Diversity-oriented approach to pyrrole-imidazole alkaloid frameworks

Article abstract of DOI:10.1021/ol200067e

An exploration of imidazolylpropargyl amides as linchpin synthons for the construction of a diverse array of heterocyclic frameworks, many of which are related to those found in the oroidin derived alkaloids, is described. One such intermediate has been u

Full text of DOI:10.1021/ol200067e

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1382–1385
Diversity-Oriented Approach to Pyrrole-
Imidazole Alkaloid Frameworks
Manojkumar R. Bhandari,† Muhammed Yousufuddin,‡ and Carl J. Lovely*,†
Department of Chemistry and Biochemistry, The University of Texas at Arlington,
Arlington, Texas 76019, United States, and Center for Nanostructured Materials,
The University of Texas at Arlington, Arlington, Texas 76019, United States
lovely@uta.edu
Received January 10, 2011
ABSTRACT
An exploration of imidazolylpropargyl amides as linchpin synthons for the construction of a diverse array of heterocyclic frameworks, many of
which are related to those found in the oroidin derived alkaloids, is described. One such intermediate has been used in a formal total synthesis of
cyclooroidin.
Nature is the ultimate synthetic chemist using a rela-
tively limited group of building blocks with a large variety
of enzymes to construct a vast array of secondary meta-
bolites, usingwhatcan be thought of asreagent-controlled,
diversity-orientedsynthesis.1,2 These so-called natural pro-
ducts have attracted the attention of organic chemists not
only for the challenge they often present to contemporary
synthetic methods3 but also for their potential as lead
compounds in medicinal chemistry endeavors.4,5 Attempts
have been made to harness the latent reactivity embedded
within these building blocks in synthetic programs, but
even state of the art synthetic methods cannot compete
with biosynthetic machinary to produce the same levels of
control, selectivity, and diversity. An additional limitation
of such an approach is that using biosynthetic precursors
(or close analogs) can often restrict synthetic options for
accessing different cyclic frameworks or for postcycliza-
tion functionalization from a common precursor and thus
can reduce structural diversity in medicinal chemistry
programs. One way to circumvent these limitations is to
utilize a minimally functionalized substrate which contains
a functional group or groups which by suitable choice of
reagents has multiple reaction pathways available to it
leading to diverse cyclic frameworks and which can under-
go additional postreaction chemistry.
Our group6 has over the past few years developed an
interest in inventing synthetic approaches to the oroidin
family of alkaloids (e.g., 1-8, Figure 1).7,8 These marine
sponge-derived natural products exhibit the characteristics
described above, wherein a single building block (oroidin
(1) in this case) gives rise to several different natural
products through various modes of presumably enzyme-
catalyzed cyclization or oligomerization/cyclization (to
date >150 family members have been reported). As a
result, oroidin monomers 4-6,9-14 dimers 7-8,15-17 and
tetramers18 are known to display a wide variety of
(6) He, Y.; Du, H.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965.
(7) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2010, 27, 165.
(8) (a) For recent reviews, see: Forte, B.; Malgesini, B.; Piutti, C.;
Quartieri, F.; Scolaro, A.; Papeo, G. Mar. Drugs 2009, 7, 705. (b)
Weinreb, S. M. Nat. Prod. Rep. 2007, 24, 931.
(9) Fattorusso, E.; Taglialatela-Scafati, O. Tetrahedron Lett. 2000,
41, 9917.
† Department of Chemistry and Biochemistry.
‡ Center for Nanostructured Materials.
(1) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47,
48.
(2) Cordier, C.; Morton, D.; Murrison, S.; Nelson, A.; O’Leary-
Steele, C. Nat. Prod. Rep. 2008, 24, 719.
(3) Morris, J. C.; Phillips, A. J. Nat. Prod. Rep. 2010, 27, 1186.
(4) Newman, D. J.; Cragg, G. M. J. Nat. Prod 2008, 70, 461.
(5) Capon, R. J. Eur. J. Org. Chem. 2001, 633.
(10) For total synthesis, see: (a) Mukherjee, S.; Sivappa, R.; Yousu-
fuddin, M.; Lovely, C. J. Org. Lett. 2010, 12, 4940 and references cited
therein. See also: (b) Trost, M. B.; Osipov, M.; Dong, G. J. Am. Chem.
Soc. 2010, 132, 15800.
(11) Albizati, K. F.; Faulkner, D. J. J. Org. Chem. 1985, 50, 4163.
r
10.1021/ol200067e
Published on Web 02/21/2011
2011 American Chemical Society

Scheme 1
Figure 1. Selected oroidin-derived alkaloids.
connectivities and functionalization. While we and others
have been interested in developing total syntheses of
several members of this family of natural products, we
have also developed an interest in accessing new frame-
works that can be formally derived from oroidin through
heretofore undiscovered cyclization pathways. It is worth
noting that Lindel pointed out in a seminal review of the
oroidin alkaloids that, intrisically at least, various other
connectivities not yet observed in nature are not only
conceivable for this family of natural products but also
energetically reasonable.19
It is with this notion in mind that we have pursued a
strategy to the oroidin alkaloids in which we have at-
tempted to mimic nature’s approach to secondary meta-
bolite construction by utilizing a common type of building
block and using reagent control to access a variety of
different frameworks. To begin to accomplish these goals,
our attention has been focused on imidazolylpropargyl
amides (e.g., 9, Figure 1). This substrate was selected for
exploration due to a combination of ease of preparation
(Sonogashira reaction with terminal acetylenes and haloi-
midazole derivatives), we have used such intermediates in
total synthesis endeavors, and the potential spectrum of
chemistry which it could undergo.20 Specifically, intramo-
lecular cyclization reactions were targeted for investiga-
tion, and as a result, several pathways can be identified
depending on which position of the pyrrolecarboxamide
(C4-carbon, N1-nitrogen, or carbonyl oxygen, Figure 1)
and the mode of alkyne cyclization (exo vs endo) engage in
the reaction. Thespecificreaction pathwayfollowedwould
then depend upon the reagents chosen and the specific
characteristics of the substrate.
(12) Xu, Y.-z.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1997, 62,
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2010, 12, 4532. Ma, Z.; Lu, J.; Wang, X.; Chen, C. Chem. Commun. 2011,
47, 427.
Our initial experiments toward these goals focused on
the use of a parent system 11 (Scheme 1) wherein both the
pyrrole and amide nitrogen atoms were left unsubstituted;
this substrate would provide an idea of the baseline
reactivity of these systems. Gratifyingly, when 11 was
treated with a combination of Pd(OAc)2 and TFA at room
temperature cyclization occurred to provide the oxazoline
(17) Araki, A.; Kubota, T.; Aoyama, K.; Mikami, Y.; Fromont, J.;
Kobayashi, J. Org. Lett. 2009, 11, 1785.
(19) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753.
(20) Bhandari, M. K.; Sivappa, R.; Lovely, C. J. Org. Lett. 2009, 11,
1535.
(18) (a) Grube, A.; Koeck, M. Org. Lett. 2006, 8, 4675. See also:(b)
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Org. Lett., Vol. 13, No. 6, 2011
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14 (Scheme 1).21 A related structural fragment is found in
the oroidin dimers nagelamide R and T (8),17,22,23 and
therefore this chemistry may have value in approaches to
these natural products.23 To redirect this cyclization mani-
fold, two substrates were prepared in which the participa-
tion of the enol tautomer was not feasible. In the first case,
the ester analog of 11 was subjected to Pd-catalyzed
hydroamination (Pd(OAc)2, Cs2CO3), leading to forma-
tion of the morpholinone ring (13f16, 45%, Scheme 1),
the connectivity, and in particular the location and geo-
metry of the olefin, was established by X-ray crystallogra-
phy. Similarly, it was found that the Tr-protected amide 12
participated in the cyclization with Pd-catalysis providing
the corresponding pyrazinone 16 (∼80%, Scheme 1). In-
terestingly, we found that both reactions proceeded
equally or more efficiently in the absence of the Pd-
catalyst, indicating that the reaction is simply base-
mediated.24 Of particular note is the relative efficiency of
the base-induced formation of 16, which is presumably a
result of the buttressing effect of the Tr-moiety.25
Scheme 2
Given our success with the cyclization of substrates via
the pyrrole nitrogen (Scheme 1), we decided to introduce
substituents on this nitrogen to prevent cyclization via this
manifold to establish whether cyclization would occur via
C-H insertion at the pyrrole C4 atom (net hydroaryla-
tion).26,27 For convenience only, an N-methyl group was
employed. Under Pd-catalysis smooth cyclization of 17
occurred (Scheme 2) to provide what we initially antici-
pated was an isocyclooroidin skeleton; however, X-ray
crystallography provided something of a surprise. While
cyclization had occurred to provide a piperidine-type ring
system, there was net acyl migration resulting in the
formation of 18. While this result was unexpected, a rear-
ranged pyrrole moiety has been observed recently in two
examples of the oroidin alkaloids, e.g., cylindradine A
(22),28 and this modification may in fact be a more
common structural feature than currently realized. A
similar type of rearrangement has been noted previously
in the literature during a study of oxidative Heck-type
reactions with N-allyl pyrrolecarboxamides.29 This out-
come was rationalized mechanistically through ipso addi-
tion to form a spirocyclic intermediate, which then
rearranges to form fused systems. A similar mechanistic
proposal through spiro adduct 19 rearranging to the more
ꢀ
stable intermediate 20 (vis a vis the alternative rearrange-
ment pathway to 21) presumably accounts for the forma-
tion of the observed product 18.
Gold-catalyzed reactions of alkynes have recently at-
tracted considerable attention in the literature,30 and it
seemed relevant to establish the reactivity patterns of this
system. In particular, we were motivated by the notion that
access to stevensine-like systems (cf. 5 in Figure 1) might be
possible via a gold-catalyzed addition of the pyrrole to the
alkyne (hydroarylation).31 In an initial attempt, alkyne 17
was exposed to a Au(I) precatalyst resulting in conversion
of the starting material into a new cyclic product. Pre-
liminary structural assignment was complicated by signals
from the trityl moiety dominating the aromatic region of
1
the H NMR spectrum. Treatment of the initial product
withTFA resultedinthe cleavageofthe tritylmoietywhich
substantially simplified the spectroscopic data and allowed
us to assign the product structure as the N-methyl aniline
derivative 24 (Scheme 3). This structure was subsequently
confirmed through X-ray crystallography. Given the rela-
tively high temperatures required to effect this reaction,
it would suggest that this product is formed as a result
of an intramolecular Diels-Alder/ring-opening reaction
(21) Jia, C.; Piao, D.; Kitamura, T.; Fujiwara, Y. J. Org. Chem. 2000,
65, 7516.
(22) Appenzeller, J.; Tilvi, S.; Martin, M.-T.; Gallard, J.-F.; El-bitar,
H.; Dau, E. T. H.; Debitus, C.; Laurent, D.; Moriou, C.; Al-Mourabit,
A. Org. Lett. 2009, 11, 4874.
(23) Mukherjee, S.; Sivappa, R.; Yousufuddin, M.; Lovely, C. J.
Synlett 2010, 817.
(24) Llauger, L.; Bergami, C.; Kinzel, O. D.; Lillini, S.; Pescatore, G.;
Torrisi, C.; Jones, P. Tetrahedron Lett. 2009, 50, 172.
(25) Choony, N.; Dadabhoy, A.; Sammes, P. G. Chem. Commun.
1997, 513.
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J. Org. Chem. 2009, 74, 1826.
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Chem. 2009, 74, 9517.
(28) Kuramoto, M.; Miyake, N.; Ishimaru, Y.; Ono, N.; Uno, H.
(30) For recent reviews of gold chemistry, see: (a) Hashmi, A. S. K.
Chem. Rev. 2007, 107, 3180. (b) Hashmi, A. S. K. Angew. Chem., Int. Ed.
2008, 47, 6754. (c) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108,
3239. (d) Muzart, J. Tetrahedron 2008, 64, 5815. (e) Skouta, R.; Li, C.-J.
Tetrahedron 2008, 64, 4917. (f) Shen, H. C. Tetrahedron 2008, 64, 3885.
Org. Lett. 2008, 10, 5465.
€
(29) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Paladino, G.
Tetrahedron 2005, 61, 1077.
(31) Gruit, M.; Michalik, D.; Kruger, K.; Spannenberg, A.; Tillack,
A.; Pews-Davtyan, A.; Beller, M. Tetrahedron 2010, 66, 3341.
1384
Org. Lett., Vol. 13, No. 6, 2011

Scheme 3
Scheme 4
synthesis efforts. In Scheme 4 we illustrate an application
of one of these derivatives in a formal total synthesis of
cyclooroidin (4).10 Pyrazinone 15 was treated with TFA to
remove the Tr-protecting group providing 28; X-ray crys-
tallography clearly indicated that the double bond was
exocyclic with the geometry shown. Subjection of the
resulting enamine 28 to catalytic hydrogenation resulted
in the formation of the reduction product 29, a compound
which has servedasan intermediate in the total synthesis of
cyclooroidin (4) reported by our group.10
In this manuscript we have reported a diversity-oriented
approach to several structurally distinct frameworks some
of which are found in the oroidin alkaloids from a common
type of building block. Our strategy is predicated on a
pseudo biomimetic approach, wherein a common precursor
type is employed in a number of different reagent-controlled
reactions. We have demonstrated the value of this approach
in a formal total synthesis of cyclooroidin (4). While at this
stage there is room for optimization of individual cycliza-
tion manifolds, we anticipate the real value of this chemistry
is the generation of multiple ring systems amenable to
further elaboration and in SAR evaluations.
between the pyrrole and the alkyne.32 A control reaction
conducted in the absence of the Au(I) complex indicated
that the cycloaddition proceeds under the same conditions,
but the efficiency is somewhat attenuated and additional
byproducts are formed. This result provides circumstantial
evidence that there may be catalysis by Au(I). Changing the
catalyst from a Au(I) to a Au(III) salt resulted in a change-
over in the product, leading to the formation of the azepine
derivative 25 (confirmed by X-ray analysis) as the only
isolated product.33 This result mirrors the observations of
the Beller lab which reported on the cyclization reactions of
related substrates.31 As with these literature examples,
rearrangement of the pyrrole carboxamide moiety oc-
curred. Mechanistically, a similar ipso addition-rearrange-
ment pathway was proposed (cf. Scheme 2) to account for
the acyl migration. We noted that there was substantial loss
of the trityl moiety in this chemistry, and thus we prepared
and evaluated the corresponding Namide-methyl derivative
23. Interestingly, we found that this change results in the
formation of two azepine derivatives 26 and 27 (confirmed
by X-ray crystallography), of which the major product
resembles the core framework of stevensine (5).
Acknowledgment. Wethank Prof. R. Sivappa(UMAss-
Dart) for valuable discussions during the initial phases of
this project. This work was supported by the Robert A.
Welch Foundation (Y-1362) and the NIH (GM065503).
The NSF (CHE-0234811 and CHE-0840509) is thanked
for partial funding of the purchases of the NMR spectro-
meters used in this work.
One of the reasons that we initiated this program was to
use these cyclic derivatives as launching points for total
Supporting Information Available. Detailed experimen-
tal procedures and copies of 1H and 13C NMR spectra for
all new compounds. CIFs for compound 16, 18, 24, 25, 27,
28. This material is available free of charge via the
Internet at http://pubs.acs.org.
(32) Jung, M. E.; Rohloff, J. C. J. Chem. Soc., Chem. Commun. 1984,
630.
(33) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.;Eur. J.
2007, 13, 1358.
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