylAlEt2 to give diyne 28 in good
yield after deprotection of the silyl acetylene 27 with catalytic
silver triflate.14 Pleasingly, the Buchwald procedure proved
effective for the coupling of diaryl ether fragments 26 and 28
providing the macrocyclic precursor 29 in 50% yield.12
Scheme 2 Synthesis of dehalogenated chrysophaentin 11
The stage was now set to enact our endgame strategy, which
sought to use alkyne metathesis for the critical macrocyclization
reaction.15,16 Pleasingly, this proved remarkably efficient as,
after some optimization, triyne 29 was transformed into
macrocyclic diyne 30 in near quantitative yield using Schrock’s
alkylidyne catalyst in toluene at 80 °C for 12 h under high
dilution.16 Success was confirmed by X-ray crystallographic
analysis (Figure 2). Selective hydrogenation of 30 using Lindlar’s
catalyst in the presence of quinoline next provided bis-cis-
alkene 31, leaving us the task of unmasking the six phenol
residues. Although the double bonds in 31 proved sensitive to
an array of standard deprotection protocols, a combination of
BCl3 and tetrabutylammonium iodide in DCM gave our target 11
in 92% yield (Scheme 2).17
The total synthesis of chrysophaentin F 8 became our next
target with the preparation of the keystone diaryl ether 38
becoming the immediate goal (Scheme 3). To that end, benzoic
acid 32 was reduced with LiAlH4 to diol 33, which was in turn
was protected as its benzyl ether 34. Arene bromination to 35
then facilitated a Miyaura borylation to 37 enabling it’s coupling
Figure 2 X-ray crystal structure of macrocyclic diyne 30
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previously, readily providing the B-O-C and A-O-D diaryl ether
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DOI: 10.1039/C9CC01666J
subunits 44 and 46 (Scheme 3). These were coupled using the
Buchwald procedure to give triyne 47, setting the stage for our
end-game strategy.
Pleasingly, after some optimization, triyne 47 was transformed
into macrocyclic diyne 48 in modest yield using Fürstner’s
molybdenum·phenanthroline pre-catalyst in toluene at 40 °C
for 12 h.15 Hydrozirconation of 48 with Schwartz reagent
(generated in situ by reduction of Cp2ZrCl2) followed by
chlorination with NCS gave a complex mixture of products,19,20
that was partially separated by column chromatography (see
Supplementary Information p S124-5). The main fractions were
then combined and treated with BCl3 and tetrabutylammonium
iodide to unmask the phenolic residues. Purification of the
product mixture by column chromatography gave a major
fraction exhibiting spectral characteristics consistent with the
formation of chrysophaentin F 8 in an impure state (see
1
Supplementary Information for LRMS, H and 13C NMR data).1
Alas, attempts to purify the natural product further by
preparative TLC and HPLC proved unrewarding with material
losses putting paid to further endeavours.
In summary, we have developed a synthetic approach to
chrysophaentin F 8 with the flexibility to allow all members of
this family to be targeted. The approach demonstrates the
value of i) Chan-Lam-Evans coupling reactions for the
preparation of diaryl ethers with high steric demand;10 ii)
Buchwald’s, Gau’s and Stille’s procedures for effecting sp-sp3
coupling reactions between alkynes and benzyl halides;12,13 and
iii) Fürtsner’s alkylidyne pre-catalyst for macrocyclisation
through ring-closing alkyne metathesis.15,16
Conflicts of interest
There are no conflicts to declare.
We thank Prof. A. Fürstner for his kind donation of the
molybdenum.phenanthroline pre-catalyst. The University of
Southampton VC Scholarship Scheme, the A*STAR ARAP
Scheme, the ERDF (LabFact: InterReg V project 121) and the
EPSRC [EP/K039466/1, EP/P013341/1 and EP/L003325/1] are
thanked for their financial support.
Notes and references
1
A. Plaza, J. Keffer, G. Bifulco, J. Lloyd and C. Bewley, J. Am.
Chem. Soc., 2010, 132, 9069; J. R. Davison and C. Bewley, J.
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Scheme 3 A tentative synthesis of chrysophaentin F
2
3
J. L. Keffer, J. T. Hammill, J. R. Lloyd, A. Plaza, P. Wipf and C. A.
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to phenol 16 using a Chan-Lam-Evans procedure. Finally,
conversion of the resulting benzyl alcohol 36 to the
corresponding chloride 38 delivered the required diaryl ether.
The divergent strategy used to prepare dehalochrysophaentin
11 was now applied to the synthesis of chrysophaentin F 8.
While most of the steps were easy to replicate, it proved
advantageous to use a Stille coupling to advance chloride 38 to
alkyne 39 as it proceeded reliably in near quantitative yield.18
All other steps in the sequence mirrored those demonstrated
D. C. Harrowven and S. L. Kostiuk, Nat. Prod. Rep., 2012, 29,
223. For our work on macrocyclic bis-bibenzyl total synthesis
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DOI: 10.1039/C9CC01666J
In common with others, our first approach to chrysophaentin F
was based on a cyclodimerization strategy, e.g. 49  50.
Indeed, after much optimization, this gave a cyclodimer in 6%
yield that could not be assigned unambiguously to either dimer
50 or its regioisomer 51 using the spectral data attained.
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