A strategy for the total synthesis of dragmacidin E. construction of the core ring system

Article abstract of DOI:10.1021/ol0617547

(Chemical Equation Presented) The construction of the dragmacidin core ring system by a route that features the application of a new indole annelation reaction sequence is described.

Full text of DOI:10.1021/ol0617547

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4775-4778
A Strategy for the Total Synthesis of
Dragmacidin E. Construction of the
Core Ring System
Raymond J. Huntley and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
rlf@chem.psu.edu
Received July 17, 2006
ABSTRACT
The construction of the dragmacidin core ring system by a route that features the application of a new indole annelation reaction sequence
is described.
Dragmacidins D, E, and F are an intriguing collection of
bisindole alkaloids isolated from marine sponges.1 They are
structurally more complex than the dragmacidin A, B, and
C congeners2 that lack the guanidinium functionality and
possess a piperazine linker instead of a pyrazinone between
the two indole moieties (Figure 1). It has been suggested
that dragmacidin D is the biosynthetic precursor to both
dragmacidins E and F via bond formation between C(5′′′)
and C(5)1a or C(4′′′) and C(6′′)1b, respectively. Moreover,
dragmacidins D and E displayed antibiotic activity against
E. coli (MIC ) 9 and 12 µM, respectively) and C. albicus
(MIC ) 11 and 20 µM, respectively). In addition, dragma-
cidins D and E have been reported to be potent inhibitors of
serine-threonine protein phosphatases,1a biological targets
of potential therapeutic value.3 However, in a subsequent
review,3 the protein phosphatase (PP1 and PP2a) inhibitory
activity was claimed to be quite low, although no experi-
mental evidence was provided. The promising biological
activity coupled with the challenging architecture of these
natural products has stimulated effort directed toward their
total synthesis.4 The Stoltz group is the front runner in this
endeavor and has reported the first and only syntheses of
dragmacidins D and F.4f-h The Feldman group has recently
disclosed an approach to dragmacidin E that features the
early, stereoselective construction of the cycloheptannelated
indole substructure.4i
We became interested in the synthesis of dragmacidin E
following the development of a method in our laboratories
(3) McCluskey, A.; Sim, A. T. R.; Sakoff, J. A. J. Med. Chem. 2002,
45, 1151.
(4) (a) Jiang, B.; Gu, X.-H. Bioorg. Med. Chem. 2000, 8, 363. (b) Jiang,
B.; Gu, X.-H. Heterocycles 2000, 53, 1559. (c) Yang, C.-G.; Wang, J.;
Jiang, B. Tetrahedron Lett. 2002, 43, 1063. (d) Miyake, F. Y.; Yakushijin,
K.; Horne, D. A. Org. Lett. 2002, 4, 941. (e) Yang, C.-G.; Liu, G.; Jiang,
B. J. Org. Chem. 2002, 67, 9392. (f) Garg, N. K.; Sarpong, R.; Stoltz, B.
M. J. Am. Chem. Soc. 2002, 124, 13179. (g) Garg, N. K.; Caspi, D. D.;
Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 9552. (h) Garg, N. K.; Caspi,
D. D.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5970. (i) Feldman, K.
S.; Ngernmeesri, P. Org. Lett. 2005, 7, 5449.
(1) (a) Capon, R. J.; Rooney, F.; Murray, L. M.; Collins, E.; Sim, A. T.
R.; Rostas, J. A. P.; Butler, M. S.; Carroll, A. R. J. Nat. Prod. 1998, 61,
660. (b) Cutignano, A.; Bifulco, G.; Bruno, I.; Casapullo, A.; Fomez-Paloma,
L.; Riccio, R. Tetrahedron 2000, 56, 3743.
(2) (a) Kohmoto, S.; Kashman, Y.; McConnell, O. J.; Rinehart, K. L.,
Jr.; Wright, A.; Koehn, F. J. Org. Chem. 1988, 53, 3116. (b) Morris, S. A.;
Andersen, R. J. Tetrahedron 1990, 46, 715. (c) Fahy, E.; Potts, B. C. M.;
Faulkner, D. J.; Smith, K. J. Nat. Prod. 1991, 54, 564.
10.1021/ol0617547 CCC: $33.50
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Scheme 2. Thus, we planned to introduce the potentially
problematic guanidine functionality at the end of the
synthesis via the DuBois rhodium-mediated intramolecular
C-H amination reaction of the N-trichloroethoxysulfonyl
guanidine 8.7 In the key disconnection, the indole 8 could
Scheme 2
Figure 1. Selected members of the dragmacidin family of natural
products.
that is especially useful for constructing indoles that are
bridged at the C(3) and C(4) positions (Scheme 1).5 For
example, we discovered that the Stille coupling reaction of
2-iodoenone 1 with the stannane 2 gave a trienecarbamate 3
that underwent a smooth 6π-electrocyclic ring closure to
cyclohexadiene 4 and oxidation in the same pot with DDQ
to afford the protected aniline 5. Removal of the Boc group
with TFA was uneventful, and a reductive amination of the
resultant aniline with glyoxylic acid provided acid 6.
be elaborated from the 2-iodoenone 9 and stannane 10 by
the previously discussed reaction sequence. A number of
schemes for the preparation of the cycloheptenone 9 could
be envisaged, one of which involves an intramolecular Heck
reaction of the halopyrazine 11. It seemed likely that the
haloindole substituent would tolerate this transformation
based on the well-precedented superior reactivity of pyrazinyl
halides toward oxidative addition.4e-h Finally, the pyrazine
11 could be assembled by addition of the appropriate
metalated pyrazine8 to the readily available, optically pure
aldehyde 12.9
Scheme 1
To quickly validate this synthesis plan, we elected to
initially prepare the core ring system without the methyl,
bromo, and guanidine functionalities, and accordingly, the
preparation of 2-iodoenone 20 (Scheme 3) became our
(6) To the best of our knowledge, only two indoles had been synthesized
from aryl ketones/aldehydes by this type of cyclization, prior to our own
work. Indole: (a) Gluud, W. Ber. Dtsch. Chem. Ges. 1915, 48, 421. (b)
Tighineanu, E.; Chiraleu, F.; Råileanu, D. Tetrahedron 1980, 36, 1385.
5-Methoxyindole: Blaikie, K. G.; Perkin, W. H., Jr. J. Chem Soc., Trans.
1924, 125, 296. We thank a referee for pointing out the latter example.
(7) Kim, M.; Mulcahy, J. V.; Espino, C. G.; DuBois, J. Org Lett. 2006,
8, 1073.
(8) (a) Turck, A.; Trohay, D.; Mojovic, L.; Ple´, N.; Que´guiner, G. J.
Organomet. Chem. 1991, 412, 301. (b) Turck, A.; Ple´, N.; Dognon, D.;
Harmoy, C.; Que´guiner, G. J. J. Heterocycl. Chem. 1994, 31, 1449. (c)
Toudic, F.; Turck, A.; Ple´, N.; Que´guiner, G. J.; Darabantu, M.; Lequeux,
T.; Pommelet, J. C. J. Heterocycl. Chem. 2003, 40, 855.
Completion of the indole annelation sequence was ac-
complished by heating acid 6 in acetic anhydride, which
effected cyclization to the N-acetylindole 7, presumably via
a mu¨nchnone intermediate.6
A retrosynthetic analysis for the synthesis of dragmacidin
E that takes advantage of this methodology is outlined in
(5) (a) Greshock, T. J.; Funk, R. L. J. Am. Chem. Soc. 2006, 128, 4946.
(b) Greshock, T. J.; Funk, R. L. Org. Lett. 2006, 8, 2643.
(9) Hori, K.; Hikage, N.; Inagaki, A.; Mori, S.; Nomura, K.; Yoshii, E.
J. Org. Chem. 1992, 57, 2888.
4776
Org. Lett., Vol. 8, No. 21, 2006

immediate goal. To that end, the easily accessible pyrazine
144f was metalated by employing a procedure used for related
halopyrazines8 and added to 5-hexenal to afford an alcohol
Scheme 4
Scheme 3
enecarbamate 13. Regioselective Vilsmeier-Haack formy-
lation of enecarbamate 1314 gave the vinylogous imide 23
that was converted to diene 24 using standard Wittig
olefination conditions. Finally, metalation of the dienecar-
bamate 24 with butyllithium followed by stannylation of the
resulting vinyl anion gave the desired stannane 10.
Scheme 5
that was transformed to the TIPS ether 15. Previous studies
had shown that the chemoselective coupling of dihalopyra-
zines similar to 15 with indoloboronic acids analogous to
stannane 16 proceeds cleanly.4e-h Our case was no exception,
affording the fully substituted pyrazine 17 in good yield,
under Stille coupling conditions developed by Corey.10
We were pleased to discover that the bromopyrazine 17
underwent a smooth cyclization to the cycloheptannelated
pyrazine 18 upon subjection to standard Heck reaction
conditions. Oxidative cleavage of the alkene moiety of
pyrazine 18 followed by dehydrogenation of the resulting
ketone following the Saegusa protocol afforded cyclohep-
tenone 19 that was converted to the initial target, 2-iodoenone
20, via treatment with iodine in pyridine.11
We now turned our attention to the preparation of the
dienylstannane 10 required for the indole annelation (Scheme
4). The known acid 2112 was converted to the oxazoline 13
following a route that had previously been reported for the
analogous 2-tert-butyl oxazolidine.13 Thus, oxidative decar-
boxylation of acid 21 with lead tetraacetate gave oxazolidine
22, which was subjected to ammonium bromide in order to
promote the elimination of acetic acid and thereby furnish
(10) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121,
7600.
(11) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Sennayake, C. B. W.;
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett. 1992, 33, 917.
(12) Chambers, D. J.; Evans, G. R.; Fairbanks, A. J. Tetrahedron:
Asymmetry 2005, 15, 45.
The stage was now set for the execution of the indole
annelation reaction sequence (Scheme 5). The Stille coupling
Org. Lett., Vol. 8, No. 21, 2006
4777

of the 2-iodoenone 20 with dienylstannane 10 proceeded
smoothly to provide the trienecarbamate 25. Heating trien-
ecarbamate 25 in toluene promoted an electrocyclic closure
that could be monitored by TLC. When the transformation
to the corresponding cyclohexadiene was judged to be
complete (2 h), the temperature was lowered (rt) and 2 equiv
of DDQ was added to effect aromatization to the benzox-
azolidine 26. Although we were able to successfully remove
the Boc protecting group from carbamate 26, all attempts to
subsequently append the acetic acid side chain to the resulting
benzoxazoline via reductive amination or alkylation protocols
failed. Accordingly, both the Boc group and N,O-acetal were
removed to afford a hydroxy aniline whose hydroxyl
functionality was converted to the benzyl ether 27. Alkylation
of the aniline 27 with methyl iodoacetate provided the methyl
ester (62%; aniline 27 was also recovered, 28%), which
underwent saponification to give the desired anilinoacetic
acid 28. Acid 28 was then converted to the bisindole 29 using
our standard conditions for ring closure.
In conclusion, we have prepared the core ring system of
dragmacidin E by a route that features our 6π-electrocyclic
ring-closure-based method for the construction of complexly
substituted indoles. The incorporation of additional func-
tionality that will permit the completion of the total synthesis
is now warranted and will be reported in due course.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM28663).
(13) (a) Renaud, P.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1986,
25, 843. (b) Seebach, D.; Stucky, G. Angew. Chem., Int. Ed. Engl. 1988,
27, 1351. (c) Lamatsch, B.; Seebach, D. HelV. Chim. Acta 1992, 75, 1095.
(d) Ghosez, L.; Yang, G.; Cagnon, J. R.; Bideau, F. L.; Marchand-Brynaert,
J. Tetrahedron 2004, 60, 7591.
(14) Seebach has shown that oxazolidines of this type prefer to undergo
electrophilic addition at C(5), presumably due to the greater stability of an
N-acyliminium ion vis-a`-vis an oxonium generated by attack at C(4); see
refs 13b and 13c.
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0617547
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