β-tert-Butyl aspartate as an organocatalyst for the asymmetric α-amination of α,α-disubstituted aldehydes

Article abstract of DOI:10.1016/j.tet.2013.04.103

The enantioselective α-amination reaction of α,α- disubstituted aldehydes can lead to a variety of enantioenriched amino aldehydes, amino alcohols, and amino acids. After screening a variety of amino acids and their derivatives, we identified a cheap, simple, commercially available aspartic acid derivative that can catalyze efficiently the reaction between α,α-disubstituted aldehydes and dialkyl azodicarboxylates. The reaction proceeds smoothly leading to the corresponding α-aminated adducts in moderate to quantitative yields and moderate to high enantioselectivities (up to 96% ee). Finally, the conversion of these adducts to α,α-disubstituted quaternary amino acids is also described.

Full text of DOI:10.1016/j.tet.2013.04.103

Tetrahedron xxx (2013) 1e6
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b-tert-Butyl aspartate as an organocatalyst for the asymmetric
a-amination of a,a-disubstituted aldehydes
*
Alexis Theodorou, Giorgos N. Papadopoulos, Christoforos G. Kokotos
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, 15771 Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective
a-amination reaction of a,a-disubstituted aldehydes can lead to a variety of
Received 5 February 2013
Received in revised form 14 April 2013
Accepted 23 April 2013
Available online xxx
enantioenriched amino aldehydes, amino alcohols, and amino acids. After screening a variety of amino
acids and their derivatives, we identified a cheap, simple, commercially available aspartic acid derivative
that can catalyze efficiently the reaction between
ylates. The reaction proceeds smoothly leading to the corresponding
quantitative yields and moderate to high enantioselectivities (up to 96% ee). Finally, the conversion of
these adducts to -disubstituted quaternary amino acids is also described.
Ó 2013 Elsevier Ltd. All rights reserved.
a,a
-disubstituted aldehydes and dialkyl azodicarbox-
a
-aminated adducts in moderate to
Keywords:
a,a
a
-Amination
Organocatalysis
Amino Acids
Aspartic acid
Quaternary centers
1. Introduction
Non-proteogenic a-amino acids, especially a,a-disubstituted
amino acids that are known to be sterically constrained, are bound
to play key roles in improving the conformational properties and
Stereoselective transformations for the creation of functional-
ized optically active molecules with structural diversity were al-
ways the ultimate target for organic chemists. Since the appearance
of Organocatalysis,1,2 a plethora of simple to complex molecular
architectures that have been employed in numerous organic
transformations providing elegant solutions to long-standing
problems and affording novel reactions. Optically active nitrogen-
containing molecules are versatile and important building blocks
activity of peptides. Herein, we report the use of simple
a-amino
acid derivatives, such as -tert-butyl aspartate, which were found
b
to be excellent in promoting the same transformation leading to
products in high yields and enantioselectivities.
2. Results and discussion
After the initial report from Brase,5a Barbas, and co-workers
utilized proline tetrazole as the catalyst for the a-amination of 3-
(4-bromophenyl)-2-methylpropanal (95% yield, 80% ee) to provide
a route to a product of pharmaceutical importance.6 In 2011, three
publications from different groups reported the use of primary
in organic synthesis. Especially a-amino acids and their derivatives
are key intermediates for the construction of important biological
and pharmaceutical units. A variety of methods for their con-
struction have been developed, among them the
carbonyl compounds has received a lot of attention.3 Shortly after
the simultaneous report on the -amination of aldehydes by Jor-
gensen and co-workers and List,4 Brase, and co-workers reported
the -amination of
-disubstituted aldehydes.5a However,
a-amination of
a
amine catalysts that efficiently catalyzed the reaction between a,a-
disubstituted aldehydes and azodicarboxylates (Fig. 1).7e9 Xu,
Wang, and co-workers utilized non-natural amino acid hydro-
chloride 1 as the catalyst for the reaction between aryl, alkyl al-
dehydes, and diethyl or di-isopropyl azodicarboxylate.7 Utilizing
20 mol % catalyst, the reaction proceeded smoothly affording the
products in moderate to excellent yields and enantioselectivities.
a
a,a
50 mol % proline had to be employed to provide moderate to high
yield and enantioselectivities of up to 86% ee. Later on, the same
group reported a full account of their work, as well as how the use
of microwave irradiation can reduce the reaction time from a few
days to just hours.5bec A route to transform these organocatalyzed
However, in order to provide a direct route to
a,a-disubstituted
products to
a,a
-disubstituted amino acids was also reported.5b
amino acids, di-tert-butyl azodicarboxylate has to be employed,
since it is easier to cleave the NeN bond. Unfortunately, catalyst 1
provided high enantioselectivity but low yield (33%).7 Lu and co-
workers reported that a combination of 9-amino(9-deoxy)epi-
quinine with (ꢀ)-camphorsulfonic acid could catalyze efficiently
* Corresponding author. Tel.: þ30 210 7274281; fax: þ30 210 7274761; e-mail
address: ckokotos@chem.uoa.gr (C.G. Kokotos).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.103
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2
A. Theodorou et al. / Tetrahedron xxx (2013) 1e6
the reaction between aryl, alkyl aldehydes, and di-tert-butyl azo-
dicarboxylate leading to excellent yields and selectivities utilizing
10 mol % catalyst loading.8 They have also demonstrated that in
principle lower amount of the catalytic pair 2 can catalyze the re-
action in prolonged reaction time (0.5 mol %, 36 h).8 The similar
catalytic motif 3 was employed by Greck and co-workers at 5 mol %
leading to slightly inferior results.9
disubstituted carbonyl compounds, primary aminocatalysts can
more easily form the required enamine intermediate. Thus, based
on our previous knowledge on organocatalysis,11 a number of pri-
mary aminocatalysts were tested. Although amino alcohols and
glucosamine led to inferior results (entries 3 and 4, Table 1), amino
acids and their derivatives proved in some cases quite efficient
catalysts (entries 5e14, Table 1). Histidine, aspartic acid, and as-
paragine led only to traces, but phenylalanine and b-phenylalanine
provided 6a in quantitative yields and slightly inferior enantiose-
lectivity than proline in shorter reaction time (entries 5e9, Table 1).
Although aspartic acid did not catalyze the reaction,
partates proved to be far more efficient than proline (entries 10e12,
Table 1). -tert-Butyl aspartate provided 6a in quantitative yield,
with high enantioselectivity in 24 h (entry 11, Table 1). -tert-Butyl
b-alkyl as-
b
a
aspartate led to high enantioselectivity but poor yield (entry 12,
Table 1), while di-tert-butyl aspartate provides the opposite enan-
tiomer of the product, although in low yield and enantioselectivity
after prolonged reaction time (entry 13, Table 1). Dipeptide H-
Fig. 1. Primary amine organocatalysts employed in the reaction between
substituted aldehydes and di-tert-butyl azocarboxylate.
a,a-di-
Asp(OtBu)-Val-OtBu proved to be equally efficient with
b-tert-butyl
aspartate, but prolonged reaction time was required (entry 14,
Table 1).
Initially, the reaction between aldehyde 4a and di-isopropyl
azocarboxylate 5a was evaluated (Table 1). A number of second-
ary and primary amines were tested for their efficiency in this
transformation. Proline was rather a poor catalyst for this reaction
since prolonged reaction time was required and the enantiose-
lectivity of the reaction was mediocre (entry 1, Table 1), in accor-
dance with literature.7 Proline sulfonamides are known to perform
in some reactions better that proline itself,10 but, in this reaction
Once the optimum catalyst was found, the reaction conditions
were scrutinized in order to obtain optimum results (Table 2).
Initially, a number of different solvents were evaluated (entries
1e9, Table 2). Although a number of solvents provided the product
in quantitative yield, THF proved to give the higher enantiose-
lectivity (entry 9, Table 2). It is known that in some organocatalyzed
processes, acid additives have positive impact on the outcome of
the reaction.12 Thus, the addition of a number of acid additives and
provided inferior results (entry 2, Table 1). In the case of
a,a-
Table 2
Table 1
Reaction between aldehyde 4a and di-isopropyl azocarboxylate 5a utilizing b-tert-
Reaction between aldehyde 4a and di-isopropyl azocarboxylate 5a utilizing a variety
butyl aspartate as the catalysta
of organocatalystsa
Entry
1
Catalyst
Proline
Reaction time (h)
96
Yield (%)b
71
ee (%)c
66
Entry
Reaction conditions
Reaction time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
24
24
24
120
120
24
48
48
24
24
24
24
24
24
24
24
24
100
100
100
71
84
82
80
60
59
73
0
75
90
88
85
83
85
91
90
93
91
2
120
21
n.d.
1,2-DCE
Toluene
Benzene
Dioxane
H2O
Et2O
THF
THF, AcOH
THF, 4-NBA
THF, 4-NBA, H2O
THF
65
100
100
67
100
72
3
72
30
51
4
5
6
7
8
9
10
11
12
13
Glucosamine. HCl
120
120
24
d
d
9
L
L
L
L
L
L
L
L
L
-Histidine
-Phenylalanine
Traces
100
92
Traces
Traces
84
100
26
50
n.d.
66
61
n.d.
n.d.
78
84
90
ꢀ51
10
11
12
13d
14e
15f
16e,g
17e,i
77
89
-b
-Phenylalanine
24
-Aspartic acid
-Asparigine
120
120
72
24
24
100
100
72
THF
THF
THF
THF
-Asp(OBn)eOH
-Asp(OtBu)eOH
-Asp-OtBu
100h
100
-Asp(OtBu)eOtBu
120
a
Reaction conditions: b-tert-butyl aspartate 20 mol %, solvent (1.0 mL), aldehyde
4a (0.40 mmol), and 5a (0.20 mmol).
b
Yield determined by 1H NMR of the crude reaction mixture.
The ee was determined by chiral HPLC.
14
48
100
82
c
d
10 mol % of catalyst was used.
e
The reaction was performed at 0 ꢁC.
a
f
Reaction Conditions: catalyst 20 mol %, CH2Cl2 (1.0 mL), aldehyde 4a
(0.40 mmol) and 5a (0.20 mmol).
The reaction was performed at ꢀ20 ꢁC.
g
Aldehyde:azocarboxylate 1.5:1.
b
h
Yield determined by 1H NMR of the crude reaction mixture.
The enantiomeric excess (ee) was determined by chiral HPLC. n.d.: not
93% isolated yield.
c
i
Aldehyde:azocarboxylate 1.2:1. 1,2-DCE:1,2-dichloroethane, 4-NBA: 4-
determined.
nitrobenzoic acid.
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A. Theodorou et al. / Tetrahedron xxx (2013) 1e6
3
Table 4
Enantioselective
utilizing
water were tested, but none of them provided better results (en-
tries 10e12, Table 2). Upon reducing the catalyst loading to
10 mol %, the enantioselectivity of the reaction drops significantly
(entry 13, Table 2). When the reaction was performed at 0 ꢁC, the
enantioselectivity slightly increased (entry 14, Table 2). However,
further cooling down to ꢀ20 ꢁC inhibited the catalytic activity
(entry 15, Table 2). Finally, the optimum ratio of the reactants was
found (entries 16e17, Table 2).
a
-amination of
a
,
a
-disubstituted aldehydes with azocarboxylate 5c
b
-tert-butyl aspartate as the catalysta
Once the optimum reaction conditions were identified, the effect
of the alkyl moiety of dialkyl azocarboxylate was studied (Table 3).
Diethyl azocarboxylate performed equally well but led to lower
enantioselectivity than di-isopropyl azocarboxylate (entry 2 vs en-
try 1, Table 3). Similar trends have been observed in the literature.7,9
When the bulkier di-tert-butyl azocarboxylate was utilized, the best
results were obtained leading to product 6c in 98% yield and 94% ee
(entry 3, Table 3). Literature data also indicates similar higher
enantioselectivities relative to other azocarboxylates.7e9 A further
advantage of di-tert-butyl azocarboxylate is its easy removal. Un-
fortunately, in our protocol, di-benzyl azocarboxylate that would
lead to the Cbz-protected product, did not afford 6d (entry 4,
Table 3).
Entry
R1, R2
Reaction time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Me, Ph
24
24
48
48
72
72
48
48
24
24
48
48
48
48
24
98
98
52
70
40
55
52
68
57
69
80
88
97
62
74
94
93
93
96
94
92
88
87
n.d.
91
50
51
65
89
47
Me, 4-Me-C6H4
Me, 4-FeC6H4
Me, 4-BreC6H4
Me, 2-BreC6H4
Me, 3-BreC6H4
Me, naphthyl
Me, 4-MeOeC6H4
Me, 4-NO2eC6H4
Et, Ph
Me, PhCH2
Me, Pr
Me, (CH2)2C]C(Me)2
Me, CH2OTBDMS
Me, NHCbz
9
10
11
12
13
14
15
Table 3
Reaction between aldehyde 4a and various di-alkyl azocarboxylates 5 utilizing
b-
tert-butyl aspartate as the catalysta
a
Reaction conditions: b-tert-butyl aspartate 20 mol %, THF (1.0 mL), aldehyde 4
(0.30 mmol), and 5c (0.20 mmol) at 0 ꢁC.
b
Isolated yield after column chromatography.
The ee was determined by chiral HPLC. n.d.: not determined.
c
employed leading to mediocre yields and slightly decreased
enantioselectivities (entries 7 and 8, Table 4). For the case of aro-
matic moieties bearing electron-withdrawing substituents, like p-
nitrophenyl, the reaction can provide the desired product, but we
were unable to determine the enantioselectivity of the product
(entry 9, Table 4). Although this is a known product,8 all our efforts
to determine the enantioselectivity met with failure. When the
phenyl moiety was kept intact and the methyl group was replaced
by an ethyl group, a slight drop in the enantioselectivity was ob-
served (entry 10, Table 4). This can be explained, when the pro-
posed reaction intermediate is taken into account (Fig. 2). In this
proposed reaction intermediate, the enamine is formed from the
Entry
1
5
Produce
Yield (%)b
93
ee (%)c
6a
93
90
2
3
6b
100
6c
98
94
primary amine of the catalyst and the a,a-disubstituted aldehyde.
The two substituents adopt the positions where minimum steric
repulsions occur. In this manner, the bulkier aryl moiety is placed at
the position of R2, while the smaller methyl group at the place of R1
(Fig. 2). When R1 and R2 start to be of the same bulkiness, then both
moieties can be placed in both positions. This distribution in both
positions leading to the slightly bulkier substituent to the least
hindered position leads to lower enantioselectivity. Thus, when
benzylemethyl aldehyde is employed, the enantioselectivity of
reaction is mediocre (entry 11, Table 4). Employing linear
alkylemethyl aldehydes led to slightly higher enantioselectivity,
while the yield remained high (entries 12 and 13, Table 4). When
one of the groups utilized is getting more bulky than the other, the
adoption of the R1/R2 positions in the model resembles more the
aryl/alkyl case leading back to increased selectivities. Thus, the use
of an aldehyde bearing a bulky TBDMS-protected alcohol led to
4
6d
d
n.d.
a
Reaction conditions: : b-tert-butyl aspartate 20 mol %, THF (1.0 mL), aldehyde 4a
(0.30 mmol), and 5 (0.20 mmol) at 0 ꢁC for 24 h.
b
Isolated yield after column chromatography.
The ee was determined by chiral HPLC. n.d.: not determined.
c
Having established di-tert-butyl azocarboxylate as the best
azocarboxylate, the scope and limitations of this
action was explored (Table 4). Although Brase and co-workers in-
troduced a synthetic protocol for the synthesis of -disubstituted
a-amination re-
a,a
aldehydes,5 that method in our hands led to unsatisfactory results
and thus, a number of different synthetic routes had to be followed
for the preparation of the substrates (See Supplementary data).
para-Substituted aromatic-methyl aldehydes performed similarly
to the parent aldehyde leading from moderate to excellent yields
and excellent enantioselectivities (entries 2e4, Table 4). ortho-
Substituted and meta-substituted aromatic-methyl aldehydes are
also well tolerated leading to products in mediocre yields, but in
high enantioselectivities (entries 5 and 6, Table 4). Other aromatic-
methyl aldehydes and electron rich aryl-methyl aldehydes can be
Fig. 2. Proposed transition-state.
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4
A. Theodorou et al. / Tetrahedron xxx (2013) 1e6
high enantioselectivity (entry 14, Table 4). This is the first example
where an aldehyde that bears a protected heteroatom is utilized in
such a reaction. Building on this result, racemic Cbz-protected
alanilal was then employed (entry 15, Table 4). Unfortunately, the
enantioselectivity of the reaction was not high.
As mentioned earlier, a possible transition-state is proposed in
Fig. 2. After the formation of the enamine, the bulky side chain of
aspartic acid catalyst bearing the tert-butyl ester moiety shields
efficiently the back face of the enamine. Simultaneously, the free
carboxylate drives the addition to the azocarboxylate from the front
face by hydrogen bond interactions with the azocarboxylate.
Finally, to prove the utility of this methodology, the product of
the organocatalyzed reaction 6c was transformed into the pro-
t¼triplet, q¼quartet, m¼multiplet, bs¼broad signal, bs m¼broad
signal multiplet), coupling constant and assignment. Data for 13C
NMR spectra are reported in terms of chemical shift (
d ppm).
Rotamers are reported in brackets. Mass spectra were recorded on
a Finnigan Surveyor MSQ Plus, with only molecular ions and major
peaks being reported with intensities quoted as percentages of the
base peak. High Performance Liquid Chromatography (HPLC) was
used to determine enantiomeric excesses and was performed on
a Agilent 1100 Series apparatus using ChiralpakÒ AD-H, OD-H and
AS-H columns. Aldehydes 4a and 4kem are commercially available.
Aldehydes 4bej and 4neo were synthesized (see Supplementary
data). The configuration of the products has been assigned by
comparison to literature data.
tected a,a-disubstituted phenyl glycine derivative 8 (Scheme 1).
4.2. General procedure for the organocatalytic
of -disubstituted aldehydes
a-amination
a,a
To a stirring solution of HeAsp(OtBu)eOH (15 mg, 0.08 mmol) in
dry THF (5 mL), the appropriate azodicarboxylate (0.40 mmol) and
-disubstituted aldehyde (0.60 mmol) were added at 0 ꢁC and the
a,a
reaction mixture was stirred for 24e72 h. The solvent was evapo-
rated and the crude product was purified using flash column
chromatography eluting with the appropriate mixture of petro-
leum ether (40e60 ꢁC): EtOAc to afford the desired product.
Scheme 1. Transformation of organocatalyzed product 6c to
cine 8.
a-methyl a-phenyl gly-
3. Conclusions
4.3. Characterization of the products
In conclusion, an enantioselective a-amination protocol of a,a-
4.3.1. (R)-Di-isopropyl 1-(1-oxo-2-phenylpropan-2-yl)hydrazine-1,2-
disubstituted aldehydes is highlighted. Simple
rivatives can be employed as the catalysts, with
a
-amino acid de-
dicarboxylate (6a).13 Colorless oil (125 mg, 93%); [
a
]
20 þ45.7 (c 1.00,
b-tert-butyl aspar-
D
CHCl3), {lit.7 [
a]
20 þ57.0 (c 0.64, CH2Cl2), 95% ee}; 1H NMR (CDCl3)
d:
tate providing the best results. This is the first time that a simple
aspartic acid derivative is utilized efficiently in an organic trans-
formation as a catalyst. Among a number of dialkyl azocarboxylates,
di-tert-butyl azocarboxylate afforded the highest enantioselectiv-
ities. A variety of aromatic-alkyl aldehydes were utilized success-
fully. Switching the aromatic moiety to benzyl or linear alkyl led to
a significant decrease on the enantioselectivity of the reaction. For
D
9.72 (0.25H, s, CHO), 9.57 (0.75H, s, CHO), 7.53e7.33 (5H, m, ArH),
6.49 (0.75H, br s, NH), 6.33 (0.25H, br s, NH), 5.02e4.89 (2H, m, 2ꢂ
CH), 1.77 (3H, s, CH3), 1.26e1.19 (12H, m, 4ꢂ CH3); 13C NMR (CDCl3)
d
: 192.7 (193.8), 156.0 (158.7), 155.6 (158.4), 136.9, 128.9, 128.1,
126.8, 73.0, 71.4 (70.8), 70.2 (70.6), 21.9 (21.8), 21.7 (21.6), 17.8
(17.7); 93% ee determined by HPLC analysis Daicel Chiralpak AD-H,
i-PrOH/hexane (1/99),1.0 mL/min, tR¼52.81 min (major), 58.66 min
(minor).
the first time, a-amino protected aldehydes were employed for this
transformation leading to poor results, while the use of a bulky
protected oxygen-bearing aldehyde led to high enantioselectivity.
The importance of the products obtained by this protocol was
highlighted by the transformation of one of the products to the
4.3.2. (R)-Diethyl 1-(1-oxo-2-phenylpropan-2-yl)hydrazine-1,2-
20
dicarboxylate (6b).5a Colorless oil (123 mg, 100%); [
a
]
D
þ51.8 (c
20
1.00, CHCl3), {lit.7
[
a]
þ39.3 (c 0.30, CH2Cl2), 91% ee}; 1H NMR
corresponding a,a-disubstituted amino acid derivative.
D
(CDCl3) d: 9.73 (0.3H, s, CHO), 9.57 (0.7H, s, CHO), 7.52e7.25 (5H, m,
ArH), 6.62 (0.7H, br s, NH), 6.54 (0.3H, br s, NH), 4.28e3.99 (4H, m,
4. Experimental section
2ꢂ OCH2) 1.77 (3H, s, CH3), 1.26e1.19 (6H, m, 2ꢂ CH3); 13C NMR
(CDCl3) d: 192.8, 156.3, 156.0, 136.9, 129.0, 128.2, 126.9, 73.2, 63.3,
4.1. General information
62.4, 17.7, 14.4, 14.2; 90% ee determined by HPLC analysis Daicel
Chiralpak AS-H, i-PrOH/hexane (10/90), 0.8 mL/min, tR¼32.45 min
(major), 46.93 min (minor).
Organic solutions were concentrated under reduced pressure on
€
a Buchi rotary evaporator. Chromatographic purification of prod-
ucts was accomplished using forced-flow chromatography on
Merck Kieselgel 60 F254 Organic solutions were concentrated under
4.3.3. (R)-Di-tert-butyl 1-(1-oxo-2-phenylpropan-2-yl)hydrazine-1,2-
20
dicarboxylate (6c).8 Colorless oil (143 mg, 98%); [
a
]
þ48.8 (c
D
20
reduced pressure on a Buchi rotary evaporator. Chromatographic
1.00, CHCl3), {lit.7
[a]
þ50.0 (c 0.26, CH2Cl2), 92% ee}; 1H NMR
€
D
purification of products was accomplished using forced-flow
chromatography on Merck Kieselgel 60 F254 230e400 mesh. Thin-
layer chromatography (TLC) was performed on aluminum-backed
silica plates (0.2 mm, 60 F254). Visualization of the developed
chromatogram was performed by fluorescence quenching using
phosphomolybdic acid, anisaldehyde or ninhydrin stains. Optical
rotations were measured on a Perkin Elmer 343 polarimeter. IR
spectra were recorded on a Nicolet IR200 FT-IR spectrometer and
(CDCl3) d: 9.68 (0.3H, s, CHO), 9.54 (0.7H, s, CHO), 7.53e7.24 (5H, m,
ArH) 6.30 (0.7H, br s, NH), 6.18 (0.3H, br s, NH), 1.73 (3H, s, CH3), 1.43
[9H, s, C(CH3)3], 1.39 [9H, s, C(CH3)3]; 13C NMR (CDCl3)
d: 192.8,
155.4,154.7,137.2,128.8,128.4,127.9,126.7, 83.1, 81.6, 72.8, 27.9,17.4;
94% ee determined by HPLC analysis Daicel Chiralpak AD-H, i-PrOH/
hexane (10/90), 1.0 mL/min, tR¼27.11 min (major), 33.56 min
(minor).
are reported in terms of frequency of absorption (cmꢀ1). 1H and 13
C
4.3.4. (R)-Di-tert-butyl
1,2-dicarboxylate (6e).8 Colorless oil (149 mg, 98%); [
1.00, CHCl3); 1H NMR (CDCl3)
1-(1-oxo-2-p-tolylpropan-2-yl)hydrazine-
NMR spectra were recorded on Varian Mercury (200 or 50 MHz) as
noted, and are internally referenced to residual solvent signals
(CDCl3). Data for 1H NMR spectra are reported as follows: chemical
a]
20 þ46.5; (c
D
d
: 9.66 (0.2H, s, CHO), 9.51 (0.8H, s,
CHO), 7.43e7.19 (4H, m, ArH), 6.20 (0.8H, br s, NH), 5.94 (0.2H, br s,
shift (
d
ppm), integration, multiplicity (s¼singlet, d¼doublet,
NH), 2.33 (3H, s, CH3), 1.73 (3H, s, CH3), 1.43 [9H, s, C(CH3)3], 1.41
Please cite this article in press as: Theodorou, A.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.103

A. Theodorou et al. / Tetrahedron xxx (2013) 1e6
5
[9H, s, C(CH3)3]; 13C NMR (CDCl3)
d
: 192.7, 155.3, 155.1, 137.7, 129.5,
9.49 (0.6H, s, CHO), 7.43 (0.8H, d, J¼8.7 Hz, ArH), 7.28 (1.2H, d, J¼8.7,
ArH) 6.88 (2H, d, J¼8.7, ArH), 6.25 (0.6H, br s, NH), 6.07 (0.4H, br s,
NH), 3.79 (3H, s, OCH3), 1.74 (3H, s, CH3), 1.44 [18H, s, 2ꢂ C(CH3)3];
129.2, 126.7, 83.0, 81.5, 72.7, 28.1, 27.9, 21.0, 17.2; 93% ee determined
by HPLC analysis Daicel Chiralpak AD-H, i-PrOH/hexane (5/95),
0.5 mL/min, tR¼28.18 min (minor), 35.43 min (major).
13C NMR (CDCl3)
d: 192.6,159.2,155.3,155.0,128.1,114.2,113.8, 83.0,
81.5, 72.4, 55.2, 28.0, 27.9, 17.1; 87% ee determined by HPLC analysis
Daicel Chiralpak AD-H, i-PrOH/hexane (10/90), 0.5 mL/min,
tR¼29.84 min (major), 40.37 min (minor).
4.3.5. (R)-Di-tert-butyl
hydrazine-1,2-dicarboxylate (6f). Colorless oil (81 mg, 52%); [
þ47.0 (c 1.00, CHCl3); IR (film) 3320, 2980, 2933, 1730, 1698, 1510,
1368, 1248, 1161, 1059, 836, 763 cmꢀ1 1H NMR (CDCl3)
: 9.66
1-(2-(4-fluorophenyl)-1-oxo-propan-2-yl)
23
a
]
D
;
d
4.3.11. (R)-Di-tert-butyl 1-(2-(4-nitrophenyl)-1-oxo-propan-2-yl)hy-
drazine-1,2-dicarboxylate (6l).8 Colorless oil (96 mg, 57%); [
þ28.0 (c 1.00, CHCl3); H NMR (CDCl3)
a]
D
20
(0.25H, s, CHO), 9.55 (0.75H, s, CHO), 7.55e7.29 (2H, m, ArH),
7.10e6.95 (2H, m, ArH), 6.28 (1H, br s, NH), 1.72 (3H, s, CH3), 1.46
1
d: 9.70 (0.15H, s, CHO), 9.62
[9H, s, C(CH3)3], 1.41 [9H, s, C(CH3)3]; 13C NMR (CDCl3)
d: 193.0,
(0.85H, s, CHO), 8.20 (2H, d, J¼8.8 Hz, ArH), 7.78e7.48 (2H, m, ArH),
162.3 (d, J¼247.7 Hz), 155.6, 154.8, 133.4 (d, J¼3.2 Hz), 128.5 (d,
6.96 (0.15H, br s, NH), 6.67 (0.85H, br s, NH),1.66 (3H, s, CH3),1.46 [9H,
J¼7.0 Hz), 115.6 (d, J¼21.3 Hz), 83.3, 81.8, 72.1, 28.1, 27.9, 18.0; 19F
s, C(CH3)3],1.42 [9H, s, C(CH3)3]; 13C NMR (CDCl3)
d
: 193.1,155.7,155.4,
NMR (CDCl3)
d
: ꢀ59.2 (s); MS (ESI) m/z (%): 383 [MþH, 45]þ; HRMS
147.0, 145.1, 127.5, 123.6, 83.8 (83.6), 82.7 (82.0), 72.0, 28.0, 27.8, 19.3.
exact mass calculated for [MþH]þ (C19H28FO5N2) requires m/z
383.1977, found m/z 383.1968; 93% ee determined by HPLC analysis
Daicel Chiralpak AD-H, i-PrOH/hexane (5/95), 1.0 mL/min,
tR¼24.82 min (major), 30.41 min (minor).
4.3.12. (R)-Di-tert-butyl
1,2-dicarboxylate (6m).8 Colorless oil (107 mg, 69%); [
1.00, CHCl3); 1H NMR (CDCl3)
: 9.74 (0.35H, s, CHO), 9.53 (0.65H, s,
1-(1-oxo-2-phenylbutan-2-yl)hydrazine-
20
a
]
þ77.7 (c
D
d
CHO), 7.62e7.25 (5H, m, ArH), 6.43 (0.35H, br s, NH), 6.19 (0.65H, br
s, NH), 2.53e2.05 (2H, m, 2ꢂ CHH), 1.48e1.14 [21H, m, CH3, 2ꢂ
4.3.6. (R)-Di-tert-butyl 1-(2-(4-bromophenyl)-1-oxo-propan-2-yl)
23
hydrazine-1,2-dicarboxylate (6g).8 Colorless oil (124 mg, 70%); [
a
]
C(CH3)3]; 13C NMR (CDCl3)
d: 193.0, 155.5, 154.7, 136.3, 128.5, 127.4,
þ33.2 (c 1.00, CHCl3), {lit.7 [
a
]
20 þ33.0 (c 0.55, CH2Cl2), 85% ee}; 1DH
126.8, 82.8, 81.2, 60.4, 28.1, 27.9, 21.0, 14.1; 91% ee determined by
HPLC analysis Daicel Chiralpak AD-H, i-PrOH/hexane (10/90),
0.5 mL/min, tR¼23.21 min (major), 30.03 min (minor).
D
NMR (CDCl3) d: 9.62 (0.35H, s, CHO), 9.52 (0.65H, s, CHO), 7.48 (2H,
d, J¼8.7 Hz, ArH), 7.26 (2H, d, J¼8.7 Hz, ArH), 6.29 (1H, br s, NH),1.68
(1.95H, s, CH3), 1.66 (1.05H, s, CH3), 1.44 [9H, s, C(CH3)3], 1.40 [9H, s,
C(CH3)3]; 13C NMR (CDCl3)
d: 193.3, 156.2, 155.7, 136.8, 131.9, 128.4,
4.3.13. (R)-Di-tert-butyl
1-(2-methyl-1-oxo-3-phenylpropan-2-yl)
20
122.2, 83.5, 81.9, 72.3, 28.0, 27.9, 17.9; 96% ee determined by HPLC
analysis Daicel Chiralpak AD-H, i-PrOH/hexane (2/98), 1.0 mL/min,
tR¼50.18 min (major), 60.94 min (minor).
hydrazine-1,2-dicarboxylate (6n).9 Colorless oil (124 mg, 80%); [
a]
D
þ47.7 (c 1.00, CHCl3); 1H NMR (CDCl3)
d: 9.65 (0.6H, s, CHO), 9.51
(0.4H, s, CHO), 7.35e7.20 (3H, m, ArH), 7.05e6.95 (2H, m, ArH), 5.43
(0.6H, br s, NH), 5.31 (0.4H, br s, NH), 3.36 (1H, d, J¼13.9 Hz, PhCHH),
2.87 (1H d, J¼13.9 Hz, PhCHH),1.48 [9H, s, C(CH3)3],1.43 (3H, s, CH3),
4.3.7. (R)-Di-tert-butyl 1-(2-(2-bromophenyl)-1-oxo-propan-2-yl)
20
hydrazine-1,2-dicarboxylate (6h).8 Colorless oil (71 mg, 40%); [
a
]
1.38 [9H, s, C(CH3)3]; 13C NMR (CDCl3)
d: 199.2 (198.4), 155.2, 155.0,
D
ꢀ35.2 (c 1.00, CHCl3); 1H NMR (CDCl3)
d
: 10.15 (0.6H, s, CHO), 10.01
136.8 (136.5), 130.1 (130.0), 128.7 (128.5), 126.7 (126.9), 82.5 (82.4),
81.4 (81.7), 69.2 (70.0), 37.5 (38.6), 28.1, 28.0, 18.1 (18.2); 50% ee
determined by HPLC analysis Daicel Chiralpak AD-H, i-PrOH/hexane
(5/95), 0.7 mL/min, tR¼10.06 min (major), 17.12 min (minor).
(0.4H, s, CHO), 7.62e7.11 (4H, m, ArH), 6.49 (0.6H, br s, NH), 6.29
(0.4H, br s, NH), 1.83 (1.2H, s, CH3), 1.72 (1.8H, s, CH3), 1.47 [9H, s,
C(CH3)3], 1.43 [9H, s, C(CH3)3]; 13C NMR (CDCl3)
d: 195.2, 155.5.
154.0, 135.2, 134.4, 129.3, 128.6, 128.0, 120.2, 82.7, 82.3, 72.9, 28.1,
27.9, 19.5; 94% ee determined by HPLC analysis Daicel Chiralpak
AD-H, i-PrOH/hexane (10/90), 0.5 mL/min, tR¼22.45 min (major),
37.56 min (minor).
4.3.14. (R)-Di-tert-butyl 1-(2-methyl-1-oxopentan-2-yl)hydrazine-
20
1,2-dicarboxylate (6o).8 Colorless oil (116 mg, 88%); [
a
]
þ5.2 (c
D
1.00, CHCl3); 1H NMR (CDCl3)
d: 9.47 (0.75H, s, CHO), 9.39 (0.25H, s,
CHO), 6.38 (0.75H, br s, NH), 6.35 (0.25H, br s, NH), 1.78e1.57 (2H,
m, 2ꢂ CHH), 1.43 [9H, s, C(CH3)3], 1.38 [9H, s, C(CH3)3], 1.24e1.13
(2H, m, 2ꢂ CHH), 1.22 (3H, s, CH3), 0.85 (3H, t, J¼7.0 Hz, CH3); 13C
4.3.8. (R)-Di-tert-butyl 1-(2-(3-bromophenyl)-1-oxo-propan-2-yl)
20
hydrazine-1,2-dicarboxylate (6i).8 Colorless oil (98 mg, 55%); [
a]
D
þ35.0 (c 1.00, CHCl3); 1H NMR (CDCl3)
d
: 9.61 (0.4H, s, CHO), 9.53
(0.6H, s, CHO), 7.55e7.15 (4H, m, ArH), 6.48 (0.4H, br s, NH), 6.47
NMR (CDCl3) d: 198.8, 155.8, 154.9, 81.9, 81.3, 69.2, 35.9 (35.6), 28.0,
27.9, 18.1 (17.5), 16.8 (16.5), 14.5 (14.4); 51% ee determined by HPLC
analysis Daicel Chiralpak AD-H, i-PrOH/hexane (5/95), 0.5 mL/min,
tR¼20.20 min (major), 27.22 min (minor).
(0.6H, br s, NH), 1.67 (3H, s, CH3), 1.44 [9H, s, C(CH3)3], 1.40 [9H, s,
C(CH3)3]; 13C NMR (CDCl3)
d: 193.0, 155.6, 155.2, 140.1, 131.2, 130.0,
129.7, 128.6, 128.5, 83.6, 81.8, 72.2, 28.0, 27.9, 18.8; 92% ee de-
termined by HPLC analysis Daicel Chiralpak AD-H, i-PrOH/hexane
(10/90), 1.0 mL/min, tR¼16.31 min (major), 27.40 min (minor).
4.3.15. (R)-Di-tert-butyl
drazine-1,2-dicarboxylate (6p). White solid (144 mg, 97%); [
þ9.7 (c 1.00, CHCl3); IR (film) 3335, 2976, 2930, 1733, 1698, 1367,
1248, 1159, 1074 cmꢀ1; 1H NMR (CDCl3)
: 9.51 (0.8H, s, CHO), 9.42
1-(2,6-dimethyl-1-oxohept-5-en-2-yl)hy-
20
a
]
D
4.3.9. (R)-Di-tert-butyl 1-(2-(naphthalene-2-yl)-1-oxo-propan-2-yl)
d
20
hydrazine-1,2-dicarboxylate (6j).8 Colorless oil (88 mg, 52%); [
a
]
(0.2H, s, CHO), 6.27 (0.8H, br s, NH), 6.10 (0.2H, br s, NH), 5.10e4.95
(0.8H, m, ]CH), 4.75e4.68 (0.2H, m, ]CH), 2.02e1.85 (3H, m, 3ꢂ
CHH), 1.76e1.65 (1H, m, CHH), 1.67 (2.4H, s, CH3), 1.64 (0.6H, s, CH3),
1.59 (2.4H, s, CH3),1.55 (0.6H, s, CH3),1.47 [9H, s, C(CH3)3],1.43 [9H, s,
D
þ26.2 (c 1.00, CHCl3); 1H NMR (CDCl3)
d: 9.80 (0.3H, s, CHO), 9.67
(0.7H, s, CHO), 7.87e7.70 (4H, m, ArH), 7.56e7.40 (3H, m, ArH), 6.34
(0.7H, br s, NH), 6.20 (0.3H, br s, NH), 1.88 (3H, s, CH3), 1.43 [18H, s,
2ꢂ C(CH3)3]; 13C NMR (CDCl3)
d
: 193.3, 155.6, 155.5, 133.2, 132.7,
C(CH3)3], 1.25 (3H, s, CH3); 13C NMR (CDCl3)
d: 198.9, 155.8, 155.0,
128.5, 128.2, 128.1, 127.4, 126.5, 126.3, 126.1, 124.4, 83.2, 81.5, 72.9,
28.0, 27.9, 18.2; 88% ee determined by HPLC analysis Daicel Chir-
alpak AD-H, i-PrOH/hexane (10/90), 1.0 mL/min, tR¼13.16 min
(major), 23.03 min (minor).
132.2,124.0, 82.0, 81.4, 68.7, 33.6, 33.0, 28.1, 28.0, 25.6, 22.0,17.6; MS
(ESI) m/z (%): 371 [MþH, 100]þ; HRMS exact mass calculated for
[MþH]þ (C19H35O5N2) requires m/z 371.4911, found m/z 371.4904;
65% ee determined by HPLC analysis Daicel Chiralpak AD-H, i-PrOH/
hexane (3/97), 0.4 mL/min, tR¼37.10 min (major), 44.41 min (minor).
4.3.10. (R)-Di-tert-butyl 1-(2-(4-methoxyphenyl)-1-oxo-propan-2-
yl)hydrazine-1,2-dicarboxylate (6k).8 Colorless oil (110 mg, 68%);
4.3.16. (R)-Di-tert-butyl 1-(1-((tert-butyldimethylsilyl)oxy)-2-
methyl-3-oxopropan-2-yl)hydrazine-1,2-dicarboxylate
20
[
a]
þ47.5 (c 1.00, CHCl3); 1H NMR (CDCl3)
d: 9.61 (0.4H, s, CHO),
D
Please cite this article in press as: Theodorou, A.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.103

6
A. Theodorou et al. / Tetrahedron xxx (2013) 1e6
20
(6q). Colorless oil (107 mg, 62%); [
a
]
þ19.5 (c 1.00, CHCl3); IR
7.52e7.18 (5H, m, ArH), 5.90 (1H, br s, NH), 3.67 (3H, s, OCH3), 1.90
(3H, s, CH3), 1.35 [9H, s, C(CH3)3]; 13C NMR (CDCl3)
: 173.4, 154.2,
140.0, 128.5, 127.8, 126.5, 81.0, 64.9, 52.9, 28.1, 23.2; 93% ee de-
termined by HPLC analysis Daicel Chiralpak OD-H, i-PrOH/hexane
(1/99), 1.0 mL/min, tR¼14.60 min (minor), 15.99 min (major).
D
(film) 3341, 2931, 2857, 1731, 1699, 1473, 1367, 1251, 1155, 1104, 839,
d
815, 779 cmꢀ1; 1H NMR (CDCl3)
d
: 9.54 (0.8H, s, CHO), 9.45 (0.2H, s,
CHO), 6.35 (0.8H, br s, NH), 6.04 (0.2H, br s, NH), 3.90 (1H, d,
J¼10.8 Hz, OCHH), 3.70 (1H, d, J¼10.8 Hz, OCHH), 1.45 [9H, s,
C(CH3)3], 1.42 [9H, s, C(CH3)3], 1.28 (3H, s, CH3), 0.85 [9H, s,
SiC(CH3)3], 0.02e0.00 (6H, m, 2ꢂ SiCH3); 13C NMR (CDCl3)
d: 199.4
Acknowledgements
(198.8), 155.4, 155.0, 82.4 (84.0), 81.1 (81.6), 69.5 (70.2), 65.1 (66.2),
64.7 (63.9), 28.1, 28.0, 25.7, 18.0 (16.2), ꢀ5.7, ꢀ5.8; MS (ESI) m/z (%):
433 [MþH, 65]þ; HRMS exact mass calculated for [MþH]þ
(C20H41O6N2Si) requires m/z 433.2728, found m/z 433.2717; 89% ee
determined by HPLC analysis Daicel Chiralpak AD-H, i-PrOH/hex-
ane (5/95), 0.5 mL/min, tR¼15.30 min (major), 18.90 min (minor).
C.G.K. gratefully acknowledge the Operational Program ‘Educa-
tion and Lifelong Learning’ for financial support through the NSRF
program ‘ENISXYSH METADIDAKTOPUN EPEYNHTUN’ (PE 2431)’
co-financed by ESF and the Greek State.
Supplementary data
4.3.17. (R)-Di-tert-butyl 1-(2-(((benzyloxy)carbonyl)amino)-1-
oxopropan-2-yl)hydrazine-1,2-dicarboxylate
(6r). Colorless
oil
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.tet.2013.04.103.
(130 mg, 74%); [
a
]
20 ꢀ11.7 (c 1.00, CHCl3); IR (film) 3311, 2979, 2935,
D
1714, 1500, 1368, 1254, 1154, 1072, 886, 754 cmꢀ1; 1H NMR (CDCl3)
d: 9.36 (0.35H, s, CHO), 9.30 (0.65H, s, CHO), 7.35e7.18 (6H, m, ArH
and NH), 6.46 (0.65H, br s, NH), 6.38 (0.35H, br s, NH), 5.06 (2H, s,
OCH2), 1.49 (3H, s, CH3), 1.45 [9H, s, C(CH3)3], 1.40 [9H, s, C(CH3)3];
References and notes
13C NMR (CDCl3)
d: 191.8 (191.4), 155.1, 154.6, 154.1, 135.9, 128.5,
1. For books, see: (a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis - From
Biomimetic Concepts to Powerful Methods for Asymmetric Synthesis; Wiley-VCH:
Weinheim, Germany, 2005; (b) Dalko, P. I. Enantioselective Organocatalysis
Reactions and Experimental Procedure; Wiley-VCH: Weinheim, Germany, 2007.
2. For selected reviews, see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471e5569; (b) Dondoni, A.; Massi, A. Angew. Chem., Int.
Ed. 2008, 47, 4638e4660; (c) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G.
Angew. Chem., Int. Ed. 2008, 47, 6138e6171; (d) Bertelsen, S.; Jorgensen, K. A.
Chem. Soc. Rev. 2009, 38, 2178e2189; (e) Zhong, C.; Shi, X. Eur. J. Org. Chem.
2010, 2999e3025; (f) Pihko, P. M.; Majander, I.; Erkkila, A. Top. Curr. Chem. 2010,
291, 29e75.
3. For reviews, see: (a) Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem.
2004, 1377e1385; (b) Vilaivan, T.; Bhanthumnavin, W. Molecules 2010, 15,
917e958.
4. (a) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2002, 41, 1790e1793; (b) List, B. J. Am. Chem. Soc. 2002,
124, 5656e5657.
5. (a) Vogt, H.; Vanderheiden, S.; Brase, S. Chem. Commun. 2003, 2448e2449; (b)
Baumann, T.; Vogt, H.; Brase, S. Eur. J. Org. Chem. 2007, 266e282; (c) Baumann,
T.; Bachle, M.; Hartmann, C.; Brase, S. Eur. J. Org. Chem. 2008, 2207e2212.
6. Chowdari, N. S.; Barbas, C. F., III. Org. Lett. 2005, 7, 867e870.
7. Fu, J.-Y.; Yang, Q.-C.; Wang, Q.-L.; Ming, J.-N.; Wang, F.-Y.; Xu, X.-Y.; Wang, L.-X. J.
Org. Chem. 2011, 76, 4661e4664.
8. Liu, C.; Zhu, Q.; Huang, K.-W.; Lu, Y. Org. Lett. 2011, 13, 2638e2641.
9. Desmarchelier, A.; Yalgin, H.; Coeffard, V.; Moreau, X.; Greck, C. Tetrahedron
Lett. 2011, 52, 4430e4432.
10. For selected papers, see: (a) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal.
2004, 346, 1141e1146; (b) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J.
B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84e96; (c) Bellis, E.; Vasilatou, K.;
Kokotos, G. Synthesis 2005, 2407e2413; (d) Barbayianni, E.; Bouzi, P.; Con-
stantinou-Kokotou, V.; Ragoussis, V.; Kokotos, G. Heterocycles 2009, 78,
1243e1252; (e) Tsandi, E.; Kokotos, C. G.; Kousidou, S.; Ragoussis, V.; Kokotos,
G. Tetrahedron 2009, 65, 1444e1449.
11. (a) Kokotos, C. G.; Limnios, D.; Triggidou, D.; Trifonidou, M.; Kokotos, G. Org.
Biomol. Chem. 2011, 9, 3386e3395; (b) Fotaras, S.; Kokotos, C. G.; Tsandi, E.;
Kokotos, G. Eur. J. Org. Chem. 2011, 1310e1317; (c) Trifonidou, M.; Kokotos, C. G.
Eur. J. Org. Chem. 2012, 1563e1568; (d) Kokotos, C. G. J. Org. Chem. 2012, 77,
1131e1135; (e) Tsakos, M.; Kokotos, C. G. Eur. J. Org. Chem. 2012, 576e580; (f)
Tsakos, M.; Kokotos, C. G.; Kokotos, G. Adv. Synth. Catal. 2012, 354, 740e746; (g)
Tsakos, M.; Elsegood, M. R. J.; Kokotos, C. G. Chem. Commun. 2013, 2219e2221.
12. (a) Mase, N.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2003, 5, 4369e4372; (b)
Gryko, D.; Zimnicka, M.; Lipinski, R. J. Org. Chem. 2007, 72, 964e970; (c) Zotova,
N.; Franzke, A.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2007, 129,
15100e15101; (d) Zhou, J.; Chang, Q.; Gan, L.-H.; Peng, Y.-G. Org. Biomol. Chem.
2012, 10, 6732e6739.
128.1, 127.5, 83.2 (84.8), 81.0 (81.3), 74.9, 66.5, 28.1, 27.8, 18.5 (18.7);
MS (ESI) m/z (%): 438 [MþH, 72]þ; HRMS exact mass calculated for
[MþH]þ (C21H32O7N3) requires m/z 438.2235, found m/z 438.2229;
47% ee determined by HPLC analysis Daicel Chiralpak AD-H, i-PrOH/
hexane (3/97), 0.5 mL/min, tR¼21.03 min (minor), 25.44 min
(major).
4.3.18. (R)-Methyl
2-[(tert-butoxycarbonyl)amino}-2-phenyl-
propanoate (8). Aldehyde 6c (0.25 g, 0.46 mmol) was dissolved in
MeCN (2.5 mL) along with NaH2PO4 (23 mg, 0.019 mmol), H2O
(1 mL) and 30% H2O2 (0.7 mL, 0.69 mmol). A solution of NaClO2
(0.104 g, 1.20 mmol) in H2O (2.5 mL) was added dropwise, keeping
the temperature of the mixture below 10 ꢁC. After the mixture
was stirred at room temperature for 18 h, Na2SO3 (0.007 g,
0.05 mmol) was added and the resulting mixture was acidified
(pH¼2e3) with 10% aqueous HCl. The resulting mixture was
partitioned between brine (5 mL) and CH2Cl2 (10 mL), the layers
were separated, and the aqueous layer was extracted with
dichloromethane (3ꢂ10 mL). The combined organic layers were
washed with brine (20 mL), dried, and concentrated under re-
duced pressure to give a residue that was taken up in MeOH/EtOH
(1:1) (10 mL) and treated with an ethereal solution of TMSCHN2 at
0
ꢁC until yellow color persisted. The reaction mixture was left
stirring for 1 h at room temperature. The reaction was then
quenched with a few drops of acetic acid until the yellow color
disappeared. The solvent was removed in vacuo and purified by
column chromatography.
The ester was dissolved in MeOH (10 mL) and argon was bub-
bled through the solution for 5 min SmI2 (0.1 M in THF, 18 mL,
1.80 mmol) was carefully added under Argon. Once the reaction
was complete, judged by TLC, the reaction solvent was removed.
The crude product was diluted in saturated aqueous NH4Cl (10 mL)
and extracted with AcOEt (3ꢂ10 mL). The combined organic layers
were dried and the solvent was removed. The product was purified
13. Fu, J.-Y.; Xu, X.-Y.; Li, Y.-C.; Huang, Q.-C.; Wang, L.-X. Org. Biomol. Chem. 2010, 8,
4524e4526.
14. Gopula, B.; Lee, W.-Z.; Wu, H.-L. Chem.dAsian J. 2013, 8, 80e83.
by column chromatography. 67 mg, 52%; [
a
]
D
20 ꢀ34.8 (c 1.00, CHCl3),
20
{lit.14
[
a]
ꢀ42.6 (c 0.90, CHCl3), 99% ee}; 1H NMR (CDCl3)
d:
D
Please cite this article in press as: Theodorou, A.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.04.103