Synthesis of α,β-diamino acid derivatives via asymmetric Mannich reactions of glycine imino esters catalyzed by a chiral phosphoramidite·silver complex Dedicated to the memory of Prof. Ekkehard Winterfeldt

Article abstract of DOI:10.1016/j.tetasy.2014.11.009

AgOTf·phosphoramidite complexes efficiently catalyze the enantioselective Mannich-type reaction between benzophenone-imine glycine methyl ester and N-tosyl aldimines in the absence of a base. The corresponding syn-adducts, which are the direct precursors of α,β-diamino acids, are obtained with moderate to good syn-diastereoselectivities (up to 9:1) and high enantioselectivities (up to 99% ee).

Full text of DOI:10.1016/j.tetasy.2014.11.009

Tetrahedron: Asymmetry 25 (2014) 1647–1653
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of
a,b-diamino acid derivatives via asymmetric Mannich
reactions of glycine imino esters catalyzed by a chiral
phosphoramiditeÁsilver complex
Alberto Cayuelas, Loane Serrano, Carmen Nájera, José M. Sansano
⇑
Departamento de Química Orgánica, Instituto de Síntesis Orgánica (ISO), and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universidad de Alicante, Apdo. 99,
E-03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 October 2014
Accepted 17 November 2014
AgOTfÁphosphoramidite complexes efficiently catalyze the enantioselective Mannich-type reaction
between benzophenone-imine glycine methyl ester and N-tosyl aldimines in the absence of a base.
The corresponding syn-adducts, which are the direct precursors of a,b-diamino acids, are obtained with
moderate to good syn-diastereoselectivities (up to 9:1) and high enantioselectivities (up to 99% ee).
Dedicated to the memory of
Prof. Ekkehard Winterfeldt
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
diastereoisomers were isolated with excellent enantioselectivities,
a bulky N-(8-quinolyl)sulfonyl protecting group being needed.8i
The asymmetric Mannich reaction is a very useful methodology
for the preparation of enantioenriched b-amino carbonyl com-
pounds where the absolute configuration of two stereogenic cen-
ters can be defined simultaneously.1–3 There are many types of
enolates which are able to add to imines by the intermediacy of
chiral metal complexes or organocatalysts. In the case of using
Copper salts are mainly employed and only one contribution
employed
a
chiral 15Ásilver acetate complex affording the
syn-diastereoisomers as major products.8k
We have recently described that complexes formed by silver
salts and privileged chiral ligands10 such as Binap 1611 and phos-
phoramidites 17 and 1812 are excellent catalysts for the enantiose-
lective 1,3-dipolar cycloadditions13,14 of azomethine ylides derived
from imino esters 1 in the construction of enantiomerically
enriched highly substituted prolines.15,16 Herein we report the
application of these silver chiral complexes17 in the Mannich type
reaction of glycine benzophenone Schiff bases and protected
aldimines (Fig. 2).
Schiff bases derived from
imines 2, protected ,b-diamino esters 3 can be prepared straight-
forwardly. After deprotection,
a-amino esters 1 as nucleophiles and
a
a
,b-diamino acids 4 are easily gener-
ated, which are biologically relevant4 and also chemically
attractive due to their use as chiral building blocks5 (Scheme 1).
Apart from this Mannich-type reaction, the asymmetric amination
of
tion of bis-(amido)acrylates diamino are two additional routes.6
The enantioselective reaction of imino esters with
a,b-unsaturated acid derivatives, and the catalytic hydrogena-
2. Results and discussion
1
N-protected imines shown in Scheme 1 has been successfully
performed in the presence of chiral organocatalysts 57a and 67b
or chiral metal complexes 7–158 (Fig. 1). The reactions involving
organocatalysts 5 and 6 afforded almost exclusively the syn-3 dia-
stereoisomer with excellent enantioselections.9 The syn-diastereo-
isomer was also the major product isolated when chiral copper
complexes were employed. The unique exception was noted when
the major anti-3 diastereoisomer was isolated in good enantiose-
lectivities after the reaction with copper(I) complexes 11 and 12.
In the case of aldimino esters 1 (R1 = H, R2 = Ph) the anti-3
The selected reaction for the optimization conditions involved
the glycine benzophenone imine derivative 1a (R1 = R2 = Ph,
R3 = H, and R4 = Me), benzaldehyde N-tosylimine 2a (PG = Ts), tri-
ethylamine (5 mol %) as the base, and AgOAc (5 mol %) in toluene
as the solvent at room temperature for 1 day (Scheme 2). The reac-
tion performed with (S)-Binap 16 was first evaluated in the pres-
ence and in the absence of triethylamine. High conversions and
67:33 syn:anti diastereomeric ratios of compound 3a were
obtained in both cases. The highest enantioselection was observed
for the syn-diastereoisomer when no base was added (Table 1,
entries 1 and 2). The same behavior was exhibited by the chiral
catalyst formed by Monophos 17 and silver acetate. A higher
75:25 dr was observed but with lower enantioselection (Table 1,
⇑
Corresponding author. Tel./fax: +34 965 903 549.
E-mail address: jmsansano@ua.es (J.M. Sansano).
http://dx.doi.org/10.1016/j.tetasy.2014.11.009
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1648
A. Cayuelas et al. / Tetrahedron: Asymmetry 25 (2014) 1647–1653
GP
NH
*
O
R4
R2
OR3
*
R4
N
N
PG
chiral catalyst
2
O
NH2
O
R1
NH
*
R2
N
syn-3
OR3
R4
OH
*
*
GP
R1
O
NH2
1
4
R4
R2
OR3
*
N
R1
anti-3
Scheme 1. General Mannich-type reaction between imino esters and N-protected imines.
entries 3 and 4). Phosphoramidite 18 and AgOAc gave a higher
enantioselectivity (80% ee) and 80:20 dr when the reaction was
carried out in the absence of a base (Table 1, compare entries 5
and 6). Copper(I) and copper(II) triflates were also tested (not
shown in Table 1) giving a complex crude reaction mixture (1H
NMR) from complete. The reactions under the conditions shown
in entries 5 and 6 were very slow at 0 °C.
and 6 with 8). In light of all these tests, the reaction with different
silver salts was next essayed without triethylamine. Thus, AgTfa
(Tfa = trifluoroacetate), AgOBz, AgSbF6, and Ag2CO3 did not
improve the enantioselection generated by the employment of sil-
ver perchlorate (Table 1, entries 9–12). However, the best results
were observed when AgOTf was employed as the silver salt
(Table 1, entry 13).
Silver perchlorate was a suitable metal salt for phosphoramidite
18 and afforded the major syn-stereoisomer 3a in high conversion
but with lower diastereoselection (72:28) than that observed for
the reaction run with AgOAc (Table 1, compare entries 5 with 6,
In order to improve the diastereoselectivity of the process while
also gaining some enantioselection, different nitrogen protecting
groups for the imines such as nosyl (p-nitrophenylsulfonyl, Ns)
and N-(8-quinolyl)sulfonyl (8-Q) were evaluated. In both cases
F
-
BF4
C6H4-4-Me
N
N
+
+
O
O
C6H4-4-Me
C6H4-4-Me
Bn
OH
-
N
BF4
C6H4-4-Me
Cy2N
NCy2
F
57a
67b
SBut
PPh2
O
N
O
O
Fe
PAr2
N
N
(R)-Fesulphos
Ph
Ph
· CuClO4
· Cu(OTf)2
88b
· Cu(MeCN)4PF6
78a
98c,f,i
CF3
O
F3C
NH2
NH2
+
+
N
O
N
O
N
H
H
N
_
_
Fe
Ph
N
PR2
F3C
Ar
Ar
O
· Cu(OAc)2
O
Ar = 4-Br-C6H4
· CuClO4
CF3
118e
108d
· Cu(MeCN)4BF4
128g
O
Ph
NH
N
HN
O
O
PAr2
PAr2
Ph
Fe
Ph
Ph2P
N
N
N
N
N
Bn
Bn
· Cu(OTf)2
138h
ButS
O
Ph
Ar = 4-MeO-3,5-(But)2C6H2
·CuHMDS
·AgOAc
158k
148j
Figure 1. Chiral catalysts employed in the Mannich-type reaction between imino esters and N-protected imines.

A. Cayuelas et al. / Tetrahedron: Asymmetry 25 (2014) 1647–1653
1649
The influence of the solvent was also noticeable. Toluene was
the best solvent whereas THF, Et2O, DCM, and MeCN furnished
both lower dr and ee (Table 1, entries 19–22). The mechanism of
this reaction is very similar to that reported for the asymmetric
synthesis of polysubstituted prolines through a 1,3-dipolar cyclo-
addition reaction using the same catalytic system.12b
O
O
PPh2
PPh2
P
N
(Ra)-Monophos 17
(Sa)-Binap 16
The scope of the reaction was investigated under the optimized
reaction conditions using toluene as the solvent at room tempera-
ture. When the reaction was catalyzed by the complex AgOTfÁ(Sa,-
R,R)-18, it gave the same results as those reported when using
(Ra,S,S)-18 ligand but with the opposite enantiomeric form ent-3
(Table 2, entry 2). Different aldimines were prepared according
to known methods and employed directly as electrophiles in the
Mannich type reaction with imino ester 1a. In general, if a compar-
ison is established between product 3a (Table 2, entry 1) and the
different 3b–3l molecules, the presence of a substituent at the
ortho-position in the arene moiety decreased the enantioselection
of the corresponding major syn-3 diastereoisomers (Table 2,
entries 3–5). However, halogenated aryl groups provided the high-
est ee in these series (Table 2, entries 4 and 5) with moderate dia-
stereoselection. The m-substituted chloroarene in the imine 2
moiety afforded the best diastereoselection, but again very low
Ph
O
O
P
N
Ph
(Sa,R,R)-18
Figure 2. Chiral privileged ligands 16–18 employed herein.
conversions were high but the enantioselection was very poor
(Table 1, entries 14 and 15), even when the tert-butyl (diphenylm-
ethylene)glycinate was used (Table 1, entries 16–18).
Ph
N
PG
2
GP
GP
NH
O
NH
O
chiral ligand
(5 mol%)
O
Ph
Ph
OMe
Ph
Ph
OMe
Ph
N
+
OMe
AgX (5 mol%)
PhMe, rt
N
N
Ph
Et3N or not
1a
Ph
Ph
syn-3a
Scheme 2. Optimization reaction model.
anti-3a
Table 1
Optimization reactions
Ent.
AgX
Ligand
Base
PG
Yielda (%)
dra (syn:anti)
eeb (syn, anti)
1
2
3
4
5
6
7
8
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgClO4
AgClO4
AgTfa
AgOBz
AgSbF6
Ag2CO3
AgOTf
AgOTf
AgOTf
16
16
17
17
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
TEA
—
TEA
—
TEA
—
TEA
—
—
—
—
—
—
—
—
—
—
—
—
—
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
100
100
100
100
90
90
100
75
85
100
85
92
94
100
90
95
100
85
89
92
91
87
67:33
67:33
75:25
75:25
80:20
80:20
86:14
72:28
60:40
75:25
60:40
84:16
72:28
90:10
72:28
80:20
>96:4
86:14
67:33
72:28
62:38
72:28
12, 20
24, 2
<10, <10
10, 6
12, 24
80, 10
12, rac.
92, 32
14, 12
78, 38
64, 16
8, 4
96, 58
24, 18
6, 2
4, 28
56, rac.
10, 6
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Ts
Nsc
8-Qd
Ts
e
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
e
e
f
Nsc
8-Qd
Ts
38, 6
g
h
i
Ts
Ts
Ts
rac., rac.
58, 86
24, 40
—
—
a
b
c
d
e
f
Determined by 1H NMR of the crude reaction mixture.
Determined by HPLC using chiral columns.
p-Nitrophenylsulfonyl group (nosyl).
N-(8-quinolyl)sulfonyl group.
The corresponding tert-butyl ester was employed.
Reaction run in the presence of THF as the solvent.
Reaction run in the presence of Et2O as the solvent.
Reaction run in the presence of DCM as the solvent.
Reaction run in the presence of MeCN as the solvent.
g
h
i

1650
A. Cayuelas et al. / Tetrahedron: Asymmetry 25 (2014) 1647–1653
enantiomeric excess was found for both the syn- and anti-isomers
3e (Table 2, entry 6). The effect of the para-substitution was very
similar to that observed in the examples run with ortho-substi-
tuted arenes, that is, low ee for the examples whose substituents
were different from halogenated atoms (Table 2, entries 7–11). In
this case 4-fluoro and 4-bromoarenes gave 99% ee and 80% ee, of
the major syn-diastereoisomers 3h and 3j, respectively. Heterocy-
clic substituents bonded to the imino group were also good precur-
sors for highly enantioselective Mannich-type additions. Thus, the
2-furyl derivative afforded 92% ee of 3k and 2-a thienyl surrogate
furnished 78% ee of 3l with a 75:25 dr in both cases (Table 2,
entries 12 and 13). Despite the reaction being completed, chemical
yields were moderate due to the instability of the final iminoesters
3 during purification using flash chromatography (Scheme 3).
3. Conclusions
The chiral complex formed by phosphoramidite 18 and AgOTf
(1:1 molar ratio) was the most effective catalyst in the Mannich-
type reaction between imino esters derived from benzophenone
and N-tosylimines. No extra base was needed for the reaction com-
pletion, meaning that it acted as a Lewis acid coordinating the
imino ester and that the corresponding counteranion has the base
role required for the
a-deprotonation. Both chemical yields and
diastereomeric ratios of the major syn-products were moderate
to good. The syn-selectivity was in agreement with the data
reported in the literature. The presence of heteroatoms and para-
halogenated arenes in the aromatic part of the imine afforded
the best enantioselection (up to 99% ee).
Table 2
4. Experimental
4.1. General
Scope of the Mannich-type reaction
Ent.
Ar
2
3
Yielda (%)
dra (syn:anti)
eeb (syn, anti)
1
2
3
4
5
6
7
8
Ph
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
70
70
50
55
67
42
30
47
48
30
35
45
45
72:28
72:28
80:20
56:44
60:40
90:10
75:25
70:30
70:30
70:30
50:50
75:25
75:25
96, 58
À96, À58
14, 4
46, <5
48, 34
14, 14
15, 2
20, 12
99, 10
42, 16
80, 10
92, 24
78, 38
Phc
N-Protected imines 2 were prepared according to the published
methods.8 Anhydrous solvents were freshly distilled under an
argon atmosphere and degassed by Freeze–Pump–Thaw method-
ology. Aldehydes were also distilled prior to use for the elaboration
of the imino esters 1 and imines 2. Melting points were determined
with a Reichert Thermowar hot plate apparatus and are uncor-
rected. Only the structurally most important peaks of the IR spec-
tra (recorded with a FT-IR 4100LE (JASCO) (PIKE MIRacle ATR) are
listed. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
obtained with a Bruker AC-300 by using CDCl3 as solvent and
TMS as the internal standard, unless otherwise stated. Optical rota-
tions were measured with a Perkin-Elmer 341polarimeter. HPLC
analyses were performed with a JASCO-2000 series equipped with
a chiral column (detailed for each compound in the main text) by
using mixtures of n-hexane/isopropyl alcohol as the mobile phase
at 25 °C. Low-resolution electron impact (EI) mass spectra were
obtained with a Shimadzu QP-5000 by injection or DIP, and high-
resolution mass spectra were obtained with a Finnigan VG Plat-
form or a Finnigan MAT 95S. Analytical TLC was performed on
Schleicher & Schuell F1400/LS 254 silica gel plates and the spots
were visualized under UV light (k = 254 nm). Merck silica gel 60
(0.040–0.063 mm) was used for flash chromatography.
2-MeC6H4
2-ClC6H4
2-BrC6H4
3- ClC6H4
4-(CF3)C6H4
4-(NO2)C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-Furyl
9
10
11
12
13
2j
2k
2l
3j
3k
3l
2-Thienyl
a
b
c
Isolated yield after column chromatography.
Determined by HPLC using chiral columns.
Reaction performed in the presence of AgOTfÁ(Ra,S,S)-18.
This Mannich type reaction can be rationalized on the basis of
the models proposed by different authors.8f The freshly generated
azomethine ylide is coordinated by a silver atom and the nucleo-
philic attack occurs at the tosyl imine whose arylsulfonyl group
is placed far away from the benzylidene moiety of the dipole
(Fig. 3). In this transition state, additional coordination between
silver and sulfonamido group cannot be ruled out.
Ar
N
2
Ts
Ts
Ts
NH
Ph
O
NH
Ph
O
O
18
(5 mol%)
Ar
OMe
Ar
OMe
Ph
N
+
OMe
AgOTf (5 mol%)
PhMe, rt
Ph
N
Ph
N
Ph
1a
anti-3
syn-3
Scheme 3.
Ph
O
O
N
P
TsHN
O
TsHN
O
Ph
O
=
Ph
Ph
OMe
Ph
Ph
OMe
Ag
Ph
SO2
OMe
N
N
N
N
Ph
syn-3a
Ph
Ph
Ph
Figure 3. Proposed transition state leading to the syn-stereoisomer.

A. Cayuelas et al. / Tetrahedron: Asymmetry 25 (2014) 1647–1653
1651
4.2. General procedure for the Mannich-type reaction
4.6. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(o-bromolphenyl)propanoate syn-3d and anti-
3d8k
In a 10 ml vial covered by aluminum foil, was added AgOTf
(1.54 mg,
0.006 mmol),
phosphoramidite
18
(3.24 mg,
0.006 mmol) and toluene (2 ml), and the mixture was stirred at
room temperature for 1 h. Benzophenone imine derivative 1
(0.120 mmol) and N-tosylimine 2 (0.144 mmol) were added. The
reaction was stirred for 1 day at room temperature and the crude
was analyzed by 1H NMR spectroscopy to determine the
diastereomeric ratio, and then purified by flash chromatography
(n-hexane–EtOAc; 15% of EtOAc), affording the products syn/anti-3.
47.6 mg; 67% yield; HPLC: (Daicel Chiralpak OD-H), hexane/
i-PrOH 90/10, flow rate 0.6 ml/min, tR: 15.2 min (syn), 16.9 min
(anti), 22.7 min (anti), and 37.8 min (syn), 254 nm. IR
mmax: 3285,
2987, 1738, 1333, 1159, 1081, 765, 697 cmÀ1 1H NMR dH: 2.24
;
(s, 3H, Meanti), 2.36 (s, 3H, Mesyn), 3.45 (s, 3H, OMeanti), 3.46 (s,
3H, OMesyn), 4.33 (d, J = 2.1 Hz, 1Hsyn), 4.49 (d, J = 5.7 Hz, 1Hanti),
4.80 (t, J = 5.5 Hz, 1Hanti), 5.50 (dd, J = 8.2, 2.0 Hz, 1Hsyn), 6.26 (d,
J = 6.7 Hz, 2Hsyn), 6.39 (d, J = 8.4 Hz, NHanti), 6.49 (d, J = 8.2 Hz,
NHsyn), 6.79–7.87 (m, 18Hsyn, 18Hanti, Ar H); 13C NMR dC: 21.4
(Me), 51.9 (CsynNH), 58.4 (CsynN@), 66.5 (OMesyn), 126.7, 127.2,
127.3, 127.5, 127.7, 128.0, 128.6, 129.0, 129.3, 129.7, 130.0,
130.9, 132.6, 135.3, 138.5, 143.1, 169.8syn, 172.6syn (CO, CN); MS
(EI) m/z (%): 591 (0.36), 258 (38), 194 (36), 165 (11), 155 (33), 91
(100), 65 (10).
4.3. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-phenylpropanoate syn-3a and anti-3a8k
42.9 mg; 70% yield; HPLC: (Daicel Chiralpak AD-H), hexane/
i-PrOH 90/10, flow rate 1 ml/min, tR: 23.7 min (syn), 36.4 min
(anti), 42.2 min (anti) and 45 min (syn), 254 nm; IR
mmax: 3297,
1736, 1628, 1328, 1157 cmÀ1 1H NMR dH: 2.27 (s, 3H, Meanti),
;
4.7. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(m-chlorophenyl)propanoate syn-3e and anti-
3e8d
2.34 (s, 3H, Mesyn), 3.49 (s, 3H, OMeanti), 3.51 (s, 3H, OMesyn),
4.14 (d, J = 2.2 Hz, 1Hsyn), 4.36 (d, J = 5.9 Hz, 1Hanti), 4.71 (dd,
J = 7.6, 5.8 Hz, 1Hanti), 5.16 (dd, J = 8.4, 2.0 Hz, 1Hsyn), 5.78 (d,
J = 7.1 Hz, NHanti), 6.37 (t, J = 8.4 Hz, 2Hsyn + NHsyn); 6.88–7.72 (m,
19Hsyn, 19Hanti, Ar H); 13C NMR dC: 21.4 (Me), 52.3 (CsynNH), 59.4
(CsynN@), 60.0 (CantiN@), 69.4 (OMeanti), 69.9 (OMesyn), 126.8,
126.9, 127.1, 127.3, 127.4, 128.1, 128.3, 128.6, 128.9, 129.2,
130.9, 135.5, 138.2, 138.5, 139.0, 142.8 (ArC), 169.6syn, 173.1syn
(CO, CN). MS (EI) m/z (%): 512 (0.12), 259 (12), 194 (40), 155
(33), 91 (100), 65 (10).
27.6 mg; 42% yield; HPLC: (Daicel Chiralpak AD), hexane/i-PrOH
90/10, flow rate 1 ml/min, tR: 40.8 min (syn) and 78.1 min (syn),
254 nm. IR
mmax: 2987, 1739, 1657, 1597, 1159, 1076, 701,
665 cmÀ1 1H NMR dH: 2.30 (s, 3H, Meanti), 2.36 (s, 3H, Mesyn),
;
3.50 (s, 3H, OMeanti), 3.51 (s, 3H, OMesyn), 4.15 (d, J = 2.3 Hz, 1Hsyn),
4.42 (d, J = 5.4 Hz, 1Hanti), 4.78 (dd, J = 7.7, 5.5 Hz, 1Hanti), 5.16 (dd,
J = 8.3, 2.3 Hz, 1Hsyn), 5.77 (d, J = 7.7 Hz, NHanti), 6.44 (t, J = 8.4 Hz,
2Hsyn + NHsyn), 6.89–7.69 (m, 16Hsyn, 16Hanti, Ar H); 13C NMR
(75 MHz, CDCl3) dC: 21.4 (Me), 29.7, 52.5 (CsynNH), 57.4 (CsynN@),
69.5 (OMesyn), 123.0, 126.6, 127.0, 128.3, 128.6, 128.9, 129.4,
129.5, 130.0, 131.2, 132.4, 134.6, 134.7, 143.2, 148.4, 148.6,
169.2syn, 173.8syn (CO, CN); MS (EI) m/z (%): 547 (0.21), 260 (17),
233 (16), 194 (38), 155 (20), 91 (100), 65 (10).
4.4. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(o-methylphenyl)propanoate syn-3b and anti-
3b8k
31.6 mg; 50% yield; HPLC: (Daicel Chiralpak AD-H), hexane/
i-PrOH 85/15, flow rate 1 ml/min, tR: 9.7 min (syn), 14.0 min (anti),
4.8. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(p-trifluoromethylphenyl) propanoate syn-3f
and anti-3f8k
15.4 min (anti) and 19.9 min (syn), 254 nm; IR
mmax: 2987, 1725,
1334, 1265, 1159, 1093, 733, 700 cmÀ1 1H NMR dH: 1.97 (s, 3H,
;
Meanti), 2.04 (s, 3H, Mesyn), 2.26 (s, 3H, Meanti), 2.33 (s, 3H, Mesyn),
3.51 (s, 3H, OMesyn), 3.53 (s, 3H, OMeanti), 4.06 (d, J = 2.1 Hz, 1Hsyn),
4.31 (d, J = 6.5 Hz, 1Hanti), 4.87 (d, J = 6.5 Hz, 1Hanti), 5.40 (dd, J = 8.5,
2.0 Hz, 1Hsyn), 6.21 (d, J = 7.5 Hz, 2Hsyn), 6.42 (d, J = 8.4 Hz, NHsyn),
6.79–7.89 (m, 16Hsyn, 16Hanti, Ar H); 13C NMR dC: 21.5 (Me), 52.4
(CsynNH), 55.9 (CsynN@), 125.6, 126.5, 126.8, 127.0, 128.3, 128.5,
128.9, 129.2, 129.7, 130.1, 132.4, 169.7syn; 172.9syn (CO, CN); MS
(EI) m/z (%): 526 (0.23), 194 (42), 165 (12), 118 (78), 117 (13), 91
(100), 65 (15).
20.9 mg; 30% yield; HPLC: (Daicel Chiralpak AD-H), hexane/
i-PrOH 90/10, flow rate 0.8 ml/min, tR: 13.5 min (syn), 16.4 min
(anti), 27.8 min (syn) and 30.5 min (anti), 254 nm; IR mmax: 3288,
2360, 1743, 1324, 1159, 1119, 1067, 700 cmÀ1; 1H NMR dH: 2.29 (s,
3H, Meanti), 2.36 (s, 3H, Mesyn), 3.52 (s, 3H, OMeanti), 3.54 (s, 3H,
OMesyn), 4.17 (d, J = 2.2 Hz, 1Hsyn), 4.43 (d, J = 5.5 Hz, 1Hanti), 4.81
(dd, J = 7.6, 5.6 Hz, 1Hanti), 5.20 (dd, J = 8.3, 1.9 Hz, 1Hsyn), 5.83 (d,
J = 7.6 Hz, NHanti), 6.39 (d, J = 7.1 Hz, 2Hsyn), 6.46 (d, J = 8.3 Hz, NHsyn),
6.87–7.70 (m, 18Hsyn, 18Hanti, Ar H); 13C NMR dC: 21.3 (Me), 52.5
(CsynNH), 59.1 (CsynN@), 69.5 (OMesyn), 126.7, 127.1, 127.3, 128.2,
128.3, 128.5, 128.8, 128.9, 129.3, 130.0, 131.2, 137.8, 138.1, 143.1,
143.2, 169.3syn, 173.6syn (CO, CN); MS (EI) m/z (%): 580 (0.25), 252
(10), 194 (35), 165 (10), 155 (46), 91 (100), 65 (10).
4.5. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(o-chlorophenyl)propanoate syn-3c and anti-
3c8k
36.1 mg; 55% yield; HPLC: (Daicel Chiralpak IB), hexane/i-PrOH
95/5, flow rate 1 ml/min, tR: 17.4 min (syn) and 21.7 min (syn),
4.9. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(p-nitrophenyl)propanoate syn-3g and anti-3g8d
254 nm; IR
mmax: 1739, 1597, 1443, 1332, 1159, 1088, 764,
697 cmÀ1 1H NMR dH: 2.23 (s, 3H, Meanti), 2.36 (s, 3H, Mesyn),
;
3.44 (s, 3H, OMesyn), 3.47 (s, 3H, OMeanti), 4.30 (d, J = 2.1 Hz, 1Hsyn),
4.48 (d, J = 5.9 Hz, 1Hanti), 4.85 (t, J = 5.8 Hz, 1Hanti), 5.54 (dd, J = 8.3,
2.0 Hz, 1Hsyn), 6.28 (d, J = 7.3 Hz, 2Hsyn), 6.32 (d, J = 6.0 Hz, NHsyn),
6.46 (d, J = 8.3 Hz, NHanti), 6.78–7.73 (m, 18Hsyn, 18Hanti, Ar H);
13C NMR dC: 21.4 (Me), 52.0 (CsynNH), 56.2 (CsynN@), 66.6 (OMesyn),
126,7, 127.1, 127.5, 127.9, 128.3, 128.6, 129.0, 129.3, 129.7, 130.0,
130.9, 132.4, 135.3, 136.4, 137.8, 138.5, 143.0, 169.9syn, 172.6syn
(CO, CN); MS (EI) m/z (%): 547 (0.15), 258 (33), 194 (35), 165
(10), 155 (33), 91 (100), 65 (10).
31.4 mg; 47% yield; HPLC: (Daicel Chiralpak OD-H), hexane/
i-PrOH 85/15, flow rate 0.6 ml/min, tR: 17.4 min (syn), 21.0 min
(anti), 23.0 min (syn), and 39.1 min (anti), 254 nm; IR
mmax: 3273,
1734, 1624, 1519, 1344, 1159, 851, 697 cmÀ1 1H NMR dH: 2.28
;
(s, 3H, Meanti), 2.37 (s, 3H, Mesyn), 3.48 (s, 3H, OMesyn), 3.49 (s,
3H, OMeanti), 4.18 (d, J = 2.2 Hz, 1Hsyn), 4.38 (d, J = 5.5 Hz, 1Hanti),
4.78 (dd, J = 7.5, 5.6 Hz, 1Hanti), 5.20 (dd, J = 8.0, 2.1 Hz, 1Hsyn),
5.91 (d, J = 7.0 Hz, NHanti), 6.45 (d, J = 7.1 Hz, 2Hsyn), 6.51 (d,
J = 8.1 Hz, NHsyn), 6.82–8.12 (m, 18Hsyn, 18Hanti, Ar H); 13C NMR

1652
A. Cayuelas et al. / Tetrahedron: Asymmetry 25 (2014) 1647–1653
dC: 21.4 (Mesyn), 25.3 (Meanti), 52.3 (CantiNH), 52.5 (CsynNH), 58.9
(CsynN@), 59.2 (CantiN@), 64.4 (OMeanti), 69.2 (OMesyn), 123.2,
123.3, 126.6, 127.0, 127.2, 127.8, 128.2, 128.3, 128.6, 128.7,
128.8, 128.9, 129.4, 131.3, 135.1, 137.7, 137.9, 143.4, 145.1,
146.7, 147.1, 169.1syn, 169.4anti, 173.9syn (CO, CN); MS (EI) m/z
(%): 557 (0.13), 194 (44), 165 (12), 155 (36), 91 (100), 65 (10).
(s, 3H, OMesyn), 4.26 (d, J = 2.3 Hz, 1Hsyn), 4.58 (d, J = 4.3 Hz, 1Hanti),
5.24 (dd, J = 9.1, 4.2 Hz, 1Hanti), 5.45 (dd, J = 8.8, 1.9 Hz, 1Hsyn), 6.35
(d, J = 9.1 Hz, NHanti), 6.75 (m, 4Hsyn + NHsyn), 7.03–7.94 (m, 14Hsyn
,
14Hanti, Ar H); 13C NMR dC: 21.4 (Me), 52.5 (CsynNH), 55.9 (CsynN@),
69.9 (OMesyn), 125.3, 126.2, 127.0, 128.2, 128.3, 128.5, 128.8, 129.1,
129.2, 130.1, 131.0, 132.4, 142.8; MS (EI) m/z (%): 502 (0.56), 194
(40), 155 (23), 92 (11), 91 (100), 65 (10).
4.10. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(p-fluorophenyl)propanoate syn-3h and anti-
3h8e
4.14. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(2-thienyl)propanoate syn-3l and anti-3l8h
30.6 mg; 48% yield; HPLC: (Daicel Chiralpak OD-H), hexane/
i-PrOH 90/10, flow rate 0.6 ml/min, tR: 13.4 min (syn), 14.8 min
28.0 mg; 45% yield; HPLC: (Daicel Chiralpak AS-H), hexane/
i-PrOH 85/15, flow rate 1 ml/min, tR: 15.3 min (syn) and 22.7 min
(anti), 17.1 min (anti), and 32.6 min (syn), 254 nm; IR
mmax: 3289,
(syn), 254 nm; IR
m
max: 3269, 2357, 1742, 1572, 1329, 1156,
2971, 1753, 1628, 1509, 1428, 1328, 1156, 1081, 736, 697 cmÀ1
;
1089, 812, 734, 700 cmÀ1
;
1H NMR dH: 2.34 (s, 3H, Meanti), 2.38
1H NMR dH: 2.29 (s, 3H, Meanti), 2.36 (s, 3H, Mesyn), 3.50 (s,
3H + 3H, OMesyn+anti), 4.12 (d, J = 2.3 Hz, 1Hsyn), 4.34 (d, J = 5.8 Hz,
1Hanti), 4.71 (dd, J = 7.1, 6.1 Hz, 1Hanti), 5.13 (dd, J = 8.1, 2.0 Hz,
1Hsyn), 5.80 (d, J = 7.5 Hz, NHanti), 6.42 (t, J = 7.5 Hz, 2Hsyn + NHsyn),
6.74–7.90 (m, 18Hsyn, 18Hanti, Ar H); 13C NMR dC: 21.4 (Me), 52.4
(CsynNH), 58.8 (CsynN@), 69.9 (OMesyn), 114.9, 126.5, 126.8, 127.0,
128.2, 128.4, 128.9, 129.2, 129.7, 130.0, 131.0, 132.4, 138.0,
142.9, 169.5syn, 173.4syn (CO, CN); MS (EI) m/z (%): 530 (0.32),
277 (10), 194 (37), 155 (35), 91 (100), 65 (10).
(s, 3H, Mesyn), 3.51 (s, 3H + 3H, OMesyn+anti), 4.37 (d, J = 2.5 Hz,
1Hsyn), 4.47 (d, J = 6.0 Hz, 1Hanti), 5.20 (dd, J = 9.3, 2.0 Hz, 1Hsyn),
6.07 (dd, J = 2.5, 0.8 Hz, 1Hsyn), 6.15 (dd, J = 3.2, 1.9 Hz, 1Hsyn),
6.22 (d, J = 9.3 Hz, 1Hsyn), 6.75 (d, J = 1.6 Hz, 1Hsyn), 6.77 (d,
J = 1.2 Hz, NHsyn), 7.08–7.89 (m, 14Hsyn, 14Hanti, Ar H); 13C NMR
dC: 21.4 (Me), 52.5 (CsynNH), 55.9 (CsynN@), 69.9 (OMesyn), 107.8,
110.4, 125.3, 125.5, 126.2, 126.4, 127.0, 127.9, 128.1, 128.5,
128.8, 129.0, 129.2, 129.3, 129.7, 131.0, 136.7, 139.0, 162.2,
169.3syn, 173.8syn (CO, CN); MS (EI) m/z (%): 518 (0.47), 194 (40),
165 (10), 155 (22), 91 (100), 65 (10).
4.11. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(p-chlorophenyl)propanoate syn-3i and anti-i8k
Acknowledgements
46.2 mg; 70% yield; HPLC: (Daicel Chiralpak OD-H), hexane/
i-PrOH 90/10, flow rate 0.6 ml/min, tR: 16.3 min (syn), 17.6 min
This work has been supported by the Spanish Ministerio de
(anti), 21.1 min (syn), and 37.4 min (anti), 254 nm; IR
mmax: 3260,
Ciencia
e Innovación (MICINN) (Consolider INGENIO 2010
2923, 1754, 1597, 1288, 1157, 1088, 698, 662 cmÀ1 1H NMR dH:
;
CSD2007-00006, CTQ2010-20387, CTQ2013-43446-P), FEDER,
Generalitat Valenciana (PROMETEO/2009/039, and PROMETEOII
2014/017), and by the University of Alicante. L. S. thanks University
of Edinburgh for an ERASMUS fellowship.
2.30 (s, 3H, Meanti), 2.37 (s, 3H, Mesyn), 3.50 (s, 3H + 3H, OMesyn+anti),
4.13 (d, J = 2.3 Hz, 1Hsyn), 4.35 (d, J = 5.7 Hz, 1Hanti), 4.69 (dd, J = 7.3,
5.8 Hz, 1Hanti), 5.11 (dd, J = 8.3, 2.1 Hz, 1Hsyn), 5.79 (d, J = 7.6 Hz,
NHanti), 6.41 (d, J = 9.1 Hz, NHsyn), 6.44 (d, J = 7.4 Hz, 2Hsyn),
6.93–7.88 (m, 18Hsyn, 18Hanti, Ar H); 13C NMR dC: 21.4 (Me), 52.4
(CsynNH), 58.9 (CsynN@), 69.7 (OMesyn), 126.4, 126.8, 127.0, 128.2,
128.5, 128.9, 129.3, 129.7, 130.0, 131.1, 133.2, 135.3, 137.5, 138.2,
143.1, 169.5syn, 173.5syn (CO, CN); MS (EI) m/z (%): 547 (0.18), 194
(36), 155 (40), 91 (100), 65 (10).
References
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4.12. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(p-bromophenyl)propanoate syn-3j and anti-
3j8h
24.8 mg; 35% yield; HPLC: (Daicel Chiralpak OD-H), hexane/
i-PrOH 90/10, flow rate 0.6 ml/min, tR:13.3 min (syn), 14.7 min
(anti), 16.8 min (syn), and 29.7 min (anti), 254 nm; IR mmax: 3296,
2971, 1754, 1630, 1328, 1157, 1075, 698 cmÀ1; 1H NMR dH: 2.31 (s,
3H, Meanti), 2.37 (s, 3H, Mesyn), 3.50 (s, 3H + 3H, OMesyn+anti), 4.13
(d, J = 2.3 Hz, 1Hsyn), 4.35 (d, J = 5.6 Hz, 1Hanti), 4.67 (dd, J = 7.5,
5.7 Hz, 1Hanti), 5.08 (dd, J = 8.3, 2.1 Hz, 1Hsyn), 5.74 (d, J = 7.4 Hz,
NHanti), 6.37 (d, J = 8.3 Hz, NHsyn), 6.45 (d, J = 7.1 Hz, 2Hsyn),
6.85–7.69 (m, 18Hsyn, 18Hanti, Ar H); 13C NMR dC: 21.4 (Me), 29.7,
52.4 (CsynNH), 58.9 (CsynN@), 69.6 (OMesyn), 126.8, 127.1, 128.2,
128.5, 128.6, 128.9, 129.3, 130.0, 131.2, 138.2, 143.1, 169.4syn; MS
(EI) m/z (%): 591 (0.48), 194 (36), 155 (47), 91 (100), 65 (10).
4.13. Methyl 2-[(diphenylmethylene)amino]-3-(4-methylphenyl-
sulfonamide)-3-(2-furyl)propanoate syn-3k and anti-3k8d
27.1 mg; 45% yield; HPLC: (Daicel Chiralpak AD), hexane/i-PrOH
90/10, flow rate 1 ml/min, tR: 15.0 min (syn), 25.1 min (anti),
40.5 min (anti), and 65.5 min (syn), 254 nm; IR
2360, 1739, 1277, 1158, 1075, 812, 700, 665 cmÀ1
2.37 (s, 3H, Meanti), 2.37 (s, 3H, Mesyn), 3.52 (s, 3H, OMeanti), 3.58
m
max: 3267, 2971,
;
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