Table 1. Screening of various reaction conditions for the Diels–Alder re-
action of (Z)-1-methyl-2-styryl-1H-indole (1a) with trans-cinnamalde-
hyde (2a).[a]
to the a,b-unsaturated aromatic aldehydes. Substrates 2a–g,
with substituents of different electronic nature on different
positions of the benzene ring, and heteroACTHNUTRGNEUNGaromatic substrates
2h and i all gave excellent ee and good d.r. in moderate to
good yields, though longer reaction times were required for
electron-rich substrates (Table 2, entries 1–9). Substrates 2j–
l, with non-aromatic R groups, were also well-tolerated and
a rate acceleration was observed in the case of 2j, which
contains an electron-withdrawing ester as its R group
(Table 2, entries 10–12). However, when acrolein (R=H,
2m) was used as the dienophile a slightly lower enantiose-
lectivity (86% ee) was obtained (Table 2, entry 13). Several
other 2-vinylindoles 1b–d were also evaluated in the reac-
tion, which, in general, provided similar good results to 1a
(Table 2, entries 14–20). The less successful results with 1e
and f may be ascribed to the increased steric hindrance of
the R2 group (R2 =allyl or benzyl (Bn); (Table 2, entries 21
and 22). When R3 is a methyl group (1g), the reaction pro-
ceeded slowly and few products were observed. On the
other hand, when the nitrogen was protected by tert-buty-
loxycarbonyl (Boc), carbobenzoxyl (Cbz), or other ester
groups none of the desired products were obtained with
starting materials recovered in each case (results not shown
in the table). The absolute configuration of the endo-prod-
uct 4o was determined to be 2R,3R,4R by X-ray crystallo-
graphic analysis (Figure 1).[12] The configurations of the
other products were determined by analogy to 4o.
Entry Catalyst Loading Additive
[mol%]
Yield of 4 d.r.
ee
G
[%][b]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
8
3a
3b
3c
20
20
20
20
20
20
20
–
20
5
10
15
15
20
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
45[e]
70
82
47
82
7:1
8:1
6:1
9:1
16:1
16:1
–
99
99
92
94
97
96
–
3d
3e
3e
3e
none
3e
3e
3e
3e
3e
3 f
CF3COOH 56
none
[f]
–
–
[g]
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
CF3SO3H
–
–
9[h]
10
11
12
13[i]
14
77
67
73
77
83
72
9:1
6:1
8:1
12:1
12:1
9:1
96
97
97
97
97
82
[a] Unless otherwise noted, all the reactions were conducted in toluene
(1.0 mL) by using 2a (0.1 mmol) and 1a (0.12 mmol), in the presence of
20 mol% catalyst and 20 mol% of an additive, at room temperature with
vigorous stirring for 24 h. [b] Isolated yields. [c] Determined by 1H NMR
analysis of the crude products. [d] Determined by HPLC analysis on a
Chiralcel AD-H column. The ent-4a was obtained if 3a–d or f were used.
[e] Yield of 4a. [f] No reaction. [g] A complex mixture of products was
obtained. [h] The reaction was conducted in chloroform. [i] Reaction
time was extended to 48 h.
the desired product 4a in 82% yield with up to 97% ee and
16:1 diastereoselectivity (Table 1, entry 5). If trifluoroacetic
acid was used as the additive, comparable ee and d.r. values
were obtained, but the resulting mixture was relatively com-
plex and the yield of 4a dropped sharply to only 56%
(Table 1, entry 6). The reaction did not proceed without an
acidic additive and the product mixture turned out to be
complex when no catalyst was added (Table 1, entries 7 and
8). Performing the reaction in the more polar solvent
chloroform gave inferior results (Table 1, entry 9). Decreas-
ing the loading of catalyst 3e did not have a negative effect
on the enantioselectivity of the product, but a reduction in
both the yield and diastereoselectivity was observed
(Table 1, entries 10–12). Realizing that the low yields ob-
tained in low catalyst loadings were mainly due to the in-
complete conversion of the starting material 2a, we extend-
ed the reaction time to 48 h and the yield was improved to
88% if 15 mol% of the catalyst was used (Table 1,
entry 13). In addition, MacMillanꢂs catalyst 3 f was tested
under these reaction conditions but gave inferior results
(Table 1, entry 14).
Figure 1. The X-ray crystal structure of enantiomerically pure 4o.
Based on previous studies[3–4] and our experimental obser-
vations, we speculate that a concerted mechanism is more
convincing, but the possible stepwise pathway cannot be
ruled out. A suggested catalytic cycle using catalyst 3e is il-
lustrated in Scheme 1. The first step should be the formation
of iminium intermediate A by reaction of catalyst 3e with
aldehyde 2 in the presence of trifluoromethane sulfonic
acid. Intermediate A then reacts with 2-vinylindole 1 with
endo selectivity to give another iminium intermediate, B,
which is followed by hydrolysis of the iminium to releases
the catalyst and the product 4 may be obtained after an in-
stant rearrangement to aromatize the initial Diels–Alder
adduct.
Having established the optimal reaction conditions
(Table 1, entry 13), we next examined the scope and limita-
tions of the above system regarding various 2-vinylindoles
and a,b-unsaturated aldehydes. The results are summarized
in Table 2. The reaction appears quite general with respect
To demonstrate the utility of the current reaction in or-
ganic synthesis, a model reaction to synthesise the core
structure of the akuammiline alkaloid vincorine was investi-
gated (Scheme 2) and the results are summarized in Table 3.
The reaction with the previously most successful catalyst 3e
5854
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 5853 – 5857