Hybrid diamines derived from 1,1′-binaphthyl-2,2′-diamine and α-amino acids as organocatalysts for 1,3-dipolar cycloaddition of aromatic nitrones to (E)-crotonaldehyde

Article abstract of DOI:10.1055/s-0029-1217808

Homochiral derivatives of 1,1′-binaphthyl-2,2′-diamine and various α-amino acids were prepared using a convenient procedure. They were tested as organocatalysts for 1,3-dipolar cycloaddition of aromatic nitrones to (E)-crotonaldehyde. The L-phenylalanine-

Full text of DOI:10.1055/s-0029-1217808

LETTER
2261
Hybrid Diamines Derived from 1,1¢-Binaphthyl-2,2¢-diamine and a-Amino
Acids as Organocatalysts for 1,3-Dipolar Cycloaddition of Aromatic Nitrones
to (E)-Crotonaldehyde
H
omochiral
De
u
rivatives of
1
k
,1
¢
-Binaphth
a
yl-2,2
¢
-dia
m
s
ine and
a
z
-AminoAcids Weseliński,a Paweł Stępniak,a Janusz Jurczak*a,b
a
Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: jurczak@icho.edu.pl
b
Received 4 May 2009
et al.,5 followed by others,6 including an interesting ap-
proach by the Benaglia’s group applying the solid-sup-
ported catalyst.7 This reaction leads to isoxazolidines,
five-membered heterocycles possessing up to three ste-
Abstract: Homochiral derivatives of 1,1¢-binaphthyl-2,2¢-diamine
and various a-amino acids were prepared using a convenient proce-
dure. They were tested as organocatalysts for 1,3-dipolar cyclo-
addition of aromatic nitrones to (E)-crotonaldehyde. The L-
phenylalanine-based catalyst 10 afforded superior results, with reogenic centers and a labile N–O bond. Therefore, these
good endo diastereoselectivity, and enantioselectivity of up to 95%
compounds can be transformed to b-amino alcohols, syn-
ee.
thetic intermediates in the synthesis of biologically impor-
tant compounds.8
Key words: a-amino acids, asymmetric organocatalysis, binaph-
thyl derivatives, 1,3-dipolar cycloaddition, nitrones
At the beginning of our studies, we decided to check two
hybrid diamines 1 and 2 as organocatalysts in model reac-
tion of N-benzylidenebenzylamine N-oxide (3a) with (E)-
Recently, we reported the synthesis of novel hybrid
crotonaldehyde (4), as depicted in Scheme 1.5,9
diamines, derived from 1,1¢-binaphthyl-2,2¢-diamine
(BINAM) and several a-amino acids.1 These compounds
R
N+
O–
combine two different stereogenic elements, namely the
chiral axis of the binaphthalene system, and the stereogen-
ic centers of the amino acid units. They can be easily syn-
thesized in a two-step procedure from commercially
available and inexpensive substrates. Originally, they
were designed as chiral ligands for the transition metal
catalysts to be used in asymmetric synthesis. However,
the recent development of organocatalytic systems turned
our attention to this new methodology.2
Me
+
CHO
Ar
3a Ar = Ph
3b Ar = 4-MeC6H4
R = Bn
4
R = Bn
R = Bn
3c Ar = 4-MeOC6H4
3d Ar = 4-ClC6H4
3e Ar = 2-ClC6H4
3f Ar = 1-C10H7
3g Ar = Ph
R = Bn
R = Bn
R = Bn
R = CH(Ph)2
R = Me
3h Ar = Ph
catalyst (10 mol%)
acid (9 mol%)
MeNO2, 4 °C
Diastereomeric hybrid proline diamides 1 and 2
(Figure 1), obtained in our laboratory,3 were successfully
applied in direct asymmetric aldol reaction. Consecutive-
ly, Nájera and co-workers started similar studies.4
R
N
R
O
N
O
These results prompted us to study other reactions, cata-
lyzed by the hybrid diamines. An interesting target was
the 1,3-dipolar cycloaddition reaction of nitrones to a,b-
unsaturated aldehydes, as recently reported by MacMillan
+
Ar
Me
Ar
Me
CHO
CHO
exo-5a–h
endo-5a–h
Scheme 1
O
O
N
H
N
H
NH
NH
NH
NH
All reactions studied were carried out in wet nitro-
methane,10 using 10 mol% of a catalyst and 9 mol% of an
acid as additive. With catalysts 1 and 2, a mixture of cy-
cloadducts endo-5a and exo-5a was obtained in a good
yield, but with low diastereoselectivity and moderate
enantiomeric excess, as shown in Table 1 (entries 1 and
2).
H
N
H
N
O
O
1
2
Figure 1
Since the secondary amines were not very much success-
ful as stereoselective catalysts in this case, we decided to
apply the hybrid compounds 6–11 previously reported by
SYNLETT 2009, No. 14, pp 2261–2264
Advanced online publication: 07.08.2009
DOI: 10.1055/s-0029-1217808; Art ID: G14709ST
x
x
.x
x
.2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

2262
Ł. Weseliński et al.
LETTER
Table 1 Results of the Model 1,3-Dipolar Cycloaddition of 3a to 4a
Me
O
Me
O
O
NH2
NH2
NH2
Entry
Catalyst Yieldb
(%)
Ratioc
Enantioselectivityd (%)
NH
NH
NH
NH
endo/exo endo-5a
exo-5a
(–48)
(–28)
19
1
2
3
4
5
6
7
8
1
2
90
80
80
85
94
86
94
71
1:2.3
1:1.7
1:2.0
1:5.0
1.8:1
1:2.5
5.6:1
1.1:1
(–36)
(–26)
93
NH2
O
Me
Me
6
6
7
7
22
38
i-Bu
i-Bu
NH2
O
O
O
8
78
15
NH2
NH
NH
NH
NH
9
35
25
10
11
92
(–2)
(–8)
NH2
NH2
i-Bu
O
48
i-Bu
a The reaction was carried out in the presence of various hybrid cata-
lysts (10 mol%) and p-TsOH (9 mol%) for 72 h12.
b Isolated yield of endo-5a + exo-5a.
9
8
Bn
O
Bn
c Determined by 1H NMR of an isolated mixture.
d Determined by chiral HPLC. Configuration of (+)-endo-5a:
3R,4S,5R; configuration of (+)-exo-5a: 3S,4S,5R.
O
NH2
NH2
NH2
NH
NH
NH
NH
In all cases, only the S configuration of binaphthyl moiety,
combined with L-amino acid, led to enhanced stereoselec-
tivity. This supports the earlier results on aldol reaction,
catalyzed by proline diamides 1 and 2.3
NH2
O
O
Bn
Bn
10
11
After the best catalyst 10 had been identified, further reac-
tion conditions were investigated. Thus we varied the
quantity and type of the acid additive (Table 2). It was
found that the optimal amount of an acid was 9 mol% (en-
tries 3–5). Use of trifluoromethanesulfonic acid (entry 6)
instead of p-TsOH led to higher diastereoselectivity,
while shortening of the reaction time. Use of benzoic acid
gave only traces of the product (entry 1), whereas trifluo-
roacetic acid produced cycloadducts in significantly low-
er yield (entry 2), compared to more acidic additives, as
shown in Table 2. This is consistent with MacMillan’s ob-
servations, that increasing pKa of the acid additive may
improve catalyst activity. Moreover, these experimental
Figure 2
us,1 that are based on a-amino acids other than proline,
containing the primary amine functionality (Figure 2).
Compared to the catalysts 1 and 2, the L-alanine derivative
6 produced the endo cycloadduct 5a with 93% ee
(Table 1, entry 3), but as the minor diastereomer. The L-
leucine diamine 8, tested under our conditions, produced
the endo cycloadduct as the major diastereomer with 78%
ee (entry 5). Switching to even bulkier L-phenylalanine
catalyst 10 improved the enantioselectivity of the product
5a to 92%, with much better diastereoselectivity (5.6:1 for
10 vs. 1.8:1 for 8, entries 7 and 5, respectively).
Table 2 Results of the Model 1,3-Dipolar Cycloaddition of 3a to 4
Entry
Acid
pKa
Amount of acid Time (h)
(mol%)
Yieldb (%)
Ratioc
endo/exo
ee (%)d of endo-5a
1
2
3
4
5
6
PhCO2H
TFA
4.2
9
9
48
48
72
72
72
40
trace
46
–
–
0.2
– 2.0
– 2.0
– 2.0
–14
3.1:1
6.1:1
5.6:1
5.3:1
7.0:1
88
76
92
80
92
p-TsOH
p-TsOH
p-TsOH
TfOH
5
85
9
94
18
9
92
75
a The reaction was catalyzed by 10 (10 mol%) in the presence of various acid additives.
b Isolated yield of 5a.
c Determined by 1H NMR of an isolated mixture.
d Determined by chiral HPLC; configuration of (+)-endo-5a: 3R,4S,5R.
Synlett 2009, No. 14, 2261–2264 © Thieme Stuttgart · New York

LETTER
Homochiral Derivatives of 1,1¢-Binaphthyl-2,2¢-diamine and a-Amino Acids
2263
results suggest an imminium ion as a catalytic intermedi-
ate.5
Acknowledgment
Financial support from the Ministry of Science and Higher Educa-
tion (Grant PBZ-KBN-126/T09/06) is gratefully acknowledged.
Next, we tested the substrate generality with a range of ar-
omatic nitrones. The results are summarized in Table 3.
The best results were obtained with N-benzyl nitrones,
with para substituents on aromatic ring (entries 1–4). Oth-
er substituents were also tolerated (entries 5 and 6). Vari-
ation in the N-substituent was possible (entries 7 and 8).
Among the other dipolarophiles tested, acrolein was also
suitable, but the yields and diastereoselectivities were
lower (with nitrone 3a: 46% yield, 2:1 endo:exo ratio,
81% ee in favor of endo). Application of cinnamic alde-
hyde was unsuccessful. By a comparison of optical rota-
tion values and HPLC peaks analysis, the configuration of
known endo-isoxazolidines (entries 1–4, 7 and 8) was as-
signed as 4S.5,11
References and Notes
(1) Kowalczyk, B.; Tarnowska, A.; Weseliński, Ł.; Jurczak, J.
Synlett 2005, 2373.
(2) (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43,
5138. (b) Berkessel, A.; Gröger, H. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, 2005.
(c) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007,
107, 5416. (d) Mukherjee, S.; Yang, J. W.; Hoffmann, S.;
List, B. Chem. Rev. 2007, 107, 5471. (e) Dalko, P. I.
Enantioselective Organocatalysis; Wiley-VCH: Weinheim,
2007. (f) Guillena, G.; Hita, M. C.; Nájera, C. Tetrahedron:
Asymmetry 2007, 18, 2249. (g) Pellissier, H. Tetrahedron
2007, 63, 9267. (h) Peng, F.; Shao, Z. J. Mol. Catal. A:
Chem. 2008, 285, 1. (i) Bartoli, G.; Melchiorre, P. Synlett
2008, 1759. (j) Dondoni, A.; Massi, A. Angew. Chem. Int.
Ed. 2008, 47, 4638. (k) Melchiorre, P.; Marigo, M.;
Carlone, A.; Bartoli, G. Angew. Chem. Int. Ed. 2008, 47,
6138.
Table 3 Results of the 1,3-Dipolar Cycloadditions of Nitrones 3a–
h to 4
Entry
Product
Yield (%)b Ratioc
endo/exo
ee (%)d
of endo-5
(3) Gryko, D.; Kowalczyk, B.; Zawadzki, Ł. Synlett 2006, 1059.
(4) (a) Guillena, G.; Hita, M. C.; Nájera, C. Tetrahedron:
Asymmetry 2006, 17, 729. (b) Guillena, G.; Hita, M. C.;
Nájera, C. Tetrahedron: Asymmetry 2006, 17, 1027.
(c) Guillena, G.; Hita, M. C.; Nájera, C. Tetrahedron:
Asymmetry 2006, 17, 1493. (d) Guizetti, S.; Benaglia, M.;
Pignataro, L.; Puglisi, A. Tetrahedron: Asymmetry 2006, 17,
2754. (e) Guillena, G.; Hita, M. C.; Nájera, C. ARKIVOC
2007, (iv), 260. (f) Guillena, G.; Hita, M. C.; Nájera, C.
Tetrahedron: Asymmetry 2007, 18, 1272. (g) Guillena, G.;
Hita, M. C.; Nájera, C. Tetrahedron: Asymmetry 2007, 18,
2300. (h) Ma, G.-N.; Zhang, Y.-P.; Shi, M. Synthesis 2007,
197. (i) Guillena, G.; Hita, M. C.; Nájera, C.; Viózquez, S. F.
J. Org. Chem. 2008, 73, 5933.
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
75
95
95
95
84
50
70
74
7.0:1
92
7.4:1
5.0:1
6.4:1
3.8:1
2.2:1
12:1
88
95
86
8013
6113
70
5g
5h
5.7:1
87
(5) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 9874.
a The reaction was catalyzed by 10 (10 mol%) in the presence of
TfOH (9 mol%).
(6) (a) Karlsson, S.; Högberg, H.-E. Tetrahedron: Asymmetry
2002, 13, 923. (b) Karlsson, S.; Högberg, H.-E. Eur. J. Org.
Chem. 2003, 2782. (c) Chow, S. S.; Nevalainen, M.; Evans,
C. A.; Johannes, C. W. Tetrahedron Lett. 2007, 48, 277.
(d) Lemay, M.; Trant, J.; Ogilvie, W. W. Tetrahedron 2007,
63, 11644.
b Isolated yield of 5.
c Determined by 1H NMR of an isolated mixture.
d Determined by chiral HPLC; configuration of (+)-endo-5: 3R,4S,5R,
configuration of (+)-exo-5: 3S,4S,5R.
(7) Puglisi, A.; Benaglia, M.; Cinquini, M.; Cozzi, F.;
Celentano, G. Eur. J. Org. Chem. 2004, 567.
(8) (a) Frederickson, M. Tetrahedron 1997, 53, 403.
(b) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98,
863.
(9) Compared to crotonaldehyde, acrolein was more difficult to
optimize, as reported in: Jen, W. S. Ph. D. Thesis; California
Institute of Technology: USA, 2004.
(10) The reaction was performed using 0 equiv, 3 equiv, 6 equiv
and 12 equiv of H2O and no significant difference in yield
and diastereoselectivity was observed in all cases, although
the enantioselectivity in the absence of H2O was slightly
lower; therefore 3 equiv of H2O were always added to the
reaction mixture.
In summary, we have developed a new family of catalysts
for 1,3-dipolar cycloaddition of aromatic nitrones with
a,b-unsaturated aldehydes.12,13 Optimal conditions were
10 mol% of catalyst 10 with 9 mol% of trifluoromethane-
sulfonic acid as an additive, providing predominantly
endo adducts with the ee values of up to 95%. According
to our own experience and to the Nájera and co-workers
procedure4a,b the catalyst may be recovered and reused.
We have further proved the utility of hybrid diamines as
catalysts for stereoselective transformations. We have
also confirmed the earlier observations on origins of
asymmetric induction generated by this class of com-
pounds. Studies on the reaction with other class of ni-
trones and a,b-unsaturated aldehydes are underway.
(11) Hashimoto, T.; Omote, M.; Kano, T.; Maruoka, K. Org. Lett.
2007, 9, 4805.
(12) General Procedure for 1,3-Dipolar Cycloaddition: A
solution of the nitrone (0.25 mmol) in nitromethane (1 mL)
was placed in a vial, and H2O (3 equiv), the catalyst and the
acid co-catalyst were added and the resulting mixture was
cooled to 4 °C. Then the freshly distilled a,b-unsaturated
Synlett 2009, No. 14, 2261–2264 © Thieme Stuttgart · New York

2264
Ł. Weseliński et al.
LETTER
aldehyde was added (4 equiv, followed by 3 equiv at 24 h
intervals) and the mixture was left for a specific period of
time. Then it was filtered through a silica gel plug with aid
of CH2Cl2, and then concentrated. After purification by flash
chromatography (hexane–EtOAc), the residual oils were
reduced to the corresponding alcohols with NaBH4 in
MeOH. The ee values of purified alcohols were determined
by chiral HPLC using CHIRALCEL OD or OD-H columns
(95–98% hexane–isopropanol, flow: 1 mL/min).
(13) All new compounds obtained here had correct analytical and
spectral data.
Synlett 2009, No. 14, 2261–2264 © Thieme Stuttgart · New York