Catalytic Asymmetric Mannich Reaction with N-Carbamoyl Imine Surrogates of Formaldehyde and Glyoxylate

Article abstract of DOI:10.1002/anie.201707005

N,O-acetals (NOAcs) were developed as bench stable surrogates for N-carbamoyl, (Boc, Cbz and Fmoc) formaldehyde and glyoxylate imines in asymmetric Mannich reactions. The NOAcs can be directly utilized in the chiral primary amine catalyzed Mannich reactions of both acyclic and cyclic β-ketocarbonyls with high yields and excellent stereoselectivity. The current reaction offers a straightforward approach in the asymmetric synthesis of α- or β-amino carbonyls bearing chiral quaternary centers in a practical and highly stereocontrolled manner.

Full text of DOI:10.1002/anie.201707005

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Catalytic Asymmetric Mannich Reaction with N-Carbamoyl Imine
Surrogates of Formaldehyde and Glyoxylate
Authors: Yang'en You, Long Zhang, Linfeng Cui, Xueling Mi, and
Sanzhong Luo
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707005
Angew. Chem. 10.1002/ange.201707005
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http://dx.doi.org/10.1002/ange.201707005

10.1002/anie.201707005
Angewandte Chemie International Edition
COMMUNICATION
Catalytic Asymmetric Mannich Reaction with N-Carbamoyl Imine
Surrogates of Formaldehyde and Glyoxylate
Yang’en You, Long Zhang, Linfeng Cui, Xueling Mi, Sanzhong Luo*
Dedicated to Prof. Jin-Pei Cheng on the occasion of his 70th birthday
Abstract: N, O-acetals (NOAcs) have been developed as bench
stable surrogates for N-carbamoyl (Boc, Cbz and Fmoc)
formaldehyde and glyoxylate imines in asymmetric Mannich
reactions. The NOAcs can be directly utilized in the chiral primary
amine catalyzed Mannich reactions of both acyclic and cyclic β-
ketocarbonyls with high yields and excellent stereoselectivity. The
current reaction offers a straightforward approach in the asymmetric
synthesis of α- or β-amino carbonyls bearing chiral quaternary
centers in a practical and highly stereocontrolled manner.
examined in Mannich reaction of silyl enol ether with low
enantioselecitvity.[6d] Herein, we reported N, O-acetals (NOAcs)
as N-carbamoyl imine surrogates for both formaldehyde and
gyloxylate ester (Scheme 1). Typical carbamoyl groups including
Boc, Cbz and Fmoc can all be incorporated and the resulting
NOAcs can be directly used in enantioselective Mannich
reactions.
Enamine-Mannich reaction has also gained prominent
progresses echoing the renaissance of organocatalysis.[3a,b]
Most of reactions have been reported with α-unsubstituted
aldehydes and ketones. In one single case, enantioselective
enamine Mannich reactions of α-branched aldehydes was
reported by Barbas and coworkers with good enantioselectivity
but moderate diastereoselectivity.[8] Catalytic asymmetric
Mannich reaction with α-branched ketones have not been
achieved to date in enamine catalysis. In general, the access to
α-quaternary carbonyls by catalytic asymmetric Mannich
reactions have been mainly achieved with cyclic ketones or
lactones via enolate processes.[9]] Based on our developed chiral
primary amine catalysts,[10] we herein reported an asymmetric
Mannich reactions of both cyclic and acyclic α-branched ketones,
particularly -ketocarbonyls with NOAc imine precursors.
The Mannich reaction with imines or iminiums is a classical and
fundamental C-C bond formation reactions in organic
synthesis.[1] Advances in asymmetric catalysis with either metal
or organic catalysts have made enantioselective Mannich
reactions the most attractive and atom-economic approaches for
the synthesis of chiral β-amino carbonyl compounds.[2,3] From
the synthetic point of view, N-carbamoyl (e.g. Boc-, Cbz- or
Fmoc-) imines are highly desirable due to their versatile
synthetic utility and readily adaptability in established synthetic
procedures. However, N-carbamoyl imines are generally
unstable and their preparation remains a major drawback in
Mannich chemistry. N-Carbamoyl imine surrogates such as α-
haloamines[4] or α-sulfonylamines[5] have been developed,
however, their syntheses are still nontrivial requiring multiple
steps and excess bases for imine generation. In particular,
simple yet synthetically important N-carbamoyl imines from
formaldehyde[6a] and glyoxylate ester[4b,6b] are difficult to access
and their enantioselective Mannich catalysis remains to be
further developed. N,O-acetals are very useful reagents and
intermediates in organic synthesis. [6, 7] However, the exploration
of N,O-acetals as N-carbamoyl imine surrogates remained
surprisingly underdeveloped in asymmetric Mannich reactions.
In one single example, N-Cbz amiomethylacetate has been
Typical surrogates for formaldehyde and glyoxylaate imines
O
O
R'
R'
PG
PG
N
O
O
HN
R
R

PG

R'
N
H
R'
CO2Et
H
FG
FG = H
FG = CO2Et
R
R
amino carbonyls
-
Unstabble
amino carbonyls
-
Ar
N
O
X
Ph
Ph
2006,Gellman/C髍dova
MeO
O
+
ArNH2
N
RO
N
CO2R'
H
H
H
N
N
AAr
Ar
2004, Córdova
X = Cl, Br, ArSO2
2017, Feng
This work: N, O-acetals as stable formaldeyde annd glyoxylate imine precursors
PG
PG
FG
HN
HN
AcO
(HCHO)n
Ac2O/AcOH = 3:1
60 oC, 24 h
AcO
PGNH2
PG = Boc, Cbz, Fmoc
FG = H, CO2R
PG
PG
[a]
Y. You, Dr. L. Zhang, Prof. Dr. S. Luo
Beijing National Laboratory for Molecular Sciences (BNLMS)
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing, 100190 (China);
HN
AAcO
HN
HCOCO2Et
AcOH
Py
Ac2O
N,O-Acetals (NOAcs)
CO2Et
HO
CO2Et
Readily prepared in large scale
Bench staable
Convenient N-protection groups
University of Chinese Academy of Sciences
Beijing, 100490
and
Collaborative Innovation Center of Chemical Science
and Engineering, Tianjin, 300071 (China)
E-mail: luosz@iccas.ac.cn
PG
N
HOTf
O
O
HN
PG
NH2
HN
EWG
+
R'
R'
FG
R EWG
AcO
NOAcs
No pre-activation required All-carbon quaaternary center
FG
Cat.
R
Broad scopes
Homepage: http://luosz.iccas.ac.cn
[b]
L. Cui, Prof. X. Mi
College of Chemistry, Beijing Normal University
Beijing, 100875 (China)
Scheme 1. N, O-Acetals as N-Carbamoyyl Imine Precursors.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
The NOAcs were readily synthesized starting from aldehyde
and carbamates in the presence of Ac2O/AcOH.[6a] The resulted
N, O-acetals can be distilled (Boc-, Cbz-) or recrystallized
This article is protected by copyright. All rights reserved.

10.1002/anie.201707005
Angewandte Chemie International Edition
COMMUNICATION
(Fmoc-) and are bench-stable for months. We first tested NOAcs
in the aminomethylation reactions. There are a few examples on
catalytic asymmetric aminomethylation. Seminal works by
Córdova, Gellman and Feng have mainly been achieved with in-
situ generated N-aryl imines from anilines, 1,3,5-trazines or α-
dibenzyl amino methyl ether.[11] Multi-steps are generally
required to reach the useful N-carbamoyl amino products in
these cases. Very recently, Stoltz reported an aminomethylation
with N-carbamoyl imines using sulfonylmethyl carbamates
precursors,[12] but the stereoselectivity was generated in the late
decarboxylative alkylations stage, not in the Mannich step.
We tested the NOAc reagents in the aminomethylation of β-
ketoester 1a, for which a highly enantioselective process has not
been achieved. Our benchmark chiral primary amine catalysts
turned out to be highly effective for the reaction in terms of both
activity and enantioselectivity (Figure 1).[9] The NOAc reagent 2a
could be directly applied without separate activation, and the
addition of a weak acid m-nitrobenzoic acid was critical for
attaining good conversion and high stereocontrol, likely via in-
situ activating the NOAc reagent. A less bulky primary amine
catalyst (B) gave slightly better activity and enantioselectivity
and under this condition the desired adduct 3a could be
obtained in 92% isolated yield as an optically pure product
(>99% ee) (Figure 1).
in 98% yield and with 99% ee (Table 1, entry 23). Other NOAcs
reagents worked equally well in the reactions.
Table 1. Substrate Scope with NOAcs[a]
.
O
1-5
6
O
R = Bn (3a), 92%, >99% ee
= Et (3b), 95%, >99% ee
Cbz
N
Cbz
Cbz
H
MeO2C
N
= Allyl (3c), 81%, >99% ee
= iPr (3d), 85%, 99% ee
= tBu (3e), 80%, >99% ee
H
RO2C
3f : 96%, 99% ee
7
8
9
O
O
O
Cbz
Cbz
N
N
N
H
H
H
BnO2C nPr
BnO2C nBu
EtO2C Bn
3g : 57%, 99% ee
3h : 94%, >99% ee
3i : 45%, >99% ee
10
13
11
14
12
15
O
O
O
O
Cbz
N
Cbz
N
H
BnO2C
H
BnO2C
HN
Cbz
3j : 51%, 99% ee
3k : 54%, >99% ee
3l : 99%, 97% ee
OMe
O
O
O
O
O
O
O
O
O
O
Cbz
Cat. (20 mol%)
+
O
Ph
N
OAc
O
Ph
N
H
m-NO2C6H4CO2H (50 mol%)
H
N
H
CHCl3, 60 o
C
NHCbz
NOAc-Cbz
HN
48 h
HN
HN
1a
2a
3a
Cbz
Cbz
Cbz
3m : 72%, 99% ee
3n : 97%, >99% ee
3o : 99%, >99% ee
92% yield, >99% ee
ee
46% yield, 98%
N
N
16
19
17
18
21
O
O
with 10 mol% of cat. :
76% yield, 99% ee
w/o m-NO2C6H4CO2H:
19% yield, 85% ee
NH2
O
NH2
O
Cbz
B
N
H
Ph
N
H
A
Cbz
N
H
CO2Et
CO2Et
HN
Cbz
Figure 1. Optimized Conditions for Aminomethylation.
3p : 92%,99% ee
3q : 99%, 99% ee
3r : 75%, >99% ee
20
23
O
O
O
O
O
Ph
HN Cbz
NHBn
The scope of our primary amine catalysis in the asymmetric
aminomethylation was then examined (Table 1). Different ester
moieties in β-keto esters, including benzyl, ethyl, allyl, isopropyl,
tert-butyl ester all gave the desired products 3a-3e with ≥99%
ee and good yields (up to 95%) (Table 1, entries 1-5). The
reactions tolerated a number of α-substituents including liner
alkyl C1-C4, benzyl, allyl and propargyl to give the desired
aminomethylation adducts 3f-3k with excellent enantioselectivity
in all cases (Table 1, entries 6-11). Desymmetric 1,3-diketones
can be applied to give the desired β-aminocarbonyls 3l and 3m
with good reactivity and high enantioselectivity (Table 1, entries
12 and 13). The substrate scope could be further extended to β-
ketoamides. Both N-aryl (3n and 3o) and N-aliphatic (3p)
amides worked well in the reactions to afford the desired
aminomethylation adducts in good yields and high
enantioselectivities (Table 1, entries 14-16).
Cbz
N
H
CO2Et
NHCbz
3s : 91%, >99% ee[b]
22
3t : 54%, 94% ee
3u : 97% yield, >99% ee
24, 25
O
O
O
O
NHPh
CN
Fmoc
N
NHCbz
NHCbz
H
RO2C
R = Et (3x) : 92%, 99% ee
R = Bn (3y) :96%, >99% ee
3v : 91% yield, 99% ee
26, 27
3w : 98% yield, 99% ee
28
29
OMe
OMe
O
O
O
Cl
O
O
Boc
N
N
H
N
H
RO2C
H
OMe
NHFmoc
NHFmoc
3ac: 86%, >99% ee
R = Et (3z) : 99%, 98% ee
R = Bn (3aa) :99%, >99% ee
3ab :
90%, 99%
ee
[a] All reactions were performed at 60 oC in 0.5 mL CHCl3, with 1
(0.1 mmol), (0.15 mmol), B/TfOH (20 mol%), m-
2
Furthermore, the reaction also worked well with cyclic
ketocarbonyls. For instance, cyclic ketoesters (3q-3s), 1,3-
diketone (3t) or ketoamides (3u and 3v) all could be transformed
to the corresponding products with high enantioselectivities
(Table 1, entries 17-22). Notably, 2-cyanocyclopentanone also
reacted well in this system to give the corresponding product 3w
nitrobenzoicacid (50 mol%), 24-48 h. Yield of isolated product.
Ee was determined by HPLC analysis. [b] Reaction was
performed at rt for 72 h.
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10.1002/anie.201707005
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Substrate Scope with NOAc-Gss[a]
.
The corresponding N-Fmoc (3x, 3y, 3ab and 3ac) (Table 1,
entries 24, 25, 28 and 29)) and N-Boc (3z and 3aa) (Table 1,
entries 26 and 27) aminomethylation adducts could be obtained
in high yields and with superb enantioselectivity under otherwise
identical conditions.
Asymmetric Mannich reaction with imino esters is one of the
important approaches for the synthesis of α-amino esters. N-
carbamoyl imino esters have been frequently explored for this
purpose.[4,5,13] However, N-carbamoyl imino esters are rather
unstable, requiring tedious procedure for their synthesis and
must be freshly prepared and handled with great care. Direct
use of imino esters surrogates in a one-pot manner is hence
highly desirable. Recently, Jacobsen reported the only examples
on asymmetric Mannich synthesis of α-amino esters with α-
chloroglycine ester as imino ester surrogate in a one-pot
operation.[4b]
1-3
O
O
NHCbz
CO2Et
4a
R = Bn ( ), 75%; >19:1 , >99%
dr
ee
ee
4b
dr
R = t- Bu ( ), 74%; >19:1 , >99%
4c
dr ee
R = allyl ( ), 63%; >19:1 , >99%
CO2R
4
5
6
NHCbz
NHCbz
CO2Et
O
NHCbz
O
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
F
4d
4e
4f
, 88%
, 81%
, 99%
19:1 dr, 92% ee
In this context, we explored the direct use of N,O-acetal of
glyoxylate ester (NOAc-G) as imino ester precursor in
asymmetric Mannich reactions. Delightfully, previous conditions
for aminomethylation process worked equally well with imino
esters. Further experiment indicated that acid additive was not
necessary in this case. Simple mixing NOAc-G reagent with β-
ketoester 1a led smoothly to the desired Mannch adduct 4a in
75% yield and with >19:1 dr and >99% ee in the presence of
chiral primary catalyst (Table 2, entry 1). Different ester moieties
on the donor part were tolerated (4b and 4c) (Table 2, entries 1-
3). Cyclic ketoesters also worked very well to give the desired
Mannich adducts as single diastereoisomers with >99% ee (4d
and 4e) (Table 2, entries 4 and 5). The reactions with larger α-
alkyl substituents beyond methyl group did not work, indicating
the reaction was quite sensitive to steric effect. Delightfully, α-
fluoro ketoester worked very well to give the amino ester 4f in
quantitative yield with 19:1 dr and 92% ee (Table 2, entry 6).
Different β-ketocarbonyls could be applied in the current
reactions (4g-4p) (Table 2, entries 7-16). α-Unsubstituted and
unsymmetric β-ketocarbonyls gave the Mannich product in 1:1
dr due to readily enolizable α-carbon, and both diastereoisomers
were obtained with excellent enantioselectivity (entries 7-11).
1,3-Diketones worked particularly well in the reactions (entries
10-16). In particular, phenyl ketones can also be incorporated
with good enantioselectivity, though the yields are low as
enamine formation with phenyl ketone is sluggish (Table 2,
entries 9 and 14). Notably, N-Fmoc (4q and 4s) and N-Boc (4r
and 4t) imino ester precursors could be equally applied in the
current protocol to give the desired products with good activity
and high enantioselectivity (Table 2, entries 17-20).
>19:1 dr, >99% ee
>19:1 dr, >99% ee
7
8
9
O
O
O
O
O
O
OEt
Ot-Bu
Ph
OEt
EtO2C
NHCbz
dr
EtO2C
NHCbz
dr
EtO2C
4i
NHCbz
dr
4g
, 76%, 51:49
>99%/ >99% ee
4h
,75%, 52:48
>99%/ >99% ee
,18%, 52:48
96%/ 95% ee
10
11
12
NHCbz
O
O
O
O
CO2Et
Ph
O
Et
EtO2C
4j
NHCbz
EtO2C
NHCbz
dr
O
, 99%, 72:28
>99%/ >99% ee
dr
4k
. 99%, 52:48
>99% />99% ee
4l
, 67%
>19:1 dr, >99% ee[b]
13
14
15
O
Ph
O
O
Et
O
CO2Et
Ph
CO2Et
Et
CO2Et
O
NHCbz
NHCbz
4n
O
NHCbz
4o
4m
67%, >99% ee
20%, 90% ee
85%, >99% ee
16
17
18
O
O
O
CO2Et
CO2Et
CO2Et
O
NHCbz
O
NHFmoc
O
NHBoc
4p
4q
4r
84%, >99% ee
88%, >99% ee
87%, >99% ee
19
22
20
23
21
24
O
NHFmoc
O
NHBoc
CO2Et
O
NHCbz
CO2Et
CO2Et
CO2Bn
CO2Bn
The imino ester Mannich reaction is not limited to β-
ketocarbonys. Simple ketone and aldehyde donors such as
acetone (4u), cyclopentanone (4v), cyclohexanone (4w) and
aliphatic aldehydes(4x) could be applied with good yields and
high enantioselectivity (Table 2, entries 21-24).
4s
, 73%
4t
, 97%
4u
65%, 94% ee[c]
>19:1 dr, >99%ee
>19:1 dr, >99%ee
NHCbz
CO2Et
CbzHN
CO2Et
CHO
O
O
NHCbz
Gram-scale reactions for both formaldehyde imine and α-
imino esters have been conducted in the presence of 10 mol%
of chiral primary amine catalyst B/TfOH (Scheme 2). In both
cases, the reaction worked well with comparable yield and
enantioselectivity and the chiral primary amine catalyst could be
quantitatively recycled by simple aqueous workup, verifying the
practicability of the current protocol in the synthesis α-amino
esters and β- amino carbonyls.[4,12,13]
CO2Et
4v
, 99%, 59:41
dr
4w
, 78%, 84:16
dr
4x, 68%, 91% ee[b]
98%/ 70% ee
95%/ 98% ee
[a] All reactions were performed at 60 oC in 0.2 mL CHCl3, with 1
(0.12 mmol), 2 (0.10 mmol), B/TfOH (20 mol%), 24-48 h. Yield of
isolated product. Dr was determined by NMR and ee was
determined by HPLC analysis. [b] At room temperature. [c]
Acetone as solvent.
This article is protected by copyright. All rights reserved.

10.1002/anie.201707005
Angewandte Chemie International Edition
COMMUNICATION
[2]
[3]
a) H. Ishitani, M. Ueno, S. Kobayyashi, J. Am. Chem. Soc. 1997, 119,
7153; b) B. List, J. Am. Chem. SSoc. 2000, 122, 9336; c) W. Notz, K.
Sakthivel, T. Bui, G. Zhong, C. F. Barbas III, Tetrahedron Lett. 2001, 42,
199; d) For an early review, see: S. Kobayashi, H. Ishitani, Chem. Rev.
1999, 99, 1069. e) S. Kobayashi, Y. Mori, J. S. Fossey, M. M. Salter,
Chem. Rev. 2011, 111, 2626.
N
HOTf
O
O
O
NH2
Cbz
Cbz
(10 mol%)
+
N
OAc
N
OEt
H
m-NO2PhCO2H (25 mol%)
CHCl3, 60 oC, 72 h
H
CO2Et
3.05 g, 90% yield, 99%
ee
10 mmol, 1.70 g
15 mmol, 3.35 g
For recent reviews on Mannich reeaction, see: a) W. Notz, F. Tanaka, C.
F. Barbas III, Acc. Chem. Res. 2004, 37, 580; b) A. Córdova, Acc.
Chem. Res. 2004, 37, 102; c) Y. LLiu, Q. Wu, D. Yin, D. Li, Chin. J. Org.
Chem. 2016, 36, 927; d) M. S. Rooselló, C. Pozo, S. Fustero, Synthesis
2016, 48, 2553; e) R. G. Arrayáás, J. C. Carretero, Chem. Soc. Rev.
2009, 38, 1940.
N
HOTf
NH2
O
CO2Et
NHCbz
OAc
O
O
(10 mol%)
60 oC, 72 h
CbzHN
+
CO2Et
O
6.0 mmol, 0.60 g
5.0 mmol, 1.48 g
1.32 g, 79% yield, 99% ee
[4]
[5]
a) Y. Nakamura, R. Matsubara, HH. Kiyohara, S. Kobayashi, Org. Lett.
2003, 5, 2481; b) M. Wasa, R.Y. Liu, S. P. Roche, E. N. Jacobsen, J.
Am. Chem. Soc. 2014, 136, 128722.
Scheme 2. Gram-Scale Synthesis.
a) J. Song, H. W. Shih, L. Deng, Org. Lett. 2007, 9, 603; b) F. Fini, V.
Sgarzani, D. Pettersen, R. P. Heerrera, L. Bernardi, A. Ricci, Angew.
Chem. 2005, 117, 8189; Angew. Chem. Int. Ed. 2005, 44, 7975; c) C.
Palomo, M. Oiarbide, A. Laso, R. López, J. Am. Chem. Soc. 2005, 127,
17622; d) C. Gianelli, L. Sambri, A. Carlone, G. Bartoli, P. Melchiorre,
Angew. Chem. 2008, 120, 8828; AAngew. Chem. Int. Ed. 2008, 47, 8700.
a) A. E. Hartman, C. L. Brophy, J. A. Cupp, D. K. Hodge, T. J. Peelen, J.
Org. Chem. 2009, 74, 3952; b) SS. P. Roche, S. S. Samanta, M. M. J.
Gosselin, Chem. Commun. 20144, 50, 2632; c) A. B. Weinstein, D. P.
Schuman, Z. X. Tan, S. S. Stahhl, Angew. Chem. 2013, 125, 12083;
Angew. Chem. Int. Ed. 2013, 522, 11867; d) D. Ferraris, B. Young, T.
Dudding, W. J. Drury III, T. Lectkaa, Tetrahedron 1999, 55, 8869; e) N. N.
Nasief, D. Hangauer, J. Med. Cheem. 2014, 57, 2315.
Plausible transition states were proposed based on previous
studies[10] as well as the determined configurations (SI for
details). ESI-MS analysis revealed imine generation is quite
facile under the aminocatalytic conditions. The enamine addition
with imine occurs from the Re-face of enamine, and the H-
bonding between the protonated N-H and imine (TS I) or imine
esters (TS II) is critical in dictating the facial selection as well as
the diastereoselectivity (Figure 2).[10]
[6]


H
H
t
H
H
But
Bu
[7]
[8]
Y.-Y. Huang, C. Cai, X. Yang, Z.-CC. Lv, U. Schneider, ACS Catal. 2016,
6, 5747.
N
N
H
H
N
C
Cbz
Cbz
O
N
O
N
a) N. S. Chowdari, J. T. Suri, C. F. Barbas III, Org. Lett. 2004, 6, 2507; b)
M. Pouliquen, J. Blanchet, M.-C. LLasne, J. Rouden, Org. Lett. 2008, 10.
1029.
N
C
R
R
O
O
O
H
H
H
O
[9]
a) M. Marigo, A. Kjærsgaard, K. JJuhl, N. Gathergood, K. A. Jørgensen,
Chem. Eur. J. 2003, 9, 2359; b) TT. B. Poulsen, C. Alemparte, S. Saaby,
M. Bella, K. A. Jørgensen, Angeew. Chem. 2005, 117, 2956; Angew.
Chem. Int. Ed. 2005, 44, 2896; c)) Y. K. Kang, D. Y. Kim, J. Org. Chem.
2009, 74, 5734; d) M. Hatano, T. HHoribe, K. Ishihara, J. Am. Chem. Soc.
2010, 132, 56; e) Y.-P. Lou, C.--W. Zheng, R.-M. Pan, Q.-W. Jin, G.
Zhao, Z. Li, Org. Lett. 2015, 17, 6888; f) B. M. Trost, T. Saget, C.-I. Hung,
J. Am. Chem. Soc. 2016, 138, 36559.
TS I
TS II
Figure 2. Proposed Transition States.
[10]
a) L. Zhang, N. Fu, S. Luo, Acc. CChem. Res. 2015, 48, 986; b) C. Xu, L.
Zhang, S. Luo, Angew. Chem. 20014, 126, 4233; Angew. Chem. Int. Ed.
2014, 53, 4149; c) L. Zhang, C. Xuu, X. Mi, S. Luo, Chem. Asian J. 2014,
9, 3565; d) Y. You, L. Zhang, S. Luo, Chem. Sci. 2017, 8, 621.
In conclusion, we have developed a catalytic asymmetric
Mannich reaction of ketones with high enantioselectivity using
six bench stable N,O-acetals as the reagents by a simple chiral
primary amine catalysis. This protocol provides a highly efficient
and stereoselective approach to synthesis α-amino esters and β-
amino carbonyls. Ongoing studies are aimed at expanding the
scope of N,O-acetals as imine surrogates and their catalytic
applications.
[11] a) I. Ibrahem, J. Casas, A. Córdoova, Angew. Chem. 2004, 116, 6690;
Angew. Chem. Int. Ed. 2004, 43, 6528; b) X. Lian, L. Lin, K. Fu, B. Ma,
X. Liu, X. Feng, Chem. Sci. 20177, 8, 1238; c) Y. Chi, S. H. Gellman, J.
Am. Chem. Soc. 2006, 128, 66804; d) I. Ibrahem, G.-L. Zhao, A.
Córdova, Chem. Eur. J. 2007, 13, 683.
[12] Y. Numajiri, B. P. Pritchett, K. Chiiyoda, B. M. Stoltz, J. Am. Chem. Soc.
2015, 137, 1040.
Acknowledgements
[13]
a) For a review, see: B. Eftekharii-Sis, M. Zirak, Chem. Rev. 2017, 117,
8326. For selected examples, ssee: b) T. Kano, Y. Yamaguchi, O.
Tokuda, K. Maruoka, J. Am. Chemm. Soc. 2005, 127, 16408; c) H. Zhang,
S. Mitsumori, N. Utsumi, M. Imaai, N. Garcia-Delgado, M. Mifsud, K.
Albertshofer, P. H.-Y. Cheong, K. N. Houk, F. Tanaka, C. F. Barbas III,
J. Am. Chem. Soc. 2008, 130, 875; d) B. T. Hahn, R. Frӧhlich, K.
Harms, F. Glorius, Angew. Chem.. 2008, 120,10134; Angew. Chem. Int.
Ed. 2008, 47, 9985; e) D. A. Yalaalov, S. B. Tsogoeva, T. E. Shubina, I.
M. Martynova, T. Clark, Angew. CChem. 2008, 120, 6726; Angew. Chem.
Int. Ed. 2008, 47, 6624.
We thank the Natural Science Foundation of China (21390400,
21521002, 21572232 and 21672217) and the Chinese Academy
of Science (QYZDJ-SSW-SLH023) for financial support. S. L. is
supported by National Program of Top-notch Young
Professionals.
Keywords: N,O-acetals • enamine catalysis • Mannich reaction
•imine surrogate •amino carbonyls
[1]
C. Mannich, W. Krӧsche, Arch. Pharm. 1912, 250, 647.
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10.1002/anie.201707005
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Yang’en You, Long Zhang, Lingfeng Cui,
Xueling Mi, Sanzhong Luo*
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Catalytic Asymmetric Mannich
Reaction with N-Carbamoyl Imine
Surrogates of Formaldehyde and
Glyoxylate
Bench stable imine surrogates: N, O-acetals (NOAcs) have been developed as bench stable surrogates for N-carbamoyl
(Boc, Cbz and Fmoc) formaldehyde and glyoxylate imines in asymmetric Mannich reactions. This reaction offers a
straightforward approach in the asymmetric synthesis of α- or β-amino carbonyls bearing chiral quaternary centers in a
practical and highly stereocontrolled manner.
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