Bifunctional amino sulfonamide-catalyzed asymmetric conjugate addition to alkenyl alkynyl ketimines as enone surrogates

Article abstract of DOI:10.1039/d0cc07842e

A bifunctional amino sulfonamide-catalyzed asymmetric conjugate addition of aldehydes to alkenyl alkynyl ketimines as reactive surrogates for enones has been developed. Use of a phenylcyclopropane-based amino sulfonamide catalyst, which can activate and orient the ketimines through hydrogen bonding, affords the desired conjugate adducts with high chemo-, diastereo- and enantioselectivity.

Full text of DOI:10.1039/d0cc07842e

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Bifunctional amino sulfonamide-catalyzed
asymmetric conjugate addition to alkenyl alkynyl
ketimines as enone surrogates†
Cite this: Chem. Commun., 2021,
57, 2808
Received 2nd December 2020,
Accepted 9th February 2021
bc
Chihiro Homma,a Taichi Kano *a and Keiji Maruoka
*
DOI: 10.1039/d0cc07842e
rsc.li/chemcomm
A bifunctional amino sulfonamide-catalyzed asymmetric conjugate conjugate addition of an aldehyde to the a,b-unsaturated
addition of aldehydes to alkenyl alkynyl ketimines as reactive surrogates ketimine bearing an alkyl group (methyl group) on the imine
for enones has been developed. Use of a phenylcyclopropane-based carbon does not proceed in the presence of an amine catalyst
amino sulfonamide catalyst, which can activate and orient the keti- and an acid co-catalyst (Fig. 1c, top).7 To increase the reactivity
mines through hydrogen bonding, affords the desired conjugate of the ketimines, we became interested in replacing the alkyl
adducts with high chemo-, diastereo- and enantioselectivity.
group of ketimines with an alkynyl group (Fig. 1c, bottom).
Alkynyl ketimines exist as Z isomers.8 Unlike enones with two
The catalytic asymmetric conjugate addition of carbon nucleo- lone pairs or an E/Z mixture of ketimines, such Z-ketimines are
philes to electron-deficient alkenes is one of the most funda-
mental and reliable C–C bond-forming reactions in synthetic
organic chemistry.1 In the area of organocatalysis, a large
number of chiral amine-catalyzed conjugate addition reactions
of aldehydes to various electron-deficient alkenes have been
developed to date.2 Reactive enones bearing an additional
electron-withdrawing group or no b-substituent have been
successfully employed in the chiral amine-catalyzed conjugate
addition of aldehydes.3 On the other hand, the use of less
reactive b-substituted enones remains a challenge due to their
low electrophilicity (Fig. 1a).4 One approach to enhance the
reactivity of the enone is in situ generation of an iminium
intermediate from the enone and an amine catalyst.5,6 How-
ever, the formation of the iminium intermediate from the
enone is much slower compared to that from an enal and
requires longer reaction times or higher temperatures. To
overcome these problems, we focused on the application of
a,b-unsaturated ketimines that can be easily activated as elec-
trophile by a Brønsted acid (Fig. 1b). These ketimines can be
considered synthetic equivalents of less reactive enones, since
the resulting conjugate adducts can be converted to the corres-
ponding ketones by hydrolysis. However, it is known that the
a Department of Chemistry, Graduate School of Science, Kyoto University,
Sakyo, Kyoto 606-8502, Japan. E-mail: kano@kuchem.kyoto-u.ac.jp
b Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501,
Japan. E-mail: maruoka.keiji.4w@kyoto-u.ac.jp
c School of Chemical Engineering and Light Industry, Guangdong University of
Technology, Guangzhou 510006, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0cc07842e
Fig. 1 Asymmetric conjugate addition of aldehydes to enones or ketimines.
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Table 1 Asymmetric conjugate addition to alkenyl alkynyl ketiminesa
suitable for high stereoinduction through highly directional
catalyst–substrate interaction. Additionally, the use of an amine
catalyst with an acidic functionality, which directs and activates
the Z-ketimines, might promote the conjugate addition. Herein,
we report the bifunctional amino sulfonamide-catalyzed asymmetric
conjugate addition of aldehydes to alkenyl alkynyl ketimines. Use of
the phenylcyclopropane-based amine catalyst with an acidic func-
tionality was critical to obtain the desired conjugate adducts in high
yields with high chemo-, diastereo- and enantioselectivities.
Amine catalysts can also promote undesired Mannich
reaction9,10 and aza-Diels–Alder reaction.7,11 To obtain the conju-
gate adduct predominantly, we first examined several chiral amine
catalysts in the reaction of propanal with N-Boc-protected ketimine
1a (Table 1). While the conjugate adduct can be isolated as an
aldehyde (for details, see the ESI†), the product was treated with
sodium borohydride in situ and was converted into the corres-
ponding alcohol to facilitate its isolation and determine the
enantiomeric excess. With 2 mol% of proline catalyst, the Mannich
adduct 3 (PG = Boc) was obtained exclusively (entry 1). On the other
hand, the reaction using the amine catalyst (S)-412 with no acidic
functionality gave the desired conjugate adduct 2a in low yield,
albeit with high diastereo- and enantioselectivity (entry 2). Next, the
reactions catalyzed by an amine catalyst with an acidic functionality
were examined. Chiral pyrrolidine-based catalyst (S)-513 possessing
a triflamide group promoted neither the conjugate addition nor
the Mannich reaction (entry 3). When the binaphthyl-based amine
(S)-614 having a distal acid functionality was used as catalyst, the
conjugate adduct 2a was obtained in high yield along with a
small amount of the Mannich adduct 3 (entry 4). The use of
phenylcyclopropane-based amino sulfonamide catalyst (S,R)-7,15
which behaves similarly to (S)-6,16 afforded the desired conjugate
adduct 2a in excellent yield with high diastereo- and enantioselec-
tivity without forming the Mannich product 3 (entry 5). The
reaction of the N-Ts- or N-sulfinyl-protected ketimine afforded
the complex mixture (entries 6 and 7). In the reactions of 1a, the
aza-Diels–Alder product was not observed.
Entry PG
Catalyst
2b (%) syn/antic eed (%) 3b (%)
1
2
3
4
5
6
7
Boc (1a)
L-proline n.d.
(S)-4
(S)-5
(S)-6
(S,R)-7
(S,R)-7
—
420/1
—
420/1
420/1
—
—
99
—
94
94
—
—
62e
n.d.
n.d.
18f
n.d.
Trace
n.d.
Boc
Boc
Boc
Boc
Ts
10
n.d.
73
94
n.d.
n.d.
TolylS(O) (S,R)-7
—
a
The reaction of propanal (0.2 mmol) with 1 (0.1 mmol) was performed
in the presence of a catalyst (0.002 mmol) in CHCl3 (200 mL).
b
Determined by 1H NMR spectroscopy by using an internal standard
technique. Determined by 1H NMR spectroscopy. The ee of the
c
d
major diastereomer was determined by HPLC using a chiral column.
e
f
dr = 2/1 (97/87% ee). dr = 1/1 (14/À85% ee). n.d. = not detected.
TolylS(O) = racemic p-toluenesulfinyl.
To compare the reactivity of the alkenyl alkynyl ketimine with
the corresponding enone, the reaction of an alkynyl-substituted
enone 8 with propanal was examined in the presence of
10 mol% of (S,R)-7; however, the desired conjugate adduct
was not obtained (Scheme 1). This result suggests that converting
enones into the corresponding ketimines is effective in increasing
the electrophilicity of enones in the reaction using a catalyst with
an acid functionality, such as (S,R)-7.
With the optimal reaction conditions, the conjugate addi-
tion of several aldehydes to a,b-unsaturated ketimines 1 was
examined in the presence of (S,R)-7 (Table 2). The reactions
between various aliphatic aldehydes and 1a proceeded to give
the corresponding conjugate adducts in excellent yields with
high diastereo- and enantioselectivities (entries 1–4). Functio-
The utility of this method has been demonstrated by trans-
nalized aldehydes bearing a protected hydroxy or amino group formations of the obtained conjugate adduct. The conjugate
were tolerated under the reaction conditions (entries 5 and 6). adduct syn-2a was converted to the dihydropyran trans-9 as a
The use of
a
TIPS-alkynyl-substituted ketimine afforded ketone equivalent by treatment with BF3ÁOEt2 (Scheme 2). The
the conjugate adduct 2g in good yield with almost perfect dihydropyran trans-10, which can be converted to the corres-
diastereo- and enantioselectivity (entry 7). The reaction of a ponding ketone, was obtained through selective hydrogenation
1-propynyl-substituted ketimine gave the conjugate adduct 2h of trans-9 with RANEYs-Ni. Additionally, the conjugate addi-
with slightly lower enantioselectivity (entry 8). Replacing R2 tion of propanal to N-Boc-protected ketimine 1a and the
(Ph) with a methyl group did not affect the diastereo- and subsequent Wittig reaction gave the corresponding olefin (for
enantioselectivity (entry 9). While the reaction of a ketimine details, see the ESI†).
bearing two alkyl groups (Me and Pr) at both ends proceeded in
The stereochemistry of the obtained adduct was assigned by
low yield, probably due to the low electrophilicity (entry 10), derivatization to the known compound and NOE analysis
increasing the catalyst loading to 4 mol% led to an improved (for details, see the ESI†). Based on the observed stereo-
yield of 2j (entry 11). In all cases examined, neither Mannich chemistry, a transition state model TS2 is proposed as shown
adducts nor aza-Diels–Alder products were observed.
in Fig. 2. We have previously reported that (S,R)-7 promotes the
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Table 2 Asymmetric conjugate addition to alkenyl alkynyl ketimines
catalyzed by (S,R)-7a
Yieldb (%)
syn/antic eed (%)
Entry R1
R2 R3
1
2
3
4
5
6
7
8
Me
Bu
Bn
i-Pr
Ph Ph
Ph Ph
Ph Ph
Ph Ph
Ph Ph
2a
2b
2c
2d
2e
2f
94
99
99
99
88
61
78
91
58
37
86
420/1
420/1
420/1
420/1
420/1
420/1
420/1
420/1
420/1
420/1
420/1
94
93
90
93
98
94
99
86
96
89
89
(CH2)2OBn
(CH2)2NHCOCF3 Ph Ph
Me
Me
Me
Me
Me
Ph TIPS 2g
Ph Me
Me Ph
Me Pr
Me Pr
2h
2i
2j
2j
Fig. 2 Proposed transition state models.
9
10
11e
a
The reaction of an aldehyde (0.2 mmol) with 1 (0.1 mmol) was
performed in the presence of (S,R)-7 (0.002 mmol) in CHCl3 (200 mL)
b
c
for 10
h at room temperature. Isolated yield. Determined by
1H NMR spectroscopy. The ee of the major diastereomer was deter-
d
e
mined by HPLC using a chiral column. Use of 4 mol% of (S,R)-7.
TIPS = triisopropylsilyl.
Fig. 3 X-ray crystal structures of (S,R)-7ÁHCl salt and (S)-6ÁHCl salt
(Cl atoms are omitted for clarity).15,17
Scheme 1 Attempted reaction of enone 8 with propanal.
closer to the Boc-group of the Z-ketimine than that of (S)-6 in
Mannich reaction of aldehydes with Z-ketimines having an TS1 and this steric repulsion could be one of the reasons for the
alkyl group on the imine carbon via TS1.16 In the case of the high chemoselectivity. It should be noted that the geometrically
a,b-unsaturated Z-ketimine, on the other hand, the conjugate controlled Z-ketimine also plays an important role in control of
addition proceeds via TS2. The reaction between the enamine the relative positions of the ketimine and the enamine inter-
and the a,b-unsaturated Z-ketimine, which is activated and mediate and acceleration of the conjugate addition.
oriented by the catalyst acidic proton, favors the conjugate
In summary, an asymmetric conjugate addition of aldehydes
addition over the Mannich reaction due to the less steric to alkenyl alkynyl ketimines as synthetic equivalents of less
repulsion between the enamine intermediate and the ketimine. reactive enones was realized by utilizing the unique property of
The X-ray crystal structures of (S,R)-7ÁHCl salt and (S)-6ÁHCl salt the phenylcyclopropane-based amino sulfonamide (S,R)-7. Use
clearly show that the phenylcyclopropane-based catalyst (S,R)-7 of the alkynyl-substituted ketimines and the bifunctional
is sterically more congested than the binaphthyl-base catalyst amino sulfonamide catalyst is the key to the success of
(S)-6 which affords the Mannich adduct as byproduct this conjugate addition. We believe that the present method
(Fig. 3).15,17 The pseudo-axial a-hydrogen atom of (S,R)-7 is provides an alternative means of activating less reactive enones.
This work was supported by by JSPS KAKENHI Grant Numbers
JP26220803, JP18H01975 and JP20H04815 (Hybrid Catalysis).
Conflicts of interest
The authors declare no conflict of interest.
Notes and references
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Scheme 2 Transformations of the conjugate adduct syn-2a.
2810 | Chem. Commun., 2021, 57, 2808À2811
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