Organic Letters
Letter
cycloadditions.6 Despite these advances, the reported amino-
catalytic [4 + 2] cycloaddition approaches have mainly
provided chiral THCs with a relatively simple ring system,
whereas the construction of chiral polycyclic THCs by the
aminocatalytic [4 + 2] cycloaddition approach is much less
explored, and thus further development is highly desirable.
In 2011, Melchiorre and coworkers found that under
aminocatalytic conditions, the highly reactive indole-2,3-
quinodimethane dienes could be generated in situ from β-
indolyl α,β-unsaturated aldehydes7 and then could react with
various electron-deficient dienophiles,8 providing a concise
route to chiral THCs, in particular, chiral polycyclic THCs
(Scheme 1, previous work: trienamine activation). Theoret-
ically, the activation of β-indolyl α,β-unsaturated aldehydes (as
dienes via trienamine activation) and α,β-unsaturated
aldehydes (as dienophiles via iminium ion activation) could
be simultaneously realized by a single aminocatalyst, thus
leading to an enantioselective Diels−Alder cycloaddition
reaction to generate chiral THCs. However, although these
two activation modes (that is, the trienamine activation of β-
indolyl α,β-unsaturated aldehydes and the iminium ion
activation of α,β-unsaturated aldehydes) have been well
established, to the best of our knowledge, their combination
for the synthesis of chiral THCs has never been reported, but it
is an efficient strategy.
As a continuation of our interest toward the application of
α,β-unsaturated aldehydes bearing an ortho-hydroxyl group in
organocatalytic enantioselective reaction sequences for access-
ing polyheterocyclic compounds,9 in particular, those bearing
acetal moieties,10 we herein describe for the first time an
aminocatalytic enantioselective Diels−Alder cycloaddition-
initiated reaction sequence, where β-indolyl α,β-unsaturated
aldehydes and α,β-unsaturated aldehydes were simultaneously
activated by the same aminocatalyst via trienamine activation
and iminium ion activation, respectively (Scheme 1, this work:
enantioselective double activation). Chiral polycyclic THCs
embedded in a hexacyclic ring system bearing four continuous
stereocenters were formed with excellent enantio- and
diastereoselectivities. It should be noted that the installed
acetal or hemiacetal moiety could potentially not only enhance
the biological activities but also introduce divergent trans-
formations of the formed polycyclic products.11
Initially, we examined the reaction of β-indolyl α,β-
unsaturated aldehyde 1a with cinnamaldehyde 2′ in the
presence of aminocatalyst 3a and PhCO2H (BA), which
should activate both 1a and 2′ via trienamine activation and
iminium ion activation, respectively. However, as shown in
Table 1, no reaction was observed after 48 h in 1,2-
dichloroethane (DCE), not to mention the formation of the
desired [4 + 2] adduct 4. Much to our surprise, under the same
reaction conditions, α,β-unsaturated aldehyde 2a bearing an
ortho-hydroxyl group, namely, 2-hydroxycinnamaldehyde,
worked well with 1a, leading to a mixture of the two
inseparable anomers of hemiacetal 5a, which, for clean high-
performance liquid chromatography (HPLC) separation, was
converted into polycyclic tetrahydrocarbazole 6a bearing a
bioactive chromane moiety in 27% yield (over two steps) by an
in situ dehydration reaction (Table 1, entry 1). It should be
noted that this cascade multibond formation process involving
[4 + 2] cycloaddition, acetalization, and hemiacetalization
proceeded in a highly regio- and stereoselective manner;
product 6a bearing four continuous chiral centers was formed
with excellent enantioselectivity (>99% ee) as a single
a
Table 1. Optimization of the Reaction Conditions
entry
solvent
additive
t (h)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
DCE
toluene
THF
BA
BA
BA
BA
BA
BA
22
12
24
>48
21
20
11
11
9
27
20
25
30
17
54
54
43
53
>99
>99
>99
>99
>99
>99
>99
>99
>99
CH3CN
acetone
CPME
CPME
CPME
CPME
CPME
CPME
m-ClC6H4CO2H
o-FC6H4CO2H
AcOH
NaOAc
m-ClC6H4CO2H
9
10
11
24
11
58
>99
a
See the Supporting Information for more details. Isolated yields
(over two steps) of 6a are given. Enantiomeric excess (ee) of 6a
determined by chiral HPLC analysis. Boc, tert-butyloxycarbonyl; Ms,
methanesulfonyl; DMAP, 4-dimethylaminopyridine; THF, tetrahy-
drofuran.
diastereomer. With respect to the much different reactivities
of the simple cinnamaldehyde 2′ and 2-hydroxycinnamalde-
hyde 2a exhibited in this cascade process, we proposed that the
acetalization and hemiacetalization sequences of 2-hydrox-
ycinnamaldehyde 2a push the reaction forward. Next, the
variation in different solvents revealed that cyclopentyl methyl
ether (CPME) was the best solvent in terms of isolated yield
(Table 1, entries 2−6). Additionally, several acidic additives
were tried (Table 1, entries 7−9), where m-ClC6H4CO2H (m-
ClBA) gave a slightly better yield; the basic additive (Table 1,
entry 10; NaOAc) gave no reaction. Finally, the use of an
excess of 2-hydroxycinnamaldehyde 2a (1.2 equiv) was
important for obtaining the desired product 6a in higher
yield (Table 1, entry 11).
With the optimal conditions in hand (Table 1, entry 12), we
investigated the scope and limitations of this [4 + 2]
cycloaddition-initiated cascade. As shown in Scheme 2a,
various electron-withdrawing and electron-donating substitu-
ents on the aryl ring of α,β-unsaturated aldehyde 2 worked well
to afford the polycyclic products 6a−n in moderate to good
isolated yields with excellent stereoselectivities (in all cases,
>99% ee, dr >20:1). Substituents with different electronic
properties at the 5-position on the indole moiety of β-indolyl
α,β-unsaturated aldehyde 1 were also well tolerated (6o−q).
The replacement of the N-Boc component of aldehyde 1 with
N-Me gave similar good results (6r), except indole,
benzofuran, and benzothiophene functionality could be
contained in the structure of α,β-unsaturated aldehyde 1 to
provide the corresponding polycyclic products 6s and 6t with
excellent stereoselectivities.
6516
Org. Lett. 2021, 23, 6515−6519
Ming, Yong-Chao
