A highly enantioselective hetero-Diels-Alder reaction of aldehydes with Danishefsky's diene catalyzed by chiral titanium(IV) 5,5′,6,6′,7,7′,8,8′-octahydro-1,1′ -bi-2-naphthol complexes

Article abstract of DOI:10.1021/jo016240u

The catalytic effect of chiral Lewis acids on the hetero-Diels-Alder reaction between aldehydes and Danishefsky's diene (1) has been investigated. A variety of combinations of different ligands and Lewis acids have been examined as catalysts for the heter

Full text of DOI:10.1021/jo016240u

J . Org. Chem. 2002, 67, 2175-2182
2175
A High ly En a n tioselective Heter o-Diels-Ald er Rea ction of
Ald eh yd es w ith Da n ish efsk y’s Dien e Ca ta lyzed by Ch ir a l
Tita n iu m (IV) 5,5′,6,6′,7,7′,8,8′-Octa h yd r o-1,1′-bi-2-n a p h th ol
Com p lexes
Bin Wang,‡ Xiaoming Feng,*,† Yaozong Huang,‡ Hui Liu,‡ Xin Cui,‡ and Yaozhong J iang*,‡
The Faculty of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China, and
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041,
People’s Republic of China
xmfeng@pridns.scu.edu.cn
Received October 26, 2001
The catalytic effect of chiral Lewis acids on the hetero-Diels-Alder reaction between aldehydes
and Danishefsky’s diene (1) has been investigated. A variety of combinations of different ligands
and Lewis acids have been examined as catalysts for the hetero-Diels-Alder reaction between
benzaldehyde and 1, and it has been found that the readily accessible Ti(IV)-H8-BINOL (TiHBOL)
complex is a very effective catalyst for the reaction, leading to products with very high
enantioselectivity (up to 99% ee) and yield (92%). The hetero-Diels-Alder reaction of other aldehydes
with 1 under the catalysis of TiHBOL is a general reaction which proceeds well with very high
enantioselectivity and isolated yield for various aldehydes at 0 °C to room temperature. Based on
the experimental results, the proposed mechanism of the hetero-Diels-Alder reaction and the
dihedral angle effects of ligands are discussed.
In tr od u ction
of the most reliable transformations for preparing pyra-
nosic synthons.4 The catalytic asymmetric HDA reaction
can be achieved by using Lewis acids, such as Eu(III),4b,c,d
Rh(II),5 V(IV),6 B(III),7 Al(III),8 Yb(III),9 Cr(III),10 Mn-
(IV),10b Ti(IV),11 Co(II),12 or Cu(II)13 ion, along with chiral
ligands containing 3-(heptafluoropropylhydroxymethylene)-
The development of chiral catalysts for asymmetric
synthesis is of tremendous synthetic importance.1 In this
context, catalytic enantioselective carbon-carbon bond-
forming reactions have attracted special attention. Par-
ticularly notable is the recent development of a number
of remarkably effective catalytic processes for the enan-
tioselective Diels-Alders reaction,2 which is one of the
most powerful and versatile methods in organic synthe-
sis. The chiral Lewis acid-catalyzed hetero-Diels-Alder
(HDA) reaction is also of particular interest due to its
very convenient access to prepare six-membered partly
saturated heterocycles, a class of compounds that have
found extensive use as starting materials for total
synthesis of many natural products and other highly
functionalized heterocycles.3
(4) (a) Danishefsky, S. J .; Kitahara, T. J . Am. Chem. Soc. 1974, 96,
7807-7809. (b) Danishefsky, S. J .; Larson, E.; Askin, D.; Kato, N. J .
Am. Chem. Soc. 1985, 107, 1246-1255. (c) Bednarski, M.; Maring, C.;
Danishefsky, S. J . Tetrahedron Lett. 1983, 24, 3451-3454. (d) Bed-
narski, M.; Danishefsky, S. J . J . Am. Chem. Soc. 1986, 108, 7060-
7067.
(5) (a) Faller, J . W.; Smart, C. J . Tetrahedron Lett. 1989, 30, 1189-
1192. (b) Motoyama, Y.; Koga, Y.; Nishiyama, H.; Tetrahedron 2001,
57, 853-860. (c) Doyle, M. P.; Phillips, I. M.; Hu, W. H. J . Am. Chem.
Soc. 2001, 123, 5366-5367.
(6) Togni, A. Organometallics 1990, 9, 3106-3113.
(7) (a) Corey, E. J .; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992,
33, 6907-6910. (b) Gao, Q.; Maruyama, T.; Mouri, M.; Yamamoto, H.
J . Org. Chem. 1992, 57, 1951-1952. (c) Gao, Q.; Ishihara, K.;
Maruyama, T.; Mouri, M.; Yamamoto, H.; Tetrahedron 1994, 50, 979-
988. (d) Gao, Q.; Ishihara, K.; Maruyama, T.; Mouri, M.; Yamamoto,
H. Tetrahedron 1994, 50, 4555. (e) Motoyama, Y.; Mikami, K. Chem.
Commun. 1994, 1563-2564.
Since its description by Danishefsky et al., the hetero-
Diels-Alder reaction between general dienophiles and
an activated diene such as 1-methoxy-3-(trimethylsily-
loxy)butadiene (Danishefsky’s diene) has proven to be one
(8) (a) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J . Am.
Chem. Soc. 1988, 110, 310-312. (b) Maruoka, K.; Yamamoto, H. J .
Am. Chem. Soc. 1989, 111, 789-790. (c) Gong, L.; Pu, L. Tetrahedron
Lett. 2000, 41, 2327-2331. (d) Simonsen, K. B.; Svenstrup, N.;
Roberson, M.; J ørgensen, K. A. Chem. Eur. J . 2000, 6, 123-128.
(9) (a) Mikami, K.; Kotera, O.; Motoyama, Y.; Sakaguchi, H. Synlett.
1995, 975-977. (b) Hanamoto, T.; Furuo, H.; Inanaga, J . Synlett. 1997,
79-80. (c) Furuno, H.; Hanamoto, T.; Sugimoto, Y.; Inanaga, J . Org.
Lett. 2000, 2, 49-52. (d) Qian, C.; Wang, L Tetrahedron Lett 2000, 41,
2203-2206.
* To whom correspondence should be addressed. Phone: 86-28-
5418249. Fax: 86-28-5412907.
† Sichuan University.
‡ Chengdu Institute of Organic Chemistry.
(1) (a) Ojima, I. Catalytic Asymmetric Synthesis; VCH Publica-
tions: New York, 1993. (b) J onathan, M. J . W. Catalysis in Asymmetric
Synthesis; Sheffield Academic Press: Sheffield, UK, 1999.
(2) Huang, Y.; Iwama, T.; Rawal, V. H. J . Am. Chem. Soc. 2000,
122, 7843-7844, and references therein.
(3) For reviews, see: (a) Danishefsky, S. J . Acc. Chem. Res. 1981,
14, 400-406. (b) Danishefsky, S. J . Chemtracts 1989, 273-279. (c)
Waldmann, H. Synthesis 1994, 535-551. (d) Boger, D. L. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
New York, 1991; Vol. 5, pp 451-512. (e) Tietze, L. F.; Kettschau, G.
In Stereoselective Heterocyclic Synthesis 1; Metz, P., Ed.; Springer:
Berlin, 1997; Vol. 189, pp 1-120. (f) J ørgensen, K. A.; J ohannsen, M.;
Yao, S.; Audrian, H.; Thorhauge, J . Acc. Chem. Res. 1999, 32, 605-
613.
(10) (a) Schaus, S. E.; Brånalt, J .; J acobsen, E. N. J . Org. Chem.
1998, 63, 403-405. (b) Aikawa, K.; Irie, R.; Katsuki, T. Tetrahedron
2001, 57, 845-851.
(11) (a) Keck, G. E.; Li, X.; Krishnamurthy, D. J . Org. Chem. 1995,
60, 5998-5999. (b) Matsukawa, S.; Mikami, K. Tetrahedron: Asym-
metry 1997, 8, 815-816. (c) Wang, B.; Feng, X.; Cui, X.; Liu, H.; J iang,
Y. Chem. Commun. 2000, 1605-1606. (d) Laurence, L.; Maurice, L.
B.; Raphae¨l, P. Tetrahedron Lett. 2000, 41, 5043-5046.
(12) (a) Li, L.; Wu, Y.; Hu, Y.; Xia, L.; Wu. Y. Tetrahedron:
Asymmetry 1998, 9, 2271-2277. (b) Kezuka, S.; Mita, T.; Ohtsuki, M.;
Ikeno, T.; Yamada, T. Chem. Lett. 2000, 824-825.
10.1021/jo016240u CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/14/2002

2176 J . Org. Chem., Vol. 67, No. 7, 2002
Sch em e 1. Tw o P ossible Mech a n ism s of th e Heter o-Diels-Ald er Rea ction
Wang et al.
D-camphorato,4b,c,d,6 carboxamidate,5c N-tosyltrytophan,7a
3,3′-disubstituted-BINOL,8a,b,c,d,f triflylamide,9a salen,10,12a,b
BINOL,11a,b bisoxazoline,5b,9d,11 and BNP11b,c ((R)-1,1′-
binaphthyl-2,2′-diylphosphonate). Other metal-catalyzed
HDA reactions using such as Ce(III),14 Nd(III),15 and Sm-
(III)15 have been reported; however, the catalytic asym-
metric process has not been realized by utilizing these
metal ions. Among those catalytic asymmetric HDA
reactions, the best chiral catalysis (97% yield and 99%
ee) is achieved in the asymmetric organoaluminum-
catalyzed HDA reaction between 1 and benzaldehyde.8d
However, there are not good catalysts which could afford
the desired product with high enantioselectivity and yield
between 1 and extensive aldehydes (Scheme 1). There
are two different reaction paths for the formation of the
product of the HDA reaction, 2,3-dihydro-2-substituent-
4-pyranone, depending on the Lewis acid catalyst used.
These paths are classified into two mechanisms formu-
lated as Mukaiyama aldol and concerted [4 + 2] cycload-
dition mechanisms. Utilizing boron5 and titanium9 cata-
lysts involves a stepwise mechanism involving an initial
Mukaiyama aldol addition, followed by cyclization. How-
ever, the concerted Diels-Alder pathway has been posi-
tively identified in reactions catalyzed by Lewis acids
based on zinc,4a europium,4b,c,d rhodium,5b aluminum,6
chromium,8 cuprum,11 and cerium.12
The enantioselective hetero-Diels-Alder reaction has
been successfully applied to the synthesis of several
natural products,8c,13a,b,f,18 and recent findings in this area
include, for example, development of a new catalyst,9d
improvement of the old catalytic system in order to obtain
high enantioselectivity,12b widening substrate generality,11e
and improvement of reaction economy.13c,d Recently, we
reported our preliminary studies of the high enantiose-
lective synthesis of optically active dihydropyranone by
using chiral titanium(IV) 5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-
bi-2-naphthol complexes.11c The present paper describes
studies of relationships among catalyst structure and
activity, substrate generality, mechanism, and limita-
tions.
Resu lts a n d Discu ssion
Liga n d a n d Lew is Acid Su r vey. A variety of differ-
ent ligands and Lewis acids have been examined as
catalysts for the hetero-Diels-Alder reaction of benzal-
dehyde and Danishefsky’s diene. The ligands were pre-
pared according to literature procedures.19 The catalyst
was in situ prepared by stirring a solution of the chiral
ligands and Ti(OiPr)4 in toluene in molar ratio of 1.1:1.
Without catalyst isolation, adding benzaldehyde to a
cooled catalyst solution at 0 °C, followed by dropwise
addition of the Danishefsky’s diene and treatment with
trifluoroacetic acid at the end of reaction, afforded the
2,3-dihydro-2-phenyl-4-pyranone. The enantioselectivity
of product was assayed by chiral GC. The absolute
configuration of the product was established by compar-
Highly enantioselective HDA reactions between less
nucleophilic dienes bearing fewer than two oxygen sub-
stituents and carbonyl compounds were also achieved by
using some chiral Lewis acids, such as Al(III) or Ti(IV)-
BINOL, Cu(II)-bisoxazoline, and Cr(III)-Schiff base.16
Another asymmetric catalytic HDA reaction between
vinyl ethers and R,â-unsaturated acyl phosphonate or â,γ-
unsaturated R-keto ester has also been realized with high
enantioselectivity and chemical yield by utilizing Cu(II)-
bisoxazoline catalyst through a concerted [4 + 2] cycload-
dition path.17
(17) (a) Evans, D. A.; J ohnson, J . S.; Othava, E. J . J . Am. Chem.
Soc. 2000, 122, 1635-1649. (b) Evans, D. A.; Olhava, E. J .; J aney, J .
M. Angew. Chem., Int. Ed. 1998, 37, 3372-3375. (c) Evans, D. A.;
J ohnson, J . S. J . Am. Chem. Soc. 1998, 120, 4895-4896. (d) J ohannsen,
M.; J ørgensen, K. A. Tetrahedron 1996, 52, 7321-7328. (e) Thorhauge,
J .; J ohannsen, M.; J ørgensen, K. A. Angew. Chem., Int. Ed. 1998, 37,
2404-2406. (f) Zhang, W.; Thorhauge, J .; J ørgensen, K. A. Chem.
Commun. 2000, 459-460.
(18) Rainier, J . D.; Allwein, S. P.; Cox, J . M. Org. Lett. 2000, 2, 231-
234.
(13) (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J .; Krishnan, K.
Tetrahedron: Asymmetry 1996, 7, 2165-2168. (b) Ghosh, A. K.;
Mathivanan, P.; Cappiello, J . Tetrahedron Lett. 1997, 38, 2427-2430.
(c) J ohannsen, M.; Yao, S.; J ørgensen, K. A. Chem. Commun. 1997,
2169-2170. (d) Yao, S.; J ohannsen, M.; Audrain, H.; Hazell, R. G.;
J ørgensen, K. A. J . Am. Chem. Soc. 1998, 120, 8599-8605.
(14) Molander, G. A.; Rzasa. R. M. J . Org. Chem. 2000, 65, 1215-
1217.
(19) Waldmann, H.; Weigerding, M.; Dreisbach, C.; Wandrey, C.
Helv. Chim. Acta. 1994, 77, 2111-2116. (b) Dobashi, Y.; Hara, S. J .
Am. Chem. Soc. 1985, 107, 3406-3411. (c) Lin, C.; Lin, C.; Li, Y.; Chan,
A. S. C. Tetrahedron Lett. 2000, 41, 4425-4429. (d) Chan, A. S. C.;
Hu, W.; Pai, C.; J iang; Y.; Mi, A.; Yan; M.; Sun, J .; Lou, R.; Deng, J .
J . Am. Chem. Soc. 1997, 119, 9570-9571. (e) Chan, A. S. C.; Lin, C.;
Sun, J .; Hu, W.; Li, Z.; Pan, W.; Mi, A.; J iang, Y.; Yang, T.; Chen, T.
Tetrahedron: Asymmetry 1995, 6, 2953-2959. (f) Lou, R.; Mi, A.; J iang,
Y.; Qin, Y.; Li, Z.; Fu, F.; Chan, A. S. C. Tetrahedron 2000, 56, 5857-
5863. (g) Peng, Y.; Feng, X.; Li, Z.; Yang, G.; J iang, Y. J . Organomet.
Chem. 2001, 619, 204-208. (h) J iang, Y.; Zhou, X.; Hu, W.; Wu, L.;
Mi, A. Tetrahedron: Asymmetry 1995, 11, 405-408. (i) Pan, W.; Feng,
X.;. Gong, L.; Li, Z.; Hu, W.; Mi, A.; J iang, Y. Synlett 1996, 337-338.
(j) Cram, D. J .; Helgeson, R. C.; Peacock, S. C.; Kaplan, L. J .; Domeier,
L. A.; Moreau, P.; Koga, K.; Mayer, J . M.; Chao, Y.; Siegel, M. G.;
Hoffman, D. H.; Sogah, G. D. Y. J . Org. Chem. 1978, 43, 1930-1946.
(k) Sogah, G. D. Y.; Gram, D. J . J . Am. Chem. Soc. 1979, 101, 3035-
3042. (l) X.-Q. Shen, H. Guo, K.-L. Ding, Tetrahedron: Asymmetry
2000, 11, 4321-4327.
(15) Yoshitsugu, A.; Tsutoma, M.; Yukio, M.; Motoo, S. Tetrahe-
dron: Asymmetry 1996, 7, 1199-1204.
(16) (a) J ohannsen, M.; J ørgensen, K. A. J . Org. Chem. 1999, 64,
299-301. (b) Dossetter, A. G.; J amison, T. F.; J acobsen, E. N. Angew.
Chem., Int. Ed. 1999, 38, 2398-2400. (c) Motoyama, Y.; Terada, M.;
Mikami, K. Synlett 1995, 967-968. (d) Engler, T. A.; Letavic, M. A.;
Takusagawa, F.; Tetrahedron Lett. 1992, 33, 6731-6734. (e) Terada,
M.; Mikami, K.; Nakai, T. Tetrahedron Lett. 1991, 32, 935-938. (f)
Mikami, K.; Tarada, M. J . Am. Chem. Soc. 1994, 116, 2812-2820. (g)
Graven. A.; J ohannsen, M.; J ørgensen, K. A. Chem. Commun. 1997,
2169-2170. (h) Mikami, K.; Terada, M.; Motoyama, Y.; Nakai, T.
Tetrahedron: Asymmetry 1991, 2, 643-646.

Enantioselective Hetero-Diels-Alder Reactions
J . Org. Chem., Vol. 67, No. 7, 2002 2177
Ta ble 1. Effects of th e Ca ta lyst Liga n d s on th e
Heter o-Diels-Ald er Rea ction of Ben za ld eh yd e w ith
Da n ish efsk y’s Dien ea
bromo-BINOL (18), (R)-2,2′-dimethyl-BINOL (17), and
(R)-H4-BINOL (20) (Table 1, entries 14-18), were also
screened. The catalyst derived from (R)-BINOL and (R)-
BINOL derivatives showed a high level of enantioselec-
tivity for the HDA reaction between benzaldehyde and
Danishefsky’s diene. More significantly, the (R)-H4-
BINOL (20) or (R)-H8-BINOL (21) ligands remarkably
enhanced enantioselectivity control and reaction rate,
apparently due to the larger steric hindrance of the
hydrogen atoms attached to sp3 carbon atoms in tetralin
rings than that of hydrogen atoms on sp2 carbon atoms
in naphthalene rings (Scheme 2). As the steric repulsion
between two far-side rings ranges (R)-H8-BINOL > (R)-
H4-BINOL > (R)-BINOL ≈ (R)-6,6′-dibromo-BINOL, the
value of the dihedral angle of the axial biaryl groups in
the titanium complex was also (R)-H8-BINOL > (R)-H4-
BINOL > (R)-BINOL ≈ (R)-6,6′-dibromo-BINOL (Figure
1). The enantioselectivity and yield showed the same
trend. The results indicated that the dihedral angle of
the axial biaryl group in BINOL series was very crucial
for the high enantiocontrol and yield of the HDA reaction.
To our surprise, the titanium complexes of (R)-3,3′-
dimethyl-BINOL (17) produced 2,3-dihydro-2-phenyl-4-
pyranone in 28% isolated yield with 4% ee (Table 1, entry
14). This indicated the 3-position substituent on BINOL
had little benefit on enantioselectivity of the Ti(IV)-
complex-catalyzed HDA reaction. In contrast, the choice
of the bulky group in BINOL’s 3-position is crucial for
the high enantiofacial differentiation of prochiral alde-
hydes in the asymmetric organoaluminum-catalyzed
HDA reaction.8a,b,d
entry
ligand
time (h)
yield (%)b
ee (%)c
config
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4
5
6
7
8
30
30
30
48
48
48
48
48
48
48
24
24
24
24
24
24
24
24
10
9
9
16
21
39
23
13
9
6
5
5
S
S
S
R
R
R
S
R
R
R
7
29
49
26
13
29
20
9
10
11
12
13
14
15
16
17
18
19
20
21
9
0
16
42
28
46
60
64
92
0
32
4
87
87
95
97
R
R
R
R
R
R
a
All reactions were carried out at 0 °C in toluene using 20 mol
% catalyst. The ratio of Ti(OiPr)4 and ligand is 1:1.1. The substrate
b
concentration was 0.25 M. Isolated yield. c The ee value was
determined by GC using a chiral column (Cyclodex-â).
ing the optical rotation of the product with that in the
literature.10 This ligand screen revealed that the hetero-
Diels-Alder product was formed in highly various yields
and enantioselectivities depending on the ligand used.
Some representative results are shown in Table 1.
According to the results shown in Table 1, the Ti(IV)
complex of (R)-H8-BINOL (21) gave the product in high
yield with high enantioselectivity. However, Ti(IV) com-
plexes prepared from chiral diols (4-8) derived from
natural tartaric acid and chiral DEA (9,10-dihydro-9,10-
ethanoanthracene-11,12-dicarboxylic acid) were poor enan-
tioselective catalysts (Table 1, entries 1-5). The Ti(IV)
complex prepared from (2R,4R)-dihydroxypentane (9)
gave moderate enantioselectivity and yield (Table 1, entry
6), while Ti(IV) complexes prepared from the (cis,cis)-
spirol-10 and (trans,trans)-spirol-11 which had a similar
five-membered hydroxy coordination group and were
more rigid than ligand 9 were not good HDA reaction
catalysts (Table 1, entries 7, 8). The Ti(IV) complexes
prepared from chiral N-methylaminoethanol (12), Schiff
base (14), and monoxazoline (13) which were derived
from (1R,2S)-1,2-diphenylaminoethanol did not produce
good enantioselectivity either (Table 1, entries 9-11). Ti-
(IV)(salen) (15) complex which had been reported to give
very high enantioselectivity in trimethylsilylcyanation of
aldehydes20 had low catalytic activity to give racemic
product in 16% isolated yield (Table 1, entry 12) in the
HDA reaction, and a new Ti(IV) salen (16) complex which
had a more bulky group and atropisomeric framework
had a little catalytic activity and afforded product in 42%
isolated yield with 32% ee (Table 1, entry 13). The (R)-
BINOL (19) and it’s derivatives in which certain positions
were substituted or hydrogenated such as (R)-6,6′-di-
Besides Ti(IV)-H8-BINOL complex, other metal-H8-
BINOL complexes in situ prepared by stirring a solution
of (R)-H8-BINOL and corresponding metal alkoxide were
also screened in the hetero-Diels-Alder reaction of
benzaldehyde with Danishefsky’s diene. The results are
shown in Table 2. Among the screened Lewis acid
complexes, the Al(III)-H8-BINOL complex provided the
product in moderate yield with 9% ee (Table 2, entry 2),
and the Ti(IV)-H8-BINOL complex afforded the product
in high enantioselectivity and yield (Table 2, entry 1) and
proved to be the optimal catalyst for the HDA reaction
of benzaldehyde with Danishefsky’s diene.
Solven ts Effects. Solubility of the Ti(IV)-H8-BINOL
complex in representative solvents was determined using
the standard procedure. The solvent survey revealed a
dramatic solvent effect: toluene and benzene were the
optimal solvents for the transformation, providing the
product of the hetero-Diels-Alder reaction in high yield
with high enantioselectivity (Table 3). Toluene and
benzene were more favorable than other solvents in the
Ti(IV)-H8-BINOL-catalyzed HDA reaction. In solvents
containing a coordinating oxygen or nitrogen atom, such
as THF, Et2O, TBME, and DMF, the reaction afforded
the product in high enantioselectivity, but the yield of
reaction was low. CH2Cl2 was also found to afford the
same result as ether-type solvents.
To optimize the reaction conditions for higher enanti-
oselectivity, the effects of the molar ratio of Ti(OiPr)4 to
(R)-H8-BINOL on enantioselectivity were examined in
detail. When the molar ratio of Ti(OiPr)4 to (R)-H8-
BINOL was 1:1.1 or 1:1.5, the optimal enantioselectivity
and yield was obtained (Table 4). The enantioselectivity
did appreciably vary with the change of molar ratio.
When the a molar ratio of Ti(OiPr)4 to (R)-H8-BINOL was
1:2, the worst result was obtained. The other feature in
(20) (a) J iang, Y.; Gong, L.; Feng, X.; Hu, W.;. Pan, W.; Li, Z.; Mi,
A. Tetrahedron 1997, 53, 14327-14338.

2178 J . Org. Chem., Vol. 67, No. 7, 2002
Wang et al.
F igu r e 1. The steric repulsion between the two far-side rings of (R)-H8-BINOL, (R)-H4-BINOL, and (R)-BINOL. The 3D structures
were constructed and optimized in SYBYL6.7. Tripos force field and Gasteiger-Hu¨ckel charges were employed throughout. Black,
carbon; red, oxygen; and gray, hydrogen.
Sch em e 2. Liga n d s Ap p lied to th e Heter o-Diels-Ald er Rea ction of Ben za ld eh yd e w ith Da n ish efsk y’s
Dien e
the present asymmetric process was the role of 4 Å
molecular sieves in obtaining the high enantioselectivity
and good yield. In the absence of 4 Å MS, the Ti(IV)-
H8-BINOL catalytic HDA reaction in toluene afforded
quite high enantioselectivity (Table 5). However, the
isolated yield was lower than the reaction carried out in
presence of 4 Å MS. If the Ti(IV)-H8-BINOL catalysis
was carried out at Et2O, a significant difference in optical
yield between the presence and absence of 4 Å MS was
observed. So, the addition of molecular sieves in the
asymmetric HDA reaction had a beneficial effect of
permitting reactions to afford product in high yield with
high enantioselectivity.
To obtain the optimal reaction conditions, the effect of
the amount of catalyst on the enantioselectivity and yield
of the HDA reaction of benzaldehyde with Danishefsky’s
diene was studied. The amount of catalyst also dramati-
cally influenced the enantioselectivity and yield. The
enantiomeric excess increased as the amount of catalyst
increased. When the amount of catalyst was 20 mol %,
the optimal enantioselectivity (97% ee) and yield (88%)
were obtained (Table 6, entry 2). The highest amount of
catalyst used was 40 mol % (Table 6, entry 1). There was
no difference in enantioselectivity and yield in compari-
son with 20 mol %. The concentration of substrate and
catalyst was found to be an important factor for obtaining
high enantioselectivity and yield. The optimal concentra-
tion of substrate was 0.25 M at 20 mol % amount of
catalyst (Table 7, entry 3). At 1.0 and 0.5 M concentra-
tion the HDA reaction of benzaldehyde with Danishef-
sky’s diene afforded the product with a dramatic de-
crease in enantioselectivity and yield (Table 7, entries
1, 2). If the concentration of substrate and catalyst
decreased to 2- and 4-fold low the optimal concentration,
the Ti(IV)-H8-BINOL catalytic HDA reactions proceeded
slowly and afforded the product with the almost same
high enantioselectivity (Table 7, entries 4, 5) as the 0.25
M concentration. At the higher concentrations, the
formation of titanium multinuclear aggregates signifi-

Enantioselective Hetero-Diels-Alder Reactions
J . Org. Chem., Vol. 67, No. 7, 2002 2179
Ta ble 2. Effects of Lew is Acid on th e
Heter o-Diels-Ald er Rea ction of Ben za ld eh yd e w ith
Da n ish efsk y’s Dien ea
Ta ble 5. Effects of 4 Å MS on th e
Ti-H8-BINOL-Ca ta lyzed Heter o-Diels-Ald er Rea ction of
Ben za ld eh yd e w ith Da n ish efsk y’s Dien ea
amount of 4 Å
mol sieves, mg
T(°C)/time
yield
(%)b
ee
entry
solvent
Et2O
(h)
(%)c
1
2
3
4
0
120
0
-30/12
-30/12
0/24
14
23
83
92
51
94
97
97
toluene
120
0/24
a
All reactions were carried out in toluene using 20 mol % of
entry
metal alkoxide
yield (%)b
ee (%)c,d
Ti-H8-BINOL catalyst. The ratio of Ti(OiPr)4 and ligand is 1:1.1.
The substrate concentration was 0.25 M. Isolated yield. c The ee
b
1
2
3
4
5
6
Ti(OiPr)4
Al(OiPr)3
Zr(OEt)4
Sm(OiPr)3
Yb(OiPr)3
Ce(OiPr)3
92
45
15
0
0
0
97 (R)
9 (S)
8 (R)
value was determined by GC using a chiral column (Cyclodex-â).
Ta ble 6. Effect of th e Am ou n t of Ca ta lyst on th e
Ti-H8-BINOL-Ca ta lyzed Heter o-Diels-Ald er Rea ction of
Ben za ld eh yd e w ith Da n ish efsk y’s Dien ea
a
entry
amount of catalyst (mol %)
yield (%)b
ee (%)c
All reactions were carried out at 0 °C in toluene using 20 mol
% catalyst. The ratio of Lewis acid and ligand is 1:1.1. The
substrate concentration was 0.25 M. The reaction time was 24 h.
1
2
3
4
5
40
20
15
10
5
90
88
83
75
62
98
97
92
73
48
Isolated yield. c The ee value was determined by GC using a
chiral column (Cyclodex-â). Absolute configurations determined
by comparison of optical rotations with literature values.
b
d
a
Ta ble 3. Effects of Solven ts on th e
Ti-H8-BINOL-Ca ta lyzed Heter o-Diels-Ald er Rea ction of
Ben za ld eh yd e w ith Da n ish efsk y’s Dien ea
All reactions were carried out at 0 °C in toluene. The ratio of
Ti(OiPr)4 and ligand is 1:1.1. The substrate concentration was 0.25
b
M. The reaction time was 12 h. Isolated yield. c The ee value was
determined by GC using a chiral column (Cyclodex-â).
Ta ble 7. Effects of Con cen tr a tion of Su bstr a te on th e
Ti-H8-BINOL-Ca ta lyzed Heter o-Diels-Ald er Rea ction of
Ben za ld eh yd e w ith Da n ish efsk y’s Dien ea
concentration of
time
(h)
yield
(%)b
ee
entry
substrate (molL-1
)
(%)c
entry
solvent
yield (%)b
ee (%)c
1
2
3
4
5
1
0.5
0.25
0.125
0.0625
24
24
24
30
30
32
46
92
73
69
73
82
97
93
96
1
2
3
4
5
6
7
THF
Et2O
11
60
23
9
21
88
75
90
83
94
95
90
97
95
CH2Cl2
DMF
TBME
toluene
benzene
a
All reactions were carried out at 0 °C in toluene using 20 mol
% of Ti-H8-BINOL catalyst. The ratio of Ti(OiPr)4 and ligand is
1:1.1. Isolated yield. c The ee value was determined by GC using
b
a chiral column (Cyclodex-â).
a
All reactions were carried out at 0 °C using 20 mol % of Ti-
H8-BINOL catalyst. The ratio of Ti(OiPr)4 and ligand is 1:1.1. The
substrate concentration was 0.25 M. The reaction time was 12 h.
Ta ble 8. Effects of Rea ction Tem p er a tu r e on th e
Ti-H8-BINOL-Ca ta lyzed Heter o-Diels-Ald er Rea ction of
Ben za ld eh yd e w ith Da n ish efsk y’s Dien ea
Isolated yield. c The ee value was determined by GC using a
b
chiral column (Cyclodex-â).
entry
temp (°C)
time (h)
yield (%)b
ee (%)c
Ta ble 4. Effects of th e Ra tio of Ti(OiP r )4 to Liga n d on
th e Ti-H8-BINOL-Ca ta lyzed Heter o-Diels-Ald er
Rea ction of Ben za ld eh yd e w ith Da n ish efsk y’s Dien ea
1
2
3
4
5
23-25
12-14
0
-15
-30
6
8
12
20
29
92
92
88
78
51
93
95
97
92
90
entry
ratio of Ti(OiPr)4 to ligand
yield (%)b
ee (%)c
1
2
3
4
5
1:2
46
92
92
73
38
75
98
97
86
80
a
1:1.5
1:1.1
1:1
All reactions were carried out in toluene using 20 mol % of
Ti-H8-BINOL catalyst. The ratio of Ti(OiPr)4 and ligand is 1:1.1.
The substrate concentration was 0.25 M. Isolated yield. c The ee
b
1:0.5
value was determined by GC using a chiral column (Cyclodex-â).
a
All reactions were carried out at 0 °C in toluene using 20 mol
% of Ti-H8-BINOL catalyst. The substrate concentration was 0.25
performed (Table 8). There was a temperature depen-
dence on the yield and enantioselectivity. At slightly
higher temperatures, the yield increased without signifi-
cant impact to selectivity. However, when the reaction
was carried out below 0 °C, dihydropyrone was obtained
in lower conversion and enantioselectivity. The optimal
temperature ranged between 0 °C and 25 °C according
to the different aldehydes. At room temperature (23-25
°C), high yield (92%) and enantioselectivity (93% ee) were
also obtained (Table 8, entry 1). It should be noted that
the enantiomeric excess of 93% was considerably high
at 23-25 °C, since most precedent catalytic asymmetric
hetero-Diels-Alder reactions required a rather low tem-
b
M. The reaction time was 24 h. Isolated yield. c The ee value was
determined by GC using a chiral column (Cyclodex-â).
cantly comprised the catalytic activity,21 since the active
complex is monomeric.
Tem p er a tu r e P r ofile. An examination of the tem-
perature profile of the Ti(IV)-H8-BINOL-catalyzed HDA
reaction of benzaldehyde with Danishefsky’s diene was
(21) (a) Corey, E. J .; Letavic, M. A.; Noe, M. C.; Sarshar, S.
Tetrahedron Lett. 1994, 35, 7553-7556. (b) Terada, M.; Mikami, K.;
Nakai, T. Chem. Commun. 1990, 1623-1624. (c) Terada, M.; Mikami,
K. Chem. Commun. 1994, 833-834.

2180 J . Org. Chem., Vol. 67, No. 7, 2002
Ta ble 9. Asym m etr ic Heter o-Diels-Ald er s Rea ction s of Ald eh yd es w ith Da n ish efsk y’s Dien ea
Wang et al.
entry
aldehyde
temp (°C)
time (h)
yield (%)b
ee (%)c
entry
aldehyde
temp (°C)
time (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
0
0
0
0
0
0
0
0
0
24
24
24
48
24
24
24
24
24
92
43
71
55
81
81
64
67
54
97d,f
85
10
11
12
13
14
15
16
17
18
2j
2k
2l
2m
2n
2o
2p
2q
2r
0
0
0
0
0
0
24
24
30
24
30
48
72
24
24
60
51
78
55
80
39
57
28
26
99
>99
96f
92e
98f
80
90
90e
94
99
95
97
98
23-25
0
0
96
35e,f
47e
a
b
All reactions were carried out using 20 mol % of catalyst as detail in the experimental procedure. All yields are isolated yields. c In
d
all cases ee was determined by HPLC using a chiral column (chiralcel OD), unless otherwise mentioned. Determined by GC using a
chiral column (Cyclodex-â). e Determined by HPLC using a chiral column (chiralpak AD). f Absolute configurations were R, which determined
by comparison of optical rotations with literature values.7a,10a,13a
perature (-78 to -30 °C) to attain a good level of
enantioselectivity. Thus, these mild reaction conditions
are amenable to large-scale application.
alkylation of aromatic aldehydes with triethylaluminum.24a
An analysis of the results from entries 8-11 in Table 9
indicated that the electron-withdrawing, conjugated para-
substituent had a negative influence on the enantiose-
lectivity while the electron-donating, conjugated para-
substituent had a positive effect. For meta-substituted
benzaldehydes, an electron-donating substituent on the
phenyl ring was found to increase the enantioselectivity
while an electron-withdrawing substituent was found to
decrease the enantioselectivity for the desired product.
From entries 2-11 in Table 9, we can observe the impact
of electronic effects on the yield. The electron-donating,
conjugated meta-substituent had a better effect on the
yield (81%) of 2,3-dihydro-2-substituent-4-pyranone while
the ortho- and para-substituent had less effect (43-71%).
We also explored the application of Ti-H8-BINOL cata-
lyst on the reaction of an activated carbonyl compound
with Danishefsky’s diene. Under general reaction condi-
tions, low enantioselectivities and yields were obtained
(Table 9, entries 17, 18).
Su bstr a te Gen er a lity. Encouraged by the result
obtained for the benzaldehyde, we investigated a variety
of other aldehydes to probe their behaviors under the
current catalytic conditions. As shown in Table 9, aro-
matic, heteroaromatic, conjugated, and aliphatic alde-
hydes afforded the corresponding product in moderate
to high isolated yield with a considerably high ee. A
comparison of the experimental results (Table 9, entries
1-4) revealed the negative effect on enantioselectivity
by ortho-substitution on benzaldehyde. The Ti(IV)-H8-
BINOL catalyzed HDA reaction of o-chloro- and o-
methoxybenzaldehyde afforded dihydropyranone of 90%
ee, which was lower than the enantioselectivity (94-99%
ee) afforded by Ti(IV)-H8-BINOL-catalyzed HDA reac-
tion of meta- or para-substituted benzaldehyde. Espe-
cially, the HDA reaction of 2,6-dichlorobenzaldehyde that
had two bulky ortho-substituents on the benzaldehyde
afforded an enantiomeric excess of 85%, which was lower
than that of the ortho-monosubstituted benzaldehyde.
This was probably due to the strong steric hindrance
effect of the ortho-substituents, which significantly weak-
ened the coordination of the aldehyde and consequently
lowered the enantioselectivity of reaction. In comparison,
meta- and para-substituents on the aromatic aldehydes
had less effect on the enantioselectivity for the products
of dihydropyranone. These results were consistent with
the expectation that the electronic effects from the
starting materials were less significant than the steric
hindrance effect on the enantioselectivity of the reaction.
Chan also observed the same effect on asymmetric
To further probe the steric and electronic effects
governing the coordination of titanium catalyst and its
potential role in controlling the enantioselectivity of
(22) (a) Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.; Kumoba-
yashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J . Org. Chem. 1996, 61,
5510-5516. (b) Trost, B. M.; Vranken, Van D. L.; Bingel, C. J . Am.
Chem. Soc. 1992, 114, 9327-9343. (c) Trost, B. M.; Breit, B.; Peukert,
S.; Zambrano, J .; Ziller, J . W. Angew. Chem., Int. Ed. Engl. 1995, 34,
2386-2388. (d) Hayashi, T.; Ohno, A.; Lu, S.; Matsumoto, Y.; Fukuyo,
E.; Yanagi, K. J . Am. Chem. Soc. 1994, 116, 4221-4226.
(23) Dijkgraff, C.; Rousseau, J . P. G. Spectrochim. Acta 1968, 2,
1213-1217.
(24) The reaction catalyzed by Ti(IV)-H8-BINOL: (a) Chan, A. S.
C., Zhang, F.; Yip, C. J . Am. Chem. Soc. 1997, 119, 4080-4081. (b)
Zhang, F.; Chan, A. S. C. Tetrahedron: Asymmetry 1997, 8, 3651-
3655.

Enantioselective Hetero-Diels-Alder Reactions
J . Org. Chem., Vol. 67, No. 7, 2002 2181
Ta ble 10. Effect of Ti Lew is Acid on th e
Ti-H8-BINOL-Ca ta lyzed Heter o-Diels-Ald er Rea ction of
Ben za ld eh yd e w ith Da n ish efsk y’s Dien ea
Sch em e 3. Com p lex 19
entry
Lewis acid
time (h)
yield (%)b
ee (%)c
1
2
3
4
Ti(OiPr)4
24
40
10
10
92
64
85
75
97
91
96
95
Ti(OnBu)4
Ti(OiPr)3Cl
Ti(OiPr)2Cl2
a
All reactions were carried out at 0 °C in toluene using 20 mol
% of Ti-H8-BINOL catalyst. The ratio of Ti(OiPr)4 and ligand is
b
1:1.1. The substrate concentration was 0.25 M. Isolated yield.
benzaldehyde by Ti-H8-BINOL complex 19, which sup-
ports some literature8a,d results that also indicated that
the real catalyst was a Lewis acid and not the Ti-H8-
BINOL complex 19 (Scheme 3).
c The ee value was determined by GC using a chiral column
(Cyclodex-â).
reaction, we chose to perform the HDA reaction of
Danishefsky’s diene and benzaldehyde catalyzed by the
complexes generated from the (R)-H8-BINOL and a
titanium-based Lewis acid other than Ti(OiPr)4. Some
representative results are given in Table 10. From the
available data it would appear that modified steric
hindrance caused by the presence of an n-butoxy group
on the titanium center instead of an isopropoxy group
has no apparent effect on the enantioselectivity. When
Ti(OiPr)2Cl2 and Ti(OiPr)3Cl were used for generating the
catalytic complex, which was expected to change the
steric effect (a chloride atom is much smaller than an
isopropoxy group in term of van de waals radius) and
lower the electron density on titanium, considerably high
enantioselectivity was also obtained in the HDA reaction
of benzaldehyde and Danishefsky’s diene. On the basis
of the experimental results, it is reasonable to question
whether Ti(OiPr)2-(R)-H8-BINOL was the actual cata-
lytically active metal complex, which affords effective
enantiocontrol in the transition state of the titanium-
catalyzed HDA reaction. To investigate the exact nature
of the catalytically active metal complex, a 1H NMR
experiment (300 MHz) was carried out at 20 °C in C6D6.
First, the catalyst was prepared in C6D6 as detailed in
the experimental procedure. Then the 1H NMR spectrum
was recorded. The methyl and methine peak correspond-
ing to the isopropoxy moiety was observed at δ 1.20 and
δ 3.91. When a 5-fold amount benzaldehyde was added
to the solution of catalyst, there was no apparent change
in 1H NMR spectrum in comparison to the previous
spectrum. Then, Danishefsky’s diene was added to the
solution of catalyst and benzaldehyde. After 10 min, the
1H NMR experiments were conducted. The spectra indi-
cated diastereotopic methyl peaks due to the isopropoxy
group bound to Ti at δ 1.21 and δ 1.33. The spectral
changes strongly suggested that the isopropoxy group
bound to Ti transmitted to be bound to the other group.
After 1 h, the peak at δ 1.21 disappeared while the peak
at δ 1.33 strengthened and became stronger than that
in the previous spectrum. That means the real catalytic
metal complex was not the Ti(OiPr)2-(R)-H8-BINOL
complex 19, which also can be inferred from the fact that
different titanium(IV) reagents have the same enantio-
control effect (Table 10).
Rea ction Mech a n ism . A reaction mechanism, which
agrees with all of the observations discussed above, is
proposed (Scheme 4). After the Danishefsky’s diene was
added to the solution of titanium complex 19, the active
catalytic species was produced. Then, the Mukaiyama
aldol11a adduct was obtained through a six-membered
cyclic transition state which involves the diene linked to
the Ti-(R)-H8-BINOL by the C-3 oxygenated substituent
and the aldehyde associated to the metal by the carbonyl
oxygen. The trimethylsilyl group transferred from Dan-
ishefsky’s diene substrate to the Mukaiyama aldol adduct
to afford an intermediate and the Ti(IV) complex. Upon
treatment with trifluoroacetic acid, the intermediates
were converted to (R)-2,3-dihydro-2-phenyl-4-pyranone.
From the proposed mechanism hypothesis, the transi-
tion state has two bicoordination ligands: one is the
seven-membered coordination, and the other is the six-
membered coordination. In comparison with six-mem-
bered or five-membered rings, the seven-membered ring
had more flexibility and less rigidity. Since the steric
effect of the hydrogen of the far-side ring in H8-BINOL
was more enhanced than the other BINOL-derived
ligands, the seven-membered ring formed by H8-BINOL
had more rigidity and a wider dihedral angle of the axial
biaryl groups than the other BINOL-derived ligands.
These conformational changes made a beneficial chiral
pocket effect on the benzaldehyde coordination sites of
the H8-BINOL-Ti complex relative to the other BINOL-
derived ligand-Ti complexes. Thus, when different
BINOL’s derivatives were used, it was observed that the
increased dihedral angle resulted in a higher ee in the
HDA reaction. These results are consistent with the
results of Takaya,22a Trost,22b,c and Hayashi22d regarding
asymmetric hydrogenation and hydroxyallylic alkylation.
Con clu sion
In conclusion, an efficient catalytic enantioselective
hetero-Diels-Alder reaction of Danishefsky’s diene and
aldehyde utilized H8-BINOL-Ti complex has been docu-
mented. A wide range of aldehydes can be employed,
utilizing in situ prepared catalyst, to provide the product
in high chemical yields with high enantioselectivities
(80-99% ee) under mild conditions. Since the BINOL can
be easily prepared in large scale with high enantiomeric
excess and H8-BINOL can be readily derived from BINOL
via hydrogenation,19j the Ti-H8-BINOL-catalyzed HDA
reaction is expected to have excellent potential for
practical applications. Future efforts will be directed
toward a new catalyst for the high enantioselective
hetero-Diels-Alder reaction of ketones.
Moreover, the Ti-H8-BINOL complex 19 and benzal-
dehyde (5-fold excess) were mixed in the benzene, and
the resulting mixture in solution was analyzed by IR
spectroscopy. No evidence for any interaction between the
complex and benzaldehyde could be detected by compar-
ing the formyl vibration in the former mixture/benzene
solution (1706 cm-1) and benzaldehyde-only/benzene
solution (1704 cm-1). These results indicate that there
was no apparent activation of the formyl group of

2182 J . Org. Chem., Vol. 67, No. 7, 2002
Wang et al.
Sch em e 4. Th e P r op osed Mech a n ism of th e Ti-H8-BINOL Ca ta lyzed Heter o-Diels-Ald er Rea ction of
Ben za ld eh yd e w ith Da n ish efsk y’s Dien e
(2H, br s), 8.25 (2H, s), 6.67-7.38 (14H, m), 4.31 (2H, s), 3.73
(6H, s), 3.52 (2H, s); 13C NMR (300 MHZ, CD3Cl): δ 164.1,
154.8, 152.0, 140.2, 139.7, 126.7, 126.6, 125.6, 124.1, 119.7,
118.0, 117.7, 114.6, 76.9, 55.8, 51.5; IR (Nujol) 3045, 3020,
1630, 1590 cm-1. Anal. Calcd for C32H28N2O4: C 76.17, H 5.59,
N 5.50; Found: C 76.14, H 5.75, N 5.56.
Exp er im en ta l Section
Gen er a l. All reaction were run under argon or nitrogen
using oven-dried glassware (at 140 °C for at least 4 h, then
stored in the drybox) and magnetic stirring. Molecular sieve
powder (4 Å) was purchased from Aldrich and used as received
without further activation. Toluene, benzene, THF, Et2O, and
TBME were distilled from a deep-blue solution of sodium-
benzophenone ketyl under nitrogen just prior to use. CH2Cl2
was distilled from powdered CaH2 under nitrogen just prior
to use. DMF was dried with powdered CaO, distilled at reduced
pressure, and stored under nitrogen and over 4 Å molecular
sieves. trans-1-Methoxy-3-(trimethylsilyloxy)-1,3-butadiene
(Danishefsky’s diene) was purchased from Lancaster with 95%
or 90% purity and used as received without further purifica-
tion. Aldehyde was distilled and handled under N2 and stored
avoiding light in the refrigerator. Ti(OiPr)4, Ti(OnBu)4, and
TiCl4 were purchased from Aldrich and distilled under nitrogen
immediately prior to use. TADDOL, (2R,4R)-pentanediol,
diisopropyl D-tartrate, and (R)- or (S)-1,1′-bi-2-naphthol were
purchased from Acros. Ti(OiPr)2Cl2 and Ti(OiPr)3Cl were
prepared as described in the literature.23
(R)-2-P h en yl-2,3-d ih yd r o-4H-p yr a n -4-on e (3a ): Gen -
er a l Ca ta lytic HDA P r oced u r e. A mixture of (R)-H8-BINOL
(16.2 mg, 0.055 mmol), 1.0 M Ti(OiPr)4 in CH2Cl2 (50 µL, 0.05
mmol), and activated powdered 4 Å molecular sieves (120 mg)
in toluene (1 mL) was heated at 35 °C for 1 h. The yellow
mixture was cooled to rt, and benzaldehyde (26 µL, 0.25 mmol)
was added. The mixture was stirred for 10 min and cooled to
0 °C. Danishefsky’s diene (60 µL, 0.30 mmol) was added. The
mixture was allowed to stir at 0 °C for 24 h and then treated
with 5 drops of TFA. After the mixture was stirred at 0 °C for
15 min, saturated NaHCO3 (1.5 mL) was added. The mixture
were stirred for 10 min and then filtered through a plug of
Celite. The organic layer was separated, and the aqueous layer
was extracted with ether (5 × 3 mL). The combined organic
layer was dried over anhydrous Na2SO4 and concentrated. The
crude residue was purified by flash chromatography (SiO2,
EtOAc:petroleum 1:4, TLC Rf: 0.5) to yield (R)-2-phenyl-2,3-
dihydro-4H-pyran-4-one-3a (40 mg, 0.23 mmol, 92% yield) as
a clear oil. The isolated material was determined to be in 97%
ee by chiral GC analysis (cyclodex-â, 159 °C, 20 min, isother-
(11R,12R)-9,10-Dihydro-9,10-ethanoanthracene-11,12-dimeth-
anol (5),19a (11R,12R)-9,10-dihydro-R,R,R′,R′-tetraphenyl-9,10-
ethanoanthracene-11,12-dimethanol (6),19a N,N′-diisopropyl-
D-tartaramide (8),19b (1S,5R,6S)-spiro[4.4′]nonane-1,6-diols
(10),19c (1S,5S,6S)-spiro[4.4′]nonane-1,6-diols (11),19d,e (1R,2S)-
1,2-diphenyl-2-(N-methylamino)ethanol (12),19f (4S,5R)-4,5-
dihydro-4,5-diphenyl-2-(2′-hydroxyl-3′-tert-butylphenyl)oxazo-
line (13),19g (1R,2S)-2-(N-(3′,5′-di-tert-butylsalicylidene)amino)-
mal, tR(minor) ) 14.43 min, tS(major) ) 14.66 min). [R]27
D
-110.83 (c ) 0.47, CH2Cl2). The absolute stereochemisty was
assigned as (-)-R based on comparison of the measured
rotation with the literature value.7a,10a
1,2-diph en yl-1-et h a n ol
(14),19h
(1S ,2S )-N,N′-bis(2′-
hydroxylphenylmethylidene)-1,2-diphenylethylenediimine (15),19i
(R)-3,3′-dimethyl-1,1′-bi-2-naphthol (17),19j (R)-6,6′-dibromo-
1,1′-bi-2-naphthol (18),19k and (R)-5,6,7,8-tertahydro-1,1′-bi-2-
naphthol (20)19l were prepared according to the literature
procedure.
Ack n ow led gm en t. This work was supported by the
National Science Foundation of China (No.29832020).
We thank Prof. L. Pu. at University of Virginia in
U.S.A., Dr X.-Y. Tan, Dr. W.-H. Hu, and Dr. M. Yan for
providing chemicals and fruitful discussion.
(11S ,12S )-N ,N -Bis-((2′-h yd r oxy-5′-m e t h oxyp h e n yl)-
m e t h y le n e )-9,10-d ih y d r o -9,10-e t h a n o a n t h r a c e n e d i-
im in e (16). To a 0.2 M solution of (+)-11(S),12(S)-diamino-
9,10-dihydro-9,10-ethanoanthracene22b in absolute ethanol was
added 3-methoxy-2-hydroxybenzaldehyde (2.0 equiv). The
reaction mixture was stirred at rt for 24 h. Then the solid is
collected by filtration to afford 16 in 85% yield as yellow
Su p p or tin g In for m a tion Ava ila ble: The experimental
procedure and analytical and spectral data for compound 3b-
r , HPLC and GC data for determination of the enantiomeric
1
excess of compound 3a -r , and the H NMR, 13C NMR, and IR
spectral for compound 16, 3a -r , and catalyst. This material
is available free of charge via the Internet at http://pubs.acs.org.
crystalline (recrystallized from EtOH): mp 202-203 °C; [R]27
D
+292.3 (c ) 1.40, CH3Cl); 1H NMR (300 MHZ, CD3Cl)‚δ 11.99
J O016240U