Total synthesis of (±)-dragmacidin e

Article abstract of DOI:10.1021/ol202535f

The bis indole sponge alkaloid dragmacidin E was synthesized in racemic form over 25 steps starting from 7-benzhydroxyindole. Key steps include (a) a Witkop cyclization to facilitate construction of the indole-spanning seven-membered ring and (b) a cyclod

Full text of DOI:10.1021/ol202535f

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5704–5707
Total Synthesis of (()-Dragmacidin E
Ken S. Feldman*,† and Paiboon Ngernmeesri‡
Chemistry Department, The Pennsylvania State University, University Park,
Pennsylvania 16802, United States, and Chemistry Department, Kasetsart University,
Bangkok, Thailand 10900
ksf@chem.psu.edu
Received September 19, 2011
ABSTRACT
The bis indole sponge alkaloid dragmacidin E was synthesized in racemic form over 25 steps starting from 7-benzhydroxyindole. Key steps
include (a) a Witkop cyclization to facilitate construction of the indole-spanning seven-membered ring and (b) a cyclodehydrative pyrazinone
synthesis that unites the two indole-containing sectors.
The bis indole alkaloid dragmacidin E (1) along with its
congener dragmacidin D was isolated from a Spongosortes
sp. collected in Australian waters (Figure 1).1 Both of these
species are described as exhibiting potent serine-threonine
protein phosphatase inhibitory activity. The challenges
inherent in the unique molecular architecture of 1 and
related species dragmacidins D and F have fueled much
synthesis effort,2,3 culminating in total syntheses of drag-
macidins D and F by Stoltz and colleagues.2 Our own
efforts have focused on dragmacidin E and, in particular,
the assembly of the cycloheptannelated indole core via
application of diradical cyclization chemistry to forge the
key C(400)ꢀC(6000) bond.4 Additionally, successful prepara-
tionof 1 willhavetoutilize chemistry that isnot derailedby
(1) severe steric congestion along the upper rim of the
cycloheptanoid unit, (2) ring strain resulting from installa-
tion of five contiguous sp2 carbons in a seven-membered
ring, and (3) the sensitive guanidine unit. Preliminary
studies that probed these issues resulted in the preparation
of the model system 2, lacking both the C(700) hydroxyl and
the C(60) bromide.4b In this report, the application and
extension of this chemistry to the total synthesis of the
intact (()-dragmacidin E target is described. The key
transformative step involves Witkop cyclization5 of a
tryptophan derivative to deliver the C(300)ꢀC(400) bridged
indole core of the target.
† The Pennsylvania State University.
‡ Kasetsart University.
(1) Capon, R. J.; Rooney, F.; Murray, L. M.; Collins, E.; Sim,
A. T. R.; Rostas, J. A. P.; Butler, M. S.; Carrol, A. R. J. Nat. Prod.
1998, 61, 660–662.
(2) (a) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc.
2002, 124, 13179–13184. (b) Garg, N. K.; Caspi, D. D.; Stoltz, B. M.
J. Am. Chem. Soc. 2004, 126, 9552–9553. (c) Garg, N. K.; Caspi, D. D.;
Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970–5978. (d) Garg, N. K.;
Stoltz, B. M. J. Chem. Soc., Chem. Commun. 2006, 3769–3779. (e) Garg,
N. K.; Caspi, D. D.; Stoltz, B. M. Synlett 2006, 3081–3087.
(3) (a) Huntley, R. J.; Funk, R. L. Org. Lett. 2006, 8, 4775–4778. (b)
Huntley, R. J. Ph.D. Thesis, Pennsylvania State University, 2008.
(4) (a) Feldman, K. S.; Ngernmeesri, P. Org. Lett. 2005, 7, 5449–
5452. (b) Feldman, K. S.; Ngernmeesri, P. Org. Lett. 2010, 12, 4502–
4505.
Figure 1. Dragmacidin E (1) and a simpler model compound 2.
r
10.1021/ol202535f
Published on Web 09/29/2011
2011 American Chemical Society

The synthesis plan commenced with preparation of the
Witkop cyclization precursor 6 from the known 7-diphe-
nylmethyl ether of indole, 3, itself available via Bartoli
indole synthesis in two steps,6 Scheme 1. Installation of the
tryptophan side chain proceeded via initial formylation of
3 at C(3) and then EmmonsꢀHorner alkene extension
with the anion of methyl (2,2-dichloropropionylamino)-
(dimethylphosphoryl)acetate to furnish the (Z)-dehydro-
tryptophan derivative 5. Exposure of 5 to catalytic
Wilkinson’s catalyst and high pressure hydrogen gas
served to both saturate the side chain and cleave the
diphenylmethyl ether function at C(700) to deliver the
Witkop substrate 6 following deprotection of the indole
nitrogen.
yielding Witkop cyclizations reported to date.8 The
Witkop cyclization has been subject to numerous
mechanistic studies7 and has been utilized as a pivotal
step in many total syntheses of cognate indole alkaloids.8
Application of the consensus Witkop mechanistic
paradigm to the chemistry of 6 is detailed below. This
speculation features two consecutive photochemically
mediated electron transfers that labilize both CꢀCl
bonds for further chemistry. In the first sequence, chloride
loss promotes diradical 8 generation, and regioselective
closure within 8 then constitutes the key CꢀC bond
forming step of this Witkop cyclization. A subsequent
photoelectron transfer within 9 provides a low-energy
pathway for Clꢀ, and then Hþ, loss to deliver the enone
product 13, although it is not unreasonable to imagine that
HCl loss may proceed from 9 without intervention of
excited state chemistry.
Scheme 1. Synthesis of the Witkop Cyclization Precursor
Scheme 2. Witkop Cyclization of 6, with Mechanistic Speculation
The key Witkop cyclization proceeded smoothly
upon irradiation of dilute solutions of 6 in acetonitrile
in a quartz vessel with 254 nm light, Scheme 2. The
isolated product, 13, represents one of the highest
(5) Yonemitsu, O.; Cerutti, P.; Witkop, B. J. Am. Chem. Soc. 1966,
88, 3941–3945.
(6) Dobson, D.; Todd, A.; Gilmore, J. Synth. Commun. 1991, 21,
611–617.
(7) (a) McCall, M. T.; Hammond, G. S.; Yonemitsu, O.; Witkop, B.
J. Am. Chem. Soc. 1970, 92, 6991–6993. (b) Naruto, S.; Yonemitsu, O.
Tetrahedron Lett. 1975, 16, 3399–3402. (c) Hamada, T.; Ohmori, M.;
Yonemitsu, O. Tetrahedron Lett. 1977, 18, 1519–1522. (d) Naruto, S.;
Yonemitsu, O. Chem. Pharm. Bull. 1980, 28, 900–909.
Conversion of the eight-membered bridging lactam
into a cycloheptanoid structure constituted the next
synthesis objective, Scheme 3. This formal one-atom
ring contraction could be effected by initial conjugate
addition of hydride to the enone unit, which promoted
a Dieckmann cyclization of the first-formed enolate 14.
The strained tetracyclic product 15 was readily hydro-
lyzed to deliver the desired cycloheptane-bridged in-
dole substructure of dragmacidin E, 16. Tricycle 16 was
formed as an inconsequential mixture of stereoisomers
at C(6000); both diastereomers later converged to the
same product.
(8) (a) Kobayashi, T.; Spande, T. F.; Aoyagi, H.; Witkop, B. J. Org.
Chem. 1969, 12, 636–638. (b) Anderson, N. G.; Lawton, R. G. Tetra-
hedron Lett. 1977, 1843–1846. (c) Bosch, J.; Amat, M.; Sanfeliu, E.;
Miranda, M. A. Tetrahedron 1985, 41, 2557–2566. (d) Klohr, S. E.;
Cassady, J. M. Synth. Commun. 1988, 18, 671–674. (e) Beck, A. L.;
Mascal, M.; Moody, C. J.; Slawin, A. M. Z.; Williams, D. J.; Coates,
W. J. J. Chem. Soc., Perkin Trans. 1 1992, 797–811. (f) Beck, A. L.;
Mascal, M.; Moody, C. J.; Coates, W. J. J. Chem. Soc., Perkin Trans. 1
1992, 813–822. (g) Mascal, M.; Moody, C. J.; Slawin, A. M. Z.; Williams,
D. J. J. Chem. Soc., Perkin Trans. 1 1992, 823–830. (h) Nagata, R.; Endo,
Y.; Shudo, K. Chem. Pharm. Bull. 1993, 41, 369–372. (i) Mascal, M.;
Moody, C. J.; Morrell, A. I.; Slawin, A. M. Z.; Williams, D. J. J. Am.
Chem. Soc. 1993, 115, 813–814. (j) Mascal, M.; Wood, I. G.; Begley,
M. J.; Batsanov, A. S.; Walsgrove, T.; Slawin, A. M. Z.; Williams, D. J.;
Drake, A. F.; Siligardi, G. J. Chem. Soc., Perkin Trans. 1 1996, 2427–
2433. (k) Bennasar, M.-L.; Zulaica, E.; Ramirez, A.; Bosch, J. Hetero-
cycles 1996, 43, 1959–1966. (l) Ruchkina, E. L.; Blake, A. J.; Mascal, M.
Tetrahedron Lett. 1999, 40, 8443–8445. (m) Bremner, J. B.; Russell,
H. F.; Skelton, B. W.; White, A. H. Heterocycles 2000, 53, 277–296. (n)
Mascal, M.; Modes, K. V.; Durmus, A. Angew. Chem., Int. Ed. 2011, 50,
4445–4446. (o) Qin, H.; Xu, Z.; Cui, Y.; Jia, Y. Angew. Chem., Int. Ed.
2011, 50, 4447–4449.
Conversion of the C(5000) carbonyl into the spiroimida-
zolone unit with correct relative stereochemistry defined
the next task, Scheme 4. Functionalizing this ketone
proved quite challenging, and curiously, related difficulties
Org. Lett., Vol. 13, No. 20, 2011
5705

Scheme 3. Synthesis of the Cycloheptannelated Indole Core
Scheme 4. Installation of the Spiro 2-Imidazolone; Structural
Determination by X-ray Analysis
did not plague the similar des-C(700)-oxy model system
preceding 2; the long-range reactivity-altering effects of
the C(700) OBn unit on the chemistry of the C(5000)
carbonyl were not anticipated. Through much trial-
and-error, an effective and reproducible Strecker re-
action-based experimental procedure utilizing metha-
nolic ammonia at elevated temperature (75 °C) in a
sealed tube, followed by rapid TMSCN addition to the
crude reaction mixture, was developed. Diastereo-
meric cyanoamines 17a and 17b were formed in an
∼5:1 ratio favoring the desired isomer 17a; in the
model system preceding 2, only the desired diastereo-
mer was produced. Epimerization at C(6000) during the
reaction ensured that only the most thermodynami-
cally favorable cis methyl/NHBOC stereochemical
arrangement emerged from these Strecker reaction
conditions. Diastereomers 17a and 17b could be sepa-
rated by chromatography, and the free amine of major
isomer 17a was immediately protected as its methyl
carbamate. Without this protection, attempted trans-
formations on 17a/17b tended to promote retro-
Strecker reaction and deliver either an imine of 16 or
16 itself following imine hydrolysis. This methyl car-
bamate was subjected to the nitrile reduction condi-
tions of Satoh.9 The crude amino carbamate product
was cyclized to furnish the imidazolone unit within
18 under base mediation, which removed the indole
N-BOC group as well. The relative stereochemistry of 18
was established by single crystal X-ray analysis, as indicated
in Scheme 4.10 Functionalization of 18 at C(6) was required
to install the pyrazinone ring of dragmacidin E, and that
operation was accomplished by DDQ-mediated oxidation
of this indolic position. Subsequent reduction of the C(6)
carbonyl to a pair of labile alcohols, and then conver-
sion of those alcohols to the diastereomeric azides 20,
proceeded through standard transformations. The rela-
tive stereochemistry at C(6) was not germane to the
synthesis effort.
Coupling the tetracyclic indole core unit 20 with the
second indole component, in the form of acid chloride
21,11 was preceded by azide reduction to the primary
amines, Scheme 5. The product amide 22 was formed
as an ∼2:1 mixture of diastereomers at C(6); both
species were useful. Pyrazinone formation proceeded
through a two-stage protocol involving first cycliza-
tion of the primary amine liberated by TFA-mediated
deprotection of the C(5) NHBOC moiety with the
indolic ketone of 22 to give a dihydropyrazinone
product. This pale yellow species immediately was
subjected to DDQ-based oxidation to deliver the
stable pyrazinone-containing product 23 as a bright
yellow solid.
Completion of the dragmacidin E synthesis required
successful execution of two transformations: (1) conver-
sion of the spiroimidazolone’s urea unit into a guanidine,
and (2) removal of the C(7000) benzyl protecting group.
A priori, it was not clear which maneuver should be
approached first. As it turned out, initial work on the
imidazolone unit proved satisfactory, Scheme 6. O-Methy-
lation of the nucleophilic carbonyl oxygen within the urea
appeared to be slightly more facile than methylation at
other potentially nucleophilic sites in 23, and so moderate
yields of the 2-methoxyamidine analogue of 23 could be
isolated under carefully controlled reaction conditions.
(9) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Tetrahedron
Lett. 1969, 10, 4555–4588.
(10) Cambridge Crystallographic Data Centre deposition number
for 18: CCDC 826169. The data can be obtained free from Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_
request/cif.
(11) Guinchard, X.; Vallee, Y.; Denis, J.-N. J. Org. Chem. 2007, 72,
3972–3975.
5706
Org. Lett., Vol. 13, No. 20, 2011

Scheme 5. Merging the Two Indole Cores; Synthesis of the
Pyrazinone 23
Scheme 6. Completion of Dragmacidin E Synthesis via
Guanidine Introduction
Acknowledgment. We thank the National Institutes of
Health, General Medical Sciences (GM 72572) for finan-
cial support of this work; the X-ray facility is supported by
NSF CHE 0131112. In addition, we thank Dr. R. Capon
(Institute for Molecular Bioscience, The University of
Queensland, St. Lucia, QLD 4072, Australia) for provid-
1
ing copies of the H and 13C NMR spectra of authentic
Replacement of the MeO function with NH2 was accomp-
lished by heating a methanolic solution of this 2-methox-
yamidine with ammonia in a sealed tube, and the sensitive
guanidine-containing product was subjected to the benzyl
ether deprotection conditions reported by Stoltz in his
dragmacidin D synthesis2a to give, following SiO2 chro-
matography, (()-dragmacidin E (1) in modest yield. The
final structural identity of synthetic 1 was derived from a
dragmacidin E in CD3OD and Andrew Piggott (The
University of Queensland) for conducting the HPLC-
based and UV-based comparisons of 1 with authentic
dragmacidin E.
Supporting Information Available. General experi-
mental and detailed experimental descriptions along
with copies of 1H and 13C NMR spectra for 4ꢀ6,
13, 15ꢀ23, and 1; X-ray data for 18; HPLC and UV
traces of synthetic and authentic dragmacidin E. This
material is available free of charge via the Internet
at http://pubs.acs.org.
1
comparison of the H and 13C NMR spectral data with
those described by Capon and by coinjection HPLC with
an authentic sample of natural dragmacidin E (see Sup-
porting Information for details).
Org. Lett., Vol. 13, No. 20, 2011
5707