Catalytic Asymmetric 1,6-Conjugate Addition of para-Quinone Methides: Formation of All-Carbon Quaternary Stereocenters

Article abstract of DOI:10.1002/anie.201506701

Described herein is a general and mild catalytic asymmetric 1,6-conjugate addition of para-quinone methides (p-QMs), a class of challenging reactions with previous limited success. Benefiting from chiral Bronsted acid catalysis, which allows in situ formation of p-QMs, our reaction expands the scope to general p-QMs with various substitution patterns. It also enables efficient intermolecular formation of all-carbon quaternary stereocenters with high enantioselectivity.

Full text of DOI:10.1002/anie.201506701

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201506701
German Edition: DOI: 10.1002/ange.201506701
Asymmetric Catalysis
Catalytic Asymmetric 1,6-Conjugate Addition of para-Quinone
Methides: Formation of All-Carbon Quaternary Stereocenters
Zhaobin Wang, Yuk Fai Wong, and Jianwei Sun*
Abstract: Described herein is a general and mild catalytic
asymmetric 1,6-conjugate addition of para-quinone methides
(p-QMs), a class of challenging reactions with previous limited
success. Benefiting from chiral Brønsted acid catalysis, which
allows in situ formation of p-QMs, our reaction expands the
scope to general p-QMs with various substitution patterns. It
also enables efficient intermolecular formation of all-carbon
quaternary stereocenters with high enantioselectivity.
p
ara-Quinone methides (p-QMs) are important molecules,
which are not only observed in various natural products and
pharmaceuticals, but also involved in a number of biologically
significant processes.[1–3] Owning to their intrinsic electro-
philic nature, p-QMs are also versatile species in a wide range
of useful organic reactions, particularly 1,6-conjugation
additions.[1,4–6] However, for a long time, the exploration of
their reactivity has been confined to the domain of non-
asymmetric synthesis, which is in sharp contrast to ortho-
quinone methides (o-QMs), whose asymmetric reactions have
received considerable attention.[7] Indeed, asymmetric induc-
tion for p-QMs upon activation by a chiral catalyst is
substantially more challenging than that for o-QMs because
of the increased distance between the catalyst activation site
(carbonyl) and the reaction center.[8] Consequently, the
development of catalytic asymmetric reactions of p-QMs is
still in its infancy.
Scheme 1. Catalytic asymmetric 1,6-addition to p-QMs.
excellent efficiency and stereoselectivity have been achieved,
and these examples represent significant advances in asym-
metric reactions of p-QMs.
Intrigued by the recent success of chiral phosphoric acid
catalyzed asymmetric reactions of o-QMs,[7d–p] as well as our
preliminary efforts,[7i] we envisioned the possibility of further
advancing the study of p-QMs with this approach (Sche-
me 1b). The compatible in situ generation of p-QMs from
stable p-hydroxybenzyl alcohols is expected to obviate pre-
synthesis of unstable p-QMs, and can significantly expand the
reaction scope and simplify operations. However, the remote
stereocontrol by a catalyst in the 1,6-conjugate addition is
necessary and substantially challenging. Herein we report the
realization of such an efficient and mild protocol, which is not
only amenable to various substitution patterns, but also
capable of forming all-carbon quaternary stereocenters with
excellent remote stereocontrol.[9]
Recently, the groups of Fan and Jørgensen sequentially
reported their pioneering studies on asymmetric 1,6-conju-
gate addition of p-QMs employing enamine and phase-
transfer catalysis, respectively (Scheme 1a).[5] There are
several features of these two examples. Mechanistically,
their approaches do not involve the activation of p-QMs.
Instead, a catalytically generated chiral nucleophile is respon-
sible for the excellent facial selectivity on the p-QMs, thereby
bypassing the above-mentioned challenging remote stereo-
control. Moreover, the p-QMs employed in these two
reactions are pre-synthesized and mostly bear two of the
same bulky a-substituents (e.g., tBu) and no b-substituent.
The d-position is uniformly monosubstituted, mostly with an
aryl group, to form a tertiary stereocenter. The structural
limitation might be partly due to the general instability of
p-QMs, particularly with small a-substituents. Nevertheless,
We started the exploration with the racemic tertiary
alcohol 1a as the p-QM precursor (Table 1). 2-Methylpyrrole
(2a) was used as a model nucleophile in view of its good
nucleophilicity, as well as the wide utility of pyrroles.[10]
Gratifyingly, various chiral phosphoric acids can smoothly
À
catalyze the intermolecular C C bond formation at room
temperature. The desired triarylethane 3a, bearing an all-
carbon quaternary stereocenter, was formed as the major
product,[11] together with minor dehydration product 4a.
Among all the evaluated acid catalysts (see the Supporting
Information for more details), the catalyst C3, substituted
with 9-anthryl groups, proved most effective (96% yield, 82%
ee, entry 6).[12] Further solvent screening indicated that CHCl3
can slightly improve the enantioselectivity (entry 7). The use
[*] Dr. Z. Wang, Y. F. Wong, Prof. J. Sun
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong SAR (China)
E-mail: sunjw@ust.hk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506701.
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Table 1: Reaction optimization.[a]
Entry
Cat.
Solvent
Yield [%][b]
4a
ee [%][b]
3a
1
2
3
4
5
(R)-A1
(R)-A2
(R)-B1
(S)-C1
(S)-C2
(S)-C3
(S)-C3
(S)-C3
(S)-C3
(S)-C3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
91
96
94
58
91
96
96
21
95
94
8
3
5
28
8
4
4
3
4
5
44
48
43
33
76
82
86
92
92
95
6
7
8[c,d]
9[d,e]
10[e,f]
Scheme 2. Reaction scope. [a] Reaction conditions: 1 (0.2 mmol), 2
(0.4 mmol), 3 Š M.S. (40 mg), solvent (2.0 mL). Yield of isolated
product is given. [b] Run at 508C with 10 mol% of (S)-C3. [c] Run for
72 h. [d] Run at RT. TBS=tert-butyldimethylsilyl.
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), solvent
1
(1.0 mL). [b] Yield was determined by H NMR analysis of the crude
reaction mixture using CH2Br2 as an internal standard. The ee value was
determined by HPLC. [c] Run with 4 Š molecular sieves (M.S.; 20 mg).
[d] Run for 24 h. [e] Run with 3 Š molecular sieves (20 mg). [f] Run at 08C
for 48 h.
can be transformed into 3a. The rapid dehydration was also
confirmed in the absence of 2a [Eq. (2)].
of either 3 Š or 4 Š molecular sieves as an additive further
enhanced the enantioselectivity, but the latter significantly
slows down the reaction (entries 8 and 9). Finally, the reaction
proceeded with both excellent efficiency and enantioselectiv-
ity at 08C.
The optimal reaction conditions are applicable to a wide
range of substrates (Scheme 2; 3a–s). They all smoothly
À
participated in the efficient C C bond-forming process.
Inspired by these results, we further confirmed that the
styrenes 4 are also competent substrates (Scheme 3). They
can achieve equally high enantioselectivity in the asymmetric
Notably, various substituents at different positions on the
substrates were tolerated. This excellent generality benefits
largely from the compatible in situ formation of the unstable
p-QMs. In addition to a d-methyl group, larger alkyl groups in
both acyclic and cyclic contexts do not affect the efficiency
(3q–s). Other substituted pyrroles are also good nucleophiles
(3t–w). The mild reaction conditions are compatible with
various functional groups, such as silyl-protected alcohols,
ethers, thioethers, alkenes, and alkynes. A gram-scale syn-
thesis of 3a, with the same protocol, also worked comparably
well. Notably, the remote stereocontrol in establishing these
acyclic all-carbon quaternary stereocenters is remarkable.[8,9]
To understand the competing dehydration process (for-
mation of 4a), the reaction progress was carefully monitored
by 1H NMR spectroscopy [Eq. (1)]. It was found that the
reaction of 1a and 2a in CDCl3 reached complete conversion
within 30 minutes to form a mixture of 3a and 4a. The ratio of
3a/4a gradually increased over time, thus indicating that 4a
À
C C bond-formation process, and is consistent with the
involvement of common intermediates. However, the reac-
Scheme 3. Reaction with styrene-type substrates. [a] Reaction condi-
tions: 4 (0.2 mmol), 2a (0.4 mmol), 3 Š M.S. (40 mg), solvent
(2.0 mL). Yield of isolated product is given. [b] Low but clean
conversion (ca. 60%). [c] Run at RT.
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tions of 4 proceed more slowly than those of the correspond-
ing tertiary alcohols 1. The long reaction time required with
1 is indeed to consume the rapidly in situ generated styrenes
4.
To further expand the utility of our process, 4,7-dihydro-
indole (2 f) was also employed as a nucleophile to synthesize
the triarylethane 5 with high efficiency and enantiosel-
ectivity [Eq. (3); DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone]. After simple protection and oxidation, it can be
easily transformed into the highly enantioenriched 2-substi-
tuted indole 6.[13] Indole can also serve as a nucleophile to
form the 3-subsituted product 7 in good yield, but with low
enantioselectivity [Eq. (4)]. However, further optimization,
inspired by our preliminary results, identified C1 to be
superior,[7i] thus furnishing the desired product with excellent
efficiency and enantioselectivity at room temperature.
Scheme 4. Proposed mechanism and transition state.
only one catalyst molecule responsible for the bifunctional
activation of both substrates. In the TS, the larger d substitu-
ent is oriented towards the back to minimize steric repulsion
with the top-front anthryl substituent, and is in agreement
with the observed product stereochemistry.
In the above mechanism, the styrene 4a can be formed as
a byproduct via IM-1 by E1 elimination (Scheme 4). Since 4a
À
is a reactive substrate, we also studied the kinetics of this C C
We carried out some control experiments to gain further
insights into the mechanism. The methyl-protected substrate
1a’ is not reactive [Eq. (5)], thus suggesting that successful
formation of the p-QM intermediate is key to the process.
Furthermore, the N-protected pyrrole 2a’ is not reactive
bond-forming process. The reaction is first-order in catalyst
(see the Supporting Information for details). Furthermore,
the deuterated styrene 4a’ was subjected to the standard
reaction conditions. No deuterium content loss on the product
methyl group was observed [Eq. (7)], thus suggesting that the
protonation step is irreversible and might be rate-limiting.[14]
Indeed, these results are consistent with the observed slow
reaction rate with 4 (vs. 1) because protonation of 4 has
a relatively high barrier.
À
either, thus indicating the important role of the N H moiety,
presumably as a hydrogen bond donor [Eq. (6)].
A possible mechanism is proposed in Scheme 4 using 1a
as the representative substrate. Initial protonation of the
tertiary alcohol followed by H2O extrusion forms the ion pair
IM-1. Next, the phosphate anion may approach the phenolic
proton to form the activated p-QM IM-2. Subsequent
nucleophilic 1,6-conjugate addition takes places to complete
the process. We also proposed the stereodetermining tran-
sition state TS, in which the phosphoryl oxygen atom interacts
In conclusion, we have developed a new general and mild
catalytic asymmetric 1,6-conjugate addition process of p-
QMs. It represents not only a new member of the small family
of asymmetric reactions of p-QMs, but also the first of such
processes with general scope enabling efficient and mild
formation of all-carbon quaternary stereocenters. Benefiting
from the in situ formation of p-QMs, our process does not
À
with the nucleophile N H through hydrogen bonding. We did
not observe obvious nonlinear effects, which is consistent with
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Acknowledgements
Financial support was provided by HKUST, Hong Kong RGC
(GRF 604513, ECS605812, and M-HKUST607/12).
Keywords: asymmetric catalysis · heterocycles ·
nucleophilic addition · organocatalysis · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13711–13714
Angew. Chem. 2015, 127, 13915–13918
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Received: July 20, 2015
Published online: September 22, 2015
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