Organocatalytic Activation of Diethyl Glutaconate for the Diastereo- and Enantioselective Assembly of NH-Free 2,3,4-Trisubstituted Pyrrolidines

Article abstract of DOI:10.1021/acs.orglett.7b00014

Organocatalyzed enantioselective consecutive Michael addition of diethyl glutaconate to a nitro-olefin/reductive cyclization sequence has been developed, directly providing NH-free trans,trans-2,3,4-trisubstituted pyrrolidines with typically >88:12 dr and >90% ee. The obtained structures are closely related to several molecules with high biological profiles, holding great promise for medicinal chemistry. In addition, their potential as direct organocatalysts in the enantioselective Michael addition promoted by enamine activation is also reported.

Full text of DOI:10.1021/acs.orglett.7b00014

Letter
pubs.acs.org/OrgLett
Organocatalytic Activation of Diethyl Glutaconate for the Diastereo-
and Enantioselective Assembly of NH-Free 2,3,4-Trisubstituted
Pyrrolidines
Adrien Quintard* and Jean Rodriguez
Aix-Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France
S
* Supporting Information
ABSTRACT: Organocatalyzed enantioselective consecutive
Michael addition of diethyl glutaconate to a nitro-olefin/
reductive cyclization sequence has been developed, directly
providing NH-free trans,trans-2,3,4-trisubstituted pyrrolidines
with typically >88:12 dr and >90% ee. The obtained structures
are closely related to several molecules with high biological
profiles, holding great promise for medicinal chemistry. In addition, their potential as direct organocatalysts in the
enantioselective Michael addition promoted by enamine activation is also reported.
To develop an alternative rapid approach to this particular
heterocyclic motif, we hypothesized that a new selective
organocatalyzed (cat) dialkyl glutaconate addition to nitro-
olefins followed by a zinc-promoted reductive cyclization should
efficiently provide the desired five-membered ring (Scheme 1).
Among the main advantages of this methodology, the highly
functionalized NH-free pyrrolidines would be directly obtained
without the requirement for any protecting groups and with two
ester functions as well as an easily adjustable R′ group. As a result,
the strategy should provide both a unique opportunity to access
rapidly new drug leads and a powerful synthetic platform to build
structurally different ligands or organocatalysts.5
The main challenge of developing such a strategy lies in the
selective activation of the dialkyl glutaconate toward the designed
nucleophilic addition. Indeed, to promote such condensation,
the pro-nucleophile must be efficiently deprotonated at the α-
position of the ester due to the cooperation of the second ester
through vinylogous delocalization.6 To our knowledge, the
unique example of catalytic enantioselective activation of dialkyl
glutaconates involved highly basic phase transfer catalysis.7 In
2009, the group of Bernardi and Fini showed that, under phase
transfer catalysis, a cycloaddition with nitrones occurred,
providing N−O heterocycles such as isoxazolidines. While
efficient, this strategy using aqueous base could hardly be applied
to the proposed Michael addition, and alternatively, we
hypothesized that bifunctional Brønsted base/acid catalysis
might promote with success the proposed key vinylogous
activation.8 Herein, we present our efforts at successfully
developing this new enantioselective one-pot strategy and
illustrate its synthetic interest by applying the obtained NH-
free pyrrolidines in aminocatalyzed Michael addition.
yrrolidines are unique heterocyclic scaffolds present in a
1
Pbroad range of biologically active molecules. In addition to
this marked bioactivity, the pyrrolidine backbone has been
abundantly used to build efficient chiral ligands and organo-
catalysts.2 Given the prevalence of this particular motif, the
development of innovative direct enantioselective access to these
structures from widely available substrates is highly desirable
with strong potential for medicinal chemistry and catalytic
applications.
Among the most straightforward and efficient routes to chiral
pyrrolidines, (3 + 2) cycloadditions notably catalyzed by copper
complexes largely lead the way. Unfortunately, most of them
provide products with substituents on both the 2- and 5-
positions of the pyrrolidine ring.3 This considerably limits the
potential of these approaches because the 2,3,4-trisubstituted
pyrrolidine chiral backbone is present in numerous highly
biologically active molecules such as in kainic acid or endothelin
receptors ETA antagonists shown in Scheme 1.4
Scheme 1. Proposed Strategy and Interest for
Enantioselective 2,3,4-Trisubstituted Pyrrolidines
To develop the most straightforward access to chiral
pyrrolidines, we focused our efforts on using commercially
Received: January 3, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00014
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Organic Letters
Letter
available diethyl glutaconate 1 and nitrostyrene 2a (Table 1).
The reaction was best performed in m-xylene at −20 °C using
Scheme 2. Scope of the Enantioselective 2,3,4-Trisubstituted
Pyrrolidines Synthesis
Table 1. Optimization of the Pyrrolidine Synthesis
a
b
entry
variation from the “standard” conditions
yield (%)
ee (%)
1
2
none
78
45
59
76
64
74
79
60
48
65
67
90
34
70
80
80
87
87
90
90
80
82
cat2 in toluene at rt, 1.5 h
cat3 in toluene at rt, 10 h
cat4 in toluene at rt, 1.5 h
cat1 in toluene at rt, 1.5 h
cat1 in toluene at 4 °C, 2 h
cat4 in toluene at −20 °C, 18 h
cat1 in toluene at −20 °C, 18 h
cat1 in toluene at −40 °C, 22 h
cat1 in THF at −20 °C, 22 h
cat1 in DCM at −20 °C, 16 h
3
4
5
6
7
8
9
10
11
a
b
Isolated yield after silica gel chromatography. Enantiomeric excess
measured by HPLC in all cases for both diastereomers (90:10 dr for all
entries).
same good diastereocontrol around 90:10. The absolute
configuration of pyrrolidine 3h was assigned as (2R,3S,4R)
based on an X-ray crystallographic study, and the configurations
of all other pyrrolidines were assigned accordingly.10 Incorporat-
ing sterically demanding anthracene was also possible, yielding
3g in excellent 84% yield and good 88% ee. Interestingly, in this
case, the initial 91:9 dr observed could be increased to >99:1 dr
by performing the reaction at −40 °C with cat4.
Finally, an aliphatic nitroalkene could also be used efficiently in
this sequence, even though the reaction had to be run at room
temperature to obtain full conversion, and product 3i was formed
in slightly decreased enantiocontrol (82% ee) with still high 92:8
dr.
Mechanistically, the final trans-2,3-diastereocontrol in the
pyrrolidines seem to be fixed during the Michael addition, as
shown by the difference in enantiocontrol observed between
both diastereomers in molecules 3b and 3c and the
diastereocontrol observed for the Michael adduct from 1 and
2b prior to reductive cyclization (see Supporting Information).
This means that the cyclization (aza-Michael) creating the third
stereocenter at C2 is totally trans-diastereoselective and under
kinetic control because, for example, the >99:1 dr in 3g does not
evolve upon prolonged time (Scheme 2).
To evaluate the practical applicability of this novel approach,
reactions using 2b and 2h were conducted on the gram scale
(Scheme 3). Interestingly, the catalyst loading could be reduced
to 2 mol % without noticeable loss of catalytic activity. Indeed,
both products 3b and 3h were easily formed on the gram scale
with more than 90% ee.
bifunctional cat1.8b After completion of the Michael addition,
acetic acid and Zn were directly added to the reaction mixture,
providing cleanly the expected pyrrolidine 3a in 78% yield. In
addition, the three newly created contiguous stereocenters were
controlled in 90:10 dr and 90% ee (Table 1, entry 1).9 When the
reaction was performed at rt in toluene (Table 1, entries 2−5),
among the organocatalysts tested, both cat1 and cat4 provided
the best levels of enantiocontrol (80% ee); however, when the
temperature was decreased to 4, −20, or −40 °C (Table 1, entries
6−9), cat1 gave the best enantiocontrol (90% ee at −20 °C,
Table 1, entry 8). Finally, m-xylene allows the best reactivity and
selectivity to be obtained, whereas other solvents, such as THF or
dichloromethane, provided lower enantiocontrol (Table 1, entry
1 vs entries 10 and 11).
With these optimized conditions in hand, we then scrutinized
the scope of the consecutive Michael addition/cyclization
sequence (Scheme 2). Gratifyingly, a broad range of substitution
patterns from functionalized aromatics to aliphatic chains were
well-tolerated, providing the expected substituted pyrrolidines in
usually good yields (42−84% yield) and good stereocontrol
(88:12 to 99:1 dr and 81 to 94% ee).
For example, a fluorinated aromatic, a thiophene, or a phenol
could be incorporated with success, providing structures 3b−d.
Starting from the nitro-olefin possessing a nitro-substitutent in
the para-position of the aromatic, as expected, the corresponding
aniline 3e was directly obtained with enantiocontrol decreased to
83%. Insertion of electron-donating substituents (OMe) yielded
either 3f (67% yield, 91% ee) or 3h (75% yield, 94% ee), with the
Given the rapid access to key NH-free pyrrolidine scaffolds, we
were intrigued to test them as organocatalysts in enamine
B
DOI: 10.1021/acs.orglett.7b00014
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Organic Letters
Letter
agents and should readily find applications in medicinal
chemistry.
Scheme 3. Preparative Scale 2,3,4-Pyrrolidine Synthesis
Finally, we have shown that the pyrrolidines directly accessed
from our methodology could serve as efficient organocatalysts for
enamine activation. This highly promising result opens new
avenues to modify structurally the obtained heterocycles and
potentially access new families of ligands and organocatalysts for
enantioselective catalysis.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00014.
Experimental procedures, additional optimization reac-
tions, characterization of compounds, spectra, kinetic
analysis (PDF)
activation. Notably, given the spatial arrangement observed
around the nitrogen atom, we felt that a good enantiodiscrimi-
nation should be observed in the Michael addition of carbonyl
compounds to nitro-olefins.11 The library of pyrrolidines
obtained in Scheme 2 was tested in the addition of cyclo-
hexanone to nitrostyrene 2a, and gratifyingly, among them, the
anthracenyl derivative 3g efficiently catalyzed the Michael
addition (Scheme 4).12 Using 20 mol % of 3g with 88% ee, the
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: adrien.quintard@univ-amu.fr.
ORCID
Adrien Quintard: 0000-0003-0193-6524
Notes
The authors declare no competing financial interest.
Scheme 4. Catalytic Application of the Obtained Pyrrolidine
in Enamine Activation
ACKNOWLEDGMENTS
■
The Agence Nationale pour la Recherche (ANR-13-PDOC-
0007-01), the Centre National de la Recherche Scientifique
(CNRS), and the Aix-Marseille Universite
acknowledged for financial support. The authors warmly thank
Marion Jean and Nicolas Vanthuyne (Aix-Marseille Universite-
CNRS) for chiral-phase HPLC analysis. Michel Giorgi (Aix-
Marseille Universite-CNRS) is acknowledge for X-ray analysis of
́
are gratefully
́
́
3h.
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DOI: 10.1021/acs.orglett.7b00014
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