Diastereoselectivity in diels-alder cycloadditions of erythrose benzylidene-acetal 1,3-butadienes with maleimides

Article abstract of DOI:10.1055/s-0031-1289785

Maleimides were combined with d-erythrose benzylidene-acetal 1,3-butadienes to study the facial selectivity of the Diels-Alder cycloadditions. The selectivity was found to range from moderate to good. The reaction diastereotopicity can be reversed with the temperature. Simultaneous coordination of the diene, having a free hydroxy group, and maleimide to a chiral bimetallic Lewis acid catalyst (LACASA-DA reaction) occurs with complete diastereocontrol to give a single adduct, using an extra chiral inductor either (R)- or (S)-BINOL.

Full text of DOI:10.1055/s-0031-1289785

LETTER
▌1765
lDettierastereoselectivity in Diels–Alder Cycloadditions of Erythrose Benzylidene-
acetal 1,3-Butadienes with Maleimides
Facial Selectivity of Diels–Alder Cycloadditions
Daniela A. L. Salgueiro, Vera C. M. Duarte, Cristina E. A. Sousa, Maria J. Alves,* António Gil Fortes
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Received: 12.03.2012; Accepted after revision: 07.05.2012
the possibility of acting as a proton donor in a hydrogen
Abstract: Maleimides were combined with D-erythrose benzyli-
bond. Thus combination of diene 2 and maleimide (3) af-
dene-acetal 1,3-butadienes to study the facial selectivity of the
fords a 3:1 (S/R) ratio of isomers; while reaction of diene
1 with maleimide (3) also yields the same ratio of isomers.
Diels–Alder cycloadditions. The selectivity was found to range
from moderate to good. The reaction diastereotopicity can be re-
versed with the temperature. Simultaneous coordination of the di- Scheme 1 depicts the four possible combinations of the re-
ene, having a free hydroxy group, and maleimide to a chiral
bimetallic Lewis acid catalyst (LACASA–DA reaction) occurs with
complete diastereocontrol to give a single adduct, using an extra
agents and reaction conditions, and the yields of products
are collected in Table 1.
chiral inductor either (R)- or (S)-BINOL.
O
Key words: maleimides, D-erythrose benzylidene-acetal 1,3-buta-
NR2
diene, Diels–Alder cycloaddition, selectivity
Ph
Ph
Ph
2'
O
O
O
O
O
O
O
H
H
5
5'
+
3, R2 = H
4, R2 = Ph
Small chiral synthons are becoming more and more ap-
pealing to synthetic chemists to build up target molecules
possessing multistereogenic centers. We have been inves-
tigating the utility of D-erythrose 1,3-butadienes, such as
1 and 2,1 as chiral counterparts in diastereoselective
Diels–Alder cycloadditions. In the past a high diastereo-
topicity was demonstrated in Diels–Alder reactions of
these dienes with 2-methoxycarbonyl-p-benzoquinones.1
In a previous study in our laboratory a complete chiral in-
S
R
OR1
1, R1 = H
2, R1 = TBS
OR1
O
OR1
O
7a
1
H
H
H
N
R2
5a–d
H
N
R2
6a–d
H
H
3
O
O
Scheme 1 Four possible combinations of dienes 1 and 2 to ma-
leimides 3 and 4 giving compounds 5 and 6
duction was also found in [4π+2π] cycloadditions of cer- Considering the unexpected behavior of maleimides in re-
tain D-erythrose benzylidene-acetal 1,3-butadienes, lation to PTAD, Figure 1 shows a possible explanation for
having ether protection at C-5, with 4-phenyl-1,2,4-tri- the observation. Reagent superimposition in situations A,
azoline-3,5-dione (PTAD),2 Maleimide (3), and N- B, and C show the dienophiles approach to the re face of
phenylmaleimide (4). The facial selectivities were moder- the diene, leading to the R configuration of products. In
ate to good under elevated temperatures, and interestingly case A the proximity in space between the two electroneg-
the topicity was reversed when the cycloadditions were ative atoms of the diene and dienophile may result in re-
carried out at 5 °C. Self-assembly of the reaction compo- pulsion between reagents and render such an approach
nents on a Lewis acid template made the selectivity com- unlikely. Approach B does not indicate repulsion due to
plete in two cases.
the nature of maleimides, which may favor such an ap-
proach. Finally, as shown in approach C, attack on the si
face would result in the least hindered interaction between
reagents, which may explain the S-configured compounds
as the major isomers in most reactions.
D-Erythrose benzylidene-acetal 1,3-butadienes possess-
ing the alcohol function protected (e.g., 2) reacted with
PTAD to give solely the adduct with the endo, S-configu-
ration at the new stereogenic center.2 The reaction turned
out to be less selective when the diene bore an unprotected Table 1 displays some relevant reaction conditions em-
hydroxy group at C-5 (1). However, when reacting diene ployed in Diels–Alder reactions between erythrose dienes
2 with N-phenylmaleimide in dichloromethane (the sol- 1 and 2 and maleimides 3 and 4. In the majority of the cas-
vent used in reactions with PTAD) the selectivity was re- es a higher yield of the S-configured product is observed.
duced to a 2:1 ratio of endo diastereomers; the major The reactions usually require several days, but in one case
being the S isomer (5) and the minor, its R diastereomer reaction was shortened from 5 days to 15 hours by in-
(6). The selectivity dropped to zero when diene 1 reacted creasing the temperature to 40 °C with some loss of selec-
with N-phenylmaleimide (4). The best selectivity with tivity (Table 1, compare entries 3 and 4). Diene 1 and
maleimides occurs when at least one of the reagents has maleimide (3) were also combined at 5 °C (Table 1, entry
2) when the R-diastereomer became the major product,
showing that the manner of approach of reagents is highly
dependent on temperature. A possible interpretation for
this fact may be the development of a hydrogen bond in
SYNLETT 2012, 23, 1765–1768
Advanced online publication: 22.06.2012
DOI: 10.1055/s-0031-1289785; Art ID: ST-2012-D0225-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1766
D. A. L. Salgueiro et al.
LETTER
Ph
O
N
O
N
N
Ph
Ph
O
Ph
O
O
O
O
O
O
O
O
N
N
O
OR
Ph
Ph
OR
OR
A
B
C
unfavored interaction
in reaction with PTAD
less unfavored interaction
in reaction with maleimide 4
favored interaction
with PTAD and maleimide 4
Figure 1 Different interaction at the rear double bond in maleimides and PTAD with the erythrose dienes (A, B, and C)
the approach of maleimide by the re face of the diene as Product 6a is an endo product as 5a, according to NOE ex-
shown in Figure 2 which is influential at lower tempera- periments; irradiation of H-5′ and H-7a leading to an in-
tures. There is a good deal of information in the literature crease in intensity of H-4 signals by 6.27% and 10.4%,
that relates the outcome of Diels–Alder cycloadditions respectively.
with possible hydrogen-bonding effects between reac-
tants.3a–g This is reinforced by the result of the experiment
carried out at 5 °C between diene 2 and N-phenylma-
leimide (4), which has no possibility of forming a hydro-
gen bond. The major isomer has the S configuration at
both temperatures (Table 1, entries 5 and 6), with some se-
lectivity improvement at the lower temperature, showing
a different trend from the one in entries 2 and 3 (Table 1).
O
O
H
N
N
O
H
O
Ph
O
Ph
O
O
O
O
H
O
H
attack on the re face
attack on the si face
Figure 2 Approach of maleimide (3) to diene 1 in the re/si face
showing the formation of a hydrogen bond between reagents
Figure 3 ORTEP view of diastereomer 5a
The R/S configurations of the products were found by
To improve the facial selectivity of these cycloadditions it
was decided to self-assemble the reagents by tethering er-
ythrose diene 1 and maleimides 3 and 4 in a LACASA–
Diels–Alder cycloaddition using bimetallic complexes of
Mg(II) and Zn(II) in which (R)- and (S)-BINOL were chi-
ral inducers. This brings an important advantage over sim-
1
comparison of H NMR spectra of both isomers in each
case to compounds 5a/6a.4 The identity of 5a was un-
equivocally confirmed by X-ray crystallography (Figure
3). The chemical shifts of H-5/H-2′ differ between iso-
mers, and the difference is reproducible in every case.5
Table 1 Diels–Alder Cycloadditions of Dienes 1 and 2 with Maleimide (3) and N-Phenylmaleimide (4)
Entry
Diene
Dienophile (2 equiv) Product
Solvent
Temp (°C) Time
dr (S/R)
η (%) 5S/6R
1
2
3
4
5
6
7
1
1
1
1
2
2
2
4
3
3
3
4
4
3
5a/6a
5b/6b
5b/6b
5b/6b
5c/6c
5c/6c
5d/6d
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
r.t.
5
3 d
18 d
5 d
1a:1
1:2
3:1
2:1
2:1
3:1
3:1
22–23
30–19
b
r.t.
40
r.t.
5
15 h
9 d
33–21
43–20
22–4c
18 d
5 d
r.t.
41–39d
a Submitted to X-ray crystal structure analysis.
b Not isolated; dr obtained by 1H NMR spectroscopy.
c An additional 11% of a 1:1 mixture of R and S isomers was isolated. The ratio was based up on 1H NMR spectroscopic analysis of the sample.
d 39% is not pure R isomer; it is formed by a 1:2.9 (S/R) mixture of isomers based on 1H NMR spectroscopic analysis of the sample.
Synlett 2012, 23, 1765–1768
© Georg Thieme Verlag Stuttgart · New York

LETTER
Facial Selectivity of Diels–Alder Cycloadditions
1767
Ph
O
Ph
O
O
O
Ph
N
Ph
O
O
Me2Zn
0 °C
Ph
O
O
O
O
N
O
O
MeMgBr
0 °C
Zn
Zn
MgBr
OH
MgBr
O
O
O
O
Scheme 2 Bimetalic complex of Mg(II) and Zn(II) assembling together diene 1, N-phenylmaleimide (4), and (R)-BINOL
Ph
O
Ph
O
O
O
Ph
O
O
Zn
O
O
O
Zn
O
O
O
H
N
N
O
O
MgBr
O
MgBr
S
O
H
OH
O
H
H
N
O
Ph
B
A
Scheme 3 Coordination of the erythrose diene 1 with maleimide (3) using bimetalic complex of Mg(II) and Zn(II) with (S)-BINOL (A) and
(R)-BINOL (B)
ple Lewis acid catalysts because covalent bonds to the isolated in moderate yields in the case of maleimide (3)
metals are established, and the reaction occurs effectively and diene 1 by using bimetallic complex templates of
by an intramolecular cycloaddition as shown in Scheme 2. Zn(II) and Mg(II) and (R)- or (S)-BINOL. Combination of
This method has been first developed by Inomata6a,b using diene 1, N-phenylmaleimide (4), and (R)-BINOL under
a tartaric acid–zinc complex in reaction of nitroso dieno- the same conditions led to the R-isomer (35% yield) to-
philes with a dienol, and later by Ward.7a,b
gether the S-isomer (15% yield).
The reaction combining (S)-BINOL (A), maleimide, and
diene 1 was completely selective, forming exclusively the
S product in 33% yield.8 Scheme 3 represents the assem-
bly of the reagents, and the direction of attack of ma-
leimide to the front face of the diene leading to the S-
configured product. The high selectivity observed is prob-
ably due to the covalent bond between the Mg and the ni-
trogen atom that forces the antarofacial interaction. The
assembly of (R)-BINOL (B), NH-maleimide, and diene 1
give also a single S-configured product (29%). This
means that although the flexibility of the complex is high-
er in the case of B, a similar approach takes place.
Acknowledgment
Thanks are due to FCT for project funding PTDC/QUI/67407/2006
and FCT and FEDER for funding the NMR spectrometer Bruker
Avance III 400 as part of the National NMR Network. V.C.M.D.
also thanks for PhD grant (SFRH/BD/61290/2009).
References and Notes
(1) Mukhopadhyay, A.; Ali, S. M.; Husain, M.; Suryawanshi,
S. N.; Bhakuni, D. S. Tetrahedron Lett. 1989, 30, 1853.
(2) Alves, M. J.; Duarte, V. C. M.; Faustino, H.; Gil Fortes, A.
Tetrahedron: Asymmetry 2010, 21, 1817.
When N-phenylmaleimide (4) was used in place of ma-
leimide (3) with (R)-BINOL and diene 1 a 2.5:1 ratio of
isomers was obtained, in 50% yield, favoring the R com-
pound. These products were isolated in 35% (R) and 15%
(S) yields. In this case no covalent bond could have been
established, and the reaction attack of the dienophile
could now occur by the less bulky rear face of the diene.
(3) (a) Jones, D. W. J. Chem. Soc., Chem. Commun. 1980, 739.
(b) Fisher, M. J.; Hehre, W. J.; Kahn, S. D.; Overman, L. E.
J. Am. Chem. Soc. 1988, 110, 4625. (c) Trost, B. M.; Lee, D.
C. J. Org. Chem. 1989, 54, 2271. (d) Macaulay, J. B.; Fallis,
A. G. J. Am. Chem. Soc. 1988, 110, 4074. (e) Macaulay,
J. B.; Fallis, A. G. J. Am. Chem. Soc. 1990, 112, 1136.
(f) Tripathy, R.; Carrol, P. J.; Thornton, E. R. J. Am. Chem.
Soc. 1990, 112, 6743. (g) Tripathy, R.; Carrol, P. J.;
Thornton, E. R. J. Am. Chem. Soc. 1991, 113, 7630.
(4) Analytical Data for Some Typical Compounds
Compound 5a: [α]D20 –92.4 (c 0.45, EtOAc). IR (Nujol): νmax
= 3441, 1690, 1457 cm–1. 1H NMR (400 MHz, CDCl3): δ =
2.22–2.32 (1 H, m, H-7), 2.75–2.90 (2 H, m, H-7 and H-3a),
In conclusion maleimides 3 and 4 reacted with erythrose
dienes 1 and 2 showing at its best a 1:3 ratio of product
isomers. It was found possible to reverse the selectivity on
lowering the reaction temperature. Pure S isomers were
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1765–1768

1768
D. A. L. Salgueiro et al.
LETTER
3.35 (1 H, tdd, J = 11.6, 5.8, 3.5 Hz, H-4), 3.60 (1 H, td, J =
11.2, 0.8 Hz, H-6′), 3.83 (1 H, br s, H-5′), 3.96 (1 H, dt, J =
15.0, 7.5 Hz, H-7a), 4.28 (1 H, t, J = 9.0 Hz, H-4′), 4.36 (1
H, ddd, J = 11.0, 5.1, 2.3 Hz, H-6′), 5.52 (1 H, s, H-2′), 6.02–
6.13 (1 H, m, H-6), 6.17 (1 H, dt, J = 9.4, 3.2 Hz, H-5), 7.11–
7.18 (2 H, m, Ph), 7.32–7.54 (8 H, m, Ph) ppm. 13C NMR
(100 MHz, CDCl3): δ = 24.27 (C-7), 39.23 (C-3a), 40.41 (C-
4), 41.43 (C-7a), 66.44 (C-5′), 71.89 (C-6′), 80.46 (C-4′),
101.10 (C-2′), 126.06 (C-H, Ph), 126.42 (C-H, Ph), 128.13
(C-6), 128.23 (C-H, Ph), 128.83 (C-H, Ph), 128.94 (C-H,
Ph), 129.12 (C-H, Ph), 130.14 (C-5), 131.56 (Cq, Ph),
137.49 (Cq, Ph), 178.53 (C=O), 179.81 (C=O) ppm. ESI-
HRMS: m/z calcd for C24H23NNaO5: 428.1467; found:
428.1468.
Compound 5c: H-5: 6.34 (dt, J = 3.6, 9.2 Hz); H-2′: 5.67 (s).
Compound 5d: H-5: 6.28 (dt, J = 3.6, 9.2 Hz); H-2′: 5.67 (s).
Compound 6a: H-5: 6.17 (dt, J = 3.2, 9.2 Hz); H-2′: 5.51 (s).
Compound 6b: H-5: 6.12 (dt, J = 3.6, 9.6 Hz); H-2′: 5.54 (s).
Compound 6c: H-5: 6.16 (br s),* H-2′: 5.42 (s).
Compound 6d: H-5: 6.08 (br t, 2.0 Hz),* H-2′: 5.42 (s).
* These signals coincide with H-6.
(6) (a) Ding, X.; Ukaji, Y.; Fujinami, S.; Inomata, K. Chem.
Lett. 2003, 32, 582. (b) Ukaji, Y.; Inomata, K. Synlett 2003,
1075.
(7) (a) Ward, D. E.; Souweha, M. S. Org. Lett. 2005, 3533.
(b) Ward, D. E.; Mohammad, S. A. Org. Lett. 2000, 3937.
(8) Preparation of Solution A
A solution of diene 1 (0.05 g, 0.22 mmol) in dry toluene (1.0
mL) was added to a solution of Me2Zn (1.2 M) in toluene
(178 μL, 0.22 mmol) at 0 °C and stirred for 5 min.
Preparation of Solution B
Compound 6a: [α]D20 –118.2 (c 0.45, EtOAc). IR (Nujol):
νmax = 3442, 1690, 1411, 1072 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 2.17–2.31 (1 H, m, H-7), 2.64–2.76 (1 H, m, H-
4), 2.83 (1 H, ddd, J = 15.4, 7.0, 1.6 Hz, H-7), 3.27 (1 H, td,
J = 8.0, 1.6 Hz, H-3a), 3.65 (1 H, t, J = 10.4 Hz, H-6′), 3.81
(2 H, dd, J = 9.0, 5.5 Hz, H-7a and H-5′), 4.27 (1 H, dd, J =
10.8, 5.1 Hz, H-6′), 4.44 (1 H, t, J = 9.6 Hz, H-4′), 5.64 (1 H,
s, H-2′), 6.02 (1 H, ddt, J = 12.9, 6.5, 3.3 Hz, H-6), 6.41 (1
H, dt, J = 9.4, 3.5 Hz, H-5), 7.19–7.22 (2 H, m, Ph), 7.35–
7.40 (4 H, m, Ph), 7.43–7.47 (2 H, m, Ph), 7.50–7.52 (2 H,
m, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.00 (C-7),
39.50 (C-3a), 40.09 (C-7a), 41.32 (C-4), 68.05 (C-5′), 71.24
(C-6′), 79.47 (C-4′), 100.79 (C-2′), 126.08 (C-H, Ph), 126.54
(C-H, Ph), 127.54 (C-6), 128.19 (C-H, Ph), 128.60 (C-H,
Ph), 128.85 (C-H, Ph), 129.08 (Cq, Ph), 130.62 (C-5),
131.89 (Cq, Ph), 137.70 (Cq, Ph), 177.21 (C=O), 179.05
(C=O) ppm. ESI-HRMS: m/z calcd for C24H23NNaO5:
428.1473; found: 428.1468.
A solution of (S)-BINOL (0.061 g; 0.22 mmol) in dry
toluene (1.0 mL) was added to a solution of MeMgBr (1.4 M
in toluene–THF; 152 μL, 0.22 mmol) at 0 °C and stirred for
5 min. Solution A was added to solution B, the mixture
diluted with dry toluene (1.8 mL) and stirred for 5 min.
This mixture was refrigerated at –78 °C and a solution of
maleimide (3; 0.02 g, 0.22 mmol) in dry toluene (1.5 mL)
was then added. The temperature was allowed to rise
gradually to r.t. The reaction was complete after 17 d and
was quenched with an aq sat. solution of NaHCO3 (1 mL),
filtered through a pad of Celite, and the Celite was washed
with EtOAc (4 × 10 mL). The filtrates were combined and
concentrated under reduced pressure to give a yellow oil that
was submitted to ‘dry-flash’ chromatography using a
mixture of PE (40–60)–Et2O. (S)-BINOL was recovered
(0.035 g, 57%) from PE–Et2O (1:1), and the product was
eluted with PE–Et2O (1:2.3; 0.024 g, 33%).
(5) Compound 5a: H-5: 6.40 (dt, J = 3.2, 9.2 Hz); H-2′: 5.64 (s).
Compound 5b: H-5: 6.38 (dt, J = 3.6, 9.2 Hz); H-2′: 5.66 (s).
Synlett 2012, 23, 1765–1768
© Georg Thieme Verlag Stuttgart · New York

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