Asymmetric syn-selective direct aldol reaction of protected hydroxyacetone catalyzed by primary amino acid derived bifunctional organocatalyst in the presence of water

Article abstract of DOI:10.1039/c0ob00898b

A new series of water compatible primary-tertiary diamine catalysts derived from natural primary amino acids bearing a hydrophobic side chain have been synthesized. These new primary-tertiary diamine-Bronsted acid conjugates bifunctional organocatalysts efficiently catalyzes the asymmetric direct syn selective cross-aldol reaction of different protected hydroxyacetone with various aldehydes in high yield (94%) and high enantioselectivity (up to 97% ee of syn) and dr of 91:9 (syn/anti) under mild reaction conditions.

Full text of DOI:10.1039/c0ob00898b

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PAPER
Asymmetric syn-selective direct aldol reaction of protected hydroxyacetone
catalyzed by primary amino acid derived bifunctional organocatalyst in the
presence of water†
Akshay Kumar, Sarbjit Singh, Vikas Kumar and Swapandeep Singh Chimni*
Received 18th October 2010, Accepted 10th January 2011
DOI: 10.1039/c0ob00898b
A new series of water compatible primary-tertiary diamine catalysts derived from natural primary
amino acids bearing a hydrophobic side chain have been synthesized. These new primary-tertiary
diamine-Brønsted acid conjugates bifunctional organocatalysts efficiently catalyzes the asymmetric
direct syn selective cross-aldol reaction of different protected hydroxyacetone with various aldehydes in
high yield (94%) and high enantioselectivity (up to 97% ee of syn) and dr of 91 : 9 (syn/anti) under mild
reaction conditions.
Therefore, the development of new and efficient catalysts for this
Introduction
transformation still remains an important goal.
Chiral 1,2-diols are common structural motifs found in a huge
In addition, the use of water in organocatalytic reactions is of
array of natural and biologically active molecules.1 The monopro-
great current interest due to its unique properties as compared to
commonly employed organic solvents.9 Our research group have a
keen interest in developing organocatalytic asymmetric reactions
in water.10 We have successfully developed organocatalysts for
asymmetric direct anti selective aldol reactions using water as
reaction medium. As part of our ongoing programme to develop
water compatible organocatalysts for direct aldol reactions, we
were interested in designing chiral primary amine organocatalysts,
since primary amines have been shown to form a Z-enamine
intermediate, which, leads to syn stereoselectivity in the aldol
adduct.11
We planned to explore the use of primary amino acid based
chiral diamine organocatalysts for the reaction of protected
hydroxyacetone with aromatic aldehydes in water. Therefore, we
selected hydrophobic primary amino acids like L-isoleucine, L-
leucine, L-valine and L-phenylalanine for synthesis of primary-
tertiary diamines, which on protonation with an acid co-catalyst
produce bifunctional organocatalysts.12 We envisaged that the hy-
drophobic alkyl chain of the catalyst enhances the hydrophobicity
of the catalysts and its interaction with the organic substrates
in water, while the tertiary amine protonated with acid additive,
activates and favourably orients the carbonyl group of the acceptor
aldehyde through hydrogen bond formation.
tected optically active 1,2-diol units have a considerable strategic
value in multistep synthesis, thus, making them an extremely at-
tractive target for synthetic organic chemistry. Several approaches
have been reported for the construction of optically active
monoprotected 1,2-diols unit. One of the approaches for synthesis
of this unit is the Mukayama aldol reaction involving enol silyl
ether.2 Another approach for the synthesis of monoprotected 1,2-
diols consists of regioselective monoprotection of a less hindered
hydroxyl group in unsymmetrical 1,2-diols.3 Unfortunately, the
selective protection of a more hindered hydroxy group is very
difficult, which limits the scope of this methodology. Recent
emergence of organocatalysis4 has provided convenient access to
these chiral monoprotected 1,2-diol units in a single step using
protected hydroxyacetone as a donor in direct aldol reactions.5,7,8
The direct enantioselective organocatalytic aldol reactions of
protected hydroxyacetone with aldehydes produce both anti and
syn configured monoprotected 1,2-diols. The organocatalytic
methods using proline and proline derived organocatalysts prefer-
ably produce anti configured monoprotected 1,2-diols.5 In 2007,
Barbas et al.6 discovered the catalytic potential of primary amine
based organocatalysts for the enantioselective synthesis of syn 1,2-
diols, around the same time Wu et al.7 reported the enantioselective
synthesis of monoprotected syn 1,2-diols using threonine based
primary amine catalysts. Since then, literature records few reports
on the enantioselective synthesis of monoprotected syn 1,2-diols.8
Results and discussion
Catalyst screening
Department of Chemistry, U.G.C. Centre of Advance Studies in Chem-
istry, Guru Nanak Dev University, Amritsar, -143005, India. E-mail:
sschimni@yahoo.com, sschimni.chem@gndu.ac.in; Fax: +91-183-2258820;
Tel: +91-183-2258809
† Electronic Supplementary Information (ESI) available: See DOI:
10.1039/c0ob00898b
A number of chiral primary amino acid based diamines were
synthesized (Fig. 1) and their effectiveness for catalyzing the
aldol reaction of TBS-protected hydroxyacetone 2b with 4-
nitrobenzaldehyde (3a) in water in the presence of trifluoroacetic
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Table 1 Screening of organocatalysts 1a–1ka
Table 2 Effect of different acid additives on the yield and stereoselectivity
of 4ba
Entry Catalyst Time (h) Yieldb (%) drc (syn:anti) eed (syn) (%)
Time Yieldb
eed (syn)
drc (syn:anti) (%)
Entry Additive
(h)
(%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
70
60
20
20
18
16
16
16
18
20
60
53
65
90
88
90
90
92
90
90
89
66
70 : 30
58 : 42
74 : 26
85 : 15
85 : 15
85 : 15
86 : 14
84 : 16
85 : 15
84 : 16
64 : 36
55
54
20
86
90
92
94
92
93
91
45
1
2
Formic acid
Acetic acid
14
14
14
12
16
14
14
14
14
14
89
91
93
94
92
94
90
91
94
95
90
88
90
74
84 : 16
84 : 16
83 : 17
86 : 14
86 : 14
80 : 20
85 : 15
82 : 14
84 : 16
86 : 14
78 : 22
83 : 17
85 : 15
80 : 20
87
88
93
96
94
84
86
89
92
93
83
91
90
76
3
4
5
6
Chloroacetic acid
Trichloroacetic acid
Trifluoroacetic acid
Benzoic acid
9
10
11
7
8
9
10
11
12
13
14
p-Nitrobenzoic acid
Dinitrobenzoic acid
p-Nitrophenol
1j
1k
2,4-Dinitrophenol
a Reaction condition: 0.75 mmol of TBS-protected hydroxyacetone,
0.25 mmol of 4-nitrobenzaldehyde, 10 eq. of water, 10 mol% of catalyst
loading 1a–1k, 10 mol% acid additive TFA, temperature 25 ◦C. b Isolated
yield determined after chromatographic purification. c Diastereoselectivity
determined from HPLC spectra of crude reaction mixture. d Enantiomeric
excess determined from HPLC using chiralpak columns.
Camphorsulfonicacid 24
p-Tolunesulfonicacid
TfOH
—
24
30
60
a Reaction condition: 0.75 mmol of TBS-protected hydroxyacetone,
0.25 mmol of 4-nitrobenzaldehyde, 10 eq. of water, 10 mol% of catalyst
loading 1g, 10 mol% acid additives, temperature 25 ◦C. b Isolated
yield determined after chromatographic purification. c Diastereoselectivity
determined from HPLC spectra of crude reaction mixture. d Enantiomeric
excess determined from HPLC using chiralpak columns.
enantioselectivity (94%) of the aldol product. Therefore, further
optimization of the catalyst structure was performed by varying
the hydrophobic group and keeping the tertiary amine component
(morphinyl) constant.
Thus, catalysts 1h, 1i and 1j were synthesized and used as
catalysts of the model aldol reaction (Table 1, entries 8–10). The
results indicate that these catalysts afford the aldol product 4b with
comparable diastereoselectivity and enantioselectivity, however on
repeating the reaction catalyzed by these catalysts, we showed that
the catalyst 1g produces the aldol product 4b with the highest
enantioselectivity. Therefore it was selected for performing all
further optimization of the reaction conditions.
Fig. 1 Structure of different organocatalysts.
Additive screening
acid (TFA) as the acid additive was studied. It has been observed
by us and others that the acid additive helps in enhancing the
stereoselectivity of thereaction byincreasingthe iminium-enamine
catalysis and suppressing the general base catalysis.13
It has been observed by different research groups14 including ours10
that addition of acid affects the enantioselectivity of the product.
In order to find the best acid additive for the aldol reaction,
we performed various reactions in the presence of different acid
additives (Table 2). The direct aldol reactions performed in the
presence of acids such as formic acid, acetic acid, chloroacetic
acid and trichloroacetic acid (TCA) show that with increase in the
acidity of the acid the enantioselectivity increases (Table 2, entries
1–4). The highest ee of 96% was obtained with tricholoroacetic
acid (TCA). The aromatic acids in general result in moderate
enantioselectivity (Table 2, entries 6–8). The aldol reactions
performed in the presence of 4-nitrophenol and 2,4-dinitrophenol
gave aldol addition product with 92% and 91% ee, respectively
(Table 2, entries 9 and 10). Sulfonic acids such as camphorsulfonic
acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid
(TfOH) gave 4b with upto 91% ee. All the acid additives show a
similar level of diastereoselectivity but camphorsulfonic acid and
Initially, the direct aldol reaction of TBS-protected hydroxyace-
tone 2b and 4- nitrobenzaldehyde (3a) catalyzed by chiral diamine
1a using 10 mol% of TFA as acid additive in water produced
aldol product 4b in 53% yield, dr of 70 : 30 (syn:anti) and ee
of 55% (Table 1, entry 1). A similar reaction with chiral amide
catalyst 1b affords the product in 65% yield, dr of 58 : 42 (syn:anti)
and ee of 54% (Table 1, entry 2), while reaction with the amino
alcohol catalyst 1c gave 4b in very low enantioselectivity. Further,
screening with primary-tertiary diamine catalysts having N,N-
dioctyl 1d, pyrrolidinyl 1e, piperidinyl 1f and morphinyl 1g groups
gave the aldol product in moderate to high enantioselectivity
and nearly similar diastereoselectivity (Table 1, entries 4–7). The
catalyst 1g having a morphinyl group gave the highest level of
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Table 3 Variation in the amount of water using catalyst 1ga
Table 4 Effect of variation in the amount of ketone and catalyst loading
on the yield and stereoselectivity of 4ba
Amount of
Entry water (eq)
Amount of Catalyst load- Time Yieldb
eed (syn)
drc (syn:anti) (%)
Time (h) Yieldb (%) drc (syn:anti) eed (syn) (%)
Entry ketone (eq) ing (mmol%) (h)
(%)
1
2
3
4
5
6
7
8
2.5
5
10
15
22
33
55
—
12
12
12
30
30
36
48
18
94
92
94
83
80
74
70
93
85 : 15
84 : 14
86 : 14
85 : 15
86 : 14
86 : 14
86 : 14
82 : 16
95
95
96
94
94
96
95
85
1
2
3
4
5
6
7
8
9
4
3
2.5
2
1.5
3
3
3
2
10
10
10
10
10
15
5
10
12
18
30
36
12
30
60
40
93
94
88
85
80
92
90
81
87
86 : 14
86 : 14
85 : 15
83 : 17
84 : 16
85 : 15
85 : 15
80 : 20
85 : 15
96
96
95
94
93
95
95
89
92
2
5
a Reaction condition: 0.75 mmol of TBS-protected hydroxyacetone,
0.25 mmol of 4-nitrobenzaldehyde, x eq. of water, 10 mol% of catalyst
loading 1g, 10 mol% acid additive TCA, temperature 25 ◦C. b Isolated
yield determined after chromatographic purification. c Diastereoselectivity
determined from HPLC spectra of crude reaction mixture. d Enantiomeric
excess determined from HPLC using chiralpak columns.
a Reaction condition:
x mmol of TBS-protected hydroxyacetone,
0.25 mmol of 4-nitrobenzaldehyde, 10 eq. of water, x mol% of catalyst load-
ing, x mol% acid additive, temperature 25 ◦C. b Isolated yield determined
after chromatographic purification. c Diastereoselectivity determined from
HPLC spectra of crude reaction mixture. d Enantiomeric excess determined
from HPLC using chiralpak columns.
benzoic acid afford the product with the lowest diastereoselectivity.
Further, the aldol reaction in the absence of acid additives
produces the aldol product in low enantioselectivity (Table 2, entry
14). This study shows that tricholoroacetic acid (TCA) is the best
acid additive, which affords 4b with 96% ee, diastereoselectivity of
86 : 14 (syn:anti) and yield of 92%. Thus all further optimizations
of the direct aldol reaction catalyzed by 1g were performed using
tricholoroacetic acid (TCA) as the additive.
(Table 5, entry 1). In order to see the effect of different protecting
groups on hydroxyacetone, it was protected with other groups like
tert-butyldiphenylsilane (TBDPS), tri-isopropylsilane (TIPS) and
benzyl (Bn) and were used for aldol reactions. The aldol reactions
of ketones 2b–2d with 4-nitrobenzaldehyde (3a) under standard
reaction conditions was performed (Table 5). Moderate level of
enantioselectivity and yield was observed with ketone 2c (Table 5,
entry 3). Whereas excellent level of enantioselectivity was observed
with benzyl protected ketone 2e but the product was obtained in
poor yield (Table 5, entry 5). Unfortunately, aldol product formed
by the reaction of ketone 2d and 4-nitrobenzaldehyde (3a) could
not be resolved on HPLC under various conditions tried (Table 5,
entry 4).
Effect of water
The optimization of the reaction conditions by varying the amount
of water shows little effect on the enantioselectivity of 4b, but an
increase in the amount of water lowers the yield of 4b and slows
down the reaction (Table 3). The reaction performed in the absence
of water results in lower enantioselectivity of the aldol addition
product 4b (Table 3, entry 8). The addition of 10 equivalents of
water was found to be optimum in terms of reaction time and
enantioselectivity and thus was used for all further aldol reactions
(Table 3, entry 3).
Scope of reaction
In order to study the scope and limitation of the catalyst 1g,
the aldol reaction of 2b was performed with different aromatic
aldehydes 3a–3r. All the aldol products were obtained with high
stereoselectivities and yield, reflecting the catalytic versatility of
1g (Table 6). Excellent level of enantioselectivities were observed
with 2-nitro (97% ee), 3-nitro (96% ee), 4-nitro (96% ee), 3-
trifluoromethyl (96% ee) and 4-trifluoromethyl (95% ee) substi-
tuted benzaldehydes (Table 6, entries 1–5). The aldol products 4k–
4q, 4s and 4v were obtained in enantiomeric excess range of 90% to
93% (Table 6, entries 7–13, 15 and 18). The electron rich aldehydes
3p and 3q are slow to react with 2b, however they produce aldol
adducts 4t (ee 91%) and 4u (ee 84%) in yield of 75% (70 h)
and 74% (96h), respectively (Table 6, entries 16–17). Moderate
enantioselectivity and diastereoselectivity was observed with 2-
naphthaldehyde (Table 6, entry 19). Unfortunately, aldol product
formed from 2-trifluoromethyl- and 3,4-dichloro-benzaldehydes
could not be resolved on HPLC under any condition despite our
best efforts (Table 6, entries 6 and 14).
Effect of substrate ratio and catalyst loading
Further, optimizing the amount of ketone shows that decreasing
the amount of ketone slows down the reaction rate and results in
the formation of 4b in low yield and slightly low enantioselectivity.
The use of 3 eq. of ketone was found to be optimum for high
enantiomeric excess (96%), and diastereoisomeric ratio of 86 : 14
(syn:anti). Decreasing the catalyst loading to 5 mol% led to an
increase in the reaction time with no change in the stereoselectivity
of 4b (Table 4, entries 4–5). The catalyst loading of 2 mol% of
catalyst 1g results in slight lowering in enantioselectivity (Table 4,
entry 8).
Effect of protecting group
The aldol reaction of hydroxyacetone (2a) with 4-
nitrobenzaldehyde (3a) using catalyst 1g in aqueous medium
produced aldol adduct 4a in very low yield and enantioselectivity
Further, study of the scope of the aldol reaction was extended to
include different dihydroxyacetone derivatives (Scheme 1). Using
the optimized conditions, the 1,3-dibenzyloxyacetone 2f produced
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Scheme 1 Direct aldol reactions of protected-dihydroxyacetone derivatives.
Table 5 Effect of protecting groupsa
Scheme 2 Gram scale preparation of aldol adduct 4b.
Time Yieldb
eed (syn)
drc (syn:anti) (%)
and HPLC analysis data of free diol, obtained after deprotection
of 4b, with that reported in literature.12f The remaining aldol
products are assigned analogously. The absolute stereochemistry
of aldol addition product 4y and 4z has been assigned as (3R,4S) by
comparison of the HPLC data with that reported in the literature.8a
The catalyst 1g, on reaction with hydroxyacetone derivatives,
form an enamine intermediate, which reacts with aldehyde result-
ing in the formation of the aldol products. The acid additives
protonate the tertiary amine of the catalyst 1g, which helps in
activation and orientation of the aldehyde through H-bonding.12
The syn diastereoselectivity could be explained by the preferential
formation of Z-enamine (TS-1b), which is stabilized over the E-
enamine (TS-1a) via intramolecular hydrogen bonding (Fig. 2).6,16
Entry Donor Product
(h)
(%)
1
2
3
2a
2b
2c
60
20
74 : 26
86 : 14
92 : 08
31
96
83
12
36
94
81
4
5
2d
2e
60
60
72
70
—
—
94
Conclusions
70 : 30
In conclusion, we have successfully performed direct asymmetric
syn-selective aldol reactions between a variety of aromatic aldehy-
des with protected hydroxyacetone and protected dihydroxyace-
tone derivatives in the presence of water catalyzed by L-isoleucine
derived primary-tertiary diamine organocatalysts. The method-
ology developed is very simple, environmentally benign, and
highly enantioselective. Further, exploration of primary-tertiary
diamine catalysts for other asymmetric reactions is ongoing in our
laboratory and the results will be reported in due course.
a Reaction condition: 0.75 mmol of ketone, 0.25 mmol of 4-nitro ben-
zaldehyde, 10 eq. of water, 10 mol% of catalyst loading 1g, 10 mol%
acid additive TCA, temperature 25 ◦C. b Isolated yield determined
after chromatographic purification. c Diastereoselectivity determined from
HPLC spectra of crude reaction mixture. d Enantiomeric excess determined
from HPLC using chiralpak columns.
Experimental Section
the aldol addition product 4y with 86% ee and dr of 81 : 19
(syn:anti). The TBS-protected dihydroxyacetone 2g, under similar
conditions, produced the aldol adduct 4z in high yield (93%) and
with excellent enantioselectivity (95%).
General remarks
NMR spectra were obtained at 300 MHz (Jeol AL-300) and
500 MHz (Bruker Avance 500 MHz) using CDCl3 as solvent with
Me4Si in CDCl3 as the internal standard. Chemical shifts (d) are
expressed in ppm and Hz downfield from internal TMS. Spectral
patterns are designated as s = singlet; d = doublet; dd = doublet of
doublets; t = triplet; br = broad; m = multiplet. Infrared spectra
were recorded on a FT-IR Bruker (270–30) spectrophotometer.
MS were recorded on Bruker Esquire 3000 LC Mass spectrom-
eter. Optical rotation was determined with JASCO DIP-360
To demonstrate the practical utility, the aldol reaction of 4-
nitrobenzaldehyde (3a) and TBS-protected hydroxyacetone 2b was
performed at 10 mmol scale (Scheme 2). The aldol addition prod-
uct 4b was obtained in high yield (88%) and high enantioselectivity
(94% of syn isomer). The optically pure catalyst could be recovered
in 90% yield after workup.15
The absolute configuration of syn aldol product 4b has been as-
signed as (3R,4S) in comparison to the direction of optical rotation
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Table 6 Screening of various aromatic aldehydes using catalyst 1ga
Entry
1
R = 3a–3r
Product (4b, 4f–4v)
Time (h)
12
Yieldb (%)
94
drc (syn:anti)
eed (syn) (%)
4-NO2C6H4 3a
86 : 14
96
2
3
3-NO2C6H4 3b
2-NO2C6H4 3c
18
20
91
89
90 : 10
93 : 7
96
97
4
4-CF3C6H4 3d
24
89
86 : 14
95
5
3-CF3C6H4 3e
2-CF3C6H4 3f
30
30
84
82
84 : 16
86 : 14
96
6e
NR
7
8
4-CNC6H4 3g
4-FC6H4 3h
18
30
91
83
83 : 17
77 : 23
91
91
9
4-ClC6H4 3i
4-BrC6H4 3j
30
30
84
82
83 : 17
82 : 18
90
92
10
11
2-FC6H4 3k
30
81
85 : 15
93
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Table 6 (Contd.)
Entry
12
R = 3a–3r
Product (4b, 4f–4v)
Time (h)
30
Yieldb (%)
82
drc (syn:anti)
eed (syn) (%)
2-ClC6H4 3l
84 : 16
90
13
2-BrC6H4 3m
3, 4-Cl2C6H4 3n
30
30
85
78
82 : 18
78 : 22
91
14e
NR
15
C6H4 3o
48
74
81 : 19
93
16
17
18
19
4-CH3C6H4 3p
2-OMeC6H4 3q
1-Naph 3r
70
96
70
70
75
74
65
70
73 : 27
68 : 32
82 : 18
68 : 32
91
84
92
83
2-Naph 3s
a Reaction condition: 0.75 mmol of TBS-protected hydroxyacetone, 0.25 mmol of 4-nitrobenzaldehyde, 10 eq. of water, 10 mol% of catalyst loading 1g,
10 mol% acid additive TCA, temperature 25 ◦C. b Isolated yield determined after chromatographic purification. c Diastereoselectivity determined from 1H
NMR of crude reaction mixture. d Enantiomeric excess determined from HPLC using chiralpak columns. e NR = Not resolved on HPLC using chiralpak
columns.
Fig. 2 Proposed transition state of syn selective aldol reaction of protected hydroxyacetone with aldehyde.
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polarimeter at 25 ◦C. Enantiomeric excess was determined by
using Shimadzu LC-20AD using Daicel Chiralpak AD-H, OD-
H, AS-H and IB column. Analytical thin-layer chromatogra-
phy(TLC) was performed on either (i) aluminium sheets pre-
coated with silica gel 60F254 (Merck, India) or (ii) glass plates
(7.5 ¥ 2.5 cm) coated with silica gel GF-254 (Spectrochem,
India) containing 13% calcium sulfate as binder, using various
combinations of ethyl acetate and hexane as eluents. Visualization
of the spots was accomplished by exposing to UV light or iodine
vapours. Column chromatography was performed on 60–120 and
100–200 mesh silica (Spectrochem, India) using mixtures of hexane
and ethyl acetate or chloroform and methanol as an eluents.
(2S,3S)-N¢-butyl-3-methylpentane-1,2-diamine (1a)
Yield, 48%; brown oil; [a]2D5 +15 (c 0.1 in MeOH); dH(300 MHz;
CDCl3; Me4Si) 0.87–0.94 (9H, m, 3 ¥ CH3), 1.14–1.21 (1H, m,
CH), 1.31–1.38 (3H, m, CH2), 1.44–1.52 (3H, m, CH2), 2.01 (2H,
br s, NH2), 2.37 (1H, dd, J 12.1 Hz and J 10.3 Hz, CH) and
2.56–2.73 (4H, m, CH and CH2); dC(100 MHz; CDCl3; Me4Si)
11.6, 14.4, 15.1, 20.5, 25.2, 32.1, 39.8, 49.7, 53.4, 55.2 and 57.8;
HRMS (TOF MS) calcd for C10H24N2 (M++H): 173.2018, found:
173.2002.
(2S,3S)-3-methyl-N¢, N¢-dioctylpentane-1,2-diamine (1d)
Yield, 52%; brown oil; [a]2D5 +18 (c 0.1, MeOH); dH(300 MHz;
CDCl3; Me4Si) 0.58–0.92 (12H, m, 4 ¥ CH3), 1.12–158 (27H, br
m, 13 ¥ CH2 and CH), 2.05 (2H, br s, NH2), 2.14–2.51 (6H, m, 3 ¥
CH2), 2.64–2.71(1H, m, CH); dC(75 MHz; CDCl3; Me4Si) 11.5,
14.1, 15.1, 22.6, 25.3, 27.1, 27.5, 28.4, 29.2, 29.3, 29.6, 31.7, 31.8,
38.7, 49.1, 54.6 and 58.7; HRMS (TOF MS) calcd for C9H20N2O
(M++H): 341.3896, found: 341.3721.
Materials
Different amino acids and aldehydes, dicyclohexylcarbodiimide
and di-tert-butylpyrocarbonate were purchased from Aldrich,
Spectrochem India and S.d. fine-chem. Ltd., India and were
used as received. Lithium aluminium hydride (reagent grade,
95%, pellets) and hydroxyacetone were purchased from Aldrich
and Merck, respectively. TBS-protected hydroxyacetone 2b was
prepared according to the reported procedure.17 TIPS-protected
hydroxyacetone 2c and TBDPS-protected hydroxyacetone 2d was
prepared following the same procedure as for TBS-protected
hydroxyacetone 2b. Protected dihydroxyacetone derivatives 2g and
2f were prepared according to the literature method.18
(2S,3S)-2-amino-3-methyl-1-(pyrrolidin-1-yl)pentane (1e)
Yield, 51%; brown oil; [a]2D5 +10 (c 0.1 in MeOH); dH(300 MHz;
CDCl3; Me4Si) 0.88–0.93 (6H, m, 2 ¥ CH3), 1.14–1.26 (1H, m,
CH), 1.34–1.53 (2H, m, CH2), 1.78 (2H, br s, NH2), 2.23–2.28
(5H, m, 2 ¥ CH2), 2.33–2.63 (5H, m, 2 ¥ CH2) and 2.64–2.83
(1H, m, CH); dC(75 MHz; CDCl3; Me4Si) 11.6, 14.9, 23.5, 25.2,
38.8, 53.6, 54.2 and 59.8; HRMS (TOF MS) calcd for C10H22N2
(M++H): 171.1861, found: 171.1863.
General procedure for synthesis of organocatalyst 1a, 1d–1j
To an ice cold stirred solution of N-Boc protected amino
acids (4.3 mmol) and morpholine (0.453 mL, 5.1 mmol) in
dichloromethane (15 mL), a solution of dicyclohexylcarbodiimide
(0.98 g, 4.75 mmol) in dichloromethane was added dropwise. The
resulting mixture was stirred and the temperature of the reaction
mixture was allowed to rise to room temperature. The progress of
the reaction was monitored by TLC (ethyl acetate–hexane). After
completion of the reaction, the reaction mixture was filtered and
concentrated under reduced pressure to obtain the crude product,
which was purified on column chromatography to obtain a thick
liquid in 75–85% yield. The thick liquid was redissolved in CH2Cl2
and cooled to 0 ◦C, then TFA in CH2Cl2 (TFA/CH2Cl2) was added
dropwise. The resulting mixture was stirred for 8 to 12 h until
the reaction was complete (TLC) and then concentrated under
reduced pressure. The resulting residue was redissolved in CH2Cl2
and neutralized with saturated solution of sodium carbonate and
extracted with ethyl acetate. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated. The crude product
was purified by column chromatography using CHCl3–MeOH
as an eluent to obtain a light yellow/orange liquid in 80–85%
yield. The liquid was dissolved in dry THF and cooled to 0 ◦C
followed by slow addition of LiAlH4. The solution was refluxed
for 5–8 h until the reaction was complete (TLC). After cooling
to 0 ◦C ethyl acetate was added followed by water. The solid
was filtered and washed with THF (4–5 times). The combined
organic solvent was dried over anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography using CHCl3–MeOH as eluent to afford
product as a oil in 48–62% yield.
(2S,3S)-2-amino-3-methyl-1-(piperidin-1-yl)pentane (1f)
Yield, 58%; yellow oil; [a]2D5 +13 (c 0.1 in MeOH); dH(300 MHz;
CDCl3; Me4Si) 0.83–0.92 (6H, m, 2 ¥ CH3), 1.15–1.22 (1H, m,
CH), 1.29–1.61 (8H, m, 4 ¥ CH2) 1.97 (2H, br s, NH2), 2.09–2.25
(4H, m, 2 ¥ CH2), 2.50 (2H, br s, CH2) and 2.75–2.82 (1H, m,
CH); dC(75 MHz; CDCl3; Me4Si) 11.4, 14.8, 24.3, 25.3, 26.0, 29.6,
38.5, 51.7, 54.9 and 62.3; HRMS (TOF MS) calcd for C11H24N2
(M++H): 185.2018, found: 185.2027.
(2S,3S)-2-amino-3-methyl-1-morpholinopentane19 (1g)
Yield, 57%; yellow oil; [a]2D5 +17 (c 0.1, MeOH); dH(300 MHz;
CDCl3; Me4Si) 0.88–0.93 (6H, m, 2 ¥ CH3), 1.17–1.24 (1H, m,
CH), 1.35–1.39 (1H, m, CH2), 1.45–1.52 (1H, m, CH2), 2.09 (2H,
br s, NH2), 2.15–2.35 (4H, m, 2 ¥ CH2) 2.54–2.60 (2H, m, 2 ¥
CH2) 2.79–2.86 (1H, m, CH) and 3.65–3.75 (4H, m, 2 ¥ CH2);
dC(75 MHz; CDCl3; Me4Si) 11.5, 14.9, 25.2, 38.7, 51.2, 54.0,
62.6 and 67.1; HRMS (TOF MS) calcd for C10H22N2O (M++H):
187.1810, found: 187.1808.
(S)-2-amino-4-methyl-1-morpholinopentane (1h)
Yield, 56%; brown oil; [a]2D5 +25 (c 0.1 in MeOH); dH(300 MHz;
CDCl3; Me4Si) 0.88–0.93 (6H, m, 2 ¥ CH3), 1.13–1.25 (2H, m,
CH2), 1.71–1.78 (1H, m, CH), 2.00 (2H, br s, NH2), 2.10–2.26 (2H,
m, CH2), 2.32–2.37 (2H, m, CH2), 2.53–2.59 (2H, m, CH2), 2.97–
3.02 (1H, m, CH) and 3.64–3.75 (4H, m, 2 ¥ CH2); dC(100 MHz;
CDCl3; Me4Si) 22.1, 23.5, 24.7, 44.9, 45.1, 54.1, 66.2 and 67.1;
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HRMS (TOF MS) calcd for C10H22N2O (M++H): 187.1810, found:
187.1806.
(d, 1H, J 8.8 Hz, CHOH (syn)), 7.53 (2H, d, J 7.8 Hz, ArH),
8.21–8.24 (1H, m, ArH); dC(125 MHz; CDCl3; Me4Si) -5.6, -5.1,
18.0, 25.6, 27.3, 74.6, 81.8, 123.4, 127.0, 147.5, 148.2 and 210.8;
m/z (ESI): 361.9 (M++Na).
(S)-2-amino-3-methyl-1-morpholinobutane (1i)
Yield, 54%; brown oil; [a]2D5 +28 (c 0.1 in MeOH); dH(300 MHz;
CDCl3; Me4Si) 0.93–0.99 (6H, m, 2 ¥ CH3), 1.65–1.76 (1H, m,
CH), 2.24–2.39 (4H, m, 2 ¥ CH2), 2.55–2.61 (2H, m, CH2), 2.77–
2.84 (1H, m, CH), 3.07 (2H, br s, NH2) and 3.60–3.75 (4H, m,
2 ¥ CH2); dC(75 MHz; CDCl3; Me4Si) 18.5, 18.9, 30.9, 53.1, 53.8,
61.3 and 66.9; HRMS (TOF MS) calcd for C9H20N2O (M++H):
173.1654, found: 173.1650.
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(3¢-
nitrophenyl)butan-2-one8b (4f)
Yield: 91%; syn/anti = 90 : 10; enantiomeric excess: 96% of syn
diastereomer determined by HPLC (Diacel Chiralpak OD-H;
hexane/i-PrOH 92 : 8; flow rate 0.2 mL min-1; l = 211 nm; tR
(syn, major) = 48.9 min, tR (syn, minor) = 36.4 min; [a]2D5 +28 (c
0.1 in CHCl3); IR (CHCl3): n/cm-1 3410, 2930, 2858, 1700, 1531
and 1349; dH(300 MHz; CDCl3; Me4Si) -0.35 (3H, s, SiCH3 (syn)),
-0.24 (3H, s, SiCH3 (anti)), -0.03 (3H, s, SiCH3 (syn)), -0.01 (3H, s,
SiCH3 (anti)), 0.86 (9H, s, SiC(CH3)3), 2.16 (3H, s, COCH3 (anti)),
2.22 (3H, s, COCH3 (syn)) 3.17 (1H, d, J 9 Hz, OH), 4.18 (1H, d,
J 2.7 Hz CHOTBS (syn)), 5.01–5.05 (1H, m, CHOH (syn)) 7.54
(1H, t, J 7.8 Hz, ArH), 7.68 (1H, d, J 7.8 Hz, ArH), 8.14–8.18
(1H, m, ArH) and 8.26 (1H, br s, ArH); dC(100 MHz; CDCl3;
Me4Si) -5.6, -5.1, 17.9, 25.6, 27.3, 74.4, 81.7, 121.3, 122.7, 129.2,
132.1, 143.1, 148.2 and 210.8; m/z (ESI): 361.9 (M++Na).
(S)-2-amino-1-morpholino-3-phenylpropane (1j)
Yield, 62%; brown oil; [a]2D5 +21 (c 0.1 in MeOH); dH(300 MHz;
CDCl3; Me4Si) 1.94 (2H, br s, NH2), 2.23–2.40 (4H, m, 2 ¥ CH2),
2.49–2.56 (3H, m, CH and CH2) 2.74 (1H, dd, J 4.4 and J 4.6,
CH2), 3.17–3.26 (1H, m, CH) 3.64–3.75 (4H, m, 2 ¥ CH2) and
7.19–7.32 (5H, m, ArH); dC(125 MHz; CDCl3; Me4Si) 42.0, 48.9,
54.0, 65.1, 67.1, 126.3, 128.4, 129.1 and 139.0; HRMS (TOF MS)
calcd for C13H20N2O (M++H): 221.1654, found: 221.1653.
General procedure for enantioselective aldol reactions
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(2¢-
To a stirring mixture of catalyst (0.025 mmol), TBS-protected
hydroxyacetone2b (143 uL, 0.75 mmol) in water (45 uL, 2.5 mmol),
the additive TCA (4.07 mg, 0.025 mmol) was added at 25 ◦C and
the mixture was allowed to stir for 5 min followed by addition
of aldehyde (0.25 mmol). The mixture was stirred for 9–70 h and
the progress of the reaction was monitored at regular intervals
by TLC. On the completion of reaction, saturated solution of
NH4Cl (5 mL) was added to it and resulting mixture was extracted
with ethyl acetate (3 ¥ 15 mL). The organic layer was separated,
dried over anhydrous sodium sulfate, filtered, and evaporated to
obtained crude aldol product. The 1H NMR of the crude reaction
mixture was recorded to determine the diastereoselectivity. The
column chromatography on silica gel (mesh 60–120) using hexane–
ethyl acetate (9/1) as an eluent gave the corresponding aldol
adducts as a syn:anti mixture. The enantiomeric excess of aldol
addition products 4a–4x was derermined using various chiral
columns. The enantiomeric excess of aldol addition product 4y and
4z was determined after their acetylation on chiral HPLC. Racemic
standards were prepared using ( ) 3-methyl-1-morpholinobutan-
2-amine catalyst synthesized form ( ) valine.
nitrophenyl)butan-2-one (4g)
Yield: 89%; syn/anti = 93 : 7; enantiomeric excess: 97% of syn
diastereomer determined by HPLC (Diacel Chiralpak OD-H;
hexane/i-PrOH 95 : 5; flow rate 0.5 mL min-1; l = 209 nm; tR
(syn, major) = 16.6 min, tR (syn, minor) = 18.1 min; [a]2D5 +27
(c 0.1 in CHCl3); IR (CHCl3): n/cm-1 3423, 2928, 2856, 1722,
1556 and 1346; dH(300 MHz; CDCl3; Me4Si) -0.44 (3H, s, SiCH3
(syn)), -0.09 (3H, s, SiCH3 (syn)), 0.77 (9H, s, SiC(CH3)3 (syn)),
0.89 (9H, s, SiC(CH3)3 (anti)), 2.22 (3H, s, COCH3 (anti)), 2.37
(3H, s, COCH3 (syn)), 3.14 (1H, br s, OH), 4.49 (1H, d, J 1.8 Hz,
CHOTBS (syn)), 5.78 (1H, br s, CHOH (syn)), 7.45–7.51 (1H,
m, ArH), 7.65–7.71 (1H, m, ArH), 7.76–7.79 (1H, m, ArH) and
8.07 (1H, dd, J 8.1 Hz and J 1.5 Hz, ArH); dC(100 MHz; CDCl3;
Me4Si) -6.0, -5.2, 18.2, 25.6, 26.5, 70.2, 80.2, 124.8, 128.6, 129.8,
133.3, 137.1, 147.1 and 207.0; m/z (ESI): 361.9 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(4¢-
trifluoromethylphenyl)butan-2-one (4h)
Yield: 89%; syn/anti = 86 : 14; enantiomeric excess: 95% of syn
diastereomer determined by HPLC (Diacel chiralpak AS-H;
hexane/i-PrOH 98 : 2; flow rate 1 mL min-1; l = 218 nm; tR (syn,
major) = 7.7 min, tR (syn, minor) = 13.9 min; [a]2D5 +32 (c 0.1 in
CHCl3); IR (CHCl3): n/cm-1 3525, 2929, 2858, 1709, 1618 and
1326; dH(300 MHz; CDCl3; Me4Si) -0.37 (3H, s, SiCH3 (syn)),
-0.23 (3H, s, SiCH3 (anti)), -0.05 (3H, s, SiCH3 (syn)), -0.02
(3H, s, SiCH3 (anti)), 0.85 (9H, s, SiC(CH3)3), 2.12 (3H, s, COCH3
(anti)), 2.21 (3H, s, COCH3 (syn)), 3.07 (1H, d, J 8.4 Hz, OH),
4.08 (1H, d, J 6.3 Hz, CHOTBS (anti)), 4.14 (1H, d, J 2.7 Hz,
CHOTBS (syn)), 4.84 (1H, d, J 6.6 Hz, CHOH (anti)), 4.97 (1H,
d, J 6 Hz, CHOH (syn)), 7.44–7.49 (2H, m, ArH) and 7.59–7.63
(2H, m, ArH); dC(100 MHz; CDCl3; Me4Si) -5.2, -3.6, 18.0, 25.6,
27.3, 74.8, 82.2, 125.1, 126.5, 127.5, 129.9, 144.8 and 211.1; m/z
(ESI): 385.0 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(4¢-
nitrophenyl)butan-2-one7,8b (4b)
Yield: 94%; syn/anti = 86 : 14; enantiomeric excess: 96% of
syn diastereomer determined by HPLC (Diacel Chiralpak IB;
hexane/i-PrOH 92 : 8; flow rate 0.2 mL min-1; l = 211; tR (syn,
major) = 30.6 min, tR (syn, minor) = 24.4 min; [a]2D5 +22 (c 0.1 in
CHCl3); IR (CHCl3): n/cm-1 3508, 2929, 2856, 1706, 1600, 1516
and 1346; dH(300 MHz; CDCl3; Me4Si) -0.35 (3H, s, SiCCH3
(syn)), -0.20 (3H, s, SiCCH3 (anti)), -0.02 (3H, s, SiCCH3 (syn))
0.01 (3H, s, SiCCH3 (anti)), 0.86 (9H, s, SiC(CH3)3), 2.14 (3H, s,
COCH3 (anti)), 2.21 (3H, s, COCH3 (syn)), 3.17 (1H, d, J 9 Hz,
OH), 4.10 (1H, d, J 6 Hz, CHOTBS (anti)), 4.18 (1H, dd, J 1.5 Hz
and J 2.7 Hz, CHOTBS (syn)), 4.91 (1H, br s, CHOH (anti)), 5.02
2738 | Org. Biomol. Chem., 2011, 9, 2731–2742
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(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(3¢-
trifluoromethylphenyl)butan-2-one (4i)
1509; dH(300 MHz; CDCl3; Me4Si) -0.31 (3H, s, SiCH3 (syn)),
-0.21 (3H, s, SiCH3 (anti)), -0.05 (3H, s, SiCH3 (syn)), -0.03
(3H, s, SiCH3 (anti)), 0.86 (9H, s, SiC(CH3)3 (anti)), 0.87 (9H, s,
SiC(CH3)3 (syn)), 2.03 (3H, s, COCH3 (anti)), 2.12 (3H, s, COCH3
(syn)), 4.01 (1H, d, J 6 Hz, CHOTBS (anti)), 4.03 (1H, d, J 3 Hz,
CHOTBS (syn)), 4.70 (1H, d, J 6.3 Hz, CHOH (anti)), 4.81 (1H,
br s, CHOH (syn)), 6.96–7.03 (2H, m, ArH) and 7.24–7.32 (2H,
m, ArH); dC(125 MHz; CDCl3; Me4Si) -5.7, -5.2, 18.1, 25.6, 27.3,
74.7, 82.4, 115.0, 115.2, 127.7, 128.7, 136.2, 161.4, 163.3 and 211;
m/z (ESI): 335.0 (M++Na).
Yield: 84%; syn/anti = 84 : 16; enantiomeric excess: 96% of syn
diastereomer determined by HPLC (Diacel Chiralpak AS-H;
hexane/i-PrOH 95 : 5; flow rate 0.5 mL min-1; l = 217 nm; tR
(syn, major) = 9.0 min, tR (syn, minor) = 15.2 min; [a]2D5 +39
(c 0.1 in CHCl3); IR (CHCl3): n/cm-1 3413, 2932, 2860, 1701
and 1331; dH(300 MHz; CDCl3; Me4Si) -0.41 (3H, s, SiCH3
(syn)), -0.29 (3H, s, SiCH3 (anti)), -0.06 (3H, s, SiCH3 (syn)),
-0.05 (3H, s, SiCH3 (anti)), -0.84 (9H, s, SiC(CH3)3), 2.13 (3H, s,
COCH3 (anti)), 2.22 (3H, s, COCH3 (syn)), 4.05 (1H, d, J 6.9 Hz,
CHOTBS (anti)), 4.15 (1H, d, J 2.7 Hz, CHOTBS (syn)), 4.80
(1H, d, J 6.9 Hz, CHOH (anti)), 4.98 (1H, d, J 2.4 Hz, CHOH
(syn)), 7.44–7.58 (3H, m, ArH) and 7.63–7.65 (1H, m, ArH);
dC(125 MHz; CDCl3; Me4Si) -6.0, -5.2, 17.9, 25.5, 27.3, 74.7,
82.1, 122.9, 125.2, 126.4, 127.5, 129.9, 130.2, 144.7 and 211.2; m/z
(ESI): 385.0 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(4¢-
chlorophenyl)butan-2-one5a (4m)
Yield: 84%; syn/anti = 83 : 17; enantiomeric excess: 90% of syn
diastereomer determined by HPLC (Diacel Chiralpak AD-H;
hexane–ethanol 98 : 2; flow rate 0.5 mL min-1; l = 223; tR (syn,
major) = 23.2 min, tR (syn, minor) = 21.6 min; [a]2D5 +31 (c 0.1,
CHCl3); IR (CHCl3): n/cm-1 3450, 2948, 2867, 1714, 1523 and
1346; dH(300 MHz; CDCl3; Me4Si) -0.31 (3H, s, SiCH3 (syn)),
-0.19 (3H, s, SiCH3 (anti)), -0.05 (3H, s, SiCH3 (syn)), -0.03 (3H, s,
SiCH3 (anti)), 0.87 (9H, s, SiC(CH3)3), 2.10 (3H, s, COCH3 (anti)),
2.18 (3H, s, COCH3 (syn)), 4.07 (1H, d, J 6.3 Hz, CHOTBS (anti)),
4.11 (1H, d, J 3.3 Hz, CHOTBS (syn)), 4.75 (1H, d, J 6.3 Hz,
CHOH (anti)), 4.89 (1H, d, J 3.0 Hz, CHOH (anti)), 7.25–7.27
(2H, m, ArH), 7.30–7.34 (2H, m, ArH); dC(100 MHz; CDCl3;
Me4Si) -5.6, -5.1, 18.0, 25.6, 27.3, 74.7, 81.7, 123.3, 127.0, 147.5,
148.1 and 210.8; m/z (ESI): 350.9 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(2¢-
trifluoromethylphenyl)butan-2-one (4j)
Yield: 82%; syn/anti = 86/14; [a]2D5 +35 (c 0.1 in CHCl3); IR
(CHCl3): n/cm-1 3457, 2932, 2859, 1714 and 1312; dH(300 MHz;
CDCl3; Me4Si) -0.45 (1H, s, SiCH3 (syn)), -0.13 (1H, s, SiCH3
(syn)), 0.81 (9H, s, SiC(CH3)3 (anti)), 0.82 (9H, s, SiC(CH3)3 (syn)),
2.21 (3H, s, COCH3 (anti)), 2.28 (3H, s, COCH3 (syn)), 2.96 (1H,
br s, OH), 4.19 (1H, d, J 6 Hz, CHOTBS (anti)), 4.22 (1H, d, J
2.1 Hz, CHOTBS (syn)), 5.45 (1H, br s, CHOH (syn)), 7.41 (1H, t,
J 7.5 Hz, ArH), 7.58 (1H, t, J 7.5 Hz, ArH), 7.65 (1H, d, J 8.1 Hz,
ArH) and 7.73 (1H, d, J 7.8 Hz, ArH); dC(100 MHz; CDCl3;
Me4Si) -6.1, -5.4, 18.1, 25.7, 27.4, 70.4, 81.8, 123.1, 125.7, 126.5,
127.9, 129.6, 131.6, 139.3 and 208.6. m/z (ESI): 385.0 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(4¢-
bromophenyl)butan-2-one (4n)
Yield: 82%; syn/anti = 82 : 18; enantiomeric excess: 92% of syn
diastereomer determined by HPLC (Diacel Chiralpak AD-H;
hexane–ethanol 95 : 5; flow rate 0.5 mL min-1; l = 224 nm; tR (syn,
major) = 14.0 min, tR (syn, minor) = 13.3 min; [a]2D5 +34 (c 0.1,
CHCl3); IR (CHCl3): n/cm-1 3440, 2929, 2857, 1711 and 1352;
dH(300 MHz; CDCl3; Me4Si) -0.31 (3H, s, SiCH3 (syn)), -0.19
(3H, s, SiCH3 (anti)), -0.05 (3H, s, SiCH3 (syn)), -0.03 (3H, s,
SiCH3 (anti)), 0.87 (9H, s, SiC(CH3)3), 2.09 (3H, s, COCH3 (anti)),
2.18 (3H, s, COCH3 (syn)), 4.06 (1H, d, J 6.3 Hz, CHOTBS (anti)),
4.09 (1H, d, J 0.9 Hz, CHOTBS (syn)), 4.74 (1H, d, J 6.3 Hz,
CHOH (anti)), 5.10 (1H, d, J 5.7 Hz, CHOH (syn)), 7.21 (2H, d,
J 8.7 Hz, ArH), 7.46–7.49 (2H, d, J 8.1 Hz, ArH); dC(125 MHz;
CDCl3; Me4Si) -5.7, -5.2, 18.0, 25.6, 27.3, 74.7, 82.1, 121.6, 127.8,
131.3, 139.6 and 211.2; m/z (ESI): 394.9 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(2¢-
cyanophenyl)butan-2-one8b (4k)
Yield: 91%; syn/anti = 83 : 17; enantiomeric excess: 91% of syn
diastereomer determined by HPLC (Diacel Chiralpak AS-H;
hexane–ethanol 95 : 5; flow rate 0.5 mL min-1; l = 234 nm; tR
(syn, major) = 15.1 min, tR (syn, minor) = 20.6 min; [a]2D5 (c 0.1
in CHCl3); IR (CHCl3): n/cm-1 3509, 2930, 2857, 2229, 1711 and
1353; dH(300 MHz; CDCl3; Me4Si) -0.37 (3H, s, SiCH3 (syn)),
-0.23 (3H, s, SiCH3 (anti)), -0.04 (3H, s, SiCH3 (syn)), -0.02 (3H, s,
SiCH3 (anti)), 0.87 (9H, s, SiC(CH3)3), 2.13 (3H, s, COCH3 (anti)),
2.21 (3H, s, COCH3 (syn)), 3.09 (1H, d, J 8.7 Hz, OH), 4.06 (1H,
d, J 6.3 Hz, CHOTBS (anti)), 4.13 (1H, d, J 2.7 Hz, CHOTBS
(syn)), 4.96 (1H, dd, J 8.7 Hz and J 2.4 Hz, CHOH (syn)), 7.46–
7.48 (2H, m, ArH) and 7.62–7.67 (2H, m, ArH); dC(125 MHz;
CDCl3; Me4Si) -5.7, -5.1, 18.0, 25.6, 27.3, 74.7, 81.8, 111.5, 118.6,
126.9, 127.9, 132.0, 146.3 and 210.9; m/z (ESI): 342.0 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(2¢-
fluorophenyl)butan-2-one (4o)
Yield: 81%; syn/anti = 85 : 15; enantiomeric excess: 93% of syn
diastereomer determined by HPLC (Diacel Chiralpak AS-H;
hexane/i-PrOH 95 : 5; flow rate 0.5 mL min-1; l = 208 nm; tR
(syn, major) = 10.2 min, tR (syn, minor) = 11.7 min; [a]2D5 +29 (c
0.1, CHCl3); IR (CHCl3): n/cm-1 3449, 2930, 2857, 1713, 1460
and 1355; dH(300 MHz; CDCl3; Me4Si) -0.40 (3H, s, SiCH3
(syn)), -0.14 (3H, s, SiCH3 (anti)), -0.08 (3H, s, SiCH3 (syn)),
0.82 (9H, s, SiC(CH3)3 (syn)), 0.87 (9H, s, SiC(CH3)3 (anti)), 2.15
(3H, s, COCH3 (anti)), 2.27 (3H, s, COCH3 (syn)), 2.94 (1H, br s,
OH), 4.21 (1H, d, J 6 Hz, CHOTBS (anti)), 4.25 (1H, d, J 2.7 Hz,
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(4¢-
fluorophenyl)butan-2-one (4l)
Yield: 83%; syn/anti = 77 : 23; enantiomeric excess: 91% of syn
diastereomer determined by HPLC (Diacel Chiralpak AS-H;
hexane–ethanol 95 : 5; flow rate 0.5 mL min-1; l = 205 nm; tR
(syn, major) = 9.9 min, tR (syn, minor) = 11.7 min; [a]2D5 +35 (c
0.1 in CHCl3); IR (CHCl3): n/cm-1 3441, 2930, 2858, 1711 and
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CHOTBS (syn)), 5.10 (1H, d, J 5.7 Hz, CHOH (anti)), 5.27 (1H,
br s, CHOH (syn)), 6.99–7.05 (1H, m, ArH), 7.12–7.18 (1H, m,
ArH), 7.24–7.31 (1H, m, ArH) and 7.38–7.46 (1H, m, ArH);
dC(100 MHz; CDCl3; Me4Si) -6.1, -5.2, 17.9, 25.7, 26.9, 69.7,
81.0, 115.0, 115.3, 124.1, 128.0, 129.3, 158.3, 160.7 and 209.4; m/z
(ESI): 334.9 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-
(phenyl)butan-2-one8b (4s)
Yield: 74%; syn/anti = 81 : 19; enantiomeric excess: 93% of syn
diastereomer determine by HPLC (Diacel Chiralpak OD-H,
hexane/i-PrOH 98 : 2; flow rate 0.5 mL min-1; l = 210; tR (syn,
major) = 33.3 min, tR (syn, minor) = 24.3 min; [a]2D5 +20 (c 0.1,
CHCl3); IR (CHCl3): n/cm-1 3452, 2929, 2857, 1714, 1390 and
1255; dH(300 MHz; CDCl3; Me4Si) -0.36 (3H, s, SiCH3 (syn)),
-0.23 (3H, s, SiCH3 (anti)), -0.08 (3H, s, SiCH3 (syn)), -0.05
(3H, s, SiCH3 (anti)), 0.85 (9H, s, SiC(CH3)3 (anti)), 0.86 (9H, s,
SiC(CH3)3 (syn)), 2.08 (3H, s, COCH3 (anti)), 2.18 (3H, s, COCH3
(syn)), 4.10 (1H, d, J 6.6 Hz, CHOTBS (anti)), 4.14 (1H, d, J
2.7 Hz, CHOTBS (syn)), 4.76 (1H, d, J 6.6 Hz, CHOH (anti)),
4.91 (1H, d, J 3.0 Hz, CHOH (syn)), 7.27–7.37 (5H, m, ArH);
dC(100 MHz; CDCl3; Me4Si) -6.0, -5.2, 17.9, 25.5, 27.3, 74.7,
82.0, 123.0, 124.5, 128.6, 129.3, 130.5, 141.7 and 211.2.
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(2¢-
chlorophenyl)butan-2-one (4p)
Yield: 82%; syn/anti = 84 : 16; enantiomeric excess: 90% of syn
diastereomer determined by HPLC (Diacel Chiralpak OD-H;
hexane/i-PrOH 95 : 5; flow rate 0.3 mL min-1; l = 206 nm; tR
(syn, major) = 21.5 min, tR (syn, minor) = 20.6 min; [a]2D5 +32 (c
0.1 in CHCl3); IR (CHCl3): n/cm-1 3460, 2929, 2857, 1714 and
1410; dH(300 MHz; CDCl3; Me4Si) -0.50 (3H, s, SiCH3 (syn)),
-0.13 (3H, s, SiCH3 (syn)), -0.03 (3H, s, SiCH3 (anti)), 0.04 (3H, s,
SiCH3 (anti)), 0.80 (9H, s, SiC(CH3)3 (syn)), 0.90 (9H, s, SiC(CH3)3
(anti)), 2.17 (3H, s, COCH3 (anti)), 2.33 (3H, s, COCH3 (syn)),
2.93 (1H, d, J 9 Hz, OH), 4.34 (1H, d, J 5.4 Hz, CHOTBS (anti)),
4.41 (1H, d, J 1.8 Hz, CHOTBS (syn)), 5.37 (1H, d, J 8.7 Hz,
CHOH (syn)), 7.21–7.36 (3H, m, ArH) and 7.46–7.49 (m, 1H,
ArH); dC(100 MHz; CDCl3; Me4Si) -6.3, -5.4, 18.1, 25.6, 26.9,
71.8, 79.4, 126.6, 128.5, 128.9, 129.3, 131.2, 138.1 and 208.9; m/z
(ESI): 350.9 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(4¢-
methylphenyl)butan-2-one8b (4t)
Yield: 75%; syn/anti = 73 : 27; enantiomeric excess: 91% of
syn diastereomer determine by HPLC (Diacel Chiralpak AS-H,
hexane/i-PrOH 95.5; flow rate 0.5 mL min-1; l = 207 nm; tR (syn,
major) = 11.1 min, tR (syn, minor) = 16.9 min; [a]2D5 +31 (c 0.1,
CHCl3); IR (CHCl3): n/cm-1 3461, 2929, 2857, 1709, 1466 and
1255; dH(300 MHz; CDCl3; Me4Si) -0.32 (3H, s, SiCH3 (syn)),
-0.18 (3H, s, SiCH3 (anti)), -0.07 (3H, s, SiCH3 (syn)), -0.04
(3H, s, SiCH3 (anti)), 0.86 (9H, s, SiC(CH3)3 (anti)), 0.87 (9H, s,
SiC(CH3)3 (syn)), 2.06 (3H, s, COCH3 (anti)), 2.16 (3H, s, COCH3
(syn)), 2.33 (3H, s, PhCH3), 4.11 (1H, d, J 3.3 Hz, CHOTBS (syn)),
4.73 (1H, d, J 6.3 Hz, CHOH (anti)), 4.85 (1H, br s, CHOH (syn))
and 7.12–7.23 (4H, m, ArH); dC(100 MHz; CDCl3; Me4Si) -5.5,
-5.2, 18.0, 21.1, 25.6, 27.3, 75.2, 82.7, 126.0, 126.9, 128.9, 136.7,
137.4, 137.9 and 211.3.
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(2¢-
bromophenyl)butan-2-one (4q)
Yield: 85%; syn/anti = 82 : 18; enantiomeric excess: 92% of syn
diastereomer determined by HPLC (Diacel Chiralpak OD-H;
hexane/i-PrOH 96 : 4; flow rate 0.3 mL min-1; l = 254; tR (syn,
major) = 19.7 min, tR (syn, minor) = 20.8 min; [a]2D5 +31 (c 0.1,
CHCl3); IR (CHCl3): n/cm-1 3446, 2930, 2857, 1712, 1466 and
1353; dH(300 MHz; CDCl3; Me4Si) -0.51 (3H, s, SiCH3 (syn)),
-0.13 (3H, s, SiCH3 (syn)), 0.05 (3H, s, SiCH3 (anti)), 0.09 (3H, s,
SiCH3 (anti)), 0.79 (9H, s, SiC(CH3)3 (syn)), 0.91 (9H, s, SiC(CH3)3
(anti)), 2.13 (3H, s, COCH3 (anti)), 2.34 (3H, s, COCH3 (syn)), 2.95
(1H, d, J 9 Hz, OH), 4.36 (1H, d, J 5.1 Hz, CHOTBS (anti)), 4.45
(1H, d, J 1.5 Hz, CHOTBS (syn)), 5.33 (1H, d, J 8.7, CHOH
(syn)), 7.14–7.19 (1H, m, ArH), 7.32–7.37 (1H, m, ArH), 7.45–
7.48 (1H, dd, J 7.8 Hz and J 1.5 Hz, ArH) and 7.523–7.553 (1H,
m, ArH); dC(125 MHz; CDCl3; Me4Si) -6.3, -5.1, 18.1, 25.6, 26.9,
73.8, 79.3, 121.2, 127.2, 129.0, 129.2, 132.6, 139.5 and 208.8; m/z
(ESI): 394.9 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(2¢-
methoxyphenyl)butan-2-one (4u)
Yield: 74%; syn/anti = 68 : 32; enantiomeric excess: 84% of syn
diastereomer determine by HPLC (Diacel Chiralpak OD-H,
hexane/i-PrOH 95.5; flow rate 0.5 mL min-1; l = 206 nm; tR
(syn, major) = 25.9 min, tR (syn, minor) = 13.4 min; [a]2D5 +21 (c
0.1, CHCl3); dH(400 MHz; CDCl3; Me4Si) -0.47 (3H, s, SiCH3
(syn)), -0.22 (3H, s, SiCH3 (anti)), -0.15 (3H, s, SiCH3 (syn)),
-0.07 (3H, s, SiCH3 (anti)), 0.80 (9H, s, SiC(CH3)3 (syn)), 0.83
(9H, s, SiC(CH3)3 (anti)), 2.2 (3H, s, COCH3 (anti)), 2.27 (3H, s,
COCH3 (syn)), 3.85 (3H, s, OCH3 (syn)), 3.86 (3H, s, OCH3 (anti)),
4.29 (1H, d, J 6.6 Hz, CHOTBS (anti)), 4.31 (1H, d, J 2.4 Hz,
CHOTBS (syn)), 4.87 (1H, d, J 6.4 Hz, CHOH (anti)), 5.27 (1H,
br s, CHOH (syn)), 6.84–6.99 (2H, m, ArH) and 7.24–7.28 (2H,
m, ArH); dC(100 MHz; CDCl3; Me4Si) -6.2, -5.3, 18.1, 25.6, 26.9,
55.2, 70.6, 80.6, 109.9, 120.4, 127.1, 128.8, 155.7, 156.6 and 209.9;
MS (ESI-TOF) 347.0736 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(3¢,4¢-
dichlorophenyl)butan-2-one (4r)
Yield: 78%; syn/anti = 78 : 22; [a]2D5 +19 (c 0.1 in CHCl3); IR
(CHCl3): n/cm-1 3438, 2928, 2856, 1712 and 1470; dH(300 MHz;
CDCl3; Me4Si) -0.29 (3H, s, SiCH3 (syn)), -0.19 (3H, s, SiCH3
(anti)), -0.03 (3H, s, SiCH3 (syn)), -0.02 (3H, s, SiCH3 (anti)),
0.88 (9H, s, SiC(CH3)3), 2.12 (3H, s, COCH3 (anti)), 2.19 (3H, s,
COCH3 (syn)), 3.03 (1H, d, J 9 Hz, OH), 4.03 (1H, d, J 6.6 Hz,
CHOTBS (anti)), 4.09 (1H, d, J 2.7 Hz, CHOTBS (syn)), 4.86 (1H,
d, J 5.4 Hz, CHOH (syn)), 7.13–7.16 (1H, m, ArH) and 7.39–7.46
(m, 2H, ArH); dC(125 MHz; CDCl3; Me4Si) -5.6, -5.1, 18.1, 25.6,
27.4, 74.2, 81.8, 125.3, 128.3, 130.2, 131.7, 132.5, 141.0 and 211.1;
m/z (ESI): 384.9 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(1¢-
naphthyl)butan-2-one (4v)
Yield: 65%; syn/anti = 83 : 17; enantiomeric excess: 93% of
syn diastereomer determined by HPLC (Diacel Chiralpak
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AD-H, hexane/i-PrOH 95 : 5; flow rate 0.5 mL min-1; l = 217;
tR (syn, major) = 21.8 min, tR (syn, minor) = 15.5 min; [a]D25
+32 (c 0.1, CHCl3); IR (CHCl3): n/cm-1 3455, 2929, 2857 and
1709; dH(300 MHz; CDCl3; Me4Si) -0.93 (3H, s, SiCH3 (syn)),
-0.50 (3H, s, SiCH3 (anti)), -0.33 (3H, s, SiCH3 (syn)), -0.14
(3H, s, SiCH3 (anti)), 0.71 (9H, s, SiC(CH3)3 (anti)), 0.79 (9H, s,
SiC(CH3)3 (syn)), 2.11 (3H, s, COCH3 (anti)), 2.31 (3H, s, COCH3
(syn)), 4.26 (1H, d, J 1.5 Hz, CHOTBS (syn)), 4.31 (1H, d, J
6.6 Hz, CHOTBS (anti)), 5.64 (1H, br s, CHOH (syn)), 7.41–7.49
(2H, m, ArH), 7.53–7.88 (4H, m, ArH) and 7.94–8.06 (2H, m,
ArH); dC(100 MHz; CDCl3; Me4Si) -6.4, -5.7, 17.9, 25.5, 26.9,
72.5, 80.7, 122.2, 123.8, 124.9, 125.5, 126.5, 128.3, 129.1, 129.7,
133.7, 136.0 and 211.9; m/z (ESI): 367.0 (M++Na).
+35 (c 0.1 in CHCl3); dH(400 MHz; CDCl3; Me4Si) -0.42 (1H, s,
SiCH3 (syn)), -0.09 (1H, s, SiCH3 (syn)), 0.01 (1H, s, SiCH3 (anti)),
0.02 (1H, s, SiCH3 (anti)), 0.03 (1H, s, SiCH3 (anti)), 0.04 (1H, s,
SiCH3 (anti)), 0.09 (1H, s, SiCH3 (syn)), 0.1 (1H, s, SiCH3 (syn)),
0.85 (9H, s, SiC(CH3)3 (syn)), 0.87 (9H, s, SiC(CH3)3 (anti)), 0.89
(9H, s, SiC(CH3)3 (anti)), 0.93 (9H, s, SiC(CH3)3 (syn)), 2.12 (3H, s,
OCOCH3 (anti)), 2.13 (3H, s, OCOCH3 (syn)), 4.11 (1H, d, J
19.3 Hz, CH2OTBS (anti)), 4.46 (2H, d, J 6.1 Hz, CH2OTBS
(syn)), 4.51 (1H, d, J 2.5 Hz, CH2OTBS (anti)), 4.57 (1H, d, J
3.3 Hz, CHOTBS (syn)), 4.62 (1H, d, J 4.6 Hz, CHOTBS (anti)),
6.07 (1H, d, J 4.6 Hz, CHOAc (anti)), 6.13 (1H, d, J 3.3 Hz,
CHOAc (syn)), 7.47–7.53 (2H, m, ArH) and 8.18–8.23 (2H, m,
ArH); dC(100 MHz; CDCl3; Me4Si) -5.8, -5.4, -5.3, -4.9, 18.0,
18.5, 20.9, 25.5, 25.8, 68.7, 75.5, 78.3, 123.5, 127.9, 144.1, 147.7,
169.5 and 207.2; MS (ESI-TOF): 534.1389 (M++Na).
(3R,4S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-4-(2¢-
naphthyl)butan-2-one8b (4x)
(3R,4S)-3-(tert-butyldiphenylsilyloxy)-4-hydroxy-4-(4¢-
nitrophenyl)butan-2-one (4c)
Yield: 70%; syn/anti = 68 : 32; enantiomeric excess: 83% of
syn diastereomer determine by HPLC (Diacel Chiralpak AS-H,
hexane/i-PrOH 80 : 20; flow rate 1 mL min-1; l = 226 nm; tR (syn,
major) = 4.1 min., tR (syn, minor) = 6.2 min; [a]2D5 +24 (c 0.1 in
CHCl3); IR (CHCl3): n/cm-1 3450, 2928, 2856, 1713 and 1255;
dH(300 MHz; CDCl3; Me4Si) -0.46 (3H, s, SiCH3 (syn)), -0.27
(3H, s, SiCH3 (anti)), -0.10 (3H, s, SiCH3 (syn)), -0.05 (3H, s,
SiCH3 (anti)), 0.84 (9H, s, SiC(CH3)3), 2.08 (3H, s, COCH3 (anti)),
2.20 (3H, s, COCH3 (syn)), 2.75 (1H, br s, OH (anti)), 3.12 (1H,
br s, OH (syn)), 4.21 (1H, d, J 3.3 Hz, CHOTBS (anti)), 4.23
(1H, d, J 2.7 Hz, CHOTBS (syn)), 4.94 (1H, d, J 6.6 Hz, CHOH
(anti)), 5.06–5.08 (1H, m, CHOH (syn)), 7.40–7.51 (3H, m, ArH)
and 7.79–7.84 (4H, m, ArH); dC(125 MHz; CDCl3; Me4Si) -5.7,
-5.2, 18.0, 25.6, 27.4, 75.4, 82.2, 123.9, 125.1, 125.9, 126.1, 127.6,
128.9, 128.0, 133.0, 137.9 and 211.4; m/z (ESI): 367.0 (M++Na).
Yield: 81%; syn/anti = 92 : 08; enantiomeric excess: 83% of syn
diastereomer determine by HPLC (Diacel Chiralpak IB, hexane/i-
PrOH 99 : 1; flow rate 1.5 mL min-1; l = 210 nm; tR (syn, major) =
46.6 min., tR (syn, minor) = 51.8 min.; [a]2D5 -14.3 (c 0.1 in CHCl3);
IR (CHCl3): n/cm-1 3443, 2931, 2858, 1715, 1522 and 1346;
dH(300 MHz; CDCl3; Me4Si) 1.08 (9H, s, SiC(CH3)3 (syn)), 1.11
(9H, s, SiC(CH3)3 (anti)), 1.82 (3H, s, COCH3 (syn)), 1.92 (3H, s,
COCH3 (anti)), 3.23 (1H, d, J 7.8 Hz, OH (syn), 3.47 (1H, d,
J 5.1 Hz, OH (anti) 4.27 (1H, d, J 6 Hz, CHOTBDPS (anti)),
4.41 (d, 1H, J 3.6 Hz, CHOTBDPS (syn)), 4.87–4.89 (1H, m,
CHOH (syn)), 7.22–7.57 (12H, m, ArH) and 8.07–8.14 (2H, m,
ArH); dC(125 MHz; CDCl3; Me4Si) 19.2, 26.9, 27.4, 74.4, 81.7,
123.3, 127.2, 127.3, 127.8, 127.9, 128.0, 130.2, 130.3, 130.4, 131.8,
131.9, 135.6, 135.7, 135.8, 147.4, 147.6 and 210.1; m/z (ESI): 485.4
(M++Na).
(3R,4S)-4-acetoxy-1,3-bis(benzyloxy)-4-(4¢-nitrophenyl)butan-2-
one8a (4y)
(3R,4S)-3-(benzyloxy)-4-hydroxy-4-(4¢-nitrophenyl)butan-2-one.12f
(4e)
Yield: 87%; syn/anti = 81 : 19; enantiomeric excess: of syn diastere-
omer determine by HPLC (Diacel Chiralpak AD-H, hexane/i-
PrOH 80 : 20; flow rate 1.0 mL min-1; l = 254 nm; tR (syn,
major) = 18.8, tR (syn, minor) = 30.3; [a]2D5 +11 (c 0.1 in CHCl3);
dH(400 MHz; CDCl3; Me4Si) 2.06 (3H, s, OCOCH3 (anti)), 2.07
(3H, s, OCOCH3 (syn)), 4.05 (1H, d, J 18.5 Hz, CH2Ph (anti)),
4.18 (1H, d, J 11.8 Hz, CH2Ph (syn)), 4.24 (1H, d, J 18.1 Hz,
CH2Ph (syn)), 4.26–4.50 (3H, CH2Ph and CHOBn) 4.44 (1H, d, J
11.6 Hz, CH2Ph (syn)), 4.50 (1H, d, J 11.6 Hz, CH2Ph (anti)), 4.51
(2H, s, CH2OBn (anti)), 4.56 (2H, s, CH2OBn (syn)), 6.11 (1H, d, J
5.4 Hz, CHOAc (anti)), 6.23 (1H, d, J 2.8 Hz, CHOAc (syn)), 6.94
(2H, d, J 7.2 Hz, ArH), 7.11–7.44 (10H, m, ArH) and 8.12 (2H,
d, J 8.4 Hz, ArH); dC(100 MHz; CDCl3; Me4Si) 20.7, 73.5, 74.0,
74.1, 74.3, 83.5, 123.5, 127.5, 128.1, 128.3, 128.4, 128.5, 128.6,
128.7, 135.7, 136.8, 143.9, 147.7, 169.5 and 205.8; MS (ESI-TOF)
486.0552 (M++Na).
Yield: 70%; syn/anti = 70 : 30; enantiomeric excess: 94% of syn
diastereomer determine by HPLC (Diacel Chiralpack AS-H,
hexane/i-PrOH 70 : 30; flow rate 0.5 mL min-1; l = 254 nm; tR
(syn, major) = 16.6 min., tR (syn, minor) = 27.7 min.; [a]2D5 +52 (c
0.1 in CHCl3); IR (CHCl3): n/cm-1 3446, 2946, 2867, 1714, 1523
and 1346; dH(300 MHz; CDCl3; Me4Si) 2.21 (3H, s, COCH3), 3.96
(1H, d, J 3.6 Hz, CHOBn), 4.34 (1H, d, J 11.7 Hz, CHaHbPh),
4.59 (1H, d, J 11.7 Hz, CHaHbPh), 5.08 (1H, d, J 3.3 Hz, CHOH),
7.08–7.11 (2H, m, ArH), 7.25–7.35 (3H, m, ArH), 7.48 (2H, d, J
9.0 Hz, ArH) and 8.18 (2H, d, J 9.0 Hz, ArH); dC(75 MHz;
CDCl3; Me4Si) 27.8, 73.5, 73.8, 87.0, 123.4, 127.0, 127.7, 128.0,
128.2, 128.4, 128.5, 130.1, 135.9, 147.5 and 209.8; m/z (ESI): 338.0
(M++Na).
(3R,4S)-4-acetoxy-1,3-bis(tert-butyldimethylsiloxy)-4-(4¢-
Catalyst Recovery
nitrophenyl)butan-2-one8a (4z)
After workup of the reaction, the aqueous portion was separated
and neutralized with saturated solution of sodium carbonate. The
neutralized aqueous solution was extracted with ethyl acetate (3 ¥
10 mL), dried over anhydrous Na2SO4, and distilled to obtain the
desired catalyst in 90% yield.
Yield: 92%; syn/anti = 84 : 16; enantiomeric excess: 95% of syn
diastereomer determine by HPLC (Diacel Chiralpak OD-H,
hexane/i-PrOH 99.5 : 0.5; flow rate 1.0 mL min-1; l = 254 nm;
tR (syn, major) = 19.9 min., tR (syn, minor) = 37.1 min.; [a]D25
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(c) N. Mase and C. F. Barbas III, Org. Biomol. Chem., 2010, 8, 4043–
4050.
Acknowledgements
10 (a) S. S. Chimni, D. Mahajan and V. V. S. Babu, Tetrahedron Lett.,
2005, 46, 5617–5619; (b) S. S. Chimni and D. Mahajan, Tetrahedron:
Asymmetry, 2006, 17, 2108–2119; (c) S. S. Chimni, S. Singh and D.
Mahajan, Tetrahedron: Asymmetry, 2008, 19, 2276–2284; (d) S. S.
Chimni, S. Singh and A. Kumar, Tetrahedron: Asymmetry, 2009, 20,
1722–1724.
We are thankful for financial support from CSIR, India to
SSC (research grant No. 01/2168/07/EMR-II) and SRF(NET)
fellowship to AK and SS. The financial support of Department of
Science and Technology (DST), India under FIST program and
UGC, India, under CAS-I is gratefully acknowledged.
11 For selected reports on syn selective aldol reactions of hydroxy and
dihydroxyacetone, see: (a) S. S. V. Ramasastry, K. Albertshofer, N.
Utsumi, F. Tanaka and C. F. Barbas III, Angew. Chem., Int. Ed.,
2007, 46, 5572–5575; (b) X.-Y. Xu, Y.-Z. Wang and L.-Z. Gong, Org.
Lett., 2007, 9, 4247–4249; (c) M.-K. Zhu, X.-Y. Xu and L.-Z. Gong,
Adv. Synth. Catal., 2008, 350, 1390–1396; (d) S. S. V. Ramasastry, K.
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