A highly diastereoselective decarboxylative mannich reaction of β-keto acids with optically active N-sulfinyl α-imino esters

Article abstract of DOI:10.1021/ol301180z

A range of protected γ-oxo-α-amino esters have been prepared in a highly regio- and stereoselective manner through the decarboxylative Mannich reaction of β-keto acids with optically active N-tert-butanesulfinyl α-imino esters in the presence of 3 mol % La(OTf)₃ or 5 mol % Y(OTf)₃ at 20 °C. Preliminary mechanistic studies indicate that the reaction proceeds through imine addition followed by decarboxylation.

Full text of DOI:10.1021/ol301180z

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3092–3095
A Highly Diastereoselective
Decarboxylative Mannich Reaction of
β-Keto Acids with Optically Active
N-Sulfinyl R-Imino Esters
Cui-Feng Yang,† Chen Shen,† Jian-Yong Wang,† and Shi-Kai Tian*,†,‡
Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, China, and Key Laboratory of
Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
tiansk@ustc.edu.cn
Received May 1, 2012
ABSTRACT
A range of protected γ-oxo-r-amino esters have been prepared in a highly regio- and stereoselective manner through the decarboxylative
Mannich reaction of β-keto acids with optically active N-tert-butanesulfinyl r-imino esters in the presence of 3 mol % La(OTf)3 or 5 mol % Y(OTf)3 at
20 °C. Preliminary mechanistic studies indicate that the reaction proceeds through imine addition followed by decarboxylation.
The asymmetric Mannich reaction of R-imino esters
constitutes a facile synthetic route to optically active
functionalized R-amino acid derivatives that are widely
employed in the construction of biologically important
compounds.1 Although enolizable ketones can serve as the
carbon nucleophiles, the reaction suffers from insufficient
reactivity with many simple ketones and unsatisfactory
regioselectivity with unsymmetrical dialkyl ketones.2 Em-
ployment of silyl enol ethers as surrogates of ketones
significantly improves the reactivity, but control of the
regioselectivity still remains problematic with silyl enol
ethersderived from unsymmetricaldialkylketones.3 Inthis
context, it seemed interesting and rewarding to explore
whether reactive and readily accessible surrogates of ke-
tones would undergo asymmetric additions to R-imino
estersin a highly regio- and stereoselective manner. Herein,
we report that β-keto acids do undergo a diastereoselective
† University of Science and Technology of China.
‡ Chinese Academy of Sciences.
(1) For reviews, see: (a) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter,
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r
10.1021/ol301180z
Published on Web 05/31/2012
2012 American Chemical Society

decarboxylative Mannich reaction with optically active N-
tert-butanesulfinyl R-imino esters at 20 °C to give a range
of functionalized R-amino acid derivatives in high dr.
Whereas β-keto acids are unstable to heat, acids, and
bases, it has been reported that they can undergo decar-
boxylative carbonꢀcarbon bond-forming reactions under
appropriate conditions with carbon electrophiles such as
aldehydes,4 ketones,5 1-pyrroline/zinc iodide,6 electron-
deficient alkenes,7 allylic electrophiles,8 and N-benzylic
sulfonamides.9 These biomimetic reactions have demon-
strated that β-keto acids can serve as attractive surrogates
of ketones in the formation of carbonꢀcarbon bonds due
to their higher reactivity and regioselectivity. We therefore
envisioned that it would be possible to develop a decarbox-
ylative Mannich reaction of β-keto acids with R-imino
esters under appropriate acidic conditions through extru-
sion of carbon dioxide. Nevertheless, it is a formidable
challenge to fine-tune reaction conditions that allow one to
execute imine addition prior to decarboxylation.
Due to their stability and easy accessibility, optically
active N-tert-butanesulfinyl R-imino esters were selected as
the carbon electrophiles in our proposed asymmetric
Mannich reaction.10 Initially, we took advantage of the
acidity of β-keto acids to activate N-tert-butanesulfinyl R-
imino esters and found that β-keto acid 1a underwent a
decarboxylative Mannich reaction with chiral imine 2a in
dioxane at 20 °C to give γ-oxo-R-amino ester 3a in 12%
yield and with 70:30 dr (Table 1, entry 1). Addition of 5 A
molecular sieves (ms) to the reaction mixture dramatically
improved the yield and dr to 47% and 96:4, respectively
(Table 1, entry 2). Reasoning that an external acid might
activate the β-keto acid and the chiral imine in a synergistic
manner,11 we examined a range of metal triflates and
found that the employment of 3 mol % La(OTf)3 led to
the formation of product 3a in 79% yield and with 98:2 dr
(Table 1, entry 9). Further investigation revealed that
toluene was the solvent of choice, and the reaction per-
formed in toluene gave the desired product in 89% yield
and with >99:1 dr (Table 1, entry 10).
Table 1. Optimization of Reaction Conditionsa
entry
catalyst
solvent
dioxane
yield (%)b
drc
1d
2
none
12
47
38
51
71
46
52
67
79
89
61
70
55
71
83
76
70:30
96:4
none
dioxane
3
TfOH
dioxane
94:6
4
Cu(OTf)2
Zn(OTf)2
Fe(OTf)3
Bi(OTf)3
Y(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
dioxane
61:39
84:16
93:7
5
dioxane
6
dioxane
7
dioxane
87:13
75:25
98:2
8
dioxane
9
dioxane
10
11
12
13
14
15
16
toluene
>99:1
98:2
dichloromethane
chloroform
ether
98:2
97:3
ethyl acetate
acetonitrile
nitromethane
96:4
97:3
98:2
a Reaction conditions: β-keto acid 1a (0.24 mmol), imine 2a
(0.20 mmol), catalyst (if any, 3 mol %), 5 A molecular sieves (40 mg), solvent
(0.40 mL), 20 °C, 5 h. b Isolated yield. c Determined by HPLC analysis as
described in the Supporting Information. d Without molecular sieves.
(4) (a) Rohr, K.; Mahrwald, R. Org. Lett. 2011, 13, 1878–1880.
(b) Kourouli, T.; Kefalas, P.; Ragoussis, N.; Ragoussis, V. J. Org. Chem.
2002, 67, 4615–4618. (c) Grayson, D. H.; Tuite, M. R. J. J. Chem. Soc.,
Perkin Trans. 1 1986, 2137–2142. (d) Stiles, M.; Wolf, D.; Hudson, G. V.
In the presence of 3 mol % La(OTf)3, a range of β-keto
acids smoothly underwent a decarboxylative Mannich
reaction with optically active N-tert-butanesulfinyl R-imi-
no esters at 20 °C to give structurally diverse protected
γ-oxo-R-amino esters in good yields and with excellent
diastereoselectivity (Table 2, entries 1ꢀ12). The R1 group
in the β-keto acid could be an aryl or a heteroaryl group,
and the reaction tolerated electron-rich and electron-poor
aromatic moieties. However, such reaction conditions
failed to afford excellent diastereoselectivity when the R1
group in the β-keto acid was an alkyl group. Gratifyingly,
alternative employment of Y(OTf)3 (5 mol %) as the
catalyst led to excellent diastereoselectivity with regard to
such substrates (Table 2, entries 13ꢀ17), and importantly,
no regioisomeric product was obtained from the reaction
with β-keto acids 1kꢀn (Table 2, entries 13ꢀ16).
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The optically active γ-oxo-R-amino esters we obtained
could undergo a range of chemical transformations under
appropriate conditions. For example, when γ-oxo-R-
amino ester 3a was treated with hydrogen chloride in
dioxane under reflux, γ-oxo-R-amino acid 4a (HCl salt)
was formed in 94% yield (Scheme 1). In contrast,
Org. Lett., Vol. 14, No. 12, 2012
3093

ESI-mass spectroscopic analysis of the mixture of β-keto
acid 1a and imine 2a allowed us to identify intermediate 7a
(Figure 1) according to the high resolution mass data
[HRMS (ESI) calcd for C18H26NO6Sþ (M þ Hþ)
384.14753, found 384.14781]. Nevertheless, isolation of
β-keto acid 7a was not successful by chromatography on
silica gel due to rapid decomposition. Although acetophe-
none was detected in a significant amount in the reaction
mixture, it could not react with imine 2a under our
standard conditions. These observations clearly indicate
that the imine addition step occurs prior to the decarbox-
ylation step in the asymmetric decarboxylative Mannich
reaction.
Table 2. Decarboxylative Mannich Reaction of β-Keto Acids
with Optically Active N-Sulfinyl R-Imino Estersa
time yield
entry
1, R1
1a, Ph
2, R2
3
(h)
(%)b
drc
1
2a, CHMe2 3a
2b, Et 3b
2c, CH2Ph 3c
5
5
89
89
67
71
85
75
81
71
61
66
79
87
82
77
69
80
70
>99:1
99:1
96:4
>99:1
99:1
99:1
99:1
97:3
99:1
94:6
98:2
99:1
99:1
98:2
97:3
97:3
>99:1
2
1a, Ph
1a, Ph
3
8
4
1b,4-MeOC6H4 2a, CHMe2 3d
5
5
1c, 4-FC6H4
1d,4-ClC6H4
1e, 4-BrC6H4
2a, CHMe2 3e
2a, CHMe2 3f
2a, CHMe2 3g
10
11
10
10
12
24
5
6
7
8
1f, 4-O2NC6H4 2a, CHMe2 3h
1g, 3-O2NC6H4 2a, CHMe2 3i
9
10
11
12
13d
14d
15d
16d
17d
1h,2-ClC6H4
1i, 2-furyl
2a, CHMe2 3j
2a, CHMe2 3k
2a, CHMe2 3l
2a, CHMe2 3m
Figure 1. Structure of intermediate 7a.
1j, 2-thienyl
1k, PhCH2
5
12
10
14
10
10
1l, MeCH2CH2 2a, CHMe2 3n
1m, Me(CH2)10 2a, CHMe2 3o
For comparison, wefurther examinedthe reactivityofβ-
keto esters under our standard conditions. Although the
reaction of β-keto ester 8a with imine 2a smoothly pro-
ceeded in the presence of 3 mol % La(OTf)3 to give adduct
9a in 84% yield, the product was transformed in three steps
intoCbz-protectedγ-oxo-R-amino ester 5a with only 82:18
er (Scheme 2). These experiments clearly show that the
reaction with β-keto ester 8a is much less diastereoselective
than that with β-keto acid 1a (>99:1 dr, Table 2, entry 1)
and indicate that the carboxylic acid group in the
β-keto acid plays a crucial role for the asymmetric dec-
arboxylative Mannich reaction to proceed with excellent
diastereoselectivity.
1n, Me2CH
1o, Me3C
2a, CHMe2 3p
2a, CHMe2 3q
a Reaction conditions: β-keto acid 1 (0.24 mmol), imine 2 (0.20 mmol),
La(OTf)3 (3 mol %), 5 A molecular sieves (40 mg), toluene (0.40 mL),
20 °C. b Isolated yield. c Determined by HPLC analysis as described in
the Supporting Information. d La(OTf)3 was replaced with Y(OTf)3
(5 mol %), and 1.0 mL of toluene was used.
treatment of compound 3awithhydrogen chlorideatroom
temperature just removed the N-tert-butanesulfinyl group,
and when the resulting mixture was treated with benzyl
chloroformate (CbzCl) and triethylamine, it gave Cbz-
protected γ-oxo-R-amino ester 5a in 75% yield (two steps).
It is noteworthy that no epimerization took place at the R-
chiral center. In addition, compound 3a was oxidized with
meta-chloroperoxybenzoic acid (MCPBA) to give N-sul-
fonyl γ-oxo-R-amino ester 6a in 81% yield. The absolute
configuration of compound 6a was assigned to be R by
single-crystal X-ray analysis.
Scheme 2. Reaction of β-Keto Ester 8a with Imine 2a
Scheme 1. Transformations of Compound 3a
Based on our experimental results, we propose the
following reaction pathway for the asymmetric decarbox-
ylative Mannich reaction of β-keto acids with N-sulfinyl R-
imino esters (Scheme 3). Displacement of La(OTf)3 cata-
lyst by β-keto acid 1 results in the formation of salt 10,
which undergoes addition to N-sulfinyl R-imino ester 2 to
3094
Org. Lett., Vol. 14, No. 12, 2012

β-keto acid moiety sits far away from the N-sulfinyl group
due to steric repulsion.
Scheme 3. Proposed Mechanism
In summary, we have developed, for the first time, a
highly diastereoselective decarboxylative Mannich reac-
tion of β-keto acids with optically active N-tert-butanesul-
finyl R-imino esters. In the presence of 3 mol % La(OTf)3
or 5 mol % Y(OTf)3, a variety of β-keto acids smoothly
undergo a decarboxylative Mannich reaction with N-tert-
butanesulfinyl R-imino esters at 20 °C to give structurally
diverse protected γ-oxo-R-amino esters in good yields and
with extremely high regioselectivity and excellent diaster-
eoselectivity. Preliminary mechanistic studies indicate that
the reaction proceeds through imine addition followed by
decarboxylation.
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation of
China (21172206, 20972147, and J1030412), the National
Basic Research Program of China (973 Program
2010CB833300), and the Program for Changjiang Scholars
and Innovative Research Team in University (IRT1189).
give salt 12. Displacement of salt 12 by β-keto acid 1 gives
β-keto acid 7 and regenerates salt 10. Decarboxylation of
β-keto acid 7 leads to the formation of product 3. Such an
imine addition/decarboxylation sequence should account
for the extremely high regioselectivity observed in the
reaction (Table 2, entries 13ꢀ16). The excellent diastereo-
selectivity probably originates in the imine addition step.
The coordination of salt 10 with N-sulfinyl R-imino ester 2
might form a chairlike transition state, 11, in which the
Supporting Information Available. Experimental pro-
1
cedures; characterization data; copies of H NMR, 13C
NMR, and HPLC spectra for products; and crystal data
of compound 6a. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
3095