Highly enantioselective Hetero-Diels - Alder reaction of Brassard diene with aromatic aldehydes

Article abstract of DOI:10.1021/ol049364c

Hetero-Diels - Alder reactions of Brassard diene with aromatic aldehydes were carried out smoothly in the presence of titanium(IV) tridentate Schiff base complexes to give the corresponding chiral δ-lactones in high enantioselectivities (up to 99% ee) und

Full text of DOI:10.1021/ol049364c

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2185-2188
Highly Enantioselective
Hetero-Diels−Alder Reaction of Brassard
Diene with Aromatic Aldehydes
,†
Qian Fan,† Lili Lin,† Jie Liu,† Yaozong Huang,† Xiaoming Feng,* and
Guolin Zhang‡
Key Laboratory of Green Chemistry & Technology (Sichuan UniVersity), Ministry of
Education, College of Chemistry, Sichuan UniVersity, Chengdu 610064, China, and
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China
xmfeng@scu.edu.cn
Received April 8, 2004
ABSTRACT
Hetero-Diels−Alder reactions of Brassard diene with aromatic aldehydes were carried out smoothly in the presence of titanium(IV) tridentate
Schiff base complexes to give the corresponding chiral δ-lactones in high enantioselectivities (up to 99% ee) under mild conditions.
As one of the most powerful reactions in organic synthesis,
the catalytic asymmetric hetero-Diels-Alder (HDA) reac-
tion1 provides an effective protocol for preparing optically
active six-membered ring compounds, dihydropyrans, dihy-
dropyranones, etc.2 Chiral 5,6-dihydropyran-2-one or R,â-
unsaturated δ-lactone derivatives are key structural subunits
of natural products with a wide range of biological activity,3
such as antifungal and antitumor. Thus, synthetic methodol-
ogy of δ-lactones has been an area of intense research efforts.
Many methods have been developed, such as the annulation
of open-chained precursors,4 the derivatization from a 2,3-
dihydropyran-4-one,2d,4e and the two-step addition reaction
of ene to dicarbonyl compounds.4f From the synthetic
viewpoint, one of the most convenient ways to δ-lactones is
based on a HDA reaction of Brassard diene5 1a (Figure 1)
with suitable aldehydes or ketones.
Figure 1. Structures of Brassard dienes 1a,b.
The reactions of Brassard diene with aliphatic aldehydes
in the presence of Eu(hfc)3 were performed smoothly in high
enantioselectivity.6 However, the enantioselective approach
of Brassard diene with aromatic aldehydes only gave a
disappointing result; the enantiomeric excess (ee) value
obtained was less than 5%.6e As the Brassard diene is prone
to being destroyed by Lewis acids, recently a kind of
polymer-supported Brassard diene6f was used in this reaction
† Sichuan University.
‡ Chengdu Institute of Biology.
(1) For some recent reviews on the hetero-Diels-Alder reaction, see:
(a) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650. (b) Nicolaou, K.
C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem.,
Int. Ed. 2002, 41, 1668. (c) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000,
39, 3558. (d) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
10.1021/ol049364c CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/02/2004

for a racemics library. As known, however, there is little
research on Brassard diene in the HDA reaction, and no
effective catalytic asymmetric system has been reported for
the cycloaddition reaction of Brassard diene with aromatic
aldehydes.
BINOL and its derivatives,2d,e,i-m,7a-e chiral C2- symmetric
bisoxazolines,7f,g and Schiff-base ligands2f,g,4e,7h-l such as
salen ligands, aminoindanol-derived Schiff base ligand, and
Nobin-derived Schiff base ligand, complexed with suitable
metals such as aluminum, chromium, titanium, and other
transition metals or nonmetals such as boron, have been
successfully applied in the enantioselective HDA reaction.
The tridentate Schiff base ligands derived from (1R,2S)-2-
amino-1,2-diphenylethanol complexed with titanium have
been used in the reactions of asymmetric cyanosilylation of
aldehydes8a and asymmetric oxidation of tert-butyl disulfides.8b
Figure 2. Chiral ligands (2a-f) used in this paper.
Herein we describe an example of a highly enantioselective
HDA reaction of Brassard diene with aromatic aldehydes
catalyzed by titanium(IV) tridentate Schiff base complexes
(Figure 2, Scheme 1).
(2) For some recent works on the hetero-Diels-Alder reaction, see: (a)
Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498. (b)
Audrain, H.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
2000, 65, 4487. (c) Thorhauge, J.; Johannsen, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 1998, 37, 2404. (d) Yamashita, Y.; Saito, S.; Ishitani, H.;
Kobayashi, S. J. Am. Chem. Soc. 2003, 125, 3793. (e) Yamashita, Y.; Saito,
S.; Ishitani, H.; Kobayashi, S. Org. Lett. 2002, 4, 1221. (f) Chavez, D. E.;
Jacobsen, E. N. Org. Lett. 2003, 5, 2563. (g) Joly, G. D.; Jacobsen, E. N.;
Org. Lett. 2002, 4, 1795. (h) Du, H.-F.; Ding, K.-L. Org. Lett. 2003, 5,
1091. (i) Long, J.; Hu, J.-Y.; Shen, X.-Q.; Ji, B.-M..; Ding, K.-L. J. Am.
Chem, Soc. 2002, 124, 10. (j) Yuan, Y.; Li, X.; Ding, K.-L. Org. Lett.
2002, 4, 3309. (k) Wang, B.; Feng, X.-M.; Cui, X.; Liu, H.; Jiang, Y.-Z.
Chem. Commun. 2002, 1605. (l) Wang, B.; Feng, X.-M.; Huang, Y.-Z.;
Liu, H.; Cui, X.; Jiang, Y.-Z. J. Org. Chem. 2002, 67, 2175. (m) Huang,
Y.-Z.; Feng, X.-M.; Wang, B.; Zhang, G.-L.; Jiang, Y.-Z. Synlett 2002,
2122.
Scheme 1. Hetero-Diels-Alder Reactions of Brassard Diene
with Aldehydes
(3) (a) Bindeseil, K. U.; Zeeck, A. HelV. Chem. Acta 1993, 76, 150. (b)
Boyer, F. E.; Prasad, J. V. N. V.; Domagala, J. M.; Ellsworth, E. L.; Gajda,
C.; Hagen, S. E.; Markoski, L. J.; Tait, B. D.; Lunney, E. A.; Palovsky, A.;
Ferguson, D.; Graham, N.; Holler, T.; Hupe, D.; Nouhan, C.; Tummino, P.
J.; Urumov, A.; Zeikus, E.; Zeikus, G.; Gracheck, S. J.; Sanders, J. M.;
Roest, S. V.; Brodfuehrer, J.; Iyer, K.; Sinz, M.; Gulnik, S. V.; Erickson,
J. W. J. Med. Chem. 2000, 43, 843. (c) Harris, J. M.; O’Doherty, G. A.
Tetrahedron Lett. 2000, 41, 183. (d) Yasui, K.; Tamura, Y.; Nakatani, T.;
Kawada, K.; Ohtani, M. J. Org. Chem. 1995, 60, 7567.
(4) For some recent works on the syntheses of δ-lactones, see: (a)
Mulzer, J.; O¨ hler, E. Chem. ReV. 2003, 103, 3753. (b) N’Zoutani, M.-A.;
Pancrazi, A.; Ardisson, J. Synlett 2001, 769. (c) Chakraborty, T. K.; Tapadar,
S.; Tetrahedron Lett. 2003, 44, 2541. (d) Hanefeld, U.; Hooper, A. M.;
Stauton, J. Synthesis 1999, 401. (e) Dossetter, A. G.; Jamison, T. F.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 1999, 38, 2398. (f) Audrain, H.;
Jørgensen, K. A. J. Am. Chem. Soc. 2000, 122, 11543.
Considering the stability of Brassard diene, the methoxy
group of Brassard diene 1a was replaced with the ethoxy
group to diene 1b. Although there is only a small change in
the structure, diene 1b is more stable and easier to purify
than 1a and is synthesized easily through the Brassard
procedure.5
Our studies started with benzaldehyde, 2a, toluene, 0 °C,
and 72 h as test substrate, ligand, solvent, reaction temper-
ature, and reaction time, respectively. Several metals, such
as Et2Zn, AlEt3, Et2AlCl, TiCl4, Zr(OiPr)4, Ti(OiPr)2Cl2, and
Ti(OiPr)4, were screened in the initial experiments. Most of
them gave an ee value less than 33%. Only Ti(OiPr)4 can
give a high ee, up to 93%. It was indicated that the
counterions could decide the asymmetric induction capability
of chiral catalysts in the HDA reaction.9 Some additives, such
as 4 Å MS2k-m,7l and acids7l applied successfully in the HDA
(5) Savard, J.; Brassard, P. Tetrahedron Lett. 1979, 20, 4911.
(6) (a) Midland, M. M.; Graham, R. S. J. Am. Chem. Soc. 1984, 106,
4294. (b) Midland, M. M.; Koops, R. W. J. Org. Chem. 1990, 55, 4647.
(c) Midland, M. M.; Koops, R. W. J. Org. Chem. 1990, 55, 5058. (d)
Midland, M. M.; Afonso, M. M. J. Am. Chem. Soc. 1989, 111, 4368. (e)
Togni, A. Organometallics 1990, 9, 3106. (f) Pierres, C.; George, P.; Hijfte,
L.; Ducep, J.-B.; Hibert, M.; Mann, A. Tetrahedron Lett. 2003, 44, 3645.
(7) Some BINOL derivatives in HDA reaction: (a) Maruoka, K.; Itoh,
T.; Araki, Y.; Shirasaka, T.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1988,
61, 2975. (b) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J. Am.
Chem. Soc. 1988, 110, 310. (c) Ooi, T.; Uraguchi, D.; Kagoshima, N.;
Maruoka, K. J. Am. Chem. Soc. 1998, 120, 5327. (d) Simonsen, K. B.;
Svenstrup, N.; Roberson, M.; Jørgensen, K. A. Chem. Eur. J. 2000, 6, 123.
(e) Gao, Q.-Z.; Maruyama, T.; Mouri, M.; Yamamoto, H. J. Org. Chem.
1992, 57, 1951. Some chiral bisoxazolines in HDA reaction: (f) Evans, D.
A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; Matt, P.; Miller, S. J.; Murry,
J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. J. Am. Chem.
Soc. 1999, 121, 7582 and references therein. (g) Audrian, H.; Thorhauge,
J.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2000, 65, 4487 and
references therein. Some Schiff base ligands in HDA reaction: (h) Schaus,
S. E.; Brånalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 403. (i)
Gademann, K.; Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2002,
41, 3059. (j) Ruck, R. T.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
2882. (k) Yuan, Y.; Long, J.; Sun, J.; Ding, K.-L. Chem. Eur. J. 2002, 8,
5033. (l) Ji, B.-M.; Yuan, Y.; Ding, K.-L.; Meng, J.-B. Chem. Eur. J. 2003,
9, 5989.
(8) (a) Jiang, Y.-Z.; Zhou, X.-G.; Hu, W.-H.; Wu, L.-J.; Mi, A.-Q.
Tetrahedron: Asymmetry 1995, 6, 405. (b) Cogan, D. A.; Liu, G.-C.; Kim,
K.; Backes, B. J.; Ellman, J. A. J. Am. Chem. Soc. 1998, 120, 8011.
(9) (a) Evans, D. A.; Murry, J. A.; Matt, P.; Norcross, R. D.; Miller, S.
J. Angew. Chem., Int. Ed. 1995, 34, 798. (b) Ghosh, A. K.; Matsuda, H.
Org. Lett. 1999, 1, 2157. (c) Adam, W.; Roschmann, K. J.; Saha-Mo¨ller,
C. R.; Seebach, D. J. Am. Chem. Soc. 2002, 124, 5068.
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Org. Lett., Vol. 6, No. 13, 2004

reaction previously, were added to the system, but there
followed much worse results. When 4 Å MS and benzoic
acid were used, the ee decreased sharply from 93% to 76%
and 74%, respectively. Perhaps the different structure of
Brassard diene with Danishefsky’s diene is the key reason.
Togni speculated that double substitution at the terminus had
deleterious consequences upon the enantioselectivity of this
cycloaddition reaction.6e
9). The catalyst loading can be reduced to 5 mol % without
loss of enantioselectivity, and the yields were decreased
slightly, from 76% to 71% (Table 1, entries 9 and 13).
However, when 1 mol % catalyst loading was used, the
enantioselectivity was reduced to 78% and the yield was
decreased sharply to 20%. Extensive screening showed the
optimized catalytic system as 5 mol % 2a-Ti(OiPr)4, 0.25
M aldehyde, 1.5 equiv of diene in 1 mL of CH2Cl2 at 0 °C.
Encouraged by the result obtained for the benzalde-
hyde, we investigated the enantioselective HDA reaction of
Brassard diene with a variety of other aromatic aldehydes
catalyzed by titanium(IV)-ligand 2a complex, all of which
gave rise to products with high enantioselectivities (up to
99% ee, Table 2). As can be seen from data for the reactions
By using the prescribed conditions to survey the chiral
induction of these ligands (2a-f), the results (Table 1, entries
Table 1. Catalytic Enantioselective HDA Reactions of
Brassard Diene with Benzaldehydea
catalyst loading
(mol %)b
T
yield
(%)
ee
(%)c
entry ligand
(°C) solvent
Table 2. Asymmetric Hetero-Diels-Alder Reaction of
Brassard Diene with Aromatic Aldehydes Promoted by Ligand
2aa
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
20
20
20
20
20
20
20
20
20
20
20
10
5
0
0
0
0
0
0
0
0
0
toluene
toluene
toluene
toluene
toluene
toluene
THF
58
43
45
35
54
48
46
42
76
74
48
73
71
20
92
81
76
64
85
47d
61
89
93
81
94e
93
93
78e
entry
aldehyde
benzaldehyde
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
71
45
24
53
36
70
70
87
53
61
56
61
93
96
92
93
90
99
90
97
93
90
91
96
m-methoxy-benzaldehyde
o-methyl-benzaldehyde
m-methyl-benzaldehyde
p-methyl-benzaldehyde
o-chloro-benzaldehyde
m-chloro-benzaldehyde
p-chloro-benzaldehyde
p-fluoro-benzaldehyde
p-cyano-benzaldehyde
p-nitro-benzaldehyde
2-naphthyl-aldehyde
7
8
9
10
11
12
13
14
2a
2a
2a
2a
2a
2a
2a
2a
Et2O
CH2Cl2
23 CH2Cl2
-20 CH2Cl2
0
0
0
CH2Cl2
CH2Cl2
CH2Cl2
9
1
10
11
12
a All reactions were performed with benzaldehyde (1 mmol) and Brassard
diene (1.5 mmol) in 1 mL of solvent for 72 h. b Catalysts were composed
of a 1.1:1 molar ratio of ligands to Ti(OiPr)4. c Enantioselectivities were
determined by HPLC, using commercially Chiralpak AD-H column. d The
product has a reverse configuration compared to the others. e Reaction time
is 7 days.
a All reactions were performed in 1 mL of CH2Cl2 with aldehyde (0.25
mmol) and Brassard diene (0.375 mmol), in the presence of 0.0125 mmol
of Ti(OiPr)4 and 0.01375 mmol of 2a at 0 °C for 72h. b Isolated yield.
c Enantioselectivities were determined by HPLC, using commercially
Chiralpak AD-H column or Chiralcel OJ column (entries 2 and 5).
1-6) showed that the ortho groups of phenol hydroxy in
the ligand impact strongly the enantioselectivity of the
catalyst. The bulkier ortho group, such as tert-butyl, can
achieve a high ee value (Table 1, entry 1). However,
adamantanyl resulted in a lower enantioselectivity (Table 1,
entry 5). This can be attributed to its large steric hindrance.
It was obvious that a suitable group in the ligand can enhance
the match between substrate and catalyst and therefore result
in higher enantioselectivity, but ligand 2f would not perform
the reaction with high enantioselectivity. It maybe partly
attributed to the less flexible five-membered ring structure
of 2f; moreover, Ti was an inappropriate metal to the
Jacobsen’s catalyst2f,g in which the central metal was Cr.
of substituted benzaldehydes, there are significant electronic
and steric effects of aromatic ring groups on reactivity. With
the enhancement of a groups’ electron-donating capability
from Cl, CH3, to OCH3, the reactivity is reduced (Table 2,
entries 7, 4, and 2). With the enhancement of a groups’
electron-withdrawing capability from Cl, CN, to NO2, the
reactivity is also reduced (Table 2, entries 8, 10, and 11).
Therefore, appropriate electron-withdrawing groups of sub-
stituted benzaldehydes can give higher enantioselectivities
and yields (Table 2, entries 6 and 8); the stronger electron-
withdrawing groups result in a drop in yield (Table 2, entries
9-11) and the electronic-donating groups generally show
lower reactivity (Table 2, entries 2-5). The reactions of
chlorine-substituted benzaldehydes with diene 1b were
carried out smoothly (Table 2, entries 6-8). Moreover, the
meta position of substituted benzaldehydes has more influ-
ence on both reactivity and enantioselectivity than ortho or
para position (Table 2, entries 2, 4, and 7). Condensed ring
aldehyde also shows high enantioselectivity with moderate
yield (Table 2, entry 12). In all cases, the reactions proceeded
smoothly to give the desired lactones in high enantioselec-
Solvent survey revealed that toluene, Et2O, and CH2Cl2
can provide products from the HDA reaction in high
enantioselectivities (Table 1, entries 1, 8, and 9) with 58%,
42%, and 76% yield, respectively, but THF shows a strong
solvent effect in which a rather low ee was found (Table 1,
entry 7). Reaction temperature also influences the enantio-
selectivities of the HDA reaction of Brassard diene with
aldehydes (Table 1, entries 9-11). Both enantioselectivity
and yield can be achieved smoothly at 0 °C (Table 1, entry
Org. Lett., Vol. 6, No. 13, 2004
2187

tivities. It is noted that this is the first example of the highly
enantioselective HDA reaction of Brassard diene with
aromatic aldehydes.
Acknowledgment. The authors thank the National Natu-
ral Science Foundation of China (nos. 20225206 and
20390050) and the Ministry of Education, P. R. China (nos.
01144, 104209, 20030610021, and others) for financial
support.
In summary, we developed a kind of titanium(IV) triden-
tate Schiff base complex to promote the synthesis of
δ-lactone by the HDA reaction. Titanium(IV)-ligand 2a
complex exhibits excellent chiral induction in the reaction
of Brassard diene with aromatic aldehydes under mild
conditions. Further studies are being directed toward eluci-
dating the mechanism, as well as toward enlarging the
substrate generality of this reaction.
Supporting Information Available: Experimental details
and characterization data, including 1H and 13C NMR, HRMS
spectra, and HPLC conditions. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL049364C
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Org. Lett., Vol. 6, No. 13, 2004