Modular Total Syntheses of the Alkaloids Discoipyrroles A and B, Potent Inhibitors of the DDR2 Signaling Pathway

Article abstract of DOI:10.1021/acs.orglett.5b03672

(Chemical Equation Presented). The title natural product 1 has been synthesized by treating the 1,2,3,5-tetrasubstituted pyrrole 23 with oxoperoxymolybdenum(pyridine) (hexamethylphosphoric triamide) (MoOPH). Compound 23 was itself prepared in seven steps

Full text of DOI:10.1021/acs.orglett.5b03672

Letter
pubs.acs.org/OrgLett
Modular Total Syntheses of the Alkaloids Discoipyrroles A and B,
Potent Inhibitors of the DDR2 Signaling Pathway
Yiwen Zhang, Martin G. Banwell,* Paul D. Carr, and Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 2601, Australia
S
* Supporting Information
ABSTRACT: The title natural product 1 has been synthesized by treating the 1,2,3,5-tetrasubstituted pyrrole 23 with
oxoperoxymolybdenum(pyridine) (hexamethylphosphoric triamide) (MoOPH). Compound 23 was itself prepared in seven
steps from parent pyrrole using Ullmann−Goldberg and Suzuki−Miyaura cross-coupling, Vilsmeier−Haack formylation,
electrophilic bromination, and Wittig olefination reactions as key steps. Related chemistry has been used to prepare discoipyrrole
B (2).
n 2013 MacMillan and co-workers reported1 the isolation,
derivative of the (−)-enantiomer obtained using chiral-phase
Iusing a functional signature-based ontology (FUSION) map HPLC techniques.
approach,1,2 of four new alkaloids from the marine-derived
Bacillus hunanensis strain SNA-048. Using a range of relatively
conventional spectroscopic techniques, they assigned structures
1−4 (Figure 1) to these compounds and named them
discoipyrroles A−D, respectively.1 Each was isolated as the
racemate and the structure of the first (viz. 1) was confirmed by
single-crystal X-ray analysis of the bis-p-bromobenzoate
Discoipyrroles 1, 2, and 4 are the first examples of natural
products that embody a 3H-benzo[d]pyrrole[1,3]oxazine-3,5-
dione core. All four compounds proved to be particularly strong
inhibitors of the discoidin domain receptor 2 or DDR2-
dependent migration of BR5 fibroblasts.1 They also showed
selective cytotoxicity toward DDR2 mutant lung cancer cell lines
(IC50 120−400 nM). As such, these natural products and their
analogues could provide important new tools for interrogating
the DDR2 signaling pathway, one that has been implicated in
various cancers,3 fibroblast migration and proliferation,4 as well
as obstructive diseases of blood vessels.5
The biogenesis of the racemic discoipyrroles is believed to be
nonenzymic in nature and involves, in the case of compound 1,
for example, oxidative coupling of 2-hydroxy-1-(p-hydroxyphen-
yl)-5-methylhexan-3-one and p-hydroxybenzaldehyde with the
resulting 1,3,4-trione engaging in successive inter- then intra-
molecular condensation reactions with the amine and carboxylic
acid residues, respectively, of anthranilic acid.1 Various feeding
experiments have served to support such proposals, and by
mixing the three reaction partners just mentioned in dimethyl
sulfoxide containing 1% trifluoroacetic acid at 50 °C then modest
amounts of discoipyrrole A were obtained as an admixture with a
number of side products.1 A variation on this theme has been
Received: December 27, 2015
Figure 1. Discoipyrroles A−D.
© XXXX American Chemical Society
A
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employed by May and co-workers in an approach to
discoipyrrole D (4).6
yield. Suzuki−Miyaura cross coupling of this last compound with
5 molar equiv of commercially available p-methoxyphenylbor-
onic acid (9) provided the previously unreported, diarylated
pyrrole 10 in 75% yield.9
On reaction with isopropylmagnesium bromide in THF
aldehyde 10 afforded the expected but unstable secondary
alcohol that was treated, in situ, with lithium aluminum hydride
(LiAlH4), thereby effecting reductive cleavage of the hydroxy
group to produce the isobutyl-substituted pyrrole 11 in 77% yield
(from 10).10
The fascinating origins, structures, and biological activities of
the discoipyrroles together with the potential for “tuned”
analogues to serve as molecular probes of the DDR2-mediated
cellular signaling processes prompted us to investigate means for
establishing completely modular (and rational) syntheses of such
systems. Herein, we report the assembly, via successive cross-
coupling and alkenylation chemistries, of compounds of the
general form 5 (Figure 2) and their successful oxidative
Unfortunately, all attempts to effect the N-arylation of
compound 11 using various methyl o-halobenzoates under a
range of different conditions, including modern variants of the
Ullmann−Goldberg reaction,11 failed. Such outcomes are
attributed to the sterically congested environment about the
nitrogen of pyrrole 11 resulting from the presence of the flanking
aryl and isobutyl groups at C2 and C5, respectively.
In an effort to address the difficulties described immediately
above, a reordering of the cross-coupling and alkylation
processes was investigated as shown in Scheme 2. Thus, pyrrole
(13) was cross-coupled with methyl o-iodobenzoate (14) using
conditions very similar to those reported by Buchwald11a,b and
thereby affording the anticipated and previously reported
product 1512 (99%). Subjection of the latter compound to a
standard Vilsmeier−Haack formylation reaction using N,N-
dimethylformamide (DMF) and POCl3 afforded aldehyde 1613
(59%), which could be dibrominated with NBS under the same
conditions as described earlier and so delivering the dihalo-
genated product 17 in 99% yield.
Two-fold Suzuki−Miyaura cross-coupling of this last com-
pound with boronic acid 9 then gave the 1,2,3-triarylated pyrrole-
2-carboxaldehyde 18 (73%) that was itself subjected to a Wittig
olefination reaction using the ylide obtained by treating
isopropyltriphenylphosphonium iodide with potassium tert-
butoxide. The isobutene 19 (78%) so formed was subjected to
hydrogenation at atmospheric pressures using palladium on
carbon as catalyst and the targeted C5-isobuylated and triaryl-
substituted pyrrole 12 thereby obtained in 95% yield.
Figure 2. Proposed oxidative cyclization of a 1,2,3,5-tetrasubstituted
pyrrole 5 to afford the 3H-benzo[d]pyrrole[1,3]oxazine-3,5-dione
framework 6 of discoipyrroles A, B, and D.
cyclization to generate the corresponding 3H-benzo[d]pyrrole-
[1,3]oxazine-3,5-diones 6 including discoipyrroles A and B (1
and 2, respectively).7
The first approach used in attempts to prepare pyrroles of the
general form 5 is shown in Scheme 1 and started with the 2-fold
electrophilic bromination of readily available 1H-pyrrole-2-
carboxaldehyde (7) using N-bromosuccinimide (NBS) and so
affording the previously reported8 dibromo-derivative 8 in 99%
Scheme 1. Attempted Synthesis of the 1,2,3,5-
Tetrasubstituted Pyrrole 12 via N-Arylation of Precursor 11
On the basis that the pyrrole ester 12 might undergo an
oxidative cyclization reaction of the type shown in Figure 2, it was
treated with a freshly prepared solution of dimethyldioxirane
(DMDO) in acetone at −78 °C. A rather complex mixture of
products was formed and, after chromatography, the oxidatively
ring-cleaved product 20 was obtained in 50% yield. The structure
of this rather unstable compound was secured by single-crystal X-
ray analysis (details provided in the SI). This conversion is
believed to involve initial epoxidation of the Δ4,5-double bond
within substrate 12 with the resulting oxirane then fragmenting,
via successive C−O and C−N bond cleavages, to give the
observed product.
Various studies have been conducted on the oxidation of the
indole C2−C3 double bond using MoO5-based systems, and the
primary products so-generated have been trapped by a range of
external nucleophiles such as methanol so as to generate, for
example, 2-methoxyindolin-3-ones.14 No analogous studies
appear to have been carried out with pyrroles or with any
systems incorporated internal nucleophiles. Since a carboxylic
acid residue was required as an internal nucleophile in the
present instance, the ester 12 was saponified (Scheme 3) using
potassium hydroxide and, after workup with aqueous HCl, the
corresponding carboxylic acid 21 was obtained in 99% yield.
Gratifyingly, when a solution of compound 21 in dichloro-
methane/methanol was treated, at 20 °C for 16 h, with freshly
B
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Scheme 2. Synthesis of the 1,2,3,5-Tetrasubstituted Pyrrole
12 and an Attempt To Effect Its Oxidative Cyclization
Scheme 3. Successful Oxidative Cyclization Reactions
Leading to Discoipyrrole A (1) and Its Bis-O-methyl Ether 22
A second substrate, bis-phenol 23, used to examine the scope
of the oxidative cyclization process was obtained in 90% yield
through the boron tribromide-mediated demethylation of
compound 21. On treatment with MoOPH in dichloromethane,
compound 23 was converted into discoipyrrole (1)1 (56%), the
derived spectral data for which proved an excellent match with
those reported for the natural product (see the SI for the 1H and
13C NMR spectral data sets).
The utility of the modular syntheses of 3H-benzo[d]pyrrole-
[1,3]oxazine-3,5-diones reported here is enhanced by the
observation that regioselective Suzuki−Miyaura arylation
reactions of the dibromopyrrole 17 are possible (Scheme
4).8a,16 Thus, for example, when this compound was cross-
coupled with 1.2 molar equiv of boronic acid 9, the diarylated
pyrrole 24 (not isolated) was obtained and immediately engaged
in a second cross-coupling reaction with phenylboronic acid (25)
to give the triarylated pyrrole 26 in 77% yield.
The acquisition of the differentially triarylated pyrrole 26
allowed for the completion of a total synthesis of discoipyrrole B
(2) using the same protocols as described above for the assembly
of congener A (1). Specifically then, compound 26 was
converted into olefin 27 (70%) using the same ylide as employed
previously and the double bond associated with the latter
hydrogenated under conventional conditions to afford the
isobutyl-substituted pyrrole 28 in 95% yield. Saponification of
the last compound then gave, after acidic workup, benzoic acid
29 (99%), the structure of which was confirmed by single-crystal
X-ray analysis. When treated with boron tribromide, aryl methyl
ether 29 was cleaved to give the phenol 30 (82%) that upon
reaction with MoOPH in dichloromethane afforded lactone 2 in
55% yield. The structure of compound 2 was confirmed by
single-crystal X-ray analysis. Furthermore, the derived NMR and
prepared oxoperoxymolybdenum(pyridine) (hexamethylphos-
phoric triamide) (MoOPH),15 the desired 3H-benzo[d]pyrrole-
[1,3]oxazine-3,5-dione 22 was obtained in 48% yield after
chromatographic purification. All of the spectroscopic data
acquired on this oxidative cyclization product (see the SI for
details) were in complete accord with the assigned structure.
Most particularly, the 13C NMR spectrum displayed the expected
25 resonances, including ones at δC 194.3 and 168.6 that are
assigned to the ketone and lactone carbonyl carbons,
respectively. Furthermore, the infrared spectrum of compound
22 displayed carbonyl stretching bands at 1740 and 1700 cm−1,
while the electrospray ionization mass spectrum revealed
molecular associated ions at m/z 470 [(M + H)+] and 492
[(M + Na) +].
C
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Scheme 4. Regioselective Diarylation of Dibromopyrrole 17
and Completion of a Synthesis of Discoipyrrole B (2)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: martin.banwell@anu.edu.au.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council and the Institute of
Advanced Studies for financial support. Y.Z. gratefully acknowl-
edges the China Scholarship Council for support.
REFERENCES
■
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discoipyrroles developed by MacMillan1 have yet to be
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03672.
(15) Vedejs, E.; Larsen, S. Org. Synth. 1985, 64, 127.
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Hamel, E.; Hockless, D. C. R. Chem. Commun. 1997, 207. (b) Zhang, Y.;
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Experimental procedures, spectroscopic and analytical
data, NMR spectra of compounds 1, 2, 8, 10−12, 15−19,
21−23, and 26−30 together with X-ray data for
compounds 2, 20, 21, and 29 (PDF)
D
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