Total synthesis of the natural product (±)-dibromophakellin and analogues

Article abstract of DOI:10.1021/ol201741r

(±)-Dibromophakellin has been synthesized in two steps from a known alkene intermediate. The key step in the synthesis is the NBS olefin activation to facilitate the addition of a guanidine molecule across the double bond.

Full text of DOI:10.1021/ol201741r

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4550–4553
Total Synthesis of the Natural Product (()-
Dibromophakellin and Analogues
Nicole M. Hewlett and Jetze J. Tepe*
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824,
United States
tepe@chemistry.msu.edu
Received June 28, 2011
ABSTRACT
(()-Dibromophakellin has been synthesized in two steps from a known alkene intermediate. The key step in the synthesis is the NBS olefin
activation to facilitate the addition of a guanidine molecule across the double bond.
The oroidin family of alkaloids is a highly diverse and
complex class of biologically active secondary marine
sponge metabolites containing characteristic pyrrole-2-
carboxamide and 2-aminoimidazoline (or derivatives
thereof) moieties. Arguably the most well-known member
of the pyrrole-imidazole family is palau’amine (Figure 1),
which exhibits exciting cytotoxic and immunosuppressive
activity.1 The architecturally daunting natural product
finally succumbed to total synthesis by Baran and co-
workers in 2010.2
dibromophakellstatin has been completed, both racemi-
cally and asymmetrically.5ꢀ15 Additionally, the syntheses
of the analogues bromophakellstatin8,9 and phakellstatin
have been accomplished,6,13ꢀ15 the latter often as an inter-
mediate in the total synthesis of dibromophakellstatin.
The closely related natural product (ꢀ)-dibromophakel-
lin was first isolated in 1969 by Sharma,16,17 and its enantio-
mer, (þ)-dibromophakellin, was later isolated in 1985 by
Ahond and Poupat.18 Since that time, the total synthesis of
dibromophakellin has been completed racemically,11,12,19 as
Recently, much attention has been given to other mem-
bers of this family of pyrrole-imidazole marine alkaloids,
including dibromophakellin and dibromophakellstatin
(Figure 1), which share a similar tetracyclic framework
with palau’amine. The structural similarities between
palau’amine and the phakellins and phakellstatins sparked
our interest in the synthesis of these agents and their
analogues, in order to further explore their biological
properties.3,4
(5) Wiese, K. J.; Yakushijin, K.; Horne, D. A. Tetrahedron Lett.
2002, 43, 5135.
(6) Chung, R.; Yu, E.; Incarvito, C. D.; Austin, D. J. Org. Lett. 2004,
6, 3881.
(7) Feldman, K. S.; Skoumbourdis, A. P. Org. Lett. 2005, 7, 929.
€
(8) Jacquot, D. E. N.; Zollinger, M.; Lindel, T. Angew. Chem., Int.
Ed. 2005, 44, 2295.
€
(9) Zollinger, M.; Mayer, P.; Lindel, T. J. Org. Chem. 2006, 71, 9431.
(10) Lu, J.; Tan, X.; Chen, C. J. Am. Chem. Soc. 2007, 129, 7768.
(11) Feldman, K. S.; Fodor, M. D.; Skoumbourdis, A. P. Synthesis
2009, 3162.
(12) Feldman, K. S.; Skoumbourdis, A. P.; Fodor, M. D. J. Org.
Chem. 2007, 72, 8076.
The phakellins and phakellstatins have been the focus
of a number of synthetic efforts. The total synthesis of
(13) Poullennec, K. G.; Romo, D. J. Am. Chem. Soc. 2003, 125, 6344.
€
(14) Zollinger, M.; Mayer, P.; Lindel, T. Synlett 2007, 2756.
(15) Imaoka, T.; Akimoto, T.; Iwamoto, O.; Nagasawa, K. Chem.;
Asian J. 2010, 5, 1810.
(16) Burkholder, P. R.; Sharma, G. M. Lloydia 1969, 32, 466.
(17) Sharma, G. M.; Burkholder, P. R. J. Chem. Soc., Chem. Com-
mun. 1971, 151.
(1) Kinnel, R. B.; Gehrken, H. P.; Scheuer, P. J. J. Am. Chem. Soc.
1993, 115, 3376.
(2) Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi, J.;
Baran, P. S. Angew. Chem., Int. Ed. 2010, 49, 1095.
€
(3) Zollinger, M.; Kelter, G.; Fiebig, H.-H.; Lindel, T. Bioorg. Med.
Chem. Lett. 2007, 17, 346.
(18) de Nanteuil, G.; Ahond, A.; Guilhem, J.; Poupat, C.; Dau,
E. T. H.; Potier, P.; Pusset, M.; Pusset, J.; Laboute, P. Tetrahedron
1985, 41, 6019.
(4) Pettit, G. R.; McNulty, J.; Herald, D. L.; Doubek, D. L.; Chapuis,
J. C.; Schmidt, J. M.; Tackett, L. P.; Boyd, M. R. J. Nat. Prod. 1997,
60, 180.
€
(19) Foley, L. H.; Buchi, G. J. Am. Chem. Soc. 1982, 104, 1776.
r
10.1021/ol201741r
Published on Web 07/28/2011
2011 American Chemical Society

Scheme 1. Retrosynthetic Analysis of the Synthesis of Dibromo-
phakellin
trichloroketone to the carboxylic acid25 4 in 67% overall
yield.
Figure 1. Structures of oroidin, palau’amine, phakellins, and
phakellstatins.
well as asymmetrically.15,20 In addition, the enantioselective
synthesis of related (þ)-bromophakellin21 and (þ)-
phakellin15,20,21 has also been accomplished.
Scheme 2. Synthesis of Alkene Intermediate 2 from Pyrrole
In order to prepare the natural product dibromopha-
kellin as well as its un-natural analogues, we pursued a
general divergent route into this class of compounds.
Herein, we report the total synthesis of dibromophakellin
via a one-pot addition of protected guanidine across a
double bond, mediated by N-bromosuccinimide (NBS).
This methodology has also been applied as a general
approach to access several of its analogues.
In our retrosynthetic analysis of dibromophakellin, we
envisioned that guanidine could serve as a nucleophile to
open a bromonium ion (1), followed by a subsequent
intramolecular displacement of the bromide, to complete
the tetracyclic natural product (Scheme 1). Alternatively,
the electrons on the amide nitrogen may open the bromo-
nium ion, forming an N-acyliminium ion, which could be
attacked by the guanidine nucleophile. We planned on
forming the intermediate bromonium ion 1, by treatment
of alkene intermediate 2 with a source of electrophilic
bromine, such as NBS.
The synthesis of pivotal alkene intermediate 2 was
accomplished via a modified route as previously repor-
ted,22,23 starting from inexpensive pyrrole (Scheme 2). The
synthesis began with the acetylation of pyrrole with tri-
chloroacetyl chloride in good yield.24 This was followed
by bromination of 2-(trichloroacetyl)pyrrole (3) with
bromine in acetic acid and subequent hydrolysis of the
Next, coupling of 4 with L-proline methyl ester hydro-
chloride with EDCI gave amide 5 in 89% yield. Reduction
of the ester was achieved with lithium borohydride in
refluxing THF to afford the primary alcohol 6 in 69%
yield. Oxidation with IBX in DMSO22 afforded hemiam-
inal 7 as a single diastereomer in 68% yield, which is in
agreement withthe spectroscopic datareportedby Lindel’s
(20) Imaoka, T.; Iwamoto, O.; Noguchi, K.; Nagasawa, K. Angew.
Chem., Int. Ed. 2009, 48, 3799.
(21) Wang, S.; Romo, D. Angew. Chem., Int. Ed. 2008, 47, 1284.
(22) Jacquot, D. E. N.; Hoffmann, H.; Polborn, K.; Lindel, T.
Tetrahedron Lett. 2002, 43, 3699.
(23) Travert, N.; Martin, M.-T.; Bourguet-Kondracki, M.-L.; Al-
Mourabit, A. Tetrahedron Lett. 2005, 46, 249.
(24) Bailey, D. M.; Johnson, R. E.; Albertson, N. F. Org. Synth.
1971, 51, 100.
(25) Garg, N. K.; Caspi, D. D.; Stoltz, B. M. Synlett 2006, 3081.
Org. Lett., Vol. 13, No. 17, 2011
4551

group.22 Treatment of 7 with methane sulfonic acid led to
the desired elimination product 2 in 74% yield.23
Scheme 4. Synthesis of Alkene Intermediate 11
With alkene intermediate 2 in hand, we set out to form
the final cyclic guanidine ring, in what is the key step of this
synthesis. In early attempts to make dibromophakellin,
guanidine hydrochloride was employed as the nucleophilic
counterpart. The desired product was observed by mass
spectrometry; however isolation of the very polar com-
pound proved difficult. Inspired by work done in the Al-
Mourabit group,26,27 we decided to protect the guanidine
as its Boc or Cbz derivative in order to ease the isolation
and purification. Both guanidine derivatives were em-
ployed successfully; however, the Boc-guanidine gave
slightly better yields and is reported here (Scheme 3).
Scheme 3. Two-Step Synthesis of Dibromophakellin from
Alkene Intermediate 2
(Scheme 2). Subsequent dehydration with methane sulfonic
acid gave the alkene 11 in 81% yield.
Treatment of 11 with NBS in the presence of Boc-
protected guanidine gave intermediate 12 in 40% yield
(Scheme 5). It should be noted that it was necessary to use
at least 2 equiv of NBS, because the 3-position of the indole
was brominated prior to bromination of the alkene. Next,
removal of the bromine from the indole ring by Pd-
catalyzed hydrogenation afforded13in 87% yield. Finally,
removal of the Boc protecting group was completed by
treatment of 13 with 5% TFA in DCM to furnish the
indole analogue of dibromophakellin (14) in only six steps
and 15.4% overall yield from indole-2-carboxylic acid.
Treatment of alkene 2 with NBS in the presence of Boc-
protected guanidine gave the Boc-proctected natural pro-
duct 8 in 29% yield. Deprotection of the Boc group with
trifluoroacetic acid in dichloromethane afforded dibromo-
phakellin in 89% yield, as the TFA salt. This methodology
represents a convenient method to access the natural
product in only two steps from a readily available alkene
intermediate (2) and eight steps from commercially avail-
able pyrrole.
Scheme 5. Synthesis of Indole Analogue of Dibromophakellin
(14)
We next used this methodology to synthesize the indole
analogue of dibromophakellin (14). The synthesis of the
indole derivative of the natural product followed a similar
overall strategy. The synthesis began with the EDCI
coupling of commercially available indole-2-carboxylic
acid with L-proline methyl ester hydrochloride to give
amide 9 in good yield (Scheme 4).
Interestingly, reduction of 9 occurs with concomitant
attack of the indole nitrogen on the newly generated
aldehyde to give the isolated hemiaminal 10 in 76% yield.
This obviated the need for the reductionꢀoxidation
sequence used in the synthesis of the natural product
(26) Salvatori, M. D.; Abou-Jneid, R.; Ghoulami, S.; Martin, M. T.;
Zaparucha, A.; Al-Mourabit, A. J. Org. Chem. 2005, 70, 8208.
(27) Schroif-Gregoire, C.; Travert, N.; Zaparucha, A.; Al-Mourabit,
A. Org. Lett. 2006, 8, 2961.
Upon replacement of the guanidine nucleophile with
urea, we obtained a second analogue of dibromophakellin
4552
Org. Lett., Vol. 13, No. 17, 2011

(Scheme 6). Treatment of alkene intermediate 2 with NBS
in the presence of urea gave oxazoline 15 in 50% yield,
which was confirmed by an X-ray crystal structure (see
Supporting Information). Extension of this methodology
to access the phakellstatins (Figure 1) and their analogues
is currently ongoing in our laboratory.
guanidine nucleophile. This methodology allows rapid
entry into the pyrrole-imidazole family of molecules and
has also been extended to the indole and oxazoline analo-
gues of dibromophakellin. The biological activities of the
natural product as well as its analogues will be reported by
our group in the near future.
Acknowledgment. The authors gratefully acknowledge
the finiancial support provided by the National Insti-
tutes of Health (CA142644-01) and Michigan State
University. We also thank Dr. Richard J. Staples from
Michigan State University for X-ray analysis, as well
as the Michigan State University Max T. Rogers
NMR Facility and Michigan State University-RTSF-
Mass Spectrometry Core for allowing us use of their
instruments.
Scheme 6. Synthesis of 15 When Guanidine Is Replaced with
Urea
Supporting Information Available. Experimental pro-
cedures and characterization data for compounds 1, 2,
5ꢀ15. X-ray crystal data are available for compound 15.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, the total synthesis of dibromophakellin
has been achieved in eight linear steps from pyrrole, in
4.9% overall yield. The key step involves activation of an
alkene intermediate by NBS in the presence of a protected
Org. Lett., Vol. 13, No. 17, 2011
4553