Bench-stable imine surrogates for the one-pot and catalytic asymmetric synthesis of α-amino esters/ketones

Article abstract of DOI:10.1039/d0cc06055k

N,O-Bis(tert-butoxycarbonyl)hydroxylamines are readily accessible as imine surrogates, which are bench stable and could quantitatively generate the corresponding imines for in situ applications. An unpresented catalytic asymmetric method for the synthesis of α-amino esters and ketones from novel imine surrogates, N,O-bis(tert-butoxycarbonyl)hydroxylamines, as well as its preliminary mechanistic studies are reported. A variety of optically enriched products were obtained in excellent yields and enantioselectivities (up to 99% yield and >99% ee). This journal is

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Bench-stable Imine Surrogates for the One-pot and Catalytic
Asymmetric Synthesis of α-Amino Esters/Ketones
Huacheng Xu, a Adila Nazli, a Cheng Zou, a Zhi-Peng Wang *b and Yun He *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
N,O-Bis(tert-butoxycarbonyl) hydroxylamines are readily accessible
as imine surrogates, which are bench stable and could
quantitatively generate the corresponding imines for in situ
applications. An unpresented catalytic asymmetric method for the
synthesis of α-amino esters and ketones from novel imine
surrogates, N,O-bis(tert-butoxycarbonyl) hydroxylamines, as well
as its preliminary mechanistic studies are reported. A variety of
optically enriched products were obtained in excellent yields and
enantioselectivities (up to 99% yield and >99% ee).
A. -Chloroglycine ester as an imine surrogate generated in situ (Roche)

PgNH2
cat. AcOH
O
O
H
N
O
H
then Nu-H
or Nu-SiR3
OH
N
RO
RO
Pg
RO
Pg
AcCl (excess)
OH
Cl
Nu
B. -Chloroglycine ester as a N-carbamoyl imine surrogate (Roche & Jacobsen)

O
O
R1
R2
O
O
Cl
Cl
Et3N (cat.)
Cbz
R1
Cbz
R2
H/F
Cbz
N
H
CO2Et
H/F
N
H
CO2Et
Chiral thiourea
catalyst
N
H
CO2Et
As one class of the most active organic intermediates, imines
have found numerous synthetic applications in the past
hundred years.1 In particular, the development of different
imines or iminiums for Mannich reactions has attracted
significant attention of organic chemists. Owing to their
versatile utility and adaptability, N-carbamoyl imines are a class
of highly desirable reagents for the synthesis of various types of
unnatural α-substituted amino acids or esters.2 However, N-
carbamoyl imines generally require cumbersome preparations
and strictly controlled conditions for catalytic reactions.
Although N-carbamoyl imine surrogates such as α-haloamines,
α-oxygenicamines or α-sulfonylamines have been reported,
their syntheses are still nontrivial, requiring multiple steps and
excess bases for the imine preparation.3 Noteworthy, α-
haloamines are generally unstable even in refrigerator.4
C. N,O-Acetal as a stable N-carbamoyl imine surrogate (Luo)
O
EWG
PG
FG
H
PG
FG
R`
O
HN
Amine
catalyst
N
GP
R
N
R`
AcO
R
EWG
FG
PG = Boc, Cbz, Fmoc; FG = H, COOR
D. N,O-Bis(tert-butoxycarbonyl) hydroxylamine as an imine surrogate (this work)
O
EWG
H/F
R1
O
H
R2
Boc
Chiral thiourea
catalyst
-CO2, -tBuOH
R1
+
EWG
H/F
O
O
R2

N
N
O
Boc
O
H
O
 Simple preparation Bench stable Imines generation in different way
Scheme 1 Catalytic asymmetric reactions with different N-carbamoyl
imine surrogates
coworkers reported a scalable, one-pot Mannich route to
access enantioenriched α-amino esters and α-allyl amino esters
with α-chloroglycine ester as direct imine surrogate in 2014 and
2019 (Scheme 1, B).5 And Luo group developed a catalytic
asymmetric Mannich reaction with stable N,O-acetals as the N-
carbamoyl imine surrogates in 2017 (Scheme 1, C).6 Although
these imine surrogates facilitated the development of imine
chemistry in organic synthesis, their applications are still
handicapped by their instability and cumbersome preparation.
Thus, developing stable imine surrogates in a convenient and
simple way would significantly facilitate and expand imine’s
applications in asymmetric synthesis.
In the past decade, Roche group developed an efficient one-
pot, three components method for the synthesis of α-
substituted amino esters with α-chloroglycine ester as a
practical imine surrogate generated from benzyl carbamate and
ethyl glyoxylate (Scheme 1, A).4 Roche, Jacobsen, and
a. Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School
of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, P. R. China.
E-mail: yun.he@cqu.edu.cn.
b. Chongqing Institute of Green and Intelligent Technology, Chinese Academy of
Sciences, Chongqing, 400714, P. R. China. E-mail: wangzhipeng@cigit.ac.cn.
† Electronic Supplementary Information (ESI) available: Experimental procedures,
spectroscopic data, copies of 1H and 13C NMR spectra, CCDC 2007033 (3e). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/x0xx00000x.
All reported imine generations were based on the traditional
N-H-elimination of imine surrogates with a leaving group at the
vicinal position of nitrogen. During our total synthetic studies of
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natural products, we occasionally observed that the readily moieties on 2 with different electronic effect substituents, no
View Article Online
DOI: 10.1039/D0CC06055K
accessible
intermediate
N,O-bis(tert-butoxycarbonyl) reaction happened under this condition. Several bifunctional
hydroxylamine methyl glycinate could generate the thiourea catalysts were also evaluated for their promoting
corresponding imine via N-αH-elimination with a leaving group effects, but did not improve the enantioselectivity. (See ESI for
on the nitrogen atom under mild conditions. Continuing our details)
efforts in developing novel asymmetric synthesis
With the optimized condition in hand, we explored the scope
methodologies,7
we envisioned that N,O-bis(tert- of this reaction. A variety of symmetrical 1,3-diketones were
butoxycarbonyl) hydroxylamines could serve as novel, efficient found to react effectively under the optimized condition, and
and direct N-carbamoyl imine surrogates for the synthesis of α- the results are summarized in Scheme 2. Introduction of
substituted amino esters or ketones (Scheme 1, D).
electron-donating groups p-Me and p-OMe on the phenyl group
To validate our hypothesis, we optimized the reaction resulted in products 3b-c with excellent enantioselectivities
conditions (Table 1). The initial exploration utilized diketone 1a (93%-95%) and good yields (77%-87%). Similarly, substrates
and α-N-OBoc-benzyl ester 2 with varying R1, R3 and R4, and with electron-withdrawing groups p-F/Cl/Br on the phenyl ring,
chiral thiourea as the catalyst.5a,8 To our delight, the reaction or with 2-thiophenyl as R2 led to the corresponding products
proceeded as expected, leading to the corresponding amino (3d-g) in almost quantitative yields (only a slight loss for 3f) and
ester 3 in 95% yield and 92% ee at room temperature using uniformly
excellent
enantioselectivities
(95%-99%).
toluene as the solvent (Table 1. Entry 1). Encouraged by this Unfortunately, the common nucleophile dibenzyl malonate
exhilarating result, we investigated the effects of R3 group on only gave the corresponding product in 21% yield and moderate
the nitrogen atom. Replacing Boc with Bz resulted in enantioselectivity with substrate recovery (3h), due to the low
dramatically decrease in yield and enantioselectivity (Table 1, reactivity, the dimer of imine surrogate and the cycloaddition
Entry 2), suggesting that Boc at this position was critical for the product of imine with catalyst could be observed (See Scheme
smooth reaction. Varying temperatures and solvents did not 6). Although the steric hindrance and electronic effect were
benefit the reaction (Table 1. Entries 3-6). We then evaluated changed with introduction of a fluorine atom at the α position
whether the ester moiety of α-amino esters might have a steric of diketone, there was no significant influence on yields and
effect on the performance of the catalyst (Table 1. Entries 7-9), enantioselectivities of the reactions (3i-k). Interestingly,
and found that the small OMe ester gave the highest yield as replacement of the phenyl group in the substrate diketone with
well as enantioselectivity (Table 1. Entry 9). Other leaving 1,3-cyclohexanediones led to the corresponding product 3l with
groups such as OPiv, OCO2Et and OFmoc were also examined moderate yield (60%) and enantioselectivity (50%). The poor
under the same condition, but the yields and result was likely due to the structure of the diketone, making it
enantioselectivities could not be retained simultaneously a less efficient H-bond donor for the thiourea catalysts.9
(Table1. Entries 10-12). Besides, when the α-proton of 2 was Furthermore, to examine the diversity of ester motif on 2, two
replaced with aryl and alkynyl, or modification of α-carbonyl
additional N,O-bis(tert-butoxycarbonyl) hydroxylamines were
subjected to the optimized condition, affording the products
(3m-n) in good to excellent yields (83%-98%). Product 3m had
Table 1 Optimization of reaction conditions.a
O
O
O
O
O
O
Ph
Ph
N
H
H
1a
O
O
N
N
CF3
Ph
Ph
R1
conditions
R2
R2
R1
O
Boc
N
H
O
Cat. 1
(10 mol%)
+
H
O
R2
R2
H/F
O
R3
N
Boc
+
R1
O
S
HN
R3
HN
Boc
toluene, r.t., 24 h
H/F
R1
OR4
O
CF3
3
N
H
2
1
2
3
Cat. 1
R
O
R
Temp. Yieldb
eec
(%)
92
10
92
92
77
69
90
94
96
96
96
87
3a
3b
3c
3d
3e
(X-ray,
, R = H, 99%, 96% ee
Entry
R1
R3
R4
Solvent
R
O
, R = 4-Me, 87%, 95% ee
, R = 4-OMe, 77%, 93% ee
, R = 4-F, 99%, 96% ee
, R = 4-Cl, 99%, 97% ee
(℃)
r.t.
r.t.
0
(%)
95
15
95
87
50
46
90
93
99
44
88
99
O
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
HN
Boc
, R = 2-Thienyl, 99%, >99% ee
CO2Me
1
2
OBn
OBn
OBn
OBn
OBn
OBn
OtBu
OEt
Boc
Bz
toluene
toluene
toluene
Et2O
O
R
3g
HN
Boc
CO2Me
R
CCDC 2007033
)
3
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
3h, R = OBn, 21%, 58% ee
3f
, R = 4-Br, 80%, 95% ee
4
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
5
THF
O
O
6
CHCl3
O
F
O
O
O
7
toluene
toluene
toluene
toluene
toluene
toluene
R
O
HN
CO2Me
HN
Boc
CO2Bn
HN
8
Boc
Boc R'
9
OMe
OMe
OMe
OMe
3i
3j
3k
3l
, 60%, 50% ee 3m
, R = H, 99%, 95% ee
, R = 4-Me, 92%, 91% ee
, R = 4-Cl, 99%, 94% ee
, R' = Ph, 83%, 55% ee
, R' = Me, 98%, 86% ee
10
11
12
Piv
3n
-CO2Et
Fmoc
Scheme 2 Substrate scope with symmetrical 1,3-diketones.a-c
aCondition: diketone 1 (0.2 mmol), imine surrogate 2 (0.3 mmol), Cat. 1 (10
mol%), toluene (2.0 mL), rt, 24 h. bIsolated yields. ee of the product was
aConditions: diketone 1a (0.2 mmol), imine surrogates 2 (0.3 mmol), Cat. 1
c
(10 mol%), solvent (2.0 mL), 24 h. bIsolated yields. ee of the product was
c
determined by HPLC analysis using a chiral stationary phase.
determined by HPLC analysis using a chiral stationary phase.
2 | J. Name., 2012, 00, 1-3
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O
O
O
O
O
O
O
O
View Article Online
DOI: 10.1039/D0CC06055K
O
O
Boc
N
R2
R2'
Cat. 1
(10 mol%)
Ph
Ph
CO2Me
R2
R2'
Boc
b
+
a
H/F
Ph
Ph
CO2Me
Ph
PhCOOH
+
MeO
O
toluene, r.t., 24 h
HN
Boc
HN
Boc
CO2Me
H/F
Boc
N
H
N
COOH
FmocHN
H
O
4
2a
5
3aa
74%, dr > 20:1
3a
, 2.03 g (gram scale)
99%, 96% ee
3ab
, 99%
OMe
OMe
Scheme 5 Gram scale synthesis and further modifications of 3a.a
aConditions: a) DCM:TFA = 3:1, rt; Fomoc-Ala-OH, EDCI, HOBt, DIPEA, DMF,
0 oC, rt; b) LiOH, sillica gel, MeOH:H2O = 3:1, rt.
O
O
O
O
O
O
F
HN
CO2Me
Boc
Cl
HN
Boc
CO2Me
Cl
HN
Boc
5b, 98%, 3:2 dr, 92% ee
CO2Me
yield, and 96% ee). To highlight the utility of the products in
organic synthesis, we explored the transferability of 3a.
Deprotection of Boc group followed by condensation with
Fomoc-Ala-OH gave the desired product 3aa in good yield and
diastereoselectivity. However, hydrolysis of the methyl ester
could not produce the corresponding acid or lactone, instead, a
de-benzoyl product 3ab was obtained in quantitative yield via
the reverse Claisen condensation pathway.12
5c
5a
, 99%, 1:1 dr, 94% ee
, 99%, 1:1 dr, 96% ee
O
O
OEt
O
O
O
O
F
O
OEt
CO2Me
CO2Et
HN
Boc
5d
CO2Me
HN
CO2Me
HN
Boc
5f
HN
CO2Me
Boc
5e
Boc
5g
, 84%
1:1 dr, 86% ee
, 93%
3:2 dr, 86% ee
, 99%
, 99%
1:1 dr, 81% ee 1:1 dr, 94% ee
Scheme
3
Substrate scope with unsymmetrical 1,3-diketones.a-c
In an effort to better understand the reaction, mechanism
verification experiments were carried out (Scheme 6). For the
convenience of monitoring, the reaction was conducted in C6D6.
After addition of the reactants, lot of bubbles (CO2) were
released immediately, tBuOH could be observed via both NMR
and GC-MS (See ESI for details), while the imine intermediate
2a’ cannot be detected (Scheme 6, A). In order to obtain imine
2a’, 2a was treated with Cat. 1, unfortunately, no desired
product was observed even by increasing the catalyst loading to
1 equivalent. In contrast, an unstable cycloaddition product I,
detected by LC-MS (See ESI for details), was formed as Drach
reported manner (Scheme 6, B),13 and addition of 1a to the
resulting reaction mixture could not promote the reaction
anymore. Other reactions including using organic bases (TEA,
DBU) or inorganic bases (K2CO3, NaOH) for the imine generation
were also performed, however, there was no product formed,
instead, a hydroxyl substituted dimer adduct 2aa was obtained
(Scheme 6, B). To further explore the catalytic process, control
experiment was performed by adding 2a to a solution of
diketone 1a and catalyst Cat. 1, to our delight, product 3a was
aCondition: diketone 4 (0.2 mmol), imine surrogate 2a (0.3 mmol), Cat. 1 (10
c
mol%), toluene (2.0 mL), rt, 24 h. bIsolated yields. ee of the product was
determined by HPLC analysis using a chiral stationary phase.
reduced enantioselectivity, presumably due to the different
electronic effects from the phenyl and methyl group. The
relative and absolute configuration of 3e were established by
single crystal X-ray analysis, and those of other products were
assigned by analogy (See ESI for details).10
Subsequently, unsymmetrical 1,3-diketones and β-ketoesters
were subjected to the reaction condition (Scheme 3). The
diketones with aryl groups (5a-b) or alkyl groups (5c-g) could all
proceed smoothly to furnish products in good to excellent yields
(84%-99%) and enantioselectivities (81%-96%), but a nearly
statistical mixture of diastereomers was obtained in all cases,
which bear a non-epimerizable β-dicarbonyl stereocenter.
As at least two H-bond receptors exist in diketones, they
could potentially influence the interactions of substrates with
the thiourea catalyst. To reduce the effect, β-monocarbonyl
compounds were used as nucleophiles following the catalytic
protocol (Scheme 4).11 To our delight, the reaction of 6a with 2a
could clearly improve the diastereoselectivity (8:1), albeit the
enantioselectivity was reduced (69% ee). Interestingly, when β-
carbonylnitrile 6b was employed as the nucleophile, the
reaction could proceed twice, giving rise to the double-addition
product 7b in good yield and excellent stereoselectivity (>20:1
dr, >99% ee).
O
O
O
O
A
Ph
Ph
Ph
Ph
CO2Me
+
tBuOH
NMR/MS (Bubbles)
1a
CO2
+
Cat. 1
Boc
+
Boc
N
N
H
C6D6, r.t., 1 h
MeO2C
3a
OBoc
99%, 96% ee
2a
Boc
N
Cat. 1
MeO2C
N
B
Boc
NHBoc
x
MeO2C
Base
2a'
OBoc
tBuOH, CO2
2a
We further performed a preparative scale experiment to
evaluate the practicability of this protocol (Scheme 5). The
desired product 3a was obtained smoothly under standard
condition without loss of reactivity and enantioselectivity (99%
O
CO2
tBuOH
N
S
N
CF3
1a
+
No reaction
N
O
CO2Me
H
N
Boc
Boc
N
N
CF3
H
MeO2C OH
I
, (unstable)
LC-MS confirmed
CO2Me
2aa
Ph
CO2Me
CN
H
Bz
CN
Ph
CN
NC Bz
H H
O
O
6a
6b
O
C
N
N
Cat. 1
Boc
Boc
MeO2C
N
Boc
Boc Boc
MeO2C CO2Me
7b
, 87%
>20:1 dr, >99% ee
C6D6
(1+1)
(2+1)
Standard
condition
N
H
CO2Me
Ph
Ph
CO2Me
+
MeO2C
N
+
Boc
Standard
condition
OBoc
r.t., 1 h
Boc
O
O
2a
N
H
7a
, 99%
8:1 dr, 69% ee
2a
3a
Ph
Ph
1a
99%, 96% ee
Scheme 4 Reaction of 2a with β-monocarbonyl nucleophiles.
Scheme 6 Mechanism studies.
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J. Name., 2013, 00, 1-3 | 3
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N
N
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CF3
CF3
View Article Online
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N
O
O
O
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BocO
OMe
S
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F3C
2a
N
F3C
N
H
N
O
N
N
N
H
H
O
H
O
H
H
H
O
O
OMe
O
O
N
A
B
Ph
O
Ph
Ph
Boc
Ph
2
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Z.-R. Li, X.-J. Peng, P.-L. Shao and Y. He, Org. Chem. Front.,
2018, 5, 36; (e) Z.-P. Wang, S. Xiang, P.-L. Shao and Y. He, J.
Org. Chem., 2018, 83, 10995.
(a) M. S. Taylor, N. Tokunaga and E. N. Jacobsen, Angew.
Chem. Int. Ed., 2005, 44, 6700; (b) J. Song, H.-W. Shih and L.
Deng, Org. Lett., 2007, 9, 603; (c) Y. Sohtome, S. Tanaka, K.
Takada, T. Yamaguchi and K. Nagasawa, Angew. Chem. Int.
Ed., 2010, 49, 9254.
O
O
CO2, tBuOH
O
Ph
Ph
1a
N
CF3
N
H
N
H
N
CF3
S
H
O
S
O
O
O
F3C
N
N
H
N
O
H
CF3
Ph
Ph
H
N
(R)
O
OMe
Boc
OMe
O
N
Cat. 1
O
Ph
N
H
O
C
Ph
3a
Scheme 7 Possible mechanistic pathway.
3
obtained in 99% yield without loss of enantioselectivity
(Scheme 6, C). These results indicated that N-carbamoyl imine
2a’ is very unstable and would be immediately trapped by the
nucleophiles once generated, the catalyst Cat. 1 couldn’t
chelate with imine to form a stable intermediate.
Although the detailed mechanism of this reaction requires in-
depth studies, a plausible mechanistic pathway is depicted
based on our studies and previous reports (Scheme 7).9 In this
process, as a strong H-bond accepter, dicarbonyl compound 1a
could be easily deprotonated and chelate to Cat. 1 via
hydrogen-bonding to form complex A. Next, the α-proton of 2a
would be abstracted by the tertiary amine of the catalyst, and
4
5
t
after releasing CO2 and BuOH, the resulting imine would be
hydrogen-bonded to the catalyst with nitrogen and oxygen on
the ester motif. Owing to the steric hindrance, the imine motif
is situated below the phenyl group. Subsequently, the imine
would be attacked by enol from the upside to form product 3a
with newly generated stereocenters and release of the catalyst.
In summary, we have successfully developed novel imine
surrogates, N,O-bis(tert-butoxycarbonyl) hydroxylamines,
which are simple to prepare, air stable at room temperature
and easy to use. The utility of such imine surrogates has been
demonstrated for the first one-pot catalytic asymmetric
synthesis of both α-amino esters and ketones with excellent
yield (up to 99%) and enantioselectivity (up to >99% ee). Further
applications of such imine surrogates in catalytic
transformations, medicinal chemistry as well as natural product
synthesis are ongoing, and shall be reported in due course.
We are grateful for the financial support from the Ministry of
Science and Technology of China (2019ZX09301-164) and
Natural Science Foundation of Chongqing, China (cstc2019jcyj-
zdxmX0021). We sincerely thank Dr. Wenshan Ren (Southwest
University) for the X-ray crystallographic analysis.
6
7
8
9
(a) Y. Takemoto, Org. Biomol. Chem., 2005, 3, 4299; (b) A. G.
Doyle and E. N. Jacobsen, Chem. Rev., 2007, 107, 5713; (c) M.
Hideto and T. Yoshiji, Bull. Chem. Soc. Jpn., 2008, 81, 785; (d)
Y. Takemoto, Chem. Pharm. Bull., 2010, 58, 593; (e) R. R.
Knowles and E. N. Jacobsen, Proc. Natl. Acad. Sci. U.S.A., 2010,
107, 20678.
10 CCDC 2007033 (3e) contains the crystallographic data for this
paper. The data can be obtained free of charge from the
Cabridge
Crystallographic
Data
Centre
via
Conflicts of interest
There are no conflicts to declare.
www.ccdc.cam.ac.uk/data_re-quest/cif. Selected data are
also included in the Electronic Supplementary Information.
11 T. B. Poulsen, C. Alemparte, S. Saaby, M. Bella and K. A.
Jǿgensen, Angew. Chem. Int. Ed., 2005, 44, 2896.
12 S. Chacko and R. Ramapanicker, Eur. J. Org. Chem., 2012, 36,
7120.
13 A. G. Balya, A. N. Chernega, S. A. But, A. N. Vasilenko, V. S.
Brovarets and B. S. Drach, Russ. J. Gen. Chem., 2008, 78, 1427.
Notes and references
1
(a) C. Mannich and W. KrÖsche, Arch. Pharm., 1912, 250, 647;
(b) Z. Bernstein, D. Ben-Ishai, Tetrahedron, 1976, 33, 881; (c)
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC06055K
O
O
Boc
N
O
EWG
H/F
O
R2
Boc

Thiourea catalyst
CO2
tBuOH
R1
O
O
EWG
H/F
R2
+
R1
H
N
H
,
Imine surrogates
O
R1 = OMe, Bn, Ph, Me
up to 99% yield, >20:1 dr, >99% ee
Bench stable
Readily available
Open to air Mild condition
An unpresented catalytic asymmetric method for the synthesis of α-amino esters and ketones
from novel imine surrogates is reported.