Construction of chiral α-tert-amine scaffoldsviaamine-catalyzed asymmetric Mannich reactions of alkyl-substituted ketimines

Article abstract of DOI:10.1039/d0sc05269h

Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine moiety. However, the structural variation of the ketimines is limited due to the formation of inseparableE/Zisomers, low reactivity, and other synthetic difficulties. In this study, a highly diastereodivergent synthesis of hitherto difficult-to-access β-amino aldehydes that bear a chiral α-tert-amine moiety was achieved using the amine-catalyzed Mannich reactions of aldehydes with less-activatedZ-ketimines that bear both alkyl and alkynyl groups.

Full text of DOI:10.1039/d0sc05269h

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DOI: 10.1039/D0SC05269H
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Construction of Chiral α-tert-Amine Scaffolds via Amine-catalyzed
Asymmetric Mannich Reactions of Alkyl-substituted Ketimines
Chihiro Homma,a Aika Takeshima,a Taichi Kano*a and Keiji Maruoka*b,c
Received 00th January 20xx,
Accepted 00th January 20xx
Stereoselective Mannich reactions of aldehydes with ketimines provide chiral β-amino aldehydes that bear an α-tert-amine
moiety. However, the structural variation of the ketimines is limited due to the formation of inseparable E/Z isomers, low
reactivity, and other synthetic difficulties. In this study, a highly diastereodivergent synthesis of hitherto difficult-to-access
β-amino aldehydes that bear a chiral α-tert-amine moiety was achieved using the amine-catalyzed Mannich reactions of
aldehydes with less-activated Z-ketimines that bear both alkyl and alkynyl groups.
DOI: 10.1039/x0xx00000x
reactive ketimines. We thus became interested in developing a
catalytic asymmetric Mannich reaction using both alkyl and
alkynyl-substituted ketimines under mild conditions.
Introduction
The asymmetric Mannich reaction is one of the most basic and
useful methods for the synthesis of chiral β-amino carbonyl
compounds,1 which are fundamental and frequent motifs in
bioactive compounds, as well as versatile building blocks for the
synthesis of structurally complex molecules.2 In particular, the
use of ketimines provides an efficient access to β-amino
carbonyl compounds that bear an α-tert-amine moiety, and a
wide variety of Mannich reactions with ketimines have been
developed to date.3-8 During the face-selective nucleophilic
addition to ketimines, the geometry of the N-substituent of the
ketimine significantly affects the enantioselectivity because the
chiral catalyst interacts with the N-substituent or the lone pair
of the imine nitrogen atom. Therefore, dialkyl-substituted
ketimines, which exist as an inseparable mixture of nearly equal
amounts of the E- and Z-ketimine,9 are rarely used in
asymmetric synthesis compared to ketimines that exist as single
geometric isomers.3-7
Recently, we found that the Z isomer of ketimines can be
obtained selectively by replacing one alkyl substituent with a
less sterically hindered alkynyl group.10 This type of ketimine
can be considered a synthetic equivalent of the dialkyl-
substituted ketimine, since the alkynyl group can be converted
to an alkyl group by simple hydrogenation. Via the introduction
of a chiral auxiliary to the alkynyl-substituted ketimines, the
asymmetric synthesis of α-tert-amine derivatives has been
realized (Scheme 1a).11 However, stoichiometric quantities of
the chiral auxiliary are required, as well as highly reactive
reagents to achieve the nucleophilic addition to the less-
a) Asymmetric synthesis of dialkyl-substituted α-tert-amines
Aux*
Aux*
R" NH
Aux*
Pd/C
H2
N
R" NH
Me3Al;
R"Li
(Z)
R'
R'
R'
O
R
R
R
Aux* =
S
t-Bu
b) Asymmetric Mannich reactions of alkynyl-substituted ketimines
O
1) Trost
O
OR
HN RF
R"
N
OR
cat. [Zn]*
(E)
+
O
RF
R''
O
R'
R'
O
R'
R'
O
2) Shao
O
Boc
HN CO2Et
Boc
(E)
amine
catalyst
N
O
+
EtO2C
R"
R"
activated ketimines
(no α-proton)
c) Problems of N-Boc-protected alkyl-substituted ketimines
Boc
Boc
O
N
HN
(Z)
R'
R'
R'
enecarbamates
1
R
R
R
less activated
ketimines
(no synthetic example)
Scheme 1 Alkynyl-substituted ketimines for asymmetric reactions.
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 Science and Graduate School of Pharmaceutical Sciences,
Kyoto University, Kyoto 606-8502, 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
Some alkynyl-substituted ketimines have been used for
asymmetric reactions12 including Mannich reactions, although
the applicable ketimines are limited to those activated by an
electron-withdrawing perfluoroalkyl or ester group (Scheme
†
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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1b).8 To the best of our knowledge, examples of catalytic
asymmetric reactions of alkynyl-substituted ketimines that bear
an electron-donating alkyl group on the imine carbon have not
yet been reported. This can be attributed in part to the limited
number of available alkyl- and alkynyl-substituted ketimines11,13
and difficulties associated with their synthesis. For example, N-
Boc-protected ketimines 1 cannot be synthesized from the
corresponding ketones (Scheme 1c, left). Furthermore, unlike
ketimines that bear a perfluoroalkyl or ester group, alkyl-
substituted ketimines 1 can isomerize to the corresponding
enecarbamates due to the presence of the ketimine α-protons
(Scheme 1c, right). Herein, we report amine-catalyzed
asymmetric Mannich reactions of less-activated alkyl- and
alkynyl-substituted ketimines.14 The use of newly synthesized
N-Boc-protected ketimines 1 and appropriate amine catalysts
provides an effective solution to the aforementioned problems.
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PG
PG
DOI: 10.1039/D0SC05269H
N
O
HO
L-proline
(20 mol%) (excess)
NaBH4
HN Pent
+
Pent
MeCN
rt, 24 h
MeOH
0 ºC, 1 h
Me
Bn
(1 eq.)
Bn
Me
(
anti
)
(2 eq.)
PG = p-TolylS(O), Ts : not detected
PG = Boc (2a)
: 19%, dr = >20/1, 97% ee
Scheme 2 Amine-catalyzed asymmetric Mannich reaction of Z-ketimines.
a)
Boc
Boc
Li
(1.1–1.5 eq.)
R3
N
N
R2
N
R2
N
THF
R3
–78 ºC or –40 ºC, 3 h
44–99% yield
b)
BuLi (1.1 eq.)
THF
–60 ºC or –78 ºC, 10 min;
Boc
Boc
N
HN
R2
R2
Cl
t-Bu
Results and discussion
S
N
R3
R3
Our initial investigation focused on the installation of a
protecting group on the alkyl- and alkynyl-substituted ketimines
to facilitate their amine-catalyzed Mannich reaction with an
aldehyde (Scheme 2). The resulting product was treated in situ
with sodium borohydride and converted into the corresponding
alcohol to facilitate its isolation and avoid product
decomposition. First, the Mannich reaction of an N-sulfinyl-
protected ketimine, which was prepared following a known
procedure,11 with 3-phenylpropanal in the presence of L-proline
was examined; however, the desired Mannich adduct was not
obtained probably due to the low reactivity of the ketimine.
Next, an N-Ts-protected ketimine, which was synthesized by the
oxidation of the N-sulfinyl-ketimine (for details, see the ESI),
was used in the Mannich reaction. Although this ketimine is
considered to be more reactive than the N-sulfinyl-ketimine,
the desired product was not observed, probably due to the
deactivation of the catalyst through its addition to the ketimine.
We then decided to use a ketimine activated by a Boc protecting
group. However, the N-Boc-protected ketimine was
unfortunately not accessible via common approaches, such as
dehydrative condensation11,13d or an aza-Wittig reaction with
the corresponding ketone.8 This may be due to the instability of
N-Boc-ketimines at high reaction temperatures.15 In seeking to
develop new methods for the synthesis of such ketimines, we
found that the nucleophilic substitution of amidines that bear a
benzimidazole moiety with organolithium reagents could
provide the desired ketimines at low temperature (Scheme 3a).
We also found that these Z-ketimines could be prepared by the
oxidation of N-Boc-protected amines (Scheme 3b).16 The
Mannich reaction of the thus obtained ketimine furnished the
desired adduct 2a with high diastereo- and enantioselectivity,
albeit in low yield due to undesired side reactions such as
homoaldol condensation, hydrolysis of the ketimine and
isomerization to the enecarbamate.
(1.5 eq.)
Ph
32–54% yield
–60 ºC or –78 ºC, 1 h
Scheme 3 Synthesis of N-Boc-protected Z-ketimines.
Table 1 Asymmetric Mannich reaction of 3-phenylpropanal with 1a.a
Boc
Boc
O
N
HO
HN Pent
1. catalyst
solvent
+
Pent
2. NaBH4
MeOH
Bn
Me
Bn
Me
1a
2a
Entry
Catalyst (mol%) Solvent
Yield (%)b anti/sync
ee (%)d
97
95
97
-
99
99
99
98
1
2
3
4
5
6
7e
8e
9e,f
L-proline (20)
L-proline (20)
L-proline (20)
(S)-3 (20)
(S)-4 (20)
(S,R)-5 (20)
(S)-6 (10)
MeCN
DMSO
CHCl3
CHCl3
CHCl3
CHCl3
MeCN
MeCN
MeCN
19
37
67
n.d.
45
9
31
33
84
>20/1
>20/1
>20/1
-
10/1
>20/1
1/4
(S,R)-7 (10)
(S,R)-7 (10)
1/6
1/13
99
a Performed using 3-phenylpropanal (0.1 mmol) and 1a (0.2 mmol) in the specified
solvent (100 µL) for 24 h at room temperature. b Isolated yield. c Determined by 1H
NMR spectroscopy. d The ee of the major diastereomer was determined via HPLC
using a chiral column. e Performed for 48 h using 3-phenylpropanal (0.2 mmol) and
1a (0.1 mmol). f Performed at 5 °C. n.d. = not detected.
TBSO
Ph
Ph
OH
(S)-3
O
N
N
N
N
N
H
H
H
HN
N
OH
(S)-4
(S,R)-5
NHTf
N
NHTf
H
N
H
(S)-6
(S,R)-7
2 | J. Name., 2012, 00, 1-3
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Encouraged by this promising result, the reaction conditions the desired adduct with slightly lower anti-selectivity (entry 2).
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were optimized to suppress these side reactions (Table 1). Other alkyl-substituted ketimines (R2 = mDeOthI:y1l0o.1r0i3s9o/bDu0StyCl0)5w26e9rHe
Solvent screening revealed that the Mannich reaction in also applicable to this reaction (entries 7 and 8). Replacing the
chloroform proceeded to give 2a in moderate yield with high R3 (Me) group on Z-ketimine 1a with a butyl, phenyl, or TIPS
anti- and enantioselectivity (entry 3). When diphenylprolinol group, did not affect the anti- and enantioselectivity (entries 9–
(S)-3 was used as the catalyst instead of proline, the reaction did 11).
not proceed (entry 4). This result indicates that the present
Next, we examined the syn-selective Mannich reaction
Mannich reaction requires the activation of the ketimine by a catalyzed by (S,R)-7 (Table 3). The reactions between various
catalyst with an acidic functionality, such as a carboxylic acid. aldehydes and Z-ketimines furnished Mannich products with
Catalyst (S)-4 with a tetrazole moiety, which is a bioisostere of high syn- and enantioselectivity. While the use of aldehydes
carboxylic acid, gave the Mannich adduct in 45% yield with that bear a protected amino group, an isobutyl-substituted
lower anti-selectivity (entry 5). When the TBS-protected ketimine, or a phenylethynyl-substituted ketimine resulted in
hydroxyproline (S)-5 was used to improve the solubility of the poor syn-selectivity (syn/anti = <10/1), lowering the reaction
catalyst, anti-2a was obtained in low yield (entry 6).
temperature increased the syn-selectivity (entries 6, 8, and 10).
We have previously developed the axially chiral amino
sulfonamide catalyst (S)-617 and the chiral phenylcyclopropane-
based amine catalyst (S,R)-7.18 In the Mannich reaction with
aldimines, (S)-6 and (S,R)-7 show a diastereoselectivity opposite
to proline and related catalysts. Fortunately, the binaphthyl-
based amine catalyst (S)-6 promoted the reaction of 3-
phenylpropanal with 1a to preferentially afford syn-2a, albeit
with low syn-selectivity (entry 7). Use of the recently developed
catalyst (S,R)-7 improved the syn-selectivity, although the yield
remained low due to the isomerization and hydrolysis of 1a
(entry 8). Further investigations revealed that 2a was obtained
in good yield with high syn- and enantioselectivity when the
reaction was performed at 5 °C (entry 9).
Table 3 Syn-selective Mannich reaction catalyzed by (S,R)-7.a
Boc
HN R2
Boc
1. (S,R)-7
(10 mol%)
O
N
HO
MeCN
+
R2
NaBH4
MeOH
2.
R3
R1
R1
R3
1
syn-2
Entry R1
R2
R3
Yield (%)b
syn/antic ee (%)d
1
Bn
Me
Bu
Allyl
(CH2)2OBn
Pent
Pent
Pent
Pent
Pent
Me
Me
Me
Me
Me
Me
Me
Me
Bu
2a 84
2b 84
2c 81
2d 77
2e 68
2f 61
2g 63
2h 60
2i 76
2j 71
2k 80
13/1
>20/1
>20/1
>20/1
>20/1
>20/1
10/1
>20/1
16/1
15/1
99
99
99
99
99
99
99
99
98
99
99
2e
3e
4e
5
6e,f
7
8f
9
10f
11
(CH2)2NHCOCF3 Pent
Table 2 Anti-selective Mannich reaction catalyzed by L-proline.a
Bn
Bn
Bn
Bn
Bn
Me
i-Bu
Pent
Pent
Pent
Boc
HN R2
Boc
1. L-proline
(20 mol%)
CHCl3
O
N
HO
Ph
TIPS
+
R2
20/1
NaBH4
MeOH
2.
R3
R1
R1
R3
a Performed using an aldehyde (0.2 mmol) and 1 (0.1 mmol) in MeCN (100 µL) for
48 h at 5 °C. b Isolated yield. c Determined by 1H NMR spectroscopy. d The ee of the
major diastereomer was determined via HPLC using a chiral column. e The ee was
determined after benzoylation. f Performed at 0 °C.
1
anti-2
Entry R1
R2
R3
Yield (%)b anti/sync ee (%)d
1
Bn
Me
Bu
Allyl
(CH2)2OBn
Pent
Pent
Pent
Pent
Pent
Me
Me
Me
Me
Me
Me
Me
Me
Bu
2a 67
2b 49
2c 73
2d 45
2e 45
2f 61
2g 61
2h 64
2i 62
2j 77
2k 42
>20/1
8/1
>20/1
>20/1
>20/1
17/1
97
99
98
99
96
99
98
96
97
99
96
2e
3e
4e
5
Boc
6e
7
8
9
10
11
(CH2)2NHCOCF3 Pent
HO
HN Pent
=
Bn
Bn
Bn
Bn
Bn
Me
13/1
2R
3R
i-Bu
Pent
Pent
Pent
>20/1
>20/1
>20/1
>20/1
Bn
TIPS
Ph
TIPS
syn-2k
a Performed using an aldehyde (0.1 mmol) and 1 (0.2 mmol) in CHCl3 (100 µL) for
24 h at room temperature. b Isolated yield. c Determined by 1H NMR spectroscopy.
d The ee of the major diastereomer was determined via HPLC using a chiral column.
e The ee was determined after benzoylation.
Using the optimal reaction conditions, the anti-selective
Mannich reaction of several aldehydes with Z-ketimines was
examined in the presence of L-proline as the catalyst (Table 2).
Both aliphatic aldehydes and functionalized aldehydes bearing
a protected hydroxy or amino group were tolerated under the
applied reaction conditions (entries 1–6). However, when
propanal was used as the nucleophile, the reaction furnished
Fig. 1 X-ray crystal structure of syn-2k
A structural analysis of syn-2k using X-ray crystallography
provided clear proof that the Mannich reaction catalyzed by
(S,R)-7 gave syn-products with a 2R,3R configuration (Fig. 1).
The absolute configuration of anti-2a, which was obtained from
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the reaction catalyzed by L-proline, was determined to be 2S,3R
by comparison of the HPLC retention times of syn-2a ((2R,3R)-
2a) and the epimer of anti-2a (for details, see the ESI).
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Boc
a)
O
Boc
DOI: 10.1039/D0SC05269H
57% yield
1. L-proline
N
O
HN Pent
(3 steps)
98% ee
+
Pinnick Ox.
TMSCHN2
2.
3.
Pent
Boc
MeO
Based on the absolute configuration of the products, we
would like to propose transition state models TS2 and TS3 (Fig.
2). Since ketimines generally exist in an equilibrium between
the E and Z isomers,19 a reaction of aldehydes with in-situ-
generated E-ketimines might occur. In transition state TS1, the
E-ketimine approaches the s-trans-enamine, wherein the steric
repulsion between the enamine moiety derived from the
aldehyde and the carboxy group derived from L-proline is
minimized, to give (2S,3S)-2. On the other hand, the Mannich
product (2S,3R)-2 is formed from the Z-ketimine via transition
state TS2. An analysis of the observed stereochemistry shows
that the dominant Z-ketimine reacts with the s-trans-enamine
(TS2). In the reaction catalyzed by (S,R)-7, both the s-trans-
enamine and the s-cis-enamine can be formed, as the distal
triflamide of (S,R)-7 does not cause steric repulsion with the
enamine moiety. However, the reaction site of the s-trans-
enamine is too far from the Z-ketimine activated by the
triflimide group, and only the s-cis-enamine can react with the
distant Z-ketimine to give predominantly syn-isomer (2R,3R)-2
(TS3).17,18 A computational study of the Mannich reaction of a
ketimine using proline and a similar catalyst by Fu is consistent
with the proposed transition state models TS2 and TS3.20
Bn
Me
Bn
Me
1a
8
b)
Boc
HO
HO
HN Pent
HN Pent
Pd/C, H2
86% yield
Me
Bn
Me
Bn
anti-2a
9
c)
Boc
Boc
HO
HN Pent
HO
HN Pent
Lindlar cat., H2
69% yield
Bn
Me
Bn
Me
10
anti-2a
Scheme 4 Transformations of the Mannich product anti-2a.
Conclusions
We have developed a diastereodivergent Mannich reaction of
aldehydes with alkyl- and alkynyl-substituted Z-ketimines
catalyzed by L-proline or the chiral phenylcyclopropane-based
amine (S,R)-7. The newly synthesized N-Boc-protected
ketimines, which cannot be accessed via conventional method,
are effective for the present Mannich reaction. Hydrogenation
of the obtained Mannich product provides access to less-
accessible chiral α-tert-amine with two similar carbon chains.
We believe that these results will find a broad range of
applications in organic synthesis, enabling the preparation of
valuable molecules for biological and pharmaceutical research.
O
O
NTf
N
N
H
N
H
H
Boc
R2
Boc
Boc
O
O
N
N
N
R2
R1
R2
R1
R1
TS1
R3
R3
R3
Conflicts of interest
TS2
TS3
There are no conflicts to declare.
Boc
Boc
Boc
HN R2
HN R2
HN R2
O
O
O
2S
3S
2S
3R
2R
3R
Acknowledgements
R1
R3
R1
R3
R1
R3
This work was supported by JSPS KAKENHI grants JP26220803,
JP18H01975 and JP20H04815 (Hybrid Catalysis). The authors
are grateful to Mr. Y. Omatsu for performing X-ray
crystallographic analyses.
(2S,3S)-2 (syn)
(2S,3R)-2 (anti)
(2R,3R)-2 (syn)
Fig. 2 Transition state models for asymmetric Mannich reactions catalyzed by L-proline
(TS2) or (S,R)-7 (TS3)
The synthetic utility of this method has been demonstrated
via the transformation of the obtained Mannich product into
previously less-accessible chiral α-tert-amine derivatives.
Pinnick oxidation of the anti-Mannich product and methylation
with trimethylsilyldiazomethane (TMSCHN2) provided the
Notes and references
1
For review, see: (a) S. Kobayashi and H. Ishitani, Chem. Rev.,
1999, 99, 1069–1094; (b) A. E. Taggi, A. M. Hafez and T. Lectka,
Acc. Chem. Res., 2003, 36, 10–19; (c) A. Córdova, Acc. Chem.
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Barbas III, Acc. Chem. Res., 2004, 37, 580–591; (e) M. M. B.
Marques, Angew. Chem., Int. Ed., 2006, 45, 348–352; (f) S.
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J. C. van Hemert, Chem. Soc. Rev., 2008, 37, 29–41; (j) P.
Melchiorre, M. Marigo, A. Carlone and G. Bartoli, Angew.
Chem., Int. Ed., 2008, 47, 6138–6171; (k) R. Gómez Arrayás
corresponding β-amino ester
8 without affecting the
enantiomeric excess (Scheme 4a). Hydrogenation of anti-2a
gave the chiral γ-amino alcohol derivative 9 with two similar
alkyl groups (propyl and pentyl groups) (Scheme 4b). The chiral
γ-amino alcohol 10, which bears a cis-olefin moiety, was
obtained from the semi-hydrogenation of anti-2a with Lindlar
catalyst (Scheme 4c).
4 | J. Name., 2012, 00, 1-3
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Dixon, Chem. Eur. J., 2018, 24, 17660–D1O76I:6140..1039/D0SC05269H
For representative Mannich reactions with isatin-derived
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6
2
3
For representative Mannich reactions using cyclic ketimines,
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7
For representative Mannich reactions with ketimines bearing
a carbonyl moiety, see: (a) S. Lin, N. Kumagai and M.
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To the best of our knowledge, there are only two examples of
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4
8
9
5
For representative Mannich reactions with non-cyclic
ketimines, see: (a) Y. Suto, M. Kanai and M. Shibasaki, J. Am.
Chem. Soc., 2007, 129, 500–501; (b) R. Yazaki, T. Nitabaru, N.
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reactions using amine catalysts, see: (a) B. List, J. Am. Chem.
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ARTICLE
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DOI: 10.1039/D0SC05269H
15 The reaction between the ketone (1.0 eq.) and N-Boc-imino-
(triphenyl)phosphorene (1.1 eq.) in toluene at 80 °C furnished
only the enecarbamate.
16 To confirm the stereochemistry, ketimine 1, which bears
pentyl and 1-hexynyl groups, was synthesized by a known
method that affords Z-ketimines. Although the ketimine could
not be isolated due to the simultaneous formation of
inseparable byproducts, the observed stereoisomer was
identical to the one prepared using our method. See also: B.
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