Br?nsted-Acid-Catalyzed Asymmetric Three-Component Reaction of Amines, Aldehydes, and Pyruvate Derivatives. Enantioselective Synthesis of Highly Functionalized γ-Lactam Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b03397

Chiral phosphoric acids are efficient organocatalysts for the asymmetric three-component reaction of amines, aldehydes, and pyruvate derivatives. Simultaneous condensation of amines with both carbonylic compounds followed by a hydrogen bonding activated nucleophilic addition of enamines to imines affords densely functionalized enantioenriched 1,5-dihydro-2H-pyrrol-2-ones. These substrates can be used in subsequent diastereoselective transformations to afford enantiopure γ-lactam derivatives.

Full text of DOI:10.1021/acs.orglett.7b03397

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
̈
Bronsted-Acid-Catalyzed Asymmetric Three-Component Reaction of
Amines, Aldehydes, and Pyruvate Derivatives. Enantioselective
Synthesis of Highly Functionalized γ‑Lactam Derivatives
Xabier del Corte, Aitor Maestro, Javier Vicario, Edorta Martinez de Marigorta,
and Francisco Palacios*
́
Departamento de Química Organica I, Facultad de Farmacia, University of the Basque Country, UPV/EHU Paseo de la Universidad
7, 01006 Vitoria-Gasteiz, Spain
S
* Supporting Information
ABSTRACT: Chiral phosphoric acids are efficient organocatalysts
for the asymmetric three-component reaction of amines, aldehydes,
and pyruvate derivatives. Simultaneous condensation of amines with
both carbonylic compounds followed by a hydrogen bonding
activated nucleophilic addition of enamines to imines affords densely
functionalized enantioenriched 1,5-dihydro-2H-pyrrol-2-ones. These
substrates can be used in subsequent diastereoselective transformations to afford enantiopure γ-lactam derivatives.
yrrole and pyrrolidine derivatives occur in numerous
pharmaceutically active natural and unnatural products.1
of 3-amino-1,5-dihydro-2H-pyrrol-2-ones II plays an important
role in rational drug design.
P
1,5-Dihydro-2H-pyrrol-2-ones2 I (Figure 1) contain the γ-
On the other hand, multicomponent reactions (MCRs)9 are
valuable synthetic processes in organic chemistry affording
structures with a high degree of molecular diversity for
biomedical research. Consequently, MCRs are very powerful
tools in diversity oriented synthesis10 with a huge potential in the
field of medicinal chemistry.11 The biological activity of chiral
drugs in general is known to be strongly dependent on the
absolute configuration of their stereocenters.12 For that reason,
the development of asymmetric approaches for the synthesis of
enantiopure organic molecules is an imperative task in science,
and in this matter, asymmetric MCRs (AMCRs) are particularly
interesting instruments.13
Figure 1. Dihydro-pyrrol-2-ones I and II and biologically active 3-
amino-dihydro-pyrrol-2-one structures III and IV.
lactam ring and are the core structures in the skeleton of many
bioactive natural products, such as cytotoxic polyketides
Myceliothermophins E, C, and D,3a the endothelin receptor
antagonist Oteromicyn,3b and antibiotic Pyrrocides A and B.3c
Moreover, 1,5-dihydro-2H-pyrrol-2-one structure is present in a
wide range of drug candidates with assorted pharmacological
activities such as FPR1 antagonists,4a antivirals HIV-1,4b
antitumorals,4c or anticancer VEGF-R enzyme inhibitors.4d
Furthermore, the ring conjugate system of these functionalized
lactams contributes to its high regio- and stereoselectivity and
favors its potential as intermediates in synthetic chemistry.5
In addition, when an amino substituent is present at the 3-
position, these heterocycles II (Figure 1) are also cyclic
enamines and, therefore, excellent synthetic intermediates.6
These cyclic dehydro α,β-amino acid derivatives II7 contain an
essential moiety of the dithiopyrrolone group antibiotics
Holothin, Holomycin, Thiolutin, Aureothricin IIIa−d (Figure
1), or Thiomarinol A−F,8a and they are key intermediates for the
synthesis of Amarillidaceae and Sceletium alkaloids.8b,c Addi-
tionally, 3-amino dihydro-pyrrol-2-one skeleton IV is also
present in many new bioactive ingredients (Figure 1) such as
antimicrobials8d with antibiofilm activity,8e caspase-3 inhib-
itors,8f antipyretics,8g or analgesics.8h Accordingly, the synthesis
Several synthetic procedures for the preparation of dihydro-
pyrrol-2-ones have been reported.2,14 In particular, some years
ago we reported an acid-catalyzed three-component reaction of
aldehydes 1, ethyl pyruvate 2a, and amines 3 to afford 3-amino-
1,5-dihydro-1H-pyrrol-2-ones 4 (Scheme 1).15 This reaction
consists of an initial Mannich reaction between aldimines 5 and
enamines 6, both generated by a concomitant condensation of
Scheme 1. Three-Component Reaction of Aldehydes 1, Ethyl
Pyruvate 2, and Amines 3
Received: October 31, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03397
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
amines 3 with aldehydes 1 and ethyl pyruvate 2a, respectively,
followed by an intramolecular formation of an amide bond in
adduct 7 due to the addition of the resulting amine to the
carboxylic group (Scheme 1). Some modifications of our
synthetic procedure have been described later, such as the
uncatalyzed16 or solvent-free17 reaction or the use of recyclable
catalysts.18 Ithasbeen alsoestablished thatsuch areaction can be
performed under organocatalysis.19 Although in this latter case
good yields can be achieved, only one example is reported for the
asymmetric reaction of ethyl pyruvate, benzaldehyde, and p-
Having identified a suitable catalyst for the enantioselective
multicomponent reaction, next we performed a study on the
influence of the solvent on the enantioselectivity of the process
using the most promising phosphoric acid catalyst VI. The
results observed for the organocatalytic three-component
reaction of p-toluidine 1a, ethyl pyruvate 2a, and p-nitro-
benzaldehyde 3a in different solvents are summarized in Table 2.
23
N
The normalized molar electronic translation energies (ET
)
are used as an indicator of the polarity of the solvent.
a
̈
anisidine using several chiral Bronsted acids as catalyst, and
Table 2. Screening of the Solvent
unfortunately, the enantiomeric excesses are not higher than
44%.19 Continuing with the interest of our research group in the
preparation of functionalized heterocyles20 and in the asym-
metric synthesis of amino acid and amino phosphonic acid
derivatives,21,22 we report here a highly enantioselective three-
component reaction (AMCR) of several amines, aldehydes, and
pyruvate derivatives to afford densely functionalized γ-lactam
derivatives, using chiral phosphoric acids as organocatalysts.
Initially we chose phosphoric acids V−XII (Figure 2) as
b
entry
solvent
ETN (kcal/mol)
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
9
toluene
iPr2O
0.099
0.105
0.117
0.124
0.207
0.231
0.309
0.460
-
100
100
100
100
100
100
100
100
100
82
78
96
85
58
66
67
89
95
Et2O
MTBE
THF
̈
Bronsted acid catalysts for the three-component reaction of p-
DME
CH2Cl2
MeCN
Et2O/CH2Cl2
a
Reaction conditions: p-nitrobenzaldehyde 1a (1 equiv), ethyl
pyruvate 2a (3 equiv), and p-toluidine 3a (2 equiv) were stirred at
rt in the presence of MgSO4 and catalyst VI (0.1 equiv). Determined
̈
Figure 2. Bronsted acid catalysts tested in this study.
b
by chiral HPLC.
nitrobenzaldehyde 1a with 3 equiv of ethyl pyruvate 2a and 2
equiv of p-toluidine 3a in the presence of MgSO4. The results are
summarized in Table 1.
With respect to noncoordinating solvents, in comparison with
dichloromethane (Table 2, entry 7), toluene showed a slight
improvement in the enantioselectivity (Table 2, entry 1).
Surprisingly, when the reaction was performed using diethyl
ether as solvent, a dramatic increase in the enantioselectivity was
observed (Table 2, entry 3). Although this type of solvent effect
is normally attributed to a dependence of the energy of activation
of ionic transition states with the polarity of the solvent, in our
case, we thought that this effect could be explained by a
participation of the solvent in the transition state as described for
other reactions.24 This idea is supported by the fact that similar
enantiomeric excess is obtained when the reaction is performed
in a mixture of dichloromethane/diethyl ether 10:1 (Table 2,
entry 9). This result may suggest a participation of the ether
molecule in the transition state for the initial hydrogen bonding
assisted nucleophilic addition of enamine to imine intermediate
by means of a coordination of the heteroatom with the
organocatalyst. Following this idea, several ethers were tested
as solvents in the multicomponent reaction; however, disparate
results were observed, and lower enantiomeric excesses were
obtained using di(iso)-propylether, methyl-(tert)-butylether,
tetrahydrofuran, or dimethoxyethane (Table 2, entries 2−6).
In addition, the reaction performed in acetonitrile showed also a
good enantioselectivity (Table 2, entry 8). In order to check
whether the Mg2+ cation from drying agent had any influence on
the enantioselectivity of the reaction, two control experiments
were conducted where MgSO4 was replaced by Na2SO4 or
molecular sieves. Since no significant changes were observed in
the reactivity or enantioselectivity we conclude that Mg does not
play any role in the catalytic system. Moreover, while the same
enantiomeric excess was obtained when the catalyst loading was
a
Table 1. Screening of the Catalyst
b
entry
cat.
time (h)
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
V
VI
VII
VIII
IX
X
XI
XII
18
18
18
18
18
18
18
18
100
100
100
100
100
100
100
100
1
67
61
5
11
3
45
2
a
Reaction conditions: p-nitrobenzaldehyde 1a (1 equiv), ethyl
pyruvate 2a (3 equiv), and p-toluidine 3a (2 equiv) in CH2Cl2
were stirred at rt in the presence of MgSO4 and catalyst V−XII (0.1
b
equiv). Determined by chiral HPLC.
Phosphoric acids V−XII proved to be efficient catalysts, and
the reaction of the amine, aldehyde, and pyruvate proceeded in
full conversion in a few hours showing disparate enantiose-
lectivity (Table 1, entries 1−8). Importantly, good enantiomeric
excesses were observed when triphenylsilyl and 2,4,6-triisopro-
pylphenyl-substituted BINOL derived phosphoric acids VI and
VII were used in a 10% ratio with respect to the aldehyde (Table
1, entries 2−3)
B
DOI: 10.1021/acs.orglett.7b03397
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
increased to 20% with respect to the aldehyde, a substantial drop
of the enantioselectivity was observed when the catalyst loading
was reduced to 5%.
Once the optimal conditions for the enantioselective three-
component reaction were established, the synthetic protocol was
generalized to the use of several aldehydes 1 and amines 3 using
substituted BINOL-derived phosphoric acids V−XII. The result
for the best catalyst is reported in Figure 3 (see SI for
optimization for each substrate).
meta-substituted aromatic aldehydes in the three-component
reaction led to the formation of lactams 4l−m in good yields. In
these cases, while a good ee is observed when m-nitro-
benzaldehyde is used as substrate, the use of less electrophilic
m-tolualdehyde requiresheating of the reaction which results in a
drop in the ee (Figure 3). The reaction can be also extended to
the use of other aliphatic aldehydes 1 as electrophiles, such as
cinnamaldehyde or ethyl glyoxalate (Figure 3, 4n−o), as well as
enolizable aldehydes as iso-butyraldehyde, or cyclohexanecar-
boxaldehyde (Figure 3, 4p−q) with acceptable enantioselectiv-
ities. Finally, when heteroaromatic aldehydes were used as
substrates, the three-component reaction only afforded lactams
4 upon heating. Although heating the reaction results in a
substantial drop in the enantioselectivity, 2-thiophene-substi-
tuted lactam 4r can be obtained with a reasonably good ee.
In order to further broaden the possibilities of the reaction, p-
nitrobenzaldehyde 1a, some substituted pyruvate substrates, and
p-toluidine 3a were stirred under reflux in methyl-(tert)-
̈
butylether in the presence of Bronsted acid catalyst VII.
Although good yields were obtained for tetrasubstituted lactam
derivatives 4s−t, lower enantioselectivities were observed, which
may be possibly again attributed to the necessity of performing
the reaction at higher temperature (Figure 3). It should be also
noted that when the reaction was performed in 0.5 mmol scale
for the synthesis of lactam 4h same enantiomeric excess was
obtained.
The absolute configuration of γ-lactams 4 could not be directly
determined since these compounds did not provide suitable
monocrystals for X-ray diffraction. To overcome that obstacle
and additionally explore the synthetic use of these pyrrolidones
4, we used freshly prepared γ-lactam 4h as enamine reagent in a
formal [3 + 3] annulation reaction26 with α,β-unsaturated
ketoester 8 in the presence of ytterbium triflate to afford bicyclic
azaheterocycles 9 (Scheme 2). Only the cis diastereoisomer was
detected by 1H NMR, and no racemization was observed
Figure 3. Scope of the three-component reaction. Reaction conditions:
aldehyde 1 (1 equiv), pyruvate derivative 2 (3 equiv), amine 3 (2 equiv),
and phosphoric acid catalyst VI−IX (0.1 equiv) in Et2O at rt (4a−l and
4n−q) or MTBE at 55 °C (4m and 4r−t).
With respect to the amine substrate, very good enantiomeric
excesses are obtained when weak activating or deactivating
groups such as p-methyl, p-bromo, or o-fluor are present in the
aromatic substituent of the amine 3 (Figure 3, compounds 4a−
c). Very good enantioselectivity is also observed when a strong
activated aromatic amine such as p-anisidine is used (Figure 3,
4d), but a slower reaction is observed in this case, which may be
due to a higher deactivation of the imine electrophile 5 with
respect to the activation of enamine nucleophile 6. Although a
substantial drop in the enantioselectivity is observed using
amines with strong electron-withdrawing groups as substituents
in the aromatic ring such as m-trifluoromethylaniline25 (Figure 3,
4e), the reaction using m-chloroaniline affords lactam 4f with
excellent enantioselectivity. A slower reaction is observed again
in these cases, which may be due to a higher deactivation of the
enamine nucleophile 6 with respect to the activation of imine 5.
Regarding the aldehyde component 1, the reaction can be
performed in the same conditions and with good enantiose-
lectivities using the less electrophilic benzaldehyde instead of p-
nitrobenzaldehyde (Figure 3, 4g−h). Good reactivity and
enantioselectivity are also obtained using other electron-poor
aldehydes such as p-trifluoromethylbenzaldehyde (Figure 3, 4i−
j). However, a substantial drop in the enantiomeric excess
together with an increase in the reaction time was observed when
p-fluorobenzaldehyde was used as substrate (Figure 3, 4k).
Moreover, although ortho substitution is not allowed in the
aldehyde substrate, which may be due to sterical issues, using
Scheme 2. Diastereoselective Reactions of γ-Lactam 4h
Bicyclic compound 9 can also be prepared in a one-pot
procedure starting from the three-component reaction, without
isolating the intermediate lactam 4h with an overall yield of 80%
and 90% ee. Monocrystals of the major enantiomer of bicycle 9
were isolated after several crystallizations, and a 4S, 5R absolute
configuration of the stereocenters was determined from its X-ray
diffraction spectrum (see SI). Therefore, a 5S configuration of
the stereocenter formed in γ-lactam 4h through the asymmetric
three-component reaction was established. Moreover, in order
to demonstrate the potential of the asymmetric three-
component reaction of amines, pyruvate derivatives, and
aldehydes, the reduction of γ-lactam derivative 4h was
performed under hydrogen pressure and in the presence of
palladium as catalyst. After a few hours, saturated γ-lactam 10
was obtained in very good yield, with an excellent diaster-
C
DOI: 10.1021/acs.orglett.7b03397
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Takanashi, N.; Nagano, T.; Suizu, H.;Suzuki, T.; Kobayashi, S. Org. Lett.
2012, 14, 4886.
eoselectivity and without racemization (Scheme 2). The 3S, 5S
absolute configuration of the stereocenters in γ-lactam 10 was
determined indirectly by nuclear Overhauser effect (see SI).
These 1H NMR data showed a cis relative configuration, which is
the result, as expected, from a syn addition of hydrogen that
approaches to the double bond from the less hindered face, that
is, opposite to the phenyl substituent. Compound 10 can also be
prepared in a one-pot procedure starting from the three
components 1b, 2a, and 3d, without isolating the intermediate
lactam 4h and with an overall yield of 95% and 90% ee.
In conclusion, we report here the first highly enantioselective
three-component reaction of pyruvate derivatives, amines, and
aldehydes to efficiently afford 3-amino-1,5-dihydro-2H-pyrrol-
2-ones. The reaction has been generalized to several aromatic
amines, aromatic and aliphatic aldehydes, and some substituted
pyruvate derivatives, allowing the asymmetric synthesis of highly
functionalized γ-lactam derivatives. Moreover, enantioenriched
lactam derivatives can be used in subsequent diastereoselective
transformations, such as formal [3 + 3] annulation and
hydrogenation of the double bond.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03397.
(9) Multicomponent Reactions in Organic Synthesis; Zhu, J., Wang, Q.,
Wang, M.-X., Eds.; Wiley-VCH: Weinheim, 2015.
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Chem., Int. Ed. 2017, 56, 3758 and references therein.
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Thermal ellipsoid plot for 8 and full experimental details,
characterization, and copies of 1H and 13C NMR spectra
for compounds 4, 8, and 9 (PDF)
Accession Codes
CCDC 1581117 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
́
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AUTHOR INFORMATION
Corresponding Author
■
*Fax: (+34) 945 013049. E-mail: francisco.palacios@ehu.eus.
ORCID
́
́
Javier Vicario: 0000-0002-8976-0991
Francisco Palacios: 0000-0001-6365-0324
Notes
́
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Ministerio de Economıa, Industria y
Competitividad (MINECO, CTQ-2015-67871R), and Gobier-
no Vasco (GV, IT 992-16) is gratefully acknowledged. We also
thank SGIker (UPV/EHU) technical support for NMR spectra
(MINECO, GV/EJ, and European Social Found).
■
́
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