Novel cyclic β-aminophosphonate derivatives as efficient organocatalysts for the asymmetric Michael addition reactions of ketones to nitrostyrenes

Article abstract of DOI:10.1016/j.tetasy.2010.05.049

Three novel catalysts based upon cyclic β-aminophosphonate derivatives 13 were designed to catalyze the asymmetric Michael addition reactions of ketones to β-nitrostyrenes. Among the catalysts that have been prepared in this study, cyclic β-aminophosphonic acid monoethylester 3 showed the highest catalytic ability, giving the corresponding Michael adduct in good yields, high enantioselectivities (up to 92%ee), and high diastereoselectivities (syn:anti up to 95:5).

Full text of DOI:10.1016/j.tetasy.2010.05.049

Tetrahedron: Asymmetry 21 (2010) 1861–1868
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Novel cyclic b-aminophosphonate derivatives as efficient organocatalysts
for the asymmetric Michael addition reactions of ketones to nitrostyrenes
*
Triana Widianti, Yoshikazu Hiraga , Satoshi Kojima, Manabu Abe
Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Three novel catalysts based upon cyclic b-aminophosphonate derivatives 1–3 were designed to catalyze
the asymmetric Michael addition reactions of ketones to b-nitrostyrenes. Among the catalysts that have
been prepared in this study, cyclic b-aminophosphonic acid monoethylester 3 showed the highest cata-
lytic ability, giving the corresponding Michael adduct in good yields, high enantioselectivities (up to 92%
ee), and high diastereoselectivities (syn:anti up to 95:5).
Received 17 April 2010
Accepted 26 May 2010
Available online 3 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
(Fig. 1). Although chiral pyrrolidine-based phosphinyl oxides have
been reported to catalyze asymmetric direct aldol reactions and asym-
Over the last decade, the study of asymmetric organocatalysis
has grown to be a significant field in synthetic organic chemistry.1
Organocatalysis is considered to be the promising answer to the de-
mand of easy-to-handle and environmentally friendly reaction con-
metric Michael addition reactions,19 to the best of our knowledge,
there is no example using either cyclic b-aminophosphonic acids or
cyclic b-aminophosphonates in the asymmetric organic reactions so
far. We envisaged that replacement of the carboxylic group in the
b-homoproline with a phosphonic group might provide better reac-
tion activity and selectivity due to the higher acidity and bulkier size
of a phosphonic acid compared to a carboxylic acid. Furthermore,
ditions. Among organocatalysts that have been reported, L-proline 4
is the most well-known compound because of its versatility and
availability.2 Previously, various proline-based asymmetric organo-
catalysts, such as 2,20-bipyrrolidine,3 1-(2-pyrrolidinylmethyl)-
pyrrolidine,4 pyrrolidine-pyridine,5 pyrrolidin-triazole derivatives,6
5-pyrrolidin-2-yltetrazole,7 prolinamide derivatives,8 proline-
based dendritic catalysts,9 proline-derived triamines,10 b-homopro-
line 5,11 diphenylprolinol silyl ether,12 pyrrolidine sulfonamide,13
proline-thiourea self-assembled catalysts,14 and polymer-
supported catalysts,15 were also reported to have catalytic abilities
in a varied range of organic reactions. One of the proline-based
catalysts, b-homoproline 5, was found to be a better catalyst than
proline in the Michael addition reactions, that is, the enantioselec-
tivity (up to 96% ee) of the b-homoproline-catalyzed Michael
addition reactions was reported to be higher than that (up to 23%
ee) of proline-catalyzed reactions.2b,11
Aminophosphonic acids and aminophosphonates, which are
analogues of aminoacids, have been the subject of studies in the
field of medicinal chemistry on account of their diverse and useful
biological activities.16 However, despite of having been well stud-
ied on their synthesis and biological properties,17 there are only
a few reports on their application as organocatalysts for asymmet-
ric organic reactions.18
the enantioselectivity of
a-aminophosphonate-catalyzed Michael
addition reactions has been found to be higher than that reported
for the proline-catalyzed reactions.18b
O
P
O
P
O
P
OH
OH
OEt
OEt
OEt
OH
N
H
N
H
N
H
1
4
3
2
5
CO2H
CO2H
N
H
N
H
Figure 1. Novel cyclic b-aminophosphonates 1–3, proline 4, and b-homoproline 5.
Herein, we report the preparation of cyclic b-aminophophonic
acid derivatives 1–3 and their application in the asymmetric
Michael addition reaction of various ketones to b-nitrostyrenes.
In the class of aminophosphonic acid and aminophosphonate com-
pounds, cyclic b-aminophosphonic acids 1 and cyclic b-aminophos-
phonates 2 and 3 have a structural resemblance to b-homoproline 5
2. Results and discussion
2.1. Synthesis of the organocatalysts
Aminophosphonic acid 1, diethylaminophosphonate 2, and
aminophosphonic acid monoester 3 were synthesized from the
* Corresponding author. Tel.: +81 82 424 0727; fax: +81 82 424 0727.
E-mail address: yhiraga@sci.hiroshima-u.ac.jp (Y. Hiraga).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.049

1862
T. Widianti et al. / Tetrahedron: Asymmetry 21 (2010) 1861–1868
common precursor aminophosphonate 9, which was prepared
from -proline 4 as described in Scheme 1. As shown in Scheme 1,
-proline 4 was reduced with LiAlH4 to give
-prolinol 6.20 The ami-
no group of 6 was then protected with a benzyloxycarbonyl (Cbz)
moiety to furnish N-Cbz- -prolinol 7 in 63% yield. The mesylation
of N-Cbz- -prolinol 7 by mesyl chloride with Et3N followed by
iodination using NaI gave the corresponding iodide 8. The Michae-
lis–Becker reaction of the resulting iodide 8 then afforded amin-
ophosphonate 9 (76% over three steps).21
6 M HCl followed by treatment with propylene oxide gave amino-
phosphonic acid 1 in 76% yield. The deprotection of the Cbz group
of 9 by catalytic hydrogenation with Pd(OAc)2 provided the diet-
hylaminophosphonate 2 in >99% yield. Aminophosphonic acid
monoethylester 3 was prepared by treatment of aminophospho-
nate 9 with LiBr and HCl,23 followed by Cbz deprotection of the
resulting Cbz-aminophosphonic monoester 10 by catalytic hydro-
genation with Pd(OAc)2 (88% yield over three steps).
L
L
L
L
L
2.2. Asymmetric Michael addition reaction of acetone to trans-
b-nitrostyrene
a
b
OH
OH
CO2H
N
H
N
H
N
The catalytic ability of organocatalysts 1–3 was initially tested
in the asymmetric Michael addition of acetone to trans-b-nitrosty-
Cbz
4
6
7
rene using DMSO as the solvent. The reactions using
L-proline 4 or
O
P
L
-b-homoproline 5 as the catalyst were also carried out for compar-
c, d
e
I
ison. All the reactions were performed at room temperature (25 °C)
for 24 h in the presence of 20 mol % of catalyst. The results were
summarized in Table 1. The reaction was very sluggish when
aminophosphonic acid 1 was used, giving the Michael adduct 11
in only a trace amount (entry 1). This low catalytic ability of 1
was probably caused by its poor solubility in DMSO. When diet-
hylaminophosphonate 2 was used, a small increase in the chemical
yield of 11 was observed (entry 2). However, the enantioselectivity
catalyzed by 2 was low, affording 11 in only 4% ee.
OEt
OEt
N
N
Cbz
Cbz
8
9
Scheme 1. Synthesis of aminophosphonate 9. (a) LiAlH4 (1.5 equiv), reflux, 2 h,
>99%. (b) Cbz-Cl (1.2 equiv), Et3N (1.3 equiv), CH2Cl2, rt, 18 h, 63%. (c) MsCl
(1.6 equiv), Et3N (1.8 equiv), CH2Cl2, 0 °C to rt, 3 h. (d) NaI (3 equiv), acetone, reflux,
12 h. (e) (EtO)2P(O)H (6 equiv), NaH (6 equiv), DMF, 55 °C, 5 d, 76% (over three
steps).
To our delight, aminophosphonic acid monoester 3 gave adduct
11 in a high yield of 88% with an enantioselectivity of 36% ee
(entry 3). The result indicates a considerable improvement in the
As shown in Scheme 2, according to the reported methods,18a,22
the deprotection and hydroxylation of aminophosphonate 9 using
O
a, b
P
OH
OH
N
H
1
2
O
O
P
c
P
OEt
OEt
OEt
OEt
N
N
H
Cbz
9
O
P
O
P
d,e
f
OEt
OH
OEt
OH
N
N
H
Cbz
3
10
Scheme 2. Synthesis of catalysts 1, 2, and 3. (a) 6 M HCl, reflux, 29 h, >99%. (b) Propylene oxide (excess), EtOH, 35 °C, 10 h, 76%. (c) H2, Pd(OAc)2, EtOH, rt, 4 d, >99%. (d) LiBr
(1.4 equiv), MeCN, reflux, 15 h. (e) 0.6 M HCl (1.4 equiv), rt, 30 min. (f) H2, Pd(OAc)2, EtOH, rt, 4 d, 88% (over three steps).
Table 1
The asymmetric Michael addition reaction of acetone to trans-b-nitrostyrene in DMSO in the presence of various catalysts
O
O
Ph
Ph
O
Ph
cat. (20 mol%)
NO2
+
+
Ph
NO2 O2N
NO2
DMSO
rt, 24 h
12
11
Entry
Catalyst
Yielda,b (%)
ee of 11c (%)
11
12
1
2
3
4
1
2
3
7
12
88 (81)
91 (87)
Trace
Trace
11
n.d.d
4
36
9
9
L
-Proline 4
5e
33
67
28
L
-b-HomoprolineꢀHCl 5
a
b
c
Determined by 1H NMR analysis of the crude products.
Isolated yield in parenthesis.
Determined by HPLC using a Daicel Chiralpak AD-H column or a Daicel Chiralpak IC column.
Not determined.
20 mol % of Et3N was added.
d
e

T. Widianti et al. / Tetrahedron: Asymmetry 21 (2010) 1861–1868
1863
enantioselectivity compared to the reactions catalyzed by
L
-proline
The results were summarized in Table 3. The Michael addition of
2-butanone to trans-b-nitrostyrene provided the corresponding
internal Michael adduct 13a (40% yield, 54% ee) and terminal
Michael adduct 13b (28% yield, 80% ee) (entry 1). The internal
Michael adduct 13a was obtained with high diastereoselectivity
(d.r. 91:9). Interestingly, only the major diastereomer syn-13a
showed the opposite enatioselectivity as compared with the syn-
4 and -b-homoproline 5 (entries 4 and 5). Since the aminophos-
L
phonic acid monoester 3 provided the best result, we decided to
use the catalyst for further examination.
2.3. Influence of solvent and temperature on the asymmetric
Michael addition reaction using organocatalyst 3
product from the L
-proline-catalyzed reaction.2a When 3-pentanone
The influence of organic solvent was investigated in the Michael
addition reaction of trans-b-nitrostyrene and acetone at 25 °C in
the presence of 20 mol % of catalyst 3. The results are summarized
in Table 2. In aprotic organic solvents with low polarity such as
CH2Cl2, 1,4-dioxane, and THF, the reactions were very slow due
to the low solubility of catalyst 3 in the organic solvents (entries
1–3). When polar aprotic solvents such as MeCN, acetone, and
DMF were used, the reactions provided the adduct 11 in higher
yields with moderate enantioselectivities (entries 4–6). The high-
est yield of 11 was obtained when DMSO was used as a solvent
(entry 7). On the other hand, protic solvents such as MeOH and
EtOH decreased the chemical yields of 11 (entries 10 and 11). How-
ever, the enantioselectivities of 11 from the reaction using the
protic solvents were slightly improved.
was used as a Michael donor, the reaction proceeded slowly, giving
the corresponding product 13c in 14% yield after 24 h, although the
diastereoselectivity and enantioselectivity were both high (d.r. 92:8,
88% ee of syn isomer) (entry 2). In the case of cyclic ketones, the ring
size of the ketones strongly influenced the reactivity (entries 3 and
4). The reaction rate of cyclopentanone with trans-b-nitrostyrene
was very slow, only 3% yield of the Michael adduct 13d (84% ee) with
moderate diastereoselectivity was obtained after 24 h together with
the double Michael adduct 13e (16% yield). Due to the difficulty in
the separation of the stereoisomers of 13e on column chromatogra-
phy, the diastereoselectivity and enantioselectivity of 13e were not
established. In contrast, the reaction of cyclohexanone gave adduct
13f in a remarkably high yield (94%) with high diastereoselectivity
(d.r. 95:5) and enantioselectivity (82% ee) without the formation
of the double Michael adduct (entry 4).
Table 2
Substitution at the para-position of the aromatic ring of trans-
b-nitrostyrenes with either an electron-donating or an electron-
withdrawing group reduced the diastereoselectivities of the
corresponding Michael adducts 13g and 13h (entries 5 and 6).
When trans-2-chloro-b-nitrostyrene which has an electron-with-
drawing group at the ortho-position of its aromatic ring was used
as a Michael acceptor, an increase in the diastereoselectivity of
corresponding adduct 13i was observed as compared with the case
of trans-4-chloro-b-nitrostyrene (entries 6 and 7). However, the
yield of the products 13h and 13i seemed to be unaffected by
the position of the substituent group.
In order to achieve higher selectivity, we tried to conduct the
Michael addition reaction of cyclohexanone to trans-b-nitrostyrene
at several temperatures in a solvent mixture of DMSO and DMF (1:1
v/v), because the enantioselectivity in DMF was higher than that in
DMSO (Table 2, entries 6 and 7). As can be seen in entries 4, 8–10
of Table 3, when the reaction was performed in a mixture of DMSO
and DMF (1:1 v/v), the enantioselectivity was improved from 82%
ee to 87% ee and the diastereoselectivity remained high (entry 8).
Furthermore, reducing the reaction temperature to 0 °C gave a slight
increase in the enantioselectivity (entry 9). However, it required a
longer reaction time to complete. When the reaction temperature
was further reduced to ꢁ25 °C and ꢁ10 °C, the highest enantioselec-
tivity was obtained (92% ee, entry 10). Unfortunately, at this temper-
ature, the reaction proceeded very slowly, providing the Michael
adduct in a low yield (15%) after 6 days.
Solvent screening for the asymmetric Michael addition reaction of acetone to trans-b-
nitrostyrene using organocatalyst 3a
Entry
Solvent
Yieldb,c (%)
11
ee of 11d (%)
12
1
2
3
4
5
CH2Cl2
1,4-Dioxane
THF
MeCN
Acetone
DMF
DMSO
DMSO
DMSO
MeOH
EtOH
1
2
2
—
n.d.e
n.d.e
n.d.e
37
45
46
36
39
29
47
Trace
Trace
4
8 (3)
28 (9)
39 (37)
88 (81)
79 (71)
70 (58)
10 (9)
8 (5)
6
6
7
10
11
21
19
5
8f
9g
10
11
2
44
a
b
c
d
e
f
All reactions were carried out at 25 °C for 24 h in the presence of 20 mol % of 3.
Determined by 1H NMR analysis of the crude products.
Isolated yield in parenthesis.
Determined by HPLC using a Daicel Chiralpak AD-H column.
Not determined.
Reactions were carried out at 20 °C for 24 h in the presence of 20 mol % of 3.
Reactions were carried out at 15 °C for 24 h in the presence of 20 mol % of 3.
g
The influence of reaction temperature was examined in the Mi-
chael addition reactions of acetone and trans-b-nitrostyrene in the
presence of 20 mol % of catalyst 3 in DMSO. As can be seen in
Table 2, the reactions at 25 °C yielded adduct 11 in 88% yield with
36% ee (entry 7). When the reaction was carried out at 20 °C, the
adduct 11 was obtained in 79% yield with a slightly higher enanti-
oselectivity (39% ee) (entry 8). However, lowering of the reaction
temperature to 15 °C resulted in a considerable decrease in chem-
ical yield (70%) and enantioselectivity (29% ee) (entry 9).
These results indicated that DMSO is the most suitable solvent
and 20 °C is the most suitable reaction temperature for asymmetric
Michael addition reaction of acetone to trans-b-nitrostyrene using
organocatalyst 3.
These results indicated that the addition of various ketones to
nitrostyrene using organocatalyst 3 gave the corresponding mono
Michael adducts with high diastereoselectivity and enantioselec-
tivity, except for the reaction with cyclopentanone. The investiga-
tion of the unusual product selectivity of the cyclopentanone is
currently ongoing.
3. Conclusion
2.4. Asymmetric Michael addition reaction of various ketones to
various trans-b-nitrostyrenes
In summary, we have found for the first time that the cyclic
b-aminophophonic acid monoester 3 could be used as an organo-
catalyst in the asymmetric Michael addition of ketones to
trans-b-nitrostyrenes to provide high yield of the corresponding
Michael adducts with high diastereoselectivities and enantioselec-
tivities. Further studies on the applications of this novel organocat-
alyst in other asymmetric reactions are in progress.
The performance of catalyst 3 was then examined in the
Michael addition reaction of various ketones and various trans-
b-nitrostyrene. On the basis of solvent and temperature effects,
all reactions were carried out in DMSO at 20 °C for 24 h in the
presence of 20 mol % of catalyst 3.

1864
T. Widianti et al. / Tetrahedron: Asymmetry 21 (2010) 1861–1868
Table 3
The asymmetric Michael addition reaction of various ketones to various trans-b-nitrostyrenes using organocatalyst 3a
Entry
1
Ketone
Product
Yieldb,c (%)
d.r.b (syn:anti)
eed (%)
54
O
O
Ph
Ph
Ph
NO2
40
91:9
13a
O
O
O
28
80
NO2
13b
O
NO2
2
3
14(9)
92:8
88
13c
O
Ph
Ph
NO2
3
83:17
84 (36)e
13d
O
Ph
16
O
2N
O
NO2
13e
O
O
O
Ph
NO2
4
5
94 (87)
95 (93)
95:5
82
79
13f
O
O
C6H4-p-OMe
NO2
81:19
13g
C6H4-p-Cl
NO2
6
7
>99 (93)
>99 (99)
77:23
95:5
82
87
13h
C6H4-o-Cl
NO2
O
O
13i
O
O
O
8f
13f
13f
13f
92 (85)
84 (78)
15(7)
95:5
95:5
95:5
87
89
92
9g
10h
a
b
c
Unless otherwise stated, all reactions were carried out at 20 °C for 24 h in DMSO in the presence of 20 mol % of 3.
Determined by 1H NMR analysis of the crude products. Yield was calculated by the mole of b-nitrostyrene as starting material.
Isolated yield in parenthesis.
d
e
f
Ee of the syn-diastereomer was determined by HPLC using a Daicel Chiralpak AD-H column or a Daicel Chiralpak AD-RH column.
Ee of the anti-diastereoisomer in parenthesis.
Reaction was carried out at 20 °C for 24 h in a mixture of DMSO and DMF (1:1).
Reaction was carried out at 0 °C for 6 d in a mixture of DMSO and DMF (1:1).
Reaction was carried out at ꢁ25 °C (21 h) to ꢁ10 °C (6 d) in a mixture of DMSO and DMF (1:1).
g
h

T. Widianti et al. / Tetrahedron: Asymmetry 21 (2010) 1861–1868
1865
tracted with CH2Cl2 (3 ꢂ 20 mL). The combined organic phases
were washed with brine (20 mL) and dried over anhydrous MgSO4.
The solvent was evaporated to afford 3.42 g of crude product con-
taining mesylate as a yellow oil. The mesylate was used in the next
step without purification; 1H NMR (500 MHz, CDCl3) d (ppm)
7.36ꢁ7.30 (m, 5H), 5.12 (s, 2H), 4.37ꢁ4.09 (m, 3H), 3.45ꢁ3.43
(m, 2H), 2.92 (s, 2H), 2.82 (s, 1H), 2.03ꢁ1.83 (m, 4H); EI-MS m/z
313 [M]+; FAB-HRMS calcd for C14H20NO5S [M+H]+, 314.1062;
found 314.1069.
4. Experimental
4.1. General
All chemicals were purchased from Wako Chemicals, Tokyo
Kasei, and Sigma–Aldrich in their highest purity. Flash column
chromatography was performed on 230–430 mesh silica gel. 1H
NMR (500 MHz and 600 MHz), 13C NMR (125 MHz and 150 MHz),
and 31P NMR (202 MHz and 242 MHz) spectra were recorded in
CDCl3, CD3OD, C6D6, and D2O with JEOL NM-ECP500, JEOL NM-
LA500, and JEOL NM-ECA600 spectrometers. Chemical shifts in
1H NMR, 13C NMR, and 31P NMR are given in parts per million
(ppm) relative to internal TMS or DSS (d 0.00 ppm), CDCl3 (d
7.24 ppm), CD3OD (d 3.31 ppm), C6D6 (d 7.16 ppm), and D2O (d
4.79 ppm) for 1H NMR, TMS or DSS (d 0.00 ppm), CDCl3 (d
77.0 ppm), CD3OD (d 49.0 ppm), and C6D6 (d 128.1 ppm) for 13C
NMR, and H3PO4 (d 0.00 ppm) for 31P NMR. HRMS were recorded
on JEOL SX-102A spectrometer. Optical rotations were measured
on a Horiba SEPA-300 polarimeter. Enantioselectivity (%ee) was
determined by HPLC analysis of the reaction mixture with a system
consisting of a Jasco 980-PU pump and a Jasco 970-UV detector.
To a stirred solution of the mesylate (3.20 g, 8.72 mmol) in
26 mL of dried acetone was added sodium iodide (3.73 g,
24.90 mmol). The reaction mixture was refluxed for 12 h under
an N2 atmosphere. The reaction mixture was filtered to remove
the precipitate and then concentrated. The resulting residue was
then extracted with Et2O (3 ꢂ 50 mL). The combined organic
phases were dried over anhydrous MgSO4 and the solvent was
evaporated. The resulting residue was flashed over a short pad of
neutral silica gel (hexane/EtOAc, 1:1) and then dried by azeotropic
evaporation with benzene to afford 2.98 g of crude product con-
taining (S)-benzyl 2-(iodomethyl)pyrrolidine-1-carboxylate 8 as a
dark orange oil. The iodide 8 was used in the next step without fur-
ther purification; 1H NMR (500 MHz, C6D6) d 7.27 (d, J = 7.3 Hz,
2H), 7.13 (t, J = 7.6 Hz, 2H), 7.06 (t, J = 7.0 Hz, 1H), 5.14ꢁ5.03 (m,
2H), 3.74ꢁ3.61 (m, 1H), 3.37ꢁ3.05 (m, 4H), 1.48ꢁ1.17 (m, 3H),
4.2. Preparation of catalysts 1–3
1.10ꢁ1.03 (m, 1H); FAB-HRMS calcd for
C
13H17INO2 [M+H]+
4.2.1.
To a stirred suspension of LiAlH4 (2.48 g, 65.3 mmol) in freshly
distilled THF (65 mL), -proline 4 (5.00 g, 43.5 mmol) was added un-
L-Prolinol 6
346.0304; found 346.0325.
The iodide 8 (514 mg, 1.49 mmol) was dissolved in 5 mL of
freshly distilled DMF under N2 atmosphere. Then NaH (60% disper-
sion in mineral oil, 358 mg, 8.96 mmol) was prewashed with hex-
ane three times and dissolved in 6 mL of freshly distilled DMF. To
the stirred suspension of NaH in dried DMF, dimethyl phosphite
(1.15 mL, 8.99 mmol) was added slowly under cooling in an ice-
water bath under an N2 atmosphere. The suspension was then
warmed slowly to room temperature and stirred for 45 min. To
the stirred suspension, the solution of iodide 8 in dried DMF was
added dropwise at room temperature. The reaction mixture was
then heated at 55 °C and the stirring was continued for 5 days at
the same temperature. Saturated aqueous NH4Cl (5 mL) was added
to quench the reaction. The solvents were evaporated and the res-
idue was extracted with EtOAc (4 ꢂ 30 mL). The organic phase
was dried over anhydrous MgSO4 and concentrated. The residue
was purified by column chromatography (hexane/EtOAc, 3/1?1/
1) on silica gel to afford aminophosphonate 9 (403 mg, 76%, three
L
der cooling in an ice-water bath. The reaction mixture was refluxed
for 2 h under N2 atmosphere. After cooling to room temperature,
the reaction was quenched by adding 6.0 mL of 20% KOH solution.
The reaction mixture was filtered off to separate THF phase and res-
idue. The residue was refluxed with a new portion of 50 mL of THF
for 45 min, and then the reaction mixture was filtered. The com-
bined THF phase was dried over anhydrous MgSO4 and evaporated
to afford 4.72 g (quant.) of L
-prolinol 6 as a yellow oil; 1H NMR
(CDCl3) d 3.50 (m, 1H), 3.29 (m, 2H), 2.92 (m, 1H), 2.85 (m, 1H),
1.85–1.65 (m, 3H), 1.41 (m, 1H). The hydroxy proton and amino
proton were not observed because of broadening of the signal.
4.2.2. N-Cbz-L-prolinol 7
To a stirred solution of
L
-prolinol 6 (0.98 g, 9.65 mmol) and tri-
ethylamine (1.75 mL, 12.5 mmol) in 18 mL of dried CH2Cl2, benzyl
chloroformate (1.65 mL, 11.6 mmol) was added slowly under cool-
ing in an ice-water bath. The stirring was continued for 18 h at the
same temperature under N2 atmosphere. Water (5 mL) was added
to quench the reaction. The organic phase and aqueous phase were
separated and the aqueous phase was extracted with CH2Cl2
(3 ꢂ 20 mL). The combined organic phases were washed with brine
(20 mL) and dried over anhydrous MgSO4. The solvent was evapo-
rated and the resulting residue was purified by column chromatog-
raphy (hexane/EtOAc, 1:3) on silica gel to give 1.42 g (63%) of
steps) as a pale yellow liquid; ½a D25
ꢃ
¼ ꢁ27:6 (c 3.01, MeOH), 1H
NMR (500 MHz, CDCl3) d 7.36ꢁ7.30 (m, 5H), 5.17ꢁ5.12 (m, 2H),
4.14ꢁ3.95 (m, 5H), 3.43ꢁ3.40 (m, 2H), 2.64ꢁ2.27 (m, 1H),
2.11ꢁ2.07 (m, 2H), 1.88ꢁ1.75 (m, 3H), 1.35ꢁ1.22 (m, 6H); 13C
NMR (125 MHz, CDCl3) d 154.7, 154.6*, 136.9, 136.7*, 128.6 (ꢂ2),
128.3 (ꢂ2), 128.2*, 128.1, 128.0 (ꢂ2), 127.9* (ꢂ2), 67.2, 66.7*,
2
61.8 (d, JCP = 5.7 Hz) (ꢂ2), 61.7* (d, 2JCP = 5.7 Hz) (ꢂ2), 53.5, 52.8*,
1
46.7, 46.4*, 31.5, 30.9 (d, JCP = 134.3 Hz), 30.8*, 29.7 (d,
1JCP = 134.3 Hz), 23.8, 23.0*, 16.5 (d, JCP = 5.0 Hz) (ꢂ2) (* is the
3
N-Cbz-L
-prolinol 6 as a pale yellow oil; 1H NMR (500 MHz, CDCl3)
chemical shift of a rotamer); 31P NMR (202 MHz, CDCl3) d 27.9 (ma-
jor), 27.5 (minor); The rotamer ratio (1.2:1.0) was determined by
31P NMR; FAB-HRMS calcd for C17H27NO5P [M+H]+ 356.1627; found
356.1627.
d 7.40ꢁ7.30 (m, 5H), 5.16 (d, J = 12.7 Hz, 1H), 5.14 (d, J = 12.7 Hz,
1H), 4.34 (m, 1H), 4.01 (m, 1H), 3.71ꢁ3.53 (m, 3H), 3.42ꢁ3.37
(m, 1H), 2.07ꢁ2.00 (m, 1H), 1.90ꢁ1.77 (m, 2H), 1.65ꢁ1.58 (m, 1H).
4.2.3. (S)-Benzyl 2-((diethoxyphosphoryl)methyl)pyrrolidine-1-
carboxylate 9
4.2.4. Aminophosphonic acid 1
An aqueous solution of aminophosphonate
9
(1.70 g,
To a stirred solution of N-Cbz-L-prolinol 6 (2.20 g, 9.34 mmol)
4.79 mmol) in 20 mL of 6 M HCl was refluxed for 29 h. The reaction
mixture was then concentrated in vacuo to afford 965 mg (>99%) of
HCl salt of aminophosphonic acid as a pale yellow liquid. The HCl
salt of the acid was used in the next step without purification.
To a stirred solution of the HCl salt of acid (965 mg, 4.79 mmol)
in 4.2 mL of EtOH, an excess of propylene oxide (8.4 mL) was added
dropwise at room temperature. The reaction mixture was then
and triethylamine (2.30 mL, 16.5 mmol) in dried CH2Cl2 (28 mL),
methanesulfonyl chloride (1.15 mL, 14.86 mmol) was added drop-
wise under cooling in an ice-water bath. The stirring was contin-
ued for 3 h at room temperature under N2 atmosphere. Water
(7 mL) was added to quench the reaction. The organic phase and
aqueous phase were separated, and the aqueous phase was ex-

1866
T. Widianti et al. / Tetrahedron: Asymmetry 21 (2010) 1861–1868
heated at 35 °C. The stirring was continued for 10 h at the same
temperature. The volatiles were evaporated to give a yellow oily
residue, which was then crystallized from MeOH-Et2O to afford
aminophosphonic acid 1 (598 mg, 76%) as a colorless solid; mp
NMR (500 MHz, D2O) d 3.97ꢁ3.92 (m, 2H), 3.78ꢁ3.73 (m, 1H),
3.36ꢁ3.32 (m, 2H), 2.35ꢁ2.30 (m, 1H), 2.15ꢁ1.99 (m, 4H),
1.83ꢁ1.75 (m, 1H), 1.27 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
2
3
D2O) d 63.6 (d, JCP = 5.8 Hz), 59.7, 47.7, 33.6 (d, JCP = 7.7 Hz),
230 °C (decomposes);
½
a 2D5
ꢃ
¼ þ9:30 (c 1.00, H2O), 1H NMR
31.8 (d, JCP = 133.4 Hz), 25.8, 18.8 (d, JCP = 5.8 Hz); 31P NMR
(202 MHz, D2O) d 20.3; FAB-HRMS calcd for C7H17NO3P [M+H]+
194.0946; found 194.0950; Anal. Calcd for C7H16NO3P: C, 43.52;
H, 8.35; N, 7.25; found C, 43.40; H, 8.54; N, 6.97.
1
3
(500 MHz, D2O)
d
3.82ꢁ3.76 (m, 1H), 3.37ꢁ3.32 (m, 2H),
2.36ꢁ2.31 (m, 1H), 2.15ꢁ1.98 (m, 4H), 1.84ꢁ1.76 (m, 1H); 13C
2
NMR (125 MHz, D2O) 59.8 (d, JCP = 1.7 Hz), 47.6, 33.6 (d,
3JCP = 6.9 Hz), 33.3 (d, JCP = 130.9 Hz), 25.7; 31P NMR (202 MHz,
1
D2O) d 18.0; FAB-HRMS calcd for C5H13NO3P [M+H]+ 166.0633;
found 166.0647; Anal. Calcd for C5H12NO3P: C, 36.37; H, 7.32; N,
8.48; found C, 36.40; H, 7.32; N, 8.39.
4.3. General procedure for the Michael addition reactions
between ketones and trans-b-nitrostyrene
Procedure A: To a solution of the chosen catalyst (0.04 mmol) in
DMSO (1.60 mL) was added ketone (0.40 mL, 20 vol %). The mix-
ture was stirred at room temperature. After 15 min of stirring,
trans-b-nitrostyrene (29.8 mg, 0.20 mmol) was added to the mix-
ture. The reaction mixture was then stirred at the chosen temper-
ature for 24 h. The reaction was quenched with saturated aqueous
NH4Cl solution (1 mL) and extracted with EtOAc (5 ꢂ 2 mL). The
organic extracts were combined, dried over MgSO4, and concen-
trated. The residue was purified by flash column chromatography
on silica gel (hexane/EtOAc, 1:1) to afford the corresponding
product.
Procedure B: To a solution of the catalyst 3 (7.64 mg, 0.04 mmol)
in DMSO (2 mL) was added cyclohexanone (0.10 mL, 0.97 mmol).
The mixture was stirred at room temperature for 15 min. trans-
b-Nitrostyrene (29.85 mg, 0.20 mmol) was then added to the
mixture. The stirring was continued for 24 h at the chosen temper-
ature. Saturated NH4Cl (1 mL) was added to quench the reaction.
The reaction mixture was extracted with EtOAc (5 ꢂ 2 mL). The
combined organic portions were dried over anhydrous MgSO4
and concentrated. The residue was purified by flash column
chromatography on silica gel (hexane/EtOAc, 1:1) to afford the
corresponding product.
4.2.5. Diethyl aminophosphonate 2
To a solution of aminophosphonate 9 (191 mg, 0.54 mmol) in
5 mL of ethanol was added Pd(OAc)2 (20.3 mg). The mixture was
stirred at room temperature under H2 atmosphere (1 atm) for
4 days. The reaction mixture was filtered through Celite and con-
centrated. The resulting residue was dissolved in water and washed
with EtOAc (3 ꢂ 5 mL). The aqueous phase was concentrated to give
diethyl aminophosphonate 2 (120 mg, >99%) as a yellow oil;
½
a 2D5
ꢃ
¼ þ16:7 (c 0.54, MeOH), 1H NMR (500 MHz, D2O)
d
4.19ꢁ4.16 (m, 4H), 3.50ꢁ3.48 (m, 1H), 3.11ꢁ3.01 (m, 2H),
2.28ꢁ2.17 (m, 3H). 1.92ꢁ1.88 (m, 2H), 1.60ꢁ1.55 (m, 1H),
1.36ꢁ1.33 (m, 6H); 13C NMR (125 MHz, D2O) d 66.4 (d, 2JCP = 5.5 Hz)
2
3
(ꢂ2), 56.5 (d, JCP = 2.4 Hz), 48.0, 34.5 (d, JCP = 9.1 Hz), 31.7 (d,
1JCP = 139.2 Hz), 26.4, 18.4 (d, JCP = 5.7 Hz) (ꢂ2); 31P NMR
3
(202 MHz, D2O) d 30.7; FAB-HRMS calcd for C9H21NO3P [M+H]+
222.1259; found 222.1265.
4.2.6. Aminophosphonic acid monoester 3
To
a stirred solution of aminophosphonate 9 (648 mg,
1.82 mmol) in freshly distilled MeCN (1.00 mL), a solution of LiBr
(227 mg, 2.61 mmol) in dried MeCN (2.00 mL) was slowly added
at room temperature. The reaction mixture was refluxed under
N2 atmosphere for 15 h. The reaction mixture was then cooled to
room temperature and concentrated. The resulting residue was
dissolved in water (5 mL) and washed with EtOAc (3 ꢂ 2 mL).
The aqueous phase was then concentrated to 3 mL and 2 M HCl
aqueous solution (1.3 mL) was added. The stirring was continued
for 30 min at room temperature. The aqueous mixture was then
extracted with EtOAc (3 ꢂ 5 mL). The organic extracts were com-
bined, dried over anhydrous MgSO4, and concentrated to afford
N-Cbz-phosphonic acid monoethyl ester 10 (523 mg, 88%) as a col-
orless liquid. The monoethyl ester 10 was used in the next step
Relative and absolute configurations of the products in Tables
1–3 were determined by comparison with the reported NMR and
HPLC data and enantiomeric excess of the product was determined
by HPLC on chiral stationary phase of Chiralpak AD-H, Chiralpak IC,
or Chiralpak AD-RH columns (Daicel Co. Ltd., 4.6 ꢂ 250 mm). Dia-
stereomeric ratio was determined by 1H NMR analysis of the crude
products. For comparison and in all cases, pure racemic and chiral
Michael adducts were prepared by using
as catalysts, respectively.
D,L-proline, and L-proline
4.3.1. (R)-5-Nitro-4-phenylpentan-2-one 112a,24
without purification;
½
a 2D5
ꢃ
¼ ꢁ18:1 (c 0.96, MeOH), 1H NMR
Prepared according to procedure A. ½a D25
¼ ꢁ6:8 (c 0.50, CHCl3),
ꢃ
(500 MHz, CD3OD) d 7.41ꢁ7.31 (m, 5H), 5.19ꢁ5.11 (m, 2H),
4.13ꢁ4.05 (m, 2H), 3.93 (m, 1H), 3.44–3.40 (m, 2H), 2.50ꢁ2.22
(m, 1H), 2.08ꢁ1.81 (m, 5H), 1.32 and 1.22* (t, J = 7.0 Hz, 3H); 13C
NMR (125 MHz, CD3OD) d 156.4, 138.2, 138.0*, 129.6, 129.5*,
1H NMR (500 MHz, CDCl3) d 7.35ꢁ7.21 (m, 5H), 4.69 (dd, J = 12.3,
6.9 Hz, 1H), 4.60 (dd, J = 12.3, 7.6 Hz, 1H), 4.04ꢁ3.98 (m, 1H),
2.91 (d, J = 7.0 Hz, 2H), 2.12 (s, 3H); EI-HRMS calcd for C11H13NO3
[M]+ 207.0895; found 207.0902. Ee = 36%, the ee value was deter-
mined by HPLC analysis using Chiralpak AD-H column (hexane/i-
PrOH = 10:1, kmax 254 nm, flow rate = 1.0 mL/min), tR = 10.6 min
(minor) and 11.5 min (major).
2
129.2, 129.1*, 128.8, 68.2, 67.9*, 62.4 (d, JCP = 5.0 Hz), 62.3* (d,
2JCP = 5.0 Hz), 55.0, 54.4*, 47.6, 47.3*, 32.3, 31.7*, 31.9 (d,
1
1JCP = 133.2 Hz), 31.0* (d, JCP = 133.2 Hz), 24.5, 23.7*, 16.8 (d,
3JCP = 6.0 Hz) (* is the chemical shift of a rotamer); 31P NMR
(202 MHz, D2O) d 23.3 (minor), 23.0 (major); The rotamer ratio
(1.0:1.7) was determined by 31P NMR; FAB-HRMS calcd for
4.3.2. 1,7-Dinitro-2,6-diphenylheptan-4-one 1225
Prepared according to procedure A. 1H NMR (500 MHz, CDCl3) d
(ppm) 7.33ꢁ7.24 (m, 6H), 7.15ꢁ7.11 (m, 4H), 4.55 (dd, J = 12.4, 7.4,
Hz, 2H), 4.48 (dd, J = 12.4, 7.4 Hz, 2H), 3.98ꢁ3.92 (m, 2H),
2.91ꢁ2.85 (m, 2H), 2.82ꢁ2.74 (m, 2H).
C
15H23NO5P [M+H]+ 328.1314; found 328.1318.
To a stirred solution of N-Cbz-phosphonic acid monoethyl ester
10 (494 mg, 1.51 mmol) in ethanol (15 mL) was added Pd(OAc)2
(100 mg). The mixture was stirred under an H2 atmosphere
(1 atm) at room temperature for 4 days. The catalyst was filtered
through Celite, and the solvent was removed to give a residue.
The resulting residue was dissolved in water (10 mL) and washed
with EtOAc (3 ꢂ 5 mL). The aqueous phase was concentrated to af-
ford 291 mg (>99%, two steps from 9) of aminophosphonic acid
4.3.3. (3R,4S)-3-Methyl-5-nitro-4-phenylpentan-2-one 13a2a,26
Prepared according to procedure A. ½a D25
¼ ꢁ2:1 (c 0.48, CHCl3),
ꢃ
1H NMR (500 MHz, CDCl3) d 7.35ꢁ7.26 (m, 3H), 7.20ꢁ7.15 (m, 2H),
4.72ꢁ4.61 (m, 2 H), 3.81ꢁ3.76 (m, 1H, anti), 3.67 (dt, J = 9.3, 5.1 Hz,
1H, syn), 3.01ꢁ2.95 (m, 1 H), 2.23 (s, 3H, syn), 1.95 (s, 3H, anti), 1.21
(d, J = 7.1 Hz, 3H, anti), 0.98 (d, J = 7.2 Hz, 3H, syn). Syn:anti = 91:9.
monoester 3 as a yellow oil; ½a D25
ꢃ
¼ þ13:4 (c 2.32, MeOH), 1H

T. Widianti et al. / Tetrahedron: Asymmetry 21 (2010) 1861–1868
1867
Ee = 54% (syn), the ee value was determined by HPLC analysis using
a Diacel Chiralpak AD-RH column (H2O (0.1% TFA)/MeCN = 72:28,
kmax 254 nm, flow rate = 0.5 mL/min), syn-diastereomer: tR = 33.7
min (minor) and 35.5 min (major).
rate = 1.0 mL/min), syn-diastereomer: tR = 10.8 min (minor) and
13.5 min (major).
4.3.9. (S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)
cyclohexanone 13g25,28
4.3.4. (R)-6-Nitro-5-phenylhexan-3-one 13b2a,26
Prepared according to procedure B. ½a D25
¼ ꢁ18:2 (c 1.53, CHCl3),
ꢃ
Prepared according to procedure A. ½a D25
ꢃ
¼ þ2:8 (c 0.46, CHCl3),
1H NMR (500 MHz, CDCl3) d 7.07 (d, J = 8.8 Hz, 2H), 6.84 (d,
J = 8.8 Hz, 2H), 4.90 (dd, J = 12.2, 4.6 Hz, 1H), 4.58 (dd, J = 12.2,
10.0, 1H), 3.78 (s, 3H), 3.71 (dt, J = 10.0, 4.6 Hz, 1H), 2.67ꢁ2.62
(m, 1H), 2.49ꢁ2.44 (m, 1 H), 2.41ꢁ2.34 (m, 1H), 2.08ꢁ2.04 (m,
1H), 1.81ꢁ1.54 (m, 4H), 1.26ꢁ1.19 (m, 1H). Syn:anti = 81:19.
Ee = 79% (syn), the ee value was determined by HPLC analysis using
a Diacel Chiralpak AD-H column (hexane/i-PrOH/MeCN = 290:10:4,
kmax 254 nm, flow rate = 0.5 mL/min), syn-diastereomer: tR =
46.7 min (major) and 90.0 min (minor).
1H NMR (500 MHz, CDCl3) d 7.34ꢁ7.21 (m, 5H), 4.70 (dd, J = 12.4,
6.9 Hz, 1H), 4.61 (dd, J = 12.4, 7.7 Hz, 1H), 4.05ꢁ3.99 (m, 1 H),
2.88 (d, J = 7.1 Hz, 2H), 2.44ꢁ2.30 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H).
Ee = 80%, the ee value was determined by HPLC analysis
using a Diacel Chiralpak AD-H column (hexane/i-PrOH = 100:1,
kmax 254 nm, flow rate = 0.5 mL/min), tR = 105.1 min (minor) and
115.5 min (major).
4.3.5. (4S,5R)-4-Methyl-6-nitro-5-phenyl-hexan-3-one 13c13b
Prepared according to procedure A. ½a D25
ꢃ
¼ þ8:6 (c 0.14, CHCl3),
4.3.10. (S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)
1H NMR (500 MHz, CDCl3) d 7.33ꢁ7.25 (m, 3H), 7.15ꢁ7.14 (m, 2H),
4.65 (dd, J = 12.4, 9.1 Hz, 1H), 4.58 (dd, J = 12.4, 4.8 Hz, 1H),
3.73ꢁ3.68 (m, 1H), 3.01ꢁ2.94 (m, 1H), 2.63–2.54 (m, 1H),
2.43ꢁ2.35 (m, 1H), 1.05 (t, J = 7.3 Hz, 3H), 0.95 (d, J = 7.1 Hz, 3H).
Syn:anti = 92:8. Ee = 88% (syn), the ee value was determined by
HPLC analysis using a Diacel Chiralpak AD-H column (hexane/i-
PrOH = 20:1, kmax 254 nm, flow rate = 1.0 mL/min), syn-diastereo-
mer: tR = 8.9 min (minor) and 10.3 min (major).
cyclohexanone 13h29
Prepared according to procedure B. ½a D25
¼ ꢁ23:7 (c 1.00, CHCl3),
ꢃ
1H NMR (500 MHz, CDCl3) d 7.28 (d, J = 8.4 Hz, 2H), 7.10 (d,
J = 8.4 Hz, 2H), 4.91 (dd, J = 12.6, 4.6 Hz, 1H), 4.59 (dd, J = 12.6,
9.9 Hz, 1H), 3.74 (dt, J = 9.9, 4.6 Hz, 1H), 2.66ꢁ2.60 (m, 1H),
2.48ꢁ2.43 (m, 1H), 2.39ꢁ2.32 (m, 1H), 2.10ꢁ2.03 (m, 1 H),
1.81ꢁ1.51 (m, 4H), 1.25ꢁ1.17 (m 1 H). Syn:anti = 77:23. Ee = 82%
(syn), the ee value was determined by HPLC analysis using a Diacel
Chiralpak AD-H column (hexane/i-PrOH = 10:1, kmax 254 nm, flow
rate = 0.5 mL/min), syn-diastereomer: tR = 28.1 min (minor) and
40.3 min (major).
4.3.6. (S)-2-[(R)-2-Nitro-1-phenylethyl]cyclopentanone 13d4,27
Prepared according to procedure A. 1H NMR (500 MHz, CDCl3) d
7.31ꢁ7.23 (m, 3H), 7,18ꢁ7.13 (m, 2H), 5.33 (dd, J = 12.8, 7.5 Hz, 1H,
syn), 5.01 (d, J = 7.7 Hz, 2H, anti), 4.71 (dd, J = 12.8, 9.8 Hz, 1H, syn),
3.83 (dt, J = 7.7, 4.4 Hz, 1H, anti), 3.69 (dt, J = 9.4, 5.7 Hz, 1H, syn),
2.54ꢁ1.44 (m, 7H). Syn/anti = 83:17. Ee = 84% (syn) and 36% (anti),
the ee values were determined by chiral HPLC analysis using a Dia-
cel Chiralpak AD-H column (hexane/i-PrOH = 95:5, kmax 254 nm,
flow rate = 0.5 mL/min), anti-diastereomer: tR = 24.0 min (major)
and 27.8 min (minor), syn-diastereomer: tR = 31.1 min (minor) an-
d = 43.2 min (major). The relative and absolute configuration of
13d has been assigned by assumption of an identical reaction using
proline as catalyst, and comparison of reported NMR and HPLC
data.4,27b
4.3.11. (S)-2-((R)-1-(2-Chlorophenyl)-2-nitroethyl)
cyclohexanone 13i29
Prepared according to procedure B. ½a D25
¼ ꢁ43:7 (c 0.96, CHCl3),
ꢃ
1H NMR (500 MHz, CDCl3) d 7.36 (d, J = 7.7 Hz, 1H), 7.22ꢁ7.17 (m,
3H), 4.92ꢁ4.84 (m, 2H), 4.30ꢁ4.24 (m, 1H), 2.93ꢁ2.87 (m, 1 H),
2.49ꢁ2.43 (m, 1 H), 2.40ꢁ2.33 (m, 1H), 2.11ꢁ2.05 (m, 1H),
1.82ꢁ1.54 (m, 4H), 1.36ꢁ1.27 (m, 1H). Syn:anti = 95:5. Ee = 87%,
the ee value was determined by HPLC analysis using a Diacel Chir-
alpak AD-H column (hexane/i-PrOH = 95:5, kmax 254 nm, flow
rate = 0.5 mL/min), syn-diastereomer: tR = 26.4 min (minor) and
36.4 min (major).
4.3.7. 2,5-Bis-(2-nitro-1-phenylethyl)cyclopentanone 13e
Acknowledgments
The double Michael adduct 13e was isolated as a mixture of two
diastereomers (major:minor = 70:30); 1H NMR (500 MHz, CDCl3) d
7.34ꢁ7.08 (m, 10H), 5.26ꢁ5.22 (m, 2H, major), 5.03ꢁ4.96 (m, 4H,
minor), 4.70ꢁ4.66 (m, 2H, major), 3.80ꢁ3.68 (m, 2H), 2.49ꢁ2.32
(m, 2H), 2.14ꢁ2.00 (m, 1H), 1.78ꢁ1.71 (m, 1H), 1.55ꢁ1.48 (m,
1H), 1.40ꢁ1.34 (m, 1H); 13C NMR (125 MHz, CDCl3) d 217.3,
216.8*, 137.1 (ꢂ2), 137.0 (ꢂ2)*, 129.1 (ꢂ2)*, 129.0 (ꢂ4), 128.9
(ꢂ2)*, 128.4 (ꢂ2), 128.2 (ꢂ2)*, 128.1 (ꢂ2), 128.0 (ꢂ2)*, 128.0
(ꢂ2), 127.9 (ꢂ2)*, 77.9 (ꢂ2), 77.7 (ꢂ2)*, 52.2, 51.7, 51.3 (ꢂ2)*,
44.3 (ꢂ2)*, 44.1, 43.9, 25.7, 25.4 (ꢂ2)*, 24.2 (* is the chemical shift
We are indebted to the Natural Science Center for Basic Re-
search and Development (N-BARD), Hiroshima University, for mea-
surements of NMR and MS, and elemental analysis, and Hiroshima
Prefectural Institute of Industrial Science and Technology for NMR.
This work was supported by a Grant-in-Aid for Scientific Research
(No. 19350021, 20036038, 19020034, 20611012) from the Minis-
try of Education, Culture, Sports, Science, and Technology, Japan.
of minor isomer); FAB-HRMS calcd for C21H21N2O5 [MꢁH]ꢁ
=
References
381.1450; found 381.1454.
1. For selected reviews on organocatalysts see: (a) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2001, 40, 3726–3748; (b) Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 2–25; (c) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis,
from Biomimetic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH:
Weinheim, 2005; (d) Dalko, P. I. Enantioselective Organocatalysis, Reactions and
Experimental Procedures; Wiley-VCH: Weinheim, 2007.
2. For selected examples, see: (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem.
Soc. 2000, 122, 2395–2396; (b) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001,
3, 2423–2425; (c) List, B. Tetrahedron 2002, 58, 5573–5590; (d) Cordova, A.;
Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III J. Am. Chem. Soc. 2002, 124,
1866–1867; (e) Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J.
T.; Thayumanavan, R.; Barbas, C. F., III J. Org. Chem. 2003, 68, 9624–9634; (f)
Cordova, A.; Barbas, C. F., III Tetrahedron Lett. 2003, 44, 1923–1926; (g) Kotsuki,
H.; Ikishima, H.; Okuyama, A. Heterocycles 2008, 75, 493–529; (h) Kotsuki, H.;
Ikishima, H.; Okuyama, A. Heterocycles 2008, 75, 757–797.
4.3.8. (S)-2-((R)-2-Nitro-1-phenylethyl)cyclohexanone 13f25,28
Prepared according to procedure B. ½a D25
¼ ꢁ14:9 (c 0.18, CHCl3),
ꢃ
1H NMR (500 MHz, CDCl3) d 7.33ꢁ7.25 (m, 3H), 7.16ꢁ7.12 (m, 2H),
4.93 (dd, J = 12.6, 4.6 Hz, 1H), 4.61 (dd, J = 12.6, 9.9 Hz, 1H), 3.74
(dt, J = 9.9, 4.6 Hz, 1H), 2.72ꢁ2.66 (m, 1H), 2.50ꢁ2.46 (m, 1H),
2.42ꢁ2.35 (m, 1H), 2.11ꢁ2.04 (m, 1H), 1.81ꢁ1.52 (m, 4H),
1.28ꢁ1.20 (m, 1H); EI-HRMS calcd for C14H17NO3 [M]+ 247.1208;
found 247.1196. Syn:anti = 95:5. Ee = 92% (syn), the ee
value was determined by HPLC analysis using a Diacel Chiralpak
AD-H column (hexane/i-PrOH = 10:1, kmax 254 nm, flow

1868
T. Widianti et al. / Tetrahedron: Asymmetry 21 (2010) 1861–1868
3. (a) Alexakis, A.; Tomassini, A.; Chouillet, C.; Roland, S.; Mangeney, P.;
Bernardinelli, G. Angew. Chem., Int. Ed. 2000, 39, 4093–4095; (b) Alexakis, A.;
Andrey, O. Org. Lett. 2002, 4, 3611–3614.
4. Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F., III Tetrahedron
Lett. 2001, 42, 4441–4444.
16. Kukhar, V. P.; Hudson, H. R. Aminophosphonic and Aminophosphinic Acids,
Chemistry and Biological Activity; John Wiley: Chichester, 2000.
17. (a) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 63, 193–
215; (b) Ordóñez, M.; Rojas-Cabrera, H.; Cativiela, C. Tetrahedron 2009, 65, 17–
49.
5. Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J. Am. Chem. Soc. 2004, 126, 9558–
9559.
18. (a) Dinér, P.; Amedjkouh, M. Org. Biomol. Chem. 2006, 4, 2091–2096; (b)
Tao, Q.; Tang, G.; Lin, K.; Zhao, Y.-F. Chirality 2008, 20, 833–838; (c)
Malmgren, M.; Granander, J.; Amedjkouh, M. Tetrahedron: Asymmetry
2008, 19, 1934–1940.
19. (a) Liu, X.-W.; Le, T. N.; Lu, Y.; Xiao, Y.; Ma, J.; Li, X. Org. Biomol. Chem. 2008, 6,
3997–4003; (b) Tan, B.; Zeng, X.; Lu, Y.; Chua, P. J.; Zhong, G. Org. Lett. 2009, 11,
1927–1930.
20. Wallén, E. A. A.; Christiaans, J. A. M.; Saario, S. M.; Forsberg, M. M.; Venäläinen,
J. I.; Paso, H. M.; Männistö, P. T.; Gynther, J. Bioorg. Med. Chem. 2002, 10, 2199–
2206.
6. (a) Chandrasekhar, S.; Tiwari, B.; Parida, B. B.; Raji Reddy, Ch. Tetrahedron:
Asymmetry 2008, 19, 495–499; (b) Zhao, Y.-B.; Zhang, L.-W.; Wu, L.-Y.; Zhong, X.;
Li, R.; Ma, J.-T. Tetrahedron: Asymmetry 2008, 19, 1352–1355; (c) Karthikeyan, T.;
Sankararaman, S. Tetrahedron: Asymmetry 2008, 19, 2741–2745.
7. (a) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558–560; (b) Cobb, A. J. A.;
Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2004, 1808–1809; (c)
Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol.
Chem. 2005, 3, 84–96.
8. (a) Puleo, G. L.; Iuliano, A. Tetrahedron: Asymmetry 2008, 19, 2045–2050; (b)
Cheng, Y.-Q.; Bian, Z.; He, Y.-B.; Han, F.-S.; Kang, C.-Q.; Ning, Z.-L.; Gao, L.-X.
Tetrahedron: Asymmetry 2009, 20, 1753–1758.
21. Anderson, G. T.; Alexander, M. D.; Taylor, S. D.; Smithrud, D. B.; Benkovic, S. J.;
Weinreb, S. M. J. Org. Chem. 1996, 61, 125–132.
22. Rabasso, N.; Louaisil, N.; Fadel, A. Tetrahedron 2006, 62, 7445–7454.
23. Rensing, S.; Arendt, M.; Spinger, A.; Grawe, T.; Schrader, T. J. Org. Chem. 2001,
66, 5814–5821.
24. Schionato, A.; Paganelli, S.; Botteghi, C.; Chelucci, G. J. Mol. Catal. 1989, 50, 11–
18.
25. Alza, E.; Cambeiro, X. C.; Jimero, C.; Pericas, M. A. Org. Lett. 2007, 9,
3717–3720.
26. Andrey, O.; Alexakis, A.; Tomassini, A.; Bernardinelli, G. Adv. Synth. Catal. 2004,
346, 1147–1168.
27. (a) Seebach, D.; Lyapkalo, I. M.; Dahinden, R. Helv. Chim. Acta 1999, 82, 1829–
1842; (b) Kotrusz, P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. Org. J. Chem. 2004,
1577–1583.
28. Pansare, S. V.; Pandya, K. J. J. Am. Chem. Soc. 2006, 128, 9624–9625.
29. Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J.-P. Angew. Chem., Int. Ed. 2006,
45, 3093–3097.
9. (a) Li, Y.; Liu, X.-Y.; Zhao, G. Tetrahedron: Asymmetry 2006, 17, 2034–2039; (b)
Lv, G.; Jin, R.; Mai, W.; Gao, L. Tetrahedron: Asymmetry 2008, 19, 2568–2572.
10. (a) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624–9625; (b) Chen,
H.; Wang, Y.; Wei, S.; Sun, J. Tetrahedron: Asymmetry 2007, 18, 1308–1312.
11. Terakado, D.; Takano, M.; Oriyama, T. Chem. Lett. 2005, 34, 962–963.
12. (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44,
4212–4215; (b) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307–5309.
13. (a) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369–1371; (b)
Wang, J.; Li, H.; Lou, B.; Zu, L.; Gao, H.; Wang, W. Chem. Eur. J. 2006, 12, 4321–
4332.
14. Demir, A. S.; Eymur, S. Tetrahedron: Asymmetry 2010, 21, 112–115.
15. (a) Benaglia, M.; Cinquini, M.; Cozzi, F.; Puglisi, A.; Celentano, G. J. Mol. Catal. A
2003, 204/205, 157–163; (b) Gu, L.; Wu, Y.; Zhang, Y.; Zhao, G. J. Mol. Catal. A
2007, 263, 186–194.