Catalytic enantioselective aldol additions of α-isothiocyanato imides to α-ketoesters

Article abstract of DOI:10.1039/c0cc00556h

A readily available bifunctional thiourea catalyst promotes aldol additions of α-isothiocyanato imides to α-ketoesters under mild reaction conditions to form β-hydroxy-α-amino acid derivatives with high levels of enantioselectivity.

Full text of DOI:10.1039/c0cc00556h

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Catalytic enantioselective aldol additions of a-isothiocyanato imides
to a-ketoestersw
Matthew K. Vecchione, Le Li and Daniel Seidel*
Received 24th March 2010, Accepted 27th April 2010
First published as an Advance Article on the web 19th May 2010
DOI: 10.1039/c0cc00556h
A readily available bifunctional thiourea catalyst promotes aldol
additions of a-isothiocyanato imides to a-ketoesters under mild
reaction conditions to form b-hydroxy-a-amino acid derivatives
with high levels of enantioselectivity.
reported catalytic enantioselective additions of a-isothiocyanato
esters to aryl alkyl ketones, employing chiral magnesium
Schiff base catalysts.6 Most recently, Wang and coworkers
have reported catalytic enantioselective additions of a-iso-
thiocyanato imides to a-ketoesters, using a rosin derived
amine-thiourea catalyst.7
The development of methods that allow for the enantioselective
construction of b-hydroxy-a-amino acid derivatives remains
an important goal as these structural motifs constitute impor-
tant building blocks.1,2 In addition to chiral auxiliary based
diastereoselective approaches,3,4 a number of catalytic enantio-
selective methods have been reported.5 While these methods
have mostly focused on the addition of glycine equivalents to
aldehydes, the corresponding reaction with ketones as electro-
philes has seen much less development.6 Here we report
catalytic enantioselective additions of a-isothiocyanato imides
to a-ketoesters.7
We initiated our studies by evaluating reactions between
a-isothiocyanato imides 14 and ketoesters 4 using catalysts
that had previously provided aldol and Mannich products in
Table 1 Optimization of reaction parametersa
ð1Þ
ð2Þ
Yieldb
eed
(%)
Entry Catalyst sm R0 Solvent Time/h (%) drc
1
2
3
4
5
6
7
8
7b
8
1b Me PhMe
1b Me PhMe
1b Me PhMe 48
1b Me PhMe 48
1b Me PhMe
1b Me PhMe
1b Ph PhMe
1b Ph PhMe
1.5
2
85
92
81
80
73
76
85
98
81
93
99
50
60
70
70
95
93
99
95
99
93
71
71
75 : 25
75 : 25
80 : 20
75 : 25
75 : 25
75 : 25
75 : 25
71 : 29
75 : 25
80 : 20
83 : 17
67 : 33
67 : 33
67 : 33
67 : 33
67 : 33
67 : 33
75 : 25
88 : 12
71 : 29
80 : 20
83 : 17
83 : 17
75
72
74
71
61
72
86
74
72
90
79
60
69
74
84
77
83
74
70
92
95
90
81
6a
6b
7a
7c
7b
8
3
1
3
2
We have recently reported catalytic enantioselective aldol
reactions between a-isothiocyanato imide 1a and aldehydes
(eqn (1)).8 The bifunctional thiourea compound 7b proved to
be an excellent catalyst for this reaction, providing products 2
with high levels of stereoselectivity. In addition, we have
reported Mannich additions of a-isothiocyanato imide 1b to
benzenesulfonyl imines to give rise to protected syn-a,b-diamino
acid derivatives in good yields and stereoselectivities, using the
quinidine based catalyst 6a (eqn (2)).9 Prior to our work with
organocatalysts, Willis and coworkers have used imide 1b in
highly enantioselective magnesium catalyzed aldol and Mannich
reactions.10 Subsequently, Zhong et al. reported an approach
to syn-a,b-diamino acid derivatives that is related to the
process outlined in eqn (2).11 More recently, Shibasaki et al.
9
6a
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
7b
1b Ph PhMe 36
10
11
12
13
14
15
16
17
18
19
20
21
22e
23f
1a Ph PhMe
1a Me PhMe
1b Ph Ether
1b Ph Xylenes
1b Ph CHCl3 12
1b Ph CH2Cl2 12
2
4
8
5
1b Ph THF
7
4
1.5
4.5
3
3
9
9
1b Ph CPME
1b Me MTBE
1a Me MTBE
1b Ph MTBE
1a Ph MTBE
1a Ph MTBE
1a Ph MTBE
a
Reactions were performed at rt on a 0.17 mmol scale in solvent
(0.15 M) using 1.1 equiv. of ketoester. Reactions were run to full con-
version as judged by TLC analysis. The ee’s were determined by HPLC
Department of Chemistry and Chemical Biology, Rutgers,
The State University of New Jersey, 610 Taylor Road, Piscataway,
New Jersey 08854, USA. E-mail: seidel@rutchem.rutgers.edu
w Electronic supplementary information (ESI) available: Experimental
details and characterization data for all new compounds. See DOI:
10.1039/c0cc00556h
b
c
analysis. Combined yield of both diastereomers. Determined by
d
e
1H-NMR. ee of major diastereomer shown. Run at 0.1 M con-
f
centration. Run at 0.25 M concentration. CPME = cyclopentyl methyl
ether; MTBE = methyl tert-butyl ether.
ꢀc
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good yields and stereoselectivities (eqn (3)).12–14 The results
of this investigation are summarized in Table 1. Different
catalysts readily promoted reactions between imides 1 and
ketoesters (ethyl pyruvate or ethyl 2-oxo-2-phenylacetate) in
toluene at room temperature. The more sterically encumbered
imide 1a gave rise to the formation of products with higher
levels of diastereo- and enantioselectivity. Amine-thiourea 7b
was identified as the most efficient and selective catalyst. An
evaluation of different solvents revealed methyl tert-butyl
ether (MTBE) to be superior to toluene with regard to overall
efficiency. The best result for the reaction of imide 1a and ethyl
2-oxo-2-phenylacetate was obtained in MTBE at 0.15 M
concentration, using 5 mol% of catalyst 7b (Table 1, entry 21).
In this instance, the reaction went to completion within 3 hours
and product 5a was obtained in 93% yield (dr = 80 : 20; 95%
ee, major diastereomer). Reactions conducted at lower (entry 22)
or higher concentration (entry 23) gave rise to poorer results.15
With the optimized reaction conditions in hand, a series of
different a-ketoesters was evaluated (Table 2). Electron rich
and electron poor aromatic substituents with different sub-
stitution patterns provided products in generally good yields
and with high enantioselectivities and moderate diastereo-
selectivities (entries 1–13). Heteroaromatic a-ketoesters were
also viable substrates (entry 14). While Wang and coworkers
achieved excellent selectivities at low catalyst loadings,7 our
best catalyst (7b) is more readily available and requires fewer
steps for its preparation.
Fig. 1 ORTEP view (50% probability thermal ellipsoids) of the
molecular structure of 5e. Most hydrogen atoms have been omitted
for clarity.
enriched products by simple filtration. For instance, when a
reaction leading to product 5e was worked up by filtration,
followed by washing with a small amount of MTBE, this
product was obtained in 66% yield as diastereomerically and
enantiomerically pure material (within the limits of HPLC
detection).
The absolute configuration of product 5e was established by
X-ray crystallography (Fig. 1).z The observed sense of induction
is the same as previously established in the corresponding
reactions of 1a with aldehydes to give products such as 2,
also catalyzed by 7b. The absolute configuration for all other
products was assigned by analogy.
As is customary, for all examples reported in Table 2, the
yields and stereoselectivities correspond to all of the obtained
product (solution and solid phase combined). Gratifyingly, in
some instances, product precipitation offers the opportunity to
directly obtain highly diastereomerically and enantiomerically
In summary, we have introduced a mild and facile method for
catalytic enantioselective aldol additions of a-isothiocyanato
imides to a-ketoesters using a readily available bifunctional
thiourea catalyst that operates under mild reaction conditions.
Financial support from Rutgers, The State University of
New Jersey, is gratefully acknowledged. We thank Dr Tom Emge
for crystallographic analysis.
Table 2 Scope of the reactiona
Notes and references
z The compound 5e (C18H19ClN2O6S) crystallizes in the monoclinic
space group P21 with a = 10.4991(4) A, b = 8.7802(3) A, c =
10.6271(4) A, a = 901, b = 95.8890(10)1, g = 901, V = 974.48(6) A3,
Z = 2, d(calcd) = 1.455 g cmꢁ3 and m(MoKa) = 0.341 mmꢁ1. A
Bruker Smart APEX CCD diffractometer with graphite mono-
chromatized MoKa radiation (l = 0.71073 A) was used to collect
12 736 reflections (6370 unique) in the range 1.93 o y o 31.531 at
100(2) K giving final residual values of Rf = 0.0323 (all data) and
Rf = 0.0311 ([I > 2s (I)]).
Yieldb
Product Time/h (%)
ee
(%)
Entry
R
drc
1
2
3
4
5
6
7
8
Ph 5a
4-OMe–C6H4 5b
3
12
7
2
2.5
12
7
48
93
80
79
95
99
95
90
82
99
96
86
93
70
95
99
80 : 20 95
70 : 30 94
75 : 25 92
83 : 17 97
83 : 17 98
85 : 15 97
80 : 20 96
70 : 30 96
83 : 17 98
80 : 20 97
80 : 20 93
80 : 20 97
75 : 25 87
75 : 25 92
83 : 17 79
4-Me–C6H4
4-Br–C6H4
4-Cl–C6H4
4-CF3–C6H4
4-t-Bu–C6H4
5c
5d
5e
5f
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5g
3-OMe–C6H4 5h
3,4-Cl2–C6H3 5i
9
1.5
10
11
12
13
14
15d
3,5-F2–C6H3
2,4-Cl2–C6H3 5k
5j
2
8
5
8
5
4
2-Naphthyl
2-Cl–C6H4
2-Thienyl
Me
5l
5m
5n
5o
a
Reactions were run at rt on a 0.5 mmol scale using 1.1 equiv. of the
b
ketoester. The ee’s were determined by HPLC analysis. Combined
c
d
yield of both diastereomers. Determined by 1H-NMR. Reaction
was performed in PhMe.
3 For
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15 The use of methyl or tert-butyl a-ketoesters gave rise to inferior
results.
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This journal is The Royal Society of Chemistry 2010
4606 | Chem. Commun., 2010, 46, 4604–4606