Total synthesis of (±)-distomadines A and B

Article abstract of DOI:10.1021/ol403598k

The total synthesis of distomadines A and B, two structurally unique tetracyclic quinolines, is described. The route features a three-step process to access the pyranoquinoline butenolide rings via a Suzuki cross coupling of a 5-bromo-4-methoxycarbonylmethoxyquinoline with a vinyl boronate, followed by an α-ketohydroxylation and double cyclization by intramolecular aldol condensation and lactonization. Subsequent manipulation of the side chain to introduce the guanidine fragment completed the synthesis of distomadine B, whereas the distomadine A congener resulted from decarboxylation of a late-stage intermediate.

Full text of DOI:10.1021/ol403598k

Letter
pubs.acs.org/OrgLett
Total Synthesis of ( )-Distomadines A and B
Alexandre E. R. Jolibois, William Lewis, and Christopher J. Moody*
School of Chemistry, University Park, University of Nottingham, Nottingham NG7 2RD, U.K.
S
* Supporting Information
ABSTRACT: The total synthesis of distomadines A and B, two
structurally unique tetracyclic quinolines, is described. The route
features a three-step process to access the pyranoquinoline
butenolide rings via a Suzuki cross coupling of a 5-bromo-4-
methoxycarbonylmethoxyquinoline with a vinyl boronate, followed
by an α-ketohydroxylation and double cyclization by intramolecular
aldol condensation and lactonization. Subsequent manipulation of
the side chain to introduce the guanidine fragment completed the
synthesis of distomadine B, whereas the distomadine A congener
resulted from decarboxylation of a late-stage intermediate.
s part of our ongoing studies into the synthesis of
structurally unique heterocyclic natural products,1−3 we
We initially focused on synthesizing distomadine B (2),
anticipating that distomadine A could be accessed by a late-
stage decarboxylation. We also planned to introduce the
guanidine during the final stages from a protected alcohol 3.
The butenolide could be formed by a one-step aldol-
condensation−lactonization from the corresponding α-ketol
4, which could be accessed by oxidation of an alkene, available
via a Suzuki− Miyaura cross-coupling between the 5-
bromoquinoline 5 and the corresponding alkenylboronic ester
as outlined in Scheme 1.
A
developed an interest in the distomadines, isolated from the
New Zealand ascidian Pseudodistoma aureum by Copp and co-
workers.4 Although distomadine B was isolated in a 1:1
admixture with 2′-deoxyadenosine, the structure of the A
congener was fully elucidated by NMR spectroscopy, although
the absolute stereochemistry remained unknown. These
unusual structures possess a unique tetracyclic core that
comprises a pyrano[2,3,4-de]quinoline fused to a butenolide
(Figure 1), and only one compound has been reported which
The synthesis began with the known 6-benzyloxy-4-
quinolone 6, previously prepared via a modified Conrad−
Scheme 1. Retrosynthesis Analysis of Distomadine B (Pg =
Protecting Group)
Figure 1. Structures of distomadines A and B and kynurenic and
xanthurenic acids.
possesses a similar pyranoquinoline core, a synthetic compound
related to the aaptamine alkaloids.5 The 2-quinolinecarboxylic
acid present in distomadine B is also quite uncommon in
marine natural products,6−8 although the first example, 3,4-
dihydroxyquinoline-2-carboxylic acid, was isolated from Aplysi-
na aerophoba in the early 1970s.9 Kynurenic and xanthurenic
acid are two of the best known examples of 2-quinolinecarbox-
ylic acid natural products (Figure 1), although distomadine B is
the most complex isolated to date. We now report the first
syntheses of these unusual heterocyclic natural products.
Received: December 12, 2013
© XXXX American Chemical Society
A
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Limpach reaction10 from the commercially available 4-
benzyloxyaniline hydrochloride. Thus, aza-Michael addition to
dimethyl acetylenedicarboxylate (DMAD), followed by heating
in diphenyl ether at 245 °C, afforded the 4-quinolone 6 in 70%
yield. Alkylation with methyl chloroacetate followed by
bromination with NBS in DMF gave the desired 5-
bromoquinoline 5 in excellent yield (Scheme 2).
Scheme 3. Synthesis of the Model Tetracyclic Core of
Distomadine B
Scheme 2. Synthesis of 5-Bromoquinolines 5 and 10
It was thought that 5-bromoquinoline 5 would then
participate in Suzuki−Miyaura cross-coupling, but this gave
poor results, possibly due to steric hindrance by the benzyloxy
protecting group in addition to the peri-substituent at C-4. As a
result, it was envisioned that deprotection, followed by
installation of a smaller protecting group, could improve the
yield of the cross-coupling. Deprotection of the benzyl ether 8
followed by bromination with NBS in acetonitrile afforded 9,
which was protected as the ethoxymethyl ether 10. The
Suzuki−Miyaura cross-coupling was initially attempted using
trivinylboroxine as a model for the requisite terminal alkene
(Scheme 3). Thus, reaction of 10 and vinyl boroxine pyridine
complex using Pd(OAc)2 and SPhos11 gave coupled product 11
in 75% yield. Oxidation of the alkene with KMnO4 in acetone,
water, and acetic acid12 allowed access to the α-ketol 12 in
good yield, allowing us to attempt a model butenolide
formation. Previous syntheses of butenolides have been
reported by condensation between dimethyl malonate and α-
hydroxy ketones with sodium hydride or sodium meth-
oxide.13,14 The cyclization of model α-ketol 12 with sodium
hydride afforded the desired butenolide 13 in 48% yield, X-ray
crystallographic analysis of which confirmed the tetracyclic
structure (Figure 2).
Figure 2. X-ray crystal structure of tetracyclic pyrano[2,3,4-de]-
quinoline 13.
Hunig’s base to afford 14. The hydroboration of the alkyne was
performed by following the reported modification of Srebnik’s
conditions15,16 for the Schwartz’s reagent catalyzed hydro-
boration, affording the boronic ester 15 in 78% yield. Suzuki−
Miyaura cross-coupling between bromoquinoline 10 and
boronic ester 15 with Pd(OAc)2 and SPhos gave 16 in
excellent yield. However, the previously employed oxidation
with KMnO4 resulted in a mixture (ca. 1:1) of the α-hydroxy
ketones 17 and 18. Attempts to selectively synthesize the
desired regioisomer 17 by either selective oxidation of the
corresponding diol or by a Rubottom oxidation of an enol ether
were unsuccessful. However, treatment of the mixture of α-
ketols 17 and 18 with sodium hydride resulted in the tetracyclic
core 19 in a moderate 23% yield (Scheme 4).17
In proceeding with our synthesis toward distomadine B, it
was first necessary to synthesize a suitable boronic ester to be
used as a coupling partner in the Suzuki−Miyaura reaction. Due
to the harsh conditions of the formation of the butenolide, a
benzyloxymethyl (BOM)-protected alcohol was selected for the
side chain. But-3-yn-1-ol was protected with BOMCl and
With access to the tetracyclic core, the synthesis could be
completed by introduction of the guanidine and removal of the
protecting groups. Deprotection of the BOM group in
tetracycle 19 by transfer hydrogenation using formic acid and
palladium black gave the deprotected alcohol that could be
B
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Scheme 4. Synthesis of γ-Butenolide 19 Core of
Distomadine B (PinB = 4,4,5,5-Tetramethyl-1,3,2-
dioxaborolan-2-yl)
Scheme 5. Completion of Synthesis of Distomadine B (2)
of the dihydrochloride salt with concentrated ammonia in
methanol gave the monohydrochloride salt; 1H NMR in
CD3OD with a drop of concentrated ammonia matched the
reported data for the natural product.
In order to complete the synthesis of distomadine A, the late-
stage intermediate 19 was first hydrolyzed to give the acid
which then underwent decarboxylation on heating in diphenyl
ether at 190 °C to give quinoline 22 in 77% yield over two
steps. The structure of the decarboxylated tetracycle 22 was
confirmed by X-ray crystallography (Figure 4). Transfer
hydrogenation with palladium black and formic acid gave the
alcohol 23 that was coupled to 1,2-di-Boc-protected guanidine
coupled with 1,2-di-Boc-protected guanidine under Mitsunobu
conditions18 to afford 20 in nearly quantitative yield. Hydrolysis
of the ester with NaOH provided the acid 21, X-ray
crystallography confirming the structure (Figure 3). Finally,
treatment of the acid 21 with HCl in dioxane gave the
dihydrochloride salt of distomadine B in 89% yield (Scheme 5).
Although natural distomadine B was only reported as a mixture
with 2′-deoxyadenosine, we were able to compare the NMR
spectroscopic data with our synthetic sample. Thus, treatment
Figure 3. X-ray structure of 21.
Figure 4. X-ray crystal structure of decarboxylated tetracycle 22.
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to give 24 in nearly quantitative yield. Finally, 24 was treated
with HCl in dioxane to give the dihydrochloride salt of
distomadine A (1) in 77% yield (Scheme 6). Treatment with
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Scheme 6. Completion of the Synthesis of Distomadine A
(1)
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(17) Although only isomer 17 can lead to the correct product, in
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(19) The NMR sample necessarily now contains NH4Cl, although
the effect of NH4Cl concentration on chemical shift was not
investigated.
1
concentrated ammonia gave material whose H and 13C NMR
spectra in CD3OD were identical with a sample of the authentic
natural product, although the 13C NMR data appeared to be
concentration dependent.19
In summary, we have achieved the first total syntheses of
distomadines A and B in 14 steps (3.5% yield) and 13 steps
(5.6% yield), respectively, with key intermediate structures
being confirmed by X-ray crystallography. The pivotal steps of
the syntheses are the construction of the butenolide by Suzuki
cross-coupling, oxidation of the resulting alkene, and the
intramolecular aldol lactonization sequence. The syntheses
confirm the unusual tetracyclic pyranoquinoline structure of the
natural products.
ASSOCIATED CONTENT
* Supporting Information
■
S
All experimental procedures, copies of 1H and 13C NMR
spectra, and X-ray data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*Tel: (+44)115 846 8500. E-mail: c.j.moody@nottingham.ac.
uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Nottingham for funding and Drs
Brent Copp and Norrie Pearce (University of Auckland) for
copies of NMR spectra of the distomadines and a sample of
natural distomadine A.
D
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