A highly enantioselective four-component reaction for the efficient construction of chiral β-hydroxy-α-amino acid derivatives

Article abstract of DOI:10.1039/c3cc40546j

An enantioselective four-component reaction of a diazoketone, water, an aniline and ethyl glyoxylate in the presence of catalytic Rh₂(OAc) ₄ and a chiral Br?nsted acid was developed to efficiently produce β-hydroxy-α-amino acid derivatives in good yields with high diastereoselectivity and enantioselectivity. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc40546j

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A highly enantioselective four-component reaction for
the efficient construction of chiral b-hydroxy-a-amino
acid derivatives†
Cite this: Chem. Commun., 2013,
49, 2700
Received 22nd January 2013,
Accepted 12th February 2013
Yu Qian, Changcheng Jing, Shunying Liu and Wenhao Hu*
DOI: 10.1039/c3cc40546j
www.rsc.org/chemcomm
An enantioselective four-component reaction of a diazoketone, (MCRs) are considered to be a powerful and step-economic
water, an aniline and ethyl glyoxylate in the presence of catalytic strategy to form multiple chemical bonds from three or more
Rh2(OAc)4 and a chiral Brønsted acid was developed to efficiently starting materials in one operation, and much progress in
produce b-hydroxy-a-amino acid derivatives in good yields with MCRs has been made in recent years.8 However, only a few
high diastereoselectivity and enantioselectivity.
successful examples of enantioselective MCRs have been developed,
in which polyfunctional chiral molecules can be efficiently
b-Hydroxy-a-amino acids are important constituents of peptides assembled from simple starting materials.9 In recent years,
and other complex natural products,1 such as vancomycin2 and our group has reported several highly selective three-component
the sphingofungin family3 (Fig. 1). A number of useful strategies reactions by trapping in situ-generated active intermediates
utilizing chemical and enzymatic methods,4 such as Sharpless (including onium ylide and zwitterions) with electrophiles.10
asymmetric dihydroxylation and epoxidations,5 aldol reactions,6 The trapping process presents an extremely fast reaction rate
and catalytic hydrogenations,7 have been devised for their pre- under mild conditions and leads to an highly efficient fashion
paration. Most of these synthetic approaches, however, require to form multiple chemical bonds in one step. These results
multiple operations or are initiated from relatively complex encouraged us to seek an efficient approach for synthesizing
starting materials. It is highly desirable to develop more efficient optically active b-hydroxy-a-amino acid derivatives from simple
approaches to build chiral polyfunctional b-hydroxy-a-amino starting materials.
acid derivatives in a highly efficient manner from simple starting
materials.
To construct b-hydroxy-a-amino acid scaffolds, an electrophilic
iminoester is exquisitely designed to trap a protic oxonium ylide
One of the current focuses in organic chemistry is to that in situ generated from diazoacetophenone and water
maximize synthetic efficiency for the construction of structu- (Scheme 1). For this designed reaction, one particular challenge
rally diversified organic molecules. Multicomponent reactions is to address the compatibility issue among substrates that results
in undesired side reactions due to competitive hydrolysis of the
iminoesters in aqueous conditions. The other challenge is to
achieve highly enantioselective control in transition metal
catalyzed decomposition of acceptor diazo compounds,11
Fig. 1 Selected natural products containing b-hydroxy-a-amino acid scaffolds.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug
Development, East China Normal University, Shanghai, 200062 China.
E-mail: whu@chem.ecnu.edu.cn; Fax: +86-021-62221235
† Electronic supplementary information (ESI) available: Synthesis, characterisa-
Scheme 1 Multi-component reaction of diazoacetophenone 1a, water, amines
2a and ether glyoxylate 3.
tion of all compounds and crystal data. CCDC 918137. For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c3cc40546j
c
2700 Chem. Commun., 2013, 49, 2700--2702
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including diazoacetophenone.12 Considering the simplification
of starting materials and the stability of imine in water, the
iminoester is designed to be in situ produced from an amine
and a glyoxylate, and then a four-component reaction was taken
into account. This resulted in another big challenge to control
the chemoselectivity of this reaction. In this study, we report
asymmetric four-component reactions involving an acceptor
diazoacetophenone, water, a glyoxylate and an aniline with
good control of chemo-, diastereo-, and enantioselectivity.
We began our investigation with the Rh2(OAc)4 catalyzed
four-component coupling reaction of diazoacetophenone 1a,
water (2.2 equivalents), aniline 2a and glyoxylate 3 at 0 1C
(Scheme 1). No desired four-component reaction product was
observed, and only the N–H insertion product resulting from
diazoacetophenone with aniline was isolated. Based on our
previous work, a Brønsted acid was suggested to be essential in
the formation and activation of the key imine electrophile.10c
We then added 5 mol% racemic phosphoric acid 4a in this
reaction to activate the in situ generated imine from 2 and 3.
Gratifyingly, the desired product 5a was obtained in 37% yield
Table 2 Enantioselective four-component reactions of diazoketones 1 with
water, amines 2 and ether glyoxylate 3a
Yieldb drc
eed
Entry 1 (R)
2 (Ar1)
5
(%)
(anti/syn) (%)
1
2
3
4
5
6
7
8
1a (Ph)
2a (C6H5)
2b (p-ClC6H4)
2c(p-BrC6H4)
2d (p-MeC6H4) 5d
2e (3,5Cl2C6H3) 5e
2f (3,4F2C6H3) 5f
2g (3,4Cl2C6H3) 5g
5a
5b
5c
78
88
85
74
83
82
78
76
63
65
71
68
85
58
61
79 : 21
79 : 21
75 : 25
86 : 14
87 : 13
85 : 15
89 : 11
84 : 16
76 : 24
66 : 34
78 : 22
72 : 28
66 : 34
70 : 30
83 : 17
85
93
93
86
95
92
96
92
86
86
93
86
85
89
91
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
1b (p-MeC6H4) 2b (p-ClC6H4)
1c (m-BrC6H4) 2b (p-ClC6H4)
1d (p-BrC6H4)
1e (p-MeOC6H4) 2b (p-ClC6H4)
1f (b-naphthyl) 2b (p-ClC6H4)
1g (trans-styryl) 2b (p-ClC6H4)
1h (isobutenyl) 2b (p-ClC6H4)
1i (cyclohexyl) 2b (p-ClC6H4)
5h
5i
5j
5k
5l
5m
5n
5o
9
10
11
12
13
14
15
2b (p-ClC6H4)
as
a mixture of diastereomers (2 : 1), accompanied by
the formation of a diamino byproduct 6 in 20% yield. The
byproduct 6 was attributed to trapping an ammonium ylide by
the iminoester.13 In order to suppress the formation of the
undesired ammonium ylide, we increased the amount of water
up to 20 equivalents to improve the rate of oxonium ylide
a
b
Reaction conditions: 1/2/3 = 1.2 : 1.0 : 1.2, water = 0.1 mL. Isolated
c
d
yield. anti/syn determined by chiral HPLC with an IA column. ee for
the anti isomer, determined by chiral HPLC with an IA column.
formation. Fortunately, the yield of 5a was improved to 52% Phosphoric acid 4d, bearing bulky Ph3Si substituents, was
with a diastereomeric ratio of 63 : 37, and the yield of byproduct found to be the best co-catalyst among the tested acids and
6 was restricted to less than 5%.
provided product 5a in 80% ee for the major anti isomer with a
This promising result promoted us to further optimize the moderate diastereoselectivity and yield (entries 2–6, Table 1).
reaction by using a chiral Brønsted acid in order to achieve an Different solvents and temperatures were then examined
enantioselective variant of the four-component reaction (entries 7–10), and it was found that the best result was
(Table 1). Chiral phosphoric acids have been shown to be achieved at À10 1C when using 1,2-dichloroethane (DCE) as
excellent Brønsted acid catalysts in activating imine substrates in the solvent with 5 mol% of 4d as the Brønsted acid catalyst. The
asymmetric Mannich reactions;14 thus they are widely screened as optimized conditions gave the desired product 5a in 78% yield
the co-catalyst in this multi-component reaction.9b,10a,b,d,e as a mixture of anti/syn diastereomers (79 : 21); and the major
anti-isomer was formed in 85% ee (entry 9). It should be noted
that the minor syn-isomer was formed with a lower enantio-
selectivity (47% ee).
Table 1 Catalyst screening and reaction condition optimization for the four-
component Mannich-type reactiona
With the optimized reaction conditions in hand, we sought
to expand the scope of this MCR by examining a wide range of
diazoketone 1 and aniline 2 (Table 2). For all examples, the
enantioselectivity of the major diastereomer ranged from 85–
96% ee and all the anti isomers could be fully separated from
syn isomers. For varied electron donating and withdrawing
Entry 4 (5 mol%) Solvent T (1C) Yieldb (%) drc (anti : syn) eed (%)
substituents in anilines (Table 2, entries 2–4), the yields and
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4d
4d
4d
4d
DCM
DCM
DCM
DCM
DCM
DCM
DCE
Toluene
DCE
DCE
0
0
0
0
0
0
0
0
52
47
69
58
73
68
52
49
63 : 37
64 : 36
64 : 36
69 : 31
62 : 38
76 : 24
77 : 23
76 : 24
79 : 21
78 : 22
—
enantioselectivity of this reaction remained at a considerably
high level. And comparably, anilines with electron donating
substituents resulted in a slightly higher diastereoselectivity.
Aniline 2b gave the best result overall and provided product
anti-5b in 88% yield with 93% ee (Table 2, entry 2). In addition,
both the electron-donating and withdrawing substrates on the
phenyl rings of the diazoketone 1 gave desired products in good
yields and high ee values (Table 2, entries 8–12). It is worth
pointing out that the alkyl diazoketones 1g–i also provided the
desired products in good yields with high ee values (Table 2,
entries 13–15), which demonstrated that the reaction scope can
16 (17)
40 (62)
80 (53)
À9 (À31)
22 (26)
80 (44)
78 (55)
85 (47)
85 (45)
À10 78
10
À20 51
a
b
Reaction conditions: 1a/2a/3 = 1.2 : 1.0 : 1.2, water = 0.1 mL. Isolated
c
d
product. anti/syn determined by chiral HPLC with an IA column. ee
for the anti isomer, determined by chiral HPLC with an IA column.
Values in parentheses refer to the ee value for the syn isomer.
c
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Res., 2010, 43, 1317; for selected examples: (d) M. M. Paliann and
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Scheme 2 Proposed reaction pathway for the four-component reactions of
diazoketone 1 with water, aniline 2 and glyoxylate 3.
be extended to alkyl diazoketones. Notably, the linear alkyl vinyl
diazoketone 1j also offered the desired product 5p in 72% yield
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methodology may contribute a new strategy to synthesize
natural product D-lyxo-phytosphingosine and its analogues.
The absolute stereochemistry of product 5k was determined
via single crystal X-ray analysis (see ESI†),15 and that of other
compounds was tentatively assigned by analogy.
´
8 For some reviews in MCRs, see: (a) ed. J. Zhu and H. Bienayme,
´
Wiley-VCH, Weinheim, Germany, 2005; (b) D. J. Ramon and M. Yus,
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The proposed reaction pathway is shown in Scheme 2. The
reaction proceeds through an oxonium ylide intermediate,
which was in situ generated from carbenoid and water. The
in situ formed protic oxonium ylide was immediately trapped
by an electrophilic iminium that generated from a chiral
phosphoric acid promoted condensation of a glyoxylate and
an amine, leading to the optically active product 5.
In summary, a Rh2(OAc)4 and chiral Brønsted acid co-catalyzed
enantioselective four-component reaction of a diazoketone, water,
an aniline and ethyl glyoxylate was developed under mild
and practical conditions. Acceptor carbenoids derived from
diazoketones have been successfully employed to achieve high
enantioselective control. The novel reaction provides a highly
efficient method to produce highly valuable b-hydroxy-a-amino
acid derivatives from simple starting materials in good yields
with a good diastereoselectivity and high enantioselectivity.
Further research is currently underway to demonstrate the
application of this methodology in the synthesis of natural
products and biologically active compounds.
10 For selected examples of ylide trapping reactions: (a) X. Xu, J. Zhou,
L. Yang and W. Hu, Chem. Commun., 2008, 6564; (b) W. Hu, X. Xu,
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131, 9182.
We wish to thank the National Science Foundation of China
(20932003, 21125209) and the MOST of China (2011CB808600)
for financial support and STCSM (12JC1403800) for sponsorship.
Notes and references
1 For reviews: (a) D. L. Boger, Med. Res. Rev., 2001, 21, 356;
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Synthesis: Applications to Complex Natural Products, ACS, Washington,
DC, 2009, pp. 420; (c) Y. Luo, H. Zhang, Y. Wang and P. Xu, Acc. Chem. 15 CCDC 918137†.
c
2702 Chem. Commun., 2013, 49, 2700--2702
This journal is The Royal Society of Chemistry 2013