Application of in situ-generated Rh-bound trimethylenemethane variants to the synthesis of 3,4-fused pyrroles

Article abstract of DOI:10.1021/ja401380d

Rh-bound trimethylenemethane variants generated from the interaction of a Rh-carbenoid with an allene have been applied to the synthesis of substituted 3,4-fused pyrroles. The pyrrole products are useful starting points for the syntheses of various dipyrromethene ligands. Furthermore, the methodology has been applied to a synthesis of the natural product cycloprodigiosin, which demonstrates antitumor and immunosuppressor activity.

Full text of DOI:10.1021/ja401380d

Communication
pubs.acs.org/JACS
Application of In Situ-Generated Rh-Bound Trimethylenemethane
Variants to the Synthesis of 3,4-Fused Pyrroles
Erica E. Schultz and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
Davies and coworkers have developed an elegant related
ABSTRACT: Rh-bound trimethylenemethane variants
generated from the interaction of a Rh-carbenoid with
an allene have been applied to the synthesis of substituted
3,4-fused pyrroles. The pyrrole products are useful starting
points for the syntheses of various dipyrromethene ligands.
Furthermore, the methodology has been applied to a
synthesis of the natural product cycloprodigiosin, which
demonstrates antitumor and immunosuppressor activity.
methodology for the synthesis of substituted pyrroles that
utilizes furan starting materials.7 The 3,4-fused pyrrole
structures that we have prepared feature prominently in several
ligand motifs, especially of the dipyrromethene type. As further
testament to the utility of this methodology, we have applied it
to the total synthesis of the natural product cycloprodigiosin.
We envisioned Rh-complexed TMM equivalent C arising
from the interaction between allene moiety D and imino Rh-
carbenoid E (Scheme 1A).8 The nitrogen atom of the N-
he trimethylenemethane (TMM) moiety (Figure 1) has a
rich history in bonding and reactivity that dates back to
Scheme 1. Proposed Application of Rh−TMM to Pyrrole
Formation
T
tosylimine group in C could then engage the allyl cation to
provide dihydropyrrole derivative F, which could aromatize to
pyrrole G following double bond migration.9,10
Figure 1. Trimethylenemethane equivalents.
the seminal work of Moffitt1 and pioneering studies of Dowd.2,3
The connection between TMM and methylenecyclopropane
(MCP) is well-recognized, and many studies have shown that
the parent TMM is a ground-state triplet with a low barrier for
conversion to the singlet and thus closes almost instantaneously
to the corresponding MCP.3b To exploit the reactivity of
TMMs in synthetic applications, they are often constrained as a
part of a ring4 or complexed to a metal center. As a result, many
metal-mediated processes that convert MCPs to metal-
complexed TMMs have been reported over the last two
decades.5 By far the most recognized and utilized metal-
complexed TMM is A (Figure 1), where the Pd is intimately
associated with the cationic termini. The Pd−TMM complex A
was introduced by Trost6 and has been featured as a “three-
carbon partner“ in numerous cycloaddition reactions. Despite
the now well-established utility of metal-complexed TMM
variants, there have been comparatively few reported TMM
equivalents where the metal is bound to the anionic portion of
this reactive intermediate (see B). In this communication, we
report the generation of unique Rh-bound TMM derivatives C
that are related to B and can be applied in the synthesis of 3,4-
fused pyrrole derivatives. Contemporaneous with our studies,
The success of the general transformation outlined in
Scheme 1A hinges on the effective generation of Rh-carbenoids
related to E, which have recently been demonstrated to arise
from the decomposition of N-sulfonyl-1,2,3-triazoles by Fokin,
Gevorgyan, and co-workers (Scheme 1B).11,12 Specifically, we
were drawn to an intramolecular variant of the transformation
shown in Scheme 1A wherein allenylalkynes (4 in Scheme 2)
could be subjected to Cu-catalyzed Huisgen cycloaddition13 to
yield 5. On the basis of the observations of Fokin and co-
workers, it was anticipated that exposure of 5 to catalytic
Rh2(oct)4 would lead to the formation of N-sulfonylimino Rh-
carbenoid intermediate 6, which following the sequence
outlined in Scheme 1A would yield fused N-tosylpyrrole 7.
Pyrrole derivatives related to 7 are highly valuable starting
points for the preparation of dipyrromethene ligands, which
have various applications including use as dyes14 and scavengers
of reactive oxygen species (e.g., as in 8).15
One significant potential pitfall of our planned trans-
formation of 4 to 7 was the possibility that Rh-carbenoid
Received: February 6, 2013
Published: March 11, 2013
© 2013 American Chemical Society
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Scheme 2. Intramolecular Pyrrole Annulation Reaction for
the Formation of 3,4-Fused Pyrroles
Table 1. Scope of 3,4-Fused Pyrrole Formation
intermediates related to 6, consistent with well-documented
precedent,16 would undergo a competing 1,2-hydride shift to
yield α,β-unsaturated N-tosylimines instead of engaging the
allene group. Although 1,2-hydride shifts of α-keto Rh-
carbenoids have been shown to be minimal at lower
temperature,17 Murakami showed that this pathway is facile
for α-N-sulfonylimino Rh-carbenoids,18 especially at the high
temperatures that are required for the decomposition of N-
tosyl-1,2,3-triazoles to the corresponding Rh-carbenoids (>100
°C). As a result, the successful transformation of 4 to 7 would
require that the 1,2-hydride shift from the Rh-carbenoid
intermediates did not compete with the desired pathway.
We initiated our studies with allenylalkyne 9 (Scheme 3),
which was readily prepared in three steps from phenylacetylene
Scheme 3. Development of One-Pot Conditions for Pyrrole
Formation
of aryl substituents, including a naphthyl group (entry 1a) as
well as arenes bearing electron-withdrawing (entries 1b and c)
and electron-donating (entry 1d) groups on the allenylalkyne
substrates are tolerated. In addition, cycloalkyl- and alkyl-
bearing substrates are transformed to the corresponding pyrrole
products in good yields (entries 1e and 1f). A bicyclo[3.3.0]-
pyrrole, which is inherently more strained than the
corresponding bicyclo[4.3.0] systems,22 could also be accessed
(entry 2), albeit in a slightly diminished overall yield (55%).
The utility of the 3,4-fused pyrrole products is evident in the
conversions involving 12 (Scheme 4). For example, the related
benzyl derivative 13b was readily transformed to dipyrrome-
and trimethylsilyl (TMS)-protected hex-5-ynal.19 The copper-
(I) thiophene-2-carboxylate (CuTc)-catalyzed Huisgen cyclo-
addition of 9 with TsN3 proceeds without event to give N-tosyl-
1,2,3-triazole 10 in 70% yield following column chromato-
graphic purification. Gratifyingly, exposure of 10 to Rh2(oct)4
(5 mol %) in CHCl3 at 140 °C (microwave), following the
conditions of Fokin and Murakami,20 gives 2,3,4-substituted
pyrrole 11 in 80% yield. Since both the Cu-catalyzed Huisgen
azide−alkyne cycloaddition and the Rh-catalyzed triazole
decomposition/pyrrole formation were conducted in chloro-
form, the development of a one-pot sequence to convert 9 to
11 was straightforward. Importantly, the catalyst loadings of
both CuTc and Rh2(oct)4 could be reduced significantly (to 1
and 0.5 mol %, respectively), and 11 is obtained in higher
overall yield (77% yield over two steps) than in the sequence
where the triazole intermediate was isolated and purified.21
Under the optimized one-pot conditions, a range of
allenylalkyne substrates are efficiently transformed to the
corresponding fused pyrroles (Table 1). For example, a variety
Scheme 4. Further Functionalization of 3,4-Fused Pyrroles
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thene derivative 14, a peroxynitrite scavenger, by Neumann and
co-workers.15 Furthermore, 13a and 12 can be transformed to
ester-substituted pyrrole 15 and bromo derivative 16,
respectively, in good yields in preparation for subsequent
pyrrole functionalization reactions.
In addition to the applications detailed in Scheme 4, we
applied our method for 3,4-fused pyrrole synthesis to the total
synthesis of the natural product cycloprodigiosin (23) (Scheme
523). Although this natural product, which is produced by
should enable a full evaluation of the influence of the methyl-
bearing stereocenter on the biological properties of the natural
product.38
In conclusion, we have reported the synthesis of 2-
substituted 3,4-fused pyrroles from allenylalkyne substrates.
The one-pot transformation has its basis in a hypothesis for
accessing unique Rh-bound trimethylenemethane intermedi-
ates. The pyrrole products should prove to be versatile starting
points for a range of applications, as illustrated by the
conversion of 13b to a dipyrromethene derivative as well as
the conversion of 12 and 13a to other multiply substituted
pyrroles. We have also applied the 3,4-fused pyrrole synthesis
methodology to the synthesis of the natural product cyclo-
prodigiosin. Our current efforts are centered on exploring the
utility of this reaction in the synthesis of natural-product-like
structures and novel dipyrromethene ligands.
Scheme 5. Synthesis of Cycloprodigiosin (23)
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
rsarpong@berkeley.edu
■
Notes
bacterial strains including Pseudoalteromonas (Alteromonas)
rubra, Pseudoalteromonas denitrificans, and Vibrio gazogenes,
has been known for a long time,24 its true structure was only
secured in 1983.25 Since that time, it has emerged as a potent
proapoptotic anticancer compound26 and immunosuppres-
sant.27 Over the past two decades, there has been sustained
synthetic interest in the prodigiosin family as a whole.28
However, the only synthesis of cycloprodigiosin, which was
reported by Wasserman, appeared in 1984.29 Our synthesis of
23 began with enantioenriched allenylalkyne 18, which was
prepared in six steps from known alkyne 17 as a mixture of
diastereomers.30 Under the conditions for pyrrole annulation
outlined in Scheme 3, 18 was transformed in 83% yield to a 1:1
mixture of α,β-unsaturated imine 19 and the desired pyrrole
20.31 Presumably, the higher propensity of the methine
hydrogen atom in 18 toward migration (compared with the
methylene hydrogens as described for the substrates in Table
1) results in the competing formation of a significant amount of
19. Efforts to minimize the formation of 19 using other metal
salts or complexes known to modulate the reactivity of
carbenes,32 including Rh2(TFA)4, Rh2(cap)4, Rh(OAc)2(PC)2
(PC = ortho-metalated phosphine),33 RuCl2(PPh3)3, AgOBz,
and Cu(tert-butylsalicylimine)2,34 resulted either in low
conversion [with Cu(tert-butylsalicylimine)2 and Rh2(cap)4],
the exclusive formation of 19 [with Rh2(TFA)4], or nonspecific
decomposition. However, with access to reasonable quantities
of 20, we proceeded with the synthesis by attempting to
remove the tosyl group to give pyrrole 21. Among the many
conditions for tosyl group removal that we surveyed,35 only the
use of lithium aluminum hydride (LAH) successfully
accomplished the conversion of 20 to 21,36 which was carried
on crude to the next step. Condensation of 21 with 22 using
the conditions of Lindsley37 afforded cycloprodigiosin (23) in
71% yield over the three steps from 20. The 1H and 13C NMR
spectral data for synthetic 23 were in close agreement with
those reported by Laatsch and Thomson.25b Our synthesis of
23 is the first enantioselective synthesis of cycloprodigiosin and
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Prof. Huw Davies (Emory University) for
sharing with us unpublished results of his research group’s
study of pyrrole formation using triazoles and furans. Our work
was supported by the NSF (CAREER 0643264 to R.S.) and a
Research Scholar Grant from the American Cancer Society
(RSG-09-017-01-CDD to R.S.). R.S. is a Camille Dreyfus
Teacher Scholar. We are grateful to the NSF for a graduate
fellowship to E.E.S. and to Abbott, Eli Lilly, and Roche for
financial support.
REFERENCES
(1) Moffitt, W. Trans. Faraday Soc 1949, 45, 373.
(2) (a) Dowd, P. J. Am. Chem. Soc. 1966, 88, 2587. (b) Dowd, P. Acc.
Chem. Res. 1972, 5, 242.
■
(3) For recent reviews on TMMs, see: (a) Allan, A. K.; Carroll, G. L.;
Little, R. D. Eur. J. Org. Chem. 1998, 1. (b) Little, R. D. Chem. Rev.
1996, 96, 93.
(4) The 2-alkylidenecyclopentane-1,3-diyl moiety has been partic-
ularly prevalent in many of the applications of constrained TMMs (see
ref 3). For an early account, see: Berson, J. A. In Diradicals; Borden,
W. T., Ed.; Wiley: New York, 1982; Chapter 4.
(5) (a) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002, 344,
111. (b) Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed.
2007, 46, 7364. (c) Brandi, A.; Cicchi, S.; Cordero, F. M.; Goti, A.
Chem. Rev. 2003, 103, 1213. (d) Brandi, A.; Goti, A. Chem. Rev. 1998,
98, 589. (e) Binger, P.; Buch, H. M. Top. Curr. Chem. 1987, 135, 77.
̈
(6) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1986, 25, 1.
(7) Parr, B. T.; Green, S. A.; Davies, H. M. L. J. Am. Chem. Soc. 2013,
DOI: 10.1021/ja401386z.
(8) For recent examples of Rh-nitrenoid interactions with allenes,
see: (a) Stoll, A. H.; Blakey, S. B. J. Am. Chem. Soc. 2010, 132, 2108.
(b) Stoll, A. H.; Blakey, S. B. Chem. Sci 2011, 2, 112. (c) Feldman, K.
S.; Antoline, J. F. Org. Lett. 2012, 14, 934.
(9) For generation of furans using 2-acylidenecyclopentane-1,3-diyls,
see: Moeller, K. D.; Little, R. D. Tetrahedron Lett. 1985, 26, 3417.
4698
dx.doi.org/10.1021/ja401380d | J. Am. Chem. Soc. 2013, 135, 4696−4699

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Communication
(10) For an early example from our laboratory involving the
formation of methylenecyclopropane intermediates and its application
to the synthesis of substituted furans, see: Yao, T.; Hong, A.; Sarpong,
R. Synthesis 2006, 3605.
(11) (a) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302.
(b) Horneff, T.; Chuprakov, S.; Chernyak, N.; Gevorgyan, V.; Fokin,
V. V. J. Am. Chem. Soc. 2008, 130, 14972. For additional recent
examples, see: (c) Zibinsky, M.; Fokin, V. V. Angew. Chem., Int. Ed.
2013, 52, 1507. (d) Miura, T.; Tanaka, T.; Biyajima, T.; Yada, A.;
Murakami, M. Angew. Chem., Int. Ed. 2013, DOI: 10.1002/
anie.201209603.
32, 1867. (g) Furstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am.
̈
Chem. Soc. 1998, 120, 8305. (h) Hu, D. X.; Clift, M. D.; Lazarski, K. E.;
Thomson, R. J. J. Am. Chem. Soc. 2011, 133, 1799. (i) Clift, M. D.;
Thomson, R. J. J. Am. Chem. Soc. 2009, 131, 14579.
(29) Wasserman, H. H.; Fukuyama, J. M. Tetrahedron Lett. 1984, 25,
1387.
(30) For a synthesis of the enantiomer of 17, see: Magauer, T.;
Martin, H. J.; Mulzer, J. Angew. Chem., Int. Ed. 2009, 48, 6032. See the
SI for more details.
(31) The isomeric 3,4-fused pyrrole i was obtained in trace amounts
as well.
(12) Ni complexes have also been used to facilitate the
decomposition of 1,2,3-triazoles. See: Miura, T.; Yamauchi, M.;
Murakami, M. Chem. Commun. 2009, 1470.
(13) See refs 11a and 11b.
(14) For a general review of BODIPY dyes, see: Loudet, A.; Burgess,
K. Chem. Rev. 2007, 107, 4891.
(32) For a review of the use of metal complexes to modulate carbene
reactivity, see Chapter 5 of ref 16.
(15) Rausaria, S.; Kamadulski, A.; Rath, N. P.; Bryant, L.; Chen, Z.;
Salvemin, D.; Neumann, W. L. J. Am. Chem. Soc. 2011, 133, 4200.
(16) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley: New York, 1998;
Chapter 12.
(33) Taber, D. F.; Malcolm, S. C.; Bleger, K.; Lahuerta, P.; Sanau, M.;
́
Stiriba, S.-E.; Per
121, 860.
́
ez-Prieto, J.; Monge, M. A. J. Am. Chem. Soc. 1999,
(34) (a) Nozaki, H.; Takaya, H.; Moriuti, S.; Noyori, R. Tetrahedron
1968, 24, 3655. (b) Charles, R. G. J. Org. Chem. 1957, 22, 677.
(c) Sacconi, L.; Ciampolini, M. J. Chem. Soc. 1964, 276.
(35) For a review of the removal of the tosyl group, see: Greene, T.
W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley: New
York, 1999; pp 603 and 615.
(17) For example, see: Panne, J.; Fox, J. M. J. Am. Chem. Soc. 2007,
129, 22.
(18) Murakami has shown that the 1,2-hydride shift significantly
competes with other reactions for alkyl-substituted α-N-sulfonylimino
Rh-carbenoids. See: Miura, T.; Biyajima, T.; Fujii, T.; Murakami, M. J.
Am. Chem. Soc. 2012, 134, 194.
(36) For reductive tosyl group removal using LAH, see: LeBel, N. A.;
Balasubramanian, N. J. Am. Chem. Soc. 1989, 111, 3363.
(37) Aldrich, L. N.; Dawson, E. S.; Lindsley, C. W. Org. Lett. 2010,
12, 1048.
(38) (a) This is especially important since the reports on the
isolation and subsequent work with cycloprodigiosin do not comment
on whether it was obtained as a scalemic or racemic mixture. (b)
Small amounts of an isomeric compound derived from i (see ref 31)
were obtained along with 23 (see the SI).
(19) For the synthesis of 9 as well as the other substrates, see the
Supporting Information (SI).
(20) See refs 11b and 18 and: Miura, T.; Funakoshi, Y.; Morimoto,
M.; Biyajima, T.; Murakami, M. J. Am. Chem. Soc. 2012, 134, 17440.
(21) Slow decomposition of our substrates occurred upon silica gel
chromatography (likely because of the reactive allene group).
(22) (a) This may be extrapolated from the strain energies inherent
in cis-bicyclo[3.3.0]octane (10.67 kcal/mol) vs cis-bicyclo[4.3.0]
nonane (7.75 kcal/mol). See: Allinger, N. L. Molecular Structure:
Understanding Steric and Electronic Effects from Molecular Mechanics;
Wiley: Hoboken, NJ, 2010; Chapter 11. (b) In the cases where
moderate yields of the pyrrole products were obtained (<75% yield
over the two steps), small amounts of α,β-unsaturated imine
byproducts were also detected.
NOTE ADDED AFTER ASAP PUBLICATION
■
The Table of Contents graphic and Scheme 5 were incorrect in
the version published ASAP March 15, 2013. The corrected
version was re-posted on March 19, 2013.
(23) For a review of the prodigiosins, see: Furstner, A. Angew. Chem.,
̈
Int. Ed. 2003, 42, 3582.
(24) See: Lee, J. S.; Kim, Y.-S.; Park, S.; Kim, J.; Kang, S.-J.; Lee, M.-
H.; Ryu, S.; Choi, J. M.; Oh, T.-K.; Yoon, J.-H. Appl. Environ. Microbiol.
2011, 77, 4967 and references therein.
(25) (a) Gerber, N. N. Tetrahedron Lett. 1983, 24, 2797. (b) Laatsch,
H.; Thomson, R. H. Tetrahedron Lett. 1983, 24, 2701.
(26) (a) Pandey, R.; Chander, R.; Sainis, K. B. Curr. Pharm. Des.
2009, 15, 732. (b) Kamata, K.; Okamoto, S.; Oka, S.; Kamata, H.;
Yagisawa, H.; Hirata, H. FEBS Lett. 2001, 507, 74. (c) Yamamoto, C.;
Takemoto, H.; Kuno, K.; Yamamoto, D.; Tsubura, A.; Kamata, K.;
Hirata, H.; Yamamoto, A.; Kano, H.; Seki, T.; Inoue, K. Hepatology
1999, 30, 894. (d) Yamamoto, D.; Uemura, Y.; Tanaka, K.; Nakai, K.;
Yamamoto, C.; Takemoto, H.; Kamata, K.; Hirata, H.; Hioki, K. Int. J.
Cancer 2000, 88, 121. (e) Yamamoto, D.; Tanaka, K.; Nakai, K.;
Baden, T.; Inoue, K.; Yamamoto, C.; Takemoto, H.; Kamato, K.;
Hirata, H.; Morikawa, S.; Inubushi, T.; Hioki, K. Breast Cancer Res.
Treat. 2002, 72, 1.
(27) Pandey, R.; Chander, R.; Sainis, K. B. Indian J. Biochem. Biophys
2007, 44, 295.
(28) See the references listed here and those cited therein:
(a) Wasserman, H. H.; Lombardo, L. J. Tetrahedron Lett. 1989, 30,
1725. (b) Rapoport, H.; Holder, K. G. J. Am. Chem. Soc. 1962, 84, 635.
(c) Wasserman, H. H.; Petersen, A. K.; Xia, M.; Wang, J. Tetrahedron
Lett. 1999, 40, 7578. (d) Boger, D. L.; Patel, M. J. Org. Chem. 1988, 53,
1405. (e) Boger, D. L.; Patel, M. Tetrahedron Lett. 1987, 28, 2499.
(f) Wasserman, H. H.; Keith, D. D.; Nadelson, J. Tetrahedron 1976,
4699
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