Sterically modified chiral (salen)Cr(III) complexes - Efficient catalysts for the oxo-Diels-Alder reaction between glyoxylates and cyclohexa-1,3-diene

Article abstract of DOI:10.1055/s-2006-951535

A group of chiral [(salen)Cr(III)]⁺BF₄^- complexes, with enhanced steric hindrance in 3,3′-positions of salicylidene moiety, has been synthesized and applied for the oxo-Diels-Alder reaction of alkyl glyoxylates with cyclohexa-1,3-diene. A readily accessible complex that bears bulky adamanthyl substituents revealed its potential, leading to the cycloadducts with excellent selectivity (up to endo/exo 99:1, 98% ee), considerably better than the classic Jacobsen catalyst. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951535

LETTER
3263
Sterically Modified Chiral (Salen)Cr(III) Complexes – Efficient Catalysts for
the Oxo-Diels–Alder Reaction between Glyoxylates and Cyclohexa-1,3-diene
S
tericallyModified Chir
o
al
(
Salen)C
r
j
(III) Co
c
mplexes iech Chaładaj,a Piotr Kwiatkowski,a Janusz Jurczak*a,b
a
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01224 Warsaw, Poland
Fax +48(22)6326681; E-mail: jurczak@icho.edu.pl
b
Department of Chemistry, Warsaw University, Pasteura 1, 02093 Warsaw, Poland
Received 21 August 2006
useful mainly due to simplicity of conversion to bicyclic
crystalline lactone 47,9 (Scheme 1), a versatile chiral
building block.10
Abstract: A group of chiral [(salen)Cr(III)]+BF4– complexes, with
enhanced steric hindrance in 3,3¢-positions of salicylidene moiety,
has been synthesized and applied for the oxo-Diels–Alder reaction
of alkyl glyoxylates with cyclohexa-1,3-diene. A readily accessible
complex that bears bulky adamanthyl substituents revealed its po-
tential, leading to the cycloadducts with excellent selectivity (up to
endo/exo 99:1, 98% ee), considerably better than the classic Jacob-
sen catalyst.
A few years ago, we have published a paper concerning
the classic [(salen)Cr(III)]+-catalyzed cycloadditions of
non-activated dienes to alkyl glyoxylates; the selectivities
that we obtained, however, were usually moderate.11 Re-
cently, we have shown that increase in steric hindrance in
3,3¢-positions of salicylidene moiety of the catalyst exerts
beneficial effect on selectivity of [(salen)Cr(III)]+-cata-
lyzed high-pressure addition of allylstannanes to alde-
hydes.12 The positive effect of such enhancement of steric
hindrance on selectivity has also been observed in other
reactions catalyzed by metallosalen complexes.13
Key words: asymmetric catalysis, glyoxylates, hetero-Diels–Alder
reaction, salen–chromium complexes
Enantiomerically pure compounds are of steadily growing
interest for pharmaceutical, agrochemical or fragrance in-
dustry. Asymmetric catalysis opens an economically and
environmentally preferable route to homochiral substanc-
es. The strategy offers a unique possibility for transferring
chiral information from a catalyst to a number of product
molecules. Although thousands of catalytic systems have
been described, only a few of them prove efficient in a
wide variety of reactions. So-called ‘privileged’ chiral
ligands1 such as BINOL,2 BINAP,3 salen4 or
bisoxazoline5 have been successfully applied in numerous
asymmetric transformations including C–C bond forma-
tion. The hetero-Diels–Alder (HDA) reaction is of partic-
ular interest due to high synthetic potential of its
products.6 Vast majority of HDA reactions are cycloaddi-
tions of activated dienes (eg. Danishefsky’s diene) to sim-
ple aldehydes.6 Jørgensen was the first to concern the
reactions of activated aldehydes with non-activated
dienes.7 Although only a few papers have appeared in the
area, high state-of-the-art has been achieved.8
In this paper, we would like to apply the concept of steric
modification of salen complexes to HDA reaction. After
preparation of several sterically modified salen complex-
es of type 5 (Figure 1), we decided to screen their activity
using the [4+2] cycloaddition of 1,3-diene 2 to n-butyl
glyoxylate (1a) as a model reaction (Scheme 2).14 The re-
sults are presented in Table 1. The replacing of one among
the three methyls in tert-butyl groups positioned at 3 and
3¢ of classic Jacobsen catalyst 5a with phenyl resulted in a
significant increase in both diastereo- and enantioselectiv-
ity (entries 1 and 2). Further development of the steric hin-
drance by replacing two remaining methyl groups with
ethyl (entry 3) or even n-propyl (entry 4) caused further
improvement in the selectivity of this reaction.
Extension of steric hindrance may also be achieved by en-
largement of the aromatic group of the discussed substit-
uent. Indeed, replacement of phenyl with 2-methylphenyl
has a beneficial effect on selectivity, contrary to 4-meth-
ylphenyl that caused almost no effect (entries 2, 5, 6). Un-
fortunately, increased steric hindrance lowered the yield
Among products of the reaction of glyoxylates 1 with
non-activated dienes (e.g. cyclohexa-1,3-diene 2) of par-
ticular interest is the cycloadduct 3 (Scheme 1). It is that
OH
H
1. KOH
O
2. HCl
O
+
O
AlkO2C
H
O
CO2Alk
H
4
1
2
3
Scheme 1
SYNLETT 2006, No. 19, pp 3263–3266
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951535; Art ID: G27906ST
© Georg Thieme Verlag Stuttgart · New York

3264
W. Chaładaj et al.
LETTER
A natural consequence of the above studies was to opti-
mize the reaction conditions (Table 2). Among the inves-
tigated solvents (entries 1–5), toluene appeared to be the
most efficient in terms of stereoselectivity (endo/exo 95:5,
95% ee for endo). Better yields, though, were obtained
when the reaction was carried out in dichloromethane, but
the selectivities were significantly lower (entry 2). The
Lewis base type solvents, like acetonitrile, seemed to be
completely ineffective, probably due to strong coordina-
tion to catalyst. Of interest was the fact that the reaction
proceeded quite well without any solvent (entry 6), which
constitutes a definite advantage of this procedure. The re-
action also does not require strictly anhydrous conditions
and addition of molecular sieves (the latter usually causes
decrease in stereoselectivity).
N
O
N
+
Cr
O
–
BF4
R
R
R =
5a
5b
5c
5d
Lowering the temperature caused only an insignificant
improvement in stereoselectivity, at a cost of decrease of
yield – slight when temperature was decreased to 4 °C or
even marked for –25 °C (entries 7 and 8). Increase in the
amount of diene used enhanced the yield, but slightly
hampered both diastereo- and enantioselectivity (entries 9
and 10). On the other hand, dilution of the reaction mix-
ture had no effect on selectivity, but lowered the yield
markedly (entry 11). Finally, we examined the effect of
catalyst loading on the reaction performance (entries 12–
14). Augmentation of the amount of catalyst used exerted
a beneficial effect not only on the yield but also on the se-
lectivity. When the reaction was run with 5 mol% of cat-
alyst 5g, the product was isolated in 83% yield as an
almost pure endo-adduct (endo/exo 99:1) having 98%
enantiomeric purity (entry 13). However, decrease in cat-
alyst loading to 0.5 mol% diminished both yield and se-
lectivity (entry 14).
5e
5f
5g
Figure 1 The chromium(III) complexes used
down to 30% for 5d as a catalyst. Simple introduction of
1-adamanthyl resulted in exceptionally high both endo-
and enantioselectivity of a 95:5 ratio and 95% ee, respec-
tively, when as little as 1 mol% of catalyst was used.15
Noteworthy is the fact, that the complex 5g16 is readily
available on multigram scale in a short and efficient syn-
thesis from commercial and inexpensive materials.17,18
Table 1 Results of the Model Reaction as a Function of Catalyst
Structurea
Entry
Catalyst
Yield of 3a endo/exob
ee for endo
(%)
(%)b
Having the optimal parameters in hand, we decided to per-
form the [4+2] cycloaddition of cyclohexa-1,3-diene (2)
with various alkyl glyoxylates of type 1 (Table 3).19 The
reactions were carried out at room temperature in toluene
with 2 mol% of complex 5g as a catalyst, which seemed
to be the best balance between catalyst loading and reac-
tion results. For primary (n-Bu and Et, entries 1 and 2) as
well as for secondary (i-Pr, entry 3) alkyl groups the re-
sults were very similar. In the case of the bulky alkyl
groups (t-Bu, entry 4), both yield and selectivities were
lower.
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
62
50
47
30
42
48
48
66:34
83:17
93:7
71
92
94
95
96
91
95
95:5
91:9
82:18
95:5
5g
Prompted by excellent results of the model reaction cata-
lyzed by 5g we decided to investigate the possibility of us-
ing other dienes, e.g. 2,3-dimethylbuta-1,3-diene.
Unfortunately, the obtained results were much worse than
those for classic Jacobsen catalyst 5a.
a Conditions: 1 mol% of the catalyst, n-butyl glyoxylate (1 mmol), cy-
clohexa-1,3-diene (1.5 mmol) in 1 mL of toluene, 20 °C, 24 h.
b The endo/exo ratio and ee were determined by GC on a chiral capil-
lary b-dex 120 column (30 m × 0.25 mm); nitrogen – 100 kPa, oven
temp. 150 °C (see ref. 19).
O
CO2n-Bu
O
catalyst 5a–g
+
+
O
n-BuO2C
H
CO2n-Bu
endo-3a
exo-3a
1a
2
Scheme 2 The model reaction
Synlett 2006, No. 19, 3263–3266 © Thieme Stuttgart · New York

LETTER
Sterically Modified Chiral (Salen)Cr(III) Complexes
3265
Table 2 Dependence of the Results of the Model Reaction on Various Reaction Conditionsa
Entry
Concn of 5g Diene 2
Concn of 1a Solvent
(mol/L)
Temp (°C)
Yield of 3a
(%)
endo/exob
ee for endo
(mol%)
(equiv)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3
(%)b
95
78
67
94
7
1
2
1
1
Toluene
CH2Cl2
i-PrNO2
MTBE
20
20
20
20
20
20
4
48
63
24
46
4
95:5
82:8
76:24
91:9
54:46
90:10
96:4
96:4
92:8
91:9
95:5
97:3
99:1
84:16
1
1
3
1
1
4
1
1
5
1
1
MeCN
6
1
1
No solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Ttoluene
Toluene
62
44
9
91
96
96
93
93
95
97
98
88
7
1
1
8
1
1
–25
20
20
20
20
20
20
9
1
1
50
57
22
68
83
31
10
11
12
13
14
1
6
1
1
1.5
1.5
1.5
1.5
0.25
1
2
5
1
0.5
1
a Reaction time: 24 h.
b The endo/exo ratio and ee were determined by GC on a chiral capillary b-dex 120 column (see ref. 19).
Concluding, we have shown that extension of steric prop-
erties of the Jacobsen catalyst has beneficial effects on
diastereo- and enantioselectivity of the HDA reaction of 1
with 2. Employing of readily available catalyst 5g opened
a simple and economic route to the cycloadduct 3 of
particular interest in synthesis.
Table 3 Reactions of Various Alkyl Glyoxylates under Optimized
Conditionsa
Entry
Glyoxylate Yield (%)
(Alk)
endo/exob
ee for endo
(%)b
1
2
3
4
1a (n-Bu)
1b (Et)
68
69
66
51
97:3
94:6
94:6
73:27
97
95
94
83
Acknowledgment
1c (i-Pr)
1d (t-Bu)
This work was financially supported by Ministry of Education and
Science Grant PBZ-KBN-118/T09/16. Financial support for P.K.
from the Foundation for Polish Science is gratefully acknowledged.
a Conditions: 2 mol% of catalyst 5g, alkyl glyoxylate (1 mmol), cy-
clohexa-1,3-diene (1.5 mmol) in 1 mL of toluene, 20 °C, 24 h.
b The endo/exo ratio and ee were determined by GC on a chiral capil-
lary b-dex 120 column (see ref. 19).
References and Notes
(1) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
(2) For recent reviews, see: (a) Brunel, J. M. Chem. Rev. 2005,
105, 857. (b) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev.
2003, 103, 3155.
(3) For recent review, see: Berthod, M.; Mignani, G.;
Woodward, G.; Lemaire, M. Chem. Rev. 2005, 105, 1801.
(4) For recent reviews, see: (a) McGarrigle, E. M.; Gilheany, D.
G. Chem. Rev. 2005, 105, 1564. (b) Larrow, J. F.; Jacobsen,
E. N. Top. Organomet. Chem. 2004, 6, 123. (c) Cozzi, P. G.
Chem. Soc. Rev. 2004, 33, 410. (d) Canali, L.; Sherrington,
D. C. Chem. Soc. Rev. 1999, 28, 85. (e) Ito, Y. N.; Katsuki,
T. Bull. Chem. Soc. Jpn. 1999, 72, 603.
(5) For recent reviews, see: (a) Desimoni, G.; Faita, G.;
Quadrelli, P. Chem. Rev. 2003, 103, 3119. (b) Rechavi, D.;
Lemaire, M. Chem. Rev. 2002, 102, 3467. (c) Jørgensen, K.
A.; Johannsen, M.; Yao, S.; Audrain, H.; Thornauge, J. Acc.
Chem. Res. 1999, 32, 605. (d) Ghosh, A. K.; Mathivanan,
P.; Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 1.
The absolute configuration of major endo-3a–d products
were determined by their correlation with bicyclic lactone
4 (Scheme 1).7a,b In all cases, when (1S,2S)-salen com-
plexes 5a–g were applied for the reaction of 1 with 2, cy-
cloadduct (1R,3S,4S)-endo-3, corresponding to the
levorotatory lactone 4, was obtained.7a,b
It was consistent with our previous observations of vari-
ous metallosalen-catalyzed reactions of aldehydes.11,12,20
The results also supported the recently presented model of
chirality transfer in metallosalen-catalyzed cycloadditions
and additions to aldehydes.20
Synlett 2006, No. 19, 3263–3266 © Thieme Stuttgart · New York

3266
W. Chaładaj et al.
LETTER
(16) Analytical Data for Salen Ligand Precursor of 5g.
(6) For recent reviews, see: (a) Cycloaddition Reaction in
Organic Synthesis; Kobayashi, S.; Jørgensen, K. A., Eds.;
Wiley-VCH: Weinheim, 2002. (b) Jørgensen, K. A. Angew.
Chem. Int. Ed. 2000, 39, 2398.
(7) (a) Johannsen, M.; Jørgensen, K. A. J. Org. Chem. 1995, 60,
5757. (b) Johannsen, M.; Jørgensen, K. A. Tetrahedron
1996, 52, 7321. (c) Johannsen, M.; Jørgensen, K. A. J.
Chem. Soc., Perkin Trans. 2 1997, 52, 1183.
Mp 247–248 °C. 1H NMR (500 MHz, CDCl3): d = 1.23 (s,
18 H), 1.15–1.35 (m, 2 H), 1.40–1.50 (m, 2 H), 1.65–2.00
(m, 10 H), 2.04–2.09 (m, 6 H), 2.13–2.18 (m, 12 H), 3.26–
3,34 (m, 2 H), 6.96 (d, J = 2.2 Hz, 2 H), 7.24 (d, J = 2.2 Hz,
2 H), 8.29 (s, 2 H), 13.64 (s, 2 H). 13C NMR (125 MHz,
CDCl3): d = 24.4, 29.2, 31.4, 33.3, 34.1, 37.2, 37.2, 40.4,
25
72.4, 117.9, 126.0, 126.7, 136.6, 139.9, 158.2, 166.0. [a]D
(8) (a) Oi, S.; Terada, E.; Ohuchi, K.; Kato, T.; Tachibana, Y.;
Inoue, Y. J. Org. Chem. 1999, 64, 8660. (b) Bolm, C.;
Simić, O. J. Am. Chem. Soc. 2001, 123, 3830. (c) Mikami,
K.; Aikawa, K.; Yusa, Y.; Hatano, M. Org. Lett. 2002, 4, 91.
(d) Mikami, K.; Aikawa, K.; Yusa, Y. Org. Lett. 2002, 4, 95.
(e) Becker, J. J.; Van Orden, L. J.; White, P. S.; Gagne, M.
R. Org. Lett. 2002, 4, 727. (f) Bolm, C.; Verrucci, M.;
Simić, O.; Cozzi, P. G.; Raabe, G.; Okamura, H. Chem.
Commun. 2003, 2826. (g) Doherty, S.; Knight, J. G.;
Hardacre, C.; Lou, H.-K.; Newman, C. R.; Rath, R. K.;
Campbell, S.; Nieuwenhuyzen, M. Organometallics 2004,
23, 6127.
+325.7 (c 0.58, CHCl3). IR (KBr): 2950, 2905, 2850, 1625,
1598 cm–1. Anal. Calcd for C48H66N2O2: C, 82.00; H, 9.46;
N 3.98. Found: C, 82.06; H, 9.39, N, 3.82. Catalyst 5g:
HRMS: m/z calcd for C48H64N2O2Cr [M – BF4]+: 752.4367;
found: 752.4392.
(17) Catalyst 5g was synthesized from appropriate ligand
according to Jacobsen procedure: (a) Martínez, L. E.;
Leighton, J. L.; Carsten, D. H.; Jacobsen, E. N. J. Am. Chem.
Soc. 1995, 117, 5897. (b) Schaus, S. E.; Brånalt, J.;
Jacobsen, E. N. J. Org. Chem. 1998, 63, 403.
(18) Ligand precursor of 5g was obtained in three steps similar to
procedures known from literature: (a) Ref. 15. (b) Larrow,
J. F.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 1939.
(19) Analytical Data for Cycloadducts 3.
(9) Achmatowicz, O.; Jurczak, J.; Pyrek, J. S. Tetrahedron
1976, 32, 2113.
(10) (a) Garoflo, A.; Hursthouse, M. B.; Malik, K. M. A.; Olivio,
H. F.; Roberts, S. M.; Sik, V. J. Chem. Soc., Perkin Trans. 1
1994, 1311. (b) Hibbs, D. E.; Hursthouse, M. B.; Knutsen,
L. J. S.; Malik, K. M. A.; Olivo, H. F. Acta. Chem. Scand.
1995, 49, 122. (c) Olivio, H. F.; Yu, J. J. Chem. Soc., Perkin
Trans. 1 1998, 391. (d) Molander, G. A.; Harris, C. R. J.
Org. Chem. 1997, 62, 2944.
(11) Kwiatkowski, P.; Asztemborska, M.; Caille, J.-C.; Jurczak,
J. Adv. Synth. Catal. 2003, 345, 506.
(12) Kwiatkowski, P.; Chaładaj, W.; Jurczak, J. Synlett 2005,
2301.
(13) (a) Pietikäinen, P. Tetrahedron 2000, 56, 417.
(b) Mascarenhas, C. M.; Miller, S. P.; White, P. S.; Morken,
J. P. Angew. Chem. Int. Ed. 2001, 40, 601. (c) Huang, Y.;
Iwama, T.; Rawal, V. H. J. Am. Chem. Soc. 2002, 124,
5950. (d) Liang, S.; Bu, X. R. J. Org. Chem. 2002, 67, 2702.
(e) Gaquere, A.; Liang, S.; Hsu, F.-L.; Bu, X. R.
Tetrahedron: Asymmetry 2002, 13, 2089.
Compound 3a (ref. 11): GC (column b-dex 120, i.d. 30
m × 0.25 mm, carrier gas – nitrogen 100 kPa, oven temp.
150 °C): tR1[exo-3a] = 29.9, tR2[exo-3a] = 30.7, tR[(3S)-endo-3a]
33.1, tR[(3R)-endo-3a] = 34.1 min.
=
Compound 3b (ref. 7a,b and 8a): GC (column b-dex 120, i.d.
30 m × 0.25 mm, carrier gas – nitrogen 100 kPa, oven temp.
140 °C): tR1[exo-3b] = 18.8, tR2[exo-3b] = 19.5, tR[(3S)-endo-3b]
21.2, tR[(3R)-endo-3b] = 21.8 min.
=
Compound 3c: GC (column b-dex 120, i.d. 30 m × 0.25 mm,
carrier gas – nitrogen 100 kPa, oven temp. 140 °C):
t
t
R1[exo-3c] = 19.8, tR2[exo-3c] = 20.5, tR[(3S)-endo-3c] = 21.7,
R[(3R)-endo-3c] = 22.6 min. 1H NMR for endo-3c (500 MHz,
CDCl3): d = 1.21 (d, J = 1.8 Hz, 3 H), 1.22 (d, J = 1.8 Hz,
3 H), 1.26–1.42 (m, 2 H), 1.71–1.77 (m, 1 H), 2.03–2.10 (m,
1 H), 3.06–3.10 (m, 1 H), 4.26 (d, J = 1.8 Hz, 1 H), 4.56–
4.59 (m, 1 H), 5.01 (dq, J = 1.8, 1.8 Hz, 1 H), 6.23–6.28
(m, 1 H), 6.51–6.55 (m, 1 H). 13C NMR (125 MHz, CDCl3):
d = 20.9, 21.7, 25.7, 33.2, 66.4, 68.0, 74.2, 130.4, 134.7,
171.7.
(14) General Procedure for Cycloaddition of Cyclohexa-1,3-
diene to Alkyl Glyoxylates.
Compound 3d: GC (column b-dex 120, i.d. 30 m × 0.25 mm,
carrier gas – nitrogen 100 kPa, oven temp. 150 °C):
tR1[exo-3d] = 15.5, tR2[exo-3d] = 15.9, tR[(3S)-endo-3d] = 16.2,
To a solution of catalyst 5a–g (0.5–5 mol%) and alkyl
glyoxylate (1 mmol, freshly distilled from P2O5) in toluene
(1 mL) cyclohexa-1,3-diene (150 mL, 1.5 mmol) was added,
and the solution was stirred for 24 h at r.t. Afterwards the
reaction mixture was subjected to chromatography
(hexanes–EtOAc, 9:1).
t
R[(3R)-endo-3d] = 16.7 min. 1H NMR for endo-3d (500 MHz,
CDCl3): d = 1.18–1.28 (m, 1 H), 1.29 (s, 9 H), 1.81–1.87 (m,
1 H), 1.93–2.02 (m, 1 H), 2.16–2.24 (m, 1 H), 2.46–2.53 (m,
1 H), 4.51 (d, J = 7.3 Hz, 1 H), 4.59–4.63 (m, 1 H), 5.89–
5.94 (m, 1 H), 6.18–6.23 (m, 1 H). 13C NMR (125 MHz,
CDCl3): d = 18.1, 23.4, 27.9, 39.7, 70.7, 71.5, 75.5, 122.2,
136.0, 175.4.
(15) A bulky adamanthyl substituent in the 3-position turned out
to be essential in highly stereoselective HDA reaction
catalyzed by tridentate chromium(III) complexes:
(a) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew.
Chem. Int. Ed. 1999, 38, 2398. (b) Gademann, K.; Chavez,
D. E.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2002, 41, 3059.
(20) (a) Kwiatkowski, P.; Chaładaj, W.; Malinowska, M.;
Asztemborska, M.; Jurczak, J. Tetrahedron: Asymmetry
2005, 16, 2959. (b) Kwiatkowski, P.; Chaładaj, W.; Jurczak,
J. Tetrahedron 2006, 62, 5116.
Synlett 2006, No. 19, 3263–3266 © Thieme Stuttgart · New York