Synthetic scope and DFT analysis of the chiral binap-gold(I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

Article abstract of DOI:10.3762/bjoc.9.280

The 1,3-dipolar cycloaddition between glycine-derived azlactones with maleimides is efficiently catalyzed by the dimeric chiral complex [(Sa)-Binap AuTFA]2. The alanine-derived oxazolone only reacts with tert-butyl acrylate giving anomalous regiochemistry, which is explained and supported by Natural Resonance Theory and Nucleus Independent Chemical Shifts calculations. The origin of the high enantiodiscrimination observed with maleimides and tert-butyl acrylate is analyzed using DFT computed at M06/Lanl2dz//ONIOM(b3lyp/Lanl2dz: UFF) level. Several applications of these cycloadducts in the synthesis of new proline derivatives with a 2,5-trans-arrangement and in the preparation of complex fused polycyclic molecules are described.

Full text of DOI:10.3762/bjoc.9.280

Synthetic scope and DFT analysis of the chiral
binap–gold(I) complex-catalyzed 1,3-dipolar
cycloaddition of azlactones with alkenes
María Martín-Rodríguez1, Luis M. Castelló1, Carmen Nájera*1,§,
José M. Sansano*1,§, Olatz Larrañaga2, Abel de Cózar2,3
and Fernando P. Cossío*2,¶
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2422–2433.
1Departamento de Química Orgánica e Instituto de Síntesis Orgánica,
Universidad de Alicante, Apdo. 99, 03080-Alicante, Spain,
2Departamento de Química Orgánica I, Facultad de Química,
Universidad del País Vasco, Apdo. 1072, E-20018 San Sebastián,
Spain and 3IKERBASQUE, Basque Foundation for Science, 48011
Bilbao, Spain
doi:10.3762/bjoc.9.280
Received: 07 August 2013
Accepted: 18 October 2013
Published: 11 November 2013
This article is part of the Thematic Series "Gold catalysis for organic
synthesis II".
Email:
Carmen Nájera* - cnajera@ua.es; José M. Sansano* -
jmsansano@ua.es; Fernando P. Cossío* - fp.cossio@ua.es
Guest Editor: F. D. Toste
* Corresponding author
© 2013 Martín-Rodríguez et al; licensee Beilstein-Institut.
License and terms: see end of document.
§ Corresponding author for experimental details.
¶ Corresponding author for computational data.
Keywords:
asymmetric catalysis; DFT; 1,3-dipolar cycloaddition; gold catalysis;
NICS; NTR; oxazolones; prolines
Abstract
The 1,3-dipolar cycloaddition between glycine-derived azlactones with maleimides is efficiently catalyzed by the dimeric chiral
complex [(Sa)-Binap·AuTFA]2. The alanine-derived oxazolone only reacts with tert-butyl acrylate giving anomalous regiochem-
istry, which is explained and supported by Natural Resonance Theory and Nucleus Independent Chemical Shifts calculations. The
origin of the high enantiodiscrimination observed with maleimides and tert-butyl acrylate is analyzed using DFT computed at M06/
Lanl2dz//ONIOM(b3lyp/Lanl2dz:UFF) level. Several applications of these cycloadducts in the synthesis of new proline derivatives
with a 2,5-trans-arrangement and in the preparation of complex fused polycyclic molecules are described.
Introduction
The synthesis of α-amino acids employing an α-amino carbon- bond generation based strategy affording both quaternized and
yl template constitutes the most straightforward route to intro- non quaternized α-amino acid derivatives [2-5]. The prepar-
duce the α-side chain [1]. As a valid example, oxazol-5-(4H)- ation of azlactones is very simple and their reactivity is very
ones (azlactones) are suitable heterocycles to perform this C–C diverse due to their functional groups [2-5]. Many enantiose-
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Beilstein J. Org. Chem. 2013, 9, 2422–2433.
lective and/or diastereoselective processes have been focussed are very efficient in asymmetric catalysis [23,24]. The high
on the elaboration of enantiomerically enriched new non- amount of gold per mole of catalyst and the chiral ligand itself
proteinogenic α-amino acids, such as Michael-type additions make these processes somehow expensive.
[6,7], transition metal-catalyzed allylations [8], Mannich-type
additions [9], aldol-type reactions [10], and for other different The relative lower cost of chiral privileged ligand Binap (versus
purposes [11-17]. These substrates can be easily transformed in Cy-Segphos) and the good results obtained in the 1,3-DC of
münchnones, which are potential 1,3-dipoles, after deprotona- α-imino esters and electrophilic alkenes using the bis-gold(I)
tion and imine-activation with a chiral Lewis acid. Despite of complex 3 (where the gold atom:ligand ratio is 1:1, Figure 1)
the easy access to this mesoionic heterocycles their enantiose- [25-27] inspired us to test it in this azlactone involved cycloadd-
lective cycloadditions with electrophilic alkenes have not been ition. Previous experience in the 1,3-DC between imino esters
exploited. Toste´s group published an efficient 1,3-dipolar and electrophilic alkenes revealed that the dimeric chiral gold
cycloaddition (1,3-DC) between alanine, phenylalanine and complex 3 resulted to be unique efficient catalyst in terms of
allylglycine derived azlactones with maleimides and acrylates enantioselection rather than the bis-gold complex 4 [25-27].
employing dimetallic (S)-Cy-Segphos(AuOBz)2 complex 1 as a This data is in a clear contrast to the previously mentioned
catalyst (2 mol %) in the absence of base (Figure 1) [18,19]. result for the reactivity of azlactones [18,19]. In this work we
This catalytic system was very effective but the reactions describe a more extended study than the analogous one
performed with (R)-Binap(AuOBz)2 (Figure 1) as catalyst described in a preliminary communication [28] concerning the
offered a very low enantioselection, for example, a 8% ee was catalytic activity of complexes 3 and 4 in the 1,3-DC of
achieved in the 1,3-DC of alanine derived azlactone and oxazolones with electrophilic alkenes. Here, a deep DFT
N-phenylmaleimide (NPM).
analysis and the application of other computational experi-
ments (NRT, NICS) were compared to the experimentally
observed results in order to clarify the enantio- and anomalous
regioselectivity.
Results and Discussion
Initially, the synthesis of oxazolones 5 was accomplished under
mild reaction conditions by mixing N-acyl-α-amino acid deriva-
tives in the presence of dehydrating agents such as carbodi-
imides [2-5]. Gold(I) complexes 3 and 4, identified and charac-
terized by Puddephatt’s group [X = trifluoroacetate (TFA)] [29-
31], were obtained from NaAuCl4 and dimethyl sulfide and the
corresponding amount of the chiral Binap ligand. Finally, the
anion interchange was promoted by the addition of an equiva-
lent amount of silver(I) salt. These complexes were used imme-
diately after filtration through a celite path. Particularly,
complexes 3 and 4 (X = TFA) could be isolated in 96 and 89%
yield, respectively, but other gold(I) complexes (see Table 1)
with different anions were generated in situ and used as cata-
lysts in the same solution.
Oxazolone derived from glycine 5a was allowed to react with
N-phenylmaleimide (NPM) at room temperature (25 °C
approx.) using 5 mol % of the chiral catalytic complex and
5 mol % of base (Scheme 1). After completion, a large excess
of trimethylsilyldiazomethane was added to obtain the methyl
ester of intermediate carboxylic acid 6a (30 min). Compound
Figure 1: Chiral gold(I) complexes employed in 1,3-DC involving
azomethine ylides.
Numerous gold-catalyzed transformations employing mild reac- 7aa was obtained diastereoselectively (>98:2, by 1H NMR
tion conditions appeared during the last twelve years [20-22]. spectroscopy) after purification and its absolute configuration
Initially, coordination arrangements of chiral gold complexes was established according to the retention times of signals
avoided high enantiodiscriminations but, recently, it has been observed after HPLC analysis employing chiral columns and by
demonstrated that chiral bis-gold complexes type 2 (Figure 1) comparison with the previously reported data [18,19].
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Beilstein J. Org. Chem. 2013, 9, 2422–2433.
Scheme 1: 1,3-DC of azlactone 5a and NPM.
Using this model reaction (Scheme 1), we tested the dimeric is crucial for this transformation, it ensures both of the high
gold complex [(Sa)-Binap·AuTFA]2 according to the previous conversions and enantioselections (Table 1, entries 11–14).
experience obtained in the 1,3-DC involving imino esters and Other different bases such as DBU, and DIPEA did not improve
electrophilic alkenes and the reaction conditions employed by the result achieved by the analogous reaction carried out with
Toste’s group [18,19]. The use of fluorobenzene as solvent or triethylamine (Table 1, entries 12 and 13). Again, the presence
co-solvent did not afford neither good conversions nor enantio- of the chiral catalytic complex 4 (X = TFA) did not give the
selectivities, even working with the dimetallic complex 4 (X = expected results (Table 1, entries 6 and 10). The enantiomeri-
TFA) (Table 1, entries 1–4). After the evaluation of the influ- cally pure form of 7aa with opposite absolute configuration was
ence of the solvent, we concluded that toluene was the most isolated by working in the presence of [(Ra)-Binap·AuTFA]2
appropriate solvent for these reactions (Table 1, entries 5–9), complex (Table 1, entry 11). Surprisingly, no reaction was
being the chemical yield high (90%) and the enantiodiscrimin- observed in the presence of silver(I) complex (Sa)-
ation excellent (99% ee). The presence of triethylamine as base Binap·AgTFA (Table 1, entry 15). In this section the effect of
Table 1: Optimization of the 1,3-dipolar cycloaddition of 5a and NPM using chiral complexes.
Entry
Catalyst/Xa
Solvent
Base
Yieldb (%)
eec (%)
1
2
(Sa)-3/TFA
(Sa)-4/TFA
(Sa)-3/TFA
(Sa)-4/TFA
(Sa)-3/TFA
(Sa)-4/TFA
(Sa)-3/TFA
(Sa)-3/TFA
(Sa)-3/TFA
(Sa)-4/TFA
(Ra)-3/TFA
(Sa)-3/TFA
(Sa)-3/TFA
(Sa)-3/TFA
(Sa)-Binap·AgTFA
(Sa)-3/ClO4
(Sa)-3/OAc
(Sa)-3/OBz
PhF
PhF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
DIPEA
none
Et3N
Et3N
Et3N
Et3N
<50
___d
___d
___d
7
<5
___d
3
PhF-THF
PhF-THF
THF
4
<5
49
5
76
___d
6
THF
nd
7
DCM
88
85
80
8
Et2O
76
9
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
90
99
___d
___d
10
11
12
13
14
15
16
17
18
90
70e
90
–99
80
98
___d
___d
___d
___d
___d
___d
90
91
64
74
aThe gold catalysts were freshly generated in situ. bAfter flash chromatography (silica gel). The observed exo:endo ratio was always >98:2 (1H NMR).
cDetermined by using analytical chiral HPLC columns (Daicel, Chiralpak AS). dNot determined.
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Beilstein J. Org. Chem. 2013, 9, 2422–2433.
different anions of the metal complex was studied as well. In observed when the reaction was run at −20 °C furnishing enan-
contrast with the negligible reaction observed when poor basic tiomerically pure 7af in good chemical yields (Table 2, entries 9
anion, such as perchlorate, was essayed (Table 1, entry 16), and 10). The variation of the arene substituent of the azlactones
anions with basic character such as acetate or benzoate, incor- promoted also excellent to good enantioselections in com-
porated to the chemical structure of the gold(I) catalyst, pounds 7ba and 7ca (Table 2, entries 11 and 12). Even working
promoted the enantioselective reaction although with lower effi- with an heteroaromatic substituent, such as 2-thienyl, com-
ciency (Table 1, entries 17 and 18) [32].
pound 7da was isolated in 95% ee (Table 2, entry 13).
The scope of the reaction was next surveyed. Firstly, azlactone When benzylamine was employed as alternative quenching
5a was allowed to react with several maleimides (Scheme 2, reagent to trimethylsilyldiazomethane, the generation of the
and Table 2, entries 1–10). NPM and 4-acetoxyphenyl- corresponding N-benzylamide in 76% yield and 96% ee was
maleimide were the best entries of this series affording almost achieved after 17 h at 25 °C (Scheme 3) [18,19].
enantiomerically pure bicyclic products 7aa and 7ae, respect-
ively (Table 2, entries 1 and 8). N-Substituted methyl, ethyl and The study of the key points of the enantiodiscrimination step
benzylmaleimides did not afford compounds 7 with so high and mechanism for the 1,3-DC of azlactone 7aa and NPM can
enantioselections. Then, a lower temperature (−20 °C) was be originated by the presence of a more active homochiral
attempted but the increment of ee for N-methyl- and N-ethyl- dimer catalyst (Sa,Sa)-3 (X = TFA) with a lower TS energy with
maleimides was not very noticeable (Table 2, entries 2, 3 and 4, all the reaction components, rather than the corresponding
5, respectively). Nevertheless, a gap of 21 units of ee was heterochiral ones and even lower than homochiral dimer
achieved in the case of the reaction involving N-benzyl- catalyst (Ra,Ra)-3 (X = TFA). The clear positive non-linear
maleimide (Table 2, compare entries 6 and 7). In the case of effects (NLE) described in Figure 2 supported this hypothesis
N-(4-bromophenyl)maleimide a good enantioselection was [33].
Scheme 2: General 1,3-DC between azlactones 5 with maleimides.
Table 2: 1,3-Dipolar cycloaddition of azlactones 5a with maleimides.
Entry
Ar, 5a
R
Product 7
Yieldb (%)
eec (%)
1
2
Ph, 5a
Ph, 5a
Ph
7aa
7ab
7ab
7ac
7ac
7ad
7ad
7ae
7af
90
90
79
87
70
90
83
90
82
84
78
83
80
99
54
60
62
70
50
71
99
91
99
99
98
95
Me
3
Ph, 5a
Med
4
Ph, 5a
Et
Etd
5
Ph, 5a
6
Ph, 5a
Bn
7
Ph, 5a
Bnd
8
Ph, 5a
4-(AcO)C6H4
4-BrC6H4
4-BrC6H4d
Ph
9
Ph, 5a
10
11
12
13
Ph, 5a
7af
4-MeC6H4, 5b
4-ClC6H4, 5c
2-Thienyl, 5d
7ba
7ca
7da
Ph
Ph
aThe gold catalyst was freshly generated in situ. bAfter flash chromatography (silica gel). The observed exo:endo ratio was always >98:2 (1H NMR).
cDetermined by using analytical chiral HPLC columns (Daicel, Chiralpak AS). dReaction run at −20 °C.
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Beilstein J. Org. Chem. 2013, 9, 2422–2433.
Scheme 3: Formation of the amide 8aa.
Next, we studied the reaction between the oxazolone 5aa and
NPM catalyzed by [(Sa)-Binap-AuTFA]2. In previous works,
we have demonstrated that the stereoselectivity of the 1,3-DC
employing chiral metallic Lewis acids arises from the blockage
of one of the prochiral faces [34]. Starting from this selected
conformation of the catalyst, our results show that the
(2Re,5Re) prochiral face is less hindered than the other
prochiral face in the most stable conformation of [{(Sa)-Binap-
Au}2]-5aa complex (Figure 3). As expected, the existence of
dimeric gold units is crucial in the blockage of one of the
prochiral faces, and therefore, in the stereochemical outcome of
the final cycloadducts [26,27].
Refined computational results showed the exo-approach [35] is
the preferred one. In this analysis, only that approach was
considered. The less energetic computed TS are depicted on
Figure 2: Positive non-linear effects (NLE) observed in 1,3-DC of
azlactone 7aa and NPM.
Figure 3: Main geometrical features and relative Gibbs free energies (in kcal mol−1 at 298 K) of complexes [(Sa)-Binap-Au]2-5aa and [(Sa)-Binap-
Au]2-5aa-b computed at M06/Lanl2dz//ONIOM (b3lyp/Lanl2dz:UFF). High-level and low-level layers are represented as ball and stick and wireframe
models, respectively. Blue surface represents the solvent-accessible surface with a probe radius of 1.9 Å.
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Beilstein J. Org. Chem. 2013, 9, 2422–2433.
Figure 4 (see Supporting Information File 1 for further informa- over, lower energy to deform the initial ylide (strain energy) is
tion of additional TS’s).
required in the latter TS. With that energetic diference, the
computed ee is about 99%, in good agreement with the experi-
The computed transition structures correspond to concerted but mental results (Table 2, entry 1).
highly asynchronous cycloadditions (Figure 4). Our calcula-
tions show that there is a different overlap between the acces- The complete reaction path of the cycloaddition process is
sible-solvent surface of the catalyst and the one of the incoming shown in Scheme 4. We do not study computationaly the
dipolarophile. That implies an increase of the 4e− Pauli repul- second synthetic step, namely the ring-opening of the tricyclic-
sion between the reactives in TSNPMdown compared to cycloadduct, because that step has no relevance in the stereo-
TSNPMup, and thus an increase of the activation barrier. More- chemical outcome of the reaction.
Figure 4: Main geometrical features and relative Gibbs free energies (in kcal mol−1) of the less energetic transition states associated with the 1,3-DC
of 5aa and NPM catalyzed by (Sa)-Binap gold dimers computed at M06/Lanl2dz//ONIOM(b3lyp/Lanl2dz:UFF) level of theory. High-level and low level
layers are represented as ball and stick and wireframe models, respectively. Distances are in Å. Blue and purple surfaces represent the solvent-
accessible surface of the catalyst and NPM with a probe radius of 1.9 Å.
Scheme 4: Reaction Gibbs free energy associated with the 1,3-DC of 5aa and NPM catalyzed by (Sa)-Binap gold dimers computed at M06/Lanl2dz//
ONIOM (b3lyp/Lanl2dz:UFF) level of theory.
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Beilstein J. Org. Chem. 2013, 9, 2422–2433.
We also studied the last step of the catalytic cycle that ensures state followed by a Mannich-like ring closure in a stepwise
the recovery of the catalyst obtaining a favourable Gibbs energy mechanism yields the same cycloadduct) [38]. This fact is
of −55.3 kcal mol−1 (Scheme 5).
assumed to be a consequence of the unsymmetrical electron
density in the 1,3-dipole moiety, being higher in the carbon in
No chemical reaction occurred when 5a was combined with α-position to the carboxy group (C2).
other dipolarophiles such as fumarates, maleates, vinyl phenyl
sulfone, trans-1,2-bis(phenylsulfonyl)ethylene, chalcone,
crotonaldehyde and cinnamaldehyde at the same reaction condi-
tions [36]. Another drawback was the poor reactivity observed
when α-substituted azlactones were used as starting material in
the named reaction with NPM. However, the alanine-derived
4-methyloxazole-5-one 10, surprisingly, reacted at 25 and at
0 °C with tert-butyl acrylate yielding cycloadduct 11 in good
yields and moderate to good enantioselections (Scheme 6).
If we compare this result with previous ones obtained using
α-imino esters, this last diastereoselective cycloaddition exhib-
ited an opposite regioselection. Besides, the resulting relative
configuration of Δ1-pyrroline 11 is equivalent to the exo-ap-
proach of the dipolarophile when an endo-transition state was
the most favourable in the gold(I)-catalyzed 1,3-DC with
α-imino esters and alkenes [37].
To gain more insight into the unexpected regioselectivity of the
1,3-DC depicted in Scheme 6, calculations within the DFT
framework were performed. In the accepted mechanism of the
Figure 5: (A) Schematic representation of the model gold(I) ylides. (B)
metal catalyzed 1,3-DC of azomethine ylides and acrylates, the
α-carbon atom of the azomethine ylide (C2 in Figure 5) reacts
with the β-carbon of the acrylate moiety, independently of the
mechanism (concerted fashion or via Michael-like transition
HOMO of the ylides and expansion orbital coefficient values of carbon
atoms 2 and 5 computed at HF/Lanl2dz level of theory. Hydrogen
atoms are omitted for clarity. (C) Most stable Lewis structures of the
ylides obtained with the Natural Resonance Theory (NRT) analysis.
Scheme 5: ΔG calculation for the recovery of the catalytic active species.
Scheme 6: 1,3-DC of azlactone 10 and tert-butyl acrylate.
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Beilstein J. Org. Chem. 2013, 9, 2422–2433.
Initially, a model azomethine ylide derived from oxazolone 10 approach of the gold(I) complex·azlactone 10 to tert-butyl acry-
was considered (Figure 5). Moreover, an acyclic w-shaped ylide late (Figure 6).
analogue (Ylide-II) was also studied as a reference. We chose
this latter 1,3-dipole because it is known that with this kind of In order to have a complete view of the reaction mechanism, all
reactive species, the reaction yields cycloadducts possessing a transition structures corresponding to the endo- or exo-
standard regioselectivity in 1,3-DC with acrylates [38]. Since approaches of the acrylate moiety as well as possible regio-
our goal was to understand the origins of the unusual regiose- chemistry of the selected 1,3-DC, were considered. The main
lectivity observed in the reaction between dipoles of type Ylide- geometrical features of the less energetic transition structures
I with acrylates, trimethylphosphine was coordinated directly to are depicted in Figure 7.
the gold(I) atom in our model (Figure 5).
Our calculations show that the less energetic transition struc-
Analysis of atomic expansion coefficients of the HOMO of ture associated with the 1,3-DC of 10 and tert-butyl acrylate is
Ylide I reveal no significant difference between the azome- TS11exo (Figure 7), is in good agreement with the experimental
thine ylides reported in Figure 5. However, Natural Resonance results in which a high ee of the corresponding stereoisomer
Theory Analysis (NRT) [39-41] shows that the negative charge was observed. The formation of the enantiomer (TS11ent) was
in the Lewis structure of Ylide I is mainly placed on C5. In the found to have an activation barrier of 4.5 kcal mol−1 higher in
case of Ylide II, this negative charge is placed on the oxygen of energy. That difference can be a consequence of the higher
the carboxy group instead. The importance of these electronic strain energy necessary to deform the initial ylide. Our calcula-
distributions was verified by Nucleus Independent Chemical tions also pointed out the stabilizing interaction of the carboxy
Shifts (NICS) calculations in the ring point of the oxazoline group of the incoming acrylate and the gold atom closest to the
[42]. The NICS value of −7.3 ppm pointed to the aromaticity of ylide moiety, despite the long distance (dAu-C=O = 2.8 Å). In
that ring in Ylide I. These results explain the existence of fact, the exo-approach is ca. 11 kcal mol−1 lower in energy than
different regioselectivities for both ylides.
the endo analogue (TS11exo vs TS11endo in Figure 7). Moreover,
the a priori expected regiochemistry of the cycloaduct, in which
Following the same calculation patterns previously shown for C2–Cβ and C5–Cα are new bonds (12), was considered. In this
the reaction with NPM, the results of the main geometrical case, TS12 is 12.1 kcal mol−1 higher in energy than TS11exo. It
features an relative Gibbs free energies were determined for the is noticeable that transition structures associated with the forma-
Figure 6: Main geometrical features and relative Gibbs free energies (in kcal mol−1 at 298 K) of complexes [{(Sa)-Binap-Au}2]-I computed at M06/
Lanl2dz//ONIOM (b3lyp/Lanl2dz:UFF). High-level and low-level layers are represented as ball and stick and wireframe models, respectively. Blue
surface represents the solvent-accessible surface with a probe radius of 1.9 Å.
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Beilstein J. Org. Chem. 2013, 9, 2422–2433.
Figure 7: Main geometrical features and relative Gibbs free energies (in kcal mol−1) of the less energetic transition states associated with the 1,3-DC
of 10 and tert-butyl acrylate catalyzed by (Sa)-Binap gold dimers computed at M06/Lanl2dz//ONIOM(b3lyp/Lanl2dz:UFF). High-level and low level
layers are represented as ball and stick and wireframe models, respectively. Distances are in Å. Hydrogen atoms are omitted for clarity.
tion of C2–Cα and C5–Cβ bonds (TS11exo, TS11ent and reduced to the corresponding pyrrolidines employing sodium
TS11endo) correspond to concerted but highly asynchronous cyanoborohydride in acidic media. In this reaction, a 1:1 mix-
cycloadditions. On the other hand, TS12 is associated with a ture of 2,5-cis-pyrrolidine 13 and its 5-epimer 14 (2,5-trans)
stepwise mechanism.
was isolated in good chemical yield (71%) (Scheme 7, reaction
a). Fortunately, 5-epimer 14 (2,5-trans) was diastereoselec-
As possible applications of the resulting pyrrolines 7aa, it was tively generated through a 10% Pd/C-catalyzed hydrogenation
submitted to different transformations. For example, it could be using 4 atmospheres of hydrogen during three days at 25 °C
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Beilstein J. Org. Chem. 2013, 9, 2422–2433.
Scheme 7: Reduction of heterocycle 7aa under different conditions.
(Scheme 7, reaction b). This trans- arrangement in molecule 14 ture of the cycloaddition of 7aa with β-nitrostyrene afforded an
is not very easy to built because several steps were needed overall poor yield (~28%) of a complex 4:15:10 mixture of
using other synthetic strategies [43].
three compounds (16, 17, and 18) (Scheme 9) [44]. The desired
compound 16 was identified (almost as unique diastereoisomer)
in low chemical yield (<5%) together with two pyrrole deriva-
tives 17 (only one stereoisomer), and 18. The last compound
was formed by a retro-cycloaddition of the pyrroline 7aa with
elimination of NMM, which was favoured by a prolonged
heating [45].
Pyrrolines also possess a typical 1,3-dipole precursor structure
(azomethine ylide), so a second cycloaddition was attempted
with a new equivalent of N-methylmaleimide. The reaction took
place under microwave assisted heating (1 h, 75 W) using
triethylamine as base and toluene as solvent at 120 °C. Poly-
cyclic compound 15 was finally obtained in 50% yield as single
diastereoisomer (Scheme 8). Despite being a solid product it Conclusion
was not possible to perform an X-ray diffraction analysis. Posi- In this work it has been demonstrated the efficiency of the
tive (CH derived from NPM with the CH derived from NMM) chiral [BinapAuTFA]2 complexes in the enantioselective 1,3-
nOe experiments supported the drawn absolute configuration of DC between azlactone derived from glycine and maleimides,
15.
especially those containing a N-aromatic substituent, and
between alanine derived oxazolone with tert-butyl acrylate. In
Other different dipolarophiles were attempted to react with the last example the regiochemistry was totally opposite to the
starting 7aa obtaining very complex mixtures including decom- common trend of these cycloadditions. This behaviour has been
posed materials. In the most cases, reactions had to be refluxed explained for the first time using NRT, NICS, whilst DFT
for 24 h (110 °C, toluene) because microwave assisted irradi- calculations served to justify the elevated enantioselection
ation was not as effective as occurred in the reaction with observed in the 1,3-DC between azlactones and maleimides.
NMM. For example, the purification of the crude reaction mix- The general scope is not very wide but enantioselections
Scheme 8: Double 1,3-DC to give polycycle 15.
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Beilstein J. Org. Chem. 2013, 9, 2422–2433.
Scheme 9: Reaction between 7aa and nitrostyrene.
4. Alba, A.-N. R.; Ríos, R. Chem.–Asian J. 2011, 6, 720–734.
obtained are quite good. Very interesting pyrrolidines with a
trans-arrangement were obtained after hydrogenation of the
pyrroline precursor.
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Supporting Information
7. Uraguchi, D.; Ueki, Y.; Ooi, T. Chem. Sci. 2012, 3, 842–845.
doi:10.1039/c1sc00678a
Description of all procedures and characterization of all
new compounds, as well as computational details and
coordinate tables are reported in the Supporting
Information.
See for a recent contribution.
8. Chen, W.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2068–2071.
doi:10.1021/ja311363a
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3430–3431. doi:10.1021/ja8090643
Supporting Information File 1
Experimental and analytical data.
11.Weber, M.; Frey, W.; Peters, R. Adv. Synth. Catal. 2012, 354,
1443–1449. doi:10.1002/adsc.201200085
[http://www.beilstein-journals.org/bjoc/content/
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See for alkylations at multiple positions.
12.Trost, B. M.; Czabaniuk, L. C. J. Am. Chem. Soc. 2012, 134,
5778–5781. doi:10.1021/ja301461p
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Acknowledgements
13.Dell’Amico, L.; Albrecht, L.; Naicker, T.; Poulsen, P. H.;
Jørgensen, K. A. J. Am. Chem. Soc. 2013, 135, 8063–8070.
doi:10.1021/ja4029928
This work has been supported by the DGES of the Spanish
Ministerio de Ciencia e Innovación (MICINN) (Consolider
INGENIO 2010 CSD2007-00006, FEDER-CTQ2007-62771/
BQU, CTQ2010-20387 and by the Hispano-Brazilian project
PHB2008-0037-PC), Generalitat Valenciana (PROMETEO/
2009/039), the Basque government (Grant IT-324-07) and by
the University of Alicante. M. M.-R. and L. C. also thank
DGES for grants. The authors also thank the SGI/IZO-SGIker
of UPV/EHU for allocation of computational resources.
See for alkylations at multiple positions.
14.Breman, A. C.; Smits, J. M. M.; de Gelder, R.; van Maarseveen, J. H.;
Ingemann, S.; Hiemstra, H. Synlett 2012, 23, 2195–2200.
doi:10.1055/s-0032-1317081
See for participation of α-alkylidene azlactones in 1,3-DC as
dipolarophiles.
15.González-Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem. Commun.
2013, 49, 4649–4651. doi:10.1039/c3cc41663a
See for participation of α-alkylidene azlactones in 1,3-DC as
dipolarophiles.
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