Catalyst-Controlled, Enantioselective, and Diastereodivergent Conjugate Addition of Aldehydes to Electron-Deficient Olefins

Article abstract of DOI:10.1002/anie.201705546

A chiral-amine-catalyzed enantioselective and diastereodivergent method for aldehyde addition to electron-deficient olefins is presented. Hydrogen bonding was used as a control element to achieve unusual anti selectivity, which was further elucidated through mechanistic and computational studies.

Full text of DOI:10.1002/anie.201705546

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Title: Catalyst-Controlled, Enantioselective and Diastereodivergent
Conjugate Addition of Aldehydes to Electron-Deficient Olefins
Authors: Jennifer Kan, Hiroki Maruyama, Matsujiro Akakura, Taichi
Kano, and Keiji Maruoka
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705546
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10.1002/anie.201705546
Angewandte Chemie International Edition
COMMUNICATION
Catalyst-Controlled, Enantioselective and Diastereodivergent
Conjugate Addition of Aldehydes to Electron-Deficient Olefins
S. B. Jennifer Kan[a], Hiroki Maruyama[a], Matsujiro Akakura[b], Taichi Kano*[a] and Keiji Maruoka*[a]
Abstract:
A
chiral amine-catalyzed, enantioselective and
using either specific (Z)-olefins as acceptors (TS2),5 or
siloxyacetaldehydes as nucleophiles which form (Z)-enamines in
the presence of a primary amine catalyst (TS3).6 On the other
hand, examples of catalyst-controlled anti-selective conjugate
addition between simple aldehydes and (E)-alkenes are scarce
and limited in scope.7,8 We postulated that a conceptually different
approach to achieving anti-selectivity could be through TS5
(Scheme 1B), wherein a suitably positioned hydrogen bond donor
is engineered to the amine catalyst to stabilize an otherwise high
energy transition state TS4.9 We were pleased that incorporating
this logic into the design of axially chiral biaryl-based amine
catalyst10 transformed parent catalyst (S)-1, which preferentially
give syn-products in the conjugate addition of aldehydes to
enones,11 into (S)-2,12 a catalyst capable of delivering anti-product
4a in 2.8/1 dr and excellent enantioselectivity (96% ee) (Scheme
2).
diastereodivergent method for aldehyde addition to electron deficient
olefins is presented. Hydrogen bonding was used as a control element
to achieve unusual anti-selectivity, which was further elucidated
through mechanistic and computational studies.
Catalyst-controlled enantio- and diastereoselective reactions are
valuable tools in asymmetric synthesis as chiral molecules
possessing two or more stereocenters can be prepared in a single
step. Ideally, given
a set of reactants, access to any
stereochemical permutations of the product could be achieved
both predictably and selectively. While enantiomers can be
synthesized by choosing the appropriate enantiomeric form of a
chiral catalyst, preparing any diastereomer at will is substantially
more difficult as the inherent diastereomeric bias of the
substrate(s) need to be harnessed or overcome depending on the
need.1 This challenge has been addressed by changing the
reaction solvents or additives, employing a combination of
catalysts in tandem or cooperatively, or by using distinct catalysts
that have complementary selectivity preferences.1 On the other
hand, chiral small-molecule catalysts have seldom been rationally
engineered to switch diastereomeric specificities.2 This is in
contrast
to
how
enzymes
achieve
complementary
diastereocontrol in biocatalytic reactions, which can be attained
through single amino acid mutations in the active site.3
We describe herein our studies on engineering chiral amine
catalysts for diastereodivergent, asymmetric reactions;
specifically, we present our findings in the context of conjugate
addition of aldehydes to electron-deficient olefins. Catalytic
asymmetric conjugate addition of carbon nucleophiles to electron-
deficient alkenes is a fundamental carbon-carbon bond forming
reaction in synthetic chemistry. The use of aldehydes as
nucleophiles in this reaction is made possible through enamine
formation in the presence of a chiral amine catalyst. The vast
majority of these amine-catalyzed transformations involve
reaction between an (E)-enamine intermediate and an (E)-olefin
to give syn-conjugate adduct as the major diastereomer. The
selectivity of this process is governed by an acyclic synclinal
transition state, wherein minimal steric strain and close proximity
between the enamine nitrogen and the electron-withdrawing
group of the Michael acceptor are favored (TS1, Scheme 1A).4 To
reverse the stereochemical preference of this reaction to favor the
anti-adduct, substrate control has previously been exploited,
Scheme 1. Stereoselective conjugate addition of aldehydes to electron-
deficient olefins via enamine catalysis.
With lead catalysts (S)-1 and (S)-2 in hand, we then set out
to optimize the reactions (Scheme 3). Conjugate addition of
propanal to enone 3a under the influence of an appropriate amine
catalyst gave the Michael-adduct, which underwent (E)-selective
olefination to give 5a. Modification of the syn-catalyst backbone
led to the identification of (S)-7 as the optimal catalyst, which
performed best in toluene. Optimization of the anti-selective
reaction revealed that catalyst (S)-8, which possessed
hydroxydiphenylmethyl groups similar to (S)-2 but owned a biaryl
backbone that is more electron rich and smaller in dihedral angle,
was more reactive and exhibited moderate anti-selectivities at low
temperatures. The reaction catalyzed by (S)-8 was anti-selective
[a]
Dr. S. B. J. Kan, H. Maruyama, Prof. Dr. T. Kano, Prof. Dr. K.
Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
Prof. Dr. M. Akakura
[b]
Department of Chemistry
Aichi University of Education, Igaya-cho, Kariya, Aichi 448-8542
(Japan)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201705546
Angewandte Chemie International Edition
COMMUNICATION
was observed despite moderate anti-selectivities and the
enantioselectivities were uniformly excellent. The reaction with
enal was chemoselective, yielding anti-5n in 72% yield and good
selectivities. In both syn- and anti-selective reactions, reduced
catalyst loading (5 mol%) was tolerated (syn- and anti-5a).
Interestingly, (Z)-olefins could also be used for this chemistry as
they undergo catalyst-mediated (Z) to (E) isomerisation in situ,
yielding products of similar selectivities to those prepared from
(E)-3.13 The absolute configuration of the products was assigned
by derivatization to known compounds.13
The syn- and anti-conjugate adducts are versatile building
blocks for generating skeletal and stereochemical diversity. For
example, reductive amination of syn-4a provided access for
piperidine 11 bearing three non-contiguous stereocenters in 86%
yield with good diastereoselectivity (Scheme 4). On the other
hand, a reduction-lactonization sequence could be used to
transform anti-4a to γ-lactone 12.
Scheme 2. Switching the diastereomeric specificity of axially chiral amine
catalyst.
in all solvents examined, regardless of the polarity and hydrogen
bonding ability of the solvents.13 Other pyrrolidine-based catalysts
gave either no desired product ((S)-9 and (S,S)-10) or only trace
amount of the syn-adduct (L-proline).
Scheme 4. Synthesis of Piperidine 11 and γ-Lactone 12 from syn and anti-4a.
To account for the selectivities of the conjugate addition
reaction, mechanistic and computational studies were carried out.
Retro-conjugate addition was found not to be in operation under
the reaction conditions, as crossover experiment did not yield any
scrambled product (Scheme 5A). Epimerization studies
suggested that while the anti-selective catalyst (S)-8 could
epimerize the aldehyde α-chiral center, this process could not
shift the equilibrium to favor anti-4a as the major diastereomer
(Scheme 5B). Taken together, these observations indicate that
the anti-selectivity observed in conjugate addition most likely
originated from the carbon-carbon bond formation step. Variants
of catalyst (S)-8 were next employed to probe the role of the
hydroxydiarylmethyl groups in directing anti-selectivity.
Interestingly, while des-hydroxy catalyst (S)-14 and bis-O-methyl-
protected catalyst (S)-15 were both inactive, catalyst (S)-16 with
only one of the two alcohol moieties methylated was able to
deliver the anti-product in 95% ee, albeit at a slower rate
compared to its diol counterpart (Scheme 5C).15
DFT calculations for the (S)-8 catalyzed reaction between
propanal and enone 3a was performed at the B3LYP/6-31G(d)
level. This confirmed that the anti-selective reaction pathway is
indeed more favorable than its syn-counterpart,13 and that at least
one hydrogen bonding interaction between the enone carbonyl
oxygen and the alcohol moiety of catalyst (S)-8 is present in the
lowest lying anti-transition states (TS6 and TS7, Figure 1).13 This
spatial arrangement dictates the facial selectivity of the
electrophile, while at the same time renders the enamine Re-face
Scheme 3. Selected optimization studies of syn- and anti-selective conjugate
addition.
With these procedures in hand, the reaction scope was
investigated (Table 1). The syn-selective reaction catalyzed by
(S)-7 generally proceeded cleanly and competing self-aldol was
not observed (condition A). The reaction accommodated a broad
range of aldehydes (syn-5a−5e) and electron deficient olefins
(syn-5f−5m). Unsymmetrical ketones preferentially react at the
site β to the aromatic ketone as expected from the inherent kinetic
regioselectivity of the substrate. Reaction with enal provided
conjugate adduct (syn-5n) exclusively in 84% yield and 89% ee.14
The current protocol is not compatible with less reactive acrylate
and thio-acrylate (syn-5o and 5p). The anti-selective reaction
catalyzed by (S)-8 was explored using some of the same set of
reactants (condition B). In all cases, diastereoselectivity switch
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10.1002/anie.201705546
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COMMUNICATION
Table 1. Scope of syn- and anti-selective conjugate addition of aldehydes to electron deficient olefins.[a,b]
[a] Condition A: the reaction between aldehyde (2 equiv) and enone (1 equiv) was carried out in the presence of (S)-7 (10 mol%) in toluene (0.5 M) for 4 to 72 h.
Condition B: the reaction between aldehyde (2 equiv) and enone (1 equiv) was carried out in the presence of (S)-8 (10 mol%) in MeCN-H2O (1:1, 0.25 M) for 6 to
72 h. [b] Combined yield of syn- and anti-5 over 2 steps. Dr determined by 1H NMR. % Ee of the major diastereomer as determined by chiral HPLC. [c] The reaction
was performed on 1 mmol scale using 5 mol% of catalyst. [d] Using 1.5 equiv of aldehyde. [e] Using 1 equiv of aldehyde and 2 equiv of enal. The conjugate addition
adduct was reduced in situ (NaBH4/MeOH) to give the corresponding diol. [f] Reaction performed at 10 °C. [g] Reaction performed at 0 °C. [h] Reaction concentration
was 0.125 M.
more susceptible to react for proximity reason, consistent with the
major (2S,3S)-isomer obtained experimentally. The transition
state of the (S)-7 catalyzed reaction was B3LYP/6-31G(d)
optimized and found to be following a typical acyclic synclinal
Acknowledgements
model (TS8). This is further stabilized by non-bonding interaction
between the catalyst nitrogen atom and the α-carbon of the enone,
as well as hydrogen bonding between the catalyst benzylic proton
and the carbonyl oxygen atom of the electron withdrawing group
Cambridge (for Fellowships to S.B.J.K.), as well as the Research
at the β-position of the enone. The latter non-classical interaction
is reminiscent of that found between ammonium salts and
carbonyl compounds.16
This work was supported by a Grant-in-Aid for Scientific Research
from MEXT, Japan. We thank the Japan Society for the Promotion
of Science and Gonville and Caius College, University of
Center for Computational Science, Okazaki (Japan) for the use of
their facility in our computational studies.
We have identified two complementary catalysts suitable for
the enantioselective and diastereodivergent conjugate addition of
Keywords: stereodivergence • Michael addition • asymmetric
catalysis • aldehydes • organocatalysis
aldehydes to electron-deficient olefins. Hydrogen bonding was
used as a control element to achieve unusual anti-selectivity,
which was further elucidated through mechanistic and
computational studies. Despite moderate anti-selectivity and
limited substrate scope at this stage, the present approach
showed potential for obtaining unusual stereoisomers.
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10.1002/anie.201705546
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Entry for the Table of Contents (Please choose one layout)
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S. B. Jennifer Kan, Hiroki Maruyama,
Matsujiro Akakura, Taichi Kano*, Keiji
Maruoka*
Page No. – Page No.
Catalyst-Controlled, Enantioselective
and Diastereodivergent Conjugate
Addition of Aldehydes to Electron-
Deficient Olefins
Diastereoswitch: A chiral amine-catalyzed, enantioselective and diastereodivergent
method for aldehyde addition to electron deficient olefins is presented. Hydrogen
bonding was used as a control element to achieve unusual anti-selectivity, which was
further elucidated through mechanistic and computational studies.
This article is protected by copyright. All rights reserved.