Angewandte
Communications
Chemie
event, and II) the difficulty in controlling racemic background
reactions, which occur by direct interception of the highly
reactive intermediate A by the dienophile without the
assistance of the chiral catalyst.
attractive interactions to bind 2a[11] (see the Supporting
Information for the full results of an extensive study).
We identified the bifunctional thiourea–amine 4a, a deriv-
ative of natural cinchona alkaloids with well-known utility in
thermal asymmetric processes,[12] as a promising catalyst
(Table 1, entry 3, 55% ee). The presence of an additional
stereocontrol element on the thiourea moiety was crucial to
increasing the enantioselectivity. Derivative 4c was identified
as the catalyst of choice (Table 1, entry 5, 84% ee). A
matched/mismatched combination was observed with catalyst
4d, which has the opposite configuration at the thiourea
stereogenic center (entry 5 vs. entry 6), thus confirming the
influence of this chiral moiety on the stereodefining event. A
final cycle of optimization with catalyst 4c revealed that the
adduct 3a could be obtained with excellent results (76%
yield, d.r. > 20:1, 90% ee; Table 1, entry 7) by using a 3:1
mixture of cyclohexane and toluene and stirring the mixture
at À58C over a 24 h time period.
Herein, we report how organocatalysis offers effective
tools for the interception of photogenerated hydroxy-o-
quinodimethanes A with high stereoselectivity. We used
a chiral organic catalyst derived from natural cinchona
alkaloids to activate maleimides toward stereoselective
Diels–Alder reactions to afford stereochemically dense
cyclic products. In the developed methods, simple sources of
illumination and readily available substrates and catalysts
were used, thus avoiding the need for any tailored or
purposely designed reactant.
Our initial explorations focused on the PEDA reaction
between N-tert-butylmaleimide (2a) and 2-methylbenzophe-
none (1a; Table 1). Because of its high reactivity, this type of
Aside from providing suitable catalytic conditions for an
enantioselective PEDA reaction, the initial studies high-
lighted that the racemic background process was significantly
faster than the stereoselective reaction with the cinchona-
thiourea catalyst 4c (compare entries 1 and 5 in Table 1; see
Figure S3 for more details). Reduction of the rate of the
uncatalyzed pathway is crucial to successfully developing any
photochemical catalytic asymmetric reaction[13] and is gen-
erally accomplished through the formation of a chiral catalyst/
substrate complex that absorbs light at longer wavelengths or
with a higher extinction coefficient than the free substrate.
However, optical absorption spectroscopic studies of the
individual components of the model reaction and their
combination (see Figure S7) confirmed that 2-methylbenzo-
phenone (1a) was mainly responsible for the absorption at
365 nm (the operative wavelength in our system), thus
excluding the formation of any photoabsorbing substrate/
catalyst 4c aggregation. This puzzling observation prompted
us to evaluate other possible pathways available to 4c for
minimizing the background process. We studied the evolution
of the formation of product 3a over time to decipher the
effect of the catalyst scaffold on the reactivity of the model
reaction (Figure 2a). Specifically, we investigated the indi-
vidual behavior of the two main fragments of the organo-
catalyst, the quinuclidine and the thiourea moieties. A
catalytic amount of the achiral thiourea 4e accelerated the
reaction (violet line in Figure 2a), in consonance with the
selective activation of the maleimide 2a, which facilitates the
trapping of the photoenol. In contrast, quinuclidine 4 f greatly
inhibited the process (magenta line). The last observation can
be reconciled with the established ability of tertiary amines to
quench the triplet state of benzophenones,[14] the key
precursor intermediate in the formation of hydroxy-o-quino-
dimethanes (T1-B in Figure 1b). It is also known that
geometrically constrained amines, including quinuclidine,
use an electron-transfer quenching mechanism that returns
the benzophenone to the ground state along with the
unaltered tertiary amine (Figure 2b), since stereoelectronic
effects preclude a hydrogen-transfer pathway.[15] The emerg-
ing picture that the quinuclidine core within catalyst 4c could
diminish the formation of the photoenol derived from 1a was
Table 1: Exploratory studies on the feasibility of an organocatalytic
asymmetric PEDA process.
Entry Catalyst Solvent
Illumination Yield [%][a] ee [%]
1
2
3
4
none
none
4a
4b
4c
toluene
toluene
toluene
toluene
toluene
toluene
ON
OFF
ON
ON
ON
ON
80
0
0
–
18
30
35
18
76
55
80
84
68
90
5
6
4d
4c
7[b]
CyH/toluene (3:1) ON
[a] Yield of isolated 3a. [b] The reaction was carried out at À58C for 24 h.
CyH =cyclohexane.
process has found application in the light-triggered “click”
conjugation of polymeric building blocks.[10] The experiments
were conducted in toluene under irradiation by a single black-
light-emitting diode (black LED, lmax = 365 nm). The rate of
the background process confirmed the challenge of making
the reaction enantioselective: product 3a was obtained with
complete diastereoselectivity and 80% yield after 15 h in the
absence of a catalyst (Table 1, entry 1). As expected, a control
experiment revealed that the process was completely inhib-
ited in the dark (Table 1, entry 2).
Our approach relied on the use of a chiral organocatalyst
that could activate the dienophile 2a to trap the transient
photoenol A stereoselectively. We investigated a variety of
chiral catalysts that could use multiple, noncovalent weak
3314
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 3313 –3317