Three-component domino process for the pyrrolizine skeleton via [3 + 2]-cycloaddition-enamine cyclization triggered by a gold catalyst

Article abstract of DOI:10.1021/acs.orglett.5b00320

Pyrrolizines are bicyclic fused azaheterocycles with a bridgehead nitrogen contained in a core skeleton and are often found in biologically active compounds. Despite their importance, there have been few reports on concise and flexible syntheses of pyrrolizines. A novel one-pot, convergent method is described for pyrrolizines by simple mixing of iminoesters, acetylenes, and dipolarophiles in the presence of a cationic gold catalyst and an acid additive. This domino process affords multisubstituted pyrrolizines without handling unstable intermediates.

Full text of DOI:10.1021/acs.orglett.5b00320

Letter
pubs.acs.org/OrgLett
Three-Component Domino Process for the Pyrrolizine Skeleton via
[3 + 2]-Cycloaddition−Enamine Cyclization Triggered by a Gold
Catalyst
Kenji Sugimoto, Nozomi Yamamoto, Daisuke Tominaga, and Yuji Matsuya*
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
S
* Supporting Information
ABSTRACT: Pyrrolizines are bicyclic fused azaheterocycles with a bridgehead nitrogen contained in a core skeleton and are
often found in biologically active compounds. Despite their importance, there have been few reports on concise and flexible
syntheses of pyrrolizines. A novel one-pot, convergent method is described for pyrrolizines by simple mixing of iminoesters,
acetylenes, and dipolarophiles in the presence of a cationic gold catalyst and an acid additive. This domino process affords
multisubstituted pyrrolizines without handling unstable intermediates.
yrrolizines are an important class of heterocycles that have
Pa bicyclic 5−5 fused ring system with one nitrogen atom
on the bridgehead position. They are widespread in naturally
occurring biologically active compounds.1 For example,
antitumor alkaloid retronecine, which was isolated from Senecio
and Crotalaria species, has a partially reduced pyrrolizine core.1c
Myrmicarins from the poison gland secretions of Myrmicaria
ants are tricyclic alkaloids containing a fused pyrrolizine
skeleton.2 The structural features of such skeletons attract
much attention from medicinal chemists and have been
installed in several drugs such as Ketorolac3 and potential
thrombin inhibitors4 (Figure 1).
problem for pyrrolizine syntheses. To comply with such
requirements, we designed a novel, gold-catalyzed domino
reaction7−9 involving simultaneous formation of four covalent
bonds, which enables multicomponent assembly without
isolation of any intermediates in a one-pot manner10 (Scheme
1).
Scheme 1. Strategy for One-Pot, Three-component
Pyrrolizine Synthesis via Domino Reaction
Figure 1. Biologically active pyrrolizines.
As a result of fruitful synthetic endeavors on natural and
unnatural pyrrolizines, a number of approaches to such
skeletons has been established.1 Whereas various modes of
bond formation could be potentially applied for pyrrolizine
syntheses, most of the previous strategies employed monocyclic
pyrrolidine derivatives as starting materials and suffered from
circuitous reaction steps including protection−deprotection
stages for the reactive nitrogen atom. Thus, development of
more atom5 and step economical6 strategies has been a critical
Although the various types of gold-catalyzed dipole
generation have been reported,11 we selected iminoesters as a
precursor of dipole azomethine ylide for our task. The nitrogen
atom on imine 1 attacks the triple bond in 2 activated by the
gold catalyst. While vinylgold species usually regenerate the
Received: January 31, 2015
Published: February 20, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00320
Org. Lett. 2015, 17, 1320−1323

Organic Letters
Letter
−NTf2, −PF6, and −BF4, the reaction yield did not increase
(entries 3−5). The possibility that AgOTf served as the actual
catalyst in this reaction was excluded (entry 6), and no desired
product was obtained without the catalyst (entry 7). These
observations indicated that the cationic gold served as the active
catalyst in this transformation.11d
Despite making great efforts on the optimization of ligands
and counteranions of the gold catalyst, the chemical yield of 6a
still remained moderate. During our investigations, we noticed
that the turnover of the gold catalyst was sluggish. Therefore,
we noted recent reports on gold-adduct formation, which
revealed that nucleophilic enamines easily formed a stable
enamine−gold complex.14 According to these reports, the
enamine moiety in our cycloadduct 6a might inhibit the
catalytic turnover. To circumvent such drawbacks in our
system, we examined acid additives having various pKa values
aiming at decomposition of the supposed enamine−Au
complex (entries 8−10). Finally, benzoic acid was found to
be the most effective additive, giving the highest yield of 69%
(entry 9).
Thus, we optimized the reaction conditions for the
azomethine ylide formation followed by [3 + 2]-cycloaddition
(the first stage). However, the enamine cyclization (the second
stage) has not been realized thus far. In fact, the enamine
product 6a, isolated from the reaction of 1a and 2a, could not
participate in further cyclization to form 8a under any
circumstances such as acidic, basic, or heating conditions. To
overcome such difficulties, we envisioned that more activated
enamino-esters with a highly electron-withdrawing ester moiety
could serve as a suitable intermediate for the desired enamine
cyclization step. After considerable attempts, we found that
utilization of trifluoroethyl iminoester 9a was critical for our
final goal.15 The reaction of 9a, 2a, and 5a under the optimal
conditions for the first stage produced the activated enamino-
ester intermediate 10, which was too unstable for efficient
isolation.16 However, we found that the desired enamine
cyclization reaction from 10 efficiently proceeded to furnish the
target pyrrolizine skeleton 8a, simply by raising the reaction
temperature to 80 °C from 65 °C. This transformation worked
the best in a one-pot manner, and 8a could be produced in 68%
yield from 9a without isolation of the unstable enamine
intermediate 10 (Scheme 2).17
gold catalyst by protodeauration with an acidic proton
remaining on the nucleophilic atom, the resulting vinylgold 3,
having no proton on the nitrogen, generates an azomethine
ylide 4 and the gold catalyst by protodeauration with the most
acidic α-proton of the ester. Ylide 4, the first reactive
intermediate, is immediately captured by dipolarophile 5 via
[3 + 2]-cycloaddition, which then generates the second reactive
intermediate 6. Next, the nucleophilic enamine moiety in 6
attacks the pendant ester to cause cyclization with release of
ROH, leading to the five-membered vinylogous lactam 7.
Finally, aromatization produces the bicyclic pyrrolizine skeleton
8. Thus, our blueprint for a domino-type construction of the
pyrrolizine skeleton is characterized by two consecutive stages:
(1) gold-catalyzed azomethine ylide formation via intermo-
lecular coupling reaction between an iminoester and acetylene,
followed by [3 + 2]-cycloaddition; (2) enamine cyclization and
subsequent aromatization. The present study revealed optimal
reaction conditions for the first stage, and we successfully
extended the results for completion of the planned domino
process including the second stage to provide multisubstituted
pyrrolizines.
We started our investigations using easily prepared and
relatively stable benzylidene iminoester 1a, ethyl phenyl-
propiolate (2a),12 and N-phenylmaleimide (5a) as three-
component substrates in dichloroethane with catalytic amounts
of (Ph3P)AuCl and AgOTf (Table 1, entry 1). The main
Table 1. Three-Component Coupling between Iminoester
1a, Acetylene 2a, and N-Phenylmaleimide (5a)
entry
catalyst
additive (2 equiv) time (h) yield (%)
1
2
3
4
5
6
7
8
9
10
(Ph3P)AuCl/AgOTf
(XPhos)AuCl/AgOTf
(Ph3P)Au(NTf2)
(Ph3P)AuCl/AgPF6
(Ph3P)AuCl/AgBF4
AgOTf
−
−
−
−
−
−
−
4
3
46
14
22
26
34
10
0
Encouraged by our success in the second enamine cyclization
employing a trifluoroethyl active ester in a one-pot manner, we
examined the three-component domino reaction leading to the
pyrrolizine skeleton 8 using various combinations of substrates.
As summarized in Scheme 3, the high generality of the one-pot
8.5
4.5
5.5
4.5
11.5
3
none
Scheme 2. Successful Transformation into Pyrrolizine
(Ph3P)AuCl/AgOTf
(Ph3P)AuCl/AgOTf
(Ph3P)AuCl/AgOTf
EtOH
benzoic acid
TFA
29
69
0
1.5
2.5
product isolated in 46% yield was the endo [3 + 2]-cycloadduct
6a,13 the precursor for the desired pyrrolizine. The geometry of
enamine in 6a was determined as the (E)-configuration on the
basis of NOE experiments between structurally key protons
(Ha, Hb, and Hc). Because the second enamine cyclization did
not proceed under these conditions, we for a while pursued
optimal conditions for the first cyclization stage giving the
adduct 6a triggered by the gold catalyst. With bulkier ligands,
the yields of 6a were reduced significantly (entry 2). Although
the counteranion of the cationic gold species was changed to
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Org. Lett. 2015, 17, 1320−1323

Organic Letters
Letter
installation of substituents on the pyrrolizine core by judicious
selection of the three-component combination, namely, easily
accessible iminoesters, acetylenes, and dipolarophiles. Further
applications of this method for stereoselective syntheses of
natural and unnatural biologically active compounds are
underway in our laboratory.
Scheme 3. One-Pot, Three-Component Domino Pyrrolizine
Synthesis
ASSOCIATED CONTENT
* Supporting Information
Experimental details, spectral data, and copies of H and 13C
■
S
1
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: matsuya@pha.u-toyama.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by the KAKENHI, a Grant-in-
Aid for Young Scientist (B: 24790007), and The Uehara
Memorial Foundation.
domino process was demonstrated with a concise experimental
technique, including simply mixing the reagents and then
heating at 65 °C for 2 h and then at 80 °C for an additional 4 h.
Aromatic and aliphatic propiolates such as alkyne 2,
trifluoroethyl iminoester 9 derived from various aromatic
aldehydes, and N-substituted and unsubstituted maleimides as
dipolarophiles 5 were proven to be applicable for the domino
reaction with moderate to good yields.18 It is important to note
that key unstable intermediates involved in this domino
process, namely azomethine ylides 4 and activated enamino-
esters 10, are transiently generated and efficiently adopt a
tandem bond formation triggered by gold catalysis in a step-by-
step manner, without requiring isolation, in the same reaction
medium.
Furthermore, we successfully demonstrated that densely
carbon-substituted pyrrolizines could be elaborated via versatile
carbon−carbon bond formation within a few steps by our
strategy. Suzuki−Miyaura coupling of triflate 11, which was
smoothly prepared from pyrrolizine 8a, with trifluoroborates19
was quite effective to introduce phenyl- or trans-1-propenyl
groups on the pyrrolizine core to furnish pyrrolizines 12
(Scheme 4).
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