Tandem ring-closing metathesis/isomerization reactions for the total synthesis of violacein

Article abstract of DOI:10.1021/ol400654r

A series of 5-substituted 2-pyrrolidinones was synthesized through a one-pot ruthenium alkylidene-catalyzed tandem RCM/isomerization/nucleophilic addition sequence. The intermediates resulting from RCM/isomerization showed reactivity toward electrophiles in aldol condensation reactions which provided a new entry for the total synthesis of the antileukemic natural product violacein.

Full text of DOI:10.1021/ol400654r

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Tandem Ring-Closing Metathesis/
Isomerization Reactions for the Total
Synthesis of Violacein
Mette T. Petersen† and Thomas E. Nielsen*,†,‡
Department of Chemistry, Technical University of Denmark, DK-2800 Kgs. Lyngby,
Denmark, and Singapore Centre on Environmental Life Sciences Engineering,
Nanyang Technological University, Singapore 637551, Singapore
ten@kemi.dtu.dk
Received March 11, 2013
ABSTRACT
A series of 5-substituted 2-pyrrolidinones was synthesized through a one-pot ruthenium alkylidene-catalyzed tandem RCM/isomerization/
nucleophilic addition sequence. The intermediates resulting from RCM/isomerization showed reactivity toward electrophiles in aldol
condensation reactions which provided a new entry for the total synthesis of the antileukemic natural product violacein.
Ruthenium-catalyzed ring-closing metathesis (RCM) is
a robust and reliable method for the synthesis of cyclic
alkenes.1 The combination of RCM with concurrent
chemical transformations, frequently referred to as tan-
dem sequences, provides access to complex molecular
structures in a single synthetic step.2 Over the past decade,
several successful examples of “autotandem” and “as-
sisted tandem”3 RCM/isomerization reactions have
been reported4 along with tandem reactions, where
RCM successfully has been coupled to other chemical
transformations such as hydrogenation,5 oxidation,4e,6
† Technical University of Denmark.
‡ Nanyang Technological University.
(5) (a) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 11312. (b) Schmidt, B.; Pohler, M. Org. Biomol. Chem. 2003,
1, 2512. (c) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42,
308. (d) Børsting, P.; Nielsen, P. Chem. Commun. 2002, 2140. (e)
Menozzi, C.; Dalko, P. I.; Cossy, J. Synlett 2005, 2449.
(6) (a) Scholte, A. A.; An, M. H.; Snapper, M. L. Org. Lett. 2006, 8,
4759. (b) Beligny, S.; Eibauer, S.; Maechling, S.; Blechert, S. Angew.
Chem., Int. Ed. 2006, 45, 1900. (c) Schmidt, B.; Krehl, S. Chem. Commun.
2011, 47, 5879. (d) Nishiyama, T.; Choshi, T.; Kitano, K.; Hibino, S.
Tetrahedron Lett. 2011, 52, 3876.
(7) (a) Seigal, B. A.; Fajardo, C.; Snapper, M. L. J. Am. Chem. Soc.
2005, 127, 16329. (b) Borguet, Y.; Sauvage, X.; Zaragoza, G.; Demonceau,
A.; Delaude, L. Beilstein J. Org. Chem. 2010, 6, 1167. (c) Schmidt, B.;
Pohler, M. J. Organomet. Chem. 2005, 690, 5552.
(8) (a) Kim, B. G.; Snapper, M. L. J. Am. Chem. Soc. 2006, 128, 52.
ꢀ
(b) Mallagaray, A.; Domınguez, G.; Gradillas, A.; Perez-Castells, J.
(1) For selected reviews on metahesis, see: (a) Katz, T. Angew. Chem.,
Int. Ed. 2005, 44, 3010. (b) Schrock, R. R. J. Mol. Catal. A 2004, 213, 21.
(c) Hoveyda, A. H.; Schrock, R. R. Compr. Asymmetric Catal. Suppl.
2004, 1, 207. (d) Schrock, R. R.; Hoveyda, A. H. Angew. Chem. 2003,
115, 4740. Angew. Chem., Int. Ed. 2003, 42, 4592. (e) Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490. (f)
Deshmukh, P. H.; Blechert, S. Dalton Trans. 2007, 2479. (g) Hoveyda,
A. H.; Zhugralin, A. R. Nature 2007, 450, 243. (h) Vougioukalakis,
G. C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746. (i) Handbook of
Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vols. 1À3.
(2) For reviews on tandem metathesis/nonmetathetic reactions, see:
(a) Alcaide, B.; Almendros, P.; Luna, A. Chem. Rev. 2009, 109, 3817. (b)
Krompiec, S.; Krompiec, M.; Penczek, R.; Ignasiak, H. Coord. Chem.
Rev. 2008, 252, 1819. (c) Schmidt, B. Pure Appl. Chem. 2006, 78, 469. (d)
Schmidt, B. Eur. J. Org. Chem. 2004, 2004, 1865.
€
(3) For the taxonomy of tandem reactions, see: Fogg, D. E.; dos
Santos, E. N. Coord. Chem. Rev. 2004, 248, 2365.
Org. Lett. 2008, 10, 597.
(9) (a) Rosillo, M.; Casarrubios, L.; Domınguez, G.; Perez-Castells,
ꢀ
(4) (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L.
J. Am. Chem. Soc. 2002, 124, 13390. (b) Schmidt, B. J. Org. Chem. 2004,
69, 7672. (c) Schmidt, B.; Biernat, A. Org. Lett. 2008, 10, 105. (d)
J. Org. Biomol. Chem. 2003, 1, 1450. (b) Finnegan, D. F.; Snapper, M. L.
J. Org. Chem. 2011, 76, 3644.
(10) (a) Ascic, E.; Jensen, J. F.; Nielsen, T. E. Angew. Chem., Int. Ed.
2011, 50, 5188. (b) Ascic, E.; Le Quement, S. T.; Ishoey, M.; Daugaard,
M.; Nielsen, T. E. ACS Combi . Sci. 2012, 14, 253. (c) Cai, Q.; Liang,
X.-W.; Wang, S.-G.; Zhang, J.-W.; Zhang, X.; You, S.-L. Org. Lett.
2012, 14, 5022.
ꢀ
ꢀ
Fustero, S.; Sanchez-Rosello, M.; Jimenez, D.; Sanz-Cervera, J. F.; Del
~
Pozo, C.; Acena, J. L. J. Org. Chem. 2006, 71, 2706. (e) Coyanis, E. M.;
Panayides, J.-L.; Fernandes, M. A.; de Koning, C. B.; van Otterlo,
W. a. L. J. Organomet. Chem. 2006, 691, 5222. (f) Schmidt, B. Chem.
Commun. 2004, 742. (g) Schmidt, B. Eur. J. Org. Chem. 2003, 34, 816.
r
10.1021/ol400654r
XXXX American Chemical Society

Kharasch addition,7 cyclopropanation,8 PausonÀKhand
reaction,9 and iminium cyclization.10
Here, we report an extension of a recently developed
tandem RCM/isomerization/N-acyliminium cyclization
sequence (Scheme 1a)10a where focus is directed toward
intermolecular reactions of N-acyliminium ions with electron-
rich carbon nucleophiles. In particular, we demonstrate that
the Ru-catalyzed tandem reaction of dienes 3a and indoles is
useful for the rapid synthesis of pharmacologically interest-
ing 5-substituted 2-pyrrolidinones 3b (Scheme 1b).
Previous experiments had indicated the intermediacy of
enols 3e, presumably arising through favorable tautomeriza-
tion events,10a,11 and we envisioned how intermediates 3d
could also serve as precursors for aldol condensations with
aldehydes and ketones to give pyrrolones 3c (Scheme 1b).
Figure 1. Bisindole natural products with pyrrolone motives.
an inducer of apoptosis for cell-basedassays.13 Inaddition,
violacein displays a wide array of biological activities,
including antibacterial, antifungal, antileukemic, antipar-
asitic, and antiviral properties.12
Scheme 1. Tandem RCM/Isomerization Reaction Sequences
We initiated our efforts toward the development of a
tandem RCM/isomerization/nucleophilic addition se-
quence (3a f 3b) by investigating all relevant reaction
parameters, i.e., temperature, catalyst, and solvent (see
Table 1 for selected results). The Grubbs second-generation
catalyst gave full conversion of both the diene 4a and
the intermediate RCM product 4b to the tandem product
5a at temperatures above 65 °C (entries 6À8), whereas no
formation of tandem product was detected below 65 °C.
Experiments at room temperature indicated that the RCM
proceeded faster in THF and toluene (entries 2 and 3) than
in CH2Cl2 (entry 1). In the search for the mildest possible
reactionconditions, weconducteda catalystscreeninTHF
at 65 °C (entries 9À12), which revealed the o-tolyl-Hovey-
daÀGrubbs second-generation catalyst as most efficient.
Next, the substrate scope of the reaction was explored
with a range of dienes and nucleophiles (Table 2). In
general, good yields were obtained with electron-rich
indoles as nucleophiles (entries 1À10). In the reaction with
indole-5-boronic acid, the deboronated product 5a was
also observed, indicating the loss of boric acid (entry 11).
In reactions with electron-deficient indoles (entries
12À16), the intermediate RCM product 3d was typically
completely consumed before the indole was fully con-
verted. This indicated a side reaction of 3d, and various
dimers thereof were identified in the reaction mixture. The
yields of the desired tandem products 5lÀp were increased
by the addition of TFA to the reaction mixture upon
completion of the RCM, which presumably facilitated
the formation of the N-acyliminium ion 3g.
The pyrrolone and pyrrolidinone motives are well-
known and widespread cores in biologically active mole-
cules (Figure 1).
Much focus has recently been directed toward natural
pigments for use in food and healthcare products, and one
relevant compound is the bacterial pigment violacein (1),12
which would be directly accessible from this synthetic
scheme. Violacein belongs to the bisindole class of natural
compounds, which are biosynthesized from two molecules
of L-tryptophan. Other members of this class comprise the
topoisomerase inhibitor rebeccamycin 1a and the kinase
inhibitor staurosporine 1b, the latter being widely used as
Besides indoles, other nucleophiles, namely an alcohol
and an electron-rich benzene, were employed in the tan-
dem reaction, and these also benefitted from the addition
of TFA (entries 17 and 18).
The importance of the electronic nature of the R group
in diene 3a became evident in the case where R = Boc
(entry 5). The RCM proceeded smoothly, but no forma-
tion of the tandem product was observed until the addition
(11) Xie, Y.; Zhao, Y.; Qian, B.; Yang, L.; Xia, C.; Huang, H. Angew.
Chem., Int. Ed. 2011, 50, 5682.
ꢀ
(12) Duran, M.; Ponezi, A. N.; Faljoni-Alario, A.; Teixeira, M. F. S.;
ꢀ
Justo, G. Z.; Duran, N. Med. Chem. Res. 2012, 21, 1524.
(13) Ryan, K. S.; Drennan, C. L. Chem. Biol. 2009, 16, 351.
Org. Lett., Vol. XX, No. XX, XXXX
B

Table 1. Solvent and Catalyst Optimization for a Tandem
RCM/Isomerization/Nucleophilic Addition Sequence (Selected
Results)
Table 2. Substrate Scope of a Tandem RCM/Isomerization/
Nucleophilic Addition Sequence
4a:4b:5aa
entry
catalyst
solvent temp (°C)
2 h
21 h
1
2
3
4
5
6
7
8
9
Grubbs 2nd
Grubbs 2nd
Grubbs 2nd
Grubbs 2nd
Grubbs 2nd
Grubbs 2nd
Grubbs 2nd
Grubbs 2nd
Grubbs 1st
CH2Cl2
THF
rt
rt
67:33:0 49:51:0
0:100:0 0:100:0
35:65:0 0:100:0
52:48:0 41:59:0
0:100:0 0:100:0
0:100:0 0:0:100
0:23:77 0:0:100
0:7:93 0:0:100
62:38:0 42:11:47
40:35:25 9:1:90
0:100:0 0:35:65
0:35:65 0:0:100
toluene
m-xylene
CH2Cl2
THF
rt
rt
40
65
110
139
65
65
65
65
toluene
m-xylene
THF
10 HoveydaÀGrubbs 1st
11 HoveydaÀGrubbs 2nd
THF
THF
12
(o-tolyl)-HoveydaÀ
THF
Grubbs 2nd
a As determined by RP-HPLC at 215 nm.
of TFA ensured Boc-deprotection. This indicated a de-
creasing tendency to form the N-acyliminium ion 3g when
the R group on the diene was electron-withdrawing.
Previous experiments suggested to us that isomeriza-
tion of the double bond to the N-acyliminium inter-
mediate 3g did not proceed via a ruthenium hydride
mechanism10a,11 but rather through a favorable tauto-
merization. We envisioned that if the double bond in 3d
did in fact undergo isomerization via tautomer 3e
(Scheme 1b) it should be feasible to trap this intermedi-
ate with an electrophile, e.g., in aldol reactions. Grat-
ifyingly, the reaction indeed proceeded in tandem
with RCM from dienes 6 in the presence of Grubbs
second-generation catalyst and various carbonyl elec-
trophiles. A cleaner and faster tandem RCM/tautomer-
ization/aldol condensation sequence was generally
observed when a mild Lewis acid, such as B(OH)3,
was used as co-catalyst, presumably to facilitate the
tautomerization.
We briefly looked into the substrate scope for the
tandem sequence by employing different dienes 6 and
electrophiles (aldehydes and ketones) to give pyrrolone
tandem products 7aÀe (Table 3). Given that a significant
number of distinct synthetic transformations (ring-closing
metathesis, tautomerization, and aldol condensation) oc-
cur, the isolated yields of the rapidly degrading tandem
products 7aÀe were satisfactory. With a set of new syn-
thetic methodologies at hand, we turned our attention to
the total synthesis of violacein (1) (Scheme 2).
a All indoles reacted via the 3-position. b Isolated yield after flash
column chromatography. Detailed reaction conditions are provided in
the Supporting Information. c Grubbs 2nd generation was used in
combination with B(OH)3 (1 equiv). d TFA (11 equiv) was added upon
completion of the RCM reaction to yield the Boc-deprotected tandem
product. e Grubbs 2nd generation was used, and TFA (1 equiv) was
added upon completion of the RCM reaction. f TFA (1 equiv) was added
upon completion of the RCM reaction.
In the first step, we used the tandem RCM/isomeriza-
tion/nucleophilic addition sequence to construct the pyr-
rolidinone core of violacein. The double bond was
reintroduced in the tandem product 9 by way of phenylse-
lenation, H2O2 oxidation and elimination of the selenide,14
thereby setting the stage for attachment of the oxindole
moiety via a Ti-catalyzed tautomerization/aldol condensa-
tion with isatin. In this case, where the pyrrolone substrate
10 had a substituent in the 5-position, the yield of the
reaction sequence was 88% as compared to 17% isolated
yield of product 13 from the unsubstituted pyrrolone
substrate 12 (Scheme 3).
The total synthesis was completed by deprotection of 11
with TFA to provide violacein (1) in 49% isolated yield
(14) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975,
97, 5434.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Tandem RCM/Tautomerization/Aldol Condensation
Scheme 2. Synthesis of Violacein via a Tandem RCM/Isomer-
ization/Nucleophilic Addition Sequence
a Isolated yield after flash column chromatography. Detailed reac-
tion conditions are provided in the Supporting Information.
(>80% purity) upon crystallization.15 The final product
was extremely difficult to handle, primarily due to unfa-
vorable solubility properties in most common solvents and
LC/MS analysis indicated that the crude yield was sig-
nificantly higher than the isolated yield.
Scheme 3. Titanium-Catalyzed Tautomerization/Aldol Con-
densation of Pyrrolone 12 and Isatin
In conclusion, we have developed a new tandem RCM/
isomerization/nucleophilic addition sequence which pro-
vides access to 5-substituted 2-pyrrolidinones in a single
step from N-allylacrylamides. Furthermore, we found that
3-substituted 2-pyrrolones can be synthesized using similar
tandem reactions from the same substrates, indicating that
the isomerization step proceeds through a synthetically
versatile tautomer intermediate. The utility of the tandem
RCM/isomerization/nucleophilic addition sequence was
further illustrated by a total synthesis of the natural
product violacein.
acknowledged for financial support. We thank Professor
David Tanner and Dr. Erhad Ascic (Technical University
of Denmark) for valuable discussions and Associate Pro-
fessor Charlotte H. Gotfredsen (Technical University of
Denmark) for assistance with recording and assigning
NMR spectra.
Acknowledgment. The DSF Center for Antimicrobial
Research, Holm Foundation, Danish Council for Inde-
pendent Research (Technology and Production Sciences),
and the Technical University of Denmark are gratefully
Supporting Information Available. Comprehensive
data from optimization of tandem RCM/isomerization/
nucleophilic addition, experimental procedures, and
compound characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(15) For previous total syntheses of violacein, see: (a) Ballantine,
J. A.; Beer, R. J. S.; Crutchley, D. J.; Dodd, G. M.; Palmer, D. R.
J. Chem. Soc. 1960, 2292. (b) Wille, G.; Steglich, W. Synthesis 2001, 5, 759.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX