A convenient method for the preparation of chiral phosphonoacetamides and their Horner-Wadsworth-Emmons reaction

Article abstract of DOI:10.1016/j.tetasy.2007.09.033

Chiral phosphonoacetamides bearing (S)-(α-methylbenzyl)benzylamine, (S,S)-bis(α-methylbenzyl)amine, l-phenylglycine methyl ester and l-phenylglycinol were easily prepared in good yield by means of the Michaelis-Arbuzov reaction of chiral bromoacetamides obtained in quantitative yield, with trimethyl phosphite, which under Horner-Wadsworth-Emmons conditions with several aryl and alkyl aldehydes under Masamune-Roush procedure using LiCl and DBU in THF or toluene gave the corresponding chiral α,β-unsaturated amides. The present procedure is a convenient and efficient methodology for the preparation of phosphonoacetamides and chiral α,β-unsaturated amides in high E-selectivity.

Full text of DOI:10.1016/j.tetasy.2007.09.033

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2427–2436
A convenient method for the preparation of chiral
phosphonoacetamides and their Horner–Wadsworth–Emmons
reaction
a,
a
a
a
*
´
´
´
´
´
Mario Ordonez, Eugenio Hernandez-Fernandez, Martın Montiel-Perez, Rafael Bautista,
˜
a
a
a
´
´
Paola Bustos, Haydee Rojas-Cabrera, Mario Fernandez-Zertuche and
b
´
Oscar Garcıa-Barradas
aCentro de Investigaciones Quı´micas, Universidad Auto´noma del Estado de Morelos, Av. Universidad 1001,
62209 Cuernavaca, Mor., Mexico
bUnidad de Servicos de Apoyo en Resolucio´n Analı´tica, Universidad Veracruzana, Av. Dr. Luis Castelazo Ayala s/n,
11910 Xalapa, Ver., Mexico
Received 1 August 2007; accepted 28 September 2007
Abstract—Chiral phosphonoacetamides bearing (S)-(a-methylbenzyl)benzylamine, (S,S)-bis(a-methylbenzyl)amine, L-phenylglycine
methyl ester and L-phenylglycinol were easily prepared in good yield by means of the Michaelis–Arbuzov reaction of chiral bromo-
acetamides obtained in quantitative yield, with trimethyl phosphite, which under Horner–Wadsworth–Emmons conditions with several
aryl and alkyl aldehydes under Masamune–Roush procedure using LiCl and DBU in THF or toluene gave the corresponding chiral
a,b-unsaturated amides. The present procedure is a convenient and efficient methodology for the preparation of phosphonoacetamides
and chiral a,b-unsaturated amides in high E-selectivity.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
reactions of aldehydes with phosphonates bearing a-sub-
stituents that stabilize the carbanion preferentially furnish
the corresponding E-alkenes. Recently, we described the
highly selective synthesis of chiral (E)-a,b-unsaturated
amides bearing (S)-a-methylbenzylamine from phosphono-
acetamides via a HWE reaction.9 As an extension of this
methodology, in this work we herein report the synthesis of
several chiral a,b-unsaturated amides bearing (S)-(a-meth-
ylbenzyl)benzylamine,10 (S,S)-bis(a-methylbenzyl)amine,11
(S)-phenylglycine methyl ester12 and (S)-phenylglycinol13
via a HWE reaction from the corresponding phosphono-
acetamides 4–8.
The stereodefined synthesis of carbon–carbon double
bonds with high selectivity is critically important in organic
synthesis, since geometrically-defined olefins serve as good
building blocks in organic synthesis.1 Of particular utility
are the olefins bearing electron-withdrawing groups, such
as the carbonyl group, since these groups are not only via-
ble for further functionalization, but they also activate the
olefin moiety for reactions such as Michael addition2 and
cycloaddition reactions.3 Additionally, a,b-unsaturated
amides belong to an important class of natural products,
which show both biological4 and insecticide activities.5
For these reasons, the preparation of a,b-unsaturated
amides is a topic of great interest, in this context the Wittig
reaction and related reactions have served as the most pow-
erful method for the construction of double bonds.6 The
Horner–Wadsworth–Emmons (HWE) modification of the
Wittig reaction in particular is widely employed.7,8 The
2. Results and discussion
The starting chiral phosphonoacetamides 4–6 were easily
prepared by employing the protocol recently developed in
our laboratories.14 In this context, the treatment of the
appropriate chiral amine15 with bromoacetyl bromide in
the presence of K2CO3 in a CH2Cl2/H2O mixture at room
temperature, afforded the corresponding chiral a-bromo-
*
Corresponding author. E-mail: palacios@ciq.uaem.mx
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.09.033

2428
M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 18 (2007) 2427–2436
acetamides 1–3 in excellent yields,16 which by means of the
Michaelis–Arbuzov reaction17 with trimethyl phosphite
gave the chiral phosphonoacetamides 4–6 in 92–98% yield
(Scheme 1).18
obtained in 93% yield (Table 1, entry 1). Identical results
were obtained in the reaction of 4 with p-chlorobenzalde-
hyde, p-methoxybenzaldehyde and trimethylacetaldehyde
(Table 1, entries 2–4). However, only moderate selectivity
E:Z = 87:13 was obtained with isobutyraldehyde and iso-
valeraldehyde (Table 1, entries 5 and 6). These results sug-
gest that the stereoselectivity in the HWE reaction of 4 with
aromatic and alkyl aldehydes is determined by the steric
hindrance at the a-position in the corresponding aldehydes.
R*
H
N
O
O
R'
Br
R*
Br
N
Br
CH2Cl2:H2O
K2CO3,rt
R'
91-97%
1; R' = Bn, R* = (
2; R' = R* = ( )-CH(Me)Ph
3; R' = H, R* = ( )-CH(CO2Me)Ph
S)-CH(Me)Ph
S
Table 1. HWE reaction of 4 with several aldehydes
S
R
O
Me
O
Me
(MeO)3P
92-98%
105-110oC
RCHO
+
Ph
N
Ph
R
N
4
DBU/LiCl
THF, r.t.
Bn
Bn
O
O
(Z)-11a-f
(E)-11a-f
R*
(MeO)2P
N
Entry
R
Yielda (%)
E:Zb
R'
1
2
3
4
5
6
7
8
a
b
c
d
e
f
C6H5
p-Cl–C6H4
p-MeO–C6H4
t-Bu
i-Pr
i-Bu
i-Pr
i-Bu
93
94
97
92
94
95
92
90
98:02
98:02
98:02
98:02
83:17
83:17
96:04c
93:07c
4; R' = Bn, R* = (
5; R' = R* = ( )-CH(Me)Ph
6; R' = H, R* = ( )-CH(CO2Me)Ph
S)-CH(Me)Ph
S
S
Scheme 1.
e
f
On the other hand, reduction of the methyl ester group in
phosphonoacetamide 6 with sodium borohydride in THF/
MeOH at reflux19 produced phosphonoacetamide 7 in 89%
yield. Additionally, treatment of phosphonoacetic acid 9,
obtained by hydrolysis from the corresponding ethyl ester
derivative, with L-phenylglycinol20 in the presence of di-
cyclohexylcarbodiimide (DCC) and catalytic amounts of
4-(N,N-dimethylamino)pyridine (DMAP) in dichlorometh-
ane at room temperature, afforded phosphonoacetamide 7
in 97% yield. In a similar manner, 8 was obtained in 93%
yield from the corresponding phosphonoacetic acid 10
(Scheme 2).21
a Isolated yield after purification by column chromatography.
b The E:Z ratio was determined by 1H NMR on crude product on the basis
of the olefinic protons.
c The reaction was carried out in toluene at 100 ꢁC.
On the other hand, it is generally accepted that the stereo-
selectivity in the HWE reactions is a result of both kinetic
and thermodynamic control upon the reversible formation
of the erythro and threo adducts and their decomposition
to olefins.7 Therefore, the stereochemistry is determined
by a combination of the stereoselectivity in the initial
carbon–carbon bond-forming step and reversibility of the
intermediate adducts. The predominant formation of the
E-olefins in the case of dialkylphosphono derivatives can
be explained by the formation of thermodynamically more
stable threo adducts. In this context, when we carried out
the HWE reaction of 4 with isobutyraldehyde and isovaler-
aldehyde in toluene at 100 ꢁC, a good E-selectivity and
yield of a,b-unsaturated amides 11e–f were obtained (Table
1, entries 7 and 8).25
6
NaBH4
89%
THF:MeOH
Ph
H2N
O
O
O
Ph
O
OH
(RO)2P
(RO)2P
OH DCC, DMAP
CH2Cl2
N
H
OH
9
; R = Me
10; R = Et
93-97%
7
8
; R = Me
; R = Et
In a similar way, the reaction of phosphonoacetamide 5
afforded the chiral a,b-unsaturated amides 12a–f with
excellent E-selectivity and yield. The results are summa-
rized in Table 2.26
Scheme 2.
With phosphonoacetamides 4–8 in hand, we initiated our
own investigation by examining the HWE reaction of 4–8
with several aryl and alkyl aldehydes to obtain the corres-
ponding chiral a,b-unsaturated amides. Thus, in the first
instance and following the Masamune–Roush procedure,22
phosphonoacetamide 4 in dry THF was treated with
8-diazabicyclo[5.4.0]undec-7-ene in the presence of LiCl,
followed by the addition of benzaldehyde at room temper-
ature.23 The reaction was completed within 2 h, and a
>98:02 ratio24 of E:Z a,b-unsaturated amide 11a was
On the other hand, the HWE reaction of 6 with benzalde-
hyde, p-chlorobenzaldehyde, p-methoxybenzaldehyde and
trimethylacetaldehyde at room temperature provided the
(S)-(E)-a,b-unsaturated amides 13a–d as the only product
(Table 3, entries 1–4).27 However, the reaction of 6 with
isobutyraldehyde and isovaleraldehyde under the same
conditions, gave the a,b-unsaturated amides 13e–f with
low selectivities E:Z (Table 3, entries 5 and 6), whereas at

M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 18 (2007) 2427–2436
Table 2. HWE reaction of 5 with several aldehydes Table 4. HWE reaction of 7 and 8 with several aldehydes
2429
R
R
O
Me
O
O
Ph
Me
O
Ph
+
RCHO
+
RCHO
Ph
N
Ph
R
N
N
H
5
R
N
H
8
DBU/LiCl
THF, r.t.
DBU/LiCl
THF, r.t.
OH
OH
Me
Me
Ph
Ph
(Z)-14a-f
(E)-14a-f
(Z)-12a-f
(E)-12a-f
Entry
R
Yielda (%)
(E):(Z)b
Entry
R
Yielda (%)
(E):(Z)b
1
2
3
4
5
6
7
8
a
b
c
d
e
f
C6H5
89
84
87
89
81
89
97
88
98:02
98:02
98:02
98:02
98:02
90:10
70:30c
94:06c
1
2
3
4
5
6
7
8
a
b
c
d
e
f
C6H5
93
94
91
92
99
99
95
93
98:02
98:02
98:02
98:02
81:19
85:15
95:05c
95:05c
p-Cl–C6H4
p-MeO–C6H4
t-Bu
i-Bu
i-Pr
p-Cl–C6H4
p-MeO–C6H4
t-Bu
i-Pr
i-Bu
f
i-Pr
i-Bu
e
f
i-Pr
i-Bu
e
a Isolated yield after purification by column chromatography.
b The E:Z ratio was determined by 1H NMR in the crude product.
c The reaction was carried out using the phosphonoacetamide 7.
a Isolated yield after purification by column chromatography.
b The E:Z ratio was determined by 1H NMR on the crude product.
c The reaction was carried out in toluene at 100 ꢁC.
ment, in which 6 and 8 were submitted to the reaction
conditions in the absence of the aldehyde at room temper-
ature and 50 ꢁC, recovering the corresponding phospho-
noacetamides 6 and 8 without any loss in specific rotation.
50 ꢁC the chiral a,b-unsaturated amides 13e–f were ob-
tained with better E-selectivities (Table 3, entries 7 and 8).
Table 3. HWE reaction of 6 with several aldehydes
R
O
O
Ph
Ph
O
O
+
RCHO
3. Conclusions
N
H
R
N
H
6
DBU/LiCl
THF, r.t.
OMe
OMe
In conclusion, we have developed a practical and efficient
methodology for the synthesis of chiral phosphonoaceta-
mides 4–8, and chiral a,b-unsaturated amides 11–14 in
excellent E-selectivity under thermodynamic control. These
chiral (E)-a,b-unsaturated amides should be excellent
building blocks in organic synthesis.
(Z)-13a-f
(E)-13a-f
Entry
R
Yielda (%)
(E):(Z)b
1
2
3
4
5
6
7
8
a
b
c
d
e
f
C6H5
80
90
90
70
88
90
90
91
98:02
98:02
98:02
98:02
47:53
65:35
62:38c
83:17c
p-Cl–C6H4
p-MeO–C6H4
t-Bu
i-Pr
i-Bu
i-Pr
i-Bu
e
f
4. Experimental
a Isolated yield after purification by column chromatography.
b The E:Z ratio was determined by 1H NMR on the crude product.
c The reaction was carried out at 50 ꢁC.
Optical rotations were taken on a Perkin–Elmer 241 polar-
imeter in a 1 dm tube; concentrations are given in
g/100 mL. For the flash chromatography, Silica Gel 60
1
(230–400 mesh ASTM) was used. H NMR spectra were
registered on a Varian Mercury 200 and 300 MHz, INOVA
400 (400 MHz) and 13C NMR on a Varian Mercury 50 and
75 MHz, and INOVA (100 MHz), and 31P NMR on a Var-
ian Mercury 200 (81 MHz). The spectra were recorded in
CDCl3, DMSO-d6 and CD3OD solution, using TMS as
the internal reference. HRMS spectra were recorded on a
JEOL JMS-700. Microanalyses were registered on an Ele-
mental VARIO EL III. Flasks, stirrings bars, and hypoder-
mic needles used for the generation of organometallic
compounds were dried for ca. 12 h at 120 ꢁC and allowed
to cool in desiccators over anhydrous calcium sulfate.
Anhydrous solvents (ethers) were obtained by distillation
from benzophenone ketyl.
Finally, an excellent E-selectivity and good yield were ob-
tained in the reaction of phosphonoacetamide 8 with benz-
aldehyde, p-chlorobenzaldehyde, p-methoxybenzaldehyde,
trimethylacetaldehyde and isovaleraldehyde (Table 4,
entries 1–5), where only the (S)-(E)-a,b-unsaturated amides
14a–e were detected by 1H NMR, whereas the reaction of 8
with isobutyraldehyde afforded the a,b-unsaturated amides
14f with a selectivity E:Z = 90:10 and 89% (Table 4, entry
5). On the other hand, the reaction of 7 with isobutyralde-
hyde gave the a,b-unsaturated amides 14f with a selectivity
E:Z = 70:30 and 97% yield (Table 4, entry 7), whereas the
reaction with isovaleraldehyde produced the chiral a,b-
unsaturated amides 14e with a selectivity E:Z = 94:06
and 88% yield (Table 4, entry 8). These results show that
diethylphosphonoacetamide 8 gave an E-selectivity higher
than dimethylphosphonoacetamide 7.
4.1. Typical procedure for the preparation of chiral
a-bromoacetamides
No loss in the enantiomeric purity for phosphonoaceta-
To a mixture of K2CO3 (0.77 g, 5.6 mmol) and (S)-(a-
mides 6 and 8 was observed in the process by control experi-
methylbenzyl)benzylamine (0.85 g, 4.0 mmol) in dichloro-

2430
M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 18 (2007) 2427–2436
methane/water (3:2) (50 mL) at 0 ꢁC, was added dropwise
bromoacetyl bromide (0.81 g, 0.82 mL, 4.0 mmol). The
reaction mixture was stirred overnight at 25 ꢁC, quenched
with water (30 mL) and extracted with dichloromethane
(3 · 30 mL). The combined organic extracts were dried
over anhydrous Na2SO4, filtered and concentrated
in vacuum. The crude product was purified by flash column
chromatography on silica gel (Hex/EtOAc, 9:1), obtaining
(S)-2-bromoacetyl-(a-methylbenzyl)benzylamine 1 (1.29 g,
(CH3O)2P), 3.83* (d, J = 11.2 Hz, 3H, (CH3O)2P), 3.86*
(d, J = 11.2 Hz, 3H, (CH3O)2P), 4.01* (AB system,
J = 15.8 Hz, 1H, CH2Ph), 4.31 (AB system, J = 18.4 Hz,
1H, CH2Ph), 4.66 (AB system, J = 18.4 Hz, 1H, CH2Ph),
4.97* (AB system, J = 15.8 Hz, 1H, CH2Ph), 5.40* (q,
J = 6.8 Hz, 1H, CH(CH3)Ph), 6.15 (q, J = 7.2 Hz, 1H,
CH(CH3)Ph), 7.08–7.37 (m, 10H, Harom), 7.08–7.37* (m,
10H, Harom). 13C NMR (72:28 rotamer ratio, asterisk de-
notes minor rotamer peaks, 100 MHz, CDCl3, 25 ꢁC): d
17.3 (CH3(CH)Ph), 19.5* (CH3(CH)Ph), 33.4* (d, J =
132.8 Hz, CH2P), 33.9 (d, J = 132.8 Hz, CH2P), 46.7*
(CH2Ph), 47.9 (CH2Ph), 52.5 (CH(CH3)Ph), 53.3 (d,
J = 5.7 Hz, (CH3O)2P), 53.4* (d, J = 6.9 Hz, (CH3O)2P),
53.5 (d, J = 6.9 Hz, (CH3O)2P), 53.6* (d, J = 6.9 Hz,
(CH3O)2P), 57.3* (CH(CH3)Ph), 125.9, 126.8*, 126.8,
127.2*, 127.4, 127.5, 127.6*, 127.9*, 128.4, 128.6*, 128.9,
137.8, 138.7*, 140.4*, 140.6, 165.7* (d, J = 6.1, (C@O)),
166.3 (d, J = 6.1, (C@O)). 31P NMR (121 MHz, DMSO-
d6, 100 ꢁC): d 24.85. HRMS (FAB+, CH4) m/z: (MH+)
calcd for C19H25O4NP, 362.1521; found, 362.1510.
1
95%) as a viscous oil, [a]D = ꢀ115.1 (c 2.8, CHCl3). H
NMR (300 MHz, DMSO-d6, 100 ꢁC): d 1.41 (d, J =
7.2 Hz, 3H, CH3(CH)Ph), 4.06–4.17 (m, 3H, CH2Br and
CH2Ph), 4.55 (AB system, J = 16.7 Hz, 1H, CH2Ph), 5.45
(br, 1H, CH(CH3)Ph), 7.04–7.30 (m, 10H, Harom). 13C
NMR (75 MHz, DMSO-d6, 100 ꢁC): d 18.6 (CH3(CH)Ph),
46.8 (CH2Ph), 54.4 (CH(CH3)Ph), 61.5 (CH2Br), 127.2,
127.6, 127.8(2), 128.7, 129.0, 139.1, 141.5, 173.0 (C@O).
HRMS (CI+, CH4) m/z: (MH+) calcd for C17H19BrNO,
332.0650; found, 332.0656. Anal. Calcd for C17H18BrNO:
C, 61.46; H, 5.46; N, 4.22. Found: C, 61.62; H, 5.55; N,
4.33.
4.2.1. (S,S)-2-(Dimethoxyphosphorylacetyl)-bis(a-methyl-
benzyl)amine 5. The crude product was purified by flash
column chromatography EtOAc/Hex/MeOH (5:4:1), to
give (S,S)-5 (95%) as viscous oil, [a]D = ꢀ112.3 (c 2.02,
4.1.1. (S,S)-2-Bromoacetyl-bis(a-methylbenzyl)amine 2.
The crude product was purified by flash column chromato-
graphy on silica gel (Hex/EtOAc, 7:3), obtaining (S,S)-2
(97%) as a white solid, mp 93–94 ꢁC, [a]D = ꢀ127 (c
3.52, CHCl3); lit.28 mp 94–95 ꢁC, [a]D = ꢀ125 (c 3.52,
CHCl3).
1
CHCl3). H NMR (300 MHz, DMSO-d6, 120 ꢁC): d 1.69
(d, J = 6.9 Hz, 3H, CH3(CH)Ph), 3.08 (dd, JH/P = 21.3,
Jgem = 9.0 Hz, 1H, CH2P), 3.11 (dd, JH/P = 21.3, Jgem
=
9.0 Hz, 1H, CH2P), 3.64 (d, J = 10.9 Hz, 3H, (CH3O)2P),
3.65 (d, J = 10.9 Hz, 3H, (CH3O)2P), 5.05 (br, 1H,
CH(CH3)Ph), 7.09–7.14 (m, 10H, Harom). 13C NMR
(75 MHz, DMSO-d6, 120 ꢁC): d 19.4 (CH3(CH)Ph), 34.9
(d, J = 133.2 Hz, CH2P), 53.2 (d, J = 6.2 Hz, (CH3O)2P),
53.3 (d, J = 6.2 Hz, (CH3O)2P), 54.9 (CH(CH3)Ph),
127.3, 128.1, 128.3, 141.7, 165.0 (d, J = 5.1, (C@O)). 31P
NMR (121 MHz, DMSO-d6, 100 ꢁC): d 25.86. HRMS
(CI+, CH4) m/z: (MH+) calcd for C20H27NO4P, 376.1678;
found, 376.1668.
4.1.2. (S)-Methyl 2-(2-bromoacetamide)-2-phenylacetate
3. The crude product was purified by flash column chro-
matography on silica gel (Hex/EtOAc, 50:50), obtaining
(S)-3 (91%) as a white solid, mp 72 ꢁC, [a]D = +120.79 (c
1
1.16, CHCl3). H NMR (400 MHz, CDCl3, 25 ꢁC): d 3.75
(s, 3H, CO2CH3), 3.86 (AB system, J = 13.6 Hz, 1H,
CH2Br), 3.91 (AB system, J = 13.6 Hz, 1H, CH2Br), 5.54
(d, J = 7.2 Hz, 1H, CHPh), 7.36–7.38 (m, 5H, Harom),
7.48 (d, J = 7.2 Hz, 1H, NH). 13C NMR (100 MHz,
CDCl3, 25 ꢁC): d 28.9 (CH2Br), 53.2 (CO2CH3), 57.1
(CHPh), 127.3, 128.9, 129.2, 135.8, 165.0 (CONH), 170.8
(CO2CH3). HRMS (CI+, CH4) m/z: (MH+) calcd for
C11H13BrNO3, 286.0079; found, 286.0069.
4.2.2. (S)-Methyl 2-[2-(dimethoxyphosphoryl)acetamide]2-
phenylacetate 6. The crude product was purified by flash
column chromatography (EtOAc/Hex/MeOH, 5:3:2) to
give the chiral phosphonoacetamide (S)-6 (92%) as a white
1
4.2. Typical procedure for the preparation of the a-
(dimethoxyphosphoryl)acetamides
solid, mp 66–67 ꢁC, [a]D = +122.75 (c 1.06, CHCl3). H
NMR (400 MHz, CDCl3): d 2.90 (dd, JH/P = 19.0 Hz,
Jgem = 15.6 Hz, 1H, CH2P), 2.96 (dd, JH/P = 19.0,
Jgem = 15.6 Hz, 1H, CH2P), 3.71 (d, J = 10.8 Hz, 3H,
(CH3O)2P), 3.72 (s, 3H, CO2CH3), 3.82 (d, J = 10.8 Hz,
3H, (CH3O)2P), 5.55 (d, J = 7.0 Hz, 1H, CHPh), 7.30–
7.41 (m, 5H, Harom), 7.74 (d, J = 7.0 Hz, 1H, NH). 13C
NMR (100 MHz, CDCl3): d 34.4 (d, JC/P = 131.3 Hz,
CH2P), 53.0 (CO2CH3), 53.3 (d, J = 6.1 Hz, (CH3O)2P),
53.5 (d, J = 6.1 Hz, (CH3O)2P), 57.1 (CHPh), 127.4,
128.7, 129.1, 136.0, 163.3 (d, J = 3.8 Hz, CONH), 170.9
(CO2CH3). 31P NMR (81 MHz, CDCl3): d 25.86. HRMS
(CI+, CH4) m/z: (MH+) calcd for C13H19NO6P, 316.0950;
found, 316.0943.
A mixture of 1 (1.3 g, 3.9 mmol) and trimethyl phosphite
(1.45 g, 1.38 mL, 11.7 mmol) without solvent was heated
for 5 h at 105–110 ꢁC. The reaction mixture was cooled
and the volatile materials were evaporated in a Kugel-rohr
under a reduced pressure, after which the crude product
was purified by flash column chromatography (EtOAc/
Hex/MeOH, 5:3:2) to give (S)-2-(dimethoxyphosphoryl-
acetyl)-(a-methylbenzyl)benzylamine 4 (1.38 g, 98%) as a
viscous oil, [a]D = ꢀ80.5 (c 2.14, CHCl3). 1H NMR
(72:28 rotamer ratio, asterisk denotes minor rotamer
peaks, 400 MHz, CDCl3, 25 ꢁC): d 1.47 (d, J = 7.2 Hz,
3H, CH3CH), 1.53* (d, J = 6.8 Hz, 3H, CH3CH), 2.94
(dd, JH/P = 31 Hz, Jgem = 14.8 Hz, 1H, CH2P), 2.99* (dd,
JH/P = 31, Jgem = 14.8 Hz, 1H, CH2P), 3.22 (dd, JH/
P = 23, Jgem = 14.8 Hz, 1H, CH2P), 3.28* (dd, JH/P = 23,
Jgem = 14.8 Hz, 1H, CH2P), 3.78 (d, J = 11.2 Hz, 6H,
4.2.3. (S)-2-(2-Dimethoxyphosphoryl)acetamide-2-phenyl-
ethanol 7. To a solution of 6 (0.4 g, 1.27 mmol) in dry
THF (20 mL) at 0 ꢁC, sodium borohydride 290 mg,
(7.62 mmol) was added. The resulting solution was heated

M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 18 (2007) 2427–2436
2431
for 20 min at reflux, and then methanol (4 mL) was added
dropwise and refluxed for an additional period of 60 min.
After this time, the reaction mixture was cooled and an
HCl/i-PrOH solution was added until pH 3–4. The solid
was filtered and purified by column chromatography
(EtOAc/Hex/i-PrOH, 5:3:3), to obtain the chiral phospho-
a saturated NH4Cl solution, and extracted with ethyl ace-
tate (3 · 40 mL). The combined extracts were washed with
water (30 mL) followed by brine (30 mL), dried over
Na2SO4 and concentrated in vacuum. The E:Z ratio was
determined by H NMR on the crude product, and then
the (S)-(E)-a,b-unsaturated amides were purified by flash
1
noacetamide (S)-7 (0.32 g, 89%) as
a
viscous oil,
chromatography.
[a]D = +34.5 (c 2.98, CHCl3). 1H NMR (400 MHz,
CDCl3): d 2.93 (dd, JH/P = 16.8, Jgem = 14.8 Hz, 1H,
CH2P), 2.87 (dd, JH/P = 16.8, Jgem = 14.8 Hz, 1H, CH2P),
4.3.1. (S)-(E)-N-(Cinnamoyl)-(a-methylbenzyl)benzylamine
11a. (350 mg, 93%), as a viscous oil, [a]D = ꢀ182.8 (c
1
3.65 (d, J = 11.4 Hz, 3H, (CH3O)2P), 3.73 (ddd, Jgem
=
4.80, CHCl3). H NMR (300 MHz, DMSO-d6, 100 ꢁC): d
11.6, J = 5.0, J = 1.2 Hz, 1H, CH2OH), 3.74 (d,
J = 11.4 Hz, 3H, (CH3O)2P), 3.80 (ddd, Jgem = 11.6,
J = 7.6, J = 1.2 Hz, 1H, CH2OH), 5.04 (ddd, J = 7.6,
J = 5.0 Hz, 1H, CHPh), 7.18–7.30 (m, 5H, Harom), 7.65
(d, J = 7.6 Hz, 1H, NH). 13C NMR (100 MHz, CDCl3): d
34.8 (d, J = 130.5 Hz, CH2P), 53.3 (d, J = 6.8 Hz,
(CH3O)2P), 53.7 (d, J = 6.8 Hz, (CH3O)2P), 66.0
(CH2OH), 126.8, 127.7, 128.7, 139.0, 164.1 (d, J =
4.6 Hz, CONH). 31P NMR (81 MHz, CDCl3): d 26.77;.
HRMS (CI+, CH4) m/z: (MH+) calcd for C12H19NO5P,
288.0995; found, 288.0979.
1.49 (d, J = 6.6 Hz, 3H, CH3(CH)Ph), 4.36 (AB system,
J = 17.0 Hz, 1H, CH2Ph), 4.78 (AB system, J = 17.0 Hz,
1H, CH2Ph), 5.81 (q, J = 6.6 Hz, 1H, CH(CH3)Ph), 7.02
(d, Jtrans = 15.4 Hz, 1H, CHC@O), 7.18–7.50 (m, 15Harom),
7.56 (d, Jtrans = 15.4 Hz, 1H, CH–Ph). 13C NMR (75 MHz,
DMSO-d6, 100 ꢁC): d 18.8 (CH3(CH)Ph), 47.6 (CH2Ph),
54.4 (CH(CH3)Ph), 120.6, 127.2, 127.3, 127.7, 127.7,
128.3, 128.8, 128.9, 129.3 129.9, 135.9, 140.0, 141.9,
142.2, 167.2 (C@O). HRMS (CI+, CH4) m/z: (MH+) calcd
for C24H24NO, 342.1858; found, 342.1865.
4.3.2. (S)-(E)-N-(p-Chlorocinnamoyl)-(a-methylbenzyl)benz-
4.2.4.
ethanol 8.
(S)-2-(2-Diethoxyphosphoryl)acetamide-2-phenyl-
solution of dicyclohexylcarbodiimide
ylamine 11b. (390 mg, 94%), as
a
viscous oil,
A
[a]D = ꢀ170.7 (c 3.03 CHCl3). 1H NMR (300 MHz,
(DCC) (1.51 g, 7.3 mmol), 4-(N,N-dimethylamino)pyridine
(DMAP) (80 mg, 0.66 mmol) in 70 mL of dry dichloro-
methane was slowly added under an inert atmosphere at
0 ꢁC to a solution of L-phenylglycinol (1.0 g, 7.3 mmol)
and 2-(diethoxyphosphoryl)acetic acid 10 (1.57 g,
8.03 mmol) in 70 mL of dry dichloromethane. The reaction
mixture was stirred for 12 h at room temperature, filtered
and concentrated in vacuum. The crude product was puri-
fied by column chromatography (EtOAc/Hex/i-PrOH,
5:3:3) obtaining phosphonoacetamide (S)-8 (2.14 g, 93%
DMSO-d6, 100 ꢁC):
d
1.49 (d, J = 6.9 Hz, 3H,
CH3(CH)Ph), 4.35 (AB system, J = 16.9 Hz, 1H, CH2Ph),
4.78 (AB system, J = 16.9 Hz, 1H, CH2Ph), 5.81 (q,
J = 6.9 Hz, 1H, CH(CH3)Ph), 7.10 (d, Jtrans = 15.1 Hz,
1H, CHC@O), 7.14–7.56 (m, 14Harom
)
7.54 (d,
Jtrans = 15.1 Hz, 1H, CH(p-ClC6H4)). 13C NMR
(75 MHz, DMSO-d6, 100 ꢁC): d 18.6, (CH3(CH)Ph), 47.6
(CH2Ph), 54.6 (CH(CH3)Ph), 121.2, 127.2, 127.3, 127.6,
127.8, 128.8, 129.0, 129.3, 129.8, 134.6, 134.8, 139.6,
140.7, 141.8, 167.3 (C@O). HRMS (CI+, CH4) m/z:
(MH+) calcd for C24H23ClNO, 376.1468; found, 376.1466.
1
yield) as a viscous oil, [a]D = +41.8 (c 2.88, CHCl3). H
NMR (400 MHz, CDCl3): d 1.25 (t, J = 6.8 Hz, 3H,
(CH3CH2O)2P), 1.31 (t, J = 6.8 Hz, 3H, (CH3CH2O)2P),
2.91 (dd, JH/P = 18.4, Jgem = 14.4 Hz, 1H, CH2P), 2.96
(dd, JH/P = 18.4, Jgem = 14.4 Hz, 1H, CH2P), 3.77 (ddd,
Jgem = 10.8, J = 6.8, J = 1.2 Hz, 1H, CH2OH), 3.82 (ddd,
Jgem = 10.8, J = 4.4, J = 1.2 Hz, 1H, CH2OH), 4.05 (dq,
4.3.3. (S)-(E)-N-(p-Methoxycinnamoyl)-(a-methylbenzyl)-
benzylamine 11c. (400 mg, 97%), as
a viscous oil,
[a]D = ꢀ185.3 (c 2.42, CHCl3). 1H NMR (400 MHz,
DMSO-d6, 120 ꢁC):
d
1.51 (d, J = 6.6 Hz, 3H,
CH3(CH)Ph), 3.78 (s, 3H, CH3O), 4.37 (AB system,
J = 16.8 Hz, CH2Ph), 4.78 (AB system, J = 16.8 Hz,
CH2Ph), 5.82 (q, J = 6.6 Hz, 1H, CH(CH3)Ph), 6.91
(AA0BB0 system, J = 8.8 Hz, 2H, Harom), 7.20 (d,
Jtrans = 15.2 Hz, 1H, CHC@O ), 7.17–7.46 (m, 12H,
Harom), 7.54 (d, Jtrans = 15.2 Hz 1H, CHAr). 13C NMR
(100 MHz, DMSO-d6, 120 ꢁC): d 17.4 (CH3(CH)Ph), 46.3
(CH2Ph), 54.8 (CH(CH3)Ph), 54.8 (CH3O), 113.8, 116.8,
125.8, 126.0, 126.3, 126.4, 127.4, 127.6, 128.6, 138.9,
140.5, 140.6, 141.0, 160.0, 166.1 (C@O). HRMS (Cl+,
CH4) m/z: (MH+) calcd for C25H26NO2, 372.1964; found,
372.1956.
JH/P = 14.0, J = 6.8 Hz, 2H, CH2OP), 4.14 (dq, JH/P
=
14.0, J = 6.8 Hz, 2H, CH2O–P), 5.05–5.09 (m, 1H, CHPh),
7.23–7.35 (m, 5H, Harom), 7.72 (br, 1H, NH). 13C NMR
(100 MHz, CDCl3):
d
16.5 ((CH3CH2O)2P), 16.6
((CH3CH2O)2P), 35.0 (d, J = 129.0 Hz, CH2P), 56.3
(CH2OH), 63.0 (d, J = 6.8 Hz), (CH2OP), 63.4 (d,
J = 6.8 Hz, CH2OP), 65.9 (CH2Ph), 126.8, 127.6, 128.6,
139.1, 164.4 (CONH).31P NMR (81 MHz, CDCl3): d
24.07. HMRS (CI+, CH4) m/z: (MH+) calcd for
C14H23NO5P, 316.1314; found, 316.1301.
4.3. General procedure for the HWE reaction
4.3.4. (S)-(E)-N-(3-tert-Butylacryloyl)-(a-methylbenzyl)benz-
ylamine 11d. (330 mg, 92%), as a white solid, mp 63–
64 ꢁC, [a]D = ꢀ156.3 (c 2.63, CHCl3). 1H NMR
(300 MHz, DMSO-d6, 100 ꢁC): d 0.92 (s, 9H, (CH3)3C),
1.46 (d, J = 6.9 Hz, 3H, CH3(CH)Ph), 4.31 (AB system,
J = 16.8 Hz, 1H, CH2Ph), 4.64 (AB system, J = 16.8 Hz,
A solution of phosphonoacetamides 4–8 (1.0 equiv) in dry
THF (30 mL) was treated under a nitrogen atmosphere
with 8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.0 equiv)
and lithium chloride (3.0 equiv) at room temperature. After
stirring for 5 min, the corresponding aldehyde (1.0 equiv)
was added and the reaction mixture stirred for 4 h at room
temperature. The reaction was quenched by the addition of
1H, CH2Ph), 5.69 (br, 1H, CH(CH3)Ph), 6.08 (d, Jtrans
=
15.3 Hz, 1H, CHC@O), 6.68 (d, Jtrans = 15.3 Hz, 1H,

2432
M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 18 (2007) 2427–2436
CH(CH3)3), 7.10–7.33 (m, 10H, Harom). 13C NMR
(75 MHz, DMSO-d6, 100 ꢁC): d 18.6(CH3(CH)Ph), 29.4
((CH3)3C), 33.8 (C(CH3)3), 47.8 (CH2Ph), 54.2
(CH(CH3)Ph), 118.6, 127.2, 127.3, 127.6, 127.7, 128.7,
128.9, 139.9, 142.2, 155.3, 167.8 (C@O). HRMS (Cl+,
CH4) m/z: (MH+) calcd for C22H28NO, 322.2171; found,
322.2166.
CH3(CH)Ph), 5.31 (br, 2H, CH(CH3)Ph), 6.61 (d,
Jtrans = 15.4 Hz, 1H, CHC@O), 7.08–7.30 (m, 14H, Harom),
7.28 (d, Jtrans = 15.4 Hz, 1H, CH(p-ClC6H4)). 13C NMR
(75 MHz, DMSO-d6, 100 ꢁC): d 19.7 (CH3(CH)Ph), 53.5
(CH(CH3)Ph), 123.1, 127.6, 127.8, 128.6, 129.3, 129.6,
134.6, 134.7, 139.2, 142.0, 166.4 C@O. HRMS (FAB+,
CH4) m/z: (MH+) calcd for C25H25ClNO, 390.1625; found,
390.1638. Anal. Calcd for C25H24ClNO: C, 77.01; H, 6.20;
N, 3.59. Found: C, 76.98; H, 6.29; N, 3.69.
4.3.5.
benzylamine 11e. (320 mg, 94%), as a viscous oil. 1H
NMR (300 MHz, DMSO-d6, 100 ꢁC): 0.91 (d,
(S)-(E)-N-(3-iso-Propylacryloyl)-(a-methylbenzyl)-
d
4.3.9. (S,S)-(E)-N-(p-Methoxycinnamoyl)-bis(a-methylbenz-
yl)amine 12c. (374 mg, 91%), as a white solid, mp 102–
103 ꢁC, [a]D = +56.4 (c 3.77, CHCl3). 1H NMR
(400 MHz, DMSO-d6, 120 ꢁC): d 1.75 (d, J = 7.2 Hz, 6H,
CH3(CH)Ph), 3.77 (s, 3H, CH3O), 5.37 (q, J = 7.2 Hz,
2H, CH(CH3)Ph), 6.57 (d, Jtrans = 15.2 Hz, 1H, CHC@O),
6.88 (AA0BB0 system, J = 8.4 Hz, 2H, Harom), 7.14–7.21
(m, 10H, Harom), 6.30 (AA0BB0 system, J = 8.4 Hz, 2H,
Harom), 7.38 (d, Jtrans = 15.2 Hz, 1H, CH(p-MeOC6H4)).
J = 6.8 Hz, 3H, (CH3)2CH), 0.92 (d, J = 6.8 Hz, 3H,
(CH3)2CH), 1.45 (d, J = 7.2 Hz, 3H, CH3(CH)Ph), 2.31–
2.38 (m, 1H, CH(CH3)2), 4.28 (AB system, J = 16.8 Hz,
1H, CH2Ph), 4.65 (AB system, J = 16.8 Hz, 1H, CH2Ph),
5.69 (br, 1H, CH(CH3)Ph), 6.19 (d, Jtrans = 15.1 Hz, 1H,
CHC@O), 6.70 (dd, Jtrans = 15.1 Hz, J = 6.8 Hz, 1H,
CHi-Pr), 7.15–7.34 (m, 10H, Harom). 13C NMR
(100 MHz, DMSO-d6, 100 ꢁC): d 18.7 (CH3(CH)Ph), 22.1
((CH3)2CH), 30.9, (CH(CH3)2), 47.6 (CH2Ph), 54.2
(CH(CH3)Ph), 120.3, 127.1, 127.3, 127.6, 128.7, 128.9,
128.9, 140.0, 142.3, 151.8, 167.4 (C@O). HRMS (Cl+,
CH4) m/z: (MH+) calcd for C21H26NO, 308.2014; found,
308.2009.
13C NMR (100 MHz, DMSO-d6, 120 ꢁC):
d
19.1
(CH3(CH)Ph), 52.7 (CH(CH3)Ph), 55.4 (CH3O), 114.4,
119.4, 126.6, 127.1, 127.8, 128.0, 128.9, 139.6, 141.7,
160.4, 165.9 C@O. HRMS (FAB+, CH4) m/z: (MH+) calcd
for C26H28NO2, 386.2120; found, 386.2137. Anal. Calcd
for C26H27NO2: C, 81.01; H, 7.06; N, 3.63. Found: C,
81.08; H, 7.18; N, 3.75.
4.3.6. (S)-(E)-N-(3-iso-Butylacryloyl)-(a-methylbenzyl)benz-
ylamine 11f. (340 mg, 95%), as
a
viscous oil,
[a]D = ꢀ142.8 (c 2.0, CHCl3). 1H NMR (300 MHz,
DMSO-d6, 100 ꢁC): d 0.81 (d, J = 6.6 Hz, 3H, (CH3)2CH),
0.82 (d, J = 6.6 Hz, 3H, (CH3)2CH), 1.44 (d, J = 7.2 Hz,
3H, CH3(CH)Ph), 1.64 (n, J = 6.6 Hz, 1H, CH(CH3)2),
2.01 (t, J = 6.6 Hz, 2H, CH2CH(CH3)2), 4.26 (AB system,
J = 17.1 Hz, 1H, CH2Ph), 4.65 (AB system, J = 17.1 Hz,
1H, CH2Ph), 5.69 (br, 1H, CH(CH3)Ph), 6.27 (d,
Jtrans = 14.7 Hz, 1H, CHC@O), 6.72 (dt, Jtrans = 15.0 Hz,
J = 7.2 Hz, 1H, CHCH2i-Pr), 7.10–7.34 (m, 10H, Harom).
4.3.10. (S,S)-(E)-N-(3-tert-Butylacryloyl)-bis(a-methylbenz-
yl)amine 12d. (330 mg, 92%), as a white solid, mp 114 ꢁC,
[a]D = ꢀ170.9 (c 3.64, CHCl3). 1H NMR (300 MHz,
DMSO-d6, 100 ꢁC): d 0.79 (s, ((CH3)3C)), 1.65 (d,
J = 7.2 Hz, 6H, CH3(CH)Ph), 5.31 (br, 2H, CH(CH3)Ph),
5.67 (d, Jtrans = 15.4 Hz, 1H, CH@CO), 6.49 (d,
Jtrans = 15.4 Hz, 1H, CHC(CH3)3), 7.08–7.19 (m, 10H,
Harom). 13C NMR (75 MHz, DMSO-d6, 100 ꢁC): d 19.7
(CH3(CH)Ph), 29.3 ((CH3)3C), 33.6 (C(CH3)3), 52.8
(CH(CH3)Ph), 120.4, 127.5, 127.7, 128.6, 142.2, 154.0,
167.2 C@O. HRMS (FAB+, CH4) m/z: (MH+) calcd for
C23H30ON, 336.2327; found, 336.2332. Anal. Calcd for
C23H29ON: C, 82.34; H, 8.71; N, 4.18. Found: C, 82.54;
H, 8.81; N, 4.22.
13C NMR (100 MHz, DMSO-d6, 100 ꢁC):
d
18.7
(CH3(CH)Ph), 22.7 ((CH3)2CH), 22.8 ((CH3)2CH), 28.1
(CH2CH(CH3)2), 41.6 (CH(CH3)2), 47.4 (CH2Ph), 54.1
(CH(CH3)Ph), 123.9, 127.1, 127.2, 127.6, 127.7, 128.7,
128.9, 140.0, 142.2, 144.3, 167.2 (C@O). HRMS (Cl+,
CH4) m/z: (MH+) calcd for C22H28NO, 322.2171; found,
322.2163.
4.3.11. (S,S)-(E)-N-(3-iso-Propylacryloyl)-bis(a-methylbenz-
1
yl)amine 12e. (340 mg, 99%), as a viscous oil. H NMR
4.3.7. (S,S)-(E)-N-(Cinnamoyl)-bis(a-methylbenzyl)amine
12a. (352 mg, 93%), as a white solid, mp 151–152 ꢁC,
[a]D = +6.8 (c 3.22, CHCl3). 1H NMR (400 MHz,
(300 MHz, DMSO-d6, 100 ꢁC): d 0.82 (d, J = 6.7 Hz, 3H,
(CH3)2CH), 0.84 (d, J = 6.7 Hz, 3H, (CH3)2CH), 1.68 (d,
J = 7.2 Hz, 6H, CH3(CH)Ph), 2.20–2.27 (m, 1H,
CH(CH3)2), 5.30 (q, J = 7.2 Hz, 2H, CH(CH3)Ph), 5.87
(dd, Jtrans = 15, Jallylic = 1.2 Hz, 1H, CHC@O), 6.55 (dd,
Jtrans = 15, J = 6.7 Hz, 1H, CHi-Pr), 7.10–7.20 (m, 10H,
Harom). 13C NMR (75 MHz, DMSO-d6, 100 ꢁC): d 19.7
(CH3(CH)Ph), 21.9 ((CH3)2CH), 22.0 ((CH3)2CH), 30.7
(CH(CH3)2), 53.0 (CH(CH3)Ph), 122.2, 127.3, 127.8,
128.5, 142.4, 150.2, 166.7 C@O. HRMS (CI+, CH4) m/z:
(MH+) calcd for C22H28ON, 322.2171; found, 322.2169.
DMSO-d6, 110 ꢁC):
d
1.75 (d, J = 7.2 Hz, 6H,
CH3(CH)Ph), 5.38 (br, 2H, CH(CH3)Ph), 6.71 (d,
Jtrans = 15.8 Hz, 1H, CHC@O), 7.16–7.36 (m, 15H, Harom),
7.40 (d, Jtrans = 15.8 Hz, 1H, CHPh). 13C NMR (100 MHz,
DMSO-d6, 110 ꢁC):
d
18.9 (CH3(CH)Ph), 52.5
(CH(CH3)Ph), 121.5, 126.5, 127.0, 127.1, 127.6, 128.4,
128.9, 135.1, 139.6, 141.4, 165.4 C@O. HRMS (FAB+,
CH4) m/z: (MH+) calcd for C25H26NO, 356.2014; found,
356.2010. Anal. Calcd for C25H25NO: C, 84.47; H, 7.09;
N, 3.94. Found: C, 84.05; H, 7.14; N, 4.14.
4.3.12. (S,S)-(E)-N-(3-iso-Butylacryloyl)-bis(a-methylbenz-
yl)amine 12f. (360 mg, 99%), as a white solid, mp 64–
1
4.3.8. (S,S)-(E)-N-(p-Chlorocinnamoyl)-bis(a-methylbenz-
yl)amine 12b. (390 mg, 94%), as a white solid, mp 123–
124 ꢁC, [a]D = +48.3 (c 3.66, CHCl3). 1H NMR
(300 MHz, DMSO-d6, 100 ꢁC): d 1.69 (d, J = 6.9 Hz, 6H,
65 ꢁC, [a]D = ꢀ81.7 (c 1.66, CHCl3). H NMR (300 MHz,
DMSO-d6, 100 ꢁC): d 0.78 (d, J = 6.7 Hz, 3H, (CH3)2CH),
0.79 (d, J = 6.7 Hz, 3H, (CH3)2CH), 1.59 (m, 1H,
CH(CH3)2), 1.69 (d, J = 6.9 Hz, 6H, CH3(CH)Ph), 1.90

M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 18 (2007) 2427–2436
2433
(m, 2H, CH2i-Pr), 5.27 (q, J = 6.9 Hz, 2H, CH(CH3)Ph),
6.00 (dt, Jtrans = 15, Jallylic = 1.5 Hz, 1H, CHC@O), 6.57
(dt, Jtrans = 15, J = 7.2 Hz, 1H, CHi-Bu), 7.09–7.20 (m,
10H, Harom). 13C NMR (75 MHz, DMSO-d6, 100 ꢁC): d
19.8 (CH3(CH)Ph), 22.7 ((CH3)2CH), 22.8 ((CH3)2CH),
28.0 (CH2i-Pr), 41.6 (CH(CH3)2), 53.2 ((CH(CH3)Ph)),
125.9, 127.3, 127.8, 128.5, 142.3, 142.7, 166.4 C@O. HRMS
(CI+, CH4) m/z: (MH+) calcd for C23H30ON, 336.2327;
found, 336.2342.
((CH3)3CH), 33.7 (CH(CH3)3), 53.0 (CO2CH3), 56.5
(CHPh), 118.1, 127.4, 128.6, 129.0, 136.6, 156.0, 165.6
(CONH), 171.6 (CO2CH3). HRMS (CI+, CH4) m/z: calcd
for (MH+) C16H22NO3, 276.1600; found, 276.1606. Anal.
Calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found:
C, 69.79; H, 7.76; N, 5.19.
4.3.17. (S)-(E)-13e and (S)-(Z)-Methyl N-(3-iso-propylacry-
loyl)-2-amino-2-phenylacetate 13e.
4.3.17.1. (S)-(E)-Isomer 13e (more polar). (143 mg,
56%), as a white solid, mp 98–100 ꢁC, [a]D = +0.7 (c
2.37, CHCl3). 1H NMR (400 MHz, CDCl3): d 1.03 (d,
J = 7.0 Hz, 6H, (CH3)2CH), 2.42 (m, 1H, CH(CH3)2),
3.73 (s, 3H, CO2CH3), 5.67 (d, J = 7.2 Hz, 1H, CHPh),
5.80 (dd, Jtrans = 15.4, Jallylic = 1.5 Hz, 1H, CHCO), 6.59
(d, J = 7.2 Hz, 1H, NH), 6.85 (dd, Jtrans = 15.4,
J = 7.0 Hz, 1H, CHi-Pr), 7.31–7.39 (m, 5H, Harom). 13C
NMR (100 MHz, CDCl3): d 21.6 ((CH3)2CH), 21.6
((CH3)2CH), 30.9 (CH(CH3)2), 53.0 (CHPh), 56.5
(CO2CH3), 120.1, 127.4, 128.5, 129.0, 136.6, 152.3, 165.4
(CONH), 171.5 (CO2CH3). HRMS (CI+, CH4) m/z:
(MH+) calcd for C15H21NO3, 262.1438; found, 262.1461.
Anal. Calcd for C15H20NO3: C, 68.93; H, 7.33; N, 5.36.
Found: C, 68.80; H, 7.27; N, 5.43.
4.3.13. (S)-(E)-Methyl N-(cinnamoyl)-2-amino-2-phenylace-
tate 13a. (150 mg, 82%), as a white solid, mp 158 ꢁC,
[a]D = +39.9 (c 1.26, CHCl3). 1H NMR (400 MHz,
CDCl3): d 3.75 (s, 3H, CO2CH3), 5.74 (d, J = 6.8 Hz, 1H,
CHPh), 6.49 (d, Jtrans = 15.4 Hz, 1H, CHCO), 6.78 (d,
J = 6.8 Hz, 1H, NH), 7.33–7.49 (m, 10H, Harom), 7.63 (d,
Jtrans = 15.4 Hz, 1H, CHPh). 13C NMR (100 MHz,
CDCl3): d 53.1 (CO2CH3), 56.7 (CHPh), 119.9, 127.5,
128.1, 128.8, 128.9, 129.2, 130.1, 134.8, 136.7, 142.3,
165.3 (CONH), 171.7 (CO2Me). HRMS (CI+, CH4) m/z:
(MH+) calcd for C18H18NO3, 296.1281; found, 296.1287.
Anal. Calcd for C18H17NO3: C, 73.20; H, 5.80; N, 4.74.
Found: C, 73.17; H, 5.86; N, 4.81.
4.3.14. (S)-(E)-Methyl N-(p-chlorocinnamoyl)-2-amino-2-
phenylacetate 13b. (289 mg, 93%), as a white solid, mp
1
4.3.17.2. (S)-(Z)-Isomer 13e (less polar). (88 mg, 34%),
as a white solid, mp 125–126 ꢁC, [a]D = +7.2 (c 1.36,
183 ꢁC, [a]D = +69.8 (c 1.1 CHCl3). H NMR (400 MHz,
CDCl3): d 3.74 (s, 3H, CO2CH3), 5.71 (d, J = 7.0 Hz, 1H,
CHPh), 6.46 (d, Jtrans = 15.8 Hz, 1H, CHCO), 6.87 (d,
J = 7.0 Hz, 1H, NH), 7.29–7.40 (m, 9H, Harom), 7.56 (d,
Jtrans = 15.8 Hz, 1H, CHAr). 13C NMR (100 MHz,
CDCl3): d 53.1 (CO2CH3), 56.7 (CHPh), 120.5, 127.5,
128.8, 129.1, 129.2, 129.2, 133.2, 135.8, 136.5, 140.9,
165.0 (CONH), 171.7 (CO2CH3). HRMS (CI+, CH4)
m/z: (MH+) calcd for C18H17ClNO3, 330.0891; found,
330.0892. Anal. Calcd for C18H16ClNO3: C, 65.56; H,
4.89; N, 4.25. Found: C, 65.26; H, 4.94; N, 4.23.
CHCl3). 1H NMR (400 MHz, CDCl3):
d 0.97 (d,
J = 6.8 Hz, 3H, (CH3)2CH), 0.99 (d, J = 6.8 Hz, 3H,
(CH3)2CH), 3.57–3.69 (m, 1H, CH(CH3)2), 3.73 (s, 3H,
CO2CH3), 5.61 (d, J = 5.6 Hz, 1H, CHPh), 5.63 (dd,
Jcis = 10.4, Jallylic = 0.8 Hz, 1H, CHCO), 5.85 (dd,
Jcis = 10.4, J = 11.6 Hz, 1H, CHi-Pr), 6.50 (d, J = 5.6 Hz,
1H, NH), 7.31–7.39 (m, 5H, Harom). 13C NMR
(100 MHz, CDCl3): d 22.7 ((CH3)2CH), 22.8 ((CH3)2CH),
27.6 (CH(CH3)2), 53.0 (CHPh), 56.4 (CO2CH3), 119.0,
127.4, 128.6, 129.0, 136.7, 154.1, 165.4 (CONH), 171.5
(CO2CH3). HRMS (CI+, CH4) m/z: (MH+) calcd for
C15H21NO3, 262.1438; found, 262.1453. Anal. Calcd for
C15H20NO3: C, 68.93; H, 7.33; N, 5.36. Found: C, 68.78;
H, 7.31; N, 5.41.
4.3.15. (S)-(E)-Methyl N-(p-methoxycinnamoyl)-2-amino-2-
phenylacetate 13c. (271 mg, 86%), as a white solid, mp
146–147 ꢁC, [a]D = ꢀ2.2 (c 1.1, CHCl3). 1H NMR
(400 MHz, CDCl3): d 3.74 (s, 3H, CO2CH3), 3.81 (s, 3H,
CH3OAr), 5.73 (d, J = 7.0 Hz, 1H, CHPh), 6.36 (d,
Jtrans = 15.6 Hz, 1H, CHCO), 6.74 (d, J = 7.0 Hz, 1H,
NH), 6.86 (AA0BB0 system, J = 8.8 Hz, 2H, Harom), 7.33–
7.44 (m, 7H, Harom), 7.59 (d, Jtrans = 15.6 Hz, 1H, CHAr).
13C NMR (100 MHz, CDCl3): d 53.0 (CO2CH3), 56.7
(CHPh), 114.4, 117.5, 127.4, 127.5, 128.7, 129.1, 129.6,
136.8, 141.8, 161.2, 165.7 (CONH), 171.8 (CO2CH3).
HRMS (CI+, CH4) m/z: (MH+) calcd for C19H20NO4,
326.1387; found, 326.1379. Anal. Calcd for C19H19NO4:
C, 70.14; H, 5.89; N, 4.31. Found: C, 69.98; H, 5.90; N,
4.38.
4.3.18. (S)-(E)-13f and (S)-(Z)-Methyl N-(3-iso-butylacry-
loyl)-2-amino-2-phenylacetate 13f.
4.3.18.1. (S)-(E)-Isomer 13f (more polar). (203 mg,
75%), as a white solid, mp 100 ꢁC, [a]D = +86.15 (c 0.78,
CHCl3). 1H NMR (400 MHz, CDCl3):
d 0.90 (d,
J = 7.0 Hz, 3H, (CH3)2CH), 0.91 (d, J = 7.0 Hz, 3H,
(CH3)2CH), 1.73 (m, 1H, CH(CH3)2), 2.05 (dt, J = 7.0,
1.0 Hz, 2H, CH2i-Pr), 3.73 (s, 3H, CO2CH3), 5.66 (d,
J = 7.2 Hz, 1H, CHPh), 5.84 (dt, Jtrans = 15.1, Jallylic
=
1.2 Hz, 1H, CHC@O), 6.55 (d, J = 7.2 Hz, 1H, NH), 6.85
(dt, Jtrans = 15.1, J = 7.0 Hz, 1H, CHi-Bu), 7.30–7.39 (m,
5H, Harom). 13C NMR (100 MHz, CDCl3): d 22.6
((CH3)2CH), 22.6 ((CH3)2CH), 28.0 (CH(CH3)2), 41.6
(CH2i-Pr), 53.0 (CHPh), 56.5 (CO2CH3), 123.8, 127.4,
128.6, 129.0, 136.6, 145.1, 165.1 (CONH), 171.5 (CO2CH3).
HRMS (CI+, CH4) m/z: (MH+) calcd for C16H22NO3,
276.1594; found, 276.1609. Anal. Calcd for C16H21NO3:
C, 69.79; H, 7.69; N, 5.09. Found: C, 69.31; H, 7.65; N,
5.15.
4.3.16. (S)-(E)-Methyl N-(3-tert-butylacryloyl)-2-amino-2-
phenylacetate 13d. (184 mg, 70%), as a white solid, mp
133–134 ꢁC, [a]D = ꢀ1.1 (c 2.8, CHCl3). 1H NMR
(400 MHz, CDCl3): d 1.05 (s, 9H, (CH3)3C), 3.74 (s, 3H,
CO2CH3), 5.68 (d, J = 7.0 Hz, 1H, CHPh), 5.75 (d,
Jtrans = 15.4 Hz, 1H, CHCO), 6.56 (d, J = 7.0 Hz, 1H,
NH), 6.88 (d, Jtrans = 15.4 Hz, 1H, CHt-Bu), 7.31–7.40,
(m, 5H, Harom). 13C NMR (100 MHz, CDCl3): d 28.9

2434
M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 18 (2007) 2427–2436
4.3.18.2. (S)-(Z)-Isomer 13f (less polar). (41 mg, 16%),
as a white solid, mp 114–116 ꢁC, [a]D = +0.1 (c 0.6,
CHCl3). 1H NMR (400 MHz, CDCl3):
0.90 (d,
C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.85;
H, 6.44; N, 4.71.
d
J = 6.6 Hz, 3H, (CH3)2CH), 0.91 (d, J = 6.6 Hz, 3H,
(CH3)2CH), 1.69 (m, 1H, CH(CH3)2), 2.51 (m, 1H, CH2i-
Pr), 2.58 (m, 1H, CH2i-Pr), 3.73 (s, 3H, CO2CH3), 5.62
4.3.22. (S)-(E)-N-(3-tert-Butylacryloyl)-2-amino-2-phenyl-
ethanol 14d. (275 mg, 88%), as a white solid, mp 177 ꢁC,
[a]D = +97.5 (c 2.74, MeOH). 1H NMR (400 MHz,
CD3OD): d 1.08 (s, 9H, (CH3)3C), 3.72 (dd, Jgem = 11.6,
J = 7.2 Hz, 1H, CH2OH), 3.77 (dd, Jgem = 11.6,
J = 5.6 Hz, 1H, CH2OH), 5.05 (dd, J = 7.2, J = 5.6 Hz,
1H, CHPh), 5.99 (d, Jtrans = 15.6 Hz, 1H, CHC@O), 6.80
(d, Jtrans = 15.6 Hz, 1H, CHt-Bu), 7.24–7.34, (m, 5H, Harom).
13C NMR (100 MHz, CD3OD): d 29.3 ((CH3)3CH), 34.3
(CH(CH3)3), 57.2 (CH2OH), 66.3 (CHPh), 120.2, 128.1,
128.5, 129.6, 141.4, 155.9, 168.9 (C@O). Anal. Calcd for
C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.82;
H, 8.71; N, 5.87.
(d, J = 7.2 Hz, 1H, CHPh), 5.79 (dt, Jcis = 11.6, Jallylic
=
1.8 Hz, 1H, CHCO), 6.07 (dt, Jcis = 11.6, J = 7.2 Hz, 1H,
CHi-Bu), 6.46 (d, J = 7.2 Hz, 1H, NH), 7.30–7.39 (m,
5H, Harom). 13C NMR (100 MHz, CDCl3): d 22.5
((CH3)2CH), 22.6 ((CH3)2CH), 28.8 (CH(CH3)2), 37.7
(CH2i-Pr), 53.0 (CHPh), 56.4 (CO2CH3), 121.9, 127.4,
128.6, 129.1, 136.7, 146.4, 165.6 (CONH), 171.5 (CO2CH3).
HRMS (CI+, CH4) m/z: (MH+) calcd for C16H22NO3,
276.1594; found, 276.1592. Anal. Calcd for C16H21NO3:
C, 69.79; H, 7.69; N, 5.09. Found: C, 69.57; H, 7.62; N,
5.13.
4.3.23. (S)-(E)-N-(3-iso-Butylacryloyl)-2-amino-2-phenyl-
ethanol 14e. (254 mg, 81%), as a white solid, mp 117 ꢁC,
[a]D = +66.2 (c 0.95, CHCl3).1H NMR (400 MHz, CDCl3):
d 0.90 (d, J = 6.8 Hz, 6H, (CH3)2CH), 1.72 (m, 1H,
CH(CH3)2), 2.03 (ddd, J = 6.8, Jallylic = 1.2 Hz, 2H,
CH2i-Pr), 3.54 (br, 1H, OH), 3.82 (s, 2H, CH2OH), 5.05
(dd, J = 12.0, J = 5.2 Hz, 1H, CHPh), 5.84 (dd,
Jtrans = 15.0, Jallylic = 1.2 Hz, 1H, CHC@O), 6.59 (br, 1H,
NH), 6.82 (dt, Jtrans = 15.0, J = 7.0 Hz, 1H, CHi-Bu),
7.25–7.35 (m, 5H, Harom). 13C NMR (100 MHz, CDCl3):
d 22.7 ((CH3)2CH), 22.7 ((CH3)2CH), 28.1 (CH(CH3)2),
41.6 (CH2i-Pr), 56.2 (CH2OH), 66.5 (CHPh), 124.2,
126.8, 127.9, 128.9, 139.1, 144.9, 166.6 (C@O). HRMS
(FAB+) m/z: (MH+) calcd for C15H22NO2, 248.1651;
found, 248.1664. Anal. Calcd for C15H21NO2: C, 72.84;
H, 8.56; N, 5.66. Found: C, 72.51; H, 8.56; N, 5.78.
4.3.19. (S)-N-(Cinnamoyl)-2-amino-2-phenylethanol 14a.29
(302 mg, 89%), as a white solid, mp 197 ꢁC, [a]D = ꢀ29.8 (c
1
2.47, MeOH). H NMR (400 MHz, CD3OD): d 3.77 (dd,
Jgem = 11.4, J = 8.0 Hz, 1H, CH2OH), 3.80 (dd,
Jgem = 11.4, J = 5.4 Hz, 1H, CH2OH), 5.12 (dd, J = 7.2,
J = 5.4 Hz, 1H, CHPh), 6.76 (d, Jtrans = 15.8 Hz, 1H,
CHCO), 7.24–7.41 (m, 8H, Harom), 7.54 (d, Jtrans
=
15.8 Hz, 1H, CH=CHPh), 7.55–7.57 (m, 2H, Harom). 13C
NMR (100 MHz, CD3OD): d 57.4 (CH2OH), 66.3 (CHPh),
121.8, 128.0, 128.4, 128.8, 129.5, 129.9, 130.8, 136.3, 141.2,
142.0, 168.3 (C@O). HRMS (CI+, CH4) m/z: (MH+) calcd
for C17H18NO2, 268.1338; found, 268.1333. Anal. Calcd
for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.04; H, 6.50; N, 5.33.
4.3.20. (S)-N-(p-Chlorocinnamoyl)-2-amino-2-phenylethanol
14b.30 (290 mg, 84%), as a white solid, mp 164 ꢁC,
[a]D = ꢀ51.1 (c 2.1, MeOH). 1H NMR (400 MHz,
CD3OD): d 3.78 (dd, Jgem = 10.8, J = 7.6 Hz, CH2OH),
3.82 (dd, Jgem = 10.8, J = 5.2 Hz 1H, CH2OH), 5.11 (dd,
J = 7.6, J = 5.2 Hz, 1H, CHPh), 6.73 (d, Jtrans = 15.6 Hz,
1H, CHCO), 7.23–7.39 (m, 7H, Harom), 7.54–7.49 (d,
Jtrans = 15.6 Hz, 1H, CHAr), 7.52 (m, 2H, Harom). 13C
NMR (100 MHz, CD3OD): d 57.4 (CH2OH), 66.3 (CHPh),
122.7, 128.0, 128.5, 129.5, 130.1, 130.3, 135.0, 136.5, 140.5,
141.1, 168.0 (C@O). HRMS (CI+, CH4) m/z: (MH+) calcd
for C17H17ClNO2, 302.0948; found, 302.0946 Anal. Calcd
for C17H16ClNO2: C, 67.66; H, 5.34; N, 4.64. Found: C,
67.51; H, 5.43; N, 4.70.
4.3.24. (S)-(E)-N-(3-iso-Propylacryloyl)-2-amino-2-phenyl-
ethanol 14f. (241 mg, 89%), as a white solid, mp 123–
124 ꢁC, [a]D = +75.8 (c 2.45, CHCl3). 1H NMR
(400 MHz, CDCl3): d 1.03 (d, J = 6.8 Hz, 6H, (CH3)2CH),
2.42 (m, 1H, CH(CH3)2), 3.51 (br, 1H, OH), 3.83 (s, 2H,
CH2OH), 5.08 (dd, J = 12.4, J = 5.2 Hz, 1H, CHPh),
5.78 (dd, Jtrans = 15.6, Jallylic = 1.2 Hz, 1H, CHC@O),
6.58 (d, J = 6.8 Hz, 1H, NH), 6.83 (dd, Jtrans = 15.6,
J = 6.6 Hz, 1H, CHi-Pr), 7.25-7.35 (m, 5H, Harom). 13C
NMR (100 MHz, CDCl3): d 21.6 ((CH3)2CH), 21.7
((CH3)2CH), 31.0 (CH(CH3)2), 56.2 (CH2OH), 66.6
(CHPh), 120.5, 126.8, 127.9, 128.9, 139.1, 152.1, 166.9
(C@O). HRMS (CI+, CH4) m/z: (MH+) calcd for
C14H20NO2, 234.1494; found, 234.1504. Anal. Calcd for
C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 71.82;
H, 8.21; N, 6.07.
4.3.21. (S)-N-(p-Methoxycinnamoyl)-2-amino-2-phenyletha-
nol 14c. (328 mg, 87%), as a white solid, mp 158 ꢁC,
[a]D = ꢀ71.4 (c 2.6, MeOH). 1H NMR (400 MHz,
CD3OD):
d 3.76 (dd, Jgem = 11.2, J = 7.6 Hz, 1H,
CH2OH), 3.80 (s, 3H, CH3OPh), 3.81 (dd, Jgem = 11.2,
J = 5.6 Hz, 1H, CH2OH), 5.11 (dd, J = 7.6, J = 5.6 Hz,
1H, CHPh), 6.61 (d, Jtrans = 15.8 Hz, 1H, CHCO), 6.93
(AA0BB0 system, J = 8.8 Hz, 2H, Harom), 7.23–7.38 (m,
5H, Harom), 7.49 (d, Jtrans = 15.8 Hz, 1H, CHAr), 7.50
(AA0BB0 system, J = 8.8 Hz, 2H, Harom). 13C NMR
(100 MHz, CD3OD): d 55.9 (CH2OH), 57.3 (CH3OC6H4),
66.3 (CHPh), 115.4, 119.3, 128.1, 128.5, 128.9, 129.6,
130.6, 141.4, 141.9, 162.7, 168.9 (C@O). Anal. Calcd for
Acknowledgements
We wish to thank CONACYT-Mexico for financial sup-
port via Grants 41657-Q and 44704-Q for this work. We
also thank Victoria Labastida for her valuable technical
support in the obtention of HRMS spectra and Rosendo
Tiempos for his technical support. Two of us, E.H.-F.
and H.R.-C., also wish to thank CONACYT for a Gradu-
ate Scholarship (170288, 170296).

M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 18 (2007) 2427–2436
2435
H. A.; Park, K.; Langenhan, J. M.; Sun, L.; Akhiezer, A.;
Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237–12254; (q)
Ahmar, M.; Duyck, C.; Fleming, I. J. Chem. Soc., Perkin
Trans. 1 1998, 2721–2725; (r) Roush, W. R.; Reilly, M. L.;
Koyama, K.; Brown, B. B. J. Org. Chem. 1997, 62, 8708–
8721; (s) Norley, M.; Kocienski, P.; Faller, A. Synlett 1996,
900–902; (t) Morimoto, Y.; Iwahashi, M.; Nishida, K.;
Hayashi, Y.; Shirahama, H. Angew. Chem., Int. Ed. 1996,
35, 904–906; (u) Kobayashi, M.; Wang, W.; Ohyabu, N.;
Kurosu, M.; Kitagawa, I. Chem. Pharm. Bull. 1995, 43, 1598–
1600; (v) Roush, W. R.; Brown, B. B. J. Org. Chem. 1993, 58,
2162–2172; (w) Broka, C. A.; Ehrler, J. Tetrahedron Lett.
1991, 32, 5907–5910.
References
1. (a) Tosaki, S. Y.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J.
Am. Chem. Soc. 2005, 127, 2147–2155; (b) Nemoto, T.;
Kakei, H.; Gnanadesikan, V.; Tosaki, S. Y.; Ohshima, T.;
Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14544–14545; (c)
Caramella, P.; Reami, D.; Falzoni, M.; Quadrelli, P. Tetra-
hedron 1999, 55, 7027–7042; (d) Gothelf, R. F.; Jorgensen, K.
A. Chem. Rev. 1998, 98, 863–909; (e) Jurczak, J.; Bauer, T.;
Chapuis, C. In Stereoselective Synthesis (Houben-Weyl);
Helchem, G., Hoffmann, R. W., Mulzer, J., Schaumann, E.,
Eds.; Thieme: Sttugart, 1995; Vol. E 21c, p 2735; (f) Cardillo,
G.; Hashem, M. A.; Tomasini, C. J. Chem. Soc., Perkin
Trans. 1 1990, 1587–1590.
7. For reviews on the HWE reaction, see: (a) Maryanoff, B. E.;
Reitz, A. B. Chem. Rev. 1989, 89, 863–927; (b) Kelly, S. E. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: Oxford, 1991; Vol. 1, p 755; (c)
Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87–99; Papers
relevant to this work: (d) Pedersen, T. M.; Hansen, E. L.;
Kane, J.; Rein, T.; Helquist, P.; Norrby, P. O.; Tanner, D. J.
Am. Chem. Soc. 2001, 123, 9738–9742; (e) Ando, K.; Oishi,
T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem. 2000, 65,
4745–4749; (f) Ando, K. J. Org. Chem. 1999, 64, 6815–6821;
(g) Brandt, P.; Norrby, P. O.; Martin, I.; Rein, T. J. Org.
Chem. 1998, 63, 1280–1289; (h) Ando, K. J. Org. Chem. 1997,
62, 1934–1939.
2. (a) Almaßsi, D.; Alonso, D. A.; Najera, C. Tetrahedron:
Asymmetry 2007, 18, 299–365; (b) Streuff, J.; Osterath, B.;
Nieger, M.; Muniz, K. Tetrahedron: Asymmetry 2005, 16,
˜
3492–3496; (c) Cai, C.; Yamada, T.; Tiwari, R.; Hruby, V. J.;
Soloshonok, V. Tetrahedron Lett. 2004, 45, 6855–6858; (d)
Mpango, G. B.; Mahalanabis, K. K.; Mahdavi-Damghani,
Z.; Snieckus, V. Tetrahedron Lett. 1980, 21, 4823–4826; (e)
Mpango, G. B.; Snieckus, V. Tetrahedron Lett. 1980, 21,
4827–4830.
3. (a) Sibi, M. P.; Chen, J.; Stanley, L. Synlett 2007, 298–302; (b)
Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am.
Chem. Soc 1999, 121, 7559–7573.
8. For asymmetric version of the HWE reaction, see: (a) Rein,
T.; Pedersen, T. M. Synthesis 2002, 579–594; (b) Pedersen, T.
M.; Jensen, J. F.; Humble, R. E.; Rein, T.; Tanner, D.;
Bodmann, K.; Reiser, O. Org. Lett. 2000, 2, 535–538; (c)
Rein, T.; Reiser, O. Acta Chem. Scand. 1996, 50, 369–379.
4. (a) Amagata, T.; Minoura, K.; Numata, A. J. Nat. Prod.
2006, 69, 1384–1388; (b) Wu, Y. J.; He, H.; Sun, L. Q.;
L’Heureux, A.; Chen, J.; Dextraze, P.; Starrett, J. E., Jr.;
Boissard, C. G.; Gribkoff, V. K.; Natale, J.; Dworetzky, S. I.
J. Med. Chem. 2004, 47, 2887–2896; (c) Wu, Y. J.; Davis, C.
D.; Dworetzky, S.; Fitzpatricks, W. C.; Harden, D.; He, H.;
Knox, R. J.; Newton, A. E.; Philip, T.; Polson, C.; Sivarao,
D. V.; Sun, L. Q.; Tertyshnikova, S.; Weaver, D.; Yeola, S.;
Zoeckler, M.; Sinz, M. W. J. Med. Chem. 2003, 46, 3778–
3781; (d) Cho, H.; Beale, J. M.; Graff, C.; Mocek, U.;
Nakagawa, A.; Omura, S.; Floss, H. G. J. Am. Chem. Soc.
1993, 115, 12296–12304.
´
´
´
´
9. Hernandez-Fernandez, E.; Fernandez-Zertuche, M.; Garcıa-
´
˜
Barradas, O.; Munoz-Muniz, O.; Ordonez, M. Synlett 2006,
˜
˜
440–444.
10. For the use of chiral a,b-unsaturated amides bearing (S)-(a-
methylbenzyl)benzylamine as a Michael acceptor, see: Cast-
elot-Deliencourt, G.; Pannecoucke, X.; Quirion, J. C. Tetra-
hedron Lett. 2001, 42, 1025–1028.
11. For the use of chiral a,b-unsaturated amides bearing (S,S)-
bis(a-methylbenzyl)amine as a building block, see: (a) Sato,
M.; Gunji, Y.; Ikeno, T.; Yamada, T. Chem. Lett. 2004, 33,
1304–1305; (b) Riber, D.; Skrydstrup, T. Org. Lett. 2003, 5,
229–231; (c) Meth-Cohn, O.; Williams, D. J.; Chen, Y. Chem.
Commun. 2000, 495–496; (d) Meth-Cohn, O.; Chen, Y.
Tetrahedron Lett 1999, 40, 6069–6072; (e) Pearson, A. J.;
Chang, K.; McConville, D. B.; Youngs, W. J. Organometal-
lics 1994, 13, 4–5.
12. For the use of chiral a,b-unsaturated amides bearing (S)-
phenylglycine methyl ester as building block, see: (a) Ronald,
G.; William, A. Tetrahedron 1988, 44, 1523–1534; (b)
Norbert, E.; Boerries, K.; Wolfgang, S. Angew. Chem. 1977,
89, 408–410; For the other a-amino acids, see also: (c)
Wijdeven, M. A.; Botman, P. N. M.; Wijtmans, R.; Schoe-
maker, H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett.
2005, 7, 4005–4007; (d) Blaskovich, M. A.; Kahn, M. J. Org.
Chem. 1998, 63, 1119–1125.
5. Bohlmann, F.; Gancer, M.; Kruger, M.; Nordhoff, E.
Tetrahedron 1983, 39, 123–128.
6. (a) Dias, L. C.; Melgar, G. Z.; Jardim, L. S. A. Tetrahedron
Lett. 2005, 46, 4427–4431; (b) Diaper, C. M.; Sutherland, A.;
Pillai, B.; James, M. N. G.; Semchuk, P.; Blanchard, J. S.;
Vederas, J. C. Org. Biomol. Chem. 2005, 3, 4402–4411; (c)
Ritter, T.; Kvaerno, L.; Werder, M.; Hauser, H.; Carreira, E.
M. Org. Biomol. Chem. 2005, 3, 3514–3523; (d) Mattson, R.
J.; Catt, J. D.; Denhart, D. J.; Deskus, J. A.; Ditta, J. L.;
Higgins, M. A.; Marcin, L. R.; Sloan, C. P.; Beno, B. R.;
Gao, Q.; Cunningham, M. A.; Mattson, G. K.; Molski, T. F.;
Taber, M. T.; Lodge, N. L. J. Med. Chem. 2005, 48, 6023–
6034; (e) Cecil, A. R. L.; Brown, R. C. D. Tetrahedron Lett.
2004, 45, 7269–7271; (f) Yokokawa, F.; Asano, T.; Okino, T.;
Gerwick, W. H.; Shioiri, T. Tetrahedron 2004, 60, 6859–6880;
(g) Crackett, P.; Demont, E.; Eatherton, A.; Frampton, C. S.;
Gilbert, J.; Kahn, I.; Redshaw, S.; Watson, W. Synlett 2004,
679–683; (h) Xu, Z.; Chen, Z.; Ye, T. Tetrahedron: Asymme-
try 2004, 15, 355–363; (i) Paintner, F. F.; Bauschke, G.;
Polborn, K. Tetrahedron Lett. 2003, 44, 2549–2552; (j)
Andrus, M. B.; Meredith, E. L.; Hicken, E. J.; Simmons, B.
L.; Glancey, R. R.; Ma, W. J. Org. Chem. 2003, 68, 8162–
8169; (k) Liu, F.; Zha, H.-Y.; Yao, Z.-J. J. Org. Chem. 2003,
68, 6679–6684; (l) Mulzer, J.; Riether, D. Org. Lett. 2000, 2,
3139–3141; (m) Martin, H. J.; Drescher, M.; Mulzer, J.
Angew. Chem., Int. Ed. 2000, 39, 581–583; (n) Murakami, N.;
Wang, W.; Ohyabu, N.; Ito, T.; Tamura, S.; Aoki, S.;
Kobayashi, M.; Kitagawa, I. Tetrahedron 2000, 56, 9121–
9128; (o) Rzasa, R. M.; Shea, H. A.; Romo, D. J. Am. Chem.
Soc. 1998, 120, 591–592; (p) Romo, D.; Rzasa, R. M.; Shea,
13. For the use of chiral a,b-unsaturated amides bearing (S)-
phenylglycinol in asymmetric synthesis, see: (a) Tarver, J. E.;
´
Terranova, K. M.; Joullie, M. M. Tetrahedron 2004, 60,
´
10277–10284; (b) Leautey, M.; Castelot-Deliencourt, G.;
Jubault, P.; Pannecoucke, X.; Quirion, J. C. Tetrahedron
Lett. 2002, 43, 9237–9240; (c) Castelot-Deliencourt, G.;
Roger, E.; Pannecoucke, X.; Quirion, J. C. Eur. J. Org.
Chem. 2001, 3031–3038; (d) Dahuron, N.; Langlois, N.;
Chiaroni, A.; Richie, C. Heterocycles 1996, 42, 635–643; (e)
Dahuron, N.; Langlois, N. Synlett 1996, 51–52; (f) Michelon,
`
F.; Pouilhes, A.; Van Bac, N.; Langlois, N. Tetrahedron Lett.
1992, 33, 1743–1746; (g) Adam, W.; Guthlein, M.; Peters, K.;
¨

2436
M. Ordo´n˜ez et al. / Tetrahedron: Asymmetry 18 (2007) 2427–2436
Wirth, T. J. Am. Chem. Soc. 1998, 120, 4091–4093; (h)
Langlois, N.; Dahuron, N.; Wang, H. S. Tetrahedron 1996,
25, 15117–15126.
21. For the preparation of phosphonoamides from phosphono-
acetic acid, see: (a) Grison, C.; Coutrot, P.; Comoy, C.; Balas,
L.; Joliez, S.; Lavecchia, G.; Oliger, P.; Penverne, B.; Serre,
´
´
´
14. Ordonez, M.; Hernandez-Fernandez, E.; Xahuentitla, J.;
˜
V.; Herve, G. Eur. J. Med. Chem. 2004, 39, 333–344; (b)
Cativiela, C. Chem. Commun. 2005, 1336–1338.
15. Treatment of L-phenylglycinol with bromoacetyl bromide in
the presence of K2CO3 in a CH2Cl2/H2O mixture afforded the
ester-amide derivative, which by Michaelis–Arbuzov reaction
with trimethyl phosphite and subsequent hydrolysis using
LiOH led to phosphonoacetamide 7 in 61% overall yield from
L-phenylglycinol.
Kummeter, M.; Kazmaier, U. Eur. J. Org. Chem. 2003, 3330–
3334; (c) Saltmarsh, J. R.; Boyd, A. E.; Rodriguez, O. P.;
´
Radic, Z.; Taylor, P.; Thompson, C. M. Bioorg. Med. Chem.
Lett. 2000, 10, 1523–1526; (d) Morris, A. D.; Cordi, A. A.
Synth. Commun. 1997, 27, 1259–1266.
22. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183–2186.
16. For the application of a-chloroamides bearing phenylalanine
´
methyl ester in the preparation of b-lactams, see: Perez-
23. For the HWE reaction of phosphonoamides using DBU as a
base and additives, see: (a) Goodman, S. N.; Jacobsen, E. N.
Adv. Synth. Catal. 2002, 344, 953–956; (b) Melekhov, A.;
Fallis, A. G. Tetrahedron Lett. 1999, 40, 7867–7870; (c)
Abiko, A.; Masamune, S. Tetrahedron Lett. 1996, 37, 1077–
1080; (d) Oppolzer, W.; Dupuis, D.; Poli, G.; Raynham, T.
M.; Bernardinelli, G. Tetrahedron Lett. 1988, 29, 5885–5888.
Also, see: Refs. 6b,c,g.
´
Faginas, P.; O’Reilly, F.; O’Byrne, A.; Garcıa-Aparicio, C.;
´
´
´
´
´
Martınez-Martınez, M.; Perez de Vega, M. J.; Garcıa-Lopez,
´
M. T.; Gonzalez-Muniz, R. Org. Lett. 2007, 9, 1593–1596.
˜
17. Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81,
415–430.
18. For the biological evaluation of phosphonoamides, see: (a)
Eldo, J.; Heng, S.; Kantrowitz, E. R. Bioorg. Med. Chem.
Lett. 2007, 17, 2086–2090; (b) Gagnard, V.; Leydet, A.; Le
1
24. When the minor isomers were not detected by H NMR, a
`
Mellay, V.; Aubenque, M.; Morere, A.; Montero, J.-L. Eur.
98:02 E:Z ratio was established.
J. Med. Chem. 2003, 38, 883–891; (c) Kafarski, P.; Soroka,
M. Synthesis 1982, 219–221; (d) Goodson, J. J.; Wharton, C.
J.; Wrigglesworth, R. J. Chem. Soc., Perkin Trans. 1 1980,
2721–2727.
25. For HWE reaction at several temperatures, see: Sano, S.;
Takemoto, Y.; Nagao, Y. Arkivoc 2003, 93–101.
26. For HWE reaction of phosphonoamides with C2 symmetry
bearing (R,R)- and (S,S)-1,2-diphenyl-aziridine, see: Peder-
sen, T. B.; Jensen, K. F.; Humble, R. E.; Rein, T.; Tanner,
D.; Bodmann, K.; Reiser, O. Org. Lett. 2000, 2, 535–538.
27. For the HWE reaction of phosphonoamides bearing a-amino
acids, see: Blaskovich, M. A.; Kahn, M. J. Org. Chem. 1998,
63, 1119–1125. Also, see: Refs. 6n,q,u.
28. Reyes, A.; Juaristi, E. Tetrahedron: Asymmetry 2000, 11,
1411–1423.
29. For the preparation of (R)-14a, see Ref. 13d.
30. For the preparation of (R)-14b, see Ref. 13h.
19. (a) da Costa, J. C. S.; Pais, K. C.; Fernandes, E. L.; de
Oliveira, P. S. M.; Mendonc¸a, J. S.; de Souza, M. V. N.;
Peralta, M. A.; Vasconcelos, T. R. A. Arkivoc 2006, 128–133;
(b) Saeed, A.; Ashraf, Z. J. Chem. Sci. 2006, 118, 419–423.
20. L-Phenylglycinol was readily obtained from reduction of L-
phenylglycine with LiBH4 in the presence of Me3SiCl in dry
´
THF at 0 ꢁC, following the procedure described by: Nicolas,
E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58, 766–
770.