Yamamoto to catalyze enantioselective cyclizations of
unsaturated aldehydes.12 We decided to investigate this Lewis
acid for the Diels-Alder reactions of N-alkoxyacrylamides.
The results of the study are described in Table 4. Using a
Table 3. Reaction of 1a-g with Cyclopentadiene Catalyzed by
i-Bu3Al (0.14 equiv) and 1-NaphtTADDOL (0.25 equiv)
According to Scheme 110
substrate
RN
ORO
endo:exo
ee (endo)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Me
t-Bu
Ph
Ph
Ph
OMe
OMe
OMe
OEt
Oi-Pr
OBn
11:1
a
23% S
21% R
72% S
75% S
89% S
69% S
92% S
Table 4. Reaction of 1 with Cyclopentadiene Catalyzed by
(R)-Zn-BINOL According to Scheme 113
24:1
18:1
33:1
21:1
>50:1
equiv of
substrate
RN
ORO
OMe
catalyst endo:exo ee (endo)
Ph
Ph
1
2
3
4
5
6
1a
1b
1c
1c
1d
1e
Me
t-Bu OMe
Ph
Ph
Ph
Ph
1.1
1.1
1.1
0.25
1.1
1.1
7:1
nd
54:1
41:1
29:1
14:1
89% R
60% R
96% R
90% R
86% R
76% R
1g
Ot-Bu
a Not precisely determined, about 7:1.
OMe
OMe
OEt
similar result was already observed when hydroxamic acids
were employed with aluminum Lewis acids.1 It is worth
mentioning that an inversion of the sense of induction was
observed with the t-Bu substituent (entry 2). The role of the
alkyl group at the N-alkoxy substituent was investigated next.
Increasing the size of the alkyl group led to an enhancement
of the enantioselectivity (entries 4-7). The best substrate
for the aluminum-catalyzed reactions was found to be the
N-tert-butoxy-N-phenylacrylamide (entry 7, 92% ee).
The rationalization of these results is not clear at the
moment due to the lack of structural information about the
Lewis acid.
Oi-Pr
stoichiometric amount of the Lewis acid, the reaction with
the Weinreb amide 1a at 0 °C gave a very encouraging 89%
ee and a moderate endo selectivity (Table 4, entry 1). The
N-methoxy-N-phenylacrylamide 1c furnished under the same
reaction conditions the Diels-Alder adduct 2c in 96% ee
and excellent endo selectivity. The use of a substoichiometric
amount of Lewis acid (0.25 equiv) allows an enantioselec-
tivity of 90% (entry 3). In this case, the reaction took 5 h to
go to completion instead of 1 h when a stoichiometric amount
of catalyst was used. When bulkier alkoxy groups were used,
the level of enantioselectivity decreases slightly as demon-
strated by the results of entries 4 and 5. However, the nature
of the substrate is less important with this Lewis acid than
with the aluminum derivatives. The simplicity of the Zn-
BINOL experimental procedure makes it very attractive from
a synthetic point of view.
Zinc Lewis Acids. Dialkylzinc represents an attractive
alternative to trialkylaluminum for preparation of mild Lewis
acids.11 The Lewis acid obtained from dimethylzinc and
BINOL has been reported in the pioneering work of
(10) General procedure (Al-1-NaphtTADDOL): A solution of Me3Al
in toluene (1.11 M, 0.13 mL, 0.14 mmol) was added dropwise at room
temperature to a solution of 1-NaphtTADDOL (187 mg, 0.28 mmol) in
CH2Cl2 (5.0 mL). The reaction mixture was stirred for 30 min at room
temperature. A solution of 1g (219 mg, 1.0 mmol) in CH2Cl2 (1.0 mL) was
then added dropwise. The reaction mixture was stirred for 1 h at room
temperature and 30 min at -78 °C. Freshly distilled cyclopentadiene (660
mg, 10 mmol) was added dropwise under N2 to the solution at -78 °C,
and the mixture was allowed to warm to room temperature overnight (12
h). Volatiles were removed in vacuo, and the resulting residue was dissolved
in Et2O and stirred for 1 h at room temperature with a 1 N aqueous solution
of citric acid. After extraction with Et2O, the organic phase was dried (Na2-
SO4), filtered, and concentrated. The crude product was purified by flash
chromatography (hexane/EtOAc 12:1).
The stereochemical outcome of these reactions can be
rationalized by the formation of a bidentate complex with
an s-cis geometry (Figure 1).
(11) For a review on chiral zinc Lewis acids, see: Motoyama, Y.;
Nishiyama, H. In Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.;
Wiley-VCH: Weinheim, Germany, 2001; Vol. 1, pp 59-88.
(12) Sakane, S.; Maruoka, K.; Yamamoto, H. Tetrahedron 1986, 43,
2203.
(13) Identical results where observed when Me2Zn was employed to
prepare the complex with BINOL rather than Et2Zn. As described by
Yamamoto, the catalyst solution was clear when prepared at low temper-
atures (-78 °C) and turned to a white suspension while warming to room
temperature. In our case, this had no marked influence on the reaction
selectivity. The general procedure used for the Zn-BINOL catalyst
preparation is the following: A solution of Et2Zn (15 wt % in hexane, 1.1
mmol) was added dropwise at room temperature to a solution of (R)-BINOL
(320 mg, 1.1 mmol) in CH2Cl2 (5.0 mL). The reaction mixture was heated
at reflux for 1 h, cooled to 0 °C, and stirred for 30 min before the addition
of a solution of 1c (177 mg, 1.0 mmol) in CH2Cl2 (1.0 mL). The resulting
suspension was stirred for 1 h at 0 °C before the addition of freshly distilled
cyclopentadiene (660 mg, 10 mmol). After completion of the reaction,
volatiles were removed in vacuo and the resulting residue was dissolved in
Et2O and stirred for 1 h at room temperature with a 1 N aqueous solution
of citric acid. After extraction with Et2O, the organic phase was dried (Na2-
SO4), filtered, and concentrated. The crude product was purified by flash
chromatography (hexane/EtOAc 8:1).
Figure 1. Proposed model for the stereochemical outcome of the
reaction catalyzed by (R)-Zn-BINOL.
In conclusion, we have demonstrated that N-alkoxyacry-
lates are suitable substrates for enantioselective Diels-Alder
reactions. Interestingly, very mild and simple Lewis acids
prepared from binaphthols or TADDOLs and trialkylalumi-
num or dialkylzinc provide a good level of enantioselectivity.
The conversion of the N-alkoxyamide Diels-Alder adducts
into useful building blocks should be facilitated by the well-
Org. Lett., Vol. 4, No. 10, 2002
1737