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