Enantioselective 1,3-dipolar cycloadditions of azlactones and electrophilic alkenes catalyzed by dimeric BinapAuTFA complexes

Article abstract of DOI:10.1055/s-0030-1260334

Glycine-derived azlactones react with maleimides using (S)- or (R)-dimeric BinapAuTFA complexes affording the corresponding cycloadducts in good yields and high enantioselections (up to 99% ee). The intermediate carboxylic acids are treated with trimethylsilyldiazomethane and isolated as ¹-pyrroline methyl esters. These cycloadducts are transformed into exo-proline derivatives by reduction with NaBH₃CN in acidic media. On the other hand, N-benzoylalanine-derived oxazolone reacts with tert-butyl acrylate providing the cycloadduct with the ester group at the 3-position with a trans-relative configuration with respect to the methyl ester group. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0030-1260334

62
CLUSTER
Enantioselective 1,3-Dipolar Cycloadditions of Azlactones and Electrophilic
Alkenes Catalyzed by Dimeric BinapAuTFA Complexes
1
, 3-Dipola
r
Cycloaddit
a
ions of Az
l
r
actone
s
í
and
E
le
a
ctrophilic Alkene
M
s
artín-Rodríguez, Carmen Nájera,* José M. Sansano*
Departamento de Química Orgánica e Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias, Universidad de Alicante,
03080 Alicante, Spain
Fax +34(965)903549; E-mail: cnajera@ua.es; E-mail: jmsansano@ua.es
Received 21 July 2011
Dedicated to Professor Avelino Corma on the occasion of his 60th birthday
with primary amines to yield the expected D1-pyrrolines.8
Abstract: Glycine-derived azlactones react with maleimides using
The asymmetric version of this transformation has been
(S)- or (R)-dimeric BinapAuTFA complexes affording the corre-
accomplished by Toste’s group using (S)-Cy-Seg-
sponding cycloadducts in good yields and high enantioselections
(up to 99% ee). The intermediate carboxylic acids are treated with
phos(AuOBz)2 as catalyst (2 mol%) in the absence of a
trimethylsilyldiazomethane and isolated as D1-pyrroline methyl es- base.9 This system was effective for the cycloaddition be-
ters. These cycloadducts are transformed into exo-proline deriva-
tives by reduction with NaBH3CN in acidic media. On the other
tween alanine-, phenylalanine- and allylglycine-derived
azlactones with maleimides and acrylates. However, (R)-
hand, N-benzoylalanine-derived oxazolone reacts with tert-butyl
Binap(AuOBz)2 offered a very low enantioselection (8%
acrylate providing the cycloadduct with the ester group at the 3-po-
ee) in the 1,3-DC of alanine-derived azlactone and N-phe-
sition with a trans-relative configuration with respect to the methyl
nylmaleimide (NPM).9
ester group.
According to our previous experience in gold(I)-catalyzed
1,3-DC of a-imino esters and alkenes using chiral Binap
as privileged ligand, the dimeric chiral gold complex 2 re-
sulted to be a unique efficient catalyst in terms of enantio-
selection as compared to the bisgold complex 1.10,11 This
data is in a clear contrast to the previously mentioned re-
sult for the reactivity of azlactones.9 Thus, we decided to
study the catalytic activity of complexes 1 and 2
(Figure 1) in the 1,3-DC of oxazolones 3 with electro-
philic alkenes.
Key words: gold, Binap, cycloaddition, azomethine ylides, asym-
metric catalysis
The straightforward synthesis of enantiomerically en-
riched heterocycles can be achieved by 1,3-dipolar cy-
cloadditions (1,3-DC).1,2 Here, the unambiguous
generation of up to four stereogenic centers is produced in
just one reaction step. The interest of these five-mem-
bered heterocycles in many scientific areas such as biolo-
gy, medicine, biochemistry, pharmacy, and organic
synthesis has been demonstrated.3 In particular, D1-pyrro-
lines are present in nature as biosynthetic intermediates,
and are found as part of many biologically active alka-
loids.4 Another attractive feature of these pyrrolines is the
existence of a prochiral reactive cyclic imino group,
which offers several synthetic modifications in order to
build new chiral molecules or building blocks.5 There are
several approaches to obtain D1-pyrrolines, the intramo-
lecular 1,3-DC of azlactones to electrophilic alkenes be-
ing the most relevant.5
P
P
AuX
AuX
1
2+
P
P
Au
Au
P
P
2 X–
Azlactones are very interesting substrates for the synthe-
sis of both quaternized or nonquaternized a-amino acid
derivatives.6 They are also important from the synthetic
point of view because they exhibit a nucleophilic part and
an electrophilic site.7 The combination of both of them
can be exemplified when a Lewis base and a base afforded
a cyclic stabilized azomethine ylide (münchnone) able to
react with low LUMO alkenes. The resulting bicyclic ad-
ducts were opened and the resulting carboxylic acids un-
derwent the reaction with trimethylsilyldiazomethane or
2
P = PPh2
X = CF3CO2
Figure 1
Oxazolones 3 were synthesized under mild reaction con-
ditions by reacting N-acylated a-amino acid derivatives
with dehydrating agents such as carbodiimides.5,8,9 Com-
plexes 1 and 2 were isolated, identified, and characterized
bearing trifluoroacetate as counteranion, by Puddephatt’s
group.12 These complexes were prepared by mixing
NaAuCl4 and dimethyl sulfide and the corresponding
SYNLETT 2012, 23, 62–65
x
x
.x
x
.2
0
1
1
Advanced online publication: 27.09.2011
DOI: 10.1055/s-0030-1260334; Art ID: Y04011ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
1,3-Dipolar Cycloadditions of Azlactones and Electrophilic Alkenes
63
amount of the chiral Binap ligand. The resulting gold(I) mol% of gold(I) catalyst the reaction became slower and
chloride complexes were treated with silver trifuoroace- the enantioselection was not so high. Cycloadduct 4aa
tate for one hour in toluene and the suspension was fil- was obtained as pure stereoisomer whose absolute stere-
tered through a celite plug. The remaining solution was ochemistry was assigned by comparison with the data re-
evaporated obtaining 1 or 2 in 89% and 96% yields, re- ported in the literature for the identical structure.9
spectively.10 These cationic complexes were immediately
Table 1 Optimization of the 1,3-DC between Azlactone 3aa and
NMM
employed without any other purification in the catalytic
model reaction for the optimization tests involving gly-
cine-derived azlactone 3a and NPM. The initial N-metal-
Entry Catalyst
Solvent
Base
Yield ee
(%)a (%)b
lated tricyclic species, formed after the cycloaddition,
underwent b-elimination affording the nonisolated car-
boxylic acid 5aa, which was transformed to the corre-
sponding D1-pyrroline 4aa by treatment with
trimethylsilyldiazomethane (Scheme 1 and Table 1).
1
2
1
2
2
1
2
2
2
1
PhF
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
DIPEA
none
Et3N
–
<50c
–
<5
7
PhF
3
PhF–THF
THF
<5
nd
49
80
99
–
1. catalyst (5 mol%)
base (5 mol%)
O
MeO2C
N
O
O
4
–
solvent, r.t., 19 h
NPh
5
THF
76
88
90
–
NPh
+
N
O
2. TMSCHN2, 30 min
6
CH2Cl2
toluene
toluene
Ph
3a
O
Ph
O
NPM
4aa
7
HO2C
N
O
8
NPh
9
[(R)-BinapAuTFA]2 toluene
90
70c
90
–
–99
78
98
nd
nd
10
11
12
13
2
toluene
toluene
toluene
toluene
Ph
O
5aa
2
Scheme 1
2
(S)-BinapAgTFA
–
Unlike the results catalyzed by (S)-Cy-Seg-
phos(AuOBz)2,9 the employment of fluorobenzene as sol-
vent or co-solvent resulted to be unproductive because
neither chiral gold(I) complex 1, nor complex chiral gold
complex 2 were able to induce any notable enantioselec-
tion (Table 1, entries 1–3). The reaction carried out in
THF showed a very important difference between the two
chiral complexes in terms of enantioselection and chemi-
cal yield (Table 1, entries 4 and 5). The reactive chiral
complex 2 was next evaluated in dichloromethane and tol-
uene, with the latter proving to be the best solvent giving
a 99% ee of the heterocycle 4aa (Table 1, entries 6 and 7).
Again, the chiral bisgold(I) complex 1 resulted to be unre-
active under identical reaction conditions employing tolu-
ene as solvent (Table 1, entry 8). The analogous reaction
carried out in toluene, but using the chiral complex 2 with
opposite absolute configuration, afforded identical results
of the ent-4aa (Table 1, entry 9). The effect of the base
was also important for the final result because the reaction
performed with DBU afforded compound 4aa with a 78%
ee, which was obtained as an impurified crude mixture
(Table 1, entry 10). There was not a significant difference
in running the 1,3-DC with DIPEA or triethylamine (com-
pare entries 7 and 11 of the Table 1). However, the cy-
cloaddition process failed in the absence of base (Table 1,
entry 12). For comparison, the 1,3-DC catalyzed by (S)-
BinapAgTFA completely failed (Table 1, entry 13). In all
of these examples the amount of both catalyst and base
was 5 mol%. When this amount was reduced to a 2.5
a Isolated yield after flash chromatography (silica gel).
b Determined by HPLC analysis employing chiral columns (Daicel
Chiralpak AD-H).
c Impurified crude reaction was obtained; (nd = not determined).
The result obtained from the reaction between azlactone
3a and NPM gave us the opportunity to evaluate the reac-
tion of other aryl-substituted oxazole-5-(4H)-ones 3 with
different N-substituted maleimides (Scheme 2, and
Table 2). The reaction was carried out in toluene, at room
temperature, employing a 5 mol% amount of both the
chiral [(S)-BinapAuTFA]2 and triethylamine (5 mol%).13
N-Methylmaleimide (NMM), and N-ethylmaleimide
(NEM) reacted with azlactone 3a (Ar = Ph) giving good
yields of 4ab and 4bc with a 60% and 70% ee, respective-
ly (Table 2, entries 2 and 3). In all of these examples, the
analogous reactions were repeated at –20 ºC isolating the
corresponding bicyclic adducts 4 with identical enantiose-
lections. Thus, N-alkylmaleimides afforded, in general,
lower enantioselections than the reaction involving NPM.
However, N-aryl-substituted maleimides afforded higher
enantioselectivities in the process. Thus, 4-acetoxy- and
4-bromophenyl N-substituted maleimides reacted with 2-
phenyloxazole-5-one (3a) furnishing good chemical
yields and very good enantioselections (Table 2, entries 4
and 5). When the last example was performed at –20 ºC
the enantioselection increased from 91% to 99% ee
(Table 2, entries 5 and 6).
© Thieme Stuttgart · New York
Synlett 2012, 23, 62–65

64
M. Martín-Rodríguez et al.
CLUSTER
TMSCHN2. The best operation temperature was 0 °C af-
fording 8a in 80% chemical yield and with a 72% ee
(Scheme 4).
1. 2 (5 mol%)
MeO2C
O
O
O
O
Et3N (5 mol%)
PhMe, r.t., 19 h
NR
N
NR
+
N
2. TMSCHN2, 30 min
Ar
O
Ar
O
1. 2 (5 mol%)
Et3N (5 mol%)
PhMe, 1 d
O
O
MeO2C
3
4
CO2t-Bu
N
Ot-Bu
+
O
N
Scheme 2
Table 2 1,3-DC of Azlactones 3 with Maleimides
2. TMSCHN2, 30 min
Ph
Ph
7
8a
r.t.: 80%, 50% ee
0 °C: 80%, 72% ee
Entry Ar, 3
R
Product 4 Yield ee
(%)a (%)b
Scheme 4
1
2
3
4
5
6
7
8
9
Ph, 3a
Ph
Me
Et
4aa
4ab
4ac
90
90
87
90
82
84
78
83
80
99
60
70
99
91
99
99
98
95
Ph, 3a
The cycloaddition involving the last münchnone as 1,3-di-
pole equivalent represents two clear features, which made
it different from the rest of the 1,3-DC employing imino
esters as 1,3-metalloazomethine ylides. The first one is the
opposite regioselection exhibited by this münchnone, and
the second one obeys the type of approaching of the dipo-
larophile to the metallodipole. Such as it is shown in
Scheme 4, the final stereochemistry of the D1-pyrroline 8a
is equivalent to the product formed by a typical exo-ap-
proach of the dipolarophile, that means, the tert-butoxy-
carbonyl group is orientated far away from the complex
formed between the gold(I) moiety and the ylide.
Ph, 3a
Ph, 3a
4-(AcO)C6H4 4ad
Ph, 3a
4-BrC6H4
4-BrC6H4
Ph
4ae
4ae
4ba
4ca
4da
c
Ph, 3a
4-MeC6H4, 3b
4-ClC6H4, 3c
2-thienyl, 3d
Ph
Ph
a Isolated yield after flash chromatography (silica gel).
The cycloadduct 4aa was reduced to the corresponding
exo-prolines by employment of sodium cyanoborohydride
in acidic media, leading to the corresponding imidazoli-
dine 9 (2,5-cis) and its 5-epimeric form 10 (2,5-trans) in
good yield (71%) but with a 1:1 dr value (Scheme 5). The
structural elucidation of diastereoisomers 9 and 10 in the
purified mixture was done by analysis of NOESY experi-
ments.
b Determined by HPLC analysis employing chiral columns.
c Reaction was performed at –20 °C.
Then, when different azlactones, bearing a substituent at
the 4-position of the aromatic ring such as methyl or chlo-
ro groups, were allowed to react with NPM, cycloadducts
4ba and 4ca were obtained in 99% and 98% ee, respec-
tively (Table 2, entries 7 and 8). The reaction of the azlac-
tone 3e bearing a 2-thienyl group as aromatic surrogate
gave cycloadduct 4da in 85% yield and with a 95% ee
(Table 2, entry 9). The 1,3-DC of azlactones 3 with other
different electrophilic alkenes did not occur under the
standard reaction conditions shown in Scheme 2.
O
MeO2C
HN
Ph
NPh
O
MeO2C
N
NaBH3CN, AcOH
MeOH, r.t., 3 h
O
NPh
9
Benzylamine was also employed for the final transforma-
tion to the corresponding N-benzylamide.9 The reaction of
azlactone 3a and NPM was allowed to take place with this
amine at room temperature for 17 hours. Cycloadduct 6a
was isolated in 78% yield and 96% ee (Scheme 3).
(71%)
O
MeO2C
HN
(1:1 dr)
Ph
O
NPh
4aa (99% ee)
Ph
O
10
1. 2 (5 mol%)
Et3N (5 mol%)
PhMe, r.t., 19 h
O
BnHNOC
O
O
Scheme 5
NPh
N
NPh
+
N
O
2. BnNH2, 17 h
It seems that gold complex 2 catalyzes this 1,3-DC in a
similar energetic profile as the analogous one shown for
the 1,3-DC between imino esters and dipolarophiles.10c
On it, a notable energetic barrier was determined between
the reaction involving the homochiral versus the same re-
action of heterochiral gold(I) complexes. The clear posi-
tive non-linear effect (NLE) described in Figure 2
supports this hypothesis. Further theoretical calculations
will be performed in order to support this mechanism.
Ph
3a
O
Ph
O
6a
76%, 96% ee
Scheme 3
The alanine-derived 4-methyloxazole-5-one (7) reacted
with tert-butyl acrylate affording the cycloadduct 8a as
unique stereoisomer after in situ esterification with
Synlett 2012, 23, 62–65
© Thieme Stuttgart · New York

CLUSTER
1,3-Dipolar Cycloadditions of Azlactones and Electrophilic Alkenes
65
References and Notes
(1) For recent reviews about general 1,3-DC, see: (a) Padwa,
A.; Pearson, W. H. In Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Towards Heterocycles and
Natural Products; John Wiley & Sons: New Jersey, 2003.
(b) Nájera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7,
1105. (c) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
(d) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341.
(e) Pellissier, H. Tetrahedron 2007, 63, 3235.
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Figure 2 NLE observed in the reaction of 3a and NPM
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In conclusion, [(S)-BinapAuTFA]2 (2) induced the forma-
tion of (R)-a-amino acid precursors whilst (S)-a-amino
acid derivatives could be obtained by the enantiomeric
form of complex 2, prepared from (R)-Binap. The em-
ployment of dimeric [(S)-BinapAuTFA]2 in the 1,3-DC
between glycine-derived azlactones and maleimides was
very effective. Whilst dimeric catalyst 2 is appropriate for
the enantioselective cycloaddition between glycine-de-
rived azlactones and maleimides, bisgold(I) 1 catalyst
completely failed. In addition, chiral gold(I) complex 2 af-
forded moderate enantioselections when alanine-derived
azlactone was employed. This behavior was complemen-
tary to the catalytic enantioselective cycloaddition report-
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ed
by
Toste’s
group.
They
found
(S)-
CySegphos(AuOBz)2 as suitable catalyst for this type of
cycloadditions. In general, these stereochemical results,
as well as the regiochemistry of the process, are reversed
compared to those observed in the 1,3-DC between imino
esters and maleimides.
(10) (a) Martín-Rodríguez, M.; Nájera, C.; Sansano, J. M.; Wu, F.
L. Tetrahedron: Asymmetry 2010, 21, 1184; corrigendum:
Tetrahedron: Asymmetry 2010, 21, 2559. (b) Martín-
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Cossío, F. P. submitted for publication (c) Martín-
Rodríguez, M.; Nájera, C.; Sansano, J. M.; de Cózar, A.;
Cossío, F. P. Beilstein J. Org. Chem. 2011, 7, 988.
(11) For recent reviews, including recent examples of the use of
[(AuX)2(P–P)*] complexes in catalysis, see: (a) Hashmi, A.
S. K. Chem. Rev. 2007, 107, 3180. (b) Wiedenhoefer, R. A.
Chem. Eur. J. 2008, 14, 5382. (c) Gorin, D. J.; Sherry, B.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work has been supported by the Spanish Ministerio de Ciencia
e Innovación (MICINN) [Consolider INGENIO 2010 CSD2007-
00006, CTQ2007-62771/BQU, CTQ2010-20387, FEDER, Genera-
litat Valenciana (PROMETEO/2009/039)], and by the University of
Alicante. M.M.-R. also thanks MICINN for a grant.
(12) Wheaton, C. A.; Jennings, M. C.; Puddephatt, R. J. Z.
Naturforsch., B 2009, 64, 1469.
(13) For the typical procedure and data of the isolated products,
see Supporting Information.
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Synlett 2012, 23, 62–65

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