The total synthesis of (+)-dragmacidin F

Article abstract of DOI:10.1021/ja046695b

The first total synthesis of (+)-dragmacidin F has been accomplished, establishing the absolute configuration of this biologically important, antiviral marine alkaloid. The convergent route described features a palladium-mediated oxidative pyrrole carbocy

Full text of DOI:10.1021/ja046695b

Published on Web 07/20/2004
The Total Synthesis of (+)-Dragmacidin F
Neil K. Garg, Daniel D. Caspi, and Brian M. Stoltz*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received June 4, 2004; E-mail: stoltz@caltech.edu
Scheme 2
The dragmacidins represent a small but growing family of marine
alkaloids that possess a variety of interesting structural and
biological features.1 These novel alkaloids have attracted consider-
able attention from the synthetic community over the past decade.2
Our interest in the dragmacidins was piqued by the structurally
complex, pyrazinone-containing members, dragmacidins D, E, and
F (Scheme 1, 1-3).1 We recently completed the first and, to date,
only total synthesis of any of these three unique alkaloids with our
preparation of (()-dragmacidin D (1).3 In this communication, we
detail the enantiospecific total synthesis of (+)-dragmacidin F (3),
which features a palladium-mediated intramolecular oxidative
carbocyclization, a halogen-selective Suzuki cross-coupling reaction,
could then arise via a halogen-selective Suzuki coupling sequence
and a high-yielding late-stage Neber rearrangement.
(Scheme 1, 3 w 4 + 5 + 6). While 5 and 6 were readily available
Dragmacidin F (3) is an antiviral bromoindole alkaloid isolated
from our established routes,3 boronic ester 4 could originate from
from the ethanol extracts of the Mediterranean sponge Halicortex
pyrrole-appended bicycle 7, the key retrosynthetic intermediate. In
sp. and exhibits in vitro activity against HSV-1 (EC50 ) 95.8 µM)
conjunction with our research program focused on palladium(II)-
and HIV-1 (EC50 ) 0.91 µM).1c This structurally interesting natural
product poses a variety of synthetic challenges, namely, the
differentially substituted pyrazinone, the bridged [3.3.1] bicyclic
ring system, which is fused to both the trisubstituted pyrrole and
catalyzed dehydrogenation reactions,4 bicycle 7 was further discon-
nected to acyl pyrrole 8 by applying a heteroarene/olefin oxidative
C-C coupling transform. This key step could serve to illustrate
some of the methodology developed in these laboratories in the
aminoimidazole heterocycles, and the installation and maintenance
context of a complex total synthesis.4c The desired cyclization
of the 6-bromoindole fragment.
substrate (8) could be derived from commercially available (-)-
Scheme 1
quinic acid (9).
Our synthesis commenced with bicyclic lactone 10, a compound
available by known lactonization and selective silylation of (-)-
quinic acid (9).5 Oxidation of bicycle 10 followed by Wittig
olefination of the resultant ketone produced exo-methylene lactone
11 in 69% overall yield (Scheme 2). Following considerable effort
to execute a homogeneous Pd-catalyzed π-allyl hydride addition
to allylic lactone 11, we discovered that an exceedingly simple and
selective reduction (11 f 12) occurs via heterogeneous catalysis.
Under our reaction conditions (0.5 mol % Pd/C, 1 atm H2, MeOH,
0 °C) essentially quantitative reductive isomerization to the desired
unsaturated carboxylic acid 12 was observed.6 With 12 now readily
available, oxidative cyclization substrate 8 was prepared via
Weinreb amide formation (12 f 13) followed by the addition of
lithiopyrrole 14. To our delight, exposure of 8 to Pd(OAc)2 under
a variety of conditions led to carbocyclization, and under optimized
conditions, produced the desired pyrrole-fused bicycle 7 as a single
stereo- and regioisomer in 74% yield (Scheme 2).7 This transforma-
tion is particularly remarkable since it results in functionalization
of the deactivated C(3) position of acyl pyrrole 8.8
With the [3.3.1] bicyclic framework in hand, we set out to
construct the full carbon skeleton of dragmacidin F (Scheme 3).
The final stereocenter present in the natural product (i.e., 3, 6′′′)
was installed via catalytic hydrogenation of olefin 7 followed by
methylation to produce 3° ether 15. To advance 15 for fragment
coupling, regioselective bromination of the pyrrole followed by
metalation to boronic ester 4 proceeded smoothly. In the critical
halogen-selective Suzuki fragment-coupling reaction, pyrroloboronic
ester 4 and dibromide 16 (prepared from 5 + 6)3 were reacted under
Pd(0) catalysis. As we observed in our total synthesis of dragma-
cidin D,3 at 50 °C, an exquisitely selective bond formation
On the basis of our total synthesis of dragmacidin D, we
recognized that the aminoimidazole would best be incorporated at
a late stage in the synthesis and that the pyrazinone subunit could
be masked as an alkoxypyrazine.3 The core of dragmacidin F (3)
9
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J. AM. CHEM. SOC. 2004, 126, 9552-9553
10.1021/ja046695b CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
and (5′′′R, 6′′′S), respectively (enantiomeric to the structures
depicted in Scheme 1).
In summary, we have completed the first total synthesis of (+)-
dragmacidin F (3), establishing the absolute configuration of this
biologically important marine alkaloid and suggesting the absolute
configuration of the related dragmacidins D and E (1 and 2). Our
efficient and enantiospecific approach (19 steps from 10) relies on
a number of key steps. Specifically, a novel catalytic reductive
isomerization of lactone 11, an oxidative heteroarene/olefin cy-
clization (8 f 7), a highly selective Suzuki coupling reaction (4+16
f 17), and an unprecedented late-stage Neber rearrangement
sequence (19 f 20)9c provide access to this interesting natural
product.
Acknowledgment. We are grateful to the NIH-NIGMS (R01
GM65961-01), DOD (NDSEG graduate fellowship to N.K.G.), and
Eli Lilly (predoctoral fellowship to D.D.C.) for generous financial
support. The Dervan lab is acknowledged for helpful discussions
and the generous use of instrumentation. We also thank Drs. R.
Riccio and A. Casapullo for an authentic sample of (-)-dragmacidin
F.
constructed the dragmacidin F framework (i.e., 17) by fusion of
the pyrrole and alkoxypyrazine subunits of 4 and 16, while leaving
the indolyl bromide of 16 and, in turn, 17 intact.
Having successfully prepared the desired carbon skeleton of
dragmacidin F, we began the final stages of the synthesis. Selective
deprotection of silyl ether 17 and oxidation with Dess-Martin
periodinane produced ketone 18 (Scheme 4). We anticipated that
the introduction of an amino group R to the ketone would allow
for eventual elaboration to the aminoimidazole moiety. To this end,
a number of transformations involving enolate or enol ether
derivatives of 18 were attempted, none of which were successful.
With limited options remaining, we became interested in the
potential application of a Neber rearrangement as a solution to this
obstacle.9 Thus, conversion of ketone 18 to tosyloxime 19, followed
by sequential treatment with (i) KOH, (ii) HCl, and (iii) K2CO3
produced amino ketone 20 as a single regio- and stereochemical
isomer in excellent yield.10 Moreover, under our optimized reaction
conditions, both the tosyl and SEM protecting groups were
quantitatively removed from the corresponding heterocycles. Fi-
nally, liberation of the 3° hydroxyl and pyrazinone functionalities
by exposure of bis-ether 20 to TMSI, followed by treatment of the
penultimate amino ketone with cyanamide and aqueous NaOH
produced (+)-dragmacidin F (3).10
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Wright, A. E.; Pomponi, S. A.; Cross, S. S.; McCarthy, P. J. Org.
Chem. 1992, 57, 4772-4775. (b) 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, 660-662. (c) Cutignano, A.; Bifulco, G.; Bruno,
I.; Casapullo, A.; Gomez-Paloma, L.; Riccio, R. Tetrahedron 2000, 56,
3743-3748 and references therein.
(2) For synthetic work aimed toward the piperazine-containing dragmacidins,
see: (a) Jiang, B.; Smallheer, J. M.; Amaral-Ly, C.; Wuonola, M. A. J.
Org. Chem. 1994, 59, 6823-6827. (b) Whitlock, C. R.; Cava, M. P.
Tetrahedron Lett. 1994, 35, 371-374. (c) Kawasaki, T.; Enoki, H.;
Matsumura, K.; Ohyama, M.; Inagawa, M.; Sakamoto, M. Org. Lett. 2000,
2, 3027-3029. (d) Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Org. Lett.
2000, 2, 3185-3187. (e) Yang, C.-G.; Wang, J.; Tang, X.-X.; Jiang, B.
Tetrahedron: Asymmetry 2002, 13, 383-394. (f) Kawasaki, T.; Ohno,
K.; Enoki, H.; Umemoto, Y.; Sakamoto, M. Tetrahedron Lett. 2002, 43,
4245-4248. For studies targeting dragmacidins D, E, or F, see: (g) Jiang,
B.; Gu, X.-H. Bioorg. Med. Chem. 2000, 8, 363-371. (h) Jiang, B.; Gu,
X.-H. Heterocycles 2000, 53, 1559-1568. (i) Yang, C.-G.; Wang, J.; Jiang,
B. Tetrahedron Lett. 2002, 43, 1063-1066. (j) Miyake, F. Y.; Yakushijin,
K.; Horne, D. A. Org. Lett. 2002, 4, 941-943. (k) Yang, C.-G.; Liu, G.;
Jiang, B. J. Org. Chem. 2002, 67, 9392-9396.
Scheme 4
(3) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124,
13179-13184.
(4) (a) Stoltz, B. M. Chem. Lett. 2004, 33, 362-367 and references therein.
(b) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2003, 42, 2892-2895. (c) Ferreira, E. M.; Stoltz, B. M.
J. Am. Chem. Soc. 2003, 125, 9578-9579.
(5) (a) Philippe, M.; Sepulchre, A. M.; Gero, S. D.; Loibner, H.; Streicher,
W.; Stutz, P. J. Antibiot. 1982, 35, 1507-1512. (b) Manthey, M. K.;
Gonza´lez-Bello, C.; Abell, C. J. Chem. Soc., Perkin Trans. 1 1997, 5,
625-628.
(6) Preliminary mechanistic studies suggest that a Pd-catalyzed π-allyl
reduction is not operative.
(7) (a) Under optimized conditions,7b intramolecular Heck cyclization of
related 3-bromopyrrole derivative i resulted in competitive production of
undesired product ii.10b (b) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc.
2001, 123, 6989-7000.
Synthetic dragmacidin F was spectroscopically identical (1H
NMR, 13C NMR, IR, UV, HPLC) to the natural product1c with the
(8) Gilow, H. M.; Hong, Y. H.; Millirons, P. L.; Snyder, R. C.; Casteel, W.
J., Jr. J. Heterocycl. Chem. 1986, 23, 1475-1480.
(9) (a) Neber, P. W.; Friedolsheim, A. Justus Liebigs Ann. Chem. 1926, 449,
109-134. (b) Ooi, T.; Takahashi, M.; Doda, K.; Maruoka, K. J. Am. Chem.
Soc. 2002, 124, 7640-7641. (c) To the best of our knowledge, the Neber
rearrangement has not previously been carried out successfully in the
context of natural product total synthesis.
(10) (a) Purified by reversed-phase chromatography using trifluoroacetic acid
in the eluent. (b) See Supporting Information for details.
(11) Dragmacidin numbering convention, see ref 1.
exception of the sign of rotation (natural: [R]25 -159° (c 0.4,
D
MeOH); synthetic: [R]23 +146° (c 0.45, MeOH)).10b Thus, our
D
synthesis from (-)-quinic acid (9) establishes that the absolute
configuration of natural dragmacidin F is (4′′S, 6′′S, 6′′′S).11 On
the basis of the hypothesis that dragmacidins D, E, and F are
biosynthetically related,1,3 we propose that the absolute stereo-
chemical configurations of natural dragmacidins D and E are (6′′′S)
JA046695B
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