Total Synthesis of Waltherione F, a Nonrutaceous 3-Methoxy-4-quinolone, Isolated from Waltheria indica L. F.

Article abstract of DOI:10.1021/acs.orglett.8b02221

Waltherione F was totally synthesized in seven steps and 31% overall yield from 2-nitro-3-methylanisole without the use of protecting groups. Key steps in the sequence were a Suzuki-Miyaura coupling to attach the n-octyl chain and a microwave-promoted cyclization of an acetonyl anthranilate to give the heterocyclic core whose 3-OH was O-methylated.

Full text of DOI:10.1021/acs.orglett.8b02221

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Waltherione F, a Nonrutaceous 3‑Methoxy-4-
quinolone, Isolated from Waltheria indica L. F.
Abel A. Arroyo Aguilar, Santiago J. Bolívar Avila, Teodoro S. Kaufman,* and Enrique L. Larghi*
́
Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmaceuticas, Universidad
Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina
S
* Supporting Information
ABSTRACT: Waltherione F was totally synthesized in seven steps and 31% overall yield from 2-nitro-3-methylanisole without
the use of protecting groups. Key steps in the sequence were a Suzuki−Miyaura coupling to attach the n-octyl chain and a
microwave-promoted cyclization of an acetonyl anthranilate to give the heterocyclic core whose 3-OH was O-methylated.
atural products carrying the 3-methoxy-4-quinolone
motif were initially found in Rutaceae; however,
nonrutaceous related heterocycles have also been found in
other plant families, such as the Malvaceae. The first example
of such nonrutaceous alkaloids was melochinone, isolated in
1975 from Melochia tomentosa L.1
In 2005, Farias Morel et al. obtained the waltheriones A (1)
and B (2) from Waltheria douradinha S.-Hill (Malvaceae).
Compound 1 (Figure 1), also found in M. odorata L. F. and M.
Further, the roots of Waltheria indica L. afforded the
waltheriones E−L,5 which except for waltherione F (5) share
the structural motif 6, differing in its decoration; they have
anti-T. cruzi activity. Additional heterocycles exhibiting this
framework, such as the waltheriones M−Q6 and others, are
included in this small but fast-growing family.7 Many of them
also exhibit interesting bioactivity.8
Taking into account our continuous interest in the synthesis
of natural products,9 considering the originality of the
structures of this family members, and the scarcity of synthetic
activity in the field,10 we decided to undertake the total
synthesis of waltherione F (5).
N
In the retrosynthetic analysis of 5 (Scheme 1), the
disconnection of the C2−C3 moiety revealed the acetonyl
anthranilate 7 as a suitable precursor, which should give the
̈
quinolone core through a Friedlander-type cyclization and
rearrangement.11 Disconnection of the n-octyl moiety and the
ester group in 7 unveiled the o-nitrobenzoic acid derivative 8 as
a suitable intermediate, fitted with a proper activating group
(AG) to anchor the side chain.
Final retrosynthetic considerations led to 2-methyl-3-nitro-
anisole (9) as the most suitable starting material, which should
be oxidizable to the related acid and also properly function-
alized ortho to the carboxyl group.12
Our synthetic efforts began with oxidation of the anisole 9
with KMnO4 in H2O (Scheme 2); this gave the benzoic acid
10 in 67% yield.13 Taking into account that the proposed
strategy heavily relies on a final selective O-methylation of a
Figure 1. Waltherione F (5) and related natural products.
chamaedris St.-Hill, displays a broad spectrum of antifungal
activity.2 In 2014, the related waltheriones C (3) and D (4)
were identified in M. odorata. The heterocycle 3, also found in
M. umbellata,3 is a cancer chemopreventive agent that inhibits
the NF-κB transcription factor (IC50 ∼ 50 μM) and is
cytoprotective against HIV infection and also active toward
Trypanosoma cruzi.4
tridentate substrate, and that this is a challenging task,14a
a
simple model was first built, implementing an approach
analogous to that of Hradil et al.14b
Received: July 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02221
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Letter
different solvents (TFA, AcOH, Ph2O) under conventional
and microwave heating, it was found that AcOH was an
efficient promoter of the microwave-assisted (60 W, 150 °C)
cyclization/rearrangement sequence,19 which furnished 13 in
80% yield.
Scheme 1. Retrosynthetic Strategy toward Waltherione F
(5)
Quinolone 13 bears three different alkylation positions (N,
O3, O4), and overalkylated products are possible, depending on
the reaction conditions. A literature survey revealed that
conditions for 3-OH alkylation in 3-hydroxy-4-quinolones are
scarce. Therefore, an optimization needed to be performed,
with alcoholic solvents being preferred over polar aprotic
media (DMF, MeCN, Me2CO),18 and mild bases (K2CO3,
Na2CO3, NaHCO3) needed to be used to ensure selectivity
since NaH and the like promoted dialkylation.20
It was found that reaction of 13 with MeI in 2-PrOH gave a
61% yield of 14, accompanied by 10% of 15. Efforts to perform
the transformation 12 → 14 as a “two step-one pot” process21
did not improve the yields. The methylation position was
determined unambiguously by NOE and HMBC experiments.
The remainder of the total synthesis of 5 was thus undertaken.
Treatment of the acid 10 with Br2 in concentrated H2SO4,
under Ag2SO4 promotion,22 provided 16 in 99% yield (Scheme
3). Occasionally, the dibrominated derivative 16a was obtained
Scheme 2. Synthesis of Model Compound 14
Scheme 3. Synthesis of the Key Intermediate 19
Therefore, the acid 10 was acetonylated (88% yield) with
freshly prepared chloroacetone,15 and the nitro group of the
resulting ester 11 was subjected to a chemoselective reduction.
However, the tested reducing agents (H2, 10% Pd/C, Zn0/
NH4HCO2, TES/CHCl3, SnCl2, Fe0/NH4Cl)16 afforded
complex mixtures of esters and acids containing partial
reduction derivatives of the nitro moiety. The anthranilic
ester 12 was also detected, albeit in low yield.
An insightful analysis of the literature revealed that nickel
boride (Ni2B)17a has been used for the efficient conversion of
aromatic nitro groups to the corresponding anilines in the
presence of alkenes, halides, and esters.17b Delightfully, the
reduction of 11 with 3 equiv of freshly prepared Ni2B gave the
anthranilate 12 in 97% yield.
Next, the cyclization step was explored, but carrying the
reaction in NMP afforded a meager 34% yield of 13; hence,
alternative conditions were sought.18 After experimenting with
as a byproduct. Following Hradil’s strategy, the bromide 16
was acetonylated with chloroacetone, giving the ester 17 in
excellent yield (99%). Then the introduction of the n-octyl
group was attempted23a under conditions compatible with
acetonyl esters.23b
Due to the commercial availability of 1-octyne, a
Sonogashira reaction was initially performed. Thus, the
bromoarene 17 was treated with 1-octyne in DMF under
B
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Pd(PhP3)4 and CuI catalysis (0.35 equiv each),24 affording
78% yield of the coupled product 18 and ca. 4% of 11. The
alkyne 18 proved to be unstable to the chromatographic
purification conditions; therefore, the crude reaction product
was carried to the next step of the sequence.
Here, a simultaneous hydrogenation of the alkyne moiety
and reduction of the nitro group was envisioned, to provide the
corresponding 3-octylaniline derivative. Unfortunately, under
Pd catalysis (H2, 10% Pd/C, MeOH) a complex mixture of
products was obtained where 19 was identified in a
disappointing yield of 6%, at best.
A small amount of anthranilic acid 19a (4%) was also
isolated and unequivocally identified by conversion to its O-
acetonyl ester 19 (Scheme 3). Presumably, this byproduct
arose from hydrolysis of the acetonyl ester, which occurred
after the alkyne hydrogenation and nitro group reduction
stages. In light of these results, the strategy toward installation
of the n-octyl group was revised.
was performed on this crude material with MeI and K2CO3 in
2-PrOH at 50 °C during 3.5 h. This furnished synthetic
waltherione F (5) in 56% overall yield from 19 after silica gel
1
chromatography. The H and 13C NMR spectral data of the
synthetic compound in MeOH-d4 were in full agreement with
those of the natural product.5
In conclusion, the first total synthesis of waltherione F has
been accomplished in seven steps and 31% overall yield from
commercial 3-methyl-2-nitroanisole without the use of
protecting groups. The sequence involved the preparation of
2-nitro-3-methoxy-6-bromobenzoic acid, the synthesis of its
acetonyl ester, and its subsequent Suzuki−Miyaura coupling
with potassium n-octyltrifluoroborate under palladium catalysis
using dtbpf as ligand. A chemoselective nitro group reduction
with Ni2B, AcOH-promoted cyclization of the resulting
acetonyl anthranilate under microwave irradiation, and final
3-OH methylation completed the heterocyclic pseudane core.
ASSOCIATED CONTENT
* Supporting Information
The cross-coupling of properly activated arenes with
■
alkyltrifluoroborate salts under palladium catalysis25 is one of
S
3
2
the most powerful emerging methodologies to build Csp −Csp
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02221.
bonds. Hence, potassium n-octyltrifluoroborate (20) was
synthesized from n-octyl bromide26 and further cross-coupled
with 17 using dppf as ligand.27 After the system was stirred
overnight at 80 °C, the coupled product 21 was obtained in
81% yield (Scheme 4), accompanied by some of the proto-
debrominated precursor 11 and a small amount of the related
benzoic acid 10.
Detailed experimental procedures and characterization
data of compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Scheme 4. Synthesis of Waltherione F (5)
*E-mail: kaufman@iquir-conicet.gov.ar.
*E-mail: larghi@iquir-conicet.gov.ar.
ORCID
Teodoro S. Kaufman: 0000-0003-3173-2178
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by ANPCyT (PICT 2014-0445),
CONICET (PIP 2012-0471 and PUE IQUIR 2016), and
SECyT-UNR (BIO469). A.A.A.A. and S.J.B.A. acknowledge
CONICET for awarding their Doctoral fellowships.
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