Organocatalytic enantio- and diastereoselective synthesis of 3,5-disubstituted prolines

Article abstract of DOI:10.1039/c5cc09329e

The asymmetric synthesis of substituted pyrrolidines has been accomplished using a novel organocatalytic cyclization reaction promoted by a Cinchona alkaloid based primary amine. The reaction proceeds smoothly yielding pyrrolidine-2,2-dicarboxylates after in situ diastereoselective reduction with high levels of enantioselection. Furthermore, these adducts could be easily transformed into N-protected disubstituted prolines through the base-promoted diastereoselective C → N alkoxycarbonyl transfer reaction.

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ARTICLE TYPE
Organocatalytic Enantioꢀ and Diastereoselective Synthesis of 3,5ꢀ
Disubstituted Prolines†
Iker Riaño,a Estibaliz Díaz,a Uxue Uria,a Efraím Reyes,a Luisa Carrillo*a and Jose L. Vicario*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
In this sense, and as a part of our ongoing project focussed on
the stereocontrolled synthesis of complex heterocycles through
40 organocatalytic cascade reactions,6 we envisaged a possible
synthetic approach to enantiopure highly substituted proline
derivatives such as the one shown in Scheme 1. According to our
plans, the target highly functionalized prolines would be accessed
from pyrrolidineꢀ2,2ꢀdicarboxylates by means of our recently
45 developed intramolecular base promoted CꢀN acyl transfer
reaction which has to proceed with good diastereoselection.7 The
access to the key pyrrolidineꢀ2,2ꢀdicarboxylates in an enantiopure
form was designed to be carried out through a sequence of
organocatalytic enantioselective one pot/cascade reactions8
The asymmetric synthesis of substituted pyrrolidines has
been accomplished using a novel organocatalytic cyclization
reaction promoted by a Cinchona alkaloid base primary
amine. The reaction proceeds smoothly yielding pyrrolidineꢀ
10 2,2ꢀdicarboxylates after in situ diastereoselective reduction
with high levels of enantioselection. Furthermore, these
adducts could be easily transformed into Nꢀprotected
disubstituted
prolines
through
baseꢀpromoted
diastereoselective C→N alkoxycarbonyl transfer reaction
15
Prolines and substituted prolines constitute essential chemical
entities in organic synthesis and drug development.1 This scaffold
is the central unit of many bioactive natural or synthetic products
and is also a privileged architecture for the preparation of chiral
reagents used in the stereocontrolled versions of many organic
50 relying on
a
cascade Michael reaction/intramolecular
condensation process between aminomalonates and α,βꢀ
unsaturated ketones, followed by the diastereoselective reduction
of the resulting pyrroline in a oneꢀpot fashion. In view of this
reaction design, asymmetric organocatalysis through iminium ion
20 transformations either as chiral ligands or organocatalysts.2 As a
result of their interest, developing new approaches for the
stereocontrolled preparation of substituted prolines still remains
as an active topic amongst synthetic organic chemists.3 In
general, the existing methodologies for the stereoselective
25 preparation of this heterocyclic scaffold can be classified into two
main groups. One is based on the chemical modification of
proline or other commercially available proline derivatives and
the second one relies on the de novo construction of the
heterocyclic architecture through a ring closure process. Among
30 these later strategies (see Scheme 1), the consecutive formation of
two CꢀC bonds through enantioselective [3+2] cycloaddition has
become a very powerful tool4 but, on the contrary, methodologies
involving an atypical simultaneous CꢀC and CꢀN disconnection
are by far less explored.5
55 activation of the enone shows up as
a very reliable
methodological approach to render the initial Michael reaction
enantioselective.9 This approach has been employed in several
examples of Michael/condensation cascades but in all cases using
α,βꢀunsaturated aldehydes as substrates, which in case of being
60 afterwards subjected to reduction of the azomethine moiety
generated on the condensation step do not lead to the formation
of an additional stereocenter.10
We started our investigations using diethyl aminomalonate 1a
and transꢀ4ꢀphenylbutꢀ3ꢀenꢀ2ꢀone 2a as model substrates for
65 performing the aforementioned cascade Michael/condensation
reaction using diverse primary amines 3aꢀe as catalysts and under
various reaction conditions (Table 1). We initially surveyed the
use of primary amine catalysts derived from cinchona alkaloids,
as it has been demonstrated that these are a privileged class of
70 organocatalysts in the activation of enones via iminium ion
formation.11 In this sense, the reaction using catalyst 3a in the
presence of TFA as cocatalyst in THF proceeded smoothly
forming the expected pyrroline, which was subsequently
subjected to in situ reduction with NaBH3CN, leading to 4a in
75 good yield, high enantioselectivity and as
a
single
diastereoisomer (entry 1). This later finding indicated that the
stereocenter generated at the Michael reaction step was able to
exert a very efficient asymmetric induction on the reduction of
the imine moiety. Remarkably, the reaction was also found to be
80 fully regioselective, without any evidence on the presence of the
35
Scheme 1 Two different approaches to the proline scaffold and the access
to enantiopure 3,5ꢀdisubstituted proline esters presented in this work
possible byproduct arising from
a
competitive azaꢀ
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Michael/intramolecular aldol reaction that could eventually occur
due to the ambident nature of the aminomalonate nucleophile.
observing that those enones incorporating electronꢀdonating
groups at the aryl substituent required for longer reaction times
Changing the acidic additive to MeSO3H improved the 35 than those with electronꢀwithdrawing groups (compare entries 5,
enantioselectivity (entry 2) and these conditions were tested with
other related cinchonaꢀbased primary amine catalysts, but none of
them performed better than 3a (entries 3 and 4). The same applies
to other bifunctional primary amine/thiourea catalysts such as
10 and 12). The position of the substituent at the aryl moiety had
a moderate influence in the rate of the reaction (entries 3ꢀ5, 6ꢀ7
and 8ꢀ9). Heteroaryl substituted enones were also studied,
although in this case it was found that running the reaction in
5
3d12 and 3e13 that are also known to be effective promoters of 40 CHCl3 and using TFA (40 mol%) as coꢀcatalyst resulted in a
Michaelꢀtype reactions with enones under iminium activation
higher enantioselectivity (entries 13ꢀ14 vs 15ꢀ16). A bulkier ethyl
substituent at the α’ꢀposition of the enone reagent was also well
tolerated (entry 17), but when α’ꢀarylꢀsubstituted enones were
surveyed, the reaction did not perform satisfactorily (entries 18
10 (entries 5 and 6). Other solvents were also surveyed but none
performed better than THF (entries 7ꢀ9). Finally, we also carried
out the reaction at lower temperature, which furnished 4a in
slightly better enantioselectivity but a very prolonged reaction 45 and 19). For instance, the reaction between 1a and 1,3ꢀdiphenylꢀ
time was necessary to reach to a comparable yield to that
15 obtained in entry 2.
2ꢀpropenꢀ1ꢀone 2p furnished the intermediate pyrroline after the
initial cascade Michael/condensation process in low yield and
moderate enantioselectivity.14 This intermediate was unreactive
towards reduction under our optimized conditions, presumably
50 because of the conjugated nature of the azomethine moiety. When
1ꢀphenylꢀ2ꢀbutenꢀ1ꢀone 2q was employed, the formation of a
complex mixture of products was observed. On the other hand,
the reaction performed well when a different aminomalonate such
as 1b was used (entries 20 and 21), yielding the desired
55 heterocycles with good yields and enantioselectivities.
Table 1 Optimization of the reaction conditions.a
Table 2 Scope of the reaction. Enantioselective synthesis of
pyrrolidines.a
Entry 4 R1 R2
R3
Time Yield
ee
(h)
42
41
119
68
41
97
29
42
26
(%)b
89
70
67
77
79
63
67
78
74
78
53
70
73
72
80
81
65
(%)c
89
90
89
89
89
77
87
89
89
89
87
86
76
78
86
87
89
58
n.d.e
90
80
Entry
3
Additive Solvent Temp Yield (%)b ee (%)
1
4a Et Ph
Me
Me
Me
Me
Me
1
2
3
4
5
6
7
8
9
3a
3a
3b
3c
3d
3e
3a
3a
3a
3a
TFA
THF
rt
rt
rt
rt
rt
rt
92
89
93
79
54
62
80
81
88
82
89
83
73
81c
36c
83
80
82
90
2
3
4
5
4b Et 4ꢀMeC6H4
4c Et 2ꢀMeOC6H4
4d Et 3ꢀMeOC6H4
4e Et 4ꢀMeOC6H4
MeSO3H THF
MeSO3H THF
MeSO3H THF
ꢀ
ꢀ
MeSO3H CHCl3 rt
MeSO3H EtOAc rt
MeSO3H Toluene rt
THF
THF
6
7
4f Et 2,6ꢀ(MeO)2C6H3 Me
4g Et 3,5ꢀ(MeO)2C6H3 Me
8
9
4h Et 2ꢀFC6H4
4i Et 4ꢀFC6H4
4j Et 4ꢀClC6H4
4k Et 4ꢀCF3C6H4
4l Et 4ꢀNO2C6H4
4m Et 2ꢀFuryl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
10
11
12
13
14
27
23
20
72
10
MeSO3H THF
4ºC 83
a
Reaction conditions: 2ꢀaminomalonate (1a) (0.86 mmol), enone (2a)
(0.62 mmol), catalyst (3) (20 mol%), additive (40 mol%) in 3 mL of
20 solvent at rt for 24h; then NaBH3CN (1 mmol) in EtOH (25 mL), 10 min.
b Yield of isolated pyrrolidine 4a as a single diastereoisomer (d.r.: >95:5)
4n Et 2ꢀThienyl
96
15c 4m Et 2ꢀFuryl
16c 4n Et 2ꢀThienyl
120
120
168
1
c
as HꢀNMR analysis of crude reaction mixture indicated. The opposite
enantiomer was obtained. d Reaction was stirred for 96h
17
18
19
20
21
4o Et 4ꢀMeOC6H4
4p Et Ph
4q Et Me
Having established a good protocol for the reaction, we
25 proceeded to extend these conditions to other dialkyl
aminomalonates 1aꢀb and enones 2aꢀn (Table 2). The reaction
performed excellently when a variety of βꢀaryl and heteroarylꢀ
substituted enones were employed, regardless the electronic
Ph
Ph
Me
192d 31
120
41
72
<5
91
67
4r Me Ph
4s Me 2,6ꢀ(MeO)2C6H3 Me
a Reaction conditions: See ESI for each case. b Yield of isolated product 4
nature of the aryl substituent, leading to the expected pyrrolidines 60 as a single diastereoisomer (d.r.: >95:5) as 1HꢀNMR analysis of crude
c
30 in high yields and as single diastereoisomers of very high
enantiomeric purity after in situ reduction (entries 1ꢀ2). These
reactions needed from 20 to 168 h to reach to completion,
reaction mixture indicated. Reaction carried out using TFA as additive
d
e
and CHCl3 as solvent. The intermediate pyrroline was isolated. n.d. =
not determined.
2
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The absolute configuration was determined by Xꢀray analysis 40 reaction/intramolecular condensation/diastereoselective reduction
of compound 4q (Figure 1) that showed a 3S,5S configuration at
sequence followed by baseꢀpromoted diastereoselective
intramolecular C→N acyl transfer reaction. The key process for
the installation of the initial stereocenter relies on the capacity of
the
two
stereogenic
centers
created
during
the
Michael/condensation/reduction process.15 This was extended to
5
the other pyrrolidines 4aꢀs based on mechanistic analogy. The
a readily available primary amine catalyst derived from
configuration of the stereocentre generated in the initial Michael 45 cinchonine to promote the initial Michael reaction under iminium
reaction catalyzed by 3a is in agreement with the stereochemical
outcome of other Michael additions to enones mediated by this
catalyst.11a The 5S configuration is also in agreement with a
ion activation of the enone and all the subsequent steps rely on
diastereoselective reactions proceeding under complete substrate
control using simple experimental protocols. This method shows
up as an excellent and direct synthetic approach to stereodefined
10 diastereoselective reduction under substrate control with the
hydride reagent approaching from the less hindered face of the 50 Nꢀprotected and unprotected 3,5ꢀdisubstituted proline esters from
intermediate pyrroline leading to the diastereoselective formation
very simple and cheap starting materials.
of a 3,5ꢀcis relative arrangement.
The authors gratefully acknowledge the UPV/EHU (UFI QOSYC
11/22 and fellowships to I. R. and E. D.), MINECO (FEDERꢀ
CTQ2014ꢀ52107ꢀP), and the Basque Government (Grupos
55 IT328ꢀ10) for financial support.
Notes and references
a
Department of Organic Chemistry II, University of the Basque Country
(UPV/EHU). P.O. Box 644, 48080 Bilbao (Spain) Fax: +34 946012748. E-mail:
marisa.carrillo@ehu.es; joseluis.vicario@ehu.es.
60 † Electronic Supplementary Information (ESI) available: Detailed
experimental procedures, NMR data and chiral HPLC traces of racemic
and enantiomerically enriched pyrrolidines. See DOI: 10.1039/b000000x/
15 Figure 1. Xꢀray structure of compound 4q
Finally, and in order to access to the proline scaffold, we next
proceeded to subject to all obtained pyrrolidine adducts 4 to the
baseꢀpromoted intramolecular C→N acyl transfer reaction that
has been recently developed in our group.7 In this sense, when
20 compounds 4aꢀo and 4rꢀs were treated with one equivalent of
MeLi in THF at low temperature a fast reaction took place,
isolating proline ester derivatives 5aꢀo and 5rꢀs as the
corresponding ethyl or methyl carbamates respectively after
aqueous workꢀup. The rearrangement took place with high
25 diastereoselectivity with respect to the generation of the new
stereocenter at Cꢀ2. We also proceeded to carry out the Nꢀ
deprotection of some representative derivatives in order to
demonstrate the synthetic potential of this methodology to access
to structurally complex chiral proline ester derivatives. The
30 deprotection also took place smoothly without epimerization of
any of the stereocenters present at the starting materials.
1
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Scheme
2 Synthesis of proline ester derivatives through
intramolecular diastereoselective C→N acyl rearrangement.
35 Conclusions
100
We have demonstrated that densely substituted proline esters can
be obtained in good yields, complete diastereoselection and high
enantioselectivities directly from aminomalonates and α,βꢀ
unsaturated
ketones
through
a
oneꢀpot
Michael
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65 14 Other reducing agents and conditions were tested but in most cases
the substrate did not undergo reduction and in those cases in which
the reduced pyrrolidine product was obtained, it was isolated as a
mixture of diastereosomers.
15 CCDC 957613 contains the supplementary crystallographic data for
70
this compound. These data can be obtained free of charge from The
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