Highly enantioselective hetero-diels-alder reaction of frans-1-methoxy-2- methyl-3-trimethylsiloxybuta-1, 3-diene with aromatic and aliphatic aldehydes catalyzed by 3-substituted BINOL-titanium complex

Article abstract of DOI:10.1021/ol8001706

3-Diphenylhydroxymethyl-substituted BINOL-titanium complex prepared in situ was found to be a highly efficient catalyst for hetero-Diels-Alder reaction of diene 1 with both aromatic and aliphatic aldehydes to give 2,5-disubstituted dihydropyrone in up to 99% yield and 99% ee.

Full text of DOI:10.1021/ol8001706

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1299-1302
Highly Enantioselective Hetero-
Diels Alder Reaction of trans-1-Methoxy-
−
2-methyl-3-trimethylsiloxybuta-1,3-diene
with Aromatic and Aliphatic Aldehydes
Catalyzed by 3-Substituted
BINOL−Titanium Complex
Xin-Bin Yang,†,§ Jie Feng,† Ji Zhang,† Na Wang,† Li Wang,† Jun-Liang Liu,† and
Xiao-Qi Yu*,†,‡
Department of Chemistry, Key Laboratory of Green Chemistry and Technology
(Ministry of Education), Sichuan UniVersity, Chengdu, 610064, P. R. China, State Key
Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan
UniVersity, Chengdu, Sichuan 610041, P. R. China, and Rongchang Campus,
Southwest UniVersity, Chongqing 402460, P. R. China
xqyu@tfol.com
Received January 24, 2008
ABSTRACT
3-Diphenylhydroxymethyl-substituted BINOL−titanium complex prepared in situ was found to be a highly efficient catalyst for hetero-Diels−
Alder reaction of diene 1 with both aromatic and aliphatic aldehydes to give 2,5-disubstituted dihydropyrone in up to 99% yield and 99% ee.
The catalytic asymmetric hetero-Diels-Alder (HDA) reac-
tion of Danishefsky’s diene with aldehydes provided a
powerful approach for achieving optical active dihydro-
pyrones, which was applied widely in the synthesis of
carbohydrates and numerous natural compounds.1-16 Multi-
substituted dihydropyrones could be obtained by the modi-
fication on different positions of substrate dienes or alde-
hydes.17 In 1983, Danishefsky and co-workers first reported
the synthesis of chiral 2,5-disubstituted dihydropyrone by
asymmetric HDA reaction between trans-1-methoxy-2-
methyl-3-trimethylsiloxybuta-1,3-diene (diene 1) and benz-
aldehyde, in which moderate enantioselectivity was achieved.17a
More recently, Feng and co-workers reported much better
(1) For reviews, see: (a) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994. (b) Danishefsky, S. J.; DeNinno, M.
P. Angew. Chem., Int. Ed. 1987, 26, 15. (c) Carmona, D.; Lamata, M. P.;
Oro, L. A. Coord. Chem. ReV. 2000, 200-202, 717. (d) Corey, E. J.;
Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388. (e) Jørgensen,
K. A. Angew. Chem., Int. Ed. 2000, 39, 3558.
† Key Laboratory of Green Chemistry and Technology, Sichuan Uni-
versity.
‡ West China Medical School, Sichuan University.
§ Southwest University.
10.1021/ol8001706 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/28/2008

results between diene 1 and aromatic aldehydes with the use
of (R)-BINOL-Ti(OiPr)4 complex.17i However, to the best
of our knowledge, few catalytic systems could induce high
enantioselectivity for aromatic and aliphatic aldehydes in the
HDA reactions. Therefore, searching for universal catalysts
for asymmetric HDA reactions between diene 1 and different
kinds of aldehydes is of great importance.
Many modified BINOLs with different substituents on
naphthalene rings were prepared and used as chiral ligands
in asymmetric catalytic reactions.18-23 Herein, we wish to
report that the titanium(IV) catalysts derived from 3-mono-
substituted or 3,3′-disubstituted (R)-BINOLs could exhibit
an enhanced catalytic activity for the asymmetric HDA
reaction between diene 1 and aromatic or aliphatic aldehydes.
For this purpose, ligands L1-L4 were studied (Figure 1).
We found that L4 in combination with Ti(OiPr)4 could
Figure 1. Structure of diene 1 and chiral ligands L1-L4.
catalyze the HDA reaction with excellent enantioselectivity,
especially for aliphatic aldehydes.
Various ligands (Figure 1) were examined as catalysts for
the HDA reaction between diene 1 and benzaldehyde. The
reactions were carried out in the presence of (R)-BINOL
derivatives L1-L4 (20 mol %) and Ti(OiPr)4 (20 mol %)
in CH2Cl2 at 0 °C for 72 h. Interestingly, we found that the
Ti(IV) complex of 3-diphenylhydroxymethyl-substituted
BINOL ligand (L4) could give the desired product in the
highest yield associated with the highest enantioselectivity.
In contrast, the Ti(IV) complexes of L1-L3 displayed poor
catalytic activity. It could be considered that the monosub-
stituted diphenylhydroxymethyl group played an important
role in the catalytic process.
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The HDA reaction conditions catalyzed by Ti/L4 were
optimized, and the results are listed in Table 1. The reaction
carried out in toluene could give higher yield and ee than
those in other solvents such as dichloromethane, THF, and
diethyl ether (entries 1-4). The mole ratio 1:1 of metal/
ligand afforded best catalytic results. Slight increase of the
relative amount of L4 resulted in dramatic decrease of ee
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Table 1. HDA Reaction between Diene 1 and Benzaldehyde
Catalyzed by Ti/L4 under Various Conditionsa
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L4:Ti(OiPr)4
(mol %)
entry solvent
T (°C) yield (%)a,b ee (%)c
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6968. (b) Yang, W.-Q.; Shang, D.-J.; Liu, Y.-L.; Du, Y.; Feng, X.-M. J.
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1
2
3
4
5
6
7
8
CH2Cl2
THF
Et2O
20:20
20:20
20:20
20:20
22:20
24:20
30:20
18:20
16:20
10:20
20:20
20:20
0
0
0
0
0
0
0
0
0
87
94
87
98
99
90
81
99
96
80
88
99
86
86
45
94
45
28
-8
88
87
30
81
84
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9
10
11
12
0
(18) (a) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. ReV. 2003, 103, 3155.
(b) Kocovsky, P.; Vyskocil, S.; Smrcina, M. Chem. ReV. 2003, 103, 3213.
(c) Brunel, J. M. Chem. ReV. 2005, 105, 857.
-20
25
(19) Huang, W.-S.; Pu, L. J. Org. Chem. 1999, 64, 4222.
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4422.
a Unless indicated, all reactions were carried out on a 0.20 mmol scale
with L4 and Ti(OiPr)4 (20 mol %) in 2.0 mL of solvent at 0 °C for 72 h.
b Isolated yields. c The ee values were determined by HPLC using chiralcel
OJ column.
1300
Org. Lett., Vol. 10, No. 6, 2008

(entries 4-7). On the other hand, lower enantioselectivities
were also obtained in the reaction with less L4 (entries
8-10). When reaction temperature decreased to -20 °C,
lower yield and enantioselectivity were obtained (entry 11).
However, when the reaction was performed at 25 °C, the
enantioselectivity was also affected (entry 12).
Inspired by the previous results, we applied various
aromatic and aliphatic aldehydes to the HDA reaction
catalyzed by Ti/L4 under optimized conditions; the results
are listed in Table 2. Excellent yields and ees were obtained
for almost all of the tested substrates.
Table 2. HDA Reaction of Diene 1 with Various Aldehydes
Catalyzed by L4/Ti(OiPr)4
yield
ee
Figure 2. Relationship between ee values of L4 and HDA product
3a.
entry
aldehyde
benzaldehyde
product (%)a (%)b
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
98
91
86
94
99
99
82
89
98
99
92
98
98
98
86
91
75
94
92
86
94
99
96
92
93
95
87
93
90
93
99
92
88
86
90
99
92
92
97
91
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4-nitrobenzaldehyde
3-nitrobenzaldehyde
2-nitrobenzaldehyde
4-chlorobenzaldehyde
3-chlorobenzaldehyde
2-chlorobenzaldehyde
4-methylbenzaldehyde
3-methylbenzaldehyde
2-naphthbenzaldehyde
4-cyanobenzaldehyde
4-bromobenzaldehyde
4-trifluoromethylbenzaldehyde
2-furaldehyde
propionaldehyde
butyraldehyde
isobutyraldehyde
valeraldehyde
heptaldehyde
crotonaldehyde
Mukaiyama aldol pathway and traditional Diels-Alder
pathway were generally taken into account for Lewis acid
catalyzed HDA reactions.2b,17h,24,25A Mukaiyama aldol path-
way was reported for the HDA reaction of diene 1 with
benzaldehyde by the use of (R)-BINOL-Ti(OiPr)4 catalyst.17i
To survey the possible pathway of L4/Ti(OiPr)4 catalyst, the
reaction between diene 1 and benzaldehyde was performed
under optimized conditions. The reaction was quenched by
the addition of saturated NaHCO3 before treatment with TFA.
Only one new product could detected by TLC. The product
was isolated using silica gel column. This isolated intermedi-
ate was confirmed as 3a by NMR. The result was the same
with that after treatment with TFA. The fact indicated that
mechanism of the HDA reaction was proposed as a tradi-
tional Diels-Alder pathway (Scheme 1).
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
a Isolated yields. b The ee values were determined by HPLC using
chiralcel OJ or OD-H column (see Supporting Information for details).
Scheme 1. Possible Pathways for the HDA Reaction between
Diene 1 and Benzaldehyde
For aromatic aldehydes (entries 1-14), ortho-substitution
might lead to less enantioselectivity (entries 4 and 7).
Benzaldehyde bearing an electro-withdrawing group in the
para position exhibited the highest levels of enantioselectivity
(entries 2 and 11). Interestingly and importantly, a variety
of aliphatic aldehydes, including linear (entries 15, 16, 18,
and 19), R-branched (entry 17), and R,â-unsaturated (entry
20) aldehydes, also gave good to excellent results (entries
15-20).
The linear relationship between the ees of chiral ligand
L4 and HDA product 3a was investigated. It is obvious that
the catalytic system showed both weak positive and strong
negative nonlinear effects (Figure 2). We were interested to
find that the absolute configuration of the product 3a was
switched when the ees of partially resolved L4 were
decreased to 30%. The results suggested that the active
species of the HDA reaction might change with the decrease
of ee of the chiral ligand.13
The alkyl hydroxyl of L4 was methylated to give L5
(Figure 3), and the catalytic activity of L5 was also
investigated. Experimental results showed that comparing
with the HDA reaction between diene 1 and benzaldehyde
catalyzed by Ti/L4, Ti/L5 displayed poor catalytic activity.
This result demonstrated that the alkyl hydroxyl of L4 was
essential for the catalytic activity toward HDA reaction.
NMR study was performed for further insight into the
Org. Lett., Vol. 10, No. 6, 2008
1301

Figure 3. Chiral ligand L5 and the complex of Ti/L4.
Figure 4. 13C NMR spectrum of the carbon atom bearing the alkyl
hydroxyl of L4 (A) and L4/Ti(OiPr)4 (B). See Supporting Informa-
tion for detailed spectrum.
importance of alkyl hydroxyl of L4 in the HDA reaction.
The interaction between L4 and Ti(OiPr)4 in CDCl3 was
monitored by 13C NMR. As shown in Figure 4, the original
singlet at δ ) 82.92 ppm (Figure 4A) for the carbon atom
bearing the alkyl hydroxyl of L4 shifted to 90.35 ppm (Figure
4B) after the addition of Ti(OiPr)4. The 13C NMR data
supported this hypothesis that Ti(IV) could coordinated to
the hydroxyl on 3-substituent of L4 (Figure 3).
deduced that there might be a variety of aggregated catalyst
species involved in the catalytic system. A traditional Diels-
Alder pathway was also proposed by the analyses of reaction
intermediate.
In summary, we demonstrated that L4 displayed high
enantioselectivity in the asymmetric HDA reaction of diene
1 with both aromatic and aliphatic aldehydes. Comparing to
the catalytic results by using Ti/L1-L3 and L5, we could
conclude that the 3-diphenylhydroxymethyl group appended
to the BINOL ligand is critical for increase of catalytic
activity, and the 13C NMR provides evidence that this moiety
binds to the Ti center to form a tridentate ligand. On the
basis of the observed unusual nonlinear effect, it could be
Acknowledgment. This work was financially supported
by the National Natural Science Foundation of China (Nos.
20725206, 20732004 and 20572075), Program for New
Century Excellent Talents in University, Specialized Re-
search Fund for the Doctoral Program of Higher Education
and Scientific Fund of Sichuan Province for Outstanding
Young Scientist.
Supporting Information Available: Experimental details
1
and characterization data, including H and 13C NMR and
HPLC. This material is available free of charge via the
Internet at http://pubs.acs.org.
(24) Schaus, S. E.; Branalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63,
404.
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4141.
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