Development of an enantiodivergent strategy for the total synthesis of (+)- and (-)-dragmacidin f from a single enantiomer of quinic acid

Article abstract of DOI:10.1021/ja050586v

An enantiodivergent strategy for the total chemical synthesis of both (+)- and (-)-dragmacidin F beginning from a single enantiomer of quinic acid has been developed and successfully implemented. Although unique, the synthetic routes to these antipodes share a number of key features, including novel reductive isomerization reactions, Pd(II)-mediated oxidative carbocyclization reactions, halogen-selective Suzuki couplings, and high-yielding late-stage Neber rearrangements.

Full text of DOI:10.1021/ja050586v

Published on Web 04/02/2005
Development of an Enantiodivergent Strategy for the Total
Synthesis of (+)- and (-)-Dragmacidin F from a Single
Enantiomer of Quinic Acid
Neil K. Garg, Daniel D. Caspi, and Brian M. Stoltz*
Contribution from The Arnold and Mabel Beckman Laboratories of Chemical Synthesis,
DiVision of Chemistry and Chemical Engineering, California Institute of Technology,
1200 East California BouleVard, MC 164-30, Pasadena, California 91125
Received January 28, 2005; E-mail: stoltz@caltech.edu
Abstract: An enantiodivergent strategy for the total chemical synthesis of both (+)- and (-)-dragmacidin
F beginning from a single enantiomer of quinic acid has been developed and successfully implemented.
Although unique, the synthetic routes to these antipodes share a number of key features, including novel
reductive isomerization reactions, Pd(II)-mediated oxidative carbocyclization reactions, halogen-selective
Suzuki couplings, and high-yielding late-stage Neber rearrangements.
Introduction
Over the past several decades, the search for natural products
in marine environments has led to the discovery of a number
of biologically active bis(indole) alkaloids.1 These compounds,
as well as their unnatural analogues, have shown promise as
leads for the development of novel therapeutics, particularly in
the area of cancer.2 Of the many bis(indole) alkaloids found in
nature, the dragmacidins have received considerable attention
from the scientific community over the past decade due to their
broad range of biological activity and complex structures (1-
7, Figure 1).3,4 As part of a research program geared toward
the synthesis of complex heterocyclic natural products, we
initiated an effort to synthesize those dragmacidins that possess
a pyrazinone core, namely, dragmacidins D, E, and F (5-7).
In 2002, we reported the first total synthesis of any of these
three unique alkaloids with our preparation of (()-dragmacidin
D (5).5 Our highly convergent approach to 5 relied on a series
of halogen-selective Suzuki cross-couplings of 8, 9, and 10
(Scheme 1) to build the bis(indole)pyrazine skeleton (11) of
the natural product. We hypothesized that this general synthetic
Figure 1. Dragmacidin alkaloids.
(1) (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep,
M. R. Nat. Prod. Rep. 2004, 21, 1-49. (b) Aygu¨n, A.; Pindur, U. Curr.
Med. Chem. 2003, 10, 1113-1127. (c) Faulkner, D. J. Nat. Prod. Rep.
2002, 19, 1-48. (d) Pindur, U.; Lemster, T. Curr. Med. Chem. 2001, 8,
1681-1698.
strategy could also be applied to the other pyrazinone-containing
members of the dragmacidin family.
(2) (a) Yang, C.-G.; Huang, H.; Jiang, B. Curr. Org. Chem. 2004, 8, 1691-
1720. (b) Jin, Z. Nat. Prod. Rep. 2003, 20, 584-605. (c) Hibino, S.; Choshi,
T. Nat. Prod. Rep. 2002, 19, 148-180. (d) Sasaki, S.; Ehara, T.; Sakata,
I.; Fujino, Y.; Harada, N.; Kimura, J.; Nakamura, H.; Maeda, M. Bioorg.
Med. Chem. Lett. 2001, 11, 583-585.
(3) For the isolation of the piperazine-containing dragmacidins, see: (a)
Kohmoto, S.; Kashman, Y.; McConnell, O. J.; Rinehart, K. L., Jr.; Wright,
A.; Koehn, F. J. Org. Chem. 1988, 53, 3116-3118. (b) Morris, S. A.;
Andersen, R. J. Tetrahedron 1990, 46, 715-720. (c) Fahy, E.; Potts, B. C.
M.; Faulkner, D. J.; Smith, K. J. Nat. Prod. 1991, 54, 564-569. For the
isolation of the pyrazinone-containing dragmacidins, see: (d) Wright, A.
E.; Pomponi, S. A.; Cross, S. S.; McCarthy, P. J. Org. Chem. 1992, 57,
4772-4775. (e) 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. (f) Cutignano, A.; Bifulco, G.; Bruno, I.; Casapullo, A.;
Gomez-Paloma, L.; Riccio, R. Tetrahedron 2000, 56, 3743-3748. (g)
Wright, A. E.; Pomponi, S. A.; Jacobs, R. S. PCT Int. Appl. WO 9942092,
Aug. 26, 1999.
Perhaps the most daunting target of the dragmacidin natural
products is dragmacidin F (7), which was isolated in 2000 from
the ethanol extracts of the Mediterranean sponge Halicortex sp.
Although 7 does not contain a bis(indole) framework, it is
presumed to be derived biosynthetically from dragmacidin D
(5) via an oxidative de-aromatization/cyclization process.3f,5
Dragmacidin F (7) exhibits in vitro antiviral activity against
herpes simplex virus (HSV-I; EC50 ) 95.8 µM) and human
immunodeficiency virus (HIV-I; EC50 ) 0.91 µM)3f and thus
is an attractive target from a biological standpoint. Given the
limited supply of dragmacidin F (7) available from natural
sources, a successful synthetic approach to 7 could facilitate
9
5970
J. AM. CHEM. SOC. 2005, 127, 5970-5978
10.1021/ja050586v CCC: $30.25 © 2005 American Chemical Society

Enantiodivergent Strategy for Dragmacidin F
A R T I C L E S
Scheme 1
Scheme 2
the production of sufficient quantities of material needed for
advanced biological studies. Herein, we describe the develop-
ment of an enantiodivergent strategy to access both enantiomers
of dragmacidin F, beginning from a single enantiomer of a chiral
starting material.
quinic acid (16).10 At the time of this synthetic effort, the abso-
lute stereochemistry of natural dragmacidin F was not known;
thus, the absolute stereochemistry of our target (7) was chosen
arbitrarily.
Results and Discussion
Retrosynthesis of Dragmacidin F.6 The antiviral agent
dragmacidin F (7) possesses a variety of structural features that
make it an attractive target for total synthesis. These synthetic
challenges include the differentially substituted pyrazinone, the
bridged [3.3.1] bicyclic ring system, which is fused to both the
trisubstituted pyrrole and aminoimidazole heterocycles, and the
installation and maintenance of the 6-bromoindole fragment.
Our retrosynthetic analysis for dragmacidin F is shown in
Scheme 2. On the basis of our experience with dragmacidin D
(5), we reasoned that the aminoimidazole moiety would best
be incorporated at a late stage in the synthesis.5 The carbon
skeleton of the natural product would then arise via a series of
halogen-selective Suzuki cross-coupling reactions (12 + 9 +
10). Pyrazine 9 and indoloboronic acid 10 were both readily
accessible,5 while pyrroloboronic ester 12 perhaps could be
derived from pyrrole-fused bicycle 13, our key retrosynthetic
intermediate. We then targeted bicycle 13 from two related
directions: a Pd(0)-mediated intramolecular Heck reaction7 of
bromopyrrole 14 and a Pd(II)-promoted oxidative carbocycliza-
tion8 involving des-bromopyrrole 15. The successful imple-
mentation of the latter method was particularly attractive since
it is closely aligned with our interest in Pd(II)-catalyzed de-
hydrogenation reactions.9 Both of the cyclization substrates (14
and 15) could be prepared from commercially available (-)-
Synthesis of Cyclization Substrates. Our synthesis of 7
began with a known two-step protocol involving lactonization
and silylation of 16 to afford bicyclic lactone 17 (Scheme 3).11
Subsequent oxidation and Wittig olefination of 17 produced exo-
methylene lactone 18 in good yield. Initially, we envisioned
the direct conversion of lactone 18 to unsaturated carboxylic
acid 19 by executing a homogeneous Pd(0)-catalyzed π-allyl
hydride addition reaction.12 Despite considerable experimenta-
tion, however, exposure of lactone 18 to a variety of Pd and
hydride sources under standard conditions12 led to the formation
of complex product mixtures. As a result, a more stepwise
approach was tried. Methanolysis of lactone 18 followed by
acetylation of the resulting 2° alcohol13 gave rise to allylic
acetate 20, another potential substrate for π-allyl reduction
chemistry. Although 20 did react under most literature protocols,
undesired exocyclic olefin 22 was typically the major product
observed. After substantial optimization, we were able to access
21 as the major product by employing stoichiometric Pd(P(t-
(7) For recent reviews of the Heck reaction, see: (a) Dounay, A. B.; Overman,
L. E. Chem. ReV. 2003, 103, 2945-2963. (b) Beletskaya, I. P.; Cheprakov,
A. V. Chem. ReV. 2000, 100, 3009-3066. (c) Amatore, C.; Jutand, A. J.
Organomet. Chem. 1999, 576, 254-278.
(8) For related examples of Pd-mediated carbocyclizations in natural product
synthesis, see: (a) Baran, P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
7904-7905. (b) Williams, R. M.; Cao, J.; Tsujishima, H.; Cox, R. J. J.
Am. Chem. Soc. 2003, 125, 12172-12178.
(9) (a) Stoltz, B. M. Chem. Lett. 2004, 33, 362-367. (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. (d) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2004, 43, 6144-6148.
(10) For reviews and examples regarding the use of (-)-quinic acid in natural
product synthesis, see: (a) Barco, A.; Benetti, S.; De Risi, C.; Marchetti,
P.; Pollini, G. P.; Zanirato, V. Tetrahedron: Asymmetry 1997, 8, 3515-
3545. (b) Huang, P.-Q. Youji Huaxue 1999, 19, 364-373. (c) Hanessian,
S.; Pan, J.; Carnell, A.; Bouchard, H.; Lesage, L. J. Org. Chem. 1997, 62,
465-473. (d) Hanessian, S. In Total Synthesis of Natural Products: The
“Chiron” Approach; Baldwin, E. J., Ed.; Pergamon Press: Oxford, U.K.,
1983; pp 206-208.
(4) 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.
(11) (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, 625-628.
(12) For a review, see: Tsuji, J.; Mandai, T. Synthesis 1996, 1-24.
(13) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; John Wiley & Sons: New York, 1999.
(5) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124,
13179-13184.
(6) Recently, we reported the first total synthesis of (+)-dragmacidin F as a
communication, see: Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem.
Soc. 2004, 126, 9552-9553.
9
J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 5971

A R T I C L E S
Scheme 3
Garg et al.
(Scheme 5). The Weinreb amide functionality was then dis-
placed with the appropriate lithiopyrrole18 reagent to produce
Heck cyclization substrate 1419 and oxidative cyclization
substrate 15.
Scheme 5
Constructing the [3.3.1] Bicycle. Extensive studies were
carried out in order to achieve the intramolecular Heck cycliza-
tion of bromopyrrole 14. Attempts to utilize standard procedures
were unsuccessful,7 likely due to the thermal instability of the
bromopyrrole moiety. However, implementation of the room-
temperature conditions developed by Fu20 provided the desired
[3.3.1] bicyclic product (13), albeit in low yield (Scheme 6).
Unfortunately, the formation of 13 was hampered by competitive
production of [3.2.2] bicycle 25. Although efforts to optimize
temperature, solvent, base, and concentration were not met with
success, it was found that increased quantities of Pd improved
the ratio of the desired [3.3.1] bicycle (13) to the undesired
[3.2.2] bicycle (25). In addition, the ratio of 13 to 25 decreased
over time,21 suggesting that the active catalytic species varied
during the course of the reaction or that selectivity changed as
the concentration of R3NH+Br- increased.
Bu)3)214 in the presence of triethylsilane as a reductant. Further
refinements designed to facilitate catalysis led to a reduced Pd
loading (30 mol %) when N-methylmorpholine-N-oxide (NMO)
was used as an additive.15 Under these conditions, cyclohexene
21 was obtained in 89% yield as a single olefin regioisomer.
Unfortunately, this transformation often gave inconsistent results
and was particularly sensitive to oxygen, water, and the quality
of Et3SiH. These difficulties coupled with the high catalyst
loading resulted in substantial material throughput problems.
We therefore sought yet another method to prepare cyclohexene
21 or a closely related derivative thereof (i.e., 19) in a more
facile and preparative manner.
Scheme 6
In our revised plan, we conceived a two-step route to obtain
carboxylic acid 19 via diastereoselective reduction of olefin 18
followed by base-promoted elimination of the carboxylate
functionality of 23 (Scheme 4). The first part of this sequence
was attempted by exposing olefin 18 to standard catalytic
hydrogenation conditions (Pd/C, 1 atm H2). Surprisingly, these
conditions led to the production of a compound that was more
polar than we expected for simple olefin hydrogenation (i.e.,
23). To our delight, the product was identified as unsaturated
carboxylic acid 19. Under our optimized reaction conditions
(0.5 mol % Pd/C, 1 atm H2, MeOH, 0 °C), essentially
quantitative reductive isomerization to 19 was observed. Al-
though the mechanism of this transformation has not been
studied extensively, simple control experiments suggest that
stepwise reduction/elimination16 or π-allyl reduction processes
are not operative.17
Although the Heck reaction was useful for preparing reason-
able quantities of bicycle 13, an alternative and potentially more
selective route to 13 was desired. In conjunction with ongoing
research in our group,9 we turned to the Pd(II)-mediated C-C
(14) Despite its widespread use in modern cross-coupling chemistry, to the best
of our knowledge, this is the first report of Pd(P(t-Bu)3)2 being used for a
π-allylpalladium substitution reaction. For recent examples of Pd(P(t-Bu)3)2
in cross-coupling reactions, see: Hills, I. D.; Fu, G. C. J. Am. Chem. Soc.
2004, 126, 13178-13179, and references therein.
(15) For the use of NMO as an additive in Stille couplings, see: Han, X.; Stoltz,
B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605.
(16) Under certain conditions, we were able to produce 23 as a mixture of
diastereomers. However, upon exposure of 23 to Pd/C and H2 in MeOH,
no reaction took place.
Scheme 4
(17) Treatment of 20 under a variety of standard homogeneous π-allyl reduction
conditions12 led to the formation of 21, 22, and i, all of which presumably
arise from loss of OAc-. In stark contrast, exposure of 20 to heterogeneous
reductive isomerization conditions did not produce any of these compounds
(see Scheme 16).
(18) For the discovery and use of SEM pyrrole, see: (a) Edwards, M. P.; Ley,
S. V.; Lister, S. G.; Palmer, B. D. J. Chem. Soc., Chem. Commun. 1983,
630-633. (b) Muchowski, J. M.; Solas, D. R. J. Org. Chem. 1984, 49,
203-205. (c) Edwards, M. P.; Ley, S. V.; Lister, S. G.; Palmer, B. D.;
Williams, D. J. J. Org. Chem. 1984, 49, 3503-3516. (d) Edwards, M. P.;
Doherty, A. M.; Ley, S. V.; Organ, H. M. Tetrahedron 1986, 42, 3723-
3729.
With facile access to cyclohexene carboxylic acid 19,
preparation of the key cyclization precursors proceeded without
difficulty. Activation of acid 19 with CDI followed by the
addition of HN(OMe)Me‚HCl afforded Weinreb amide 24
9
5972 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005

Enantiodivergent Strategy for Dragmacidin F
A R T I C L E S
Scheme 7
Scheme 8
bond forming approach. In this scenario, C(3)-unsubstituted
pyrrole 15 would undergo intramolecular carbocyclization to
afford 13 (Scheme 7). Initial experimentation revealed that
pyridine and ethyl nicotinate were not effective ligands for
promoting cyclization in the presence of Pd(OAc)2.9c,d However,
by using dimethyl sulfoxide (DMSO) as a ligand22 the desired
cyclization product could be obtained in modest yield. Subse-
quent optimization of solvent, temperature, and reaction time
led to a set of improved conditions whereby the desired pyrrole-
fused bicycle 13 was formed as a single stereo- and regioisomer
in 74% yield. Interestingly, these conditions take advantage of
a similar solvent mixture employed in Pd cyclization methodol-
ogy from our laboratory.9c,d This transformation (15 f 13) is
particularly noteworthy since it results in functionalization of
the electronically deactivated and sterically congested C(3)
position of acyl pyrrole 15.23,24 Despite our best efforts, we were
unable to effect catalytic turnover of Pd with a stoichiometric
oxidant in this reaction, presumably due to extensive oxidative
decomposition of both the starting material and the desired
product.25 Nonetheless, the Pd(II)-mediated strategy provided
bicycle 13 in nearly twice the isolated yield as the Heck route
using equivalent amounts of Pd and obviated the need for
polybrominated pyrroles.19,26
of olefin 13 and was followed by methylation of the 3° alcohol
to produce bis(ether) 26. The methyl protecting group was
selected initially for its robustness13 and would presumably allow
for the exploration of late-stage chemistry in the form of a model
system.27 Methyl ether 26 was then elaborated via regioselective
bromination of the pyrrole and metalation to boronic ester 12.
In the critical halogen-selective Suzuki fragment coupling,
pyrroloboronic ester 12 was reacted with dibromide 27 (prepared
from 9 + 10)5 under Pd(0) catalysis. By analogy to our drag-
macidin D studies,5 we were pleased to find that, at 50 °C, the
desired C-C bond forming reaction took place to afford the
fully coupled product 28 in 77% yield. Importantly, the indolyl-
bromide moiety was maintained under these reaction conditions.
Completion of the Total Synthesis of (+)-Dragmacidin F.
With the carbon framework completed, few tasks remained in
order to finish the total synthesis of dragmacidin F, namely,
removal of all protecting groups and installation of the amino-
imidazole unit. Of particular note is the similarity of these
synthetic challenges to those encountered in our total synthesis
of dragmacidin D.5 Not surprisingly, we decided to utilize the
methods that were already familiar to us in order to elaborate
28 to the desired natural product (7). To this end, we anticipated
that the presence of an amino group R to the ketone would allow
for eventual introduction of the aminoimidazole moiety. There-
fore, selective deprotection of silyl ether 28, followed by
oxidation with Dess-Martin periodinane produced ketone 29
(Scheme 9).
Assembling the Carbon Skeleton of Dragmacidin F. With
the [3.3.1] bicyclic framework in hand (i.e., 13), we focused
our attention on constructing the full carbon skeleton of
dragmacidin F (28, Scheme 8). The final stereocenter present
in the natural product was installed via catalytic hydrogenation
(19) During the conversion of 24 to 14, 2,4-disubstituted pyrrole ii was formed
as a byproduct.
Scheme 9
(20) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989-7000.
(21) By conducting reactions in THF-d8, it was possible to monitor Heck
reactions by 1H NMR.
(22) DMSO has commonly been employed in oxidative Pd(II) chemistry. See:
(a) Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298-5300.
(b) Van Benthem, R. A. T. M.; Hiemstra, H.; Michels, J. J.; Speckamp,
W. N. J. Chem. Soc., Chem. Commun. 1994, 357-359. (c) Ro¨nn, M.;
Ba¨ckvall, J.-E.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749-7752.
(d) Chen, M. S.; White, M. C. J. Am. Chem. Soc. 2004, 126, 1346-1347.
(e) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400-3420. See also
references therein.
(23) Gilow, H. M.; Hong, Y. H.; Millirons, P. L.; Snyder, R. C.; Casteel, W. J.,
Jr. J. Heterocycl. Chem. 1986, 23, 1475-1480.
(24) Reactions conducted in the presence of acetic acid-d led to deuterium
incorporation in the pyrrole ring of both the starting material (15) and the
product (13), mostly at C(4).
Our first effort to functionalize the ketone R-position involved
a nitration strategy to access a compound analogous to an
intermediate employed in the dragmacidin D synthesis (Scheme
10). Both lithium enolate 30 and trimethylsilyl (TMS) enol ether
31 were exposed to electrophilic NO2 sources.28 Unfortunately,
in all of these cases, formation of the desired nitroketone product
(32) was not observed.
(25) The instability of pyrroles to oxidants is well-known. See: (a) Ciamician,
G.; Silber, P. Chem. Ber. 1912, 45, 1842-1845. (b) Bernheim, F.; Morgan,
J. E. Nature 1939, 144, 290. (c) Chierici, L.; Gardini, G. P. Tetrahedron
1966, 22, 53-56.
(26) The Heck route required the use of 2,3-dibromopyrrole, an extremely
unstable compound. For a discussion regarding the instability of bromopyr-
roles, see: Audebert, P.; Bidan, G. Synth. Met. 1986, 15, 9-22.
(27) In preliminary investigations, late-stage chemistry in the presence of a
reactive 3° alcohol was unsuccessful.
(28) (a) Rathore, R.; Kochi, J. K. J. Org. Chem. 1996, 61, 627-639. (b) Elfehail,
F. E.; Zajac, W. W., Jr. J. Org. Chem. 1981, 46, 5151-5155. (c) Elfehail,
F.; Dampawan, P.; Zajac, W. Synth. Commun. 1980, 10, 929-932. (d)
Fischer, R. H.; Weitz, H. M. Synthesis 1980, 261-282.
9
J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 5973

A R T I C L E S
Scheme 10
Garg et al.
Scheme 12
We then turned to an alternative strategy that would involve
installation of an R-amino substituent via nucleophilic displace-
ment of an alkylbromide. Therefore, ketone 29 was treated with
TMSOTf and then exposed to N-bromosuccinimide (NBS) to
afford bromoketone 33 as a single diastereomer (Scheme 11).29
Interestingly, when bromoketone 33 was treated with various
nitrogenous nucleophiles, base-promoted rearrangements were
observed.30 In fact, reaction of bromide 33 with a basic fluoride
anion source (tetrabutylammonium fluoride (TBAF) in THF)
gave [3.2.1] bicycle 34 as the major product via a Favorskii
rearrangement.31 The utilization of amine bases also led to the
formation of related Favorskii products.
best of our knowledge, this is the first example of a successful
Neber rearrangement in the context of natural product synthe-
sis.6,37
A more detailed look at the possible mechanism of the Neber
rearrangement/deprotection sequence is shown in Scheme 13.
Exposure of tosyloxime 35 to KOH in ethanol likely leads to
the formation of detosylated azirine 37, which is attacked by
ethoxide to afford ethoxyaziridine 38.33a,38 Following acid-
mediated hydrolysis, the amino ketone moiety is installed with
concomitant partial cleavage of the SEM protective group (38
f 39).34b,39 Finally, treatment of hemiaminal 39 with K2CO3
removes the remaining portion of the SEM group, thus giving
rise to the deprotected amino ketone (36).
Scheme 11
Scheme 13
With limited options remaining, we became interested in the
use of a Neber rearrangement in order to install the necessary
R-amino substituent.32,33 In this scenario, an activated oxime
derivative would undergo alkoxide-promoted rearrangement to
furnish an R-amino ketone. Thus, ketone 29 was converted to
tosyloxime 35 via standard conditions (Scheme 12). Gratify-
ingly, exposure of substrate 35 to aqueous KOH in ethanol led
to Neber rearrangement. After optimization, we found that
simply exposing tosyloxime 35 to (i) KOH, (ii) HCl, and (iii)
K2CO3 produced R-amino ketone 36 as a single regio- and
stereochemical isomer in excellent yield.34-36 Furthermore,
under these reaction conditions, both the tosyl and 2-(trimeth-
ylsilyl)ethoxymethyl (SEM) protective groups were quantita-
tively removed from their corresponding heterocycles. To the
To unveil the masked pyrazinone functionality, Neber rear-
rangement product 36 was treated with trimethylsilyl iodide
(TMSI) at 60 °C (Scheme 14).13 Fortuitously, both the pyrazi-
none and the 3° alcohol functionalities were revealed simulta-
neously (36 f 40). In the final step of the synthesis, the
penultimate amino ketone (40) was subjected to cyanamide and
aqueous NaOH to produce enantiopure dragmacidin F.5,40 Our
efficient and enantiospecific route allows access to 7 in 7.8%
overall yield in just 21 steps from (-)-quinic acid.
(29) Kreiser, W.; Ko¨rner, F. HelV. Chim. Acta 1999, 82, 1610-1629.
(30) For example, upon treatment of bromoketone 33 with NaN3, R-azidoketone
iii formed as the major product.
(31) (a) Favorskii, A. E. J. Russ. Phys. Chem. Soc. 1894, 26, 559-603. (b)
Chenier, P. J. J. Chem. Educ. 1978, 55, 286-291.
(34) (a) Purified by reversed-phase chromatography using trifluoroacetic acid
in the eluent. (b) See Supporting Information for details.
(35) Derivatives of 35 bearing a free 3° alcohol or a TMS-protected 3° alcohol
afforded complex mixtures of products when subjected to Neber rearrange-
ment conditions.
(36) Acid-promoted dimerization of the amino ketone functionalities was not
observed.
(32) Neber, P. W.; Friedolsheim, A. V. Justus Liebigs Ann. Chem. 1926, 449,
109-134.
(33) (a) For a review, see: O’Brien, C. Chem. ReV. 1964, 64, 81-89. (b) For
a recent study involving the Neber rearrangement, see: Ooi, T.; Takahashi,
M.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2002, 124, 7640-7641.
9
5974 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005

Enantiodivergent Strategy for Dragmacidin F
A R T I C L E S
Scheme 14
Scheme 15
Absolute Stereochemistry of the Pyrazinone-Containing
Dragmacidins. Synthetic 7 was spectroscopically identical (1H
NMR, 13C NMR, IR, UV, HPLC) to a sample obtained from
natural sources,3f with the exception of the sign of rotation
(natural, [R]25D -159° (c 0.4, MeOH); synthetic, [R]23D +146°
(c 0.45, MeOH)). Thus, our synthesis from 16 established, for
the first time, the absolute configuration of natural 7 to be (4′′S,
6′′S, 6′′′S) as shown in Figure 2.41 On the basis of the hypothesis
that dragmacidins D, E, and F are biosynthetically related, it is
likely that the absolute stereochemical configurations of natural
5 and 6 are (6′′′S) and (5′′′R, 6′′′S), respectively. Having
developed a route to the unnatural antipode of (+)-7, we set
out to extend our approach to the total synthesis of (-)-7.
We reasoned, however, that it might be possible to exploit 16
in an enantiodivergent manner that would allow access to both
(+)- and (-)-7 (Scheme 15).43 For such an approach to succeed,
16 would be elaborated via selective manipulation of the C(3),
C(4), and C(5) hydroxyl groups to a pseudo-C2-symmetric44
derivative (41) en route to pyrrolocyclohexene 42, the diaste-
reomer of which (i.e., 15) was employed in our synthesis of
(+)-7. Analogous to our approach to (+)-7 (i.e., 15 f 13), we
anticipated that 42 could undergo oxidative carbocyclization to
afford annulated pyrrole 43. Bicycle 43 would then be elaborated
to (-)-7. Of the key transformations outlined in Scheme 15,
we were familiar with the Pd-mediated oxidative carbocycliza-
tions and the late-stage manipulations of related compounds;
however, the successful preparation of (-)-7 would rely heavily
on the identification of a suitable quinic acid derivative (41),
the facile synthesis of that compound, and the rapid conversion
of 41 to the requisite cyclization substrate (42).
Development and Investigation of a Reductive Isomer-
ization Reaction. Fortunately, potential solutions to these
problems had become apparent during our studies of a novel
reductive isomerization reaction discovered in our synthesis of
(+)-7. Two critical results are shown in Scheme 16. In the first
experiment, treatment of lactone 18 with Pd/C and H2 in
Figure 2. Absolute stereochemical configurations of dragmacidins D, E,
and F.
(39) Hemiaminal 39 has been isolated and characterized by 1H NMR.
(40) Boehm, J. C.; Gleason, J. G.; Pendrak, I.; Sarau, H. M.; Schmidt, D. B.;
Foley, J. J.; Kingsbury, W. D. J. Med. Chem. 1993, 36, 3333-3340.
(41) Dragmacidin numbering convention, see ref 3f.
(42) (a) (+)-Quinic acid ((+)-16) is commercially available in limited quantities
from Interbioscreen Ltd. (50 mg/$305 USD). (b) (+)-Quinic acid ((+)-16)
potentially could be prepared via multistep synthesis by applying methods
used for the preparation of (-)-quinic acid (16). See: Rapado, L. P.;
Bulugahapitiya, V.; Renaud, P. HelV. Chim. Acta 2000, 83, 1625-1632,
and references therein.
(43) Surprisingly, despite its widespread use in natural product synthesis and
its near symmetry, (-)-quinic acid (16) has rarely been used in an
enantiodivergent manner. For examples, see: (a) Ulibarri, G.; Nadler, W.;
Skrydstrup, T.; Audrain, H.; Chiaroni, A.; Riche, C.; Grierson, D. S. J.
Org. Chem. 1995, 60, 2753-2761. (b) Ulibarri, G.; Audrain, H.; Nadler,
W.; Lhermitte, H.; Grierson, D. S. Pure Appl. Chem. 1996, 68, 601-604.
(c) Barros, M. T.; Maycock, C. D.; Ventura, M. R. J. Chem. Soc., Perkin
Trans. 1 2001, 166-173.
(44) If R ) R′, 41 is considered to be pseudo-C2-symmetric. Pseudo-C2-
symmetric molecules are those that would be C2-symmetric if they did not
contain a central chirotopic, nonstereogenic center. For discussions, see:
(a) Schreiber, S. L. Chem. Scr. 1987, 27, 563-566. (b) Poss, C. S.;
Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9-17. (c) Magnuson, S. R.
Tetrahedron 1995, 51, 2167-2213. (d) Eliel, E. L.; Wilen, S. H.; Mander,
L. N. Stereochemistry of Organic Compounds; Wiley-Interscience: New
York, 1994.
Enantiodivergent Strategy for the Preparation of (-)-
Dragmacidin F. As described above, naturally occurring and
readily available 1610 had served as the starting material for
our synthetic approach to (+)-7. Unfortunately, the (+)-
enantiomer of 16 is not easily accessible,42 and we were
confronted with the possibility that our synthesis would not be
amenable to the preparation of our new target molecule, (-)-7.
(37) (a) Woodward reported a Neber rearrangement during synthetic studies
involving lysergic acid. Unfortunately, the Neber rearrangement product
could not be further utilized in the synthesis. See: Kornfeld, E. C.;
Fornefeld, E. J.; Kline, G. B.; Mann, M. J.; Morrison, D. E.; Jones, R. G.;
Woodward, R. B. J. Am. Chem. Soc. 1956, 78, 3087-3114. (b) For the
use of the Neber rearrangement in drug discovery, see: Chung, J. Y. L.;
Ho, G.-J.; Chartrain, M.; Roberge, C.; Zhao, D.; Leazer, J.; Farr, R.;
Robbins, M.; Emerson, K.; Mathre, D. J.; McNamara, J. M.; Hughes, D.
L.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1999, 40, 6739-
6743.
(38) The intermediacy of azirines in Neber rearrangements is well-accepted.
These azirines presumably arise from transient nitrenes. See: (a) House,
H. O.; Berkowitz, W. F. J. Org. Chem. 1963, 28, 307-311. (b) House, H.
O.; Berkowitz, W. F. J. Org. Chem. 1963, 28, 2271-2276.
9
J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 5975

A R T I C L E S
Scheme 16
Garg et al.
Figure 3. Rational design of an optimal substrate for the key reductive
isomerization reaction.
Our synthesis of carbonate 46 began with bicyclic lactone
18, a derivative of 16 that was used in our total synthesis of
(+)-7 (Scheme 17). Addition of 2-lithio-SEM-pyrrole18 followed
by TBS protection afforded bis(silyl ether) 47 in good yield.
This pseudo-C2-symmetric compound then underwent rapid
diastereoselective mono-desilylation upon treatment with TBAF
in THF to produce the syn 1,3-diol 48.49 Importantly, this de-
symmetrization proceeded with complete selectivity and allowed
us to efficiently differentiate the C(3) and C(5) positions of the
cyclohexyl moiety. Diol 48 was smoothly converted to bicyclic
carbonate 46 in the presence of CDI, effectively restricting the
C(3) substituent to an axial disposition. Gratifyingly, exposure
of carbonate 46 to our reductive isomerization conditions (2
mol % Pd/C, H2, MeOH, 0 °C) led to the selective formation
of the desired cyclization substrate (42) in 90% yield.50
methanol at 0 °C furnished carboxylic acid 19 in essentially
quantitative yield via reductive loss of the C(5) carboxylate with
concomitant olefin migration (i.e., net SN2′ reduction). In the
second experiment, a closely related derivative (20) was exposed
to similar reaction conditions.45 Surprisingly, the reductive
isomerization reaction proceeded with loss of the C(3) silyl ether
rather than the C(5) acetate, thus producing small quantities of
allylic acetate 44 instead of the anticipated product (21).46 The
observation that (t-Bu)Me2SiO- was preferentially ejected from
compound 20 despite the clear superiority of AcO- as a leaving
group led us to consider that the C(3) silyl ether moiety was
positioned in an axial orientation, thereby facilitating its
elimination.47 This preferred conformation of 20 represents a
cyclohexane ring-flip with respect to lactone 18 and thus gives
rise to the reductive isomerization product (44) possessing a
Scheme 17
∆
olefin. Importantly, the possibility existed that the unex-
3,4
pected product obtained from this reaction (i.e., 44) could be
converted to cyclization substrate 42 (diastereomeric to 15).
Our efforts to optimize the reductive isomerization of 20 to
44 were hampered by competitive hydrogenation of the olefin
moiety of 20, a complication not observed in the high-yielding
conversion of 18 to 19. Although both processes presumably
involve the elimination of an axially disposed leaving group,47
we reasoned that the successful conversion of 18 to 19 was
due to the carboxylate being conformationally restricted to an
axial orientation, while substrate 20 possessed a poorer leaving
group (t-Bu)Me2SiO-) and was free to adopt alternate confor-
mations (Figure 3).48 We hypothesized that derivatives of 20
containing an axially locked leaving group at C(3) (e.g., 45)
would be more suitable substrates for the reductive isomerization
reaction. Thus, carbonate 46 was identified as the key (-)-quinic
acid derived intermediate en route to the desired cyclization
substrate (42) and became the focus of our efforts.
Constructing the [3.3.1] Bicycle en Route to (-)-Drag-
macidin F. After assembling target substrate 42, we turned our
attention to the key Pd(II)-mediated cyclization reaction (Scheme
18). Substrate 42 was treated with 1.2 equiv of Pd(OAc)2 under
conditions similar to those described earlier, upon which, the
(48) Derivatives of 20 bearing C(3)-acetoxy groups (conformationally flexible
and good leaving groups) were also poor substrates in the reductive
isomerization reaction as shown below (iv f v).46a The conformation of
iv was established by 1H NMR studies.
(45) Olefin 20 was also exposed to the reaction conditions used for the reductive
isomerization of 18 to 19. Only trace quantities of 44 were produced under
those conditions.34b,46b
(49) 1H NMR experiments show that the C(3) silyl ether of 47 is axially
disposed.34b For similar examples of axial-selective TBS cleavage promoted
by TBAF, see: (a) Craig, B. N.; Janssen, M. U.; Wickersham, B. M.; Rabb,
D. M.; Chang, P. S.; O’Leary, D. J. J. Org. Chem. 1996, 61, 9610-9613.
(b) Meier, R.-M.; Tamm, C. HelV. Chim. Acta, 1991, 74, 807-818.
(50) For a classic example involving the use of conformational analysis to solve
stereochemical problems in total synthesis, see: Woodward, R. B.; Bader,
F. E.; Bickel, H.; Frey, A. J.; Kierstead, R. W. Tetrahedron 1958, 2, 1-57.
(46) (a) Yield determined on the basis of 1H NMR integration. (b) The material
isolated was predominantly a mixture of diastereomeric olefin hydrogenation
products.
(47) The favored conformation of 20 depicted in Scheme 16 is consistent with
1H NMR studies.34b
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5976 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005

Enantiodivergent Strategy for Dragmacidin F
A R T I C L E S
Table 1. Pd(II)-Mediated Oxidative Carbocyclizationa
a Standard Conditions: 1 equiv of Pd(OAc)2, 2 equiv of DMSO, t-BuOH:AcOH (4:1, 0.01 M). b Isolated yield. Number in parentheses represents the
yield based on recovered starting material. c Trace product may have formed in this reaction but could not be isolated. d 20 mol % Pd(OAc)2, 40 mol %
1
DMSO, t-BuOH:AcOH (4:1, 0.01 M), O2 (1 atm). e At 80 °C, trace product formation and substantial decomposition were observed. f Yield based on H
NMR with internal standard.
Scheme 18
Scheme 19
desired pyrrole-fused bicycle (43) formed as a single regio- and
stereoisomer. Notably, bond formation between the pyrrole
functionality and C(3) of 42 occurred even in the presence of
the bulky C(5) silyl ether group positioned syn to the acyl
pyrrole subunit. Following protection of the 3° alcohol, [3.3.1]
bicycle 49 was obtained in 68% yield for the two-step process.
We also explored the Pd(II)-mediated carbocyclization of a
number of substrates related to TBS ether 42 and its diastereo-
meric counterpart 15. For instance, both TIPS ether analogues
underwent cyclization (Table 1, entries 1 and 7), although in
lower yield with respect to the parent TBS compounds.
However, if the 2° alcohol was left unprotected altogether
(entries 2 and 8)51 or the substrates possessed 3° methyl ethers
(entries 3 and 9), formation of the desired bicyclic products
was not observed. Interestingly, the diastereomeric acetate
derivatives displayed markedly different reactivity. While the
substrate possessing an anti relationship between the acetate and
acylpyrrole functionalities readily participated in the cyclization
reaction (entry 4), the syn-isomer was much less reactive (entry
10). Exposure of the anti-acetate substrate to catalytic conditions
(20 mol % Pd, 1 atm O2) also led to the formation of the desired
product, although in modest yield with a turnover number (TON)
of 1.9 (entry 5). It was also possible to annulate C(3) of related
indole substrates under our standard conditions (entries 6 and
11).
Total Synthesis of (-)-Dragmacidin F. En route to (-)-
dragmacidin F, cyclization product 49 was converted to pyrazine
50 (Scheme 19) by methods similar to those described above.34b
Despite the similarity of 50 to its diastereomeric counterpart
employed in the synthesis of (+)-7 (28, Scheme 9), selective
desilylation of 50 to afford 51 proved to be difficult. We
reasoned that the steric congestion of the axial TBS ether,
positioned syn to the methyl stereocenter, was the cause of these
problems. In fact, attempted desilylation of parent bicycle 52
was also challenging even at elevated temperatures.52 However,
in a critical reaction, the sterically less crowded TBS ether of
olefinic substrate 49 underwent smooth and selective cleavage
upon treatment with TBAF in THF to afford allylic alcohol 53.
With this result in hand, we conceived of a modified route that
would ultimately deliver (-)-7 in a more convergent manner.
Since allylic alcohol 53 was readily accessible, we chose to
employ it as an intermediate in our synthesis. Oxidation of allylic
(51) In both cases (entries 2 and 8), direct oxidation of the starting materials to
the corresponding enone was observed.
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J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 5977

A R T I C L E S
Scheme 20
Garg et al.
employed in the synthesis of (+)-dragmacidin F. Finally, Suzuki
adduct (-)-29 was converted to (-)-7 via our previously
described six-step protocol (vide supra). Synthetic and natural
(-)-73f were spectroscopically identical, including the sign of
optical rotation (natural (-)-7, [R]25 -159° (c 0.4, MeOH);
D
synthetic (-)-7, [R]23 -148° (c 0.2, MeOH)).34b
D
Conclusion
In summary, we have developed an enantiodivergent strategy
to access both antipodes of dragmacidin F (7) from a single
enantiomer of readily available (-)-quinic acid (16). Our highly
efficient syntheses provide (+)-7 in 7.8% overall yield and (-)-7
in 9.3% overall yield beginning from 16. The routes that we
have developed to (+)- and (-)-7 are concise and feature a
number of key transformations, namely, (a) highly efficient
functionalizations of (-)-16 to differentiate C(3) and C(5), (b)
novel reductive isomerization reactions, (c) sterically demanding
Pd(II)-mediated oxidative carbocyclizations, (d) halogen-selec-
tive Suzuki cross-coupling reactions, and (e) high-yielding late-
stage Neber rearrangements. Advanced biological testing of both
synthetic antipodes of dragmacidin F is currently underway.
alcohol 53 followed by olefin reduction afforded ketone 54 in
good overall yield (Scheme 20). However, because alcohol 53
and ketone 54 are in the same overall oxidation state, we
imagined that a tandem olefin isomerization/tautomerization
process would be more efficient. Upon exposure of alcohol 53
to Brown’s cationic rhodium catalyst Rh(nbd)(dppb)BF453 and
H2, ketone 54 formed directly as a single diastereomer in 98%
yield.54 Elaboration of ketone 54 to (-)-7 proceeded with little
difficulty. Position-selective bromination and low-temperature
metalation of the pyrrole in the presence of two ketones gave
rise to boronic ester 55. Subsequent halogen-selective cross-
coupling of 55 with dibromide 27 afforded the desired Suzuki
adduct (-)-29 (89% yield), the enantiomer of which had been
Acknowledgment. The authors thank the NIH-NIGMS (Grant
R01 GM65961-01), the NDSEG (predoctoral fellowship to
N.K.G.), Eli Lilly (predoctoral fellowship to D.D.C.), Astra-
Zeneca, Boehringer Ingelheim, Johnson & Johnson, Pfizer,
Merck, Amgen, Research Corp., Roche, and GlaxoSmithKline
for generous funding. Drs. R. Riccio and A. Casapullo are
acknowledged for an authentic sample of (-)-dragmacidin F.
We also thank the Dervan and MacMillan laboratories for
helpful discussions and the use of instrumentation.
Supporting Information Available: Full experimental details,
characterization data for all new compounds, and spectral
comparison for synthetic and natural (-)-dragmacidin F (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(52) Heating reactions above 50 °C led to mixtures of products involving partial
and complete cleavage of the SEM and TBS groups.
(53) Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190-203.
(54) Bergens, S. H.; Bosnich, B. J. Am. Chem. Soc. 1991, 113, 958-967.
JA050586V
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5978 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005