Synthesis of Violaceic Acid and Related Compounds through Aryl Triazene

Article abstract of DOI:10.1021/acs.orglett.7b00141

MPC1001 is a potent anticancer natural product that contains a violaceic acid moiety. Herein we report the total synthesis of the natural product violaceic acid and its derivative. In this approach, a triazene-directed Ullman coupling proved to be highly effective. We converted the triazene to a hydroxy group by means of a palladium-catalyzed reaction. Treatment of the triazene with trifluoroacetic acid generated an arenediazonium ion that produced an aryl radical, leading to the protodediazoniation and a tricyclic product.

Full text of DOI:10.1021/acs.orglett.7b00141

Letter
pubs.acs.org/OrgLett
Synthesis of Violaceic Acid and Related Compounds through Aryl
Triazene
†
†
Shin Ando, James Burrows, and Kazunori Koide*
Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, Pennsylvania 15260, United States
*
S Supporting Information
ABSTRACT: MPC1001 is a potent anticancer natural product
that contains a violaceic acid moiety. Herein we report the total
synthesis of the natural product violaceic acid and its derivative. In
this approach, a triazene-directed Ullman coupling proved to be
highly effective. We converted the triazene to a hydroxy group by
means of a palladium-catalyzed reaction. Treatment of the
triazene with trifluoroacetic acid generated an arenediazonium
ion that produced an aryl radical, leading to the protodediazo-
niation and a tricyclic product.
n 2004, MPC1001 (Scheme 1) was isolated from a fungal
Scheme 2. Attempts by Means of the Palladium-Catalyzed
Reaction or Ullman Type Reaction
I
strain, Cladorrhinum sp. KY4922 (17.6 mg/L of culture1
broth), found in a soil sample collected in Indonesia.
MPC1001 exhibited antimicrobial activities against Gram-
positive bacteria in a micromolar range. More significantly, it
showed antiproliferative activity against human prostate cancer
1
line DU145 with an IC50 value of 9.3 nM.
Scheme 1. Structure of MPC1001 and Violaceic Acid
The most convincing evidence for the chemical structure of
2
MPC1001 was the high degree of similarity to emestrin. While
3
−6
the Williams and Clive groups reported fragment syntheses,
Tokuyama et al. completed the first total synthesis of
7
(
+)-MPC1001B. Herein, we wish to report a successful
preparation of the aromatic fragment during which another
8
natural product, violaceic acid, was synthesized.
We envisioned that MPC1001 might be assembled by the
formations of the ester and C3−C7″ bonds at a late stage of the
synthesis, revealing aldehyde 1 as an advanced intermediate
the coupling between aryl bromide 2 and phenols 3−5 under
the literature conditions (Pd (dba) , L (2-di-tert-butylphosphi-
2
3
(Scheme 1). To facilitate analog synthesis, we desired a
convergent approach toward this aromatic fragment, which led
us to consider forming a biaryl ether bond by a palladium-
catalyzed biaryl ether synthesis. However, as Scheme 2a shows,
Received: January 14, 2017
9
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00141
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
no-2′,4′,6′-triisopropylbiphenyl), K PO , 1,4-dioxane−H O
Scheme 4. Synthesis of Violaceic Acid and Aromatic
Fragment 1
3
4
2
9
(
1:1), 100 °C) did not produce the desired products 1, 6,
or 7, resulting in the recovery of the starting materials.
Protection of aldehyde 2 as a cyclic acetal 8 did not enable this
coupling (Scheme 2b). Control experiments (Scheme 3)
Scheme 3. Control Experiments for Biaryl Ether Formations
revealed that the methoxy group ortho to the bromine
10
functionality is likely hampering the reaction. When we
performed the Ullman coupling using aryl bromide 2 and
7
phenol 5, using conditions similar to Tokuyama’s, biaryl ether
1
could be isolated in only 15% yield (Scheme 2c), which is
comparable to their result.
As such, we turned our attention to the triazene approach to
improve the synthesis (Scheme 4). The aryl triazene approach
was chosen due to the ability of the triazene to activate the
ortho-bromide and direct the attack of the alkoxide
1
1
nucleophile. To exploit this chemistry, we began the synthesis
with commercially available p-acetamidobenzaldehyde 11,
which was brominated to form aryl bromide 12 in 74%
1
2
yield. This aryl bromide was converted to triazene 14 in one
pot by acid-catalyzed amide ethanolysis, diazonium formation
13
(13), and the addition of pyrrolidine. A mixture of triazene 14
generated and intercepted by MeOH if the treatment of
triazene 15 with NIS proceeds by an ionic mechanism.
However, this experiment (entry 4) afforded only arene 16
and aryl iodide 17.
and phenol 5 was subjected to CuBr·SMe and K CO in
2
2
3
MeCN−pyridine (5:1) at 80 °C; to our delight, we were able to
obtain the desired biaryl ether 15 in 85% yield in a reproducible
manner.
Given the diazonium ion as an intermediate, we speculated
18
We expected that triazene 15 could be converted to the
that Cohen’s method might substitute the triazene moiety
with a hydroxy group. However, the treatment of triazene 15
with TFA followed by Cu O, Cu(NO ) , and AgNO (entry 5)
14,15
corresponding methyl ether by an ionic mechanism.
However, under acidic conditions (5% TFA in MeOH, Table
2
3 2
3
1
, entry 1), we isolated only the reduced arene 16 in 84% yield,
also provided arene 16 in 10% yield, with no expected phenol
derivative. Changing the solvent from MeOH (entry 1) to
MeCN (entry 6) generated benzofuran 18. Such a Pschorr ring
16
which might be formed by a radical mechanism.
In an attempt to trap the putative radical species with O2,
similar conditions were employed under an oxygen atmosphere,
which still afforded arene 16 in 88% yield (Table S3,
Supporting Information).
19
20
closure may occur through a cationic intermediate, although
18
a radical mechanism is also plausible. We hypothesized that
the α-hydrogen of pyrrolidine could be a hydrogen donor
17
21
When the solvent was CD OD (entry 2), the deuterated
toward the putative aryl radical intermediate.
3
arene d-16 was obtained in 84% yield, which is consistent with
the radical mechanism. Resin-bound sulfonic acid also
generated the reduced arene 16 as the sole product (entry
To test this hypothesis, pyrrolidine was added to the reaction
(entry 7); the ratio of 16:18 increased, indicating that
pyrrolidine may indeed be a hydrogen donor. With TEMPO,
the overall yield decreased to 5% and the ratio of 16:18
remained the same (entry 6 vs entry 8). This result further
20
3), indicating that this transformation is not specific with TFA.
We hypothesized that a cationic intermediate might be
B
DOI: 10.1021/acs.orglett.7b00141
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Conversion of Triazene 15
entry
acid
additive (equiv)
solvent
MeOH
temp (°C)
t (h)
yield (%) (16:18)
1
2
3
4
A
A
B
C
none
65
65
83
83
1.5
2
84 (1:0)
none
CD OD
84 (d-16) (1:0)
77 (1:0)
3
none
MeCN/H O
2.5
10
2
b
NIS (1)
MeCN
26
MeOH (20)
5
A
A
A
A
D
Cu(I) (0.9), Cu(II) (30), Ag(I) (30)
CH Cl ; H O
0; 23
83
1; 0.17
10 (1:0)
40 (1:1)
40 (3:1)
5 (1:1)
2
2
2
c
6
none
MeCN
MeCN
MeCN
MeCN
4
4
4
8
c
7
pyrrolidine (5)
TEMPO (3)
none
83
c
8
83
c
9
83
54 (3:1)
a
b
c
Acid A = TFA; Acid B = Dowex 5WX8-200; Acid C = no acid; Acid D = Ascorbic acid. Only 16 and 17 were seen in 1:6 ratio. Proportion based
1
on H NMR. Cu(I) = Cu O; Cu(II) = Cu(NO ) ; Ag(I) = AgNO .
2
3
2
3
Scheme 5. Proposed Mechanism for the Formation of 16 and 18
corroborates with the radical mechanism. When changing the
acid from TFA to ascorbic acid, the ratio of 16:18 also
increased (entry 9). The formation of arene 16 was presumably
of aryl radicals being faster than the rate of Pschorr-type ring
5
−1 −1
−1 −1 25,26
closure (5 × 10 M
s
vs 1.1 × 10 M s ).
Having failed to directly convert triazene 15 to the
corresponding methoxy or hydroxy arene, an alternative
approach was pursued for the synthesis of the target molecule
22
enhanced by ascorbic acid as a superb H· donor.
Although these results by no means excludes the cation
intermediacy, we propose that arene 16 and dibenzofuran 18
are formed through a radical pathway (Scheme 5). In this
pathway, after the protonation of triazene 15, pyrrolidine is lost
to form the diazonium ion 19. Subsequently, a single electron
transfer occurs within the ion pair to form radical species
27
1; triazene 15 was treated with I in MeCN to form aryl
2
iodide 17 in 78% yield (Scheme 4). When this iodide was
treated with Pd (dba) and Cs CO in MeOH, the reduced
2
3
2
3
arene 16 was the major product, presumably through a β-
hydride elimination−reductive elimination sequence (i.e., Ar−
23,24
28
2
0.
The loss of dinitrogen ensues, resulting in the key aryl
Pd−OMe → Ar−Pd−H + HCHO → ArH + Pd). As we were
radical intermediate 21. This radical species either abstracts a
hydrogen atom from pyrrolidine, ascorbic acid, or MeOH to
form arene 16 or reacts with the adjacent phenyl ring to form
the tricyclic radical 22. The reduction to form arene 16
becomes a more prominent pathway when a good hydrogen
radical donor (e.g., MeOH, pyrrolidine, ascorbic acid) is
present in excess. The radical species 22 then reacts with an
electron acceptor (e.g., 19) to form cation 23, which undergoes
aromatization to form dibenzofuran 18. Arene 16 is produced
in a greater proportion due to the rate of hydrogen abstraction
also interested in verifying the structure of violaceic acid, we
turned our attention to the conversion of the iodide group to a
28
hydroxy group rather than changing the phosphine ligand.
Aryl iodide 17 was treated with Pd (dba) , L, and KOH in 1,4-
2
3
8
dioxane−H O (1:1) to synthesize violaceic acid in quantitative
2
yield. This was treated with (MeO) SO to form methyl ether 1
2
2
4
in 86% yield. Here, the revised structure of violaceic acid was
confirmed by chemical synthesis for the first time.
For the next stage of our studies, we performed an aldol
24
reaction between diketopiperazine 24 and aldehyde 1 to
C
DOI: 10.1021/acs.orglett.7b00141
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
obtain alkene 25 in 75% yield (Scheme 6, not optimized). An
exocyclic olefin may be used for further functionalization to
accomplish the total synthesis of MPC1001.
(6) Dong, S.; Indukuri, K.; Clive, D. L. J.; Gao, J. M. Chem. Commun.
2
016, 52, 8271−8274.
25
(7) Kurogi, T.; Okaya, S.; Fujiwara, H.; Okano, K.; Tokuyama, H.
Angew. Chem., Int. Ed. 2016, 55, 283−287.
(
13.
8) Yamazaki, M.; Maebayashi, Y. Chem. Pharm. Bull. 1982, 30, 509−
Scheme 6. Aldol Reaction between Aldehyde 1 and
Diketopiperazine 24
5
(9) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2006, 128, 10694−10695.
10) Torraca, K. E.; Huang, X. H.; Parrish, C. A.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 10770−10771.
11) Nicolaou, K. C.; Boddy, C. N. C.; Natarajan, S.; Yue, T. Y.; Li,
H.; Brase, S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421−
422.
12) Podgorsek, A.; Stavber, S.; Zupan, M.; Iskra, J. Tetrahedron Lett.
(
(
̈
3
(
2
(
(
006, 47, 1097−1099.
13) Wallach, O. Justus Liebigs Ann. Chem. 1886, 235, 233−255.
14) Broxton, T. J.; Bunnett, J. F.; Paik, C. H. J. Org. Chem. 1977, 42,
6
(
43−649.
15) Schunk, S.; Enders, D. J. Org. Chem. 2002, 67, 8034−8042.
In summary, we synthesized aldehyde 1 in six steps from
aldehyde 11, featuring a successful application of the triazene
approach for biaryl ether formation and the two-step
conversion of a triazene to a hydroxy compound. This
endeavor also resulted in the total synthesis and structural
confirmation of violaceic acid. We also investigated the
mechanism that accounts for the formation of arene 16 and
dibenzofuran 18.
(16) Zollinger, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 141−150.
(17) TFA was chosen as an unlikely source of a hydrogen source.
(18) Cohen, T.; Dietz, A. G., Jr.; Miser, J. R. J. Org. Chem. 1977, 42,
053−2058.
2
(
19) Pschorr, R. Ber. Dtsch. Chem. Ges. 1896, 29, 496−501.
(20) Zhou, J.; Yang, W. J.; Wang, B. J.; Ren, H. J. Angew. Chem., Int.
Ed. 2012, 51, 12293−12297.
21) Kimball, D. B.; Weakley, T. J. R.; Herges, R.; Haley, M. M. J.
Am. Chem. Soc. 2002, 124, 13463−13473.
22) Crisostomo, F. P.; Martin, T.; Carrillo, R. Angew. Chem., Int. Ed.
(
(
ASSOCIATED CONTENT
Supporting Information
■
2014, 53, 2181−2185.
*
S
(23) Galli, C. Chem. Rev. 1988, 88, 765−792.
(24) Satyamurthy, N.; Barrio, J. R.; Schmidt, D. G.; Kammerer, C.;
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00141.
Bida, G. T.; Phelps, M. E. J. Org. Chem. 1990, 55, 4560−4564.
(25) Galli, C. Chem. Rev. 1988, 88, 765−792.
(26) Chandler, S. A.; Hanson, P.; Taylor, A. B.; Walton, P. H.;
Detailed experimental procedures along with analytical
and spectral data for all new compounds (PDF)
Timms, A. W. J. Chem. Soc. Perk. Trans. 2 2001, 214−228.
(27) Wu, Z. Y.; Moore, J. S. Tetrahedron Lett. 1994, 35, 5539−5542.
(28) Vorogushin, A. V.; Huang, X. H.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 127, 8146−8149.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: koide@pitt.edu.
ORCID
Shin Ando: 0000-0002-1087-5391
Kazunori Koide: 0000-0001-8894-8485
Author Contributions
†
S.A. and J.B. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Cancer Institute
R01 CA120792). J.B. was supported by the Dietrich Arts and
■
(
Science scholarship from the University of Pittsburgh.
REFERENCES
■
(
1) Tsumagari, N.; Nakai, R.; Onodera, H.; Hasegawa, A.; Rahayu, E.
S.; Ando, K.; Yamashita, Y. J. Antibiot. 2004, 57, 532−534.
(
2) Seya, H.; Nozawa, K.; Nakajima, S.; Kawai, K.; Udagawa, S. J.
Chem. Soc., Perkin Trans. 1 1986, 109−116.
3) Schuber, P. T.; Williams, R. M. Tetrahedron Lett. 2012, 53, 380−
82.
4) Schuber, P. T.; Williams, R. M. Heterocycles 2012, 84, 1193−
207.
5) Wang, L. H.; Clive, D. L. J. Tetrahedron Lett. 2012, 53, 1504−
506.
(
3
(
1
(
1
D
DOI: 10.1021/acs.orglett.7b00141
Org. Lett. XXXX, XXX, XXX−XXX