Stereoselective synthesis of chiral β2,3-disubstituted-β-amino acid derivatives using Pd/In transmetallation cascade processes

Article abstract of DOI:10.1016/j.tet.2008.06.037

A new, highly efficient synthesis of chiral β^2,3-disubstituted-β-amino acid derivatives has been developed, based on an allylation procedure employing allene and a catalytic Pd/In bimetallic process.

Full text of DOI:10.1016/j.tet.2008.06.037

Tetrahedron 64 (2008) 8177–8181
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of chiral
b
2,3-disubstituted-
b-amino acid derivatives
using Pd/In transmetallation cascade processes
,
b
a
a
c
Ronald Grigg a , John Blacker , Colin Kilner , Shaun McCaffrey , Vladimir Savic ,
*
Visuvanathar Sridharan a
a Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, Department of Chemistry, Leeds University, Leeds LS2 9JT, UK
b Avecia Ltd, Leeds Road, Huddersfield, West Yorkshire HD2 1GA, UK
c Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia
a r t i c l e i n f o
a b s t r a c t
A new, highly efficient synthesis of chiral
b b-amino acid derivatives has been de-
2,3-disubstituted-
Article history:
Received 6 March 2008
Received in revised form 29 May 2008
Accepted 12 June 2008
veloped, based on an allylation procedure employing allene and a catalytic Pd/In bimetallic process.
Ó 2008 Published by Elsevier Ltd.
Available online 14 June 2008
1. Introduction
Our strategy for the stereoselective synthesis of b-amino acid
derivatives using our methodology is outlined in Scheme 1. The
oxidative addition of the aryl iodide 1 to Pd(0) followed by reaction
with allene 2 is expected to generate an allyl-Pd(II) species a, which
would then create a nucleophilic allyl-In species b, via a redox
transmetallation process. Reaction of intermediate b with sulfin-
imine 3 would then afford the product. It was envisaged that the
stereoselectivity of this process would be controlled by the chiral
sulfinimine, which has been shown to be an efficient auxiliary in
related transformations.8,9 Although the cascade could afford two
regioisomeric products, 4 and 5, stereoelectronic factors were
expected to control the regiochemistry leading to 4 as the sole or
major product. Overall, this three-component coupling would
create two new bonds and two chiral centres.
While
a-amino acids are essential prerequisites for life, the
b
-amino isomers are far less common in living organisms. However,
they are constituents of wide variety of natural products and var-
ious polypeptides with different biological properties1 and have
attracted growing interest.2 These polypeptides have been shown
to form secondary structures analogous to those of natural poly-
peptides, but are metabolically more stable than the a-amino acid
equivalents.3 This is particularly interesting from a medicinal
chemistry point of view. Due to the increased interest in this area,
b
-amino acids have emerged as important synthetic targets and
a range of methodologies have been developed for their prepara-
tion. The majority of these procedures is based on either the
Mannich4a–d or the aza-Michael4e–g reactions, although other
methods are also known.4h–j
Ar1
I
Ar1
1
Ar1
Pd
COOR
Pd/In
In
COOR
+
•
2
COOR
2. Results and discussion
+
Ar
_
O
+
N
COOR
Our approach to the synthesis of
b
-amino acids is based on our
S +
a
Ar2
In
b
Pd/In transmetallation process5 involving allenes as key reactants.
This methodology possesses significant synthetic diversity advan-
tages in allowing access to a wide range of 2- and 2,3-disubstituted
allylic species. Othershave developedanalogous processes involving
allylic acetates.6 In recent years, the potential of this umpolung
procedure, in which a nucleophilic In species is generated from an
electrophilic Pd species, has been exemplified by the synthesis of
3
COOR
NH
COOR
NH
Ar1
Ar2
Ar1
Ar2
+
a range of compounds,7 including chiral non-natural
a
-amino acids.8
+
_
+
S
S
_
O
O
4
5
* Corresponding author. Tel./fax: þ44 113 343 6501.
E-mail address: r.grigg@leeds.ac.uk (R. Grigg).
Scheme 1.
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.06.037

8178
R. Grigg et al. / Tetrahedron 64 (2008) 8177–8181
Pd(OAc)2
_
O
(
)
3
COOEt
P
O
In
COOEt
N
S
+
Ar
COOEt
+
Ar
+
(a)
Ar
I
•
6
+
Py
NH
N
CuI
Py
NH
1
7
+
ascorbic acid
DMF
_
S
S+
O_
O
Pd(OAc)2
8a,c,e
COOEt
9
-
(
)
3
O
P
O
In
N
S
+
Ar
COOEt
+
(b)
Ar
I
•
+
CuI
NH
S+
Py
8b,d,f
N
ascorbic acid
DMF
O_
Scheme 2.
In the event stirring and heating iodobenzene, allene 6 and imine
(S)-7 in DMF in the presence of Pd(OAc)2, tri-2-furyl phosphine, In
and additives10 in a Schlenk flask at 40 ꢀC afforded the expected
product as a 15:1 mixture of separable diastereoisomers, 8 and 9, in
69% yield (Scheme 2a, Table 1, entry 1). To our delight the regioi-
someric product 5 (Scheme 1) was not observed.
a Zimmerman–Traxler chair-like transition state A, involving an
In(I) species,11 an E-allylindium species and addition to the Si face of
the sulfinimine. This transition state may be further stabilised by
the proximity of heteroatoms in the sulfinimine moieties and their
ability to coordinate indium. An additional stabilisation factor is the
potential p–p interactions between the electron deficient 2-pyridyl
When the reaction was carried out using the enantiomeric
sulfinimine (R)-7, the results were identical apart from the sense of
chiral induction (entry 1 vs entry 2, Table 1). Additional examples,
performed with both enantiomeric sulfinimine 7 and 4-methyl- or
4-phenyliodobenzene, under the same conditions, afforded analo-
gous products in good yield and with a high degree of diaster-
eoselectivity, Table 1. Although the para substituent on the aryl
iodide seems to influence the diastereoselectivity, the origin of this
effect is not at present clear. It has been previously shown that the
sulfoxy group can be easily removed8,9 from N-atom. Hence, the
process depicted by Scheme 2 is an efficient way to synthesise
substituent and the electron rich aromatic substituents. The en-
antiomeric product 8f is proposed to form via transition state B
certain classes of b b-amino acids.
2,3-disubstituted-
The absolute stereochemistries of the major products, 8e and 8f,
were established by X-ray crystallography (Fig. 1). These data
demonstrate that (S)-7 and (R)-7 engender S- and R-stereochem-
istry on both newly formed chiral centres, respectively.
Based on the absolute stereochemistry of the products and our
previous semi-empirical calculations using MOPAC v7 of related
reactions forming a
-amino acids,7 the transition state leading to the
major product was proposed (Fig. 2). Compound 8e is formed via
Table 1
Synthesis of chiral
b
-amino acid derivativesa
Entry
Ar(I)
Imine
Ratio 8/9b
Yieldc (%)
60
1
2
S
15(S,S,S):1(S,S,R)
R
15(R,R,R):1(R,R,S)
60
3
4
S
9(S,S,S):1(S,S,R)
60
60
R
19(R,R,R):1(R,R,S)
5
S
12(S,S,S):1(S,S,R)
12(R,R,R):1(R,R,S)
69
62
6
R
a
Reaction conditions: ArI (0.75 mmol), iminoester (0.5 mmol), allene (0.75 mmol),
Pd(OAc)2 (0.05 mmol), phosphine (0.1 mmol), In (0.75 mmol), CuI (0.1 mmol),
ascorbic acid (0.2 mmol) and DMF (10 mL) in a Schlenk flask, 40 ꢀC, 24 h.
b
Calculated by integration of the 1H NMR spectra of the product mixtures.
Isolated yield.
c
Figure 1.

R. Grigg et al. / Tetrahedron 64 (2008) 8177–8181
8179
Ph
In conclusion, a short, diastereoselective synthesis of
substituted-
b
2,3-di-
Ph
b
-amino acid derivatives has been developed, employ-
ing Pd/In transmetallation processes. Under very mild conditions
the three-component coupling, forming two bonds and two chiral
centres, afforded the products in good yield and with a high degree
of diastereoselectivity. Further study of this process is underway.
N
N
In
In
N
S
N
S
3. Experimental
3.1. General
_
_
+
E
+
O
O
B
Unless otherwise noted all reagents were obtained from com-
mercial suppliers and used without further purification. All solvents
were dried or purified by the literature procedures.18 Chromatog-
A
raphycolumns were prepared using Fisher chemicals 60A 35–70 mm
silica gel. Nuclear magnetic resonance spectra were recorded using
Bruker DPX300 and DRX500 MHz spectrometers. Chemical shifts
are reported inparts per million (d) downfield relative tothe internal
N
N
Ar
H
Ar
E
E
H
HN
HN
H
H
reference tetramethylsilane. Unless otherwise specified NMR spec-
tra were recorded in deuterochloroform at room temperature. Ab-
breviations used: Ar¼aromatic, d¼doublet, dd¼doublet of doublets,
dq¼doublet of quartets, dt¼doublet of triplets, m¼multiplet,
q¼quartet, s¼singlet and t¼triplet. Mass spectra were recorded
using a micromass ZMD 2000 spectrometer employing the elec-
trospray (ESþ) ionisation technique. Accurate molecular masses
were obtained from the EPSRC Swansea Mass Spectroscopy service
using perfluorotributylamine or polyethylenimine as an internal
standard. Infra-red spectra were recorded using a Perkin–Elmer FT-
IR spectrometer. IR spectra of liquids were recorded as thin films on
sodium chloride plates. IR spectra of solids were recorded using the
‘golden gate’ apparatus. Optical rotations were measured on an
Optical Activity AA-1000 polarimeter. Rotations are quoted in
10ꢁ1 deg cm2 gꢁ1 and the concentration (c) is expressed in grams per
100 mL. Unless otherwise stated chloroform was the solvent. Mi-
croanalysis was performed using a Carlo-Erber 1108 elemental
analyser and, for sulfur, by titration against barium perchlorate.
_
_
+
+
O
S
S
O
_
tBu
Ar
O
+
H
Py
_
tBu
Ar
O
+
Py
H
S
S
N
H
N
E
(S,S,R)-8e
H
H
H
(S,S,S)-8e
E
E = COOEt
Ar =
Py =
N
Figure 2.
3.2. General procedure for the synthesis of
derivatives
b-amino acid
involving the Z-allylindium species. Although this transition state
seems to be more stable due to pseudoequatorial orientation of the
Aryl iodide 1 (0.75 mmol) was added to a suspension of chiral sul-
finimine 7 (0.5 mmol), ethyl 2,3-butadienoate 6 (0.75 mmol), indium
metal powder (0.088 g, 0.75 mmol), Pd(OAc)2 (0.011 g, 0.05 mmol), tri-
2-furyl phosphine (0.024 g, 0.1 mmol), CuI (0.019 g, 0.1 mmol) and
ascorbic acid (0.0355 g, 0.2 mmol) in DMF (10 mL) in a Schlenk tube.
The flask was flushed with nitrogen and sealed. The mixture was stir-
red and heated to 40 ꢀC (oil bath temperature) for 24 h, left to cool and
vented. Ethyl acetate (20 mL) and 5% HCl aqueous solution (10 mL)
were added and the mixture stirred for 20 min. The phases were
separated and the aqueous layer extracted with ethyl acetate (20 mL).
The organic extracts were combined and washed with water (3ꢂ
40 mL), dried (MgSO4), filtered and the filtrate concentrated in vacuo.
The residue was purified by flash chromatography to give the
ester moiety, Z- and E-h
1-allylindium species are not expected to
interconvert under these conditions12 and their ratio is thus
thought to reflect the ratio of the syn- and anti-allylpalladium(II)
intermediates trapped out by indium.
This would accord with our previous experience involving
p-allylpalladium species from monosubstituted allenes where the
1,2-disubstituted E-isomer is the predominant or sole species. This
in turn would indicate that transfer of the allyl moiety from
palladium to indium occurs with retention of alkene geometry.
The mechanism of the reductive transmetallation proceeds via
Pd/In bond formation or a Pd–X–In bridged species13 resulting in
the delivery of indium to the same face of the allyl system as pal-
ladium. There is literature precedent for this in both indium and
N-sulfinyl-b-amino ester.
zinc transmetallation with p
-allyl-Pd(II).14
An unresolved problem is that if indeed indium(I) allyl is the key
allylation agent then 2 equiv of In(0) is required for the reduction of
Pd(II) and the nature of this process is unclear.15 However, we
employed only 1.5 mole equiv of In and yields/conversion were
depressed in the absence of CuI8 and ascorbic acid.
We believe a key role of the CuI additive is to promote formation
of InI and hence facilitate transfer of indium from the solid to the
solution phase. The formation of copper allyl species16 may also be
involved. Ascorbic acid was added to help recycle unproductive
higher valence states of the Pd, Cu17 and In if present. It is un-
doubtedly beneficial but its precise role(s) is unclear.
3.2.1. Ethyl (S,S,S) 2-[(2-methyl-propane-2-sulfinylamino)-pyridin-
2-yl-methyl]-3-phenyl-but-3-enoate (S,S,S)-8a
4
3
2
5
6
Ha
CO2Et
O-
•
•
Hb
S+
4
3
N
H
N
5
6

8180
R. Grigg et al. / Tetrahedron 64 (2008) 8177–8181
Obtained as a pale yellow oil (0.120 g, 60%) after flash chromato-
J¼9.4 Hz), 4.40 (1H, d, NH, J¼9.4 Hz), 4.23 (1H, d, NCHCH, J¼9.4 Hz),
3.97–3.90 (2H, m, OCH2), 1.06 (9H, s, C(CH3)3), 1.01 (3H, t, OCH2CH3,
J¼7.3 Hz). dc (75 MHz, CDCl3): 172.1 (CO), 160.3 (]C), 149.8 (Ar),
144.1 (Ar), 139.1 (Ar), 137.9 (Ar), 137.0 (Ar), 129.4 (Ar), 126.7 (Ar),
123.9 (Ar), 123.2 (Ar), 116.1 (]CH2), 63.9 (NC), 61.2 (OC), 56.7 (SC),
56.4 (NCC), 23.0 (C(CH3)3), 21.5 (ArCH3), 14.3 (OCH2CH3). m/z (ESþ):
415 (MHþ).
20
graphy (EtOAc). Rf: 0.38 (EtOAc). [
a]
ꢁ14.4 (c 1.4). Found: C, 66.10;
D
H, 7.30; N, 7.10; S, 7.80. C22H28N2O3S requires: C, 65.97; H, 7.05; N,
6.99; S, 8.01%. nmax/cmꢁ1: 3453, 3254 (NH), 3063, 2947, 2321,
2219, 2136, 1954, 1832, 1732 (CO). dH (500 MHz, CDCl3): 8.54 (1H,
d, pyridyl-6H, J¼4.7 Hz), 7.61 (1H, t, Ar-4H, J¼7.7 Hz), 7.48 (1H, d,
pyridyl-3H, J¼7.3 Hz), 7.42 (2H, d, Ar-2H, Ar-6H, J¼7.7 Hz), 7.34
(2H, t, Ar-3H, Ar-5H, J¼7.7 Hz), 7.28 (1H, t, pyridyl-4H, J¼7.3 Hz),
7.16 (1H, dd, pyridyl-5H, J¼4.7, 7.3 Hz), 5.63 (1H, s, ]CHa), 5.56
(1H, s, ]CHb), 4.97 (1H, t, NCH, J¼9.8 Hz), 4.41 (1H, d, NH,
J¼9.8 Hz), 4.25 (1H, d, NCHCH, J¼9.8 Hz), 3.98–3.92 (2H, m,
OCH2), 1.06 (9H, s, C(CH3)3), 1.02 (3H, t, OCH2CH3, J¼7.3 Hz). dc
(75 MHz, CDCl3): 172.0 (CO), 160.3 (]C), 149.6 (Ar), 144.3
(Ar), 142.0 (Ar), 137.0 (Ar), 128.7 (Ar), 128.1 (Ar), 126.8 (Ar),
126.7 (Ar), 124.1 (Ar), 123.2 (Ar), 117.2 (]CH2), 63.7 (NC), 61.2
(OC), 56.6 (SC), 56.4 (NCC), 22.8 (C(CH3)3), 14.2 (OCC). m/z (ESþ):
401 (MHþ).
3.2.4. Ethyl (R,R,R) 2-[(2-methyl-propane-2-sulfinylamino)-
pyridin-2-yl-methyl]-3-p-tolyl-but-3-enoate (R,R,R)-8d
3
2
5
6
CO2Et
O-
•
•
S+
4
5
3
N
H
N
6
3.2.2. Ethyl (R,R,R) 2-[(2-methyl-propane-2-sulfinylamino)-
pyridin-2-yl-methyl]-3-phenyl-but-3-enoate (R,R,R)-8b
Obtained as colourless prisms (0.088 g, 60%), mp 74–76 ꢀC,
20
4
after flash chromatography (EtOAc). Rf: 0.40 (EtOAc). [
a]
þ18.9 (c
D
3
2
5
6
1.4). Found: C, 66.7; H, 7.40; N, 6.80; S, 7.80%. C23H30N2O3S re-
quires: C, 66.64; H, 7.27; N, 6.76; S, 7.73%. nmax/cmꢁ1: 3254 (NH),
3181, 3056, 2411, 2219, 2051, 1926, 1823, 1738 (CO). dH (500 MHz,
CDCl3): 8.54 (1H, d, pyridyl-6H, J¼4.7 Hz), 7.61 (1H, td, pyridyl-4H,
J¼1.7, 7.7 Hz), 7.42 (1H, d, pyridyl-3H, J¼7.7 Hz), 7.38 (2H, d, Ar-3H,
Ar-5H, J¼8.1 Hz), 7.15 (3H, m, Ar-2H, Ar-6H, pyridyl-5H), 5.59 (1H,
s, ]CHa), 5.51 (1H, s, ]CHb), 4.95 (1H, t, NCH, J¼9.4 Hz), 4.40 (1H,
d, NH, J¼9.4 Hz), 4.23 (1H, d, NCHCH, J¼9.4 Hz), 3.97–3.90 (2H, m,
OCH2), 1.06 (9H, s, C(CH3)3), 1.01 (3H, t, OCH2CH3, J¼7.3 Hz). dc
(75 MHz, CDCl3): 172.1 (CO), 160.3 (]C), 149.8 (Ar), 144.1 (Ar),
139.1 (Ar), 137.9 (Ar), 137.0 (Ar), 129.4 (Ar), 126.7 (Ar), 123.9 (Ar),
123.2 (Ar), 116.1 (]CH2), 63.9 (NC), 61.2 (OC), 56.7 (SC), 56.4
(NCC), 23.0 (C(CH3)3), 21.5 (ArCH3), 14.3 (OCH2CH3). m/z (ESþ): 415
(MHþ).
Ha
CO2Et
O-
•
•
Hb
S+
4
3
N
H
N
5
6
Obtained as a pale yellow oil (0.120 g, 60%) after flash chroma-
20
tography (EtOAc). Rf: 0.38 (EtOAc). [
a]
þ12.8 (c 1.9). Found: C,
D
66.10; H, 7.10; N, 7.20; S, 8.0. C22H28N2O3S requires: C, 65.97; H,
7.05; N, 6.99; S, 8.01%. nmax/cmꢁ1: 3451, 3248 (NH), 3066, 2953,
2325, 2216, 2141, 1954, 1832, 1732 (CO). dH (500 MHz, CDCl3): 8.54
(1H, d, pyridyl-6H, J¼4.7 Hz), 7.61 (1H, t, Ar-4H, J¼7.7 Hz), 7.48 (1H,
d, pyridyl-3H, J¼7.3 Hz), 7.42 (2H, d, Ar-2H, Ar-6H, J¼7.7 Hz), 7.34
(2H, t, Ar-3H, Ar-5H, J¼7.7 Hz), 7.28 (1H, t, pyridyl-4H, J¼7.3 Hz),
7.16 (1H, dd, pyridyl-5H, 4.7, 7.3 Hz), 5.63 (1H, s, ]CHa), 5.56 (1H, s,
]CHb), 4.97 (1H, t, NCH, J¼9.8 Hz), 4.41 (1H, d, NH, J¼9.8 Hz), 4.25
(1H, d, NCHCH, J¼9.8 Hz), 3.98–3.92 (2H, m, OCH2), 1.06 (9H, s,
C(CH3)3), 1.02 (3H, t, OCH2CH3, J¼7.3 Hz). dc (75 MHz, CDCl3): 172.0
(CO), 160.3 (]C), 149.8 (Ar), 144.3 (Ar), 142.0 (Ar), 137.1 (Ar), 128.7
(Ar), 128.1 (Ar), 126.9 (Ar), 126.7 (Ar), 124.1 (Ar), 123.3 (Ar), 117.3
(]CH2), 63.9 (NC), 61.2 (OC), 56.7 (SC), 56.4 (NCC), 23.0 (C(CH3)3),
14.3 (OCC). m/z (ESþ): 401 (MHþ).
3.2.5. Ethyl (S,S,S) 3-Biphenyl-4-yl-2-[(2-methyl-propane-2-
sulfinylamino)-pyridin-2-yl-methyl]-but-3-enoate (S,S,S)-8e
4'
3'
5'
2'
6'
3
2
5
6
Ha
CO2Et
O-
•
•
3.2.3. Ethyl (S,S,S) 2-[(2-methyl-propane-2-sulfinylamino)-pyridin-
2-yl-methyl]-3-p-tolyl-but-3-enoate (S,S,S)-8c
Hb
3
S+
4
N
HdH
N
5
6
3
2
5
6
Obtained as colourless prisms (0.164 g, 69%), mp 64–67 ꢀC, after
20
flash chromatography (EtOAc). Rf: 0.27 (EtOAc). [
a
]
þ32.6 (c 1.1).
D
CO2Et
Found: 477.2214. C28H33N2O3S requires: 477.2206. nmax/cmꢁ1
:
O-
•
•
S+
3443, 3254 (NH), 3034, 2960, 2309, 2217, 2060, 1963, 1834, 1731
(CO), 1623. dH (500 MHz, CDCl3): 8.53 (1H, d, pyridyl-6H, J¼4.7 Hz),
7.62 (3H, m, ArH), 7.57 (4H, m, ArH), 7.43 (3H, m, ArH), 7.33 (1H, t,
ArH, J¼7.3 Hz), 7.14 (1H, dd, pyridyl-5H, J¼4.7, 10.3 Hz), 5.69 (1H, s,
]CHa), 5.59 (1H, s, ]CHb), 5.00 (1H, t, NCH, J¼9.6 Hz), 4.44 (1H, d,
NH, 9.6 Hz), 4.30 (1H, d, NCHCH, J¼9.6 Hz), 3.97 (2H, m, OCH2), 1.07
(9H, s, C(CH3)3), 1.02 (3H, t, OCCH3, J¼6.8 Hz). dc (75 MHz, CDCl3):
172.5 (CO), 159.3 (Ar), 149.6 (H2C]C), 140.9 (Ar), 140.7 (Ar), 136.8
(Ar), 129.3 (Ar), 128.0 (Ar), 127.4 (Ar), 127.3 (Ar), 127.2 (Ar), 127.2
(Ar), 124.1 (Ar), 123.9 (Ar), 123.3 (Ar), 116.9 (]CH2), 63.9 (OC), 61.4
(NC), 56.7 (SC), 56.4 (NCC), 23.1 (C(CH3)3), 14.6 (OCC). m/z (ESþ):
478 (MHþ).
4
5
3
N
H
N
6
Obtained as colourless prisms (0.088 g, 60%), mp 74–76 ꢀC, after
20
flash chromatography (EtOAc). Rf: 0.40 (EtOAc). [
a]
ꢁ20.3 (c 1.1).
D
Found: 415.2069. C23H30N2O3S requires: 415.2055. nmax/cmꢁ1
:
3254 (NH), 3181, 3056, 2411, 2219, 2047, 1922, 1821, 1738 (CO). dH
(500 MHz, CDCl3): 8.54 (1H, d, pyridyl-6H, J¼4.5 Hz), 7.61 (1H, td,
pyridyl-4H, J¼1.7, 7.7 Hz), 7.42 (1H, d, pyridyl-3H, J¼7.7 Hz), 7.38
(2H, d, Ar-3H, Ar-5H, J¼8.1 Hz), 7.15 (3H, m, Ar-2H, Ar-6H, pyridyl-
5H), 5.59 (1H, s, ]CHa), 5.51 (1H, s, ]CHb), 4.95 (1H, t, NCH,

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8181
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3. Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219–3232 and
references cited therein.
4. For some recent examples, see: (a) Ricci, A.; Pettersen, D.; Bernardi, L.; Fini, F.;
Fochi, M.; Herrera; Raquel, P.; Sgarzani, V. Adv. Synth. Catal. 2007, 349, 1037–
1040; (b) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413–2416; (c) Moumne, R.;
Denise, B.; Guitot, K.; Rudler, H.; Lavielle, S.; Karoyan, P. Eur. J. Org. Chem. 2007,
12, 1912–1920; (d) Song, J.; Shih, H.; Deng, L. Org. Lett. 2007, 9, 603–606; (e)
Vesely, J.; Ibrahem, I.; Rios, R.; Zhao, G.; Xu, Y.; Cordova, A. Tetrahedron Lett.
2007, 48, 2193–2198; (f) Ibrahem, I.; Rios, R.; Vesely, J.; Zhao, G.; Cordova, A.
J. Chem. Soc., Chem. Commun. 2007, 849–851; (g) Phua, P.; White, A. J. P.; de
Vries, J. G.; Hii, K. K. Adv. Synth. Catal. 2006, 348, 587–592; (h) Murakami, M.;
Ishida, N.; Miura, T. Chem. Lett. 2007, 36, 476–477; (i) Hoen, R.; Tiemersma-
Wegman, T.; Procuranti, B.; Lefort, L.; de Vries, J. G.; Minnaard, A. J.; Feringa, B.
L. Org. Biomol. Chem. 2007, 5, 267–275; (j) Swiderska, M. A.; Stewart, J. D. Org.
Lett. 2006, 8, 6131–6133; See also Ref. 1.
3.2.6. Ethyl (R,R,R) 3-Biphenyl-4-yl-2-[(2-methyl-propane-2-
sulfinylamino)-pyridin-2-yl-methyl]-but-3-enoate (R,R,R)-8f
4'
3'
2'
5'
6'
3
2
5
6
Ha
CO2Et
O-
•
•
Hb
3
S+
4
N
H
5
N
6
Obtained as colourless prisms (0.151 g, 62%), mp 65–67 ꢀC, after
5. Anwar, U.; Grigg, R.; Rasparini, M.; Savic, V.; Sridharan, V. J. Chem. Soc., Chem.
Commun. 2000, 645–646.
20
flash chromatography (EtOAc). Rf: 0.27 (EtOAc). [
Found: 477.2170.
a]
ꢁ34.5 (c 0.6).
D
6. Ohno, H.; Hamaguchi, H.; Tanaka, T. Org. Lett. 2000, 2, 2161–2163; Araki, S.;
Kamei, T.; Hirashita, T.; Yamamura, H.; Kawai, M. Org. Lett. 2000, 2, 847–849.
7. For some recent examples, see: Cleghorn, L. A. T.; Grigg, R.; Kilner, C.; MacLa-
chlan, W. S.; Sridharan, V. J. Chem. Soc., Chem. Commun. 2005, 3071–3073;
Norsikian, S.; Lubineau, A. Org. Biomol. Chem. 2005, 3, 4089–4094; Miyabe, H.;
Takemoto, Y. Synlett 2005, 1641–1655.
8. Grigg, R.; McCaffrey, S.; Sridharan, V.; Fishwick, C. W. G.; Kilner, C.; Korn, S.;
Bailey, K.; Blacker, J. Tetrahedron 2006, 62, 12159–12171.
9. Tang, T. P.; Ellman, J. A. J. Org. Chem. 2002, 67, 7819–7832.
10. Cleghorn, L. A. T.; Cooper, I. R.; Grigg, R.; MacLachlan, W. S.; Sridharan, V. Tet-
rahedron Lett. 2003, 44, 7969–7973; Cleghorn, L. A. T.; Cooper, I. R.; Fishwick, C.
W. G.; Grigg, R.; MacLachlan, W. S.; Rasparini, M.; Sridharan, V. J. Organomet.
Chem. 2003, 687, 483–493.
11. Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999, 121, 3228–3229; Law, M. C.; Cheung,
T. W.; Wong, K. Y.; Chan, T. H. J. Org. Chem. 2007, 72, 923–929; Fontana, G.;
Savona, G.; Ferrante, F. Lett. Org. Chem. 2006, 3, 98–102.
C
28H33N2O3S requires: 477.2206. nmax/cmꢁ1
:
3640, 3260 (NH), 2960, 2443, 2340, 2163, 2060, 1936, 1834, 1728
(CO), 1623. dH (500 MHz, CDCl3): 8.53 (1H, d, pyridyl-6H, J¼4.7 Hz),
7.62 (3H, m, ArH), 7.57 (4H, m, ArH), 7.43 (3H, m, ArH), 7.33 (1H, t,
ArH, J¼7.3 Hz), 7.14 (1H, dd, pyridyl-5H, J¼4.7, 10.3 Hz), 5.69 (1H, s,
]CHa), 5.59 (1H, s, ]CHb), 5.00 (1H, t, NCH, J¼9.6 Hz), 4.44 (1H, d,
NH, 9.6 Hz), 4.30 (1H, d, NCHCH, J¼9.6 Hz), 3.97 (2H, m, OCH2), 1.07
(9H, s, C(CH3)3), 1.02 (3H, t, OCCH3, J¼6.8 Hz). dc (75 MHz, CDCl3):
172.5 (CO), 159.3 (Ar), 149.6 (H2C]C), 140.9 (Ar), 140.7 (Ar), 136.8
(Ar), 129.3 (Ar), 128.0 (Ar), 127.4 (Ar), 127.3 (Ar), 127.2 (Ar), 127.1
(Ar), 124.1 (Ar), 123.9 (Ar), 123.2 (Ar), 116.9 (]CH2), 63.9 (OC), 61.4
(NC), 56.7 (SC), 56.4 (NCC), 23.1 (C(CH3)3), 14.6 (OCC). m/z (ESþ):
478 (MHþ).
12. Lee, W.; Kim, K. H.; Surnam, M. D.; Miller, M. J. J. Org. Chem. 2003, 68, 139–149;
Marshall, J. A. J. Org. Chem. 1999, 64, 696–697.
13. Steinke, T.; Gemel, C.; Winter, M.; Fisher, R. A. Chem.dEur. J. 2005, 11, 1636–
1646; Liute, G.; Schnockel, H. Coord. Chem. Rev. 2000, 206 and 207, 28–319;
Fisher, R. A.; Weiss, J. Angew. Chem., Int. Ed. 1999, 38, 2830–2850; Gemel, C.;
Steinke, T.; Cokoja, M.; Keimpster, A.; Fisher, R. A. Eur. J. Inorg. Chem. 2004,
4161–4176.
14. Tamaru, Y.; Tanaka, A.; Yasui, K.; Goto, S.; Tanaka, S. Angew. Chem., Int. Ed. Engl.
1995, 34, 787–789; Fontana, G.; Lubineau, A.; Scherrmann, M. C. Org. Biomol.
Chem. 2005, 3, 1375–1380; Norsikan, S.; Lubineau, A. Org. Biomol. Chem. 2005, 3,
4083–4094.
Acknowledgements
We thank Leeds University, the EPSRC, Avecia and the Serbian
Ministry of Science (V.Savic) for support.
References and notes
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2007, 107, 2–45.
16. Lipshutz, B. H.; Ellsworth, E. I.; Dimock, S. H.; Smith, R. A. J. J. Am. Chem. Soc.
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1. Spiteller, P.; Von Nussbaum, F. In Enantioselective Synthesis of b-Amino Acids,
II ed.; Juaristi, E., Soloshonok, V. A., Eds.; Wiley-Interscience: Hoboken, NJ,
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