Biomimetic synthesis and proposal of relative and absolute stereochemistry of heronapyrrole C

Article abstract of DOI:10.1021/ol300954s

The first synthesis of (-)-heronapyrrole C, the enantiomer of a unique farnesylated 2-nitropyrrole natural product is described. With none of the chiral centers of heronapyrrole C originally assigned, we proposed the most likely natural configuration on the basis of a putative biosynthetic pathway. The key step of the synthesis is a biomimetic polyepoxide cyclization cascade to establish the bis-THF moiety. Thus, (-)-heronapyrrole C is synthesized in eight steps from commercially available starting materials.

Full text of DOI:10.1021/ol300954s

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Biomimetic Synthesis and Proposal of
Relative and Absolute Stereochemistry
of Heronapyrrole C
Jens Schmidt and Christian B. W. Stark*
€
Fachbereich Chemie, Institut fu€r Organische Chemie, Universitat Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
stark@chemie.uni-hamburg.de
Received April 12, 2012
ABSTRACT
The first synthesis of (ꢀ)-heronapyrrole C, the enantiomer of a unique farnesylated 2-nitropyrrole natural product is described. With none of the
chiral centers of heronapyrrole C originally assigned, we proposed the most likely natural configuration on the basis of a putative biosynthetic
pathway. The key step of the synthesis is a biomimetic polyepoxide cyclization cascade to establish the bis-THF moiety. Thus, (ꢀ)-heronapyrrole
C is synthesized in eight steps from commercially available starting materials.
Terpenoid natural products are a diverse family of
compounds with a broad spectrum of bioactivities.1 Pyr-
roloterpenes constitute a small subgroup in which a terpe-
noid backbone is connected to a differently substituted
pyrrole ring.2 Examples such as pyrrolostatin3 and the
glaciapyrroles AꢀC3 were found to be highly active aslipid
peroxidation inhibitors and exhibit moderate cytotoxicity
against different tumor cell lines.3,4
Recently, Capon and co-workers reported the isolation
and characterization of three structurally unique 2-nitro-
pyrroloterpenes named heronapyrroles AꢀC (Figure 1).5
These compounds are produced by a Streptomyces sp.
(CMB-M0423) derived from a sand sample off Heron Island
(Australia). Together with the almost simultaneously re-
ported nitropyrrolins,6 described by Fenical and co-workers,
these natural products are the first examples of nitropyr-
roloterpenes. The heronapyrroles and nitropyrrolins are
structurally closely related hybrid natural products sharing
a previously unknown 2-nitropyrrole aromatic core to which
a differently oxidized sesquiterpene unit is attached in the 4
position of the heterocycle. Heronapyrroles AꢀC show
significant activity against Gram-positive bacteria without
adverse effects on mammalian cell lines.5
Based on our interest in the development of reaction
methodology for the construction of substituted oxygen
(5) Raju, R.; Piggott, A. M.; Barrientos Diaz, L. X.; Khalil, Z.;
Capon, R. J. Org. Lett. 2010, 12, 5158.
(6) Kwon, H. C.; Espindola, A. P. D. M.; Park, J.-S.; Prieto-Davo,
(1) For an overview, see: Breitmaier, E. Terpenes; Wiley-VCH:
Weinheim, 2006.
(2) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R.
ꢀ
A.; Rose, M.; Jensen, P. R.; Fenical, W. J. Nat. Prod. 2010, 73, 2047.
Nat. Prod. Rep. 2006, 23, 517.
€
(7) (a) Roth, S.; Gohler, S.; Cheng, H.; Stark, C. B. W. Eur. J. Org.
€
Chem. 2005, 4109. (b) Gohler, S.; Stark, C. B. W. Org. Biomol. Chem.
(3) Isolation: Kato, S.; Shindo, K.; Kawai, H.; Odagawa, A.; Matsuoka,
M.; Mochizuki, J. J. Antibiot. 1993, 46, 892. Synthesis: Fumoto, Y.; Eguchi,
T.; Uno, H.; Ono, N. J. Org. Chem. 1999, 64, 6518.
(4) Isolation: Macherla, V. R.; Liu, J.; Bellows, C.; Teisan, S.;
Nicholson, B.; Lam, K. S.; Potts, B. C. M. J. Nat. Prod. 2005, 68, 780.
Synthesis and determination of absolute configuration: Riclea, R.;
Dickschat, J. S. Chem.ꢀEur. J. 2011, 17, 11930.
€
€
2007, 5, 1605. (c) Gohler, S.; Roth, S.; Cheng, H.; Goksel, H.; Rupp, A.;
Haustedt, L. O.; Stark, C. B. W. Synthesis 2007, 2751. (d) Cheng, H.;
Stark, C. B. W. Angew. Chem. 2010, 122, 1632. Angew. Chem., Int. Ed.
2010, 49, 1587.
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Chem., Int. Ed. 2006, 45, 6218.
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10.1021/ol300954s
XXXX American Chemical Society

acyclic terpenoid subunit is oxidatively converted to the
bis-THF substructure (Scheme 1). In close correlation to
the biosynthesis of polyether antibiotics14 and the presumed
biogenesis of acetogenines15 as well as terpenoid oligo-
THF’s16b one may suspect a polyepoxide cascade cyclization10
pathway (Scheme 1).16
Scheme 1. Possible Biosynthesis of Heronapyrrole C
Figure 1. Structures of heronapyrroles AꢀC.
heterocycles (THFs7 and THPs8) and applications to
natural product synthesis,9 we decided to investigate a
synthetic approach to the bis-THF natural product hero-
napyrrole C. In this particular case, our strategy is
centered on a putative biomimetic polyepoxide cyclization
cascade.10,11
Capon and co-workers originally isolated 0.5 mg of hero-
napyrrole C and were able to assign the overall structure
and the cis-geometry (ROESY) across one of the THF rings
(see Figure 1).5 None of the other stereocenters, neither
absolute nor relative stereochemistry, were established. With
five chiral centers in natural heronapyrrole C one needs to
synthesize up to 32 stereoisomers (or 16 diastereoisomers) to
unambiguously determine the configuration of the natural
product. In order to narrow down this number and select our
initial target stereostructure, we decided to follow a putative
biomimetic pathway. Whereas the timing and manner of the
introduction of the nitro group during heronapyrrole bio-
synthesis may be a matter of some debate,12 other key steps
appear somewhat less speculative. Thus, after polyprenyla-
tion13 of (a potentially peptide bound2) pyrrole system the
On the basis of this biosynthetic scheme and a set of
further assumptions, we derived the structure of the most
likely natural stereoisomer of heronapyrrole C (Scheme 2).
The starting point of this chain of assumptions is the
putative biosynthetic relation of heronapyrrole C to her-
onapyrrole A already suggested by Capon and co-workers.5
Accordingly, the absolute stereochemistry at C7 and C15,
originally determined for heronapyrrole A17 only (see
Figure 1), would be identical in heronapyrrole C (7S,15R;
red in Scheme 2). Moreover, with the hypothesis that the
bis-THF backbone is biosynthetically derived from an
(E,E)-farnesol derivative13 (blue in Scheme 2) via an
epoxide cyclization cascade10 the stereocenter at C8 has to
be S-configured. The relative configuration between C8 and
C11 (cis-THF;5 see Figure 1) results in the secondary center
at C11 to be likewise S-configured (orange in Scheme 2).
The same reasoning as before (E,E-triene precursor) leads
to the S-configuration of the neighboring tertiary center at
C12 (blue in Scheme 2). We therefore propose heronapyr-
role C 3 as depicted in Scheme 2 as the most likely natural
stereoisomer (relative and absolute stereochemistry) and
decided to synthesize this compound.
€
(9) Goksel, H.; Stark, C. B. W. Org. Lett. 2006, 8, 3433.
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1923. (b) Kers, J. A.; Wach, M. J.; Krasnoff, S. B.; Widom, J.; Cameron,
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Sontag, B.; Dessoy, M. A. Organic Chemistry Highlights IV; Schmalz,
H.-G., Ed.; Wiley-VCH: Weinheim, 1999; p 79.
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Estornell, E.; Cortes, D. Nat. Prod. Rep. 2005, 22, 269.
(16) For general reviews on the biosynthesis of oligo-THF and
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related natural products, see: (a) Koert, U. Angew. Chem., Int. Ed.
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Engl. 1995, 34, 298. Angew. Chem. 1995, 107, 326. (b) Fernandez, J. J.;
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Derivation of a Likely Relative and Absolute
Stereochemistry of Heronapyrrole C
Scheme 3. Heronapyrrole C: Retrosynthetic Analysis
dihydroxylation using the CoreyꢀNoeꢀLin catalyst22
provided the dienediol (þ)-24 in a clean and highly posi-
tion- and stereoselective reaction. The enantiomeric excess
was determined to be 96% ee after conversion to the
Mosher-ester23 and by chiral HPLC.
As summarized in the retrosynthetic scheme we decided
to construct the bis-THF backbone at the end of the
synthesis (Scheme 3). Accordingly, dihydroxybisepoxide
13 is regarded as the precursor of (an N-protected) hero-
napyrrole C. The required functional groups and stereo-
chemistry wereintended tobeestablishedin asequenceofa
position- and stereoselective dihydroxylation followed by
a double Shi-epoxidation18 leading to farnesylated nitro-
pyrrole15. Duetothe somewhatrough reaction conditions
required for aromatic nitration,19 we chose to introduce
the nitro group at an early stage of the synthesis directly
after farnesylation of the pyrrole ring. This strategy seems
to be in accord with the biosynthesis of the heronapyrroles
asthe lessoxidized naturalcongeners alsocontain thesame
nitro group (in the same position).2,12 Therefore, known
3-bromopyrrole20 and E,E-farnesyl derivative containing a
leaving group at C1 (LG in Scheme 3) represent the
starting materials of our synthetic strategy.
Scheme 4. Heronapyrrole C Synthesis: Pyrrole Farnesylation
and Nitration
The synthesis commences with the coupling of commer-
cially available N-TIPS-protected 3-bromopyrrole to far-
nesyl bromide followed by N-deprotection and nitration
of the aromatic heterocycle (Scheme 4). Nitration under
standard reaction conditions (H2SO4/HNO3)19 produced
the desired product only in minute amounts and lead
to significant problems during purification. The use of
AcNO221 proved more reliable and reproducible, albeit the
desired nitropyrrole was still isolated with low selectivity.
However, the isomers were separable by standard flash
chromatography. Subsequent Boc protection of the 2,4-
substituted regioisomer delivered the precursor for the
oxidation/cyclization sequence in 91% yield. Asymmetric
Double organocatalytic asymmetric epoxidation using
the (þ)-Shi catalyst18 produced the precursor for the
cascade cyclization in high yield and good diastereoselec-
tivity (Scheme 5). Minor diastereoisomers were detectible
by TLC and NMR analysis of samples taken from crude
reaction mixtures. Also, partial cyclization seems to occur
under the buffered and slightly basic reaction conditions
and/or during workup (TLC analysis). The diepoxide 27
was therefore not purified but directly used for the next step.
(18) (a) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am.
Chem. Soc. 1997, 119, 11224. (b) Zhao, M.-X.; Shi, Y. J. Org. Chem.
2006, 71, 5377. For a review, see: Shi, Y. Acc. Chem. Res. 2004, 37, 488.
(19) (a) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods
and Mechanism; VCH: New York, 1989. (b) Schofield, K. Aromatic
Nitration; Cambridge University Press: Cambridge, 1980.
(20) Stefan, K.-P.; Schuhmann, W.; Parlar, H.; Korte, F. Chem. Ber.
1989, 122, 169.
(22) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36,
8741.
(23) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
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(21) Bordwell, F. G.; Garbish, E. W., Jr. J. Am. Chem. Soc. 1960, 82,
3588.
(b) Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17.
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Org. Lett., Vol. XX, No. XX, XXXX
C

A and C. On the other hand, the assumption of a polyepoxide
cyclization cascade and an E,E-configured triene precursor
may still be correct. Based on the close correlation of NMR
data and the coelution of our synthetic material with natural
(þ)-heronapyrrole C we do not believe that we prepared a
diastereoisomer but rather the enantiomer of the natural
product. In order to corroborate this assertion, we currently
focus on the synthesis of other stereoisomers of heronapyr-
role C as well as heronapyrrole A.
Scheme 5. Heronapyrrole C: Completion of the Total Synthesis
In summary, we have presented the first synthesis of
(ꢀ)-heronapyrrole C and proposed the relative and abso-
lute stereochemistry of the natural product. On the basis
of a putative biosynthesis we suggested a likely stereo-
structure of the bis-THF pyrroloterpene. Intriguingly, the
synthesized compound appears to match the relative but
not the absolute stereochemistry. Further, substantiation
of these findings would rise questions on the origin of
differences in the biosynthesis of the heronapyrroles. Key
steps of our approach to heronapyrrole C are a pyrrole
farnesylation and nitration followed by a two-step sequence
of stereoselective oxidations introducing five stereogenic
centers. Finally, a biomimetic polyepoxide cyclization
cascade10,11 is used to establish the bis-THF moiety.
Acid catalyzed (CSA; camphorsulfonic acid) epoxide-
opening cascade reaction yielded, after column chromato-
graphy,
a stereoisomerically pure product. Finally,
heating of compound (ꢀ)-28 in a mixture of methanol
and water led to a smooth N-deprotection, the product
was isolated in quantitative yield. Close inspection of NMR
data including correlation and NOESY spectra revealed
identity of our synthetic sample with the natural product
(see the Supporting Information for details). In addition,
the synthetic compound was found to coelute with natural
(þ)-heronapyrrole C when compared by HPLC analysis.24
To our surprise, however, the optical rotation showed a
comparable absolute value but the opposite sign (natural
heronapyrrole C: [R]D = þ7.6, c = 0.05, MeOH,5 synthetic
heronapyrrole C: [R]D = ꢀ6.7, c = 2.3, MeOH), clearly
indicating that we prepared the mirror image of natural
heronapyrrole C. Apparently, the first assumption of our
stereochemical derivation (Scheme 2, red) is wrong. An
equally obvious and intriguing explanation would be that
there is no such biogenetic relation between heronapyrrole
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (Project No. STA 634/1-3) and the Fonds der
Chemischen Industrie for financial support of this research.
We are also grateful to Prof. Dr. Robert J. Capon (University
of Queensland, Australia) for helpful discussions, generous
supply of analytical data, and experiments concerning the
comparison of synthetic and natural heronapyrrole C.
Supporting Information Available. Experimental pro-
cedures, spectral and analytical data, as well as compar-
isons between natural (þ)-heronapyrrole C and synthetic
material. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) These experiments were carried out in the laboratories of Prof.
Dr. Robert J. Capon at the University of Queensland (Australia). See the
Supporting Informations for details.
The authors declare no competing financial interest.
D
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