A Powerful Chiral Phosphoric Acid Catalyst for Enantioselective Mukaiyama–Mannich Reactions

Article abstract of DOI:10.1002/anie.201603929

A new BINOL-derived chiral phosphoric acid bearing 2,4,6-trimethyl-3,5-dinitrophenyl substituents at the 3,3′-positions was developed. The utility of this chiral phosphoric acid is demonstrated by a highly enantioselective (ee up to >99 %) and diastereoselective (syn/anti up to >99:1) asymmetric Mukaiyama–Mannich reaction of imines with a wide range of ketene silyl acetals. Moreover, this method was successfully applied to the construction of vicinal tertiary and quaternary stereogenic centers with excellent diastereo- and enantioselectivity. Significantly, BINOL-derived N-triflyl phosphoramide constitutes a complementary catalyst system that allows the title reaction to be applied to more challenging imines without an N-(2-hydroxyphenyl) moiety.

Full text of DOI:10.1002/anie.201603929

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201603929
German Edition: DOI: 10.1002/ange.201603929
Asymmetric Catalysis
A Powerful Chiral Phosphoric Acid Catalyst for Enantioselective
Mukaiyama–Mannich Reactions
Fengtao Zhou* and Hisashi Yamamoto*
Abstract: A new BINOL-derived chiral phosphoric acid
bearing 2,4,6-trimethyl-3,5-dinitrophenyl substituents at the
3,3’-positions was developed. The utility of this chiral phos-
phoric acid is demonstrated by a highly enantioselective (ee up
to > 99%) and diastereoselective (syn/anti up to > 99:1)
asymmetric Mukaiyama–Mannich reaction of imines with
a wide range of ketene silyl acetals. Moreover, this method was
successfully applied to the construction of vicinal tertiary and
quaternary stereogenic centers with excellent diastereo- and
enantioselectivity. Significantly, BINOL-derived N-triflyl
phosphoramide constitutes a complementary catalyst system
that allows the title reaction to be applied to more challenging
imines without an N-(2-hydroxyphenyl) moiety.
trimethyl-3,5-dinitrophenyl substituents at the 3,3’-position
(Scheme 1).
B
INOL-derived chiral phosphoric acids, demonstrated
independently by Akiyama[1] and Terada[2] in 2004 to serve
as powerful Brønsted acid catalysts for enantioselective
Mukaiyama–Mannich reactions, have emerged as versatile
catalysts for the enantioselective formation of carbon–carbon
and carbon–heteroatom bonds.[3,4] Chiral phosphoric acids are
recognized to be one of the ideal catalysts for the activation of
basic substrates, including imines and ketimines, through
hydrogen bonding or ion pairing in a bifunctional fashion.[3]
Asymmetric Mukaiyama–Mannich reaction of ketene silyl
acetals with aldimines using a chiral phosphoric acid catalyst
is thus a direct method for the enantioselective preparation of
b-amino acid derivatives.[5,6] Although several phosphoric
acid catalysts have recently been developed for asymmetric
Mukaiyama–Mannich reactions,[7] the selectivity of the reac-
tions is not always exclusive and the development of more
reactive and highly selective chiral Brønsted acid catalysts is
highly desirable.
Scheme 1. Asymmetric Mukaiyama–Mannich reactions catalyzed by
chiral phosphoric acids.
We began our study with the reaction of imine 1a with
ketene silyl acetal 2a and tested various phosphoric acids
(4a–4 f), and the results are shown in Scheme 2. Catalyst 4a
led to a smooth Mukaiyama–Mannich reaction to give 3a in
excellent yield (97%) within 24 h in toluene at À788C.
However, the enantioselectivity (81% ee) was moderate, as
was that of catalyst reported by Akiyama in 2004 (89% ee).[1]
We envisaged replacement of the hydrogen atom in the para
position of the 3,5-dinitrophenyl ring with an alkyl group,
which would force the nitro group out of the plane of the
The nitro group is known to be one of the strongest
electron-withdrawing groups, and can serve as a substituent
on Brønsted acids to enhance their acidity; for example,
introduction of 4-nitrophenyl groups into the 3,3’-positions of
BINOL-derived phosphoric acid improved both the yield and
enantioselectivity of various Mukaiyama–Mannich reac-
tions.[1] Herein, we report a general highly diastereo- and
enantioselective Mukaiyama–Mannich reaction catalyzed by
a new BINOL-derived chiral phosphoric acid bearing 2,4,6-
[*] Dr. F. Zhou, Prof. Dr. H. Yamamoto
Molecular Catalyst Research Center, Chubu University
1200 Matsumoto-cho, Kasugai, Aichi 487-8501 (Japan)
E-mail: fengtaozhou@163.com
Scheme 2. Optimization of the Mukaiyama–Mannich reaction with
various phosphoric acids. Unless otherwise specified, all reactions
were performed at À788C for 24 h under nitrogen with 1a (0.1 mmol,
1.0 equiv), 2a (0.3 mmol, 3.0 equiv), catalyst 4 (0.01 mmol, 10 mol%)
in toluene (1 mL). Product ee values were determined by HPLC on
a chiral stationary phase. [a] for 6 h.
hyamamoto@isc.chubu.ac.jp
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603929.
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phenyl ring so that the oxygen atoms of the nitro groups
would be located near the domain of the phosphoric acids, to
improve the enantioselectivity of the reaction. In fact, the
catalyst 4b, which bears a methyl group at the para position of
the 3,5-dinitrophenyl ring, gave the product 3a with slightly
higher enantioselectivity (93% ee). Next, catalyst 4c, which
bears 2,4,6-trimethyl-3,5-dinitrophenyl substituents at the
3,3’-positions of BINOL-derived phosphoric acid delivered
the product 3a in high yield and with amazingly high
enantioselectivity (98% yield and > 99% ee, respectively).
Steric and electronic effects may explain the origin of the high
enantioselectivity from the three methyl groups. First, the
acidities of four benzoic acids[8] were compared: 2,4,6-
trimethylbenzoic acid (pKa = 3.45), 4-nitrobenzoic acid
(pKa = 3.40), 3,5-dinitrobenzoic acid (pKa = 2.80), and 2,4,6-
trimethyl-3,5-dinitrobenzoic acid (pKa = 2.27). The electron-
withdrawing effect of the 2,4,6-trimethyl-3,5-dinitrophenyl
substituents may thus increase the acidity of the phosphoric
acid. Furthermore, with these three methyl groups, the two
nitro groups are perpendicular to the phenyl ring of the 2,4,6-
trimethyl-3,5-dinitrophenyl substituents. The oxygen atoms of
the nitro groups are thus aligned towards the phosphoric acid
moiety of the catalyst. We further tested the catalysts 4d and
4e, which were obtained by replacing the hydroxy group of 4c
with SH and SeH, respectively. However, both catalysts gave
a lower yield than 4c. The reaction proceeded very well when
catalyzed by the more acidic N-triflyl phosphoramide 4 f at
À788C for 6 h, but delivered the product with much lower
enantioselectivity (À17% ee). The reaction is believed to
proceed through a dual-activation pathway via the formation
of a cyclic transition state between the phosphoric acid and
the aldimine.[7b] The presence of a 2-hydroxyphenyl moiety on
the aldimine is essential to achieve a high level of enantio-
selectivity, and the absence of a 2-hydroxyphenyl group on the
aldimine resulted in lower yield and enantioselectivity (52%
yield and 80% ee, respectively).[9]
Scheme 3. Enantioselective Mukaiyama–Mannich reactions catalyzed
by N-trifly phosphoramide 4g. Unless otherwise specified, all reactions
were performed at À788C for 24 h under nitrogen with 1 (0.1 mmol,
1.0 equiv), 2a (0.3 mmol, 3.0 equiv), catalyst 4g (0.01 mmol,
10 mol%) in toluene (1 mL). Product ee values were determined by
HPLC on a chiral stationary phase.
catalyzed by N-triflyl phosphoramides donꢀt require the
presence of a 2-hydroxyphenyl moiety on the aldimine to
achieve high enantioselectivity.
With the optimized reaction conditions in hand, the
Mukaiyama–Mannich reaction catalyzed by phosphoric acid
4c was extended to a series of imines and the ketene silyl
acetal 2a, and the results are shown in Scheme 4. Not only
aldimines derived from aromatic aldehydes bearing either an
electron-withdrawing group, such as F, Cl, Br, or an electron-
donating group such as OMe and Me, but also aldimines
However, in the case of more acidic but bulkier N-triflyl
phosphoramides, free rotation of the triflyl group may
prevent the formation of the cyclic transition state. A
Mukaiyama–Mannich reaction catalyzed by N-triflyl phos-
phoramides might proceed through a different pathway
(Figure 1). For example, catalyst 4g was a very efficient
catalyst for both 2-(benzylideneamino)phenol 1a and N-
Benzylideneaniline 5a, affording the corresponding products
with high enatioslelectivity (92% ee and 94% ee, respectively;
Scheme 3). This result indicates that Mannich reactions
Scheme 4. Scope of the enantioselective Mukaiyama–Mannich reaction
catalyzed by phosphoric acid 4c. Unless otherwise specified, all
reactions were performed at À788C for 24 h under nitrogen with
1 (0.1 mmol, 1.0 equiv), 2 (0.3 mmol, 3.0 equiv) and catalyst 4c
(0.01 mmol, 10 mol%) in toluene (1 mL). Product ee values were
determined by HPLC on a chiral stationary phase. [a] À408C for 48 h.
[b] The imine was prepared from the corresponding aldehyde
(0.3 mmol, 1.5 equiv) and 6-amino-2,4-xylenol (0.2 mmol, 1.0 equiv)
in situ in the presence of 4 ꢀ MS. The reactions were carried out at
À508C for 24 h.
Figure 1. Proposed transition states of the reactions of aldimines with
catalysts 4c, 4 f, and 4g.
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derived from heterocyclic or bulky aromatic aldehydes
adducts 8i–8k with high diastereoselectivity and excellent
proceeded smoothly, giving the corresponding products 3a–
3h in good to high yields and with excellent enantioselectivity
(92 to > 99% ee). Furthermore, ketene silyl acetals 2b and 2c,
which bear a cyclohexyl or cyclopentyl group, also afforded
the products 3i and 3j in good yields and with excellent
enantioselectivity (> 99% ee). Significantly, imines derived
from aliphatic aldehydes are very challenging substrates for
the asymmetric Mukaiyama–Mannich reaction.[5,6d] To our
delight, imines prepared from aliphatic aldehydes underwent
successful asymmetric Mukaiyama–Mannich reaction to give
the corresponding products in good yields and with excellent
enantioselectivity.
enantioselectivity.
Encouraged by these results, we expanded the substrate
scope to more challenging ketene silyl acetals bearing two
different substituents on the vinyl carbon, and the results are
shown in Scheme 6. A ketene silyl acetal derived from methyl
2-methoxypropanoate furnished the product 10a, which bears
Next, we tested monosubstituted ketene silyl acetals to
achieve high diastereoselectivity and the results are shown in
Scheme 5. The reaction of ketene silyl acetal 7a (E/Z = 9:1)
derived from ethyl propionate proceeded smoothly and the
Scheme 6. Construction of vicinal tertiary and quaternary stereogenic
centers. Unless otherwise specified, all reactions were performed at
À508C for 72 h under nitrogen with 1 (0.1 mmol, 1.0 equiv), 9
(0.3 mmol, 3.0 equiv), catalyst 4c (0.01 mmol, 10 mol%) in toluene
(1 mL). Product ee values were determined by HPLC on a chiral
stationary phase. The diasteroselectivity ratios were determined by
1H NMR spectroscopy. [a] 9a: (1,2-dimethoxyprop-1-enyloxy)trimethyl-
silane, E/Z=91:9; [b] À788C for 48 h.
Scheme 5. Diastereoselective and enantioselective Mukaiyama–Man-
nich reactions. Unless otherwise specified, all reactions were per-
formed at À788C for 24 h under nitrogen with 1 (0.1 mmol, 1.0 equiv),
7 (0.3 mmol, 3.0 equiv), catalyst 4c (0.01 mmol, 10 mol%) in toluene
(1 mL). Product ee values were determined by HPLC on a chiral
stationary phase. The diasteroselectivit6 ratios were determined by
1H NMR spectroscopy. [a] 7a: R1 =Me, R2 =Et, E/Z=90:10; 7b:
R1 =Et, R2 =Et, E/Z=90:10; 7c: R1 =iPr, R2 =Et, E/Z=91:9; 7d:
R1 =Me, R2 =iPr, E/Z=98:2; [b] À408C for 48 h.
vicinal tertiary and quaternary stereogenic centers, in good
yields and with excellent enantioselectivity. Aldimines bear-
ing both electron-donating and electron-withdrawing group
gave the adducts 10b–10d with good diastereoselectivity (up
to 91:9) and high enantioselectivity (up to > 99% ee) The
absolute configuration of the major isomer of 10d was
determined to be (2S, 3R) by X-ray analysis.[10] Aldimines
derived from heterocyclic aldehydes were also suitable
substrates, giving the adducts 10 f and 10h with good
enantioselectivity and diastereoselectivity. Furthermore, the
ketene silyl acetals 9b and 9c, derived from 2-tetrahydro-
furoic acid methyl ester and 2-methylbutanolide, were also
applied to this process and delivered the products 10i–10k in
excellent enantioselectivity (up to 97% ee) and moderate to
good diastereoselectivity (syn/anti up to 90:10).
corresponding product 8a was obtained in 95% ee and 96:4
(syn/anti). Aromatic aldimines bearing electron-donating or
electron-withdrawing substituents gave the corresponding
adducts 8b–8e with good diastereoselectivity (syn/anti up to
97:3) and high enantioselectivity (91 to > 99% ee). Further-
more, aldimines bearing a bulky aromatic ring or a hetero-
cyclic ring were also tolerated and delivered the products 8 f–
8h in good yields with excellent diastereoselectivity (syn/anti
up to > 99:1) and high enantioselectivity (up to 98% ee).
Additionally, ketene silyl acetals derived from other esters
were also suitable substrates and delivered the corresponding
However, the Mukaiyama–Mannich reaction catalyzed by
chiral phosphoric acid required a 2-hydroxyphenyl moiety on
the aldimine to achieve a high level of enantioselectivity. A
more acidic N-triflyl phosphoramide 4g presents a comple-
mentary strategy to this type of chemistry. The substrate
scope of this catalyst system was investigated and the results
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Keywords: asymmetric catalysis · Brønsted acids ·
chiral phosphoric acids · Mukaiyama–Mannich reactions ·
quaternary stereogenic centers
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Scheme 7. Enantioselective Mukaiyama–Mannich reactions catalyzed
by N-Tf phosphoramide. Unless otherwise specified, all reactions were
performed at À908C for 24 h under nitrogen with 5 (0.1 mmol,
1.0 equiv), 2a (0.3 mmol, 3.0 equiv), catalyst 4g (0.01 mmol,
10 mol%) in toluene (1 mL). Product ee values were determined by
HPLC on a chiral stationary phase. [a] The imine was prepared from
butyraldehyde (0.3 mmol, 1.5 equiv) and aniline (0.2 mmol, 1.0 equiv)
in situ in the presence of 4 ꢀ MS. The reactions were carried out at
À788C for 12 h.
are shown in Scheme 7. A wide range of aldimines gave
products 6a–6e in good yields and with excellent enantiose-
lectivity. Additionally, the reaction of imines bearing a heter-
ocyclic ring and or aliphatic substituent proceeded smoothly
and the corresponding products 6 f–6h were obtained in high
yields and with good enantioselectivity.
In summary, we have developed a new BINOL-derived
chiral phosphoric acid bearing 2,4,6-trimethyl-3,5-dinitro-
phenyl substituents at the 3,3’-positions for highly enantiose-
lective Mukaiyama–Mannich reactions. In the presence of this
organocatalyst, both aromatic and aliphatic imines were well
tolerated and delivered the corresponding b-amino-acid
derivatives in good yields with high diastereo- and enantio-
selectivity. Furthermore, this method was successfully applied
to more challenging ketene silyl acetals bearing two different
substituents on the vinyl carbon, leading to adducts contain-
ing vicinal tertiary and quaternary stereogenic centers with
excellent enantioselectivity and moderate to good diastereo-
selectivity in one step. Significantly, the long-standing prob-
lem of enantioselective Mukaiyama–Mannich reactions cata-
lyzed by chiral phosphoric acids requiring a 2-hydroxyphenyl
moiety on the aldimine was solved by taking advantage of
a N-triflyl phosphoramide catalyst. The corresponding prod-
ucts were obtained in good yields and with high enantiose-
lectivity. Intensive investigations into the application of this
new class of chiral phosphoric acids are underway in our
laboratory.
Acknowledgements
This work was supported by ACT-C, JST. The authors thank
Dr. Y. Shimoda for helpful discussions.
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[6] Selected examples of organocatalytic asymmetric Mukaiyama–
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[9] Catalyst 4c catalyzed the reaction of the aldimine N-Benzylide-
neaniline 5a with 2a, giving adduct 6a in 52% yield and 80% ee
at À908C after 48 h.
[10] The relative and absolute stereochemistry of the major isomer of
10d was determined to be (2S, 3R) by X-ray crystallography (see
the Supporting Information) and those of the others were
surmised by analogy.
Received: April 22, 2016
Published online: && &&, &&&&
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Communications
Asymmetric Catalysis
F. Zhou,* H. Yamamoto*
&&&& — &&&&
A Powerful Chiral Phosphoric Acid
Catalyst for Enantioselective Mukaiyama–
Mannich Reactions
A selection of M&M’s: 2,4,6-trimethyl-
3,5-dinitrophenyl substituents were
introduced into the 3,3’-positions of
BINOL-derived chiral phosphoric acids.
The resulting catalysts exhibit excellent
enantioselectivity and good diastereose-
lectivity in asymmetric Mukaiyama–Man-
nich reactions of imines with a wide range
of ketene silyl acetals.
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