Efficient synthesis of β-hydroxy-α-amino acid derivatives via direct catalytic asymmetric aldol reaction of α-isothiocyanato imide with aldehydes

Article abstract of DOI:10.1002/chem.201000284

An easily available and efficient chiral N,N'-dioxide-nickel(II) complex catalyst has been developed for the direct catalytic asymmetric aldol reaction of α-isothiocyanato imide with aldehydes which produces the products in morderate to high yields (up to 98%) with excellent diastereo-(up to >99:1 d.r.) and enantioselectivities (up to >99% ee). A variety of aromatic, heteroaromatic, α,β-unsaturated, and aliphatic aldehydes were found to be suitable substrates in the presence of 2.5 mol% l-proline-derived N,N'-dioxide L5-nickel(II) complex. This process was air-tolerant and easily manipulated with available reagents. Based on experimental investigations, a possible transition state has been proposed to explain the origin of reactivity and asymmetric inductivity.

Full text of DOI:10.1002/chem.201000284

DOI: 10.1002/chem.201000284
Efficient Synthesis of b-Hydroxy-a-Amino Acid Derivatives via Direct
Catalytic Asymmetric Aldol Reaction of a-Isothiocyanato Imide with
Aldehydes
Xiaohong Chen, Yin Zhu, Zhen Qiao, Mingsheng Xie, Lili Lin, Xiaohua Liu, and
Xiaoming Feng*[a]
Abstract: An easily available and effi-
cient chiral N,N’-dioxide–nickel(II)
complex catalyst has been developed
for the direct catalytic asymmetric
aldol reaction of a-isothiocyanato
imide with aldehydes which produces
the products in morderate to high
yields (up to 98%) with excellent dia-
stereo- (up to >99:1 d.r.) and enantio-
selectivities (up to >99% ee). A varie-
ty of aromatic, heteroaromatic, a,b-un-
saturated, and aliphatic aldehydes were
found to be suitable substrates in the
presence of 2.5 mol% l-proline-de-
rived N,N’-dioxide L5–nickel(II) com-
plex. This process was air-tolerant and
easily manipulated with available re-
agents. Based on experimental investi-
gations, a possible transition state has
been proposed to explain the origin of
reactivity and asymmetric inductivity.
Keywords: aldol reaction · amino
acids · asymmetric catalysis · nickel ·
nitrogen oxides
Introduction
isothiocyanato imide by using a chiral MgII–Pybox com-
plex.[8b] Subsequently, an effective metal-free catalyst has
been developed by the Seidel group by employing chiral
thio
AHCTUNGTRENNUNG
Chiral b-hydroxy-a-amino acids are important structural
motifs for the preparation of many bioactive compounds.
Many biologically active natural products, such as vancomy-
cin ristocetin, and biphenomycin A, contain b-hydroxy-a-
urea.[8c] Quite recently, Shibasaki and co-workers
ACHTUNGTRENNUNG
the direct asymmetric aldol reaction of a-isothiocyanato
esters with ketones.[8d,9] Despite these outstanding contribu-
tions, the development of new, easily accessed, and efficient
asymmetric catalytic systems is still in high demand.
amino acids within their structural frameworks.[1–3]
A
number of highly efficient catalytic enantioselective variants
for the construction of these molecules have been estab-
lished, although the majority of methods require the use of
preformed enolate equivalents.[4–7] The direct catalytic enan-
tioselective aldol reaction between a glycine equivalent and
Dicarbonyl compounds are promising candidates as sub-
strates because they can chelate a series of metals, such as
FeII, CoII, and NiII complexes, and engage in two-point bind-
ing to the central metal, which allows a chelate-ordered
transition state to occur.[10] Meanwhile, because nickel is a
nonprecious metal, nickel complex catalysts have been
widely applied to catalytic organic synthesis. For instance,
nickel-catalyzed [4+4], [4+2], and [2+2+2] cycloadditions
have received considerable attention.[11,12] Over the past
decade, nickel-catalyzed reductive cyclizations and couplings
have evolved into a broadly useful strategy for assembling
synthetically versatile substructures and complex mole-
cules.[13] Moreover, chiral nickel complexes are becoming
potential practical catalysts in enantioselective transforma-
tions.[14] Also, as excellent chiral scaffolds, N,N’-dioxide–
metal complexes have exhibited great potential in many
À
carbonyl compounds, involving the creation of a C C bond
and two stereogenic centers in a single operation, is one of
the most attractive and atom-efficient methods to obtain
such chiral building blocks, and intense effort has been de-
voted to this area. Willis and co-workers described the first
highly enantioselective aldol reaction of aldehydes with a-
[a] X. Chen, Y. Zhu, Z. Qiao, M. Xie, Dr. L. Lin, Dr. X. Liu,
Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
asymmetric reactions.[15,16] Moreover, N,N’-dioxide–nick
(II) complexes have successfully been applied in asymmetric
ACHTUNGTRENNUNGel-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000284.
AHCTUNGTRENNUNG
10124
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 10124 – 10129

FULL PAPER
carbonyl–ene reactions and oxa–Michael additions.[17]
Herein, we present an efficient chiral catalyst system based
on an easily available N,N’-dioxide–nickel-(II) complex for
the direct asymmetric aldol reaction of a-isothiocyanato
imide with aldehydes. Excellent diastereo- (up to >99:1
d.r.) and enantioselectivities (up to >99% ee) were ob-
tained for a broad range of substrates with 2.5 mol% cata-
lyst loading under mild conditions.
showed good inductive potential in this reaction (Table 1,
entries 4–5). The cheap and air-stable [NiACTHNURTGNENG(U acac)2] was espe-
cially attractive because 72% yield, 75:25 d.r., and 57% ee
could be achieved. Furthermore, the counterion also affect-
ed the reactivity, diastereo-, and enantioselectivity greatly;
strong acidic anions resulted in a poor outcome (Table 1, en-
tries 6–9).
Subsequently, the effect of ligands L2–L7 was examined
(Figure 1). The studies on the effect of the amide moiety
demonstrated that ligand L3 with an electron-donating
group at the para position of aniline could provide better re-
sults, with 82% yield, 82:18 d.r., and 77% ee (Table 2,
Results and Discussion
Initially, N,N’-dioxide L1 (Figure 1) was coordinated with
various metal salts and used to catalyze the direct aldol re-
action of a-isothiocyanato imide 1 with benzaldehyde 2a
Table 2. Identification of the most efficient catalyst system and optimiza-
tion of the reaction conditions.[a]
Entry
Ligand
T [oC]
Yield[b] [%]
trans/cis[c]
ee[d] [%]
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
L5
L5
0
0
0
0
0
0
0
RT
À20
72
67
82
36
94
90
89
94
81
75:25
68:32
82:18
58:42
92:8
88:12
46:54
80:20
90:10
57
45
77
8
90
35
0
8[e]
9[f]
75
92
Figure 1. Ligands employed in this study.
[a] Unless otherwise noted, all reactions were carried out by using L/[Ni-
(acac)2] (10 mol%), 1 (0.1 mmol), 2a (0.2 mmol) and 5 ꢁ MS (40.0 mg)
in THF (1.6 mL) at 08C for 12 h. [b] Isolated yield of combined disaster-
eomers. [c] Determined by chiral HPLC analysis. [d] The ee of the trans
isomer was measured by using chiral HPLC with a Chiracel IB column.
[e] The reaction time was 2 h. [f] The reaction time was 28 h.
(Table 1). Unfortunately, MgACHTNUTRGNEUNG(ClO4)2, which had been
AHCTUNGTRENNUNG
proved to be effective for this kind of reaction, did not work
AHCTUNGTRENNUNG
well (Table 1, entry 1),[8b] and racemic products were ob-
tained with [Cu
ACHTUNGTRENNUNG(acac)2] and [FeACTHUNGTRENNNUG
(Table 1, entries 2–3). However, [Co
N
ACHTUNGTRENNUNG
entry 3 vs. entries 1 and 2). Ligand L4 with a bulky isopropyl
group led to a dramatic decrease in enantioselectivity
(Table 2, entry 4). l-Proline derivative L5 was superior to l-
ramipril-derived L6 and l-pipecolic-acid-derived L3 in both
reactivity, diastereoselectivity, and enantioselectivity (Ta-
Table 1. Survey of central metals in the aldol reaction of a-isothiocyana-
to imide 1 with benzaldehyde 2a.[a]
AHCTUNGTREGbNNUN le 2, entry 5 vs. entries 3 and 6). It is worth noting that
when the amide L7, the precursor of N,N’-dioxide, was used
as the ligand, a racemic product was obtained (Table 2,
entry 7), which revealed that the N-oxide group was essen-
tial for the reaction. When the reaction was performed at
À208C, a slight increase in the enantioselectivity was ob-
served, but the reactivity decreased. High temperatures
were detrimental to asymmetric induction (Table 2, en-
tries 8, 9). In addition, the configuration of product 3a’ was
assigned by comparison of the optical rotation to the report-
ed value of the corresponding enantiomer (4S,5R).[8b,18]
Encouraged by the initial results in the asymmetric aldol
reaction, various solvents were screened, and the results are
listed in Table 3. Although CH2Cl2 gave a comparable reac-
tivity for the reaction, it led to a dramatic loss of enantiose-
lectivity (Table 3, entry 2 vs. 1). Toluene provided enantiose-
lectivity equal to THF, but the diasteroselectivity was lower
Entry
Metal
Mg(ClO4)2
[Cu(acac)2]
[Fe(acac)2]
[Co(acac)2]
(acac)2]
(Tfacac)2]·2H2O[f]
Yield[b] [%]
n.r.[e]
56
78
83
trans/cis[c]
ee[d] [%]
1
2
3
4
5
6
7
8
9
G
–
–
0
0
E
45:55
60:40
58:42
75:25
68:32
n.d.[g]
48:52
–
G
R
13
57
46
n.d.[g]
0
[Ni
[Ni
N
72
69
Ni
NiBr2
Ni(OTf)2
A
trace
48
G
n.r.[e]
–
[a] Unless otherwise noted, all reactions were carried out by using L1/M
(1:1; 10 mol%), 1 (0.1 mmol), 2a (0.2 mmol), and 5 ꢁ MS (40.0 mg) in
THF (1.6 mL) at 08C for 12 h. [b] Isolated yield of the combined dia
ACHTUNGTNERsNUNG ter-
ACHTUNGTRENNUNGeomers. [c] Determined by using chiral HPLC analysis. [d] ee of the trans
isomer, measured by using chiral HPLC with a Chiracel IB column.
[e] n.r.=no reaction. [f] Tfacac=1,1,1-trifluoroacetylacetonate. [g] n.d.=
not determined.
Chem. Eur. J. 2010, 16, 10124 – 10129
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10125

X. Feng et al.
Table 3. Screening of solvents in the aldol reaction of benzaldehyde.[a]
Table 4. Substrate scope for the catalytic asymmetric aldol reaction of al-
dehydes.[a]
Entry Solvent
x [mol%] Yield[b] [%] trans/cis[c] ee[d] [%]
Entry
R
3
Yield [%][b] trans/cis[c] ee [%][d]
1
2
3
THF
10
10
10
10
10
10
94
97
63
54
84
80
95
95
95
95
92:8
88:12
65:35
68:32
78:22
96:4
97:3
97:3
97:3
97:3
90
80
90
66
87
95
97
96
96
96
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Ph
4-FC6H4
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
92
95
98
98
90
96
90
90
92
97
90
96
90
87
84
80
95
88
97:3
97:3
97:3
96:4
97:3
>99:1
95:5
91:9
92:8
93:7
96[e]
96
95
93
97
93
91
91
90
CH2Cl2
PhCH3
Et2O
4
4-BrC6H4
4-ClC6H4
4-MeC6H4
4-PhC6H4
4-CF3C6H4
2-MeC6H4
3,4-Cl2C6H3
3-BrC6H4
3-CF3C6H4
3-ClC6H4
3-MeC6H4
3-MeOC6H4
2-FC6H4
5
6
PhOMe
tBuOMe
7[e]
8[e]
9[e,f]
10[e,g]
THF/tBuOMe 10
THF/tBuOMe
THF/tBuOMe
THF/tBuOMe
5
2.5
1
>99
[a] Unless otherwise noted, all reactions were carried out by using L5/
[Ni(acac)2] (10 mol%), (0.1 mmol), 2a (0.2 mmol) and 5 ꢁ MS
91:9
93:7
90
>99
91
92
90
G
1
(40.0 mg) in solvent (1.6 mL) at 08C for 12 h. [b] Isolated yield of com-
bined diastereomers. [c] Determined by chiral HPLC analysis. [d] The ee
value of the major diastereomer was measured by using chiral HPLC
with a Chiracel IB column. [e] THF/tBuOMe=1:1. [f] The reaction time
was 24 h. [g] The reaction time was 40 h.
>95:5
>95:5
85:15
85:15
>95:5
91:9
2-MeOC6H4
3-PhOC6H4
4-MeOC6H4
92
93[e]
96[e]
19
3s
83
>95:5
97[e]
(Table 3, entry 3 vs. 1). Further solvent studies focusing on
ethers revealed that tBuOMe provided the product with fa-
vorable diastereo- and enantioselectivity, but led to moder-
ate reactivity (Table 3, entries 4–6). Fortunately, by using
THF as a cosolvent, adduct 3a’ could be obtained with the
best results (95% yield, 97:3 d.r., and 97% ee; Table 3,
entry 7). Moreover, on decreasing the catalyst loading from
10 to 2.5 mol%, the results were maintained (Table 3, en-
tries 8–9). The catalyst loading was further reduced to
1 mol%, which led to similar results with longer reaction
time (Table 3, entry 10). Further screening of the reaction
conditions identified that the best conditions were 2.5 mol%
20
21
2-naphthyl
1-naphthyl
3t
3u
90
86
94:6
93:7
95[e]
93
22
23
3v
82
80
85:15
85:15
90
92
3w
24
25
26
27
28
29
3-furyl
3x
3y
3z
3aa
3bb 68
3cc 72
86
90
89
77
92:8
90:10
95:5
92:8
85:15
90:10
93
93
95
2-thienyl
3-thienyl
n-hexyl
cyclohexyl
isobutyl
82 (>99)[f]
81
80
30
31[g]
3dd 70
3d 98
90:10
97:3
83
95
4-ClC6H4
L5–[NiACHTUNGTRENNUNG(acac)2] complex, 5 ꢁ molecular sieves (MS;
[a] Unless otherwise noted, all reactions were carried out with L5/[Ni-
(acac)2] (2.5 mol%), 1 (0.2 mmol), 2 (0.4 mmol) and 5 ꢁ MS (80.0 mg) in
40.0 mg), 0.1 mmol a-isothiocyanato imide 1, and 0.2 mmol
benzaldehyde 2a in 1.6 mL THF/tBuOMe (1:1) at 08C. Note
that the process is air and moisture tolerant.
AHCTUNGTRENNUNG
THF/tBuOMe (1/1) (3.2 mL) at 08C for 16–48 h. [b] Isolated yield of
combined diastereomers. [c] Entries 1–9: determined by chiral HPLC
analysis; entries 10–30: determined by 1H NMR spectroscopy. [d] The ee
value of the major diastereomer. [e] The ee value of the major diastereo-
mer was measured for the ethyl ester derivative. [f] Recrystallized from
CH2Cl2/petroleum ether 56% yield. [g] The reaction was carried out on a
1.0 mmol scale.
A wide range of aldehydes were examined under these
optimal reaction conditions, and the corresponding products
were obtained in high diastero- and enantioselectivities
(Table 4). Benzaldehydes with different substituents on the
aromatic ring were found to be suitable, affording the de-
sired products in good to excellent results (Table 4, en-
tries 1–21). Also, substrates with either electron-donating or
-withdrawing substituents reacted smoothly with a-isothio-
cyanato imide to give moderate to high yields and excellent
diastereo- and enantioselectivities. Moreover, a,b-unsaturat-
ed, heteroaromatic, and aliphatic aldehydes could also be
converted to the corresponding adducts with good to excel-
lent results (Table 4, entries 22–30). Other substrates, such
as ketones, also were explored, but no adduct was detect-
ed.[19] In addition, when the reaction with 2d was scaled up
fivefold with 2.5 mol% nickel complex, excellent results
with 98% yield, 97:3 d.r. and 95% ee were still obtained
(Table 4, entry 31). The transformation of 3d into amino
acid 6d was performed (Scheme 1). After oxidation of 4d
into 5d, the oxazolidinethione moiety was converted into a
protected oxazolidinone by using a reported procedure with-
out any loss of enantioselectivity.[20] Significantly, 5d can be
easily transformed into chiral b-hydroxy-a-amino acid 6d.
To understand the reaction process, a possible pathway
was assumed based on the literature (Scheme 2).[8d] We pre-
sumed that the reaction passed through the intermediate in
which the inherent instability of the aldol adducts formed by
using aldehyde 2a was trapped by the isothiocyanato imide
reagent. Also, some control experiments were performed to
provide insight into the mechanism. As shown in Table 5, no
10126
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 10124 – 10129

b-Hydroxy-a-Amino Acids
FULL PAPER
Table 5. Control experiments.[a]
Entry Ligand
[mol%]
[Ni
[mol%]
(acac)2]
Yield[b]
[%]
trans/
ee[d]
[%]
cis[c]
1
2
–
10
–
10
10
n.r.[e]
35
89
–
–
6
0
0
L5(10)
L7(10)
–
49:51
46:54
55:45
3
4[f]
92
[a] Unless otherwise noted, all reactions were carried out by using cata-
lyst (10 mol%), 1 (0.1 mmol), 2a (0.2 mmol) and 5 ꢁ MS (40.0 mg) in
THF/tBuOMe (1.6 mL) at 08C for 12 h. [b] Isolated yield of the com-
bined diastereomers. [c] Determined by using chiral HPLC analysis.
[d] The ee value of the major diastereomer, measured by using chiral
HPLC with a Chiracel IB column. [e] n.r.=no reaction. [f] 10 mol%
Et3N was added.
Scheme 1. Transformation of product 3d. Reagents and conditions:
a) MeMgBr, EtOH, 08C, 3 min; b) Boc2O, cat. 4-dimethylaminopyridine,
CH2Cl2, 08C, 30 min then H2O2, HCOOH, 08C, 30 min (Boc=tert-butyl-
oxycarbonyl).
are coordinated with nickel in the complex. On the basis of
the experimental results and the crystallographic data for
the catalyst, a possible transition state is proposed in
Scheme 2. We speculate that N,N’-dioxide L5 and a-isothio-
cyanato imide 1a coordinate with [NiACTHNUTRGEN(UNG acac)2] to form a com-
plex, which would increase the acidity of a-hydrogen of the
isothiocyanato acetyl imide and facilitate deprotonation. In
transition state TS, the a-isothiocyanato imide is much more
accessible to attack the Si face of the carbonyl of the alde-
hyde; in comparison, the Re-face attack is unfavorable due
to the steric repulsion between the phenyl groups of alde-
hyde 2a and the amide moiety of the ligand. The attack on
the Si face leads to the formation of the major (4S,5R) prod-
uct, which is in accordance with the experimental results.
Conclusion
We have developed an easily accessible and efficient direct
catalytic asymmetric aldol reaction of a-isothiocyanato
imide with aldehydes by using a chiral N,N’-dioxide–nickel-
Scheme 2. Proposed reaction pathway and transition state for the catalyt-
ic asymmetric aldol reaction.
AHCTUNGTREG(NNNU II) complex. This process provides a promising approach
for the synthesis of chiral b-hydroxy-a-amino acid deriva-
tives with broad substrate scope. In the presence of
2.5 mol% N,N’-dioxide–nickel(II) complex, excellent yields
and good to excellent diastereo- (up to >99:1) and enantio-
selectivities (up to >99% ee) were achieved for most sub-
strates under mild conditions. This pathway was air-tolerant
and easily manipulated, and the reagents are readily avail-
able. On the basis of the experimental results, a possible fa-
vorable transition state has been proposed. Furthermore,
the method has been successfully applied to the synthesis of
a protected oxazolidinone derivative, which can be easily
transformed into a chiral b-hydroxy-a-amino acid. Further
investigations of the mechanism of this catalytic system are
still in progress.
corresponding adduct 3a’ was obtained by using only [Ni-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
lyst could catalyze the aldol reaction of aldehyde with 89%
yield, but low diastereoselectivity and no enantiomeric
excess were observed (Table 5, entry 3). This important
piece of evidence demonstrates that N-oxide plays a key
role in the asymmetric inductivity. Moreover, ligand L4,
with a bulky isopropyl group at the ortho-position, led to a
dramatic decrease in enantioselectivity (Table 2, entry 4).
This showed that a large hindrance is deleterious for high
catalytic efficiency. In addition, the structure of the L4–Ni-
ACHTUNGTRENNUNG(BF4)2·6H2O complex was determined by using X-ray crys-
tallography.[21] As shown by the crystallography data, both
the carbonyl oxygen atoms and the N-oxide oxygen atoms
Chem. Eur. J. 2010, 16, 10124 – 10129
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10127

X. Feng et al.
7.48–7.45 (t, 4H), 7.25–7.13 (t, 4H), 3.69–3.60 (m, 4H), 3.59–3.44ACHTUNGTRENNUNG(m,
Experimental Section
4H), 3.43–3.25 (m, 2H), 2.83 (dd, J=6.8 Hz, 2H), 2.55–2.48 (m, 2H),
2.43–2.03 (m, 6H), 1.21–1.16 ppm (m, 12H); 13C NMR (100 MHz,
CDCl3): d=165.01, 144.98, 135.38, 126.85, 120.20, 120.09, 68.12, 64.69,
33.63, 27.59, 24.05, 20.03, 19.86 ppm; ESI-HRMS: m/z calcd for
C31H44N4O4: 537.3435 [M+H]+; found: 537.3455.
1
General Materials and Methods: H and 13C NMR spectra were recorded
on commercial instruments (1H: 400 or 600 MHz; 13C: 100 or 150 MHz).
Chemical shifts are reported in ppm relative to tetramethylsilane with
solvent peaks being used as an internal standard (1H: CDCl3, d=7.26
and [D6]-DMSO, d=3.37; 13C: CDCl3, d=77.0 and [D6]-DMSO, d=
40.45). 13C NMR spectra were recorded with complete proton decoupling.
HRMS was recorded on commercial apparatus (ESI Source). Enantio-
meric excesses and diastereoselectivities were determined by HPLC by
using the corresponding commercial chiral columns stated in the experi-
mental procedures. Unless otherwise indicated, all materials were ob-
tained from commercial sources and used as purchased, except for the al-
dehydes, which were distilled before use. Solvents were dried and dis-
tilled prior to use according to the standard methods. a-Isothiocyanato
imide 1, a white solid, was prepared according to the reported proce-
Acknowledgements
We thank the National Natural Science Foundation of China (nos.
20732003 and 20872097), PCSIRT (no. IRT0846) and National Basic Re-
search Program of China (973 Program; no. 2010CB833300) for financial
support. We also thank Sichuan University Analytical and Testing Center
for NMR spectroscopic analysis and the State Key Laboratory of Bio-
therapy for HRMS analysis.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[1] Glycopeptide Antibiotics (Ed.: R. Nagarajan), Marcel Dekker, New
York, 1994.
[2] a) K. Isono, K. Asahi, S. Suzuki, J. Am. Chem. Soc. 1969, 91, 7490;
b) G. J. Sharman, D. H. Williams, D. F. Ewing, C. Ratledge, Bio-
chem. J. 1995, 305, 187.
[3] a) R. Barclay, C. Ratledge, J. Bacteriol. 1983, 153, 1138; b) C. M.
Harris, H. Kopecka, T. M. Harris, J. Am. Chem. Soc. 1983, 105,
6915; c) M. K. Renner, Y. C. Shen, X.-C. Cheng, P. R. Jensen, W.
Frankmoelle, C. A. Kauffman, W. Fenical, E. Lobkovsky, J. Clardy,
J. Am. Chem. Soc. 1999, 121, 11273.
ACHTUNGTRENNUNG
isothiocyanato imide (372.4 mg, 0.2 mmol), and 5 ꢁ MS (80 mg) in THF/
tBuOMe (1:1, 3.2 mL) was stirred in an open vessel at ambient tempera-
ture for 30 min. The temperature was then reduced to 08C and stirred for
15 min. Benzaldehyde (40 mL, 0.4 mmol) was then added and the mixture
was stirred for a further 24 h at 08C. The trans and cis mixture of prod-
ucts were isolated by using column chromatography on silica gel
(CH2Cl2/EtOAc, 9:1). The residue was dissolved in dry THF (4.4 mL),
[4] For reviews, see: a) K. C. Nicolaou, C. N. C. Boddy, S. Brꢃse, N.
Winssinger, Angew. Chem. 1999, 111, 2230; Angew. Chem. Int. Ed.
1999, 38, 2096; b) C. Najera, J. M. Sansano, Chem. Rev. 2007, 107,
4584; c) Modern Aldol Reactions (Ed.: R. Mahrwald), Wiley-VCH,
Weinheim, 2004.
[5] For selected examples, see: a) D. L. Boger, M. A. Patane, J.-C.
Zhou, J. Am. Chem. Soc. 1994, 116, 8544 for epoxide opening;
b) I. H. Kim, K. L. Kirk, Tetrahedron Lett. 2001, 42, 8401 for amino-
hydroxylation; c) L. Dong, M. J. Miller, J. Org. Chem. 2002, 67, 4759
for dihydroxylation; d) C. Loncaric, W. D. Wulff, Org. Lett. 2001, 3,
3675 for azirdine opening; e) K. Makino, T. Goto, Y. Hiroki, Y.
Hamada, Angew. Chem. 2004, 116, 900; Angew. Chem. Int. Ed. 2004,
43, 882 for dynamic kinetic resolution; f) T. Ooi, M. Taniguchi, M.
Kameda, K. Maruoka, Angew. Chem. 2002, 114, 4724; Angew.
Chem. Int. Ed. 2002, 41, 4542; and g) N. Yoshikawa, M. Shibasaki,
Tetrahedron 2002, 58, 8289 for phase-transfer catalysis.
and cooled to 08C.
A solution of MeMgBr (3m in Et2O, 180 mL,
0.52 mmol) in EtOH (2.0 mL) at 08C was added. After 3 min, the reac-
tion was quenched by the addition of aq phosphate buffer solution
(3.0 mL, pH 7). The mixture was concentrated under reduced pressure,
and the residue was dissolved in aq HCl (1m, 1.5 mL) and CH2Cl2
(8 mL). The organic layer was separated, and the aqueous layer was ex-
tracted with CH2Cl2 (3ꢂ5 mL). The organic portions were combined,
dried (Na2SO4), and concentrated. The residue was purified by using
flash chromatography (SiO2, CH2Cl2/EtOAc, 50:1) to give 3a’ as colorless
crystals (92% isolated yield).
Typical procedure for the preparation of N,N’-dioxide ligands: 4-Methyl-
morpholine (0.48 mL, 4.4 mmol) and isobutyl carbonochloridate (520 mL,
4.0 mmol) were added to a solution of l-Boc-proline (861.0 mg, 4 mmol)
in THF (20 mL) at 08C with stirring. After 5 min, 4-isopropylaniline
(0.50 mL, 4 mmol) was added. The reaction was allowed to warm to RT
and was monitored by TLC. After 3 h, the mixture was washed with aq
KHSO4 (1m), sat. aq NaHCO3, and brine, dried over anhydrous Na2SO4,
concentrated, and purified by flash chromatograph (EtOAc/petroleum
ether, 1:5) to afford a white solid. Trifluoroacetic acid (TFA; 4 mL) was
added to a solution of the amide in CH2Cl2 (4 mL), and stirred until the
reaction was finished (2 h). The solvent was evaporated and H2O
(10 mL) was added. The pH of the mixture was brought into the range of
10–12 by the addition of aq NaOH (1m). The aqueous phase was extract-
ed with CH2Cl2 (3ꢂ30 mL). The combined organic phase was washed
with brine, dried over anhyd Na2SO4, and evaporated in vacuo to give a
residue that was directly used in the next step. K2CO3 (608 mg, 4.4 mmol)
and 1,3-dibromopropane (204 mL, 2 mmol) were added to a solution of l-
N-isopropylphenyl-2-carboxamide in CH3CN (4 mL) with stirring, then
heated at reflux and monitored by TLC. The K2CO3 was removed by fil-
tration and washed by CH2Cl2. The filtrate was concentrated and purified
by silica gel column chromatography (EtOAc/petroleum ether, 1:1) to
give the desired product (1.522 g, 76% isolated yield). N,N’-dioxide L5
was prepared by oxidation with m-chloroperoxybenzoic acid in CH2Cl2
(20 mL) at À208C for 30 min and purified by using chromatograph
[6] For approaches that involve oxazoline intermediates, see: a) Y. Ito,
M. Sawamura, T. Hayashi, J. Am. Chem. Soc. 1986, 108, 6405; b) H.
Suga, K. Ikai, T. Ibata, J. Org. Chem. 1999, 64, 7040; c) D. A. Evans,
J. M. Janey, N. Magomedov, J. S. Tedrow, Angew. Chem. 2001, 113,
1936; Angew. Chem. Int. Ed. 2001, 40, 1884.
[7] For selected examples that involve an enolate or an enolate surro-
gate, see: a) H. Sugiyama, T. Shioiri, F. Yokokawa, Tetrahedron Lett.
2002, 43, 3489; b) J. B. MacMillan, T. F. Molinski, Org. Lett. 2002, 4,
1883; c) S. Caddick, N. J. Parr, M. C. Pritchard, Tetrahedron 2001,
57, 6615; d) M. Horikawa, J. Busch-Peterson, E. J. Corey, Tetrahe-
dron Lett. 1999, 40, 3843; e) S. Kobayashi, H. Ishitani, M. Ueno, J.
Am. Chem. Soc. 1998, 120, 431; f) J. Kobayashi, M. Nakamura, Y.
Mori, Y. Yamashita, S. Kobayashi, J. Am. Chem. Soc. 2004, 126,
9192; g) S. E. Denmark, Y. Fan, J. Am. Chem. Soc. 2002, 124, 4233;
h) K. Oisaki, Y. Suto, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2003, 125, 5644; i) S. E. Denmark, Y. Fan, M. D. Eastgate, J. Org.
Chem. 2005, 70, 5235; j) K. Oisaki, D. Zhao, M. Kanai, M. Shibasa-
ki, J. Am. Chem. Soc. 2006, 128, 7164.
[8] a) M. C. Willis, V. J.-D. Piccio, Synlett 2002, 1625; b) M. C. Willis,
G. A. Cutting, V. J.-D. Piccio, M. J. Durbin, M. P. John, Angew.
Chem. 2005, 117, 1567; Angew. Chem. Int. Ed. 2005, 44, 1543; c) L.
Li, E. G. Klauber, D. Seidel, J. Am. Chem. Soc. 2008, 130, 12248;
d) T. Yoshino, H. Morimoto, G. Lu, S. Matsunaga, M. Shibasaki, J.
Am. Chem. Soc. 2009, 131, 17082.
(EtOAc/MeOH). Finally, L5 was obtained as
a white foamy solid
(1.236 g, 58% isolated yield). The synthesis and H and 13C NMR spectra
1
for the other ligands can be found in the references.[16,17]
l-Proline-based N,N’-dioxide L5: White solid; m.p.=112–1148C; [a]D15
=
À94.0 (c=1.0, in EtOH); 1H NMR (400 MHz, CDCl3): d=13.16 (s, 2H),
10128
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 10124 – 10129

b-Hydroxy-a-Amino Acids
FULL PAPER
[9] For the use of a-isothiocyanato imides in direct catalytic asymmetric
Mannich-type reactions with aldimines, see: a) G. A. Cutting, N. E.
Stainforth, M. P. John, G. Kociok-Kçhn, M. C. Willis, J. Am. Chem.
Soc. 2007, 129, 10632; b) L. Li, M. Ganesh, D. Seidel, J. Am. Chem.
Soc. 2009, 131, 11648; c) Z. G. Shi, P. Y. Yu, P. J. Chua, G. F. Zhong,
Adv. Synth. Catal. 2009, 351, 2797.
[10] For selected examples of dicarbonyl compounds as chelating candi-
dates, see: a) A. Mekonnen, R. Carlson, Eur. J. Org. Chem. 2006,
2005; b) G. H. Spikes, E. Bill, T. Weyhermꢄller, K. Wieghardt,
Angew. Chem. 2008, 120, 3015; Angew. Chem. Int. Ed. 2008, 47,
2973.
[11] a) G. Wilke, Angew. Chem. 1988, 100, 189; Angew. Chem. Int. Ed.
Engl. 1988, 27, 185; b) P. W. Jolly, Comprehensive Organometallic
Chemistry, Vol. 8 (Ed.: G. Wilkinson), Pergamon, Oxford, 1982,
p. 615; c) J. Montgomery in Science of Synthesis (Houben–Weyl
Methods of Molecular Transformations), Vol. 1 (Eds.: B. M. Trost,
M. Lautens), Thieme, Stuttgart, 2001, p. 11; d) R. Benn, B. Bꢄsse-
Franco, J. Am. Chem. Soc. 2005, 127, 10816; e) D. A. Evans, S. Mito,
D. Seidel, J. Am. Chem. Soc. 2007, 129, 11583; f) H. Suga, A. Funyu,
A. Kakehi, Org. Lett. 2007, 9, 97; g) J. Esquivias, R. G. Arrayꢅs, J. C.
Carretero, J. Am. Chem. Soc. 2007, 129, 1480; h) J. Shi, M. Zhao, Z.
Lei, M. Shi, J. Org. Chem. 2008, 73, 305; i) C. Fischer, G. C. Fu, J.
Am. Chem. Soc. 2005, 127, 4594; j) Z. Chen, H. Morimoto, S. Matsu-
naga, M. Shibasaki, J. Am. Chem. Soc. 2008, 130, 2170; k) K. Soai,
T. Hayasaka, S. Ugajin, J. Chem. Soc., Chem. Commun. 1989, 516;
l) S. Kanemasa, Y. Oderaotoshi, E. Wada, J. Am. Chem. Soc. 1999,
121, 8675; m) Y. S. Kwak, E. J. Corey, Org. Lett. 2004, 6, 3385;
n) A. D. Sadow, A. Togni, J. Am. Chem. Soc. 2005, 127, 17012;
o) J. D. Sieber, J. P. Morken, J. Am. Chem. Soc. 2008, 130, 4978.
[15] For reviews on chiral N-oxides in asymmetric catalysis, see: a) G.
Chelucci, G. Murineddu, G. A. Pinna, Tetrahedron: Asymmetry
ˇ
´
2004, 15, 1373; b) A. V. Malkov, P. Kocovsky, Eur. J. Org. Chem.
2007, 29; c) I. A. OꢇNeil, N. D. Miller, J. V. Barkley, C. M. Low, S. B.
Kalindjian, Synlett 1995, 617, and references therein.
[16] For examples of asymmetric catalytic reactions based on N,N’-diox-
ide, see: a) Z. P. Yu, X. H. Liu, Z. H. Dong, M. S. Xie, X. M. Feng,
Angew. Chem. 2008, 120, 1328; Angew. Chem. Int. Ed. 2008, 47,
1308; b) D. J. Shang, J. G. Xin, Y. L. Liu, X. Zhou, X. H. Liu, X. M.
Feng, J. Org. Chem. 2008, 73, 630; c) C. Tan, X. H. Liu, L. W. Wang,
J. Wang, X. M. Feng, Org. Lett. 2008, 10, 5305; d) X. Yang, X. Zhou,
L. L. Lin, L. Chang, X. H. Liu, X. M. Feng, Angew. Chem. 2008,
120, 7187; Angew. Chem. Int. Ed. 2008, 47, 7079; e) Y. L. Liu, D. J.
Shang, X. Zhou, X. H. Liu, X. M. Feng, Chem. Eur. J. 2009, 15,
2055; f) S. K. Chen, Z. R. Hou, Y. Zhu, J. Wang, L. L. Lin, X. H.
Liu, X. M. Feng, Chem. Eur. J. 2009, 15, 5884; g) D. H. Chen, Z. L.
Chen, X. Xiao, Z. G. Yang, L. L. Lin, X. H. Liu, X. M. Feng, Chem.
Eur. J. 2009, 15, 6807; h) M. Kokubo, C. Ogawa, S. Kobayashi,
Angew. Chem. 2008, 120, 7015; Angew. Chem. Int. Ed. 2008, 47,
6909.
ACHTUNGTRENNUNGmeier, S. Holle, P. W. Jolly, R. Mynott, I. Tkatchenko, G. Wilke, J.
Organomet. Chem. 1985, 279, 63; e) W. Keim, Angew. Chem. 1990,
102, 251; Angew. Chem. Int. Ed. Engl. 1990, 29, 235; f) P. A.
Wender, N. C. Ihle, Tetrahedron Lett. 1987, 28, 2451; g) P. A.
Wender, M. L. Snapper, Tetrahedron Lett. 1987, 28, 2221; h) P. A.
Wender, N. C. Ihle, C. R. D. Correia, J. Am. Chem. Soc. 1988, 110,
5904; i) P. A. Wender, M. J. Tebbe, Synthesis 1991, 1089; j) P. A.
Wender, J. M. Nuss, D. B. Smith, A. Suꢅrez-Sobrino, J. Vꢆgberg, D.
Decosta, J. Bordner, J. Org. Chem. 1997, 62, 4908; k) P. A. Wender,
N. C. Ihle, J. Am. Chem. Soc. 1986, 108, 4678.
[12] a) P. A. Wender, T. E. Jenkins, J. Am. Chem. Soc. 1989, 111, 6432;
b) P. A. Wender, T. E. Smith, J. Org. Chem. 1995, 60, 2962; c) P. A.
Wender, T. E. Jenkins, S. Suzuki, J. Am. Chem. Soc. 1995, 117, 1843;
d) P. A. Wender, T. E. Smith, J. Org. Chem. 1996, 61, 824; e) P. A.
Wender, T. E. Smith, Tetrahedron 1998, 54, 1255; f) M. Lautens, W.
Klute, W. Tam, Chem. Rev. 1996, 96, 49; g) P. Bhatarah, E. H. Smith,
J. Chem. Soc., Perkin Trans. 1 1992, 2163; h) Y. Sato, T. Nishimata,
M. Mori, J. Org. Chem. 1994, 59, 6133; i) S. I. Ikeda, H. Watanabe,
Y. Sato, J. Org. Chem. 1998, 63, 7026; j) M. Shanmugasundaram,
M. S. Wu, M. Jeganmohan, C.-W. Huang, C.-H. Cheng, J. Org.
Chem. 2002, 67, 7724; k) J. Louie, J. E. Gibby, M. V. Farnworth,
T. N. Tekavec, J. Am. Chem. Soc. 2002, 124, 15188.
[13] For selected examples of catalysis by nickel complexes, see: a) J.
Montgomery, Angew. Chem. 2004, 116, 3980; Angew. Chem. Int. Ed.
2004, 43, 3890; b) M. Chen, Y. Weng, M. Guo, H. Zhang, A. Lei,
Angew. Chem. 2008, 120, 2311; Angew. Chem. Int. Ed. 2008, 47,
2279; c) R. D. Baxter, J. Montgomery, J. Am. Chem. Soc. 2008, 130,
9662.
[17] a) K. Zheng, J. Shi, X. H. Liu, X. M. Feng, J. Am. Chem. Soc. 2008,
130, 15770; b) L. J. Wang, X. H. Liu, Z. H. Dong, X. Fu, X. M. Feng,
Angew. Chem. 2008, 120, 8798; Angew. Chem. Int. Ed. 2008, 47,
8670.
[18] Product 3a’: (4S,5R)-ethyl 5-phenyl-2-thioxooxazolidine-4-carboxyl-
ate.
[19] No product was obtained when acetophenone was tested as a sub-
strate by using this catalyst system.
[20] D. A. Evans, A. E. Weber, J. Am. Chem. Soc. 1987, 109, 7151. See
also reference [8c].
[21] CCDC-739905 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[14] For selected examples, see: a) K. Itoh, S. Kanemasa, J. Am. Chem.
Soc. 2002, 124, 13394; b) K. Itoh, M. Hasegawa, J. Tanaka, S. Kane-
masa, Org. Lett. 2005, 7, 979; c) D. A. Evans, D. Seidel, J. Am.
Chem. Soc. 2005, 127, 9958; d) D. A. Evans, R. J. Thomson, F.
Received: February 2, 2010
Revised: April 12, 2010
Published online: July 19, 2010
Chem. Eur. J. 2010, 16, 10124 – 10129
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10129