Synthesis of anti-tubercular marine alkaloids denigrins A and B

Article abstract of DOI:10.1016/j.tetlet.2018.06.013

The first synthesis of anti-tubercular marine alkaloids denigrins A and B were accomplished in three and five steps and 62% and 31% overall yields respectively, from maleic anhydride. The key features of the synthesis include efficient Mizoroki-Heck reaction, geometry-controlled vinylogous aldol condensation, and one-pot lactamization. The synthesis first demonstrates the serviceability of maleic anhydride in palladium-catalyzed cross-coupling reactions with diaryliodonium salt.

Full text of DOI:10.1016/j.tetlet.2018.06.013

Accepted Manuscript
Synthesis of anti-tubercular marine alkaloids denigrins A and B
Milandip Karak, Tohru Oishi, Kohei Torikai
PII:
S0040-4039(18)30742-1
https://doi.org/10.1016/j.tetlet.2018.06.013
TETL 50051
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
23 April 2018
28 May 2018
4 June 2018
Please cite this article as: Karak, M., Oishi, T., Torikai, K., Synthesis of anti-tubercular marine alkaloids denigrins
A and B, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.013
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1
Tetrahedron Letters
Synthesis of anti-tubercular marine alkaloids denigrins A and B
Milandip Karak, Tohru Oishi, and Kohei Torikai
Department of Chemistry, Faculty of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first synthesis of anti-tubercular marine alkaloids denigrins A and B were accomplished in
three and five steps and 62% and 31% overall yields respectively, from maleic anhydride. The
key features of the synthesis include efficient Mizoroki-Heck reaction, geometry-controlled
vinylogous aldol condensation, and one-pot lactamization. The synthesis first demonstrates the
serviceability of maleic anhydride in palladium-catalyzed cross-coupling reactions with
diaryliodonium salt.
Available online
Keywords:
Denigrins
2009 Elsevier Ltd. All rights reserved.
Total synthesis
Diaryliodonium salt
Mizoroki-Heck reaction
Lactamization
Vinylogous aldol condensation
Tuberculosis (TB), a highly infectious disease caused by the
pathogen M. tuberculosis, spreads by the air therefore has been
one of the leading causes of mortality worldwide for centuries.
According to the estimation of WHO, in 2016, 10.4 million
people were diagnosed with TB infection, out of which 1.3
million people died.1 The condition becomes more severe in the
case of multi-drug resistant TB, which is difficult to treat with
conventional drugs and contributes to the increased mortality.
Besides, the adverse effects against epidemic TB are common
and thus lead to the problem of nonadherence.2 Although TB is
treatable and preventable, developing nations are still suffering
due to the limited resources and the ineffectiveness of first and
second line anti-TB drugs.3 Therefore, safer, inexpensive, and
more efficacious new compounds possessing anti-TB activity are
urgently needed.
the precise amount of marine organisms used to isolate denigrins
A (45 mg) and B (9 mg) was not disclosed,5 as many other
marine natural products, denigrins also suffer from short and
difficult supply of natural specimens. Furthermore, their total
syntheses have not yet been reported to date. These facts as well
as the unprecedented structural features of 2 prompted us to
undertake the syntheses of denigrins A and B.
The pyrrole alkaloids exhibit
a
wide spectrum of
bioactivities.4 Several pyrrole alkaloids, such as denigrins A-C,5
solsodomine A,6 banegasine,7 and celastramycin A,8 exhibit
potent anti-TB activity.9 Among these, denigrins A (1), B (2) and
C (3; Figure 1), isolated from the Indian marine sponge Dendrilla
nigra, are potent inhibitors of M. tuberculosis (MIC of 16.0, 32.0,
and 4.0 μg/mL respectively).5 Denigrin A (1) features the
presence of a 3,4-diarylpyrrole structure, with C-3 and C-4
positions of the pyrrole occupied by p-hydroxyphenyl groups and
C-2 and C-5 positions by imide carbonyls which is closely
related to polycitrin A (4) isolated from an ascidian Polycitor
sp.10 On the other hand, denigrin B (2) features an unusual,
densely functionalized (Z)-γ-benzylidenelactam motif on one side
of the 3,4-diarylpyrrole unit, reminiscent of the telomerase
Figure 1. Structures of denigrin A, B and C and related pyrrole
alkaloids.
Arylated maleic anhydrides are precursors of several
biologically important natural products and their artificial
inhibitory secondary metabolite dictyodendrin E11 (5). Although
———
 Corresponding author (MK). E-mail: milandip.karak@chem.kyushu-univ.jp.
 Corresponding author (KT). Tel. and Fax: +81–92–802–4177. E-mail: torikai@chem.kyushu-univ.jp.

2
Tetrahedron
congeners.12 The preparations of mono- and diarylated maleic
We considered that methyl-protected denigrin B (6) would be
obtained from lactamization of 7, whose benzylidene moiety can
be installed via vinylogous aldol condensation, following to the
selective reduction of the anhydride moiety. If the two aryl
groups of 8 are envisaged to be introducible by Mizoroki-Heck
reaction, our synthesis was retrosynthetically analyzed to start
with maleic anhydride 9 and diaryliodonium tetrafluoroborate 10.
Herein, we report the successful implementation of this plan to
the first syntheses of denigrins A and B.
anhydrides have been well documented in the literature.13 Among
them, the most efficient and direct approach to this class of
compounds is the Mizoroki-Heck type arylation of maleic
anhydride.14 In 2006, Correia et al. first reported the Mizoroki-
Heck arylation of maleic anhydride using aryldiazonium
tetrafluoroborates with moderate to good yields.14a However, it
has been well established that diaryliodonium salts are more
favorable for the coupling of electron-rich aryl groups. Besides,
diaryliodonium salts are air- and moisture-stable, easy-to-make
compounds that have proved to be mild and non-toxic reagents.
Indeed, diazonium and iodonium salts display some similarities
in their behavior as outstanding electrophiles which make them
highly complementary partners that could be judiciously selected
according to the targeted coupling.15 We therefore sought to
Our investigation began with the synthesis of 3,4-diaryl
maleic anhydride 12, which was previously reported via
Mizoroki-Heck arylation of maleic anhydride using
aryldiazonium tetrafluoroborate.14a We started evaluating the
scope of this reaction by employing diaryliodonium salts as new
coupling partners under various reaction parameters such as
palladium sources, solvents, and bases (Table 1).
suggest
a
new coupling partner, e.g. diaryliodonium
tetrafluoroborate 10, for our targets, based on the strategy shown
in Scheme 1.
The reaction of the maleic anhydride and diaryliodonium
tosylate, catalyzed by Pd2(dba)3/NaOAc, was found only
modestly effective in providing the mixture of mono- and di-
arylated products 11 and 12 (36%, entry 1). Changing the catalyst
to Pd(OAc)2 did not improve the yield although the diarylated
product 12 was found as a major product (43%, entry 2). A slight
improvement in the yield of desired product 12 was observed
when diaryliodonium tetrafluoroborate was used under the
catalysis of Pd2(dba)3/NaOAc (49%, entry 3). The use of
PdCl2/NaOAc (entry 4), other bases (e.g. NaOTs and Na2CO3)
and solvents (e.g. DMF and MeOH) with Pd(OAc)2 seems
hopeless to the arylation of maleic anhydride (entries 7–10).
Much to our delight, the best yield was achieved by
Pd(OAc)2/NaOAc in acetonitrile, i.e., only the diarylated
compound 12 was formed as a sole detectable product in good
yield (69%, entry 5). On the other hand, when the reaction was
stopped after 3 h, monoarylated product 11, which may be useful
for the structure-activity-relationship study in the next stage of
this project, was obtained as a major product (72%, entry 6).16
Scheme 1. Retrosynthetic analysis of denigrin B.
Table 1. Optimization of Mizoroki-Heck arylation of maleic anhydride with iodonium salts.[a]
Entry
X
Pd-source (equiv)
Pd2(dba)3 (0.05)
Pd(OAc)2 (0.05)
Pd2(dba)3 (0.1)
PdCl2 (0.05)
Base (equiv)
NaOAc (4.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (3.0)
NaOAc (4.0)
NaOAc (3.0)
NaOTs (3.0)
Na2CO3 (3.0)
NaOAc (3.0)
NaOAc (3.0)
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
Yield (10:11)[b]
36 (60:40)
43 (10:90)
49 (10:90)
Trace
OTs
OTs
BF4
BF4
BF4
BF4[c]
BF4
BF4
BF4
BF4
1
2
3
4
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.05)
69 (4:96)
72 (84:16)
Trace
5
6
7
No reaction
Trace
8
9
MeOH
No reaction
10
[a] In all cases, 4.5 equiv of iodonium salts and 0.005 equiv of anisole were used and the reaction was conducted at 70 °C for 24 h. [b]
Isolated yield. The ratio of mono- and diarylated products was determined by 1H NMR. [c] The reaction was stopped after 3 h.

3
With successful Mizoroki-Heck conditions to prepare 12 in
hand, the synthesis of denigrin A was accomplished (Scheme 2).
Lactam 14 was obtained in 93% yield by heating a mixture of
compound 12 with 4-methoxyphenethylamine 13 in refluxing
acetic acid for 6 h. It is worth noting that a lower yield (40%)
was observed in basic conditions using Hünig’s base.14a Finally,
removal of the methyl groups of 14 using boron tribromide
mixtures of E/Z. Fortunately, the vinylogous aldol
condensation18 of 8 with 4-methoxybenzaldehyde 15 using
sodium carbonate in MeOH furnished the desired Z-isomer 7 as a
sole product, in 89 % yield. Next step was the lactamization of
lactone 7, which was our last key reaction.19 We expected that the
desired geometry would be attainable due to the comparatively
hindered nature of the furanone moiety. Thus, compound 7 was
treated with 4-methoxyphenethylamine 13 in dichloromethane at
room temperature for 40 h. The reaction mixture containing
intermediate 16 was then heated in refluxing acetic acid for 4 h to
produce the desired benzylidene-diarylpyrrol-2(5H)-one 6Z as a
major product (6Z : 6E = 8 : 1, separable by silica gel column
chromatography) in 74% yield in one-pot fashion. It was
necessary to use 5 equivalents of amine 13 in order to drive the
reaction to completion. Finally, methyl ether cleavage of 6 with
boron tribromide smoothly led to denigrin B (2) in 89% yield
1
provided denigrin A (1) in 97% yield (62% overall). The H and
13C NMR spectra of synthetic specimen were fully identical to
those reported previously.5
(31% overall) whose H and 13C NMR spectra were in excellent
1
agreement with those reported in the literature.5
Scheme 2. Synthesis of denigrin A.
In conclusion, the first total syntheses of denigrins A and B,
marine antitubercular pyrrole alkaloids, were accomplished in 3
and 5 steps in 62 and 31% overall yields, respectively from
commercially available maleic anhydride. This synthetic route is
reproducible, relies on inexpensive reagents, and demonstrates
the remarkable performance of maleic anhydride in Mizoroki-
Heck coupling using a diaryliodonium salt. Structure-activity-
relationship studies of denigrins enabled by this established
synthetic route are currently underway in our laboratory.
Subsequently, our attention was directed to the synthesis of
denigrin B (Scheme 3). Treatment of 12 with LiAlH4 facilitated
the selective reduction of a carbonyl group17 to afford 3,4-
diarylbutenolide 8 in 86% yield. Our first task in this synthesis
was the vinylogous aldol condensation to prepare 7. Generally,
vinylogous aldol condensations of butenolides having a bulky
C4-substituent, such as Ar, i-Pr, or Br, tend to lead to Z-products,
whereas those bearing a small substituent such as Me, provide
Scheme 3. Total synthesis of denigrin B. Ar = p-OMe-C6H4
5. Murali Krishna Kumar M, Devilal Naik J, Satyavathi K, Ramana
H, Raghuveer Varma P, Purna Nagasree K, Smitha D, Venkata Rao
D. Nat. Prod. Res. 2014; 28: 888.
6. El Sayed KA, Hamann MT, Abd El-Rahman HA, Zaghloul AM. J.
Nat. Prod. 1998; 61: 848.
Acknowledgments
M.K. thanks to the Takeda Science Foundation for a
postdoctoral research fellowship.
7. Cain CC, Lee D, Waldo Iii RH, Henry AT, Casida EJ, Wani MC,
Wall ME, Oberlies NH, Falkinham Iii JO. Antimicrob. Agents
Chemother. 2003; 47: 2113.
Supplementary Material
8. Pullen C, Schmitz P, Meurer K, v. Bamberg D, Lohmann S, De
Castro França S, Groth I, Schlegel B, Möllmann U, Gollmick F,
Gräfe U, Leistner E. Planta 2002; 216: 162.
9. Mishra SK, Tripathi G, Kishore N, Singh RK, Singh A, Tiwari
VK. Eur. J. Med. Chem. 2017; 137: 504.
Supplementary data (detailed experimental procedures,
compounds characterization data, and copies of 1H and 13C NMR
spectra for all new compounds) associated with this article can be
found, in the online version.
10. Rudi A, Goldberg I, Stein Z, Frolow F, Benayahu Y, Schleyer M,
Kashman Y. J. Org. Chem. 1994; 59: 999.
References and notes
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4
Tetrahedron
Marchesini A. Eur. J. Org. Chem. 1999; 1999: 1421; (d) Li J, Jiang
and further scope of the Mizoroki-Heck coupling against maleic
anhydride will be disclosed elsewhere.
H, Chen M. Synth. Commun. 2001; 31: 3131; (e) Pattabiraman VR,
Padakanti S, Veeramaneni VR, Pal M, Yeleswarapu KR. Synlett
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16. To verify the reaction feasibility, selected unsymmetrical
diaryliodonium salts were subjected to Mizoroki-Heck coupling with
maleic anhydride. As a result, mesityl(p-tolyl)iodonium or p-
tolyl(2,4,6-trimethoxyphenyl)iodonium tetrafluoroborates provided a
monotolylated maleic anhydride in 10 and 31% yields respectively as
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5
Highlights
 First synthesis of anti-tubercular marine alkaloids denigrins
A and B was achieved.
 Iodonium salts enabled the Mizoroki-Heck coupling of
maleic anhydride.
 Lactamization was achieved in a one-pot and geometry-
selective manner.

6
Tetrahedron
Graphical Abstract
Synthesis of anti-tubercular marine alkaloids
denigrins A and B
Leave this area blank for abstract info.
Milandip Karak, Tohru Oishi, and Kohei Torikai