AZT-prolinamide: The nucleoside derived pyrrolidine catalysts for asymmetric aldol reactions using water as solvent

Article abstract of DOI:10.1016/j.tetasy.2014.08.007

New pyrrolidine catalysts based on a nucleoside and proline, AZT-prolinamides, were synthesized and successfully employed for the enantioselective direct aldol reaction of aldehydes with ketones. These catalysts proved to be effective in promoting the rea

Full text of DOI:10.1016/j.tetasy.2014.08.007

Tetrahedron: Asymmetry 25 (2014) 1340–1345
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
AZT-prolinamide: the nucleoside derived pyrrolidine catalysts
for asymmetric aldol reactions using water as solvent
⇑
Tumma Naresh, Togapur Pavan Kumar, Kothapalli Haribabu, Srivari Chandrasekhar
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
New pyrrolidine catalysts based on a nucleoside and proline, AZT-prolinamides, were synthesized and
successfully employed for the enantioselective direct aldol reaction of aldehydes with ketones. These cat-
alysts proved to be effective in promoting the reaction, in additive free water media with 15 mol % load-
ing. The products, b-hydroxy carbonyl compounds were obtained in high yields and stereoselectivities.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 28 July 2014
Accepted 5 August 2014
Available online 10 September 2014
O
1. Introduction
O
NH
O
NH
O
Over the past decade, there has been tremendous advancement
in the development of organocatalytic methods for carbon–carbon
and carbon–heteroatom bond forming reactions. In particular,
organocatalysts with additional binding sites, that illustrate the
concept of multiple catalyst-substrate interactions during the cat-
alytic mechanism have gained much attention in recent years.1
Several catalysts designed around proline nuclei bearing a distinct
range of functionalities have been reported in the literature.2,3 Pro-
linamides were considered to be one such class of organocatalysts,
which promote enamine catalysis very effectively for various
asymmetric transformations. Several prolinamide derivatives with
graded NH acidity and varying levels of steric control have been
employed as organocatalysts for a wide range of organic transfor-
mations and found to be competent with varied levels of success.4
Despite these significant advances, still there is a need for the
design and development of new and readily accessible organocat-
alysts to overcome the common drawbacks such as strong sub-
strate dependence, organic solvent medium and catalyst loading
associated with most of the organocatalytic protocols. Our litera-
ture survey revealed that, synthetic peptides serve as effective cat-
alyst systems for a range of transformations due to their ability for
fine-tuning of the reactivity and selectivity.5 With our continued
interest in organocatalysis,6 we developed two new pyrrolidine
N
O
N
O
O
O
N
H
N
H
N
H
N
H
HO
OTBDPS
1
2
Figure 1. Structure of new nucleoside based prolinamides.
based on the assumption that the pyrrolidine ring would activate
the nucleophile, the amide group would activate the electrophile
through hydrogen bonding, while the nucleoside motif might serve
as the steric controller and also contribute to additional hydrogen
bond stabilization as the reaction progresses. In the literature, aldol
reactions were found to be particularly suitable for testing the cat-
alytic efficiency of prolinamide organocatalysts. Hence, the aldol
reaction of ketones and aldehydes was chosen to evaluate the effi-
cacy of compounds 1 and 2 as organocatalysts. The aldol reaction is
one of the most explored fundamental carbon–carbon bond form-
ing reactions in organocatalytic asymmetric synthesis.7 This reac-
tion offers the formation of chiral adducts with one or more
stereogenic centers with the possibility of stereo regulation. The
products of this reaction, b-hydroxy carbonyl compounds serve
as valuable synthetic intermediates, for the construction of various
bio-active natural products and drug molecules.8 Employing water
as the solvent media to perform organic transformations is one of
the most fundamental and challenging objectives for organic
chemists and substantial progress has been made in this direction
in recent times.9 With these objectives, we report herein the
design, synthesis, and application of AZT-prolinamide 1 and 2 as
a new catalytic system for the direct asymmetric aldol reaction
of aldehydes with ketones under eco-friendly conditions.
derivatives AZT-prolinamide 1 and 2 (Fig. 1) from L-proline and
AZT under peptide coupling reaction conditions. To the best of
our knowledge these represent the very first examples of nucleo-
side derived pyrrolidine organocatalysts to be reported. Prolina-
mides 1 and 2 bearing a nucleoside template were designed
⇑
Corresponding author. Tel.: +91 40 27193434; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
http://dx.doi.org/10.1016/j.tetasy.2014.08.007
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

T. Naresh et al. / Tetrahedron: Asymmetry 25 (2014) 1340–1345
1341
O
O
OH
2. Results and discussion
OHC
catalyst
water (0.5 mL)
rt
NO2
The AZT-prolinamide catalysts 1 and 2 were synthesized from
N-Cbz-proline 5 and commercially available AZT 3 using standard
peptide coupling conditions, followed by deprotection of the pro-
tecting groups as depicted in Scheme 1. Accordingly, the primary
hydroxy group in AZT was protected as a silyl ether using
TBDPSCl/imidazole at room temperature to give compound 4 in
79% yield. The azide group in 4 was reduced to an amine using
Pd–C/H2 in methanol and coupled with acid 5 under EDCI/HOBt
conditions to give compound 6, which on deprotection of the Cbz
group using Pd–C/H2 in methanol resulted in compound 2. Further
removal of the silyl group using ammonium fluoride/methanol
resulted in compound 1. Both compounds 1 and 2 were screened
to test their ability as organocatalysts.
Initially catalyst screening studies were conducted for the
direct asymmetric aldol reaction by taking cyclohexanone 7a and
p-nitrobenzaldehyde 8a as the model substrates (Scheme 2). The
experiments were uniformly conducted with different catalyst
loadings at room temperature using water as the reaction medium
and the results are summarized in Table 1.
NO2
7a
8a
9a
Scheme 2. Aldol reaction of cyclohexanone and p-nitrobenzaldehyde.
Table 1
Screening of catalystsa
c
Yield (%)b
46
mol%
5
Entry Catalyst
Time (h)
48
syn/anti
ee (%)d
81
1
1
91:9
2
1
2
5
48
36
36
38
71
69
96
91:9
93:7
91:9
74
92
85
2
3
4
10
10
15
15
20
20
5
1
2
1
2
24
24
24
24
95:5
95:5
96:4
97:3
97
94
95
96
6
7
94
95
8
95
a Reaction conditions: cyclohexanone (4 mmol), aldehyde (1 mmol).
b Isolated yields.
c Determined by the 1H NMR of the crude product.
d Determined by chiral HPLC for the anti-diastereomer.
Both the catalysts were found to be equally efficient in carrying
out the reaction at different loadings. The reaction performed with
15 mol % of catalyst was found to be more prominent and resulted
in aldol adducts with high yields and selectivities (Table 1, entries
5 and 6). Increasing the catalyst loading to 20 mol % had no advan-
tage and therefore 15 mol % was selected as the optimal catalyst
loading to proceed to further optimization studies. In the processes
of reaction optimization, we then conducted solvent screening
experiments for the above transformation at room temperature
using 15 mol % of catalyst and the results of this study are summa-
rized in Table 2. As evident from the survey, the reaction proceeded
well in all solvents irrespective of their polar/non-polar nature
except for slight variations in reaction time, yields, and selectivi-
ties. The reactions employing catalyst 2 were found to be slightly
inferior to those catalyzed by 1. Though all solvents worked well,
no single solvent proved to be more effective than water in pro-
moting the aldol reaction using catalyst 1 or 2. Therefore water
was chosen as the solvent of choice to carry out aldol reactions
using catalyst 1 or 2.
As summarized in Table 3, the reaction was practicable in the pres-
ence of acid additives, however it was inferior in productivity as
compared to the additive free transformation.
With these initial screening experiments we noticed that both
compounds 1 and 2 could be employed as organocatalysts to carry
out asymmetric aldol reaction between cyclohexanone 7a and alde-
hyde 8a effectively under additive-free conditions employing water
as the solvent medium. However, these results clearly indicate that
compound 1 is slightly more effective than 2 as an organocatalyst.
Having established the optimal reaction conditions, both catalysts
were then tested to explore their versatility in this reaction. Several
substrate combinations in which a variety of aldehydes 8b–l were
employed as aldol acceptors while cyclohexanone 7a (Table 4)
and other ketones 7b–e (Table 5) were taken as the donors. As
shown in Table 4, aldehydes 8b–l reacted smoothly with cyclohex-
anone 7a under the optimized reaction conditions and the corre-
sponding aldol adducts 9b–l were obtained in good yields and
with high levels of stereoselectivities regardless of the nature of
the substitution pattern in the aldehydes (Table 4, entries 1–11).
After solvent screening studies we then tested the effect of
additives on the asymmetric aldol reaction catalyzed by 1 or 2.
H
N
H
N
O
O
a) 10% Pd/C, MeOH
rt, 3 h, 85%
O
O
O
O
TBDPSCl, Imidazole
CH2Cl2, rt, 6 h, 79%
N
N
HO
TBDPSO
b) 5, EDCI, HOBt
CH2Cl2, rt,12 h, 82%
N3
N3
3
4
O
O
NH
NH
O
N
O
N
O
O
NH F MeOH
10% Pd/C, MeOH
rt, 6 h, 81%
,
4
O
O
rt, 12 h, 80%
N
H
N
Cbz
N
H
2
N
H
OTBDPS
6
OTBDPS
O
O
NH
O
N
O
N
Cbz
OH
O
5
N
H
N
H
1
HO
Scheme 1. Synthesis of AZT-prolinamide 1 and 2.

1342
T. Naresh et al. / Tetrahedron: Asymmetry 25 (2014) 1340–1345
Table 2
Screening of solventsa
Table 4
Substrate scope of aldehydesa
O
O
OH
Yieldb (%)
eed (%)
Entry
Time (h)
anti/sync
Solvent Catalyst
1 or 2 (15 mol%)
OHC
R
1
24
24
84
81
93:7
91:9
87
85
R
water (0.5 mL)
rt, 24-48 h
1
MeOH
2
7a
8b-l
9b-l
1
36
36
36
36
80
82
95:5
92:8
90
91
Hexane
2
2
(h) Yieldb
anti/sync ee
Entry
1
Product
OH
Catalyst Time
(%)
d (%)
1
79
75
80
81
85:15
85:15
3
4
5
CH3CN
2
O
O
1
2
24
24
93
87
94:6
91:9
94
91
1
2
36
36
81
83
92:8
9:1
80
76
9b
CHCl3
Br
1
36
48
81
77
78
71
91:9
88:12
OH
OH
THF
2
1
2
24
30
90
84
95:5
93:7
92
87
2
9c
1
2
24
36
70
74
84:16
8:2
85
81
6
7
DMF
Cl
NO2
O
1
48
48
76
79
75:25
72:28
78
84
1
2
24
24
89
87
96:4
95:5
95
93
Dioxan
9d
2
3
4
1
2
24
36
75
71
85:15
85:15
94:6
82
75
DMSO
8
9
O
OH
OH
NO2
1
2
24
36
87
81
96:4
92:8
91
85
1
2
48
48
83
80
90
87
9e
9f
Neat
92:8
a
O
Reaction conditions: catalyst (15 mol %), cyclohexanone (4 mmol), aldehyde
(1 mmol), solvent (0.5 mL).
1
2
24
24
94
85
94:6
93:7
93
93
5
b Isolated yields.
CF3
Determined by 1H NMR of the crude product.
c
d Determined by chiral HPLC for the anti-diastereomer.
O
O
OH
OH
1
2
36
36
90
83
95:5
91:9
90
84
O
9g
9h
6
7
Table 3
Screening of additivesa
1
2
36
48
81
74
92:8
89
87
Yieldb (%)
eed (%)
Entry
Catalyst Time (h)
anti/sync
Additive
85:15
1
2
1
2
24
24
36
72
70
76
73
86
81
82:18
85:15
8:2
75
78
83
77
90
84
Acetic acid
1
2
O
OH
1
2
36
48
86
73
91:9
86
81
9i
8
9
Formic acid
Benzoic acid
88:12
8:2
36
24
24
O
O
OH
OH
1
2
94:6
91:9
3
1
2
36
42
91
83
93:7
91:9
90
92
9j
9k
1
2
36
36
69
73
88:12
85:15
8:2
82
80
N
4
5
TFA
1
2
36
36
70
71
73
76
1
36
36
88
85
92:8
92:8
86
81
pTSA
10
11
75:25
N
2
1
2
36
36
74
68
84:16
7:3
81
77
6
7
CSA
O
OH
1
2
42
48
82
75
91:9
84
87
1
2
24
24
89
84
93:7
9:1
89
80
Anthranilic
acid
9l
90:10
OMe
a
Reaction conditions: catalyst (15 mol %), cyclohexanone (4 mmol),
a Reaction conditions: cyclohexanone (4 mmol), aldehyde (1 mmol).
b Isolated yields.
aldehyde (1 mmol), additive (5 mol %), water (0.5 mL).
b
Isolated yields.
c Determined by 1H NMR of the crude product.
d Determined by chiral HPLC for the anti-diastereomer.
c
Determined by the 1H NMR of the crude product.
d
Determined by chiral HPLC for the anti-diastereomer.
models depicted in Figure 2. We believe that the pyrrolidine ring
of the catalysts activates the ketones to result in enamine forma-
tion, while the nucleoside moiety acts as a steric controller and
also contributes to hydrogen bond stabilization along with the
amide group, and thereby activates the aldehyde substrates. The
organocatalyst 1 provides additional hydrogen bond stabilization
due to the presence of a free hydroxy group (A), while the catalyst
2 provides extensive steric coverage (B). Overall, positioning of all
components results in a perfect architecture during transition state
arrangement and lead to the formation of the desired products
with high stereoselectivities.
Reactions with other ketones 7b–e were also found to be
equally effective and the resultant products 9m–s were obtained
with good yield and selectivities (Table 5, entries 1–7). The major
adducts formed were anti diastereomers in all cases except for
the reaction of cyclopentanone, which gave the syn diastereomer
as the major product (Table 5, entry 7). Despite the observed mar-
ginal variations in catalytic efficiencies, both compounds 1 and 2
could be employed as organocatalysts to perform asymmetric
direct aldol reaction between aldehydes and ketones, as witnessed
in the screening experiments. Overall, the observed efficacy of
these new catalytic systems is in good agreement with our objec-
tives aimed toward the development of eco-friendly protocols for
organocatalytic asymmetric transformations and also in good
agreement to those reported for a variety of organocatalysts
known in the literature.4,10
3. Conclusions
In summary, we have developed an enantioselective direct
asymmetric aldol reaction between aldehydes and ketones employ-
ing newly designed nucleoside based prolinamide organocatalysts.
The absolute stereochemical outcome of this transformation
can be explained by considering the possible transition state2a,11

T. Naresh et al. / Tetrahedron: Asymmetry 25 (2014) 1340–1345
1343
Table 5
gel of 60–120 mesh. IR spectra were recorded on a Perkin–Elmer
683 spectrometer. Optical rotations were obtained on a Jasco Dip
360 digital polarimeter. 1H and 13C NMR spectra were recorded
in CDCl3 solution on a Varian Gemini 200 and Brucker Avance
300. Chemical shifts were reported in parts per million with
respect to internal TMS. Coupling constants j are quoted in Hz.
Mass spectra were obtained on an Agilent Technologies LC/MSD
Trap SL. Chiral HPLC analysis was carried out on chiral pak OD-H,
IC, IA or AD-H columns using a mixture of isopropanol and hexanes
as the eluent.
Substrate scope of ketonesa
O
O
OH
1 or 2 (15 mol%)
OHC
water (0.5 mL)
rt, 24-48 h
R
R
c
c
7b-e
Product
9m-s
8a, l, h,
Entry
1
Catalyst
(h)
Yieldb (%) anti syn
/
eed
(%)
Time
O
OH
---
---
1
2
36
36
81
78
91
90
9m
NO2
O
OH
4.1.1. 1-((2R,4S,5S)-4-Azido-5-(((tert-butyldiphenylsilyl)oxy)-
methyl) tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-
dione 4
---
---
1
2
36
48
77
72
75
77
2
3
9n
9o
OMe
O
OH
OH
To a stirred solution of azidothymidine 3 (5 g, 18.7 mmol) in
CH2Cl2 (50 mL), were added imidazole (1.91 g, 28.8 mmol) and
TBDPSCl (5.2 ml, 20.5 mmol) at 0 °C and allowed to stir at room
temperature. After 6 h, the reaction mixture was quenched with
saturated solution of NH4Cl (40 mL) and extracted with ethyl
acetate (2 Â 50 mL). The combined organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. Silica gel column chro-
matography (EtOAc/hexanes, 7:3) of the residue gave the silylether
of azidothymidine 4 (7.5 g, 79% yield) as a colorless liquid.
---
---
1
2
36
48
74
73
79
81
O
---
---
1
2
36
36
83
75
86
87
4
5
9p
9q
Cl
O
OH
1
2
24
36
85
84
93:7
91:9
89e
85e
O
O
NO2
[a
]
D
20 = +213.14 (c 0.7, MeOH); IR (Neat):
m
= 3185, 3044, 2933,
2860, 2106, 1677, 1468, 1266, 1111, 771, 105 cmÀ1 1H NMR
;
OH
OH
1
2
24
36
83
80
91:9
94:6
86e
83e
9r
9s
6
7
(CDCl3, 300 MHz): d 9.05–8.95 (br s, 1H), 7.71–7.60 (m, 4H),
7.51–7.31 (m, 7H), 6.26 (t, J = 6.798 Hz, 1H), 4.37–4.27 (m, 1H),
4.06–3.91 (m, 2H), 3.87–3.76 (m, 1H), 2.50–2.40 (m, 1H), 2.35–
2.21 (m, 1H), 1.63 (s, 3H), 1.10 (s, 9H); 13C NMR (CDCl3, 75 MHz):
d 164.0, 150.4, 135.2, 135.0, 134.6, 132.3, 131.9, 129.9, 129.8,
127.7, 127.7, 111.1, 84.0, 83.9, 63.2, 60.1, 37.4, 26.7, 19.0, 11.8;
ESIMS: m/z 506 [M+H]+; HRMS Calcd for C26H32N5O4Si: 506.2218,
found 506.2221.
S
NO2
NO2
O
1
2
36
36
79
76
15:85
15:85
88f
83f
a Reaction conditions: cyclohexanone (4 mmol), aldehyde (1 mmol).
b Isolated yields.
c Determined by 1H NMR of the crude product.
d Determined by chiral HPLC.
4.1.2. (S)-Benzyl 2-(((2S,3S,5R)-2-(((tert-butyldiphenylsilyl)oxy)-
methyl)-5-(5-methyl-2,4-dioxo-3,4 dihydropyrimidin-1(2H) yl)-
tetrahydrofuran-3 yl) carbamoyl)pyrrolidine-1-carboxylate 6
To a stirred solution of azidosilylether 4 (3 g, 13.5 mmol) in
methanol (30 mL), was added 10% Pd/C (120 mg) at room temper-
ature. The reaction mixture was subjected to hydrogen pressure
(atmospheric) for 6 h. The reaction mixture was diluted with CHCl3
(50 mL), filtered through a small pad of Celite, and concentrated
under reduced pressure to obtain the free amine (2.4 g, 85% yield)
as a white solid which was used for the next step without purifica-
tion. To the solution of N-Cbz-proline 5 (900 mg, 3.4 mmol) in dry
CH2Cl2 (15 mL), HOBt (690 mg, 5.1 mmol) and EDCI (976 mg,
5.1 mmol) were added sequentially at 0 °C and stirred at the same
temperature for 15 min. Then, the solution of the above obtained
free amine in dry CH2Cl2 was added to the reaction mixture and
stirred at room temperature for 12 h. Ethyl acetate (30 ml) was
added to dilute the reaction mixture, which was washed with sat-
urated NH4Cl solution (30 mL), aqueous NaHCO3 solution (20 mL),
and brine (20 mL). The combined organic layer was dried over
Na2SO4, concentrated in vacuo, and purified by silica gel chroma-
tography using ethylacetate/hexane (96:4) to afford dipeptide 6
e Determined by chiral HPLC for the anti-diastereomer.
f
Determined by chiral HPLC for the syn-diastereomer.
O
O
NH
NH
O
N
O
N
O
O
O
O
N
H
N
H
N
N
Ph
O
Si
O
O
O
H
Ph
Ar
Ar
A
B
Figure 2. Possible transition state structures.
These catalysts exhibit great catalytic efficacy and led to the forma-
tion of aldol adducts with high yields and stereoselectivities. The
best results were obtained under additive free water mediated
reaction conditions. Further investigations on catalyst structure
modification to extend the catalytic capacity of these new proline
derivatives toward other organocatalytic asymmetric transforma-
tions are in progress.
(2 g, 82% yield) as a white solid. Mp: 115–118 °C; [
0.5, MeOH); IR (Neat): = 3322, 3191, 3069, 2956, 2930, 1690,
1467, 1422, 1114, 753, 703 cmÀ1 1H NMR (CDCl3, 300 MHz): d
a]
20 = +8.40 (c
D
m
;
10.02–9.90 (br s, 1H), 8.20–8.33 (m, 1H), 7.75–7.60 (m, 5H),
7.54–7.26 (m, 12H), 6.64–6.51 (m, 1H), 5.25 (s, 2H), 4.75–4.60
(br, 1H), 4.35–4.20 (br, 1H), 4.08–3.98 (m, 2H) 3.68–3.41 (m, 3H),
2.42–2.21 (m, 2H), 1.95–1.81 (m, 2H), 1.38 (s, 3H), 1.10 (s, 9H);
13C NMR (CDCl3, 75 MHz): d 172.4, 163.6, 156.1, 151.3, 136.2,
135.5, 135.1, 134.9, 133.5, 132.2, 130.0, 129.8, 128.4, 128.2,
128.0, 127.9, 127.8, 112.1, 86.6, 84.0, 67.8, 65.0, 60.1, 51.2, 47.0,
4. Experimental
4.1. General
All solvents and reagents were purified by standard techniques.
Crude products were purified by column chromatography on silica

1344
T. Naresh et al. / Tetrahedron: Asymmetry 25 (2014) 1340–1345
36.9, 29.6, 28.9, 27.1, 24.8, 19.5, 11.6; ESIMS: m/z 711 [M+H]+;
HRMS Calcd for C39H47N4O7Si: 711.3209, found 711.3219.
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4.1.3. (S)-N-((2S,3S,5R)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-
5-(5-methyl-2,4-dioxo-3,4 dihydropyrimidin-1(2H) yl)tetrahy-
drofuran-3-yl)pyrrolidine-2-carboxamide 2
To a stirred solution of dipeptide 6 (2 g, 2.8 mmol) in methanol
(30 mL), was added 10% Pd/C (120 mg) at room temperature. The
reaction mixture was subjected to hydrogen pressure (atmo-
spheric) for 6 h. The reaction mixture was diluted with CHCl3
(50 mL), filtered through a small pad of Celite, and concentrated
under reduced pressure to obtain the free amine compound 2
(1.3 g, 81% yield) as a colorless liquid. [
a]
20 = +1.86 (c 0.7, MeOH);
D
IR (Neat): ;
m
= 2924, 2853, 1745, 1680, 1460, 1219, 772 cmÀ1 1H
NMR (CDCl3, 300 MHz): d 8.09 (d, J = 6.798 Hz, 1H), 7.75–7.62 (m,
4H), 7.50–7.33 (m, 7H), 6.42 (t, J = 7.55, 6.043 Hz, 1H), 4.77–4.63
(m, 1H), 4.05–3.88 (m, 2H), 3.76–3.66 (m, 1H), 3.09–2.86 (m,
1H), 2.42–2.21 (m, 2H), 2.01–1.86 (m, 2H), 1.80–1.65 (m, 4H),
1.53 (br s, 4H), 1.10 (br s, 10H); 13C NMR (CDCl3, 75 MHz): d
173.6, 164.1, 151.3, 135.4, 135.0, 134.6, 133.2, 132.1, 129.8,
129.7, 129.2, 127.8, 127.4, 111.7, 80.0, 83.9, 64.4, 60.9, 49.7, 46.8,
37.7, 29.9, 29.5, 26.8, 26.4, 25.6, 19.3, 11.7; ESIMS: m/z 577
[M+H]+; HRMS Calcd for C31H41N4O5Si: 577.2841, found 577.2839.
4.1.4. (S)-N-((2S,3S,5R)-2-(Hydroxymethyl)-5-(5-methyl-2,4-di-
oxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl)pyrro-
lidine-2-carboxamide 1
To a stirred solution of compound 2 (2 g, 34.7 mmol) in metha-
nol (20 mL), was added NH4F (192 mg, 52 mmol) at 0 °C and
allowed to stir at room temperature for 12 h. The reaction mixture
was diluted with CHCl3 (50 mL), filtered through a small pad of Cel-
ite, and concentrated under reduced pressure to obtain free amino
alcohol 1 (940 mg, 80% yield) as a white solid. Mp: 170–173 °C;
[a
]
D
20 = À7.60 (c 0.5, MeOH); IR (Neat):
m
= 3340, 3062, 2928,
1684, 1548, 1472, 1272, 1099, 1059, 875, 771, 560 cmÀ1
;
1H
NMR (DMSO-d6, 300 MHz): d 7.92 (br, s, 1H), 7.60–7.45 (m, 1H),
6.10–5.90 (m, 1H), 4.65 (br, s, 3H), 4.42 (br, s, 1H), 3.67–3.57 (m,
3H), 3.55–3.42 (m, 2H), 2.16–2.01 (m, 2H), 1.95–1.82 (m, 1H),
1.70–1.58 (m, 4H), 1.54–1.39 (m, 2H), 1.05–0.95 (m, 1H); 13C
NMR (DMSO-d6, 75 MHz): d 172.9, 164.2, 150.8, 136.7, 109.9,
85.0, 83.9, 61.6, 60.2, 49.2, 46.8, 37.3, 30.6, 25.4, 12.6; ESIMS: m/z
339 [M+H]+; HRMS Calcd for C15H23N4O5: 339.1663, found
339.1651.
4.1.5. General procedure for the aldol reaction of ketones to
aldehydes
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Kazuhiko, M.; Sarah, A. H.; Daniel, A. T.; Christopher, M. H.; Parquette, J. R.
Chem. Commun. 2009, 3261–3263; (f) Rafael, P.; Jose, M. A.; Ruben, M.; David,
R.; Silvia, T. Org. Biomol. Chem. 2011, 9, 935–940.
6. (a) Chandrasekhar, S.; Narsihmulu, Ch.; Reddy, N. R.; Sultana, S. S. Chem.
Commun. 2004, 2450–2451; (b) Chandrasekhar, S.; Reddy, N. R.; Sultana, S. S.;
Narsihmulu, Ch.; Reddy, K. V. Tetrahedron 2006, 62, 338–345; (c)
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4935–4937; (d) Chandrasekhar, S.; Mallikarjun, K.; Reddy, G. P. K.; Rao, K. V.;
Jagdeesh, B. Chem. Commun. 2009, 4985–4987; (e) Chandrasekhar, S.; Tiwari,
B.; Parida, B. B.; Rajireddy, C. Tetrahedron: Asymmetry 2008, 19, 495–499; (f)
Chandrasekhar, S.; Johny, K.; Rajireddy, Ch. Tetrahedron: Asymmetry 2009, 20,
1742–1745; (g) Chandrasekhar, S.; Kumar, T. P.; Haribabu, K.; Rajireddy, Ch.
Tetrahedron: Asymmetry 2010, 21, 2372–2375; (h) Chandrasekhar, S.; Kumar, T.
P.; Haribabu, K.; Rajireddy, Ch.; Kumar, C. R. Tetrahedron: Asymmetry 2011, 22,
697–702; (i) Kumar, T. P.; Sattar, M. A.; Sarma, V. U. M. Tetrahedron: Asymmetry
2013, 24, 1615–1619; (j) Kumar, T. P.; Vavle, N. C.; Patro, V.; Haribabu, K.
Tetrahedron: Asymmetry 2014, 25, 457–461; (k) Kumar, T. P.; Balaji, S. V.
Tetrahedron: Asymmetry 2014, 25, 473–477; (l) Chandrasekhar, S.; Kumar, T. P.;
Kumar, C. P.; Haribabu, K.; Jagadeesh, B.; Lakshmi, J. K.; Mainkar, P. S. RSC Adv.
2014, 4, 30325–30331.
To a mixture of catalyst 1 or 2 (15 mol %) and cyclohexanone
(4 mmol) in H2O (0.5 mL) was added aldehyde (1 mmol) and the
resulting mixture was stirred for the appropriate time (Tables 4
and 5) at room temperature. After completion of the reaction
(monitored by TLC), the mixture was purified by silica-gel column
chromatography to afford the desired product. The relative and
absolute configurations of the products were determined by com-
parison of 1H NMR, 13C NMR, and specific rotation values with
those reported in the literature.4
Acknowledgements
T.P.K. thanks DST New Delhi for INSPIRE Faculty Award
(IFA12-CH-30). T.N. thanks CSIR, New Delhi for the award of
research fellowship. Authors thank DST and CSIR for Funding.
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