Enantioselective Synthesis of Pyrrolizidinone Scaffolds through Multiple-Relay Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c03344

A triple-tandem protocol for the synthesis of the pyrrolizidinone skeleton has been devised. It involves a cross metathesis-intramolecular aza-Michael reaction-intramolecular Michael addition tandem sequence, starting from N-pentenyl-4-oxo-2-alkenamides and conjugated ketones. In the presence of two cooperative catalysts, namely the second-generation Hoveyda-Grubbs catalyst and (R)-TRIP-derived BINOL phosphoric acid, this multiple-relay catalytic process takes place in good yields and outstanding levels of diastero- and enantioselectivity with the simultaneous generation of three contiguous stereocenters

Full text of DOI:10.1021/acs.orglett.0c03344

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Letter
Enantioselective Synthesis of Pyrrolizidinone Scaffolds through
Multiple-Relay Catalysis
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́
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Marcos Escolano, Javier Torres Fernandez, Fernando Rabasa-Alcaniz, María Sanchez-Rosello,
and Carlos del Pozo*
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ABSTRACT: A triple-tandem protocol for the synthesis of the pyrrolizidinone skeleton has been devised. It involves a cross
metathesis−intramolecular aza-Michael reaction−intramolecular Michael addition tandem sequence, starting from N-pentenyl-4-
oxo-2-alkenamides and conjugated ketones. In the presence of two cooperative catalysts, namely the second-generation Hoveyda−
Grubbs catalyst and (R)-TRIP-derived BINOL phosphoric acid, this multiple-relay catalytic process takes place in good yields and
outstanding levels of diastero- and enantioselectivity with the simultaneous generation of three contiguous stereocenters
he pyrrolizidine skeleton, an azabicycle with two aliphatic
five-membered rings and a nitrogen atom at the
pyrrolam A (Figure 1, D), presents herbicidal activity,5
whereas conjugation with a sugar provides the antifungal
properties of burnettramic acids (Figure 1, E).6 Compound F
(Figure 1) is a highly potent second-generation phosphodies-
terase IVb inhibitor and a candidate for the treatment of
asthma.7 Due to its great biological relevance, multiple
synthetic efforts have been devoted to the synthesis of highly
functionalized pyrrolizidinone derivatives, and several ap-
proaches have been established.8 However, these small bicyclic
ring systems turned out to be challenging targets for synthetic
chemists, especially in an asymmetric manner. Chiral-pool and
chiral-auxiliary strategies are the most common approaches for
the asymmetric synthesis of these derivatives. The use of
catalytic enantioselective methodologies is scarce, and most of
them involve enantioselective [3 + 2] dipolar cycloadditions
for the generation of the bicyclic structure.9 Therefore, the
development of efficient and general enantioselective ap-
proaches to access these relatively simple scaffolds remains a
challenge.
T
bridgehead position, is a structural motif present in a wide
variety of natural products. The number of pyrrolizidine-
containing alkaloid species reaches up to 6000, most of which
are hepatotoxic secondary metabolites synthesized by plants.1
Specifically, the pyrrolizidinone subunit deserves a special
mention as recently isolated pyrrolizidinone-containing com-
pounds display a wide range of biological activities. In this
context, compound CJ-16,264 (Figure 1, A)2 and penibru-
guieramine A (Figure 1, B)3 exhibit potent antibacterial
properties, while UCS1025A is a strong inhibitor of telomerase
(Figure 1, C).4 One of the simplest pyrrolizidinone derivatives,
On the other hand, domino or tandem reactions entail two
or more bond-forming reaction steps occurring in a single
Received: October 6, 2020
Figure 1. Biologically active pyrrolizidinone-derived compounds.
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operation under the same reaction conditions. The combina-
tion of domino reactions and asymmetric catalysis results in a
simple and effective way to create multiple stereocenters. Thus,
the field of enantioselective tandem catalysis has witnessed
tremendous progress in recent years.10
The simultaneous use of several catalysts with different
modes of action (multicatalysis) is one of the most fruitful
strategies to design new domino processes, enabling
unprecedented transformations not accessible using each
catalyst separately. In this context, the combination of
transition metal catalysts and organocatalysts has emerged as
a powerful strategy, thereby creating novel concepts within
catalysis.11
One of the main challenges in the design of multicatalytic
processes is related to ensuring the compatibility of the
catalysts. Chiral Brønsted acids are suitable catalysts for
domino and multicomponent reactions as they have shown to
be compatible with several catalysts, both metal catalysts and
organocatalysts.12 Among those combinations, the combina-
tion of a chiral BINOL phosphoric acid (BPA) with a metal
catalyst has found a wide range of applications in organic
synthesis.13
enantioselective IMAMR is less common due to their low
nucleophilicity, usually performing with moderate levels of
enantioselectivity.17
Considering this background, we decided to explore the
feasibility of the unprecedented IMAMR−IMCA tandem
protocol by employing compound 3a as a model substrate. It
bears an amide functionality as the nitrogen source and was
prepared by means of the cross-metathesis (CM) reaction of
N-(2,2-dimethyl-4-pentenyl)-4-oxo-2-pentenamide 1a with
methyl vinyl ketone 2a. With conveniently functionalized
amide 3a in hand, the screening of the reaction conditions to
carry out the projected tandem process began with catalyst I
(9-amino-9-deoxy-epi-hydroquinine) and trifluoroacetic acid as
the cocatalyst (1:1 ratio), since this catalytic system had
provided excellent results in the IMAMR of conjugated
ketones with either carbamates or sulfonamides as nitrogen
sources.16 However, in this case the reaction did not proceed at
all, recovering the starting material unaltered (Table 1, entry
Table 1. Optimization of the Tandem IMAMR−IMCA
Reaction
Herein we report another example of the synergistic
combination of a chiral BPA with the second generation
Hoveyda−Grubbs catalyst (HG-II) in a triple-tandem process.
The reaction of N-(4-pentenyl)-4-oxo-2-alkenamides with
conjugated ketones in the presence of a chiral BPA and HG-
II afforded enantiomerically enriched pyrrolizidinones with the
simultaneous generation of three contiguous stereocenters.
The formation of these compounds involves an unprecedented
multiple-relay catalytic process, which comprises a tandem
cross metathesis−intramolecular aza-Michael addition−intra-
molecular conjugated addition strategy (Scheme 1).
Scheme 1. Tripe-Tandem Strategy to Access Chiral
Pyrrolizidinone Derivatives
a
b
entry
catalyst
solvent
4 (% yield)
ee (%)
1
2
3
4
5
6
7
8
9
I/TFA
II
III
IV
V
VI
V
V
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCM
toluene
THF
DCM
17
57
63
59
65
67
34
61
18
c
83
c
89
c
>99
81
97
c
c
c
42
Our initial aim was the evaluation of a novel organocatalytic
tandem intramolecular aza-Michael reaction (IMAMR)−intra-
molecular conjugated addition (IMCA) protocol. The
participation of intramolecular aza-Michael reactions in
tandem processes usually involves a nucleophilic nitrogen
generated in situ by means of different organocatalyzed
reactions. In this regard, a wide variety of examples can be
found in the literature.14 However, organocatalytic tandem
reactions initiated by an IMAMR are scarcely reported.15
On the other hand, the generation of a Michael acceptor in
the presence of the nitrogen nucleophile is not obvious since a
spontaneous cyclization can take place in a noncatalyzed
manner. In this context, the use of nitrogen sources with an
attenuated nucleophilicity, such as carbamates or sulfonamides,
has been crucial to overcome this issue.16 However, the use of
amides as nitrogen sources in an organocatalytic and
c
V
>99
a
b
Isolated yield after flash column chromatography. Enantiomeric
ratios were determined by HPLC analysis on a chiral stationary phase
(see the Supporting Information for details). Final product 4a was
formed as a single diastereoisomer.
c
1). The next attempt was performed with thiourea II derived
from quinine derivative I, leading to the desired tandem adduct
4a in 17% yield and low enantioselectivity (Table 1, entry 2).
Fortunately, the use of chiral BINOL-derived phosphoric acids
dramatically changed the situation.18 When the reaction was
performed with naphthyl-derived catalyst III, we observed the
complete conversion of the starting material, and the tandem
pyrrolizidinone product 4a was obtained in 57% isolated yield
and 83% enantiomeric excess (Table 1, entry 3). Changing the
B
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a b c
, ,
catalyst to chiral BPA IV translated to a small improvement in
the final ee value (Table 1, entry 4); meanwhile with (R)-
TRIP-derived BPA V, the tandem process took place in good
yield and with outstanding enantiocontrol, giving rise to
compound 4a as a single enantiomer (Table 1, entry 5). When
the more acidic triflimide VI was employed, a remarkable drop
in the enantioselectivity was observed (Table 1, entry 6). The
use of other solvents, such as toluene or THF, did not improve
the tandem process (Table 1, entries 7 and 8, respectively),
while dichloromethane afforded comparable results to those
obtained in CHCl3 (Table 1, entry 9).
Scheme 3. Scope of the Triple-Tandem Protocol
In view of the above results, the treatment of amide 3a with
(R)-TRIP-BPA (10 mol %) in dichloromethane at room
temperature for 12 h was established as the optimal conditions
for the tandem IMAMR−IMCA reaction (Table 1, entry 9).
As was mentioned previously, chiral BINOL phosphoric
acids are compatible with a wide variety of catalysts, including
metathesis ruthenium carbenes. The synergy between the
second generation Hoveyda−Grubbs catalyst (HG-II) and
chiral BPAs in tandem protocols was previously described by
several authors.19 Hence, we envisioned the possibility of
merging our organocatalytic tandem IMAMR−IMCA protocol
with the initial cross-metathesis reaction to perform the whole
sequence in a single operation. To our delight, when substrate
1a was treated with the HG-II catalyst, chiral BPA V, and
methyl vinyl ketone 2a in dichloromethane at room temper-
ature for 12 h, compound 4a, which arose from a triple-tandem
reaction, was obtained in a 61% yield with complete diastereo-
and enantioselectivity (Scheme 2). This multiple-relay catalytic
process was further extended to other starting N-pentenyl-4-
oxo-2-alkenamides 1. The results obtained are summarized in
Scheme 3.
a
Unless otherwise noted, reactions were carried out with 1 (0.2
mmol), catalyst V (10 mol %), HG-II (10 mol %), and the
corresponding conjugated ketone 2 (4 equiv) in dichloromethane (2
b
mL) at room temperature for 12 h. In all examples, only one
Scheme 2. CM/IMAMR−IMCA Sequence on Substrate 1a
diastereoisomer was detected by 1H NMR of the crude reaction
c
mixtures. Enantiomeric ratios were determined by HPLC analysis on
a chiral stationary phase (see the Supporting Information for details).
ray analysis. Crystals of pyrrolizidinone 4a suitable for single-
crystal X-ray diffraction were grown from an i-Pr2O solution,
and its structure was found unambiguously. An identical
stereochemical outcome was assumed for all other pyrrolizi-
dinones 4.
Regarding the vinyl ketone counterpart, both aliphatic (4a−
d) and aromatic (4e) conjugated ketones readily undergo the
tandem CM−IMAMR−IMCA process, providing the corre-
sponding pyrrolizidinone derivatives 4 in reasonable yields and
excellent enantiocontrol. The modification of the starting
alkenamides 1 at the conjugated ketone substituent was also
possible, rendering final products 4f−h in a very efficient
manner. Substitution at the pyrrolidinone ring was evaluated
next. Either unsubstituted pyrrolidinone 4i or pyrrolidinones
4j−m bearing spirocyclic moieties such as cyclopropyl,
cyclohexyl, tetrahydropyranyl, or N-Boc-piperidinyl at position
6 were obtained very efficiently. Likewise, the inclusion of a
gem-diester moiety was able to give compound 4n in an
efficient manner. Finally, the 7-gem-dimethyl derivative 4o was
not obtained, but the corresponding starting amide remained
unaltered under the reaction conditions. This could be
explained because of the increasing steric requirements at the
double bond, thus avoiding the initial CM reaction.20
A possible explanation to rationalize the stereochemical
outcome of the process with a simple model can be proposed
as follows. The chiral Brønsted acid catalyst plays a
bifunctional role, activating both the nucleophile and the
electrophile for the IMAMR simultaneously. Therefore, chiral
phosphoric acid V would establish hydrogen bonds with the H
of the amide nitrogen and also with the ketone carbonyl of the
Michael acceptor, thus promoting the nucleophilic attack to
the si-face of the double bond. The subsequent IMCA would
again be activated by the chiral catalyst through the double
hydrogen-bonding interaction with the enol nucleophile and
the second conjugated ketone moiety. In this manner, the
nucleophilic attack to the re-face of the double bond would
produce the observed cis-substituted adduct in the second
cyclization (Scheme 4).
As a further extension of this work, an intramolecular aldolic
event, followed by dehydration, occurred when compound 4a
was treated with TsOH at room temperature, giving rise to
tricyclic derivative 5 in 65% yield. With this result in hand, we
envisioned the possibility of performing the whole sequence in
The absolute configuration of the three newly created
stereocenters in the triple-tandem reaction was assigned by X-
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Scheme 4. Plausible Mechanistic Pathway for the IMAMR−
IMCA Tandem Process
Scheme 6. Scale-Up of the Triple-Tandem Protocol
pentenyl-4-oxo-2-alkenamides in their reaction with conju-
gated ketones. This multiple-relay-catalyzed process takes
advantage of the synergy between the second generation
Hoveyda−Grubbs catalyst and chiral (R)-TRIP-derived
BINOL phosphoric acid. This catalytic system enables the
overall transformation in a cooperative manner, rendering final
products with three contiguous stereocenters in good yields,
total diastereoselectivity, and excellent enantioselectivity. It is
important to note that the intramolecular aza-Michael reaction
takes place with amides as the nucleophilic nitrogen source.
Furthermore, the triple tandem reaction was coupled with a
third cyclization process (Robinson annulation) in a one-pot
manner just by heating the reaction mixture.
a one-pot manner taking advantage of the phosphoric acid to
effect the final cyclization. Hence, a solution of compound 1a
in dichloroethane was subjected to the standard triple-tandem
reaction conditions until TLC revealed the complete formation
of pyrrolizidinone 4a. Then, the reaction mixture was heated at
86 °C; after 48 h, the disappearance of compound 4a was
observed, while final tricycle derivative 5 could be isolated in a
43% overall yield (Scheme 5).
Scheme 5. CM/IMAMR/Robinson Annulation Sequence for
the Synthesis of Tricyclic Derivative 5
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03344.
General procedures; synthesis information of 1j, 1k, 3a,
and 5a; X-ray data; HPLC traces of 4 and 5; and NMR
and HMBC spectra (PDF)
Accession Codes
CCDC 2032501 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Carlos del Pozo − Department of Organic Chemistry,
University of Valencia, 46100 Burjassot-Valencia, Spain;
orcid.org/0000-0002-0947-5999; Email: carlos.pozo@
uv.es
Finally, the synthesis of pyrrolizidinone 4a was tested on a
multigram scale. As it was shown in Scheme 3, starting from 42
mg of 1a (0.2 mmol), 29 mg of the triple-tandem product 4a
was obtained (61% yield). When the reaction was performed
with 600 mg of 1a and the catalyst loading was also reduced to
5 mol %, 500 mg of compound 4a was obtained (69% yield)
without erosion of the enantioselectivity. In addition, the
tandem protocol was effected on a 1200 mg scale, in this case
decreasing the catalyst loading to 2%. Again, the reaction was
found to be highly efficient, giving 1011 mg of the final product
4a as well as no erosion of the ee value (Scheme 6).
In conclusion, the enantioselective synthesis of a new family
of pyrrolizidinone derivatives has been described. These
scaffolds are present in a wide variety of natural products
and biologically relevant compounds. The synthetic strategy
involved a triple-tandem cross metathesis−intramolecular aza-
Michael reaction−intramolecular Michael addition of N-
Authors
Marcos Escolano − Department of Organic Chemistry,
University of Valencia, 46100 Burjassot-Valencia, Spain
́
Javier Torres Fernandez − Department of Organic Chemistry,
University of Valencia, 46100 Burjassot-Valencia, Spain
Fernando Rabasa-Alcaniz − Department of Organic
̃
Chemistry, University of Valencia, 46100 Burjassot-Valencia,
Spain
́
́
María Sanchez-Rosello − Department of Organic Chemistry,
University of Valencia, 46100 Burjassot-Valencia, Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03344
D
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Krasinski, A.; Jurczak, J. Facile Stereocontrolled Synthetic Route
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Asymmetric Synthesis of Pyrrolizidines, Indolizidines and Quinolizi-
dines via a Double Reductive Cyclisation Protocol. Synlett 2017, 28,
2697. (e) Martinez, S. T.; Belouezzane, C.; Pinto, A. C.; Glasnov, T.
Synthetic Strategies towards the Azabicyclo-[3.3.0]-Octane Core of
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2016, 48, 223.
(9) For representative examples, see: (a) Kalaitzakis, D.; Sofiadis,
M.; Triantafyllakis, M.; Daskalakis, K.; Vassilikogiannakis, G.
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J.; Takayama, H.; Futamura, Y.; Aono, H.; Bauer, J. O.; Strohmann,
C.; Antonchick, A. P.; Osada, H.; Waldmann, G. Catalytic
Enantioselective Synthesis of a Pyrrolizidine−Alkaloid Inspired
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Acc. Chem. Res. 2017, 50, 2809. (c) Wang, Y.; Lu, H.; Xu, P.-F.
Asymmetric Catalytic Cascade Reactions for Constructing Diverse
Scaffolds and Complex Molecules. Acc. Chem. Res. 2015, 48, 1832.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
We gratefully thank the Spanish Ministerio de Economia y
Competitividad (CTQ-2017-85026-R to C.d.P.). M.E. thanks
́
the Spanish Ministerio de Educacion, Cultura y Deporte for a
predoctoral fellowship (FPU16/04533). J.T. thanks the
Generalitat Valenciana for a predoctoral fellowship (ACIF/
2018/078). Technical and human support provided by SGIker
(UPV/EHU, MINECO, GV/DJ, ERDF, and ESF) is gratefully
acknowledged.
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Organic Letters
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OEt) in the second cyclization instead of conjugated ketones, the
tandem process was interrupted after the IMAMR step.
(16) For recent examples, see: (a) Escolano, M.; Guerola, M.;
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Torres, J.; Gavina, D.; Alzuet-Pina, G.; Sanchez-Rosello, M.; del Pozo,
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Enantioselective Synthesis of 2-Aryl-2,3-dihydro-4-quinolones by
F
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