Synthesis and application of L-proline and R-phenylglycine derived organocatalysts for direct asymmetric Michael addition of cyclohexanone to nitroalkenes

Article abstract of DOI:10.3906/kim-1110-25

Novel R-phenylglycine derived organocatalysts were prepared from the reaction of Cbz-R-phenylglycine with indoline, pyrrolidine, or (S)-(-)-2-(diphenylmethyl)pyrrolidine in 3 steps. The asymmetric Michael addition of cyclohexanone to nitroolefins was investigated using R-phenylglycine derivatives along with L-prolinamides as chiral catalysts. The desired products were obtained in excellent yields with enantioselectivities up to 90% ee and diastereomeric ratio up to 98:2 of the syn addition product. TUeBITAK, 2012.

Full text of DOI:10.3906/kim-1110-25

Turk J Chem
36 (2012) , 659 – 670.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1110-25
Synthesis and application of L-proline and
R-phenylglycine derived organocatalysts for direct
asymmetric Michael addition of cyclohexanone to
nitroalkenes
1
2,∗
˘
Hayriye Nevin NAZIROGLU , Abdulkadir SIRIT
e-mail: asirit42@hotmail.com
1Department of Chemistry, Karamano˘glu Mehmetbey University, 70100 Karaman-TURKEY
2Department of Chemistry, Konya University, 42099 Konya-TURKEY
Received: 17.10.2011
Novel R-phenylglycine derived organocatalysts were prepared from the reaction of Cbz-R-phenylglycine
with indoline, pyrrolidine, or (S)-(-)-2-(diphenylmethyl)pyrrolidine in 3 steps. The asymmetric Michael
addition of cyclohexanone to nitroolefins was investigated using R-phenylglycine derivatives along with
L-prolinamides as chiral catalysts. The desired products were obtained in excellent yields with enantioselec-
tivities up to 90% ee and diastereomeric ratio up to 98:2 of the syn addition product.
Key Words: Amines, asymmetric catalysis, Michael addition, nitroolefins, organocatalysis
Introduction
Asymmetric synthesis using organocatalysts has been a convenient and highly useful synthetic method for the
preparation of enantiomerically pure compounds in the past few years.1 Operational simplicity and the ready
availability and low toxicity of the catalysts, as well as its high efficiencies and selectivities attained in many
organocatalytic transformations made this methodology very attractive for the formation of enantiomerically
pure compounds.2
The Michael addition is one of the most efficient, atom-economical, and powerful carbon–carbon bond-
forming reactions in organic synthesis. The direct asymmetric Michael addition of aldehydes and ketones
∗Corresponding author
659

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Synthesis and application of L-proline and R-phenylglycine..., H. N. NAZIROGLU, A. SIRIT
with nitroalkenes to produce enantiomerically enriched nitroalkanes has been described. These compounds are
versatile building blocks owing to the various possible transformations of the nitro functionality into other useful
functional groups such as amines, nitrile oxides, ketones, and carboxylic acids.3
Barbas4 and List5 independently published their pioneering studies on the asymmetric Michael addition
reactions using L-proline as the catalyst with good yields but very low enantioselectivities (0%-23% ee). Since
then, a variety of organocatalysts have been synthesized and studied for the direct addition of ketones and
aldehydes to β-nitrostyrenes. Examples include chiral diamines,6 modified L-prolines,7 pyrrolidine-based
diamines,8 chiral guanidines,9 urea(thiourea)-based bifunctional organocatalysts,10 and cinchona alkaloid-
based bifunctional organocatalysts.11
Among them, pyrrolidine-based chiral compounds such as chiral pyrrolidinyl triazole,12 tetrazole,13
aminomethylpyrrolidine,14 2,2-bipyrrolidine,15 pyrrolidine-pyridine,16 pyrrolidine sulfonamide,17 pyrrolidine-
thiourea,18 diphenylprolinol ethers,19 ionic liquid supported pyrrolidine-based catalysts,20 and others21 were
reported to show high catalytic activity and enantioselectivity for asymmetric organic transformations. The
rational design and synthesis of an efficient organocatalyst for direct asymmetric Michael addition of ketones
and aldehydes to β-nitroalkenes is still receiving considerable attention, although numerous chiral catalysts
have been developed for this purpose.
In our previous work,22 we synthesized a series of L-proline-based chiral receptors and investigated their
recognition abilities for carboxylic acids by 1 H-NMR spectroscopy. We herein report the synthesis of novel
R-phenylglycine derived organocatalysts 7-12 and their catalytic properties along with prolinamides 1 and 2
for the enantioselective Michael addition of cyclohexanone with β-nitrostyrenes.
Experimental
General
1 H-NMR spectra were recorded at room temperature on a Varian 400 MHz spectrometer in CDCl3 . Chemical
shifts were reported in ppm. Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet,
t = triplet, m = multiplet, br = broad), coupling constants (Hz), and integration. The HPLC measurements
were carried out on Agilent 1100 equipment connected with a Chiralpak Daicel AD-H column. Analytical
TLC was performed using Merck prepared plates (silica gel 60 F254 on aluminum). Flash chromatography
separations were performed on Merck Silica Gel 60 (230-400 mesh). All starting materials and reagents used
were of standard analytical grade from Fluka, Merck, and Aldrich and were used without further purification.
Dichloromethane was dried (CaCl2), distilled from CaH2 , and stored over molecular sieves. Other commercial
grade solvents were distilled, and then stored over molecular sieves. The drying agent employed was anhydrous
MgSO4 . The spectra and other data were consistent with the reported values.
Synthesis of catalysts
Chiral catalysts 1 and 2, shown in Figure 1, were obtained following the literature procedure.22 Compounds 4
7 and 10 were synthesized according to a procedure reported by Bhuniya et al.23
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Synthesis and application of L-proline and R-phenylglycine..., H. N. NAZIROGLU, A. SIRIT
Figure 1. Structure of proline-derived organocatalysts.
General procedure for the synthesis of compounds 5 and 6
N -carbonylbenzyloxy-(R)-phenylglycine (0.5 g, 1.75 mmol) was dissolved with stirring in dry dichloromethane
(20 mL) in a 50 mL round bottom flask equipped with a dropping funnel. The solution was cooled to –5
◦ C and dicyclohexylcarbodiimide (DCC, 0.36 g, 1.75 mmol) was added slowly in small portions. Appropriate
secondary amine (2.23 mmol) was added dropwise to the reaction mixture. After being stirred for 2 h at room
temperature the solution was diluted to double its volume with dichloromethane. Urea formed was separated
by filtration. The solvent was removed. In order to remove further amounts of urea the residue was dissolved in
20 mL of ethyl acetate and heated to 50 ◦ C. The remaining urea was filtered off. This procedure was repeated
until no more urea was formed. The solvent was evaporated and the crude products were purified by flash
chromatography (n-hexane/ethyl acetate, 20:1).
(R)-benzyl (2-(indolin-1-yl)-2-oxo-1-phenylethyl)carbamate (5)
Viscous yellow oil. Yield 85%; α2D5 = –143.8 (c 1.05, CHCl3); IR (KBr) 3395, 3318, 3033, 2955, 1714, 1651
1
cm−1
;
H-NMR (CDCl3 ): δ (ppm): 2.92-3.04 (m, 1H, CH2 - pyrrolidine), 3.09-3.20 (m, 1H, CH2 - pyrrolidine),
3.65-3.74 (m, 1H, CH2 - pyrrolidine), 4.09-4.20 (m, 1H, CH2 - pyrrolidine), 5.02-5.18 (AB, J = 12.4 Hz, 2H,
13
CH2 ph), 5.59 (d,J = 7.6 Hz, 1H, NHCH ph), 6.42 (d,J = 7.6 Hz, 1H, NH), 7.02- 7.52 (m, 14H, ArH);
C-NMR (100 MHz, CDCl3 ): δ (ppm): 167.92, 155.81, 142.83, 136.97, 136.60, 131.48, 129.43, 128.89, 128.73,
128.38, 128.33, 128.24, 127.84, 124.90, 124.69, 117.55, 60.65, 28.24, 21.32, 14.47; Anal. Calcd for C24 H22 N2 O3
(386.45): C, 74.59%; H, 5.74%; N, 7.25%. Found: C, 74.63%; H, 5.80%; N, 7.20%.
Benzyl ((R)-2-((S)-2-benzhydrylpyrrolidin-1-yl)-2-oxo-1-phenylethyl)carbamate (6)
1
Viscous yellow oil. Yield 80%; α2D5 = –159.4 (c 1.05, CHCl3); IR (KBr) 3300, 3029, 2934, 1713, 1639 cm−1
;
H-NMR (CDCl3 ): δ (ppm): 0.96-1.09 (m, 1H, CH2 - pyrrolidine), 1.39-1.5 (m, 1H, CH2 - pyrrolidine), 1.88-1.98
(m, 2H, CH2 - pyrrolidine), 3.02 (q,J = 8.1 Hz, 1H, CH2 - pyrrolidine), 3.17-3.24 (m, 1H, CH2 - pyrrolidine),
4.73 (d,J = 5.4 Hz, 1H, CH), 4.99 (q, J = 5.4 Hz, 1H, CH), 5.04-5.21 (AB, J = 12.3 Hz, 2H, CH2 ph), 5.39
13
(d,J = 7.6 Hz, 1H, NHCH ph), 6.24 (d, J = 7.6 Hz, 1H, NH), 7.14-7.44 (m, 20H, ArH);
C-NMR (100
MHz, CDCl3 ): δ (ppm): 168.27, 155.71, 142.21, 141.68, 137.26, 136.71, 129.98, 129.25, 129.02, 128.74, 128.57,
128.25, 126.99, 126.48, 67.04, 60.91, 57.60, 51.63, 46.50, 27.52, 23.50; Anal. Calcd for C33 H32 N2 O3 (504.62):
C, 78.55%; H, 6.39%; N, 5.55%. Found: C, 78.60%; H, 6.45%; N, 5.50%.
661

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Synthesis and application of L-proline and R-phenylglycine..., H. N. NAZIROGLU, A. SIRIT
General procedure for the synthesis of compounds 8 and 9
A mixture of 5 or 6 (8.8 mmol), cyclohexene (4.36 mL, 53.22 mmol) and 1.4 g of commercial Pd/C (10%) in
110 mL of EtOH was heated under reflux for 2 h in argon, cooled, and filtered over celite. The catalyst was
washed with EtOH, and the filtrate and wash liquids were evaporated under reduced pressure. Crude products
were purified by flash chromatography.
(R)-2-amino-1-(indolin-1-yl)-2-phenylethanone (8)
White solid. Yield 85%; mp 145-146 ◦ C;αD25 = –20.7 (c 1.05, CHCl3); IR (KBr) 3362, 3300, 3025, 2931, 1653,
1
1595 cm−1
;
H-NMR (CDCl3 ): δ (ppm): 2.91 (bs, 2H, NH2), 2.97-3.09 (m, 2H, CH2 - pyrrolidine), 3.53-3.65
(m, 1H, CH2 - pyrrolidine), 3.96-4.09 (m, 1H, CH2 - pyrrolidine), 4.74 (s, 1H, -CH), 6.93-7.43 (m, 8H, ArH),
13
8.31 (d, J = 8.1 Hz, 1H, ArH);
C-NMR (100 MHz, CDCl3 ): δ (ppm): 171.19, 143.18, 140.14, 131.40,
129.51, 128.45, 127.77, 127.75, 124.82, 124.32, 117.40, 59.21, 47.43, 28.22; HRMS (ESI+) calcd for C16 H16 N2 O:
253.3132; found 253.3153.
(R)-2-amino-1-((S)-2-benzhydrylpyrrolidin-1-yl)-2-phenylethanone (9)
1
Viscous oil. Yield 65%; α2D5 = –159.6 (c 1.05, CHCl3); IR (KBr) 3027, 2976, 2881, 1714, 1637 cm−1
;
H-NMR
(CDCl3 ): δ (ppm): 1.09-1.19 (m, 1H, CH2 - pyrrolidine), 1.44-1.53 (m, 1H, CH2 - pyrrolidine), 1.91-1.98 (m,
2H, CH2 - pyrrolidine), 2.05 (brs, 2H, NH2), 3.00-3.22 (m, 2H, CH2 - pyrrolidine), 4.53 (s, 1H, -CH), 4.75
13
(d, J = 5.4 Hz, 1H, -CH), 5.08 (q, J = 5.4 Hz, 1H, -CH), 7.19-7.38 (m, 15H, ArH);
C-NMR (100 MHz,
CDCl3 ): δ (ppm): 171.78, 142.58, 140.9, 130.33, 129.94, 129.07, 128.20, 127.63, 126.91, 60.61, 52.10, 46.26,
30.48, 27.56, 23.57; HRMS (ESI+) calcd for C25 H26 N2 O: 371.4936; found 371.4955.
General procedure for the synthesis of compounds 11 and 12
LiAlH4 (0.8 g, 20.63 mmol) in dry THF (10 mL) at 20 ◦ C was stirred for a few minutes under a nitrogen
atmosphere. The mixture was cooled to 0 ◦ C and compound 8 or 9 (0.98 mmol) in dry THF (10 mL) was
added dropwise over 30 min. The mixture was heated under reflux for 8 h and then cooled in an ice bath.
Aqueous NaOH (2 M) was added dropwise until a white precipitate of inorganic salts formed. The inorganic
salts were removed by filtration and washed with (3 × 20 mL) of THF. The filtrate was dried (MgSO4) and
concentrated under reduced pressure. Crude products were purified by flash chromatography.
(R)-2-(indolin-1-yl)-1-phenylethanamine (11)
1
Viscous yellow oil. Yield 50%; α2D5 = +81.0 (c 1.05, CHCl3); IR (KBr) 3345, 3284, 3027, 2926, 2847 cm−1
;
H-
NMR (CDCl3 ): δ (ppm): δ 2.16 (bs, 2H, NH2), 2.93-3.04 (m, 1H, CH2), 3.07-3.17 (m, 2H, CH2 - pyrrolidine),
3.23-3.36 (m, 1H, CH2), 3.46-3.55 (m, 2H, CH2 - pyrrolidine), 4.28 (dd, 1H, J1 = 4.3 Hz, J2 = 4.3 Hz, CH),
13
6.56 (d, 1H,J = 7.7 Hz, ArH), 6.63-6.72 (m, 1H, ArH), 7.03-7.12 (m, 2H, ArH), 7.24-7.48 (m, 5H, ArH);
C-NMR (100 MHz, CDCl3 ): δ (ppm): 151.66, 128.68, 127.64, 127.42, 126.66, 126.34, 126.05, 125.72, 123.45,
116.92, 61.62, 53.68, 28.33, 27.73; HRMS (ESI+) calcd for C16 H18 N2 : 239.3337; found 239.3365.
662

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Synthesis and application of L-proline and R-phenylglycine..., H. N. NAZIROGLU, A. SIRIT
(R)-2-((S)-2-benzhydrylpyrrolidin-1-yl)-1-phenylethanamine (12)
1
Viscous oil. Yield 51%; α2D5 = –38.3 (c 1.05, CHCl3); IR (KBr) 3374, 3300, 3059, 3025, 2961, 2792 cm−1
;
H-NMR (CDCl3 ): δ (ppm): 1.55-1.75 (m, 4H, CH2 - pyrrolidine + NH2), 1.76-1.96 (m, 1H, CH2), 2.18-2.52
(m, 4H, 2CH2 -pyrrolidine), 3.21-3.25 (m, 1H, CH2), 3.42-3.47 (m, 1H, CH), 3.79 (dd, 1H, J1 = 3.9 Hz, J2
13
= 3.9 Hz, CH), 3.99 (d, 1H, J = 8.3 Hz, CH), 7.07-7.37 (m, 15H, ArH);
C-NMR (100 MHz, CDCl3 ): δ
(ppm): 144.33, 143.80, 129.08, 128.63, 128.56, 128.45, 128.38, 126.83, 60.38, 57.81, 54.88, 54.39, 54.30, 30.15,
24.22; HRMS (ESI+) calcd for C25 H28 N2 : 357.5185; found 357.5221.
General procedure for the Michael reaction of cyclohexanone and β -nitrostyrene
To a suspension of catalyst (0.15 equiv) and cyclohexanone (5 equiv) in 0.75 mL of DMSO and water (3 equiv)
was added trans-β-nitrostyrene (1 equiv). The resulting mixture was allowed to stir at room temperature,
whereupon the reaction was quenched with saturated aqueous ammonium chloride and the aqueous layers were
extracted with ethyl acetate. The combined organic layers were dried over MgSO4 , filtered, and evaporated in
vacuo and the resulting residue was purified by flash column chromatography using ethyl acetate/hexane (2:1).
The enantiomeric excess of the product was determined by chiral HPLC analysis (Daicel Chiralpak AD-H).
Relative and absolute configurations of the products were determined by comparison with the known 1 H-NMR,
13 C-NMR, and chiral HPLC analysis.
(S)-2-((R)-2-nitro-1-phenylethyl)cyclohexanone (13a)
Colourless solid. α2D5 = –27.5 (c 1.2, CHCl3); mp 128-130 ◦ C; IR (KBr) 3024, 2955, 2865, 1698, 1549, 1444,
1
1382 cm−1
;
H-NMR (CDCl3 ): δ (ppm): 7.34-7.25 (m, 3H), 7.17 (d, J = 7.3 Hz, 2H), 4.94 (dd, J1 = 12.4 Hz,
J2 = 4.5 Hz, 1H), 4.64 (dd, J1 = 12.3 Hz, J2 = 10 Hz, 1H), 3.76 (dt, J1 = 9.9 Hz, J2 = 4.4 Hz, 1H), 2.73-2.66
13
(m, 1H), 2.51-2.46 (m, 1H), 2.43-2.32 (m, 1H), 2.12-2.05 (m, 1H), 1.82-1.70 (m, 4H), 1.29-1.19 (m, 1H).
C-NMR (100 MHz, CDCl3 ): δ (ppm): 211.9, 137.7, 128.9, 128.2, 127.8, 78.9, 52.5, 43.9, 42.7, 33.2, 28.5, 25.0;
The enantiomeric excess was determined by HPLC column (Daicel Chiralpak AD-H), Hexane:i−PrOH 90:10,
UV 254 nm, flowrate 1 mL/min, tminor = 10.0 min and tmajor = 12.8 min. All the Michael addition products
are known compounds. The absolute configuration of the products 13a-g was determined by comparison with
literature data: 13a,24 13b,25 13c-f.26
Results and discussion
As shown in Figure 2, the synthesis of novel R-phenylglycine derived organocatalysts 7-12 begins with the
Cbz-protected R-phenylglycine. Treatment of Cbz-R-phenylglycine with indoline, pyrrolidine, or (S)-(-)-2-
(diphenylmethyl)pyrrolidine by a modification of previously reported procedure27 in the presence of dicyclo-
hexylcarbodiimide (DCC) yielded compounds 4-6 in good to excellent (80%-85%) yields. Hydrogenolysis of
4-6 in the presence of 10% Pd/C deprotected the N-Cbz group to provide phenylglycine amides 7-9 in a nearly
quantitative yield. The corresponding diamines 10-12 were then prepared by reduction of the R-phenylglycine
amides 7-9 using excess LiAlH4 in 50%-51% yields.28
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Synthesis and application of L-proline and R-phenylglycine..., H. N. NAZIROGLU, A. SIRIT
O
N
O
N
iii
ii
Cbz
NH
H2N
H2N
N
(5)
(8)
(11)
i
N
H
(b)
O
N
O
N
O
i
ii
iii
Cbz
NH
H2N
Cbz
HN
Ph
OH
H2N
N
(3)
N
H
(4)
(7)
(10)
(a)
Ph
i
N
H
(c)
O
N
O
N
iii
ii
Ph
Ph
Ph
Cbz
NH
H2N
H2N
N
Ph
Ph
Ph
Figure 2. Synthesis of phenylglycine derivatives 3-12. Reagents and conditions: (i) DCC, CH2 Cl2 , reflux; (ii)
Cyclohexene, Pd/C, EtOH; (iii) LiAlH4 , THF, reflux.
With R-phenylglycine-derived receptors in hand, we then studied the catalytic properties of these
receptors for the enantioselective Michael addition of cyclohexanone with β-nitrostyrenes, which is one of
the most important C–C bond forming reactions in organic chemistry.
As a model reaction, the Michael addition of cyclohexanone to β-nitrostyrene was selected as model
substrates in the presence of organocatalysts (15 mol %). We initially focused on solvent effects in the Michael
reactions at ambient temperature. Organocatalyst 1 was first examined and high chemical yield (85%) but
moderate enantioselectivity (51% ee) was observed in CHCl3 (Table 1, entry 1) at room temperature, whereas
using i-PrOH and H2 O resulted in similar yields and enantioselectivities (Table 1, entry 2 and 6). Furthermore,
the use of a nonpolar solvent, such as toluene, slightly decreased the reactivity and enantioselectivity (43% ee,
Table 1, entry 4). As shown in Table 1, the Michael addition proceeded smoothly in DMSO to afford the desired
product in 80% yield with good stereoselectivity (81% ee and 94:6 d.r.) (Table 1, entry 8). It has been reported
that the addition of a Brønsted acid and water in the reaction might accelerate the formation of the enamine
intermediate and promote the catalytic cycle.29 Despite higher diastereoselectivities being achieved, lower yields
and poor enantioselectivities were observed in the presence of various organic acids (PhCOOH, p-TsOH or TFA)
as additives (Table 1, entries 3, 5, 7, and 10). This may be due to the fact that the protonation of the amine
catalyst subsequently hinders the enamine formation. To our delight, the addition of H2 O (3 equiv) slightly
improved the reaction yield (90%) as well as significantly improving the enantioselectivity (87% ee) when the
664

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Synthesis and application of L-proline and R-phenylglycine..., H. N. NAZIROGLU, A. SIRIT
reaction was carried out in DMSO (Table 1, entry 9). When decreased the loading of the catalyst to 10 mol%,
a similar yield but lower diasteroselectivity and enantioselectivity was afforded (Table 1, entry 11).
Table 1. Optimization of reaction conditions.
Entry
Solvent
CHCl3
Additive Time [h] Yielda [%] d.r.b eec [%]
1
2
None
None
48
96
96
72
72
48
96
72
48
72
56
85
75
70
76
72
85
78
80
90
0
92:8
94:6
98:2
91:9
93:7
96:4
98:2
94:6
93:7
n.d.d
85:15
51
49
i-PrOH
3
i-PrOH
TFA
41
4
Toluene
Toluene
H2O
None
43
5
PhCOOH
None
35
6
47
7
H2O
p-TsOH
None
39
8
DMSO
81
9
DMSO-H2O
DMSO-H2O
DMSO-H2O
None
87
n.d.d
10
11e
p-TsOH
None
88
73
a Yield of isolated product after column chromatography on SiO2 . b Diastereomeric ratio, d.r. (syn/anti), determined
by 1 H-NMR of crude product. c Determined by chiral HPLC analysis (Chiralpak AD-H). The absolute configuration
was determined by comparison with literature data. d Not determined. e 10 mol% catalyst was used.
In order to optimize the reaction conditions, the above reaction was studied in the presence of chiral
ligands 1, 2, 7-12 (15 mol%) and the results are summarized in Table 2. Organocatalysts were able to
catalyze the reaction, but the activity and enantioselectivity differed significantly. Among the chiral catalysts
examined, prolinamide 1 gave the best results in terms of chemical yield and enantiomeric excess due to
the fact that the indoline moiety presumably plays an activating role in the reaction, and contributes to
the enantiocontrol. Phenylglycine-derived catalysts 7-12 bearing primary amine groups gave relatively poor
to moderate results when the reaction was carried out in DMSO-H2 O. Primary amines 11 and 12 tended
to provide the desired products with good enantioselectivity compared with the other phenylglycine-derived
organocatalysts. Compound 12 was found to be the best catalyst, giving the product in 88% yield with 76%
enantiomeric excess (Table 2, entry 8). This is presumably due to the additional stereogenic center and steric
hindrance caused by the presence of the phenyl groups. Not much improvement was observed in either the yield
or the enantioselectivity when the reaction temperature was decreased to 0 ◦ C (Table 1, entry 9-10).
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Synthesis and application of L-proline and R-phenylglycine..., H. N. NAZIROGLU, A. SIRIT
Table 2. Screening of new chiral catalysts for asymmetric addition of cyclohexanone to trans-β -nitrostyrene.
Entry Catalyst Time [h] Yielda [%] d.r.b eec [%]
1
2
1
2
48
72
56
72
56
72
48
72
72
96
90
88
86
85
82
84
80
88
85
75
93:7
83:17
96:4
97:3
92:8
95:5
91:9
91:9
90:10
85:15
87
56
14
13
8
3
7
4
8
5
9
6
10
11
12
1d
12d
39
53
76
85
72
7
8
9
10
a Yield of isolated product after column chromatography on SiO2 . b Diastereomeric ratio, d.r. (syn/anti),
determined by 1 H-NMR of crude product. c Determined by chiral HPLC analysis (Chiralpak AD-H). The
absolute configuration was determined by comparison with literature data. d The reaction was performed at
0
◦ C.
With the optimal reaction conditions realized, we further proceeded to examine a variety of nitroalkenes
reacting with cyclohexanone to establish the general utility of this asymmetric transformation (Table 3). All
reactions were performed in DMSO-H2 O in the presence of 15 mol% of catalyst 1. Various aromatic substituted
nitroalkenes reacted well with cyclohexanone donor to give the desired Michael products (13a-g) with 86%-92%
yields and different enantioselectivities (Table 3, entries 1-7).
The introduction of various electron-withdrawing or electron-donating groups on the aromatic ring of the
nitroolefine did not affect enantioselectivities or yields (86%-92%, Table 3, entries 1-4), with the sole exception of
the highest enantioselectivity achieved with aromatic nitroolefine bearing an electron-withdrawing substituent
(Table 3, entry 7).
The stereoselectivities can be explained by a plausible transition model proposed originally by Seebach
and Golinski30 as shown in Figure 3. In this model, the pyrrolidine moiety of the catalyst 2 reacts with
cyclohexanone to form a nucleophilic enamine and the carbonyl oxygen directs the nitro group through hydrogen
bonding via a hydrogen bond with H2 O to organize a favorable transition model. The attack of this enamine on
the Re-face of the nitrostyrene leads to the formation of the observed major enantiomer of the syn diastereomer.
666

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Synthesis and application of L-proline and R-phenylglycine..., H. N. NAZIROGLU, A. SIRIT
Table 3. Catalytic asymmetric Michael addition of cyclohexanone to different aromatic nitroolefines under optimized
conditions.
a Yield of isolated product after column chromatography on SiO2 . b Diastereomeric ratio, d.r. (syn/anti), determined
c
by 1 H-NMR of crude product.
Determined by chiral HPLC analysis (Chiralpak AD-H). The absolute configuration
was determined by comparison with literature data.
667

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Synthesis and application of L-proline and R-phenylglycine..., H. N. NAZIROGLU, A. SIRIT
Figure 3. Proposed transition state.
Conclusion
The phenylglycine-based chiral receptors 7-12 were synthesized from commercially available R-phenylglycine
conveniently. The Michael addition of cyclohexanone to nitroolefins was investigated using R-phenylglycine
derivatives along with L-prolinamides as chiral catalysts. Among them, organocatalysts 1 and 12 gave the best
results in terms of chemical yield and enantiomeric excess. Further studies of the catalytic system in other
asymmetric C–C bond forming processes are currently underway.
Acknowledgments
¨
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We are grateful for the grants from the Scientific and Technological Research Council of Turkey (TUBITAK–
109T167) and the Research Foundation of Selc¸uk University (BAP–09201134).
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