A general organic catalyst for asymmetric addition of stabilized nucleophiles to acyl imines

Article abstract of DOI:10.1016/j.tet.2006.07.071

Cinchona alkaloid-derived thiourea catalysts promote nucleophilic additions to acyl imines for the asymmetric synthesis of secondary amine adducts. The hydroquinine-derived thiourea catalyst efficiently promotes the aza-Henry reaction of nitroalkane with

Full text of DOI:10.1016/j.tet.2006.07.071

Tetrahedron 62 (2006) 11499–11505
A general organic catalyst for asymmetric addition of stabilized
nucleophiles to acyl imines
*
Christiane M. Bode, Amal Ting and Scott E. Schaus
Department of Chemistry and Center for Chemical Methodology and Library Development, Life Science and Engineering Building,
Boston University, 24 Cummington Street, Boston, MA 02215, USA
Received 13 June 2006; revised 20 July 2006; accepted 24 July 2006
Available online 21 August 2006
Abstract—Cinchona alkaloid-derived thiourea catalysts promote nucleophilic additions to acyl imines for the asymmetric synthesis of
secondary amine adducts. The hydroquinine-derived thiourea catalyst efficiently promotes the aza-Henry reaction of nitroalkane with acyl
imines, affording b-nitroamines in good yields with enantioselectivities of 90–98% ee and diastereoselectivities up to 97%. The scope of
the reaction also includes dimethyl malonate as a nucleophile to access b-amino esters in high enantiopurity. Under the optimized reaction
conditions, secondary amine adducts of high enantiopurity are generated based on various aromatic and a,b-unsaturated acyl imines.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
using L-proline to synthesize Mannich products in high
enantio-andchemoselectivities. Barbasetal.laterextended
1
0
1
1
Organocatalysis is an expanding area of research in asym-
metric organic synthesis. Catalysts of organic origin are an
appealing option versus the metal catalysts often used to
achieve high enantio- and diastereoselectivities. Urea and
thiourea catalysts, first noted for their catalytic utility in
this work to include other amino acid derivatives. Our
laboratory developed the asymmetric Mannich reaction of
b-keto esters to acyl imines using cinchona alkaloids, pro-
ducing enantioenriched dihydropyrimidones and a-amino
1
1
2
alcohols. Recently, Deng et al. used a chiral cinchona
alkaloid-derived thioureas to promote the reaction of acyl
imines with different malonate nucleophiles.
1
988 and widely used since, have been shown to be capable
2
13
hydrogen bond donors, enabling selectivity in reactions.
Their stabilization of reaction components has allowed for
the development of many asymmetric urea and thiourea
catalyzed transformations, including the Strecker and
nitro-Michael reactions, the Morita–Baylis–Hillman reac-
tion, and conjugate addition reactions, to name a few.
The asymmetric nitro-Mannich reaction using organocata-
lysts has recently received much attention. Takemoto first
3
14
4
used a chiral thiourea with an N,N-dimethylamino group to
enantioselectively catalyze the addition of nitromethane to
various N-phosphinoylimines, further expanding the reac-
5
6
Two important and useful organic reactions that have been
tion scope by enantioselectively adding various nitro-
alkanes.
7
8
14,16
highly studied are the Mannich and nitro-Mannich (aza-
Henry) additions of carbon nucleophiles to electrophilic
imines. Utilizing dicarbonyls and nitroalkanes as nucleo-
philes, respectively, these reactions allow for the formation
of secondary amine adducts, which can be easily converted
to a variety of synthetically useful products such as a- and
Jørgensen used a chiral copper(II) bisoxazoline
complex, combined with cinchona alkaloids, to catalyze the
reaction of p-methoxyphenylimino ethyl esters with tertiary
nitroalkanes to form products in high enantioselectivities
1
5
(Fig. 1). Using chiral thiourea catalysts in the presence
of an external base, Jacobsen and Yoon developed another
variation of the nitro-Mannich reaction. Ricci et al. utilized
9
16
b-amino acids, 1,2-diamines, and cyclic amines.
a phase-transfer catalyst to promote the nitro-Mannich reac-
tion of N-carbamoyl imines generated from in situ a-amido
Several systems have been designed to asymmetrically
catalyze each separate reaction, with a recent surge in the
development of organocatalytic methods to achieve high
enantio- and diastereoselectivities. List et al.
developed the first organocatalyzed direct Mannich reaction,
1
7
sulfones. Following this work, they screened a variety
of cinchona organocatalysts to catalyze the addition of
nitromethane to a variety of protected imines, synthesizing
1
c,2e,f,4e,10
1
8
products in satisfactory yields and enantioselectivities.
Due to the previous work completed in our laboratory using
cinchona alkaloids as tertiary amine catalysts to asymmetri-
cally catalyze direct Mannich reactions, we initially
attempted to extend the methodology to the nitro-Mannich
Keywords: Cinchona alkaloids; Thiourea; Organic catalysis; Imines;
Mannich reaction; Aza-Henry reaction.
1
0,19
*
Corresponding author. Tel.: +1 617 353 2489; fax: +1 617 353 6466;
e-mail: seschaus@bu.edu
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.071

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C. M. Bode et al. / Tetrahedron 62 (2006) 11499–11505
Table 1. Asymmetric nitro-Mannich additions of nitromethane
a
CF3
OCH3
O
O
1
0 mol % 1
2
H
N
N
H CO
NH
CH NO (10 equiv.)
3
N
CF3
3
NO2
H
H
R
H
CH Cl
2 2
R
H
S
OCH3
N
2
a–f
3a–f
N
H
H C
OH
3
N
b
c
N
Entry
R
Adduct
Yield (%)
ee (%)
H C
3
H
d
H CO
1
2a: Ph
2b: 3-MeC
6 4
2c: 3-FC H
2d: cinnamyl
2e: 2-furyl
2f: 2-furyl-propenyl
3a
3b
3c
3d
3e
3f
91
98
98
80
60
97
93
91
98
90
92
98
3
2
3
4
5
6
6 4
H
Hydroquinine-Derived Thiourea 1
Hydroquinidine
OCH3
OCH3
H
H
OH
N
OH
a
N
Nitro-Mannich additions were carried out using 5 mmol of nitromethane,
.5 mmol of imine in CH
followed by silica gel flash chromatography.
Isolated yield of nitro-Mannich addition products.
Determined by chiral HPLC analysis.
Reaction was run for 24 h.
ꢁ
0
2
Cl
2
(0.5 M) at ꢀ10 C for 48 h under N
2
,
N
H
H
N
b
c
d
Quinine
Quinidine
H
H
OH
H
OH
While cinchona alkaloid-derived thioureas have previously
been utilized to study the nitro-Mannich addition of nitro-
methane to acyl imines, there has yet to be a thorough inves-
tigation using nitroethane as a carbon nucleophile. We
attempted to extend the scope of our work by investigating
nitroethane additions to the substrates used in Table 1. The
same general reaction conditions proved to be useful for
nitroethane additions, affording syn-addition products of
similar yields (73–98%) and enantioselectivities (90–97%)
(Table 2, entries 1–6). The nitroethane additions produced
b-nitroamines 5a–5f with adjacent stereocenters and estab-
lished that the alkaloid-derived thiourea also catalyzed with
high diastereoselectivity (ranging from 82 to 97%). Lower
yields were obtained for the more electrophilic acyl imines
N
N
H
N
N
Cinchonine
Figure 1. Cinchona alkaloid catalysts.
Cinchonidine
reaction. In the reactions of benzylidene methyl carbamate,
nitromethane, and 10 mol % of a variety of cinchona alka-
loids in CH Cl , we were able to synthesize secondary amine
products in high yields (>90%). However, our progress was
stymied by low enantioselectivities (<55%). Nevertheless,
these preliminary results led us to further investigate the
nature of cinchona alkaloids as catalysts, and possible modi-
fications that could lead to greater success.
2
2
5d and 5e; however, there was no compromise in enantio-
or diastereoselectivity.
Our attention turned to the cinchona alkaloid-derived
thiourea catalyst 1 used by Connon and Soos.
6
b,g
Thiourea
compounds have often been used in organic chemistry to
efficiently enhance reaction rates, and have been known to
catalyze nucleophilic addition reactions.
A further expansion of the methodology was investigated
upon the enantio- and diastereomeric success of the nitro-
Mannich nucleophiles. The Mannich reaction parallels the
nitro-Mannich in both the electrophilic substrate (acyl imine)
and the nucleophilic additive (carbon nucleophile); it was
2
,6
2
. Results and discussion
a
Table 2. Asymmetric nitro-Mannich additions of nitroethane
The reaction of methyl benzylidenecarbamate 2a with nitro-
methane and 10 mol % hydroquinine-derived thiourea 1 in
CH Cl yielded the corresponding b-nitroamine 3a in 91%
OCH3
O
1
2
0 mol % 1
2
2
N
O
CH CH NO (10 equiv.)
H CO
NH
3
2
3
ꢁ
isolated yield and in 93% ee after 24 h at ꢀ10 C (Table 1,
entry 1). Compared to the trifluoromethylated thiourea, the
dimethyl-substituted catalyst gave 3a in a comparable yield,
yet with lower enantioselectivity (most likely due to the
weaker electron-withdrawing capabilities of the methyl
groups, affecting the hydrogen-bonding ability of the thio-
urea portion). In contrast, the cinchona alkaloid-derived thio-
urea was quite an efficient catalyst for this nitro-Mannich
reaction.
NO2
CH3
5a–f
R
H
CH2Cl2
R
4
a–f
b
Adduct Yield (%) ee (%) de (%)
c
d
Entry
R
e
1
4a: Ph
4b: 3-MeC H
6 4
4c: 3-FC H
6 4
4d: cinnamyl
4e: 2-furyl
5a
5b
5c
5d
5e
96
98
98
80
73
90
94
97
91
90
97
97
83
90
97
92
82
83
2
3
4
5
6
4f: 2-furyl-propenyl 5f
The asymmetric nitro-Mannich reaction catalyzed by the
hydroquinine-derived thiourea was found to be successful
with other imines of varying electronics, both more electron-
rich and electron-poor acyl imines (Table 1, entries 2–6).
The reactions of electron-rich and electron-poor imine sub-
strates yielded the corresponding b-nitroamines 3b–3f in
high enantioselectivities (90–98%) and yields (60–98%).
a
Nitro-Mannich additions were carried out using 5 mmol of nitroethane
ꢁ
and 0.5 mmol of imine in CH
2
Cl
2
(0.5 M) at ꢀ10 C for 48 h under N
2
,
followed by silica gel flash chromatography.
Isolated yield of nitro-Mannich addition products.
Determined by chiral HPLC analysis.
Determined by H NMR analysis.
Reaction was run for 24 h.
b
c
d
e
1

C. M. Bode et al. / Tetrahedron 62 (2006) 11499–11505
11501
a
Table 3. Asymmetric Mannich additions of dimethyl malonate
3. Modeling
1
0 mol % 1
OCH3
O
O
CH CO CH CO CH
3
2
2
2
3
Catalyst 1 is capable of promoting the addition of stabilized
anions to acyl imines with high levels of enantiodiscrimina-
tion. The high degree of selectivity observed in these reac-
tions indicates a catalyst-associated complex with a high
N
(1 equiv.)
H CO
NH
3
CO CH
CH Cl
2
3
R
H
2
2
R
CO CH
2
3
1
0a,b
6a–f
7a–f
degree of coordination.
accounts for the observed diastereo- and enantioselectivity
Fig. 3). We modeled both nitromethane anion and malonate
anion complex with thiourea catalyst 1. A MMFF conforma-
We have developed a model that
b
c
Entry
R
Adduct
Yield (%)
ee (%)
(
d
1
6a: Ph
6b: 3-MeC H
6 4
6c: 3-FC H
6 4
6d: cinnamyl
6e: 2-furyl
6f: 2-furyl-propenyl
7a
7b
7c
7d
7e
7f
98
97
98
97
65
96
92
86
90
90
94
90
2
1
2
3
4
tion search identified the lowest energy conformer for each
complex with the quinoline ring blocking one face of the
nucleophile and the thiourea moiety forming a hydrogen
e
5
e
21a,22
6
bond with the nucleophile.
The aromatic ring of the
thiourea forms an edge-face contact with the nucleophile.
Modeling of the methyl benzylidenecarbamate re-face attack
of the nucleophile-catalyst complex provides a model of
a
Mannich reactions were carried out using 0.5 mmol of dimethyl malonate
ꢁ
and 0.5 mmol of imine in CH Cl
by silica gel flash chromatography.
2
2
at ꢀ35 C for 48 h under N
2
, followed
b
c
d
e
23
Isolated yield of Mannich products.
Determined by chiral HPLC analysis.
Reaction was run for 24 h.
selectivity for the reactions. The approach of the electro-
phile places the hydrogen of the energy-minimized Z-aldi-
mine in line with the catalyst. Also depicted in Figure 3,
the benzylidene aromatic ring forms an edge-face interaction
with the thiourea arene. The nitromethane catalyst complex
depicted in Figure 3A was modeled with re- and si-facial
attack of the nucleophile. The calculated energy difference
between the two binding modes was found to be 1.6 kcal/
mol in favor of si-facial attack of the nucleophile. While
the energy difference is modest, the model is in agreement
with the preferred sense of selectivity (Table 2). These
models illustrate the important interactions of the nucleo-
phile with the catalyst. They also provide some insight into
the factors that result in a selective reaction and how this class
of thiourea catalysts is selective for such a wide-range of
reactions.
ꢁ
Reactions were run at ꢀ50 C.
believed that this parallel should allow the HQ-derived thio-
urea to asymmetrically catalyze direct Mannich additions as
well. To test this hypothesis, methyl benzylidenecarbamate
6
a, hydroquinine-derived thiourea catalyst, and dimethyl
ꢁ
malonate in CH Cl were reacted at ꢀ35 C to produce the
2
2
corresponding Mannich adduct 7a in 98% yield and 92%
ee (Table 3). With this encouraging result, the same sub-
strates were employed in the reaction and similar good results
were obtained, with yields ranging from 65 to 98% and enan-
tioselectivities from 86 to 94%. The more electrophilic sub-
strates 6e and 6f required lower reaction temperatures to
achieve the same levels of enantioselectivity. These results
highlight the utility of the cinchona alkaloid-derived thio-
ureas, and the broad range of reaction conditions that may
be used.
4. Conclusion
In summary, hydroquinine-derived thiourea 1 was found to
catalyze nucleophilic additions of nitroalkanes and dimethyl
malonate to methyl carbamate acyl imines with good yields
and high enantioselectivities. Catalyst 1 is a representative
from a class of cinchona alkaloid-derived thiourea catalysts
that promote a wide-range of reactions asymmetrically.
The generality of these catalysts guarantees their use in the
catalytic reaction methodology development. Future work
includes the expansion of the methodology to different
substrates and investigation of the synthetic utility of the
addition products.
The relative stereochemistry and absolute stereochemistry of
the products obtained were determined via optical rotation
comparisons to known literature compounds. The absolute
stereochemistry of products 3a–3f and 7a–7f was determined
to be (S) while the nitroethane addition was determined to be
2
0
(
1S,2R) by analogy with the corresponding allyl carbamates.
Aside from the reported utilities of the nitro-Mannich addi-
tions, we have also developed a method for transforming
the Mannich products into their corresponding b-amino
esters. Dixon et al. reported a decarboxylation via reflux in
1
4d
toluene for 12 h. We successfully transformed the malo-
nate addition products to the b-amino esters using microwave
irradiation, drastically reducing the previously reported
reaction time, with only slight racemization of the resultant
ester (Fig. 2).
5. Experimental
5.1. General procedure for nitro-Mannich addition of
nitroalkanes to acyl imines
O
O
5.1.1. Synthesis of product 3a: ((S)-2-nitro-1-phenyl-
ethyl)-carbamic acid methyl ester. To an oven-dried reac-
tion vessel under argon were added acyl imine 2a and
thiourea catalyst 1 in CH Cl , (0.5 M). The mixture was
cooled to ꢀ10 C and then nitromethane (10 equiv) was
added. The reaction was run to completion (24 h) and the
crude mixture was run through a silica gel plug, eluted with
ethyl acetate (5 mL). The filtrate was concentrated under
H CO
NH
H CO
NH
3
DMSO, drop H O
3
2
CO CH3
CO CH
2 3
2
µwave, 10 min.
2
2
CO CH3
160 °C
ꢁ
2
7a: 93% ee
80% yield
5% ee
8
Figure 2. Decarboxylation of Mannich product 7a.

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C. M. Bode et al. / Tetrahedron 62 (2006) 11499–11505
A
B
F
F
F
F
F
F
F
S
S
N
N
N
N
F
F
F
N
H
N
N
N
H
H
N
H
F
F
H
O
H
O
O
O
O
O
OO
O
O
N
O
N
O
Figure 3. Proposed catalytically active thiourea 1 complexes (MMFF) approaching the re-face of methyl benzylidenecarbamate. (A) Nitromethane complex.
B) Malonate complex.
(
reduced pressure and the crude product was purified by flash
chromatography over silica gel (eluted with 15–30% ethyl
acetate in hexanes) to afford the nitro-Mannich adduct.
5.2.3. Compound 3b: ((S)-2-nitro-1-m-tolyl-ethyl)-car-
bamic acid methyl ester. Yield: 0.035 g (98%), white solid;
ee: 91%; HPLC analysis, tR minor: 4.16 min, tR major:
9
1.5 mL/min]; H NMR (400 MHz, CDCl ): d 7.25–7.06
.58 min [(R,R)-Whelk-O 1 column, hexanes:IPA¼85:15,
1
5.2. General procedure for Mannich addition of
dimethyl malonate to acyl imines
3
(m, 5H), 5.38 (m, 1H), 4.82 (br s, 1H), 4.70 (m, 2H), 3.68
(s, 3H), 2.34 (s, 3H); C NMR (75.0 MHz, CDCl3):
d 156.1, 138.8, 136.6, 129.4, 128.9, 127.0, 123.2, 78.5,
1
3
5
.2.1. Synthesis of product 7a: 2-((R)-methoxycarbonyl-
ꢀ
1
amino-phenyl-methyl)-malonic acid dimethyl ester. To
an oven-dried reaction vessel under argon were added acyl
imine 2a and thiourea catalyst 1 in CH Cl (0.5 M). The
76.6, 53.1, 52.4. 21.3; IR (thin film, cm ): 3316, 3025,
2956, 1702, 1554, 1454, 1378, 1261, 1060, 913, 781;
HRMS calcd for (M+H) C H N O : 238.0948, found
+
2
2
11 14 2 4
ꢁ
23
mixture was cooled to ꢀ35 C and dimethyl malonate
239.1031; [a]D ꢀ9.4 (c 1.10, CHCl3).
(
(
1 equiv) was added. The reaction was run to completion
24 h) and the crude mixture was run through a silica gel
5.2.4. Compound 3c: ((S)-1-(3-fluoro-phenyl)-2-nitro-
ethyl)-carbamic acid methyl ester. Yield: 0.036 g (98%),
light yellow solid; ee: 98%; HPLC analysis, tR minor:
plug, eluted with ethyl acetate (5 mL). The filtrate was
concentrated under reduced pressure and the crude product
was purified by flash chromatography over silica gel (eluted
with 15–30% ethyl acetate in hexanes) to afford the Mannich
adduct.
8.56 min, t major: 13.55 min [(R,R)-Whelk-O 1 column,
R
1
hexanes:IPA¼85:15, 1.5 mL/min]; H NMR (400 MHz,
CDCl ): d 7.32–7.22 (m, 2H), 7.08–6.92 (m, 3H), 6.14 (d,
3
J¼8.4 Hz, 1H), 5.54 (br s, 1H), 5.37 (m, 2H), 5.09 (m, 1H),
1
3
Please refer to table footnotes for specific reaction times and
temperature of each respective product.
3.69 (s, 3H); C NMR (75.0 MHz, CDCl ): d 164.3, 161.2,
3
155.9, 130.1, 122.3, 117.6, 113.7, 83.7, 55.6, 53.7; IR (thin
film, cm ): 3659, 3323, 2924, 1705, 1595, 1533, 1354,
ꢀ
1
+
5
.2.2. Compound 3a: ((S)-2-nitro-1-phenyl-ethyl)-car-
1258, 1058, 775; HRMS calcd for (M+H) C H N O :
1
242.0697, found: 243.0781; [a]D +13.9 (c 1.00, CHCl3).
0 11 2 4
2
3
bamic acid methyl ester. Yield: 0.102 g (91%), white solid;
ee: 93%; HPLC analysis, tR minor: 9.72 min, tR major:
1
1
5.91 min [(R,R)-Whelk-O 1 column, hexanes:IPA¼85:15,
5.2.5. Compound 3d: ((E)-(S)-1-nitromethyl-3-phenyl-
allyl)-carbamic acid methyl ester. Yield: 0.029 g (80%),
light yellow solid; ee: 90%; HPLC Analysis, tR minor:
9.27 min, t major: 17.92 min [(R,R)-Whelk-O 1 column,
1
.5 mL/min]; H NMR (400 MHz, CDCl ): d 7.40–7.28
3
(
(
m, 5H), 5.42 (m, 2H), 4.84 (br s, 1H), 4.70 (m, 1H), 3.69
s, 3H); C NMR (75.0 MHz, CDCl ): d 156.2, 136.7,
3
1
3
ꢀ1
1
1
29.1, 128.7, 126.3, 78.6, 53.1, 52.6; IR (thin film, cm ):
hexanes:IPA¼85:15, 1.5 mL/min]; H NMR (400 MHz,
3
(
322, 2954, 1686, 1534, 1256, 1049; HRMS (m/z)
M+Na) calculated for C H N O Na: 247.0695, found:
CDCl ): d 7.35–7.19 (m, 5H), 6.63 (d, J¼6.8 Hz, 1H),
3
+
6.14 (dd, J¼6.4, 6.8 Hz, 1H), 5.38 (br s, 1H), 4.96–4.94
1
0 12 2 4
2
3
13
2
47.0695; [a] +26.7 (c 1.00, CHCl3).
(m, 1H), 4.70–4.60 (m, 2H), 3.71 (s, 3H); C NMR
D

C. M. Bode et al. / Tetrahedron 62 (2006) 11499–11505
11503
(
75.0 MHz, CDCl ): d 156.0, 133.7, 128.6, 128.41, 127.9,
3
27.1, 126.5, 123.3, 80.9, 52.7, 51.4; IR (thin film, cm ):
5.2.10. Compound 5c: ((1S,2R)-1-(3-fluoro-phenyl)-2-
nitro-propyl)-carbamic acid methyl ester. Yield: 0.037 g
(98%), light yellow solid; ee: 91%, de: 97%; HPLC analysis,
t minor: 9.92 min, t major: 14.12 min [(R,R)-Whelk-O 1
ꢀ
1
1
3
1
2
325, 2955, 2926, 1717, 1550, 1520, 1449, 1538, 1246,
065, 969, 748; HRMS calcd for (M+H) C H N O :
50.0954, found: 251.1032; [a]D +38.9 (c 0.77, CHCl3).
+
1
2
14
2
4
R
R
2
3
1
column, hexanes:IPA¼85:15, 1.5 mL/min]; H NMR
(400 MHz, CDCl ): d 7.35–7.22 (m, 2H), 7.04–6.93 (m,
3H), 5.50 (br s, 1H), 5.22 (m, 1H), 4.89 (m, 1H), 3.68 (s,
3
5
.2.6. Compound 3e: ((R)-1-furan-2-yl-2-nitro-ethyl)-
1
3
carbamic acid methyl ester. Yield: 0.039 g (60%), orange
solid; ee: 92%; HPLC analysis, t minor: 9.04 min, t major:
9
3H), 1.53 (d, J¼6.8 Hz, 3H); C NMR (75.0 MHz,
CDCl ): d 164.5, 161.2, 156.2, 130.6, 122.5, 115.6, 114.1,
3
R
R
ꢀ
1
.92 min [(R,R)-Whelk-O 1 column, hexanes:IPA¼85:15,
85.3, 57.3, 52.7, 15.1; IR (thin film, cm ): 3316, 3067,
2955, 1703, 1593, 1550, 1452, 1357, 1248, 1026, 877,
786; HRMS calcd for (M+H) C H FN O : 256.0854;
1
1
.5 mL/min]; H NMR (400 MHz, CDCl ): d 7.36 (d,
3
+
J¼1.6 Hz, 1H), 6.33 (dd, J¼3.4, 1.6 Hz, 1H), 6.30 (d,
1
1
13
2 4
2
3
J¼2.8 Hz, 1H), 5.49 (m, 1H), 5.43 (br s, 1H), 4.86
found: 257.0938; [a]D +51.0 (c 0.90, CHCl3).
(
3
dd, J¼16.0, 8.0 MHz, 1H), 4.72 (dd, J¼13.2, 5.6 Hz, 1H),
1
3
.70 (s, 3H); C NMR (75.0 MHz, CDCl ): d 156.0,
3
5.2.11. Compound 5d: ((E)-(S)-1-((R)-1-nitro-ethyl)-3-
phenyl-allyl)-carbamic acid methyl ester. Yield: 0.032 g
(80%), light yellow solid; ee: 90%, de: 92%; HPLC analysis,
t minor: 12.30 min, t major: 21.25 min [(R,R)-Whelk-O 1
1
cm ): 3311, 3127, 2954, 2933, 1702, 1553, 1265; HRMS
(
found: 237.0487; [a] +30.3 (c 0.60, CHCl3).
49.0, 143.0, 110.7, 107.9, 76.3, 52.7, 47.5; IR (thin film,
ꢀ
1
+
m/z) (M+Na) calculated for C H N O Na: 237.0644,
8 10 2 5
R
R
2
3
1
column, hexanes:IPA¼85:15, 1.5 mL/min]; H NMR
D
(400 MHz, CDCl ): d 7.09–6.91 (m, 5H), 6.37 (d,
3
5
.2.7. Compound 3f: ((S)-3-furan-2-yl-1-nitromethyl-
J¼16.4 Hz, 1H), 5.81 (dd, J¼7.2, 7.6 Hz, 1H), 5.04 (br s,
allyl)-carbamic acid methyl ester. Yield: 0.035 g (97%),
yellow solid; ee: 98%; HPLC analysis, tR minor:
1
1H), 4.59 (m, 1H), 4.44 (m, 1H), 3.46 (s, 3H), 1.31 (d,
J¼6.8 Hz, 3H); C NMR (75.0 MHz, CDCl ): d 156.2,
1
3
3
2.55 min, t major: 18.37 min [(R,R)-Whelk-O 1 column,
R
135.9, 132.4, 128.5, 127.2, 126.6, 126.9, 85.1, 55.3, 52.5,
29.6; IR (thin film, cm ): 3323, 2954, 2927, 1731, 1547,
1
ꢀ1
hexanes:IPA¼85:15, 1.5 mL/min]; H NMR (400 MHz,
CDCl ): d 7.34 (d, J¼2.0 Hz, 1H), 6.45 (d, J¼16.0 Hz,
1519, 1296, 1247, 1197, 1049, 968, 744; HRMS calcd for
(M+H) C H N O : 263.1110, found: 264.1010; [a]
13 16 2 4 D
3
+
23
1
6
1
3
1
H), 6.35 (dd, J¼3.2, 2.0 Hz, 1H), 6.28 (d, J¼3.2 Hz, 1H),
.07 (dd, J¼16.0, 6.4 Hz, 1H), 5.25 (br s, 1H), 4.92 (m,
H), 4.66 (m, 1H), 4.59 (dd, J¼12.8, 4.8 Hz, 1H), 3.70 (s,
+58.6 (c 0.52, CHCl3).
1
3
H); C NMR (75.0 MHz, CDCl ): d 156.0, 151.0, 142.7,
5.2.12. Compound 5e: ((1R,2R)-1-furan-2-yl-2-nitro-pro-
pyl)-carbamic acid methyl ester. Yield: 0.025 g (73%),
light yellow solid; ee: 97%, de: 82%; HPLC analysis, t mi-
3
21.9, 121.5, 111.5, 109.9, 78.0, 52.6, 51.0; IR (thin film,
ꢀ
1
cm ): 3313, 2956, 2924, 2853, 1700, 1550, 1378, 1256;
HRMS (m/z) (M+Na) calculated for C H N O Na:
2
R
+
nor: 7.38 min, t major: 8.18 min [(R,R)-Whelk-O 1 column,
R
1
0
12
2
5
2
3
1
63.0800, found: 263.0644; [a]D +36.9 (c 1.00, CHCl3).
hexanes:IPA¼85:15, 1.5 mL/min]; H NMR (400 MHz,
CDCl ): d 7.35 (d, J¼1.2 Hz, 1H), 6.31 (dd, J¼3.4, 1.8 Hz,
3
5
.2.8. Compound 5a: ((1S,2R)-2-nitro-1-phenyl-propyl)-
1H), 6.27 (d, J¼3.2 Hz, 1H), 5.55 (br s, 1H, minor), 5.45
(br s, 1H, major), 5.35 (dd, J¼9.0, 6.0 Hz, 1H, major), 5.27
(br m, 1H, minor), 5.04 (m, 1H, minor), 4.88 (m, 1H, major),
carbamic acid methyl ester. Yield: 0.107 g (96%), white
solid; ee: 94%, de: 83%; HPLC analysis, tR minor:
1
1
3
8.82 min, t major: 23.16 min [(R,R)-Whelk-O 1 column,
R
3.70 (s, 3H), 1.57 (d, J¼9.2 Hz, 3H); C NMR (75.0 MHz,
1
hexanes:IPA¼90:10, 1.5 mL/min]; H NMR (400 MHz,
CDCl ): d 156.1, 148.7, 143.0, 110.6, 108.6, 84.2, 52.8,
3
ꢀ
1
CDCl ): d 7.36–7.32 (m, 3H), 7.22–7.20 (m, 2H), 5.72 (br s,
3
52.1, 15.3; IR (thin film, cm ): 3310, 2955, 2924, 1701,
1550, 1235, 1013, 743; HRMS (m/z) (M+Na) calcd for
+
1
1
1
H, minor), 5.49 (br s, 1H, major), 5.22 (dd, J¼9.0, 5.8 Hz,
23
H, major), 5.13 (s, 1H, minor), 4.92 (m, 1H), 3.67 (s, 3H),
.52 (d, J¼6.8 Hz, 3H); C NMR (75.0 MHz, CDCl3):
C H N O Na: 251.0487, found: 251.0644; [a] +49.6
9 12 2 5 D
1
3
(c 0.50, CHCl3).
d 156.2, 136.2, 128.9, 128.7, 126.7, 85.5, 57.8, 52.5, 15.1;
IR (thin film, cm ): 3311, 2924, 2853, 1691, 1544, 1291,
1
ꢀ
1
5.2.13. Compound 5f: ((S)-3-furan-2-yl-1-((R)-1-nitro-
ethyl)-allyl)-carbamic acid methyl ester. Yield: 0.065 g
(90%), yellow oil; ee: 97%, de: 83%; HPLC analysis, t mi-
+
018; HRMS (m/z) (M+Na) calculated for C H N O Na:
11 14 2 4
61.0954, found: 261.0851; [a]D +40.1 (c 1.00, CHCl3).
2
3
2
R
nor: 22.91 min, t major: 30.38 min [(R,R)-Whelk-O 1 col-
R
1
5
.2.9. Compound 5b: ((1S,2R)-2-nitro-1-m-tolyl-propyl)-
umn, hexanes:IPA¼95:5, 1.5 mL/min]; H NMR (400 MHz,
carbamic acid methyl ester. Yield: 0.037 g (98%), white
solid; ee: 97%, de: 90%; HPLC analysis, tR minor:
1
CDCl ): d 7.34 (d, J¼1.6 Hz, 1H), 6.43 (d, J¼16.0 Hz, 1H),
3
6.35 (dd, J¼3.2, 2.0 Hz, 1H), 6.27 (d, J¼3.6 Hz, 1H), 5.98
(dd, J¼15.6, 7.6 Hz, 1H), 5.26 (d, J¼8.4 Hz, 1H), 4.79 (m,
1H), 4.67 (m, 1H), 3.69 (s, 3H), 1.56 (d, J¼6.8 Hz, 3H);
1.91 min, t major: 19.11 min [(R,R)-Whelk-O 1 column,
R
1
hexanes:IPA¼85:15, 1.5 mL/min]; H NMR (400 MHz,
1
3
CDCl ): d 7.26–7.21 (m, 2H), 7.13–7.11 (m, 1H), 7.03–
3
C NMR (75.0 MHz, CDCl ): d 156.1, 151.1, 142.6,
3
6
3
.98 (m, 2H), 5.42 (m, 1H), 4.18 (m, 1H), 4.89 (br s, 1H),
C
123.0, 121.4, 111.4, 108.8, 85.0, 56.0, 52.6, 15.9; IR (thin
film, cm ): 3375, 2958, 2921, 2850, 1709, 1550, 1259,
1
3
ꢀ1
.67 (s, 3H), 2.32 (s, 3H), 1.51 (d, J¼6.4 Hz, 1H);
+
NMR (75.0 MHz, CDCl ): d 156.1, 138.5, 129.2, 128.7,
3
128.5, 126.8, 123.6, 85.57, 57.7, 52.7, 21.3, 21.2; IR (thin
film, cm ): 3326, 2954, 2857, 1732, 1547, 1449, 1355,
1
C H N O : 252.1105, found: 253.1188; [a] +17.9 (c
0
733; HRMS (m/z) (M+Na) calcd for C H N O Na:
11 14 2 5
277.0746, found: 277.0800; [a]D +5.3 (c 1.00, CHCl3).
2
3
ꢀ
1
+
243, 1027, 913, 783, 731; HRMS calcd for (M+H)
5.2.14. Compound 7a: 2-((R)-methoxycarbonylamino-
phenyl-methyl)-malonic acid dimethyl ester. Yield:
0.145 g (98%), white solid; ee: 92%; HPLC analysis, tR
2
3
1
2
16
2
4
D
.86, CHCl3).

11504
C. M. Bode et al. / Tetrahedron 62 (2006) 11499–11505
minor: 12.42 min, t major: 15.11 min [(R,R)-Whelk-O 1
R
6.09 (d, J¼8.8 Hz, 1H), 5.56 (dd, J¼9.4, 4.2 Hz, 1H), 4.02
(d, J¼4.8 Hz, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 3.67 (s, 3H);
1
column, hexanes:IPA¼85:15, 1.5 mL/min]; H NMR
1
3
(
400 MHz, CDCl ): d 7.33–7.26 (m, 5H), 6.36 (d,
3
C NMR (75.0 MHz, CDCl ): d 168.1, 167.0, 156.3,
3
J¼8.0 Hz, 1H), 5.48 (m, 1H), 3.90 (d, J¼5.6 Hz, 1H), 3.74
151.8, 142.2, 110.5, 106.9, 53.8, 53.0, 52.7, 52.4, 48.7; IR
(thin film, cm ): 3357, 2923, 2852, 1725, 1503, 1436,
1
3
ꢀ1
(
s, 3H), 3.65 (s, 3H), 3.63 (s, 3H); C NMR (75.0 MHz,
CDCl ): d 168.6, 167.6, 156.5, 139.3, 128.9, 128.0, 126.4,
+
1230, 1147; HRMS (m/z) (M+Na) calcd for C H NO Na:
12 15
3
7
ꢀ
1
23
5
2
1
3
6.7, 54.1, 53.2, 52.8, 52.5; IR (thin film, cm ): 3274,
954, 2924, 1754, 1739, 1688, 1550, 1434, 1290, 1263,
149; HRMS (m/z) (M+Na) calcd for C H NO Na:
18.0954, found: 318.0954; [a] ꢀ1.4 (c 1.00, CHCl ).
308.0746, found: 308.0746; [a]D +12.7 (c 1.00, CHCl3).
+
5.2.19. Compound 7f: 2-((S)-3-furan-2-yl-1-methoxycar-
bonylamino-allyl)-malonic acid dimethyl ester. Yield:
1
4
17
6
2
D
3
3
0
minor: 12.16 min, t major: 24.21 min [(R,R)-Whelk-O 1
.033 g (96%), a yellow oil; ee: 97%; HPLC analysis, tR
5
.2.15. Compound 7b: 2-((R)-methoxycarbonylamino-m-
R
1
tolyl-methyl)-malonic acid dimethyl ester. Yield: 0.045 g
97%), white solid; ee: 86%; HPLC analysis, tR minor:
.21 min, t major: 11.57 min [(R,R)-Whelk-O 1 column,
column, hexanes:IPA¼85:15, 1.5 mL/min]; H NMR
(
(400 MHz, CDCl ): d 7.31 (d, J¼1.6 Hz, 1H), 6.40 (d,
3
9
J¼15.2 Hz, 1H), 6.33 (dd, J¼3.2, 2.0 Hz, 1H), 6.23
(d, J¼3.2 Hz, 1H), 6.09 (dd, J¼15.4, 6.6 Hz, 1H), 5.85
(d, J¼10.4 Hz, 1H), 4.99 (br s, 1H), 3.74 (s, 6H), 3.66 (s,
R
1
hexanes:IPA¼85:15, 1.5 mL/min]; H NMR (400 MHz,
CDCl ): d 7.26–7.17 (m, 3H), 7.07–7.06 (m, 2H), 6.36 (d,
3
1
3
J¼7.2 Hz, 1H), 5.46 (br s, 1H), 3.88 (br s, 1H), 3.74 (s,
3H); C NMR (75.0 MHz, CDCl ): d 167.3, 151.4, 142.1,
3
1
3
3
(
H), 3.64 (s, 3H), 3.63 (s, 3H), 2.31 (s, 3H); C NMR
75.0 MHz, CDCl ): d 168.2, 167.2, 156.2, 138.9, 138.2,
124.2, 124.2, 120.4, 111.2, 108.8, 55.0, 52.6, 52.4, 52.1;
IR (thin film, cm ): 3379, 2956, 2852, 1724, 1511, 1436,
ꢀ
1
3
+
1
2
1
7
3
28.5, 128.4, 126.8, 123.0, 56.3, 53.8, 52.8, 52.4, 52.1,
1232, 729; HRMS (m/z) (M+Na) calcd for C H NO Na:
15
334.0903, found: 334.0903; [a]D +5.6 (c 1.00, CHCl3).
1
2
7
ꢀ
1
23
1.3; IR (thin film, cm ): 3287, 2955, 2926, 1748, 1693,
545, 1438, 1354, 1293, 1194, 1149, 1049, 1013, 913,
86; HRMS calcd for (M+H) C H NO : 335.1369, found
+
1
7
21
6
2
3
36.2093; [a] ꢀ1.7 (c 1.10, CHCl3).
D
Acknowledgements
5
.2.16. Compound 7c: 2-((R)-(3-fluoro-phenyl)-methoxy-
The authors thank Synthematix, Inc. (Durham, NC) for
assistance with chemical reaction planning software. This
research was supported by a gift from Amgen, Inc. and an
NSF CAREER grant (CHE-0349206).
carbonylamino-methyl)-malonic acid dimethyl ester.
Yield: 0.092 g (98%), light yellow solid; ee: 90%; HPLC
analysis, t minor: 16.67 min, t major: 20.19 min [(R,R)-
R
R
1
Whelk-O 1 column, hexanes:IPA¼85:15, 1.5 mL/min]; H
NMR (400 MHz, CDCl ): d 7.29–7.24 (m, 2H), 7.06–6.91
3
(
m, 3H), 6.42 (d, J¼8.4 Hz, 1H), 5.48 (d, J¼4.4 Hz, 1H),
1
3
3 C
NMR (75.0 MHz, CDCl ): d 168.9, 167.4, 164.5, 161.2,
.89 (d, J¼1.3 Hz, 1H), 3.72 (s, 3H), 3.63 (s, 6H);
References and notes
3
1
42.1, 130.2, 122.0, 114.7, 113.5, 63.7, 62.3, 52.8, 52.5;
1. (a) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev.
2003, 103, 2985–3012; (b) Yoon, T. P.; Jacobsen, E. N. Science
2003, 299, 1691–1963; (c) Tian, S.; Chen, Y. G.; Hang, J.; Tang,
L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621–631;
(d) Cordova, A. Acc. Chem. Res. 2005, 37, 102–112; (e)
Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719–724.
2. (a) Curran, D. P.; Kuo, L. H. Tetrahedron Lett. 1995, 36, 6647–
6650; (b) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc.
1998, 120, 4901–4902; (c) Schreiner, P. R. Chem. Soc. Rev.
2003, 32, 289–296; (d) Pihko, M. Angew. Chem., Int. Ed.
2004, 43, 2062–2064; (e) Joly, G. D.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 4102–4103; (f) Fuerst, D. E.;
Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 8964–8965; (g)
Dixon, D. J.; Richardson, R. D. Synlett 2006, 0081–0085.
3. (a) Vachal, P.; Jacobsen, E. N. Org. Lett. 2000, 2, 867–890; (b)
Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
10012–10014.
4. (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12671–12673; (b) Hoashi, Y.; Okino, T.; Takemoto, Y.
Angew. Chem., Int. Ed. 2005, 44, 4032–4035; (c) Ye, J.;
Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481–4483;
(d) Tsogoeva, S. B.; Yalalov, D. A.; Hateley, M. J.;
Weckbecker, C.; Huthmacher, K. Eur. J. Org. Chem. 2005,
45, 4995–5000; (e) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu,
X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119–125.
5. (a) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Tetrahedron Lett. 2004, 45, 5589–5592; (b) Li, J. W. H.; Yu,
X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293–4296.
ꢀ
1
IR (thin film, cm ): 3316, 3067, 2955, 1703, 1593, 1550,
452, 1357, 1248, 1026, 877, 786; HRMS calcd for
1
+
23
(
M+H) C H FNO : 339.1118, found: 340.0278; [a]
16 18 6 D
ꢀ
15.4 (c 1.46, CHCl3).
5
.2.17. Compound 7d: 2-((E)-(S)-1-methoxycarbonyl-
amino-3-phenyl-allyl)-malonic acid dimethyl ester. Yield:
.046 g (97%), light yellow solid; ee: 90%; HPLC analysis,
t minor: 9.18 min, t major: 11.35 min [(R,R)-Whelk-O 1
0
R
R
1
column, hexanes:IPA¼85:15, 1.5 mL/min]; H NMR
(
400 MHz, CDCl ): d 7.34–7.22 (m, 5H), 6.57 (d,
3
J¼16.0 Hz, 1H), 6.18 (dd, J¼6.8, 6.8 Hz, 1H), 5.86 (br s,
1
H), 5.02 (m, 1H), 3.74 (s, 3H), 3.73 (s, 3H), 3.67 (s, 3H);
C NMR (75.0 MHz, CDCl ): d 168.2, 156.2, 136.0,
32.4, 128.5, 127.9, 126.6, 125.9, 55.3, 52.8, 52.6, 52.3;
1
3
3
1
ꢀ
1
IR (thin film, cm ): 3376, 2955, 2854, 1735, 1511, 1442,
354, 1240, 1197, 1069, 1034, 970, 785; HRMS calcd for
1
+
23
(
(
M) C H NO : 321.1212, found: 321.1110; [a] +4.5
16 19 6 D
c 0.66, CHCl3).
5
.2.18. Compound 7e: 2-((R)-furan-2-yl-methoxycarbo-
nylamino-methyl)-malonic acid dimethyl ester. Yield:
.022 g (65%), light yellow oil; ee: 94%; HPLC analysis,
t minor: 5.96 min, t major: 6.57 min [Chiralcel OD chiral
0
R
R
1
column, hexanes:IPA¼90:10, 1.5 mL/min]; H NMR
(
(
400 MHz, CDCl ): d 7.30 (dd, J¼1.8, 0.6 Hz, 1H), 6.28
3
dd, J¼3.4, 1.8 Hz, 1H), 6.21 (dd, J¼3.2, 1.2 Hz, 1H),

C. M. Bode et al. / Tetrahedron 62 (2006) 11499–11505
11505
6
. (a) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259–
261; (b) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org.
15. Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3,
1362–1364.
3
Lett. 2005, 7, 1967–1969; (c) Linton, B. R.; Goodman, S. M.;
Hamilton, A. D. Chem.—Eur. J. 2000, 6, 2449–2455; (d)
Wenzel, A. G.; Lalonde, M. P.; Jacobsen, E. N. Synlett 2003,
16. Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44,
466–468.
17. Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.;
Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975–7978.
18. See Ref. 14c.
1
919–1922; (e) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem.
Soc. 2004, 126, 10558–10559; (f) Takemoto, Y. Org. Biomol.
Chem. 2005, 3, 4299–4306; (g) Cooey, S. H.; Connon, S. J.
Angew. Chem., Int. Ed. 2005, 44, 2–6; (h) Xu, X.; Yabuta, T.;
Yuan, P.; Takemoto, Y. Synlett 2006, 00137–00140.
. For catalytic Mannich, see: (a) Yamasaki, S.; Iida, T.;
Shibasaki, M. Tetrahedron Lett. 1990, 40, 307–310; (b)
Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
19. Ting, A.; Lou, S.; Schaus, S. E. J. Am. Chem. Soc. 2006, 8,
2003–2006.
20. For absolute stereochemistry determination of b-nitroamines
adducts: replacement of methyl benzylidenecarbamate 3a and
5a with allyl benzylidenecarbamate did not affect facial selec-
tivity of the reaction. Removal of the allyl carbamate function-
ality on the nitroamine products and subsequent conversion to
tert-butyl carbamate (Boc) adducts allowed comparison to liter-
7
1
997, 119, 7153–7154; (c) Juhl, K.; Gathergood, N.;
Jorgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2995–
997; (d) Hamashima, Y.; Hotta, M.; Sodeoka, M. J. Am.
1
5
2
ature for absolute configuration determination. Comparison
of optical rotation data assigns the absolute configuration of
our b-nitroamine adducts as (1S,2R).
Chem. Soc. 2002, 124, 11240–11241; (e) Ferraris, D.; Young,
B.; Cox, C.; Dudding, T.; Drury, W. J., III; Ryzhkov, L.;
Taggi, T.; Lectka, J. J. Am. Chem. Soc. 2002, 124, 67–77; (f)
Trost, B. M.; Terrell, L. M. J. Am. Chem. Soc. 2003, 125,
O
O
Pd(PPh ) , 1,3-dimethyl-
3
4
4712–4713; for organocatalytic Mannich, see: (g) List, B.
J. Am. Chem. Soc. 2000, 122, 9336–9337.
barbituric acid, NEt
O
NH
3
O
NH
di-t-butyldicarbonate
NO2
NO2
8
. For nitro-Mannich, see: (a) Henry, L. Bull. Acad. Roy. Belg.
THF, overnight at rt, under N2
1
1
896, 32, 33; (b) Hurd, C. D.; Strong, J. S. J. Am. Chem. Soc.
950, 72, 4813–4814; (c) Baer, H. H.; Urbas, L. The
92% ee
Chemistry of the Nitro and Nitroso Groups; Patai, S., Ed.,
Interscience: New York, NY, 1970; p 117, Part 2; (d) Adams,
H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org.
Chem. 1998, 63, 9932–9934; (e) Anderson, J. C.; Peace, S.;
Pih, S. Synlett 2000, 850–852; (f) Anderson, J. C.; Blake,
A. J.; Howell, G. P.; Wilson, C. J. Org. Chem. 2005, 70,
15b
Literature Value
(R)-enantiomer:
23
:
60%ee[
]
=–20.1°,
D
(
c = 1.00,CHCl3)
5
49–555; for catalytic nitro-Mannich, see: (g) Yamada, K.;
O
Pd(PPh ) , 1,3-dimethyl-
O
3
4
Harwood, S. J.; Groger, H.; Shibasaki, M. Angew. Chem.,
Int. Ed. 1999, 38, 3504–3506; (h) Yamada, K. Y.; Moll, G.;
Shibasaki, M. Synlett 2001, 980–982; (i) Westermann, B.
Angew. Chem., Int. Ed. 2003, 42, 151–153.
barbituric acid, NEt3
O
NH
O
NH
di-t-butyldicarbonate
NO2
NO2
THF, overnight at rt, under N2
CH3
CH3
(
S,R)-enantiomer:
9
. (a) Tafesh, A. M.; Weiguny, J. Chem. Rev. 1996, 96, 2035–
2
92% ee, 87% de
8
2% yield, 92% ee,
052; (b) Lucte, D.; Le Gall, T.; Mioskowski, C. Angew.
8
3% de
Chem., Int. Ed. 1998, 37, 2580–2627; (c) Lucte, D.; Sabelle,
S.; Kostelitz, O.; Le Gall, T.; Mioskowski, C. Eur. J. Org.
Chem. 1999, 2583–2691; (d) Sibi, M. P.; Asano, Y. J. Am.
Chem. Soc. 2001, 123, 9708–9709; (e) Ma, J. Angew. Chem.,
Int. Ed. 2003, 42, 4290–4299.
= +29.1°,
(
c = 0.73, CHCl3)
15b
:
Literature Value
(R,S)-enantiomer:
4% ee, 86% de
9
2
3
[
]
= –30.7°,
D
1
1
1
1
1
0. (a) See Ref. 7g; (b) List, B.; Porialev, P.; Biller, W. T.; Martin,
H. J. J. Am. Chem. Soc. 2002, 124, 827–833.
1. Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F.
Tetrahedron Lett. 2001, 42, 199–201.
2. Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc.
(
c = 1.00, CHCl3)
21. (a) Molecular Operating Environment 2004.03, MOE, Chemi-
cal Computing Group: Montreal, Quebec, Canada; (b) Halgren,
T. A. J. Comput. Chem. 1996, 17, 490–519.
22. Similar models have been proposed for diastereoselective
b-keto ester additions to nitroolefins, see: (a) Li, H.; Wang,
Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906–
9907; (b) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo,
C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005,
44, 105–108.
23. For conformational studies of cinchona alkaloid catalyzed
reactions, see: (a) Cortez, G. S.; Oh, S. H.; Romo, D.
Synthesis 2001, 1731–1736; (b) Taggi, A. E.; Hafez, A. M.;
Dudding, T.; Lectka, T. Tetrahedron 2002, 58, 8351–8356.
2
005, 127, 11256–11257.
3. Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128,
048–6049.
6
4. (a) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org.
Lett. 2004, 6, 625–627; (b) Palomo, C.; Oiarbide, M.; Laso, A.;
Lopez, R. J. Am. Chem. Soc. 2005, 127, 17622–17623; (c)
Bernardi, L.; Fini, F.; Herrara, R. P.; Ricci, A.; Sgarzani, V.
Tetrahedron 2006, 62, 375–380; (d) Xu, X.; Furukawa, T.;
Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006,
1
191–1193.