A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives: Via a bicyclic imidazole-catalyzed direct enantioselective C -acylation

Article abstract of DOI:10.1039/d0sc00808g

C^α-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral C^α-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding C^α-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

Full text of DOI:10.1039/d0sc00808g

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ARTICLE
A step-economic and one-pot access to chiral Cα-tetrasubstituted
α-amino acid derivatives via a bicyclic imidazole-catalyzed direct
enantioselective C-acylation
Received 00th January 20xx,
Accepted 00th January 20xx
Mo Wang,ab Muxing Zhou,b Lu Zhang,b Zhenfeng Zhang*b and Wanbin Zhang*ab
DOI: 10.1039/x0xx00000x
Cα-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and
pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more
efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient
synthesis of chiral Cα-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem
catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation;
the methodology affords the corresponding Cα-tetrasubstituted α-amino acid derivatives with excellent
enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to
important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic
chemistry.
which can be easily synthesized from imidazole in only three
steps.5f However, the efficiency of this transformation is
hindered by the prefabrication of unstable azlactones and
relatively inert O-acylated azlactones. Such inefficiencies are
present in many other transformations which lead to poor
practical applicability. 5b,6
Introduction
Cα-Tetrasubstituted α-amino acids are ubiquitous and unique
structural units in many natural products and synthetic
compounds, many of which exhibit significant biologically
activities and physiological effects (Fig. 1).1 Several feasible
methodologies have been developed for the synthesis of Cα-
tetrasubstituted α-amino acids, ranging from the use of chiral
auxiliaries to the presently reported catalytic models.2 These
include: (1) the enantioselective addition of alkyl, aryl, or even
acyl precursors (Strecker reaction followed by hydrolysis) to
ketimines,3 and; (2) the asymmetric α-alkylation, arylation, or
acylation of α-substituted amino acid derivatives.4,5 However,
due to the challenges imposed by Cα-tetrasubstituted α-amino
acids, efficient methods are still lacking, especially for the
synthesis of α-acyl-substituted Cα-tetrasubstituted α-amino
acid derivatives.5 The most commonly used approach relies on
the O-acylation of azlactones followed by a Lewis base-
catalyzed asymmetric O- to C-acyl transfer (well-known as
Steglich rearrangement, red arrows in Scheme 1). After the
initial work developed by Fu et al.,5a several improvements on
the asymmetric Steglich rearrangement have been reported by
many other research groups.5b−k Our group has also developed
an efficient bicyclic imidazole organocatalyst for this reaction,
O
Me
O
O
OH
H
OH
OH
B
HO
HO
COOH
Me NH2
H
Cl
COOH
Me NH2
CO2
H
NH
HO
NH2
H
O
Methyldopa
MABH
Salinosporamide A
OH
H2N
Altemicidin
OH
OH OH
COOH
OH
H
OH
H2
N
N
Me
NH2
OH
Me
OH
Me
HOOC
Me
COOH
COOH
O
COOH
Me
O
Methylserine
Conagenin
HMG
Myriocin
Fig. 1 Examples of Cα-tetrasubstituted α-amino acid derivatives
with biological activities and physiological effects.
In order to improve the synthetic efficiency, minimizing the
number of steps of the synthetic sequence is important. This
strategy, termed step-economy, has frequently been
employed in advanced total syntheses by utilizing new
reactions.7 Herein, we would like to put forward a more
general approach in which a two-step rearrangement process
(AB + C → AB-C → C-AB) is replaced by a direct reaction (AB +
C → C-AB) by altering chemoselectivity. As the first example,
we recently developed a bicyclic imidazole-catalyzed direct
enantioselective C-acylation of benzofuran-2(3H)-ones and 2-
oxindoles.8 For the most part, the starting material is directly
converted to the C-acylated product but not via the relatively
a. Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of
Chemistry and Chemical Engineering, Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240, China. E-mail:
wanbin@sjtu.edu.cn; zhenfeng@sjtu.edu.cn
b. School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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inert O-acylated intermediate. As a result, the efficiency for
the synthesis of the desired products is dramatically improved
compared to the cooresponding Black rearrangement.9
Inspired by this, and in continuation of our interest in the
construction of Cα-tetrasubstituted α-amino acids,10 we
propose a direct enantioselective C-acylation of azlactones
with the purpose of improving the synthetic efficiency for the
preparation of 4-carboxyazlactones (pink arrow in Scheme
1).11 To further improve the synthetic efficiency, simplifying
the operations via a sequential process in one pot is an
applicable method. This strategy, termed pot-economy, has
been widely used for the construction of multiple bonds in one
pot.12 Generally, different catalysts are used for different
reaction steps (tandem catalysis). Obviously, carrying out all
the reaction steps with a single catalyst would be more
beneficial (auto-tandem catalysis).13 This strategy, termed
catalyst-economy, has often been employed in two-step
sequences but seldom in multi-step sequences.13c During the
initial research concerning the direct enantioselective C-
acylation of azlactones, we found that the starting azlactones
could be prepared via intramolecular O-acylation of in-situ
generated anhydrides (shown in the square brackets in
Scheme 1); the produced 4-carboxyazlactones could be readily
derivatized by another acylation to produce various Cα-
tetrasubstituted α-amino acid derivatives. Therefore, by
combining the aforementioned step-, pot-, and catalyst-
economy strategies, we aimed to design a four-step acylation
sequence for the efficient synthesis of chiral Cα-
tetrasubstituted α-amino acid derivatives and biologically
active dipeptides from simple N-acylated amino acids. The
reaction would proceed via auto-tandem catalysis using a
single bicyclic imidazole nucleophilic catalyst (blue part in
Scheme 1). To the best of our knowledge, this type of
sequential reaction that achieves excellent enantioselectivity
has not been reported previously.
View Article Online
DOI: 10.1039/D0SC00808G
Results and discussion
We initially focused on screening the reaction conditions for
the first three steps in the sequence in one pot. (4-
Methoxybenzoyl)alanine 1a was selected as the starting
material and benzylamine was used as the nucleophilic
reagent to derivatize the produced 4-carboxyazlactone shown
in the square brackets in Table 1. Over the past decade, we
have developed a series of bicyclic imidazole nucleophilic
catalysts which have been successfully applied in a number of
different reactions by our group5f,8,9,14 and other groups15. We
envisaged that the bicyclic imidazole would be able to catalyze
all the steps in the acylation sequence. Several bicyclic
imidazole catalysts were screened for the sequential acylation
of 1a with benzyl chloroformate as the acylating agent and
di(isopropyl)ethylamine (DIPEA) as a base to afford product 2a
(Table 1, entries 1−4). Catalysts bearing an alkoxy group gave
better ee than those bearing an acyloxy group, and catalyst
OBn-DPI was found to give the best result. Replacing the
acylating agent, benzyl chloroformate with allyl chloroformate
or phenyl chloroformate, afforded the desired products in
lower yield and ee (entries 5 and 6, respectively). Use of ethyl
chloroformate only afforded a trace amount of the product
(entry 7). The base triethylamine (TEA) was also applied in this
reaction but no product was observed (entry 8). The effect of
solvents was studied and toluene provided the product with
the highest ee and satisfactory conversion (entries 4, 9−14).
After preliminary screening, the catalyst OBn-DPI, acylating
agent benzyl chloroformate, base DIPEA and solvent toluene
were chosen as the optimal conditions for further study,
affording the desired product in 78% yield and with 91% ee
(entry 4).
Next, the effect of reaction temperature was researched
(Table 2). At a lower reaction temperature of 0 °C for 36 h,
product 2a was obtained with same yield and better ee
compared to that of 20 °C (entries 1 and 2). When the reaction
temperature was reduced to −20 °C for 36 h, the yield of 2a
was reduced to 68% while the enantioselectivity increased to
95% (entry 3). Extending the reaction time to 48 hours gave
the product in an increased yield (76%, entry 4). So the
reaction was conducted for a longer time (72 h) to give better
yield when reaction temperature was further decreased
(entries 5−7). Finally, −55 °C was found to be the optimized
temperature with 78% yield and 99% ee (entry 6). Then the
equivalents of ClCOOBn were investigated and it was found
that 3.0 equivalents of ClCOOBn afforded the best results
(entries 6, 8 and 9). Therefore, the sequential reaction of
substrate 1a with 3.0 equivalents of benzyl chloroformate, 4.0
equivalents of DIPEA and 20 mol % OBn-DPI at −55 °C over 72
h was optimal for both reactivity and enantioselectivity,
leading to the product 2a in 78% yield and 99% ee (entry 8).
Previous work: step-by-step process with five acylations
O
O
R'
R
O
N
O-acylation
C-acylation
Ar
Steglich
Rearrangement
O
*
O
O
R'
R
O
R
Azlactones
O
O
O
N
N
Direct C-acylation
Ar
Ar
N-acylation
or
O-acylation
two
O-acylations
Nu-H
R
O
R'
HN
O
O
O
O
Ar
R'
N
R
R
Nu
OH
O
*
HN
N
HN
OBn
O
OBn-DPI
Ar
Ar
Chiral C-tetrasubstituted -amino acids derivatives
Racemic -amino acids
30 examples
up to 83% yield and 99% ee
This work: one-pot sequence via auto-tandem catalysis
Scheme
1
Our new approach to enantiopure Cα-
tetrasubstituted α-Amino acid derivatives by a four-step
acylation sequence using auto-tandem catalysis.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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1
c
Table 1 The effect of catalyst, acylating reagent, base, and calculated from H NMR spectra. The ee values were cVailecwuAlarttieclde Ofrnolinme
d
e
DOI: 10.1039/D0SC00808G
solvent
HPLC spectra. ClCOOBn (3.0 eq). ClCOOBn (2.5 eq).
O
O
O
BnHN
PMP
H
O
BnNH2 (1.5 eq)
36 h, 20 °C
catalyst (20 mol %)
PMP
N
O
+
ClCOOR
(3.5 eq)
Having established the optimal reaction conditions, we
investigated the nucleophile in the last step of the sequential
process, employing (4-methoxybenzoyl)alanine 1a as the initial
substrate (Scheme 2). Firstly a number of different alkyl
amines and a phenyl amine were tested as nucleophiles (2a−d).
Amines with less steric hindrance showed higher yields (2a, b
vs 2c, d). Cholamine, bearing both amino and hydroxyl groups,
was also used as the nucleophile. Due to the wide difference in
the activity of the alcohols and amines for this reaction, only
the product 2e was obtained, via attack of the amino group,
with good yield and excellent enantioselectivity (98% ee).
Secondly, excess methanol was employed as a nucleophile in
this reaction to give the corresponding product 2f with similar
results. In addition, a variety of amino acid esters gave their
corresponding enantiomerically pure dipeptides, which will be
of particular use in the fields of biology and medicine (2g−r).
When using an enantiomerically pure amino acid ester which
OH
O
HN
base (4.0 eq)
solvent (2 mL)
36 h, 20 °C
OR
N
O
PMP
OR
O
1a
(0.2 mmol)
2
N
N
N
N
N
N
N
N
OAc
OMe
OMe-DPI
OEt
OBn
OAc-DPI
OEt-DPI
OBn-DPI
entrya catalyst
acylating
reagent
solvent
yield
(%)b
ee
(%)c
1
2
OAc-DPI
OMe-DPI
OEt-DPI
OBn-DPI
OBn-DPI
OBn-DPI
OBn-DPI
OBn-DPI
OBn-DPI
OBn-DPI
OBn-DPI
OBn-DPI
OBn-DPI
OBn-DPI
ClCOOBn
ClCOOBn
ClCOOBn
ClCOOBn
toluene
toluene
toluene
toluene
77
62
65
78
71
81
84
87
88
91
91
60
-
3
4
5
ClCOOallyl toluene
6
ClCOOPh
ClCOOEt
ClCOOBn
ClCOOBn
ClCOOBn
ClCOOBn
ClCOOBn
ClCOOBn
ClCOOBn
toluene
7
toluene trace
contained
a chiral center, the corresponding dipeptide
8d
9
toluene
THF
-
-
products bearing two stereocenters were obtained with high
dr (>99:1, 2l−r).
80
77
30
66
45
76
90
90
91
91
88
71
10
11
12
13
14
dioxane
Et2O
N
O
N
OBn
O
O
H
Nu
Nu-H (1.5 eq)
36 h, 20 °C
PMP
N
O
OBn-DPI
(20 mol %)
O
+
ClCOOBn
(3.0 eq)
OH
O
HN
MTBE
DCM
DIPEA (4.0 eq)
toluene (2 mL)
72 h, -55 °C
O
OBn
N
PMP
PMP
OBn
1a
(0.2 mmol)
O
2
HO
O
O
O
O
O
t-AA
BnHN
HN
N
H
N
PhHN
HN
N
O
O
O
O
O
H
H
HN
HN
HN
aConditions: 1a (0.1 M), ClCOOR (3.5 eq), catalyst (20 mol %), DIPEA
OBn
OBn
OBn
OBn
OBn
PMP
PMP
PMP
PMP
PMP
O
O
O
O
O
b
(4.0 eq), solvent (2 mL), 20 °C, 36 h, unless otherwise noted. Yields
2a
2b
2c
2d
2e
75% yield, 99% ee
78% yield, 99% ee
65% yield, 98% ee
69% yield, 98% ee
77% yield, 98% ee
1
c
were calculated from H NMR spectra. The ee values were calculated
from HPLC spectra. dTEA was used instead of DIPEA and only azlactone
without COOBn substituent was obtained together with some
NEt2COOBn.
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
O
O
O
O
O
H
H
H
H
HN
HN
HN
HN
HN
OBn
OBn
OBn
OBn
OBn
PMP
O
PMP
PMP
PMP
PMP
O
O
O
O
2f
2g
2h
2i
2j
72% yield, 98% ee
78% yield, 98% ee
75% yield, 98% ee
67% yield, 98% ee
81% yield, 98% ee
Table 2 The effect of reaction temperature
O
O
O
O
O
O
O
O
O
N
O
O
O
O
O
O
O
N
OBn
O
N
N
N
N
N
H
HN
O
BnHN
PMP
H
O
O
O
O
O
H
H
H
H
O
BnNH2 (1.5 eq)
36 h, 20 °C
OBn-DPI
(20 mol %)
PMP
N
O
HN
HN
HN
HN
+ ClCOOBn
(3.5 eq)
OH
O
HN
DIPEA (4.0 eq)
toluene (2 mL)
36-72 h, temp
OBn
OBn
OBn
OBn
OBn
OBn
N
PMP
PMP
PMP
PMP
PMP
O
PMP
O
O
O
O
O
OBn
O
1a
(0.2 mmol)
2k
2l
2m
2n
2o
2a
80% yield, 97% ee
79% yield, >99:1 dr 80% yield, >99:1 dr
78% yield, >99:1 dr
74% yield, >99:1 dr
entrya temp. (°C)
time (h)
yield (%)b ee (%)c
O
O
O
O
O
O
O
O
O
1
20
36
36
36
48
72
72
72
72
72
78
78
68
76
78
78
77
78
75
91
93
95
95
98
99
98
99
99
N
N
N
H
HN
O
O
O
OBn
H
H
2
0
HN
HN
OBn
OBn
PMP
PMP
PMP
3
4
5
6
−20
−20
−50
−55
−60
−55
−55
O
O
O
2p
79% yield, >99:1 dr
2q
2r
76% yield, >99:1 dr
80% yield, >99:1 dr
Scheme 2 Expanding the nucleophiles. All the yields are
isolated yields. 1H NMR spectroscopy of the crude reaction
products was used to assess diastereoisomeric ratios (dr).
7
8d
9e
aConditions: 1a (0.1 M), ClCOOBn (3.5 eq), OBn-DPI (20 mol %), DIPEA
(4.0 eq), toluene (2 mL), unless otherwise noted. bYields were
Various N-protected α-amino acid substrates 1 were tested
in the sequential process using methyl 3-aminopropanoate as
the nucleophile (Scheme 3). Firstly, N-substituted amino acid
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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substrates bearing a methoxy group at the para-, meta-, and
ortho-positions of the phenyl ring were tested in the domino
View Article Online
DOI: 10.1039/D0SC00808G
Having explored the substrate scope of both nucleophiles
reaction (2j, 2s and 2t). All these products were obtained in and amino acids, we focused on elucidating the effect of the
good yields and with excellent enantioselectivities. The effect catalyst OBn-DPI in each step of the acylation sequence
of different substituents at the para-position of the phenyl ring (Scheme 4). Firstly, benzoylalanine 1h was reacted with 1.0
was studied (2u−x). Substrates bearing electron-donating equivalent of benzyl chloroformate in the presence or absence
groups such as Me or tBu, and electron-withdrawing groups of catalyst OBn-DPI to test the effect of the catalyst in the first
such as F or Cl, all afforded the corresponding products in good two O-acylation steps (step I and step II). In the presence of
yields and with excellent enantioselectivities. The presence of the catalyst, 1h afforded the cyclized product 3 in 63% yield at
an electron-withdrawing group enhances the acidity of the −55 °C in 10 min; however in the absence of catalyst, 1h only
substrate and its corresponding intermediates in the two O- gave the desired product 3 in 35% yield. We next subjected 3
acylation steps and the C-acylation step (see proposed to reaction with benzyl chloroformate in the presence or
mechanism below), thus reducing the reaction time of these absence of catalyst OBn-DPI to test effect of the catalyst in the
substrates to 8 h, much shorter than the reaction time for third C-acylation step (step III). In the presence of the catalyst,
substrates bearing electron-donating groups (72 h).
A
3 afforded C-acylated product 4 in 93% yield in 10 h, whereas
substrate without a substituent group on the phenyl ring also in the absence of catalyst, 3 was unable to afford C-acylated
gave the corresponding product 2y in 80% yield and with 98% product 4 giving O-acylated compound 5 in 26% yield.
ee within 10 h. We then employed simple N-benzoyl amino Compound 5 was then employed as a reactant at −55 °C in the
acids to study the influence of the R group on the stereocenter presence of the catalyst OBn-DPI; no rearrangement product 4
(2y−ae). The substrate bearing a phenyl substituent gave the was observed after 24 h. These experimental results strongly
corresponding product 2ae with only 57% ee, and the support that 3 undergoes a direct C-acylation to afford 4.
substrate bearing an isopropyl group only gave the O-acylated Finally, 4 was reacted with an amino acid ester in order to test
byproduct. All other tested substrates gave the corresponding the effect of the catalyst in the last step (step IV). In the
products in good yields and with excellent enantioselectivities. presence of the catalyst, 4 afforded final product 2y in 85%
It’s worth mentioning that products 2ab and 2ac were both yield at 20 °C in 18 h, whereas 2y was only obtained in 46%
obtained with 99% ee.
yield in the absence of catalyst.
OBn-DPI
I
in step and step
II
The effect of catalyst
N
O
MeOOC
NH2
O
O
DIPEA (2.0 eq)
O
O
BnO
+
N
ClCOOBn (1.0 eq)
MeOOC
(1.5 eq)
36 h, 20 °C
OBn
O
O
O
O
Ph
N
CO2H
H
N
N
N
R
H
OBn-DPI
(20 mol %)
Ar
N
O
OBn-DPI
(20 mol %)
H
O
R
OH
+
ClCOOBn
(3.0 eq)
Toluene, -55 °C, 10 min
Ph
Ph
O
HN
DIPEA (4.0 eq)
I
step
1h
O
R
OBn
N
Ar
3
4
Ar
toluene (2 mL)
8-72 hb, -55 °C
&
step
OBn
O
1
(0.2 mmol)
yield: 63%
yield: 5%
II
2
OBn
O
O
O
MeOOC
MeOOC
O
O
DIPEA (2.0 eq)
ClCOOBn (1.0 eq)
O
N
O
O
N
MeOOC
MeOOC
O
H
O
H
Ph
N
CO2H
HN
N
N
HN
O
N
O
H
+
O
O
OBn
Toluene, -55 °C, 10 min
H
H
N
OBn
OBn
HN
HN
O
O
Ph
Ph
OBn
1h
O
3
5
O
O
O
O
yield: 35%
yield: 4%
2j
2s
2t
2u
OBn-DPI
III
The effect of catalyst
in step
BnO
OBn
O
81% yield, 98% ee
83% yield, 97% ee
76% yield, 98% ee
74% yield, 98% ee
O
MeOOC
OBn
O
O
O
O
O
O
O
O
DIPEA (1.0 eq)
ClCOOBn (1.0 eq)
O
MeOOC
BnO
O
O
O
O
O
+
MeOOC
MeOOC
N
N
O
OBn-DPI
N
(20 mol %)
N
N
O
N
OBn-DPI
(20 mol %)
O
N
N
N
H
Ph
Ph
Ph
Toluene, -55 °C, 24 h
O
O
O
OBn
Toluene, -55 °C, 10 h
H
H
H
Ph
HN
HN
HN
HN
Ph
OBn
4
4
5
trace
3
OBn
OBn
5
yield: 93%
O
O
O
O
F
Cl
OBn
III
step
O
OBn
O
O
O
2v
2w
2x
2y
DIPEA
(2.0 eq)
ClCOOBn
(1.0 eq)
78% yield, 98% ee
76% yield, 97% ee
73% yield, 98% ee
80% yield, 98% ee
O
MeOOC
O
BnO
O
O
O
O
O
OBn-DPI
O
(20 mol %)
DIPEA (1.0 eq)
ClCOOBn (1.0 eq)
N
O
N
BnO
O
N
Toluene, -55 °C, 24 h
O
Ph
N
+
O
O
O
N
MeOOC
MeOOC
MeOOC
Ph
5
4
Toluene, -55 °C, 10 h
Ph
Ph
N
N
N
N
Ph
O
O
O
O
OBn
H
H
H
H
Experimental proof of direct C-acylation
4
5
3
HN
HN
HN
HN
yield: 0%
yield: 26%
OBn
OBn
OBn
O
O
O
O
IV
The effect of catalyst OBn-DPI in step
O
O
O
2z
2aa
2ab
2ac
MeO2
C
BnO
CO2Me
78% yield, 98% ee
77% yield, 98% ee
O
MeOOC
74% yield, 99% ee
75% yield, 99% ee
N
H2
N
(1.5 eq)
(20 mol %)
Toluene, 20 °C, 18 h
O
N
O
H
HN
OBn-DPI
OBn
Ph
OBn
Ph
O
O
MeOOC
O
O
4
2y
N
N
O
H
O
O
H
H
yield: 85%
Ph
N
O
N
HN
HN
IV
step
OH
O
O
OBn
OBn
O
O
MeO2
C
O
O
BnO
CO2Me
N
H2
N
(1.5 eq)
O
N
O
H
2ad
82% yield, 97% ee
2ae
73% yield, 57% ee
HN
Toluene, 20 °C, 18 h
O-acylated byproduct
OBn
Ph
Ph
2y
O
4
Scheme 3 Expanding the racemic amino acid substrates. All
the yields are isolated yields. Reaction time for 2s−v is 72 h,
reaction time for 2w−x is 8 h, reaction time for 2y−ad is 10 h.
yield: 46%
4 | J. Name., 2012, 00, 1-3
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ARTICLE
Scheme 4 Experimental studies on the effect of catalyst OBn- enantiomerically pure amino acids or dipeptides which
View Article Online
DPI and direct C-acylation. Yields were calculated from 1H NMR contained a chiral center afforded products bearing three
DOI: 10.1039/D0SC00808G
spectra.
stereocenters with high dr (7b−d, 7f−g).
O
O
O
HCTU, Cl-HOBt
MeOOC
MeOOC
MeOOC
O
N
N
N
NH2R, 2,6-lutidine
O
O
O
H
H
H
Pd(OH)2/C, H2 (3 atm)
MeOH, 20 °C, 12 h
Based on these results, a mechanism for the four-step
HN
HN
HN
0 °C to 20 °C
CH2Cl2, 12 h
OBn
OH
NHR
acylation sequence has been proposed (Scheme 5). First, the
catalyst OBn-DPI and benzyl chloroformate generate active
species A. In the presence of DIPEA, N-substituted amino acid
substrates 1, such as 1h, attack A to generate the intermediate
O
O
O
O
O
2n
>99:1 dr
6
NH2R = amino acid or dipeptide
O
7
99% yield
O
O
O
MeOOC
MeOOC
N
MeOOC
MeOOC
N
N
N
O
O
O
O
H
H
H
H
HN
HN
HN
HN
HN
HN
HN
HN
Bn
mixed anhydride B. Reaction of
B
and OBn-DPI gives
via an
O
O
O
O
O
O
O
O
COOMe
COOMe
COOMe
COOMe
intermediate which generates azlactone
C
3
7a
83% yield, >99:1 dr
7b
86% yield, >99:1 dr
7c
85% yield, >99:1 dr
7d
79% yield, >99:1 dr
intramolecular cyclization. In step III, azlactone 3 attacks the
active species A to form C-acylated azlactone 4 via an
enantioselective direct C-acylation. This chiral compound 4 and
catalyst OBn-DPI form active intermediate D, which is attacked
by the amino acid ester to further generate valuable dipeptide
2y via N-acylation. Experimental studies suggest that OBn-DPI
acts as a nucleophilic catalyst in all the steps of the acylation
tripeptide
O
O
O
MeOOC
MeOOC
MeOOC
N
N
N
H
O
O
O
H
H
HN
HN
HN
HN
O
HN
O
HN
O
O
O
O
O
O
O
OMe
OMe
OMe
N
N
N
H
H
H
O
O
O
7e
78% yield, >99:1 dr
7f
7g
78% yield, >99:1 dr
89% yield, >99:1 dr
tetrapeptide
sequence with compound 4 being formed from direct C- Scheme 6 Synthesis of small peptide. All the yields are isolated
1
acylation.
yields. H NMR spectroscopy of the crude reaction products
was used to assess diastereoisomeric ratios (dr).
N
BnO
O
O
OBn-DPI
OBn
Furthermore, the utility of this acylation sequence was
demonstrated via the enantiodivergent synthesis of α-methyl
serine from 2f by manipulating the different reactivities of the
two ester groups (Scheme 7). Hydrogenation of the benzyl
ester group of 2f with Pd(OH)2/C in MeOH at 20 °C for 12 h
provided 8 in quantitative yield. Reduction of 8 with LiBH4 in
THF at ambient temperature for 12 h afforded the (R)-isomer
of N-protected α-methyl serine, (R)-10, in 83% yield. Hydrolysis
of the methyl ester group of 2f with KOH in THF/H2O at 20 °C
provided 9 in 78% yield, which was reduced with LiBH4 to give
the (S)-isomer of N-protected α-methyl serine, (S)-10, in 85%
yield.
N
OBn
O
O
Cl
N
N
O
A
BnO
DIPEA
O
O
OBn
HN
O
HN
C
O
DIPEA
OH
Ph
Ph
B
O-acylation
O-acylation
HN
O
Ph
I
Step
1h
II
Step
DIPEA
O
H
Sequential
Acylation
N
*
N
O
N
OBn
Azlactone
3
Ph
OBn-DPI
O
O
IV
Step
BnO
III
Step
NHCH2CH2CO2Me
O
N
N
HN
OBn
C-acylation
N-acylation
Ph
BnO
O
A
2y
O
O
BnO
O
BnO
O
O
N
O
N
BnO
HO
N
C-acylated
Azlactone
O
MeO
HN
4
LiBH4, THF
20 °C, 12 h
Ph
O
OH
atm)
h
HN
HN
O
3
(
NH2CH2CH2CO2Me
OH
2
1
H2
D
PMP
Ph
2/C,
20
Pd(OH)
MeOH,
°C,
O
PMP
O
O
8
99% yield
Scheme 5 Proposed mechanism for the four-step acylation
sequence via auto-tandem catalysis (the anion is omitted in A,
B, C, and D for clarity).
(R)-10
83% yield
98% ee
MeO
HN
O
KOH,
20
OBn
PMP
O
HO
O
HO
THF/H
O
°C,
2
4
O
LiBH4, THF
20 °C, 12 h
2f
98% ee
h
O
OBn
HN
HN
OH
PMP
PMP
O
9
78% yield
O
(S)-10
Small peptides play a significant role in many biological,
pharmaceutical, and environmental applications.16 Therefore
the stereoselective synthesis of such biomolecules is of great
importance. Here, we describe the concise synthesis of small
optically active peptides from the sequentially acylated
product 2n (Scheme 6). Firstly, Cα-tetrasubstituted α-amino
acid 6 could be obtained from hydrogenation of 2n under 3
atm hydrogen pressure with Pd(OH)2/C in quantitative yield.
Then, coupling of 6 with several different amino acids or
dipeptides afforded a variety of valuable small chiral peptides
in good yields (7a−g). In particular, coupling of 6 with
85% yield
98% ee
Scheme 7 Enantiodivergent synthesis of α-methyl serine. All
the yields are isolated yields.
In addition, we realized the synthesis of 4,4’-disubstituted
oxazoline from 2a, as shown in Scheme 8. Reduction of 2a with
LiBH4 in THF provided the corresponding alcohol 11.
Mesylation of 11 with methanesulfonyl chloride in DCM at 0 °C
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J. Name., 2013, 00, 1-3 | 5
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ARTICLE
Journal Name
in the presence of triethylamine, followed by intramolecular
cyclization at 20 °C in one pot, finally afforded oxazoline 12 in
94% yield (74% overall from 2a). This method allows for the
practical synthesis of chiral oxazolines, which can be used as
chiral ligands for asymmetric catalysis.17
Conflicts of interest
The authors declare that they have no conflict of interest.
View Article Online
DOI: 10.1039/D0SC00808G
Acknowledgements
This work was partially supported by National Natural Science
Foundation of China (Nos. 21572131, 21620102003 and
91856106) and Shanghai Municipal Education Commission
(No. 201701070002E00030). We thank the Instrumental
Analysis Center of Shanghai Jiao Tong University.
O
O
O
BnHN
HN
BnHN
HN
MsCl, Et3N, CH2Cl2
0 °C to 20 °C, 72 h
BnHN
PMP
LiBH4, THF
20 °C, 12 h
O
N
OBn
OH
O
PMP
PMP
O
O
2a
99% ee
11
79% yield
12
94% yield
98% ee
Scheme 8 Synthesis of 4,4’-disubstituted oxazoline. All the
yields are isolated yields.
Notes and references
1
(a) H. Bräuner-Osborne, J. Egebjerg, E. Ø. Nielsen, U. Madsen
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Experimental
Under a N2 atmosphere, the substrate 1h (0.2 mmol, 44.7 mg),
the catalyst OBn-DPI (0.04 mmol, 8.6 mg) and DIPEA (0.8
mmol, 132.2 µL) were dissolved in anhydrous toluene (2 mL)
and cooled to -55 °C in a dry two-necked flask. ClCOOallyl (0.6
mmol, 84.5 µL) was then added and the vial was sealed with a
septum. The reaction mixture was stirred at -55 °C for 10 h and
then the temperature was gradually raised to 20 °C. Methyl 3-
aminopropionate hydrochloride (0.3 mmol, 41.9 mg) and
DIPEA (0.3 mmol, 49.6 µL) were dissolved in anhydrous
toluene (1 mL) in another dry flask and stirred for 10 min. Then
the mixture was transferred into the former reaction flask and
the reaction mixture was stirred at 20 °C for 36 h. The reaction
mixture was quenched with 0.2 M HCl (5 mL) and extracted
with DCM (5 mL × 3). The combined organic phases were dried
over Na2SO4. After filtration, the residue was purified by
column chromatography (petroleum ether/ethyl acetate) to
give the corresponding product 2y. The ee value was
determined by chiral HPLC analysis after purification by
column chromatography (petroleum ether/ethyl acetate).
2
3
4
Conclusions
In summary, the first four-step sequential acylation reaction
for the concise asymmetric synthesis of Cα-tetrasubstituted α-
amino acid derivatives via auto-tandem catalysis has been
successfully developed. This step-economic, one-pot, and
auto-tandem strategy is promoted by a direct enantioselective
C-acylation. Through four acylations catalyzed by a single chiral
bicyclic imidazole, the simple N-acylated amino acids could be
smoothly converted to the corresponding Cα-tetrasubstituted
α-amino acid derivatives with excellent enantioselectivities (up
to 99% ee). Significantly, the obtained products, particularly
dipeptides, are potentially biologically active compounds.
These products can be further transformed to other
biomolecules and important chiral building blocks such as
small peptides, α-substituted serines and 4,4’-disubstituted
oxazolines.
5
Selected examples for asymmetric α-acylation of α-
substituted amino acid derivatives, see: (a) J. C. Ruble and G.
C. Fu, J. Am. Chem. Soc., 1998, 120, 11532-11533; (b) S. A.
6 | J. Name., 2012, 00, 1-3
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ARTICLE
Shaw, P. Aleman and E. Vedejs, J. Am. Chem. Soc., 2003, 125,
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DOI: 10.1039/D0SC00808G
O
O
O
R'
four-step acylation sequence
R
Nu
R
in one-pot via auto-tandem catalysis
OH
O
HN
HN
O
Ar
N
Ar
Chiral C-tetrasubstituted -amino acids derivatives
Racemic -amino acids
up to 83% yield and 99% ee
N
31 examples
OBn
OBn-DPI
N-acylation
OBn-DPI
O-acylation
ClCOR'
OBn-DPI
or
Nu-H
O-acylation
O
O
O
O
OBn-DPI
ClCOR'
R
O
R
R'
OBn-DPI
O
O
R'
O
R
N
HN
O
N
Direct C-acylation
O-acylation
Ar
Ar
Ar
The first four-step sequential reaction for the synthesis of Cα-tetrasubstituted chiral α-amino acid
derivatives via auto-tandem catalysis has been developed.