Selectivity control in enantioselective four-component reactions of aryl diazoacetates with alcohols, aldehydes and amines: An efficient approach to synthesizing chiral β-amino-α-hydroxyesters

Article abstract of DOI:10.1039/b816104f

Enantioselective four-component reactions of aryl diazoacetates with alcohols, aldehydes and amines catalyzed cooperatively by a rhodium complex and a chiral Bronsted acid produce β-amino-α-hydroxyl acid derivatives in a single step with excellent control

Full text of DOI:10.1039/b816104f

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Selectivity control in enantioselective four-component reactions of aryl
diazoacetates with alcohols, aldehydes and amines: an efficient approach
to synthesizing chiral b-amino-a-hydroxyestersw
Xinfang Xu, Jing Zhou, Liping Yang and Wenhao Hu*
Received (in College Park, MD, USA) 15th September 2008, Accepted 9th October 2008
First published as an Advance Article on the web 11th November 2008
DOI: 10.1039/b816104f
Enantioselective four-component reactions of aryl diazoacetates
with alcohols, aldehydes and amines catalyzed cooperatively by
a rhodium complex and a chiral Brønsted acid produce b-amino-
a-hydroxyl acid derivatives in a single step with excellent control
of chemo-, diastereo- and enantioselectivity.
Scheme 1
b-Amino-a-hydroxy acids are very useful building blocks and
important pharmacophores in numerous bioactive natural pro-
ducts that display antitumor, antibiotic, or antifungal properties.1
In addition, compounds of this family are incorporated into many
biologically active peptides, such as amastatin, bestatin, BACE1
amyolid, and aminopeptidases.2 Particularly, the presence of a
quaternary stereocenter in a highly substituted b-amino acid unit,
which is characterized by a conformational constraint, will inter-
act with certain proteases and resist proteolytic degradation.3
In recent years, much attention has been devoted to the
synthesis of chiral b-amino-a-hydroxy acid core structures.4
However, most of the synthetic approaches are multi-step
reactions. Recently, our group reported an enantioselective
three-component single step reaction in which an in situ gener-
ated oxonium ylide is trapped by an imine to give the b-amino-
a-hydroxy acid derivatives bearing a quaternary stereogenic
carbon center (Scheme 1).5 Since the imine could be generated
in situ from corresponding aldehyde and amine, we envisioned
that by optimizing reaction conditions, it should be possible to
conduct a four-component reaction of a diazoacetate and an
alcohol with the aldehyde and the amine. Advantages of such an
approach include: (1) reducing by one step the imine prepara-
tion; (2) facilitating the preparation of imines that are otherwise
difficult to synthesize in a pure form due to the reversibility of
their formation; and (3) increasing the flexibility of manipulation
for rapid building of a large library of compounds. These
advantages have been widely demonstrated in the literature.6
The multicomponent reactions (MCRs) offer substantial
advantages over the traditional approach because they often
use smaller quantities of reagents and reduce the time and effort
required.7 The modular character of MCRs is also suitable for
drug discovery, and it is therefore widely used for the fast
generation of bioactive compounds.8 However, one of the most
challenging issues associated with multi-component reactions is
chemoselectivity control. This is particularly difficult in the
current four-component ylide trapping process because there
are several ylide intermediates that can irreversibly lead to
undesired side products in the reaction. Since imine formation
is a reversible process, the presence of unreacted amine and
corresponding aldehyde increases the complexity of the reaction
(Scheme 2). In addition to our desired reaction pathway of
trapping the protonated oxonium ylide with the in situ
generated imine (path A), possible side reaction pathways
include: (1) trapping of onium ylides with the aldehyde
(path B);9 (2) O–H insertion and N–H insertion (path C);10
and (3) epoxidation of the aldehyde (path D).11
We envisioned that a Brønsted acid would play a dual role in
the current reaction. First, it would accelerate the imine forma-
tion, and second, it would activate the imine by iminium
formation to be a more reactive electrophile to trap the
oxonium ylide. Both effects of the acid additive would favor
the reaction kinetics of the desired reaction pathway A. To
validate this hypothesis, we screened a number of acid additives
in the four-component reaction of methyl phenyldiazoacetate,
benzyl alcohol, benzaldehyde and aniline. The results of this
reaction are summarized in Table 1. A control reaction in the
absence of an acid additive was conducted. Inherent reaction
kinetics led to a mixture of four compounds 6–9, from which
the desired four-component product 6 was isolated with a less
than 10% yield (entry 1). As anticipated, acid additives
Department of Chemistry, East China Normal University, 3663
Zhongshan Bei Road, Shanghai, 200062, China.
E-mail: whu@chem.ecnu.edu.cn
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b816104f
Scheme 2 Possible pathways of the four-component reaction.
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Table 1 Optimization of chemoselective four-component reactionsa
terms of giving higher ee (entries 3 vs. 4 and 7 vs. 8). The
reaction appears less sensitive to the electronic effect of the
aldehyde (entries 4–7).
Using the above optimized reaction conditions, the reaction
scope was extended to additional substrates, with the results
summarized in Table 3. In most cases, only syn-products were
obtained with an ee greater than 90% and moderate to good
yields. Aldehydes with o-, m-, or p-substituted, electron-poor or
electron-rich (entries 1–7), and even bulky aldehydes (entries 8
and 9) are all tolerated. p-Substituted aryldiazo compounds
were superior to o- and m-substituted substrates (entries 10–12).
In addition, ethyl aryldiazo compounds (entries 13 and 14) and
ethyl trans-styryldiazoacetate (entry 15) gave the desired pro-
duct with an excellent ee. When cyclohexyl formaldehyde was
employed, the ee dropped to 49%, with a lower yield under the
current reaction conditions (entry 16).
Entry
Cat.
Yield (%)b
6 : 7 : 8 : 9
Dr (6)c
1
2
3
4
—
o10
o10
21
33
32
22 : 7 : 54 : 17
10 : 0 : 36 : 54
25 : 0 : 21 : 54
75 : 0 : 10 : 15
49 : 0 : 33 : 18
78 : 0 : 5 : 17
76 : 0 : 6 : 18
78 : 22
—
PhCOOH
AcOH
TFA
TMSOTf
TsOH
TsOH
70 : 30
83 : 17
62 : 38
81 : 19
82 : 18
5
6
57
56
7d
a
Unless otherwise noted, the reaction was carried out on a 0.25 mmol
scale and 4 (0.30 mmol) and 1 (0.275 mmol) were added to the mixture
in 1 h. Isolated yield of 6. Determined by 1H NMR spectroscopy of
d
the crude reaction mixture. 1.5 eq. of 4 was added.
b
c
For insight into the role of phosphoric acid in promoting the
imine formation, we conducted a control reaction in a NMR
tube. While 95% conversion of the imine from benzaldehyde
and aniline was achieved within 5 min in the presence of
2 mol% 5, the same conversion was achieved only after more
than 24 hours in the absence of the acid catalyst (see ESIw).
The proposed reaction mechanism is shown in Scheme 3.
The reaction proceeds through oxonium ylide intermediates
IIa or IIb, which are generated in situ from carbenoid I and 2.
The intermediates IIa/IIb are trapped by electrophilic imines
generated in situ from aldehydes and amines, leading to the
optically active product 6.
increased the chemoselectivity (entries 2–6). TsOH was identified
as the best acid catalyst among those screened, as the desired
product 6 was isolated with a 57% yield with 81 : 19 diastereo-
selectivity favoring the syn-isomer (entry 6). The concept of
combining a metal and an organic catalyst to broaden reaction
scope has been previously demonstrated in the literature.12
Our next effort was to incorporate a chiral Brønsted acid to
achieve the enantioselective four-component reaction, taking
advantage of our previous study of the enantioselective three-
component reaction. Chiral phosphoric acid 5 was employed
as the chiral catalyst of choice. The four-component reaction
was promoted by the chiral phosphoric acid (Table 2, entry 1),
and the bulky alcohol 2b significantly increased the dr value to
99 : 1 and the ee value to greater than 81% (entry 2). The ee
value increased to 91% at a lower reaction temperature (entry 3).
p-Anisidine 3b was superior to aniline and 4-toluidine in
Table 3 Enantioselective four-component reactions of alcohol 2b
with various diazo compounds 1, amines 3 and aldehydes 4a
Table 2 The enantioselectivity of the four-component reactionsa,b
Yield
(%)b
Ee
Entry Ar1 (1)
Ar4 (4)
6
Drc
(%)d
1
2
3
PMP (1a)
PMP (1a)
PMP (1a)
p-ClC6H4
Ph
m-
6h 72
6i 79
6j 62
499 : 1 95
499 : 1 97
499 : 1 92
MeC6H4
4
5
6
7
8
PMP (1a)
PMP (1a)
PMP (1a)
PMP (1a)
PMP (1a)
p-MeC6H4 6k 54
o-BrC6H4 6l 79
m-BrC6H4 6m 61
499 : 1 91
499 : 1 95
499 : 1 97
499 : 1 95
499 : 1 96
p-BrC6H4
6n 90
6o 42
Yield
(%)c
Ee
Entry 2/3
4 (Ar4)
T (1C)
6
Drd
(%)e
1
2
3
4
5
6
7
8
2a/3a Ph
2b/3a Ph
2b/3a Ph
2b/3b Ph
2b/3b o-NO2C6H4
2b/3b p-ClC6H4
2b/3b o-BrC6H4
2b/3c p-BrC6H4
0
0
6a 58
6b 72
6b 82
6c 83
6d 81
6e 92
6f 96
6g 85
81 : 19 48
9
PMP (1a)
6p 68
499 : 1 92
499 : 1 81
499 : 1 91
499 : 1 94
82 : 18 92
499 : 1 94
499 : 1 97
95 : 5 93
–20
–20
–20
–20
–20
–20
10
11
12
13
14
15
16
p-BrC6H4 (1b)
m-ClC6H4 (1c)
o-BrC6H4 (1d)
PMP (1e)
PMP (1e)
trans-styryl (1f)
PMP (1a)
Ph
6q 78
6r 75
6s 58
6t 87
6u 90
6v 28
499 : 1 93
499 : 1 87
499 : 1 81
499 : 1 91
499 : 1 97
499 : 1 95
95: 5 49
p-BrC6H4
p-BrC6H4
p-BrC6H4
o-BrC6H4
p-BrC6H4
a
Unless otherwise noted, the reaction was carried out in 0.25 mmol
scale with 1/2/3/4 = 1.1/1/1/1.2, and 4 A MS (0.1 g) was added.
Cyclohexyl 6w 34
b
c
p-methoxyphenyl. Isolated yield. Determined by
d
a
b
c
PMP
=
For conditions, see ESI.w Isolated yield. Determined by
e
d
1H NMR spectroscopy of the crude reaction mixture. Determined
1H NMR spectroscopy of the crude reaction mixture. Determined
by chiral HPLC.
by chiral HPLC.
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In summary, we report an enantioselective four-component
reaction of diazo compounds, alcohols, aldehydes, and amines
in the presence of Rh2(OAc)4 and co-catalyzed by a chiral
Brønsted acid. The nature of the current four-component
reaction is irreversible trapping of one intermediate (reversibly
formed from two components) by another intermediate (rever-
sibly formed from two additional components). The chiral acid
catalyst plays multiple roles to drive the reaction kinetics to the
desired product, a syn b-amino-a-hydroxyl acid derivative
bearing a quaternary carbon stereogenic center, with high
chemoselectivity and excellent diastereo- and enantioselectivity.
We are grateful for financial support from the National
Science Foundation of China (Grant No. 20772033) and the
Shanghai Pujiang program. We thank the Equipment Sharing
Platform of ECNU for support.
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6566 | Chem. Commun., 2008, 6564–6566