Enantioselective synthesis of non-proteinogenic 2-arylallyl-α-amino acids via Pd/In catalytic cascades

Article abstract of DOI:10.1016/j.tet.2006.09.098

An efficient synthesis of both R- and S-enantiomers of 2-arylallyl-α-amino acids via a diastereoselective Pd/In mediated catalytic allylation of chiral N-sulfinyl-α-imino esters is described. The potential for further enhancement of molecular complexity a

Full text of DOI:10.1016/j.tet.2006.09.098

Tetrahedron 62 (2006) 12159–12171
Enantioselective synthesis of non-proteinogenic 2-arylallyl-a-
amino acids via Pd/In catalytic cascades
a
a
a
Ronald Grigg,a, Shaun McCaffrey, Visuvanathar Sridharan, Colin W. G. Fishwick,
*
Colin Kilner,a Stewart Korn,b Kevin Baileyb and John Blackerb
aMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, University of Leeds,
Leeds LS2 9JT, UK
bAvecia Ltd, Leeds Road, Huddersfield, West Yorkshire HD2 1GA, UK
Received 14 August 2006; revised 14 September 2006; accepted 28 September 2006
Available online 27 October 2006
Abstract—An efficient synthesis of both R- and S-enantiomers of 2-arylallyl-a-amino acids via a diastereoselective Pd/In mediated catalytic
allylation of chiral N-sulfinyl-a-imino esters is described. The potential for further enhancement of molecular complexity and creating con-
tiguous chiral centres by interfacing these processes with catalytic cyclisation–anion capture methodology is demonstrated.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
transmetallation in the presence of indium, furnishing
nucleophilic h1-allyl indium species 2. Allylation of the
enantiopure N-sulfinyl-a-imino ester 3, affords N-sulfinyl-
a-alkyl-a-amino esters 4 as single diastereoisomer (Scheme
1). Initial experiments employing iodobenzene and a catalyst
system comprising of 10 mol % Pd(OAc)2, 20 mol % tris-2-
furyl phosphine and 20 mol % CuI in DMF at 40 ꢀC
confirmed these expectations (Table 1, entry 1).
The synthesis of peptides and proteins containing non-natu-
ral a-amino acids vastly increases the structural and chemi-
cal diversity of polypeptides.
Novel a-amino acid side-chains and the availability of both
R- and S-stereoisomers enable tuning of pharmacokinetics,
formation of b-sheets and other peptide structural motifs
that effect biological activity and structural properties.
Ar
(II)
Allene
Pd
I
insertion
The synthesis of ‘designer’ peptidomimetics, incorporating
and/or modifying the beneficial aspects of the parent poly-
peptides whilst also possessing enhanced metabolic stability
and/or improved pharmacokinetics, is an area of burgeoning
interest.1–3
Ar
I
Ar
Oxidative
Addition
(II)
Pd
I
Start
Pd (0)
1
The asymmetric alkylation of glycine cation equivalents is
a general, efficient route to non-proteinogenic a-amino
acid derivatives. Previously, our group reported highly regio-
and diastereoselective Pd/In mediated cascade allylations of
carbonyl compounds including a highly stereoselective
allylation of chiral N-sulfinyl aldimines.4–10 We now report
further applications of the tert-butyl sulfinyl chiral auxilliary,
which has been widely used in the synthesis of chiral amines
including 1,2-amino alcohols and a- and b-amino acids,11–13
to a new approach to unusual a-amino acids.
In
Transmetallation
Ar
Ar
O–
S+
–
O
InX2
2
+
S
EtO2C
EtO2C
N
H
N
S-3
S,S-4
The Pd/In bimetallic cascade process involves generation of
an electrophilic p-allyl palladium species 1 that undergoes
Scheme 1. Reaction mechanism. Reagents and conditions: (i) ArI
(0.75 mmol), allene (1 atm), In (0.75 mmol), Pd(OAc)2 (10 mol %), tri-2-
furyl phosphine (20 mol %), CuI (20 mol %), piperidine (0.5 mmol), DMF
(20 ml/mmol), 40 ꢀC, 24 h; (ii) 4 M HCl/dioxane (5 mol equiv), EtOH
(10 ml/mmol), 30 min, rt, NaOH (2 mol equiv), 1:1 v/v EtOH/H2O
(10 ml/mmol) reflux, 2 h.
* Corresponding author. Tel.: +44 113 3436501; fax: +44 113 3436530;
e-mail: r.grigg@leeds.ac.uk
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.098

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R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
Table 1. Bimetallic cascade synthesis of chiral 4a–h and 5a–ha
Ar
Ar
Entry
ArI
Cascade product
Amino acid
–
O
Configuration Yield Configuration Yield
1) 4 M HCl/dioxane
(%)b
(%)c
S+
2) NaOH
EtO2C
N
H
EtOH/H2O
HO2C
NH2
S,S-4a
R,R-4a
92
80
S-5a
R-5a
100
100
1
2
3
4
S,S-4
S-5
I
I
Scheme 2. Deprotection of N-sulfinyl esters. Cleavage of the chiral sulfinyl
auxilliary is carried out first by treatment with 4 M HCl in dioxane (5 mol
equiv) for 30 min. Following the removal of the solvent the crude material
is treated with 1 M aqueous NaOH solution (2 mol equiv) in a 1:1 v/v EtOH/
H2O under reflux for 2 h. The amino acids 5a–h are isolated using an
Amberlyst H+ ion exchange resin (Table 1).
N
S,S-4b
R,R-4b
69
55
S-5b
R-5b
—
100
N
S,S-4c
R,R-4c
68
68
S-5c
R-5c
50
54
I
F3C
S,S-4d
R,R-4d
54
49
S-5d
R-5d
99
99
involve two possible chair-like arrangements. The heat of
formation (DHf) and imaginary vibrational frequencies (ni)
for transition states corresponding to additions to the S-sulf-
oximine indicate a marked preference for transition state 10,
which locates the ester moiety axially. Closer inspection
of this transition state reveals that the ester carbonyl oxygen
I
I
S,S-4e
R,R-4e
72
67
S-5e
R-5e
97
80
5
6
MeO
S,S-4f
R,R-4f
52
69
S-5f
R-5f
85
79
˚
is located near to the indium atom (O–In distance of 2.80 A)
I
N
Cl
Cl
indicating coordination to the indium atom. This transition
state leads to the product possessing S stereochemistry at
the newly created chiral centre. Interestingly, transition state
10 also locates the sulfoxide oxygen near to the metal centre
S,S-4g
R,R-4g
73
74
S-5g
R-5g
73
82
7
I
Cl
˚
CF3
(at a distance of 2.75 A) and this, although now involves
S,S-4h
R,R-4h
69
76
S-5h
R-5h
89
68
a four-membered ring, may also further stabilise the transi-
tion state. This type of chelation appears to be energetically
important as the next most favourable transition state 8
locates the sulfoxide oxygen close to the metal centre at a
8
F3C
I
a
Conditions as for Scheme 1.
Isolated yield.
Isolated overall yield for the two-step deprotection.
b
c
˚
distance of 2.75 A. (Note: the calculations employed para-
meters for In(III) although the valence state of the In in this
chemistry is not yet established.)
The scope of the reaction was explored through a series of
aryl iodides (Table 1). X-ray crystal structures of one such
pair S,S-6 and R,R-6 (Fig. 1), derived by partial deprotection
of S,S-4g and R,R-4g, established that the S-sulfinimine
engenders S stereochemistry at the new chiral centre and
the R-sulfinimine provides R stereochemistry at the new
chiral centre.14 Non-proteinogenic a-amino acids 5 are
obtained in good to excellent yield (Table 1) from 4 via
a two-step deprotection process (Scheme 2).
To further extend the scope of our chemistry, we have utilised
bifunctional aryl iodide/allenes 13–16 (Scheme 3) allowing
access to our catalytic cyclisation-anion capture methodol-
ogy.16 The cyclisation–allylation reaction is entirely regio-
and diastereoselective generating two contiguous chiral
centres with complete stereocontrol, affording 17–20 in
moderate to good yield (Table 2).
O–
S+
I
A rationale for the stereochemical outcome of the cascade
3/4 is summarised in Figure 2. The four possible Zimmer-
man–Traxler, chair-like transition states 7–10 have been
modelled using semi-empirical calculations.15 These corre-
spond to additions of the allyl indium intermediate to either
the re or si face of the S-sulfoximine, each of which can
•
(i)
+
N
EtO2C
X
S-3
13 X = O
14 X = NSO2Ph
15 X = CH2O
O–
S+
H
N
16 X = CONMe
S
S
R
X
17 - 20
CO2Et
Scheme 3. Tandem cyclisation–imine capture cascade. Reagents and condi-
tions: (i) ArI (0.75 mmol), In (0.75 mmol), Pd(OAc)2 (10 mol %), tri-2-furyl
phosphine (20 mol %), CuI (20 mol %), piperidine (0.5 mmol), DMF
(20 ml/mmol), 80 ꢀC, 24 h.
A matched pair of X-ray crystal structures S,S,R-18 and
R,R,S-1814 established that the R-sulfinimine engenders R
stereochemistry at the 5-position and S stereochemistry at
the 6-position (Table 2, entries 3 and 4, Fig. 3). Semi-
empirical calculations reveal a similar trend to those de-
scribed above. In this case, four chair-like transition states
Figure 1. X-ray crystal structures of a matched pair of enantiomers.

R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
12161
Ar
+
H
S
tBu
+
–
In
O
S
tBu
–
O
N
O–
N
In
HN
H
+
OEt
Ar
O
S
O
OEt
Ar
tBu
..
O
OEt
11
8
7
1S, 3R
re addition S-imine
Hf = -39.52 kcal/mol
re addition S-imine
Hf = -39.73 kcal/mol
O
OEt
Ar
O
OEt
Ar
OEt
In
+
N
In
HN
+
O
–
N
But
Ar
O
S
H
tBu
10
H
–
O
tBu
+
–
H
S
+
O
S
..
.
.
12
9
1S, 3S
si addition S-imine
Hf = -44.28 kcal/mol
si addition S-imine
Hf = -36.42 kcal/mol
Figure 2. Stereochemical rationale for Scheme 2.
Table 2. Tandem cyclisation–allylation cascadesa
Table 2. (continued)
Entry
Allene
Imine
Product
Yield
(%)b
Entry
Allene
Imine
Product
Yield
(%)b
–
1
2
O
+
CO2Et
H
3
S
4N
+
3
2
5
S
S
4
6
S
O–
6
5
S
N
H
R
S
1
R
1
13
S-3
64
62
O
N
CO2Et
7
16
S-3
28
S,S,R-17
O
S,S,R-20
–
O
H
N
+
S
CO2Et
R
R
S
S+
2
3
13
14
R-3
O–
O
CO2Et
R
N
H
R
S
8
16
R-3
32
R,R,S-17
N
–
O
R,R,S-20
O
3
H
+
4
S
N
2
S
5
6
a
S
R
1
General conditions as for Scheme 3.
Isolated yield.
S-3
44
b
N
CO2Et
SO2Ph
are possible giving rise to four possible diastereoisomeric
products.
S,S,R-18
O–
H
N
S+
The most energetically favourable transition state 21 leads to
the formation of 18. As in the case of 10 (Fig. 2), this tran-
sition state appears to be stabilised by coordination to the in-
dium involving both the sulfoxide and ester (Fig. 4). This
transition state is calculated to be nearly 8 kcal/mol lower
in energy than the next most energetically favoured transi-
tion state, thus accounting for the observed stereochemical
preference in this reaction.
R
R
S
4
14
R-3
48
CO2Et
SO2Ph
N
R,R,S-18
1
CO2Et
5
2
S+
3
S
4
6
S
N
O–
R
5
6
15
15
S-3
62
64
H
O
In conclusion, we have described a short, efficient, diastereo-
selective synthesis of 2-arylallyl-a-amino acids as single en-
antiomers with either R or S stereochemistry. Application of
bifunctional allene/aryl iodides as substrates furnishes enan-
tiopure N-sulfinyl-a-amino esters with two contiguous chiral
centres via a regioselective process. The stereochemical out-
come of both types of process has been modelled by semi-
empirical calculations, which highlight the key transition
state influence of chelation to indium by both the sulfoxide
and carbonyl oxygen atoms.
S,S,R-19
CO2Et
S+
O–
R
N
R
S
R-3
H
O
R,R,S-19
(continued)

12162
R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
Optical rotations were measured on an Optical Activity
AA-1000 polarimeter.
Rotations are quoted in 10ꢁ1 deg cm2/g and the concentra-
tion (c) is expressed in grams per 100 ml. Unless otherwise
stated chloroform was the solvent. Microanalysis was per-
formed using a Carlo-Erber 1108 elemental analyser and,
for sulfur, by titration against barium perchlorate.
2.2. General procedure for the synthesis of N-sulfinyl-
amino esters 4a–h
Aryl iodide (0.75 mmol) was added to a suspension of chiral
a-imino ester 3 (0.5 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 piperidine (0.05 ml, 0.5 mmol) in DMF (10 ml) in a
Schlenk tube. The mixture was subjected to two freeze–
pump–thaw cycles and then charged, using standard Schlenk
techniques, with allene gas (0.5 bar). The mixture was stirred
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) was 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 (3ꢂ40 ml), dried
over magnesium sulfate, filtered and the filtrate concentrated
in vacuo. The residue was purified by flash chromatography
to give the N-sulfinylamino esters.
Figure 3. X-ray crystal structures of R,R,S-18 and S,S,R-18.
OEt
O
OEt
O
O
In
O
N
H
H
HN
O–
O–
tBu
S+
H
2.2.1. Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-
4-phenyl-pent-4-enoate (S,S-4a).
tBu
S+
.
.
.
.
18
21
ΔHf = -74.84 kcal/mol
H
Figure 4. Stereochemical rationale for Scheme 3.
N
+
S
–
CO2Et
O
Ha
Hb
2. Experimental
2.1. General
Obtained as a pale yellow oil (0.149 g, 92%) after flash chro-
matography (9:1 v/v diethyl ether/hexane); Rf 0.43 (diethyl
ether); [a]2D0 +81.4 (c 1.2); Found: C, 62.90; H, 7.80; N,
4.35; S, 9.90, C17H25NO3S requires: C, 63.13; H, 7.79; N,
4.33; S, 9.91%; nmax/cmꢁ1: 3294, 2983, 2253, 1794, 1732,
1630; dH (500 MHz, CDCl3): 7.37–7.34 (3H, m, ArH), 7.29–
7.27 (2H, m, ArH), 5.34 (1H, s, ]CHa), 5.12 (1H, s, ]CHb),
4.10–4.01 (4H, m, OCH2CH3, NHCH), 3.04 (1H, dd,
NCHCH, J¼1.0, 2.9 Hz), 2.85 (1H, dd, NCHCH, J¼1.0,
3.2 Hz), 1.26 (3H, t, OCH2CH3, J¼7.1 Hz), 1.16 (9H, s,
C(CH3)3); dC (75 MHz, CDCl3): 173.3 (CO), 144.1 (H2C]
C), 140.5 (Ar), 128.9 (Ar), 128.2 (Ar), 126.6 (Ar), 117.0
(]CH2), 62.1 (OC), 57.3 (NC), 56.5 (SC), 40.8 (NCC),
23.0 (SC(CH3)3), 14.5 (OCC); m/z (ES+): 324 (MH+).
Unless otherwise noted all reagents were obtained from
commercial suppliers and used without further purification.
All solvents were dried or purified by literature procedures.
Chromatography columns were prepared using Fisher chem-
icals 60A 35–70 mm silica gel. Nuclear magnetic resonance
spectra were recorded using Bruker DPX300 and
DRX500 MHz spectrometers. Chemical shifts are reported
in parts per million (d) downfield relative to the internal
reference tetramethylsilane. Unless otherwise specified
NMR spectra were recorded in deuterochloroform at room
temperature. Abbreviations used: Ar¼aromatic, d¼doublet,
dd¼doublet of doublets, dq¼doublet of quartets, dt¼doublet
of triplets, m¼multiplet, q¼quartet, s¼singlet, t¼triplet.
Mass spectra were recorded using a micromass ZMD 2000
spectrometer employing the electrospray (ES+) ionisation
technique. Accurate molecular masses were obtained from
the EPSRC Swansea Mass Spectroscopy service using
perfluorotributylamine or polyethylenimine as an internal
standard. Infrared spectra were recorded using a Perkin–
Elmer FTIR spectrometer. IR spectra of liquids were re-
corded as thin films on sodium chloride plates. IR spectra
of solids were recorded using the ‘golden gate’ apparatus.
2.2.2. Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-
4-phenyl-pent-4-enoate (R,R-4a).
H
N
+
S
–
CO2Et
O
a
b
H
H
Obtained as a pale yellow oil (0.130 g, 80%) after flash chro-
matography (9:1 v/v diethyl ether/hexane); Rf 0.43 (diethyl

R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
12163
ether); [a]2D0 ꢁ79.9 (c 1.6); Found: C, 63.00; H, 7.80; N,
4.40; S, 9.90, C17H25NO3S requires: C, 63.13; H, 7.79; N,
4.33; S, 9.91%; nmax/cmꢁ1: 3294, 2983, 2253, 1794, 1732,
1630; dH (500 MHz, CDCl3): 7.37–7.34 (3H, m, ArH),
7.29–7.27 (2H, m, ArH), 5.34 (1H, s, ]CHa), 5.12 (1H, s,
]CHb), 4.10–4.01 (4H, m, OCH2CH3, NHCH), 3.04 (1H,
dd, NCHCH, J¼1.0, 2.9 Hz), 2.85 (1H, dd, NCHCH, J¼
1.0, 3.2 Hz), 1.26 (3H, t, OCH2CH3, J¼7.1 Hz), 1.16 (9H,
s, C(CH3)3); dc (75 MHz, CDCl3): 173.3 (CO), 144.1
(H2C]C), 140.5 (Ar), 128.9 (Ar), 128.2 (Ar), 126.6 (Ar),
117.0 (]CH2), 62.1 (OC), 57.3 (NC), 56.5 (SC), 40.8 (NCC),
23.0 (SC(CH3)3), 14.5 (OCC); m/z (ES+): 324 (MH+).
2.2.5. Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-
4-p-tolyl-pent-4-enoate (S,S-4c).
H
N
+
S
CO2Et
–
O
Ha
Hb
Obtained as a colourless oil (0.230 g, 68%) after flash chro-
matography (8:1 v/v Et2O/hexane); Rf 0.53 (8:1 v/v Et2O/
hexane); [a]2D0 +87.2 (c 2.4); Found: C, 63.90; H, 8.40; N,
3.90; S, 9.40, C18H27NO3S requires: C, 64.06; H, 8.06; N,
4.15; S, 9.50%; nmax/cmꢁ1: 3456, 3280 (NH), 3082, 1733
(CO), 1626, 1563, 1511; dH (500 MHz, CDCl3): 7.25 (2H,
d, ArH, J¼7.9 Hz), 7.14 (2H, d, ArH, J¼7.9 Hz), 5.31 (1H,
s, ]CHa), 5.07 (1H, s, ]CHb), 4.12 (2H, q, OCH2,
J¼7.1 Hz), 4.03 (1H, d, NH, J¼8.3 Hz), 4.02–3.91 (1H, m,
NCH), 3.00 (1H, dd, NCHCH, J¼5.4, 14.3 Hz), 2.80 (1H,
dd, NCHCH, J¼7.6, 14.3 Hz), 2.35 (3H, s, ArCH3), 1.25
(3H, t, OCH2CH3, J¼7.1 Hz), 1.17 (9H, s, C(CH3)3); dC
(75 MHz, CDCl3): 171.29 (CO), 142.42 (H2C]C), 136.50
(Ar), 136.05 (Ar), 128.11 (Ar), 125.21 (Ar), 114.65
(]CH2), 60.54 (OC), 55.87 (NC), 55.08 (SC), 39.41
(NCC), 21.52 (C(CH3)3), 20.05 (OCC), 13.05 (ArCH3);
m/z (ES+): 338 (MH+).
2.2.3. Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-
4-pyrazin-2-yl-pent-4-enoate (S,S-4b).
N
3
5
6
H
N
S+
N
–
CO2Et
O
Ha
Hb
Obtained as a pale yellow oil (0.112 g, 69%) after flash chro-
matography (ethyl acetate); Rf 0.37 (ethyl acetate); [a]D20
+63.5 (c 0.9); Found: C, 54.40; H, 6.90; N, 12.70,
C15H23N3O3S$0.25 M H2O requires: C, 54.61; H, 7.18; N,
12.74%; nmax/cmꢁ1: 3584, 3436 (NH), 3289, 2982, 2963,
2240, 1734 (C]O), 1468, 1367, 1067; dH (500 MHz,
CDCl3): 8.74 (1H, s, pyrazinyl-3H), 8.47 (1H, d, pyrazinyl-
6H, J¼1.3 Hz), 8.39 (1H, d, pyrazinyl-5H, J¼1.3 Hz), 5.81
(1H, s, ]CHa), 5.42 (1H, s, ]CHb), 4.14–4.04 (4H, br m,
OCH2, NHCH), 3.05 (1H, dd, NCHCH, J¼5.3, 14.3 Hz),
2.93 (1H, dd, NHCHCH, J¼8.2, 14.3 Hz), 1.18 (3H, t,
OCH2CH3, J¼7.2 Hz), 1.08 (9H, s, C(CH3)3); dC (75 MHz,
CDCl3): 172.00 (CO), 152.02 (H2C]C), 142.29 (Ar),
141.91 (Ar), 141.22 (Ar), 140.08 (Ar), 119.35 (]CH2),
60.69 (OC), 55.82 (NC), 55.13 (SC), 37.13 (NCC), 21.54
(C(CH3)3), 13.08 (OCC); m/z (ES+): 326 (MH+).
2.2.6. Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-
4-p-tolyl-pent-4-enoate (R,R-4c).
H
N
S+
–
CO2Et
O
Hb
Ha
Obtained as a colourless oil (0.233 g, 68%) after flash chro-
matography (8:1 v/v Et2O/hexane); Rf 0.53 (8:1 v/v Et2O/
hexane); [a]2D0 ꢁ88.6 (c 1.5); Found: C, 64.00; H, 8.40; N,
4.10; S, 9.40, C18H27NO3S requires: C, 64.06; H, 8.06; N,
4.15; S, 9.50%; nmax/cmꢁ1: 3276, 3085, 2980, 2958, 2926,
2869, 1737; dH (500 MHz, CDCl3): 7.25 (2H, d, ArH,
J¼7.9 Hz), 7.14 (2H, d, ArH, J¼7.9 Hz), 5.30 (1H, s,
]CHa), 5.07 (1H, s, ]CHb), 4.14–4.10 (2H, q, OCH2,
J¼7.1 Hz), 4.03 (1H, d, NH, J¼8.3 Hz), 4.0–3.9 (1H, m,
NCH), 3.00 (1H, dd, NCHCH, J¼5.4, 14.3 Hz), 2.80 (1H,
dd, NCHCH, J¼7.6, 14.3 Hz), 2.35 (3H, s, ArCH3), 1.24
(3H, t, OCH2CH3, J¼7.1 Hz), 1.16 (9H, s, C(CH3)3); dC
(75 MHz, CDCl3): 173.34 (CO), 143.84 (H2C]C), 137.96
(Ar), 137.48 (Ar), 129.54 (Ar), 126.63 (Ar), 116.09
(]CH2), 61.99 (OC), 57.28 (NC), 56.52 (SC), 40.85
(NCC), 22.96 (C(CH3)3), 21.48 (OCC), 14.47 (ArCH3);
m/z (ES+): 338 (MH+).
2.2.4. Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-
4-pyrazin-2-yl-pent-4-enoate (R,R-4b).
N
3
5
6
H
N
S+
N
–
CO2Et
O
Ha
Hb
Obtained as a pale yellow oil (0.169 g, 35%) after flash chro-
matography (ethyl acetate); Rf 0.37 (ethyl acetate); [a]D20
ꢁ63.6 (c 1.1); Found: C, 54.40; H, 6.85; N, 12.65,
C15H23N3O3S$0.25 M H2O requires: C, 54.61; H, 7.18; N,
12.74%; nmax/cmꢁ1: 3447, 2981, 1734, 1633, 1519, 1469;
dH (500 MHz, CDCl3): 8.75 (1H, s, pyrazinyl-3H), 8.46
(1H, d, pyrazinyl-6H, J¼1.3 Hz), 8.39 (1H, d, pyrazinyl-
5H, J¼1.3 Hz), 5.81 (1H, s, ]CHa), 5.42 (1H, s, ]CHb),
4.17–4.04 (4H, br m, OCH2, NHCH), 3.05 (1H, dd, NCHCH,
J¼5.3 Hz, 14.3 Hz), 2.93 (1H, dd, NCHCH, J¼8.2 Hz,
14.3 Hz), 1.18 (3H, t, OCH2CH3, J¼7.2 Hz), 1.08 (9H, s,
C(CH3)3); dC (75 MHz, CDCl3): 171.95 (CO), 152.02
(H2C]C), 142.32 (Ar), 141.89 (Ar), 141.19 (Ar), 140.57
(Ar), 119.35 (]CH2), 60.63 (OC), 55.85 (NC), 55.19 (SC),
37.09 (NCC), 21.76 (C(CH3)3), 13.08 (OCC); m/z (ES+):
326 (MH+).
2.2.7. Ethyl 2S,4S-(2-methyl-propane-2-sulfinylamino)-
4-(4-trifluoromethyl-phenyl)-pent-4-enoate (S,S-4d).
F3C
H
N
S+
–
CO2Et
O
Ha
Hb
Obtained as a colourless oil (0.422 g, 54%) after flash chro-
matography (Et2O); Rf 0.16 (Et2O); [a]2D0 +82.2 (c 1.1);

12164
R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
Found: C, 55.00; H, 6.30; N, 3.60; S, 8.10, C18H24NSO4F3
requires: C, 55.23; H, 6.18; N, 3.58; S, 8.19; F, 14.56%;
nmax/cmꢁ1: 3453, 3283 (NH), 3088, 2982, 2961, 2907,
2871, 1738 (CO), 1616; dH (500 MHz, CDCl3): 7.60 (2H,
ArH, d, J¼8.2 Hz), 7.47 (2H, ArH, d, J¼8.2 Hz), 5.41
(1H, s, ]CHa), 5.23 (1H, s, ]CHb), 4.12 (2H, m, OCH2),
4.04 (1H, d, NH, 7.5 Hz), 3.97 (1H, dt, NCH, J¼5.6,
7.5 Hz), 3.05 (1H, dd, NCHCH, J¼5.6, 14.3 Hz), 2.86
(1H, dd, NCHCH, J¼7.5, 14.3 Hz), 1.25 (3H, t, OCH2CH3,
J¼7.2 Hz), 1.16 (9H, s, C(CH3)3); dC (75 MHz, CDCl3):
172.99 (CO), 149.37 (Ar), 143.13 (H2C]C), 130.17 (q,
CF3, J¼32.39 Hz), 127.16 (Ar), 126.85 (Ar), 125.86 (q,
F3CC, 4.06 Hz), 118.89 (]CH2), 62.20 (OC), 57.02 (NC),
56.52 (SC), 40.54 (NCC), 22.89 (C(CH3)3), 14.44 (OCC);
m/z (ES+): 392 (MH+).
14.0 Hz), 2.74 (1H, dd, NCCH, J¼7.5, 14.0 Hz), 1.17 (3H,
t, OCH2CH3, J¼4.8 Hz), 1.09 (9H, s, C(CH3)3); dC
(75 MHz, CDCl3): 171.85 (CO), 158.60 (H2C]C), 150.48
(Ar), 142.52 (Ar), 140.55 (Ar), 134.76 (Ar), 117.83 (Ar),
115.61 (]CH2), 111.91 (Ar), 60.72 (NCC), 55.85 (ArOC),
55.09 (NC), 54.19 (SC), 21.61 (C(CH3)3), 13.15 (OCC);
m/z (ES+): 354 (MH+).
2.2.10. Ethyl 2R,4R-(3-methoxy-phenyl)-2-(2-methyl-
propane-2-sulfinylamino)-pent-4-enoate (R,R-4e).
H
N
S+
O
–
CO2Et
O
Ha
Hb
Obtained as a pale yellow oil (0.119 g, 67%) after flash chro-
matography (9:1 v/v diethyl ether/hexane); Rf 0.47 (3:1 v/v
ethyl acetate/hexane); [a]2D0 ꢁ77.1 (c 1.2); Found: C,
61.30; H, 7.80; N, 4.00; S, 9.20, C18H27NO4S requires: C,
61.16; H, 7.70; N, 3.96; S, 9.07%; nmax/cmꢁ1: 3282, 3082,
2980, 2958, 2907, 2869, 2836, 1737 (CO), 1627, 1598,
1577; dH (500 MHz, CDCl3): 7.18 (1H, t, Ar-5H, J¼
7.9 Hz), 6.87 (1H, d, Ar-2H, 7.9 Hz), 6.82 (1H, s, Ar-4H),
6.76 (1H, d, Ar-6H, J¼7.9 Hz), 5.27 (1H, s, ]CHa), 5.04
(1H, s, ]CHb), 4.07–4.03 (2H, m, OCH2), 3.97–3.92 (2H,
m, NHCH), 3.74 (3H, s, OCH3), 2.93 (1H, dd, NCCH,
J¼5.3, 14.0 Hz), 2.74 (1H, dd, NCCH, J¼7.5, 14.0 Hz),
1.17 (3H, t, OCH2CH3, J¼7.1 Hz), 1.09 (9H, s, C(CH3)3);
dC (75 MHz, CDCl3): 171.85 (CO), 158.61 (H2C]C),
142.22 (Ar), 140.55 (Ar), 128.44 (Ar), 117.43 (Ar), 115.61
(]CH2), 111.92 (Ar), 111.42 (Ar), 60.62 (OC), 55.87
(OCH3), 55.10 (SC), 54.19 (NC), (NCC), 21.55 (C(CH3)3),
13.05 (OCC); m/z (ES+): 354 (MH+).
2.2.8. Ethyl 2R,4R-(2-methyl-propane-2-sulfinylamino)-
4-(4-trifluoromethyl-phenyl)-pent-4-enoate (R,R-4d).
F3C
H
N
S+
–
CO2Et
O
Hb
Ha
Obtained as a colourless oil (0.385 g, 49%) after flash chro-
matography (Et2O); Rf 0.16 (Et2O); [a]2D0 ꢁ80.4 (c 0.7);
Found: C, 55.00; H, 6.20; N, 3.70; S, 8.30, C18H24NSO4F3
requires: C, 55.23; H, 6.18; N, 3.58; S, 8.19; F, 14.56%;
nmax/cmꢁ1: 3459, 3282 (NH), 2982, 3088, 2982, 2961,
2907, 2871, 1738 (CO), 1616, 1573; dH (500 MHz,
CDCl3): 7.60 (2H, ArH, d, J¼8.2 Hz), 7.47 (2H, ArH, d,
J¼8.2 Hz), 5.41 (1H, s, ]CHa), 5.23 (1H, s, ]CHb),
4.19–4.06 (2H, m, OCH2), 4.03 (1H, d, NH, J¼7.5 Hz),
3.97 (1H, dt, NCH, J¼5.6, 7.5 Hz), 3.04 (1H, dd, NCCH,
J¼5.6, 14.3 Hz), 2.87 (1H, dd, NCCH, J¼7.5, 14.3 Hz);
1.25 (3H, t, OCH2CH3, J¼7.19), 1.16 (9H, s, C(CH3)3); dC
(75 MHz, CDCl3): 172.99 (CO), 149.37 (Ar), 143.13
(H2C]C), 130.17 (q, CF3, J¼32.39 Hz), 127.16 (Ar),
126.85 (Ar), 125.86 (q, F3CC, 4.06 Hz), 118.89 (]CH2),
62.20 (OC), 57.02 (NC), 56.52 (SC), 40.54 (NCC), 22.89
(C(CH3)3), 14.44 (OCC); m/z (ES+): 392 (MH+).
2.2.11. Ethyl 2S,4S-(6-chloro-pyridin-2-yl)-2-(2-methyl-
propane-2-sulfinylamino)-pent-4-enoate (S,S-4f).
Cl
5
N
H
4
N
S+
3
–
CO2Et
O
Ha
Hb
2.2.9. Ethyl 2S,4S-(3-methoxy-phenyl)-2-(2-methyl-pro-
pane-2-sulfinylamino)-pent-4-enoate (S,S-4e).
Obtained as a pale yellow oil (0.187 g, 52%) after flash
chromatography (6:1 v/v ethyl acetate/hexane); Rf 0.41
(6:1 v/v ethyl acetate/hexane); [a]2D0 +86.7 (c 1.8); Found:
C, 53.30; H, 6.60; N, 7.80; S, 9.00, C16H23ClN2O3S
requires: C, 53.55; H, 6.46; Cl, 9.88; N, 7.81; S, 8.93%;
nmax/cmꢁ1: 3417, 3209, 2981, 2961, 1737 (CO); dH
(500 MHz, CDCl3): 8.40 (1H, d, pyridyl-5H, J¼2.3 Hz),
7.63 (1H, d, pyridyl-3H, J¼8.4 Hz), 7.32 (1H, dd, pyr-
idyl-4H, J¼2.3, 8.4 Hz), 5.41 (1H, s, ]CHa), 5.27 (1H,
s, ]CHb), 4.17–4.09 (3H, br m, NH, OCH2), 3.96
(1H, m, NHCH), 3.00 (1H, dd, NCCH, 0.6, 5.0 Hz), 2.86
(1H, dd, H2C]CCH, J¼0.6, 7.7 Hz), 1.26 (3H, t, OCH2CH3,
J¼7.2 Hz), 1.18 (9H, s, C(CH3)3); dC (75 MHz, CDCl3):
172.82 (CO), 151.06 (H2C]C), 147.96 (Ar), 140.11
(Ar), 136.86 (Ar), 135.10 (Ar), 124.36 (Ar), 119.32
(]CH2), 62.36 (OC), 56.74 (NC), 56.61 (SC), 22.95
(C(CH3)3), 14.48 (O2CC); m/z (ES+): 359 (35Cl MH+), 361
(37Cl MH+).
H
N
S+
O
–
CO2Et
O
Ha
Hb
Obtained as a pale yellow oil (0.130 g, 72%) after flash chro-
matography (9:1 v/v diethyl ether/hexane); Rf 0.47 (3:1 v/v
ethyl acetate/hexane); [a]2D0 +78.3 (c 2.1); Found: C,
60.40; H, 7.80; N, 3.70, C18H27NO4S$0.25 M H2O requires:
C, 60.39; H, 7.74; N, 3.91%; Found: 376.1552,
C18H27NO4S$Na requires: 376.1559; nmax/cmꢁ1: 3583,
3453 (NH), 3283, 2978, 2836, 1736 (CO), 1628; dH
(500 MHz, CDCl3): 7.19 (1H, t, Ar-5H, J¼7.7 Hz), 6.87
(1H, s, Ar-2H), 6.82 (1H, d, Ar-4H, J¼7.7 Hz), 6.75 (1H,
d, Ar-6H, J¼7.7 Hz), 5.27 (1H, s, ]CHa), 5.04 (1H, s,
]CHb), 4.07–4.03 (2H, m, OCH2), 3.97–3.92 (2H, m,
NHCH), 3.74 (3H, s, OCH3), 2.93 (1H, dd, NCCH, J¼5.3,

R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
12165
2.2.12. Ethyl 2R,4R-(6-chloro-pyridin-2-yl)-2-(2-methyl-
propane-2-sulfinylamino)-pent-4-enoate (R,R-4f).
Obtained as a pale yellow oil (0.146 g, 74%) after flash chro-
matography (9:1 v/v diethyl ether/hexane); Rf 0.22 (9:1
v/v diethyl ether/hexane); [a]2D0 ꢁ70.8 (c 1.2); Found: C,
52.04; H, 5.91; Cl, 18.07; N, 3.57; S, 8.17, C17H23Cl2NO3S
requires: C, 52.00; H, 5.90; Cl, 18.10; N, 3.60; S, 8.20%;
nmax/cmꢁ1: 3583, 3450 (NH), 3274, 2978, 2956, 1736
(CO), 1473, 1366, 1070; dH (500 MHz, CDCl3): 7.37 (1H,
d, Ar-2H, J¼2.0 Hz), 7.33 (1H, d, Ar-5H, J¼8.3 Hz), 7.13
(1H, dd, Ar-6H, J¼2, 8.3 Hz), 5.29 (1H, s, ]CHa), 5.11
(1H, s, ]CHb), 4.06 (2H, dq, OCH2, J¼7.6, 10.7 Hz), 3.89
(1H, dd, NCH, J¼5.5, 7.4 Hz), 2.90 (1H, dd, NCHCH,
J¼5.5, 14.5 Hz), 2.73 (1H, dd, NCHCH, J¼7.4, 14.5 Hz),
1.19 (3H, t, OCH2CH3, J¼7.2 Hz), 1.10 (9H, s, C(CH3)3);
dC (75 MHz, CDCl3): 171.50 (CO), 140.68 (C]CH2),
131.55 (Ar), 130.71 (Ar), 129.39 (Ar), 128.87 (Ar), 127.35
(Ar), 124.68 (Ar), 117.02 (]CH2), 60.82 (OC), 55.55
(NC), 55.13 (SC), 38.95 (NCC), 21.51 (C(CH3)3), 13.05
(OCC); m/z (ES+): 393 (35/35Cl MH+), 395 (35/37Cl MH+),
397 (37/37Cl MH+).
Cl
5
N
H
4
N
S+
3
–
CO2Et
O
Ha
Hb
Obtained as a pale yellow oil (0.088 g, 49%) after flash chro-
matography (6:1 v/v ethyl acetate/hexane); Rf 0.41 (6:1
v/v ethyl acetate/hexane); [a]2D0 ꢁ84.9 (c 2.5); Found: C,
53.50; H, 7.00; Cl, 9.70; N, 7.70; S, 8.80, C16H23ClN2O3S
requires: C, 53.55; H, 6.46; Cl, 9.88; N, 7.81; S, 8.93%;
nmax/cmꢁ1: 3448, 3429, 2983, 1737 (CO), 1461, 1366; dH
(500 MHz, CDCl3): 8.32 (1H, d, pyridyl-5H, J¼2.5 Hz),
7.57 (1H, dd, pyridyl-3H, J¼2.5, 8.3 Hz), 7.25 (1H, d, pyr-
idyl-4H, J¼8.3 Hz), 5.34 (1H, s, ]CHa), 5.19 (1H, s,
]CHb), 4.06–4.01 (3H, br m, NH, OCH2), 3.89 (1H, dd,
NCH, J¼5.0, 7.7 Hz), 2.92 (1H, dd, NCCH, J¼0.6,
5.0 Hz), 2.78 (1H, dd, NCCH, J¼0.6, 7.7 Hz), 1.19 (3H, t,
OCH2CH3, J¼7.2 Hz), 1.10 (9H, s, C(CH3)3); dC (75 MHz,
CDCl3): 171.39 (CO), 149.61 (H2C]C), 146.53 (Ar), 138.68
(Ar), 135.47 (Ar), 133.69 (Ar), 117.92 (]CH2), 60.72 (OC),
55.35 (NC), 54.94 (SC), 38.81 (NCC), 21.61 (C(CH3)3),
13.06 (OCC); m/z (ES+): 359 (35Cl MH+), 361 (37Cl MH+).
2.2.15. Ethyl 2S,4S-(3,5-bis-trifluoromethyl-phenyl)-2-
(2-methyl-propane-2-sulfinylamino)-pent-4-enoate (S,S-
4h).
CF3
4
2
H
N
S+
2.2.13. Ethyl 2S,4S-(3,4-dichloro-phenyl)-2-(2-methyl-
propane-2-sulfinylamino)-pent-4-enoate (S,S-4g).
F3C
6
–
CO2Et
O
Ha
Hb
Cl
Obtained as a pale yellow oil (0.159 g, 69%) after flash chro-
matography (3:1–6:1 v/v ethyl acetate/hexane); Rf 0.58 (3:1
v/v ethyl acetate/hexane); [a]2D0 +55.2 (c 3.2); Found: C,
49.50; H, 5.00; N, 3.00; S, 6.80, C19H23F6NO3S requires:
Cl
2
H
N
5
S+
6
–
CO2Et
C, 49.67; H, 5.05; F, 24.81; N, 3.05; S, 6.98%; nmax/cmꢁ1
:
O
Ha
Hb
3583, 3454 (NH), 2983, 2963, 1739 (CO), 1632, 1378,
1279, 1180, 1136, 1078; dH (500 MHz, CDCl3): 7.72 (3H,
s, ArH), 5.41 (1H, s, ]CHa), 5.28 (1H, s, ]CHb), 4.13–
4.01 (3H, br m, OCH2, NH), 3.91–3.88 (1H, m, NCH),
3.07 (1H, dd, NCHCH, J¼5.1, 14.5 Hz), 2.93 (1H, dd,
NCHCH, J¼7.3, 14.5 Hz), 1.18 (3H, t, OCH2CH3,
J¼7.2 Hz), 1.07 (9H, s, C(CH3)3); dC (75 MHz, CDCl3):
171.35 (CO), 141.74 (H2C]C), 140.72 (Ar), 130.90 (q,
Ar, J¼33.3 Hz), 125.86 (Ar), 122.2 (q, CF3, J¼272.8 Hz),
119.94 (Ar), 118.75 (]CH2), 60.98 (OC), 55.93 (NC),
55.12 (SC), 38.76 (NCC), 21.43 (C(CH3)3), 12.93 (OCC);
m/z (ES+): 460 (MH+).
Obtained as a pale yellow oil (0.144 g, 73%) after flash chro-
matography (9:1 v/v diethyl ether/hexane); Rf 0.22 (9:1 v/v
diethyl ether/hexane); [a]2D0 +68.3 (c 1.1); Found: C, 52.20;
H, 6.10; Cl, 17.80; N, 3.60; S, 7.90, C17H23Cl2NO3S
requires: C, 52.04; H, 5.91; Cl, 18.07; N, 3.57; S, 8.17%;
nmax/cmꢁ1: 3583, 3450 (NH), 3282, 2981, 2960, 1736
(CO), 1474, 1367, 1074; dH (500 MHz, CDCl3): 7.37 (1H,
s, Ar-2H), 7.33 (1H, d, Ar-5H, J¼8.3 Hz), 7.12 (1H, d, Ar-
6H, J¼8.3 Hz), 5.29 (1H, s, ]CHa), 5.11 (1H, s, ]CHb),
4.06 (2H, dq, OCH2, J¼7.2, 13.1 Hz), 3.89 (1H, dd, NCH,
J¼7.7, 6.2 Hz), 2.90 (1H, dd, NCHCH, J¼6.2, 14.5 Hz),
2.75 (1H, dd, NCHCH, J¼7.7, 14.5 Hz), 1.18 (3H, t,
OCH2CH3, J¼7.2 Hz), 1.10 (9H, s, C(CH3)3); dC (75 MHz,
CDCl3): 171.51 (CO), 140.68 (C]CH2), 131.57 (Ar),
130.73 (Ar), 129.87 (Ar), 128.87 (Ar), 127.77 (Ar), 124.67
(Ar), 117.79 (]CH2), 60.58 (OC), 55.55 (NC), 55.14 (SC),
38.96 (NCC), 21.62 (C(CH3)3), 13.05 (OCC); m/z (ES+):
393 (35/35Cl MH+), 395 (35/37Cl MH+), 397 (37/37Cl MH+).
2.2.16. Ethyl 2R,4R-(3,5-bis-trifluoromethyl-phenyl)-2-
(2-methyl-propane-2-sulfinylamino)-pent-4-enoate (R,R-
4h).
CF3
4
2
H
N
2.2.14. Ethyl 2R,4R-(3,4-dichloro-phenyl)-2-(2-methyl-
propane-2-sulfinylamino)-pent-4-enoate (R,R-4g).
S+
F3C
6
–
CO2Et
O
Ha
Hb
Cl
Cl
2
Obtained as a pale yellow oil (0.151 g, 66%) after flash chro-
matography (3:1–6:1 v/v ethyl acetate/hexane); Rf 0.58 (3:1
v/v ethyl acetate/hexane); [a]2D0 ꢁ53.0 (c 1.1); Found: C,
49.60; H, 5.10; N, 3.10; S, 6.80, C19H23F6NO3S requires:
H
N
5
S+
6
–
CO2Et
O
Ha
Hb

12166
R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
C, 49.67; H, 5.05; F, 24.81; N, 3.05; S, 6.98%; nmax/cmꢁ1
:
nmax/cmꢁ1: 3024 (br, OH), 2075, 1822, 1668, 1594 (CO),
1524, 1443, 1400, 1359; dH (500 MHz, D2O): 7.15 (2H, d,
ArH, 8.1 Hz), 7.09–6.98 (3H, m, ArH), 5.21 (1H, s,
]CHa), 4.95 (1H, s, ]CHb), 3.69 (1H, dd, NCH, J¼5.1,
8.6 Hz), 2.98 (1H, dd, NCCH, J¼5.1, 15.4 Hz), 2.71 (1H,
dd, NCCH, J¼8.6, 15.4 Hz); dC (75 MHz, D2O): 171.31
(CO), 141.18 (H2C]C), 138.08 (Ar), 128.93 (Ar), 128.67
(Ar), 126.47 (Ar), 118.40 (]CH2), 51.44 (NCH), 35.80
(NCC); m/z (ES+): 192 (MH+).
3450 (NH), 2978, 1739 (CO), 1629, 1374, 1278; dH
(500 MHz, CDCl3): 7.72 (3H, s, ArH), 5.41 (1H, s,
]CHa), 5.28 (1H, s, ]CHb), 4.13–4.02 (3H, br m, OCH2,
NH), 3.91–3.88 (1H, m, NCH), 3.07 (1H, dd, NCHCH, J¼
5.1, 14.5 Hz), 2.93 (1H, dd, NCHCH, J¼7.3, 14.5 Hz), 1.18
(3H, t, OCH2CH3, J¼7.2 Hz), 1.07 (9H, s, C(CH3)3); dC
(75 MHz, CDCl3): 171.34 (CO), 141.75 (H2C]C), 140.72
(Ar), 130.90 (q, Ar, J¼33.3 Hz), 125.54 (Ar), 122.23 (q,
CF3, J¼272.8 Hz), 119.94 (Ar), 118.75 (]CH2), 60.98
(OC), 55.93 (NC), 55.12 (SC), 38.76 (NCC), 21.43
(C(CH3)3), 12.93 (OCC); m/z (ES+): 460 (MH+).
2.3.3. 2-(S)-2-Amino-4-p-tolyl-pent-4-enoic acid (S-5c).
NH2
2.3. General procedure for the synthesis of a-amino
acids 5a–h
CO2H
Ha
Hb
HCl (4 M) in dioxane (5 equiv) was added to a 0.1 M solution
of the N-sulfinyl-a-amino ester in EtOH. The solution was
stirred at room temperature for 2 h and the solvent removed
in vacuo. NaOH solution (1 M, 2 equiv) was added to
a 0.1 M solution of the ester in a 1:1 v/v H2O/EtOH solvent
system and the mixture stirred and heated to reflux (80 ꢀC
oil bath temperature) for 4 h. The solution was left to cool
to room temperature and the solvent removed in vacuo. The
residue was dissolved in deionised water and applied to the
top of an Amberlyst 15H+ form, 20–50 mesh ion exchange
column and eluted with distilled water followed by a 1%
NH3 solution in deionised water. The ammonia fractions
were visualised under UV light and the UV active fractions
were collected and concentrated in vacuo to give the amino
acid products as pale yellow to colourless solids.
Obtained as colourless prisms (0.073 g, 61%) after ion
exchange chromatography. Mp 165–167 ꢀC; [a]D20 +10.8
(c 0.2, MeOH); Found: C, 68.70; H, 7.20; N, 6.60,
C12H15NO2$0.25 M H2O requires: C, 68.71; H, 7.45; N,
6.68%; Found: 205.1097, C12H15NO2 requires: 205.1097;
nmax/cmꢁ1: 3034 (br, OH), 2089, 1912, 1818, 1671 (CO),
1594, 1518, 1450, 1400, 1359; dH (300 MHz, D2O): 7.24
(2H, ArH, d, J¼8.0 Hz), 7.07 (2H, ArH, d, J¼8.0 Hz), 5.37
(1H, s, ]CHa), 5.10 (1H, s, ]CHb), 3.88 (1H, dd, NCH,
J¼5.0, 8.7 Hz), 3.16 (1H, dd, NCCH, J¼5.0, 14.9 Hz), 2.87
(1H, dd, NCCH, J¼8.7, 14.9 Hz), 2.14 (3H, s, ArCH3); dC
(75 MHz, D2O): 171.60 (CO), 141.2 (H2C]C), 139.4 (Ar),
135.2 (Ar), 129.7 (Ar), 126.6 (Ar), 117.8 (]CH2), 51.7
(ArCH3), 36.0 (NC), 20.4 (NCC); m/z (ES): 206 (MH+).
2.3.4. 2-(R)-2-Amino-4-p-tolyl-pent-4-enoic acid (R-5c).
2.3.1. 2-(S)-2-Amino-4-phenyl-pent-4-enoic acid (S-5a).
NH2
NH2
CO2H
Ha
Hb
CO2H
Ha
Hb
Obtained as colourless prisms (0.084 g, 51%) after ion
exchange chromatography. Mp 165–167 ꢀC; [a]D20 ꢁ10.6
(c 0.3, MeOH); Found: 205.1099, C12H15NO2 requires:
205.1097; nmax/cmꢁ1: 3030 (br, OH), 2087, 1818, 1670
(CO), 1594, 1518, 1450, 1401, 1359; dH (300 MHz, D2O):
7.30 (2H, ArH, d, J¼8.0 Hz), 7.13 (2H, ArH, d,
J¼8.0 Hz), 5.43 (1H, s, ]CHa), 5.16 (1H, s, ]CHb), 3.93
(1H, dd, NCH, J¼5.0, 8.7 Hz), 3.22 (1H, dd, NCCH,
J¼5.0, 14.9 Hz), 2.92 (1H, dd, NCCH, J¼8.7, 14.9 Hz),
2.20 (3H, s, ArCH3); dC (75 MHz, D2O): 171.66 (CO),
141.2 (H2C]C), 139.4 (Ar), 135.3 (Ar), 129.8 (Ar), 126.6
(Ar), 117.8 (]CH2), 51.7 (ArMe), 36.1 (NC), 20.5
(NCC); m/z (ES+): 206 (MH+).
Obtained as colourless prisms (0.156 g, 100%) after ion ex-
change chromatography. Mp 130–132 ꢀC; [a]D20 +26.4 (c 0.3,
MeOH); Found: 192.1021, C11H13NO2 requires: 192.1019;
nmax/cmꢁ1: 3030 (br, OH), 2065, 1590 (CO), 1395, 1340;
dH (500 MHz, D2O): 6.90 (2H, d, ArH, 7.8 Hz), 6.85–6.75
(3H, m, ArH), 4.98 (1H, s, ]CHa), 4.73 (1H, s, ]CHb),
3.45 (1H, dd, NCH, J¼5.1, 8.6 Hz), 2.76 (1H, dd, NCCH,
J¼5.1, 15.4 Hz), 2.47 (1H, dd, NCCH, J¼8.6, 15.4 Hz);
dC (75 MHz, D2O): 171.00 (CO), 140.85 (H2C]C),
137.72 (Ar), 128.62 (Ar), 128.36 (Ar), 126.12 (Ar), 118.04
(]CH2), 51.23 (NC), 35.55 (NCC); m/z (ES+): 192 (MH+).
2.3.2. 2-(R)-2-Amino-4-phenyl-pent-4-enoic acid (R-5a).
2.3.5. 2-(S)-2-Amino-4-(4-trifluoromethyl-phenyl)-pent-
4-enoic acid (S-5d).
NH2
F3C
CO2H
Ha
Hb
NH2
Obtained as colourless prisms (0.095 g, 100%) after ion
exchange chromatography. Mp 138–140 ꢀC; [a]D20 ꢁ26.2
(c 0.6, MeOH); Found: C, 66.70; H, 6.65; N, 6.95,
C11H13NO2$0.33 M H2O requires: C, 66.99; H, 6.98; N,
7.10%; Found: 192.1022, C11H14NO2 requires: 192.1025;
CO2H
Ha
Hb
Obtained as colourless prisms (0.223 g, 99%) after ion
exchange chromatography. Mp 141–143 ꢀC; [a]D20 +31.1

R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
12167
(c 0.6, MeOH), Found: C, 55.50; H, 4.80; N, 5.30,
C12H13NO2F3 requires: C, 55.60; H, 4.67; N, 5.40%;
nmax/cmꢁ1: 3007 (br, OH), 2128, 1831, 1614 (CO), 1508,
1455, 1427, 1406, 1328; dH (500 MHz, CD3OD):
7.95 (2H, d, ArH, J¼8.3 Hz), 7.88 (2H, d, ArH,
J¼8.3 Hz), 5.86 (1H, s, ]CHa), 5.62 (1H, s, ]CHb),
3.73 (1H, dd, NCH, J¼3.6, 10.5 Hz), 3.66 (1H, dd,
NCCH, J¼5.0, 15.1 Hz), 3.00 (1H, dd, NCCH, J¼10.5,
15.1 Hz); dC (75 MHz, D2O): 171.25 (CO), 162.45 (q,
CF3, J¼36.8 Hz), 141.82 (H2C]C), 129.32 (q, F3CC,
J¼32.25 Hz), 126.83 (Ar), 125.64 (Ar), 121.95 (Ar),
114.26 (]CH2), 51.44 (NC), 35.70 (NCC); m/z (ES+):
260 (MH+).
2.3.8. 2-(R)-2-Amino-4-(3-methoxy-phenyl)-pent-4-enoic
acid (R-5e).
5
4
6
NH2
CO2H
O
2
Hb
Ha
Obtained as colourless prisms (0.115 g, 80%) after ion
exchange chromatography. Mp 147–149 ꢀC; [a]D20 ꢁ9.5
(c 0.3, MeOH); Found: C, 63.60; H, 6.80; N, 6.30,
C12H15NO3$0.25 M H2O requires: C, 63.84; H, 6.92; N,
6.20%; Found: 222.1130, C12H15NO3 requires: 222.1120;
nmax/cmꢁ1: 3009 (br, OH), 2593, 2086, 1818, 1668, 1575
(CO), 1525, 1493; dH (500 MHz, CD3OD): 7.18 (1H, t,
Ar-5H, J¼8.1 Hz), 7.01 (1H, d, Ar-4H, J¼7.7 Hz), 6.99
(1H, d, Ar-2H, J¼2.1 Hz), 6.77 (1H, dd, Ar-6H,
J¼8.1 Hz), 5.41 (1H, s, ]CHa), 5.17 (1H, s, ]CHb), 3.71
(3H, s, OCH3), 3.44 (1H, dd, NCH, J¼10.7, 11.1 Hz), 3.34
(1H, dd, NCCH, J¼10.7, 15.2 Hz), 2.61 (1H, dd, NCCH,
J¼11.1, 15.2 Hz); dC (75 MHz, D2O): 174.37 (CO),
159.51 (H2C]C), 142.38 (Ar), 140.55 (Ar), 130.48 (Ar),
119.65 (Ar), 118.16 (]CH2), 114.26 (Ar), 112.57 (Ar),
55.79 (OCH3), 53.67 (NC), 36.96 (NCC); m/z (ES+): 222
(MH+).
2.3.6. 2-(R)-2-Amino-4-(4-trifluoromethyl-phenyl)-pent-
4-enoic acid (R-5d).
F3C
NH2
CO2H
Ha
Hb
Obtained as colourless prisms (0.193 g, 99%) after ion
exchange chromatography. Mp 141–143 ꢀC; [a]D20 ꢁ32.7
(c 0.5, MeOH); Found: C, 54.80; H, 4.80; N, 5.20,
C12H13NO2F3$0.25 M H2O requires: C, 54.65; H, 4.78; F,
21.61; N, 5.31%; Found: 260.0887, C12H13NO2F3 requires:
260.0898; dH (500 MHz, CD3OD): 6.84 (2H, d, ArH,
J¼8.3 Hz), 6.80 (2H, d, ArH, J¼8.3 Hz), 4.86 (1H, s,
]CHa), 4.66 (1H, s, ]CHb), 3.26 (1H, dd, NCH, J¼5.0,
9.1 Hz), 2.60 (1H, dd, NCCH, J¼5.0, 15.1 Hz), 2.30 (1H,
dd, NCCH, J¼9.1, 15.1 Hz); dC (75 MHz, D2O): 171.25
(CO), 162.45 (q, CF3, J¼36.8 Hz), 141.82 (H2C]C),
129.32 (q, F3CC, J¼32.25 Hz), 126.83 (Ar), 125.64 (Ar),
121.95 (Ar), 114.26 (]CH2), 51.44 (NC), 35.70 (NCC);
m/z (ES+): 260 (MH+).
2.3.9. 2-(S)-2-Amino-4-(6-chloro-pyridin-2-yl)-pent-4-
enoic acid (S-5f).
4
5
3
NH2
CO2H
Cl
N
Ha
Hb
Obtained as colourless prisms (0.066 g, 79%) after ion
exchange chromatography. Mp 193–195 ꢀC; [a]D20 +31.7
(c 0.1, MeOH); Found: C, 52.00; H, 5.00; N, 11.70,
C10H11ClN2O2$0.25 M H2O requires: C, 51.96; H, 5.01;
N, 12.12%; Found: 227.0579, C10H11ClN2O2 requires:
227.0587; nmax/cmꢁ1: 3456, (br, OH), 3049, 2929, 1854,
1630 (CO), 1523; dH (500 MHz, D2O): 8.43 (1H, d, pyr-
idyl-5H, J¼2.1 Hz), 7.97 (1H, dd, pyridyl-4H, J¼2.1,
8.3 Hz), 7.51 (1H, d, pyridyl-3H, J¼8.3 Hz), 5.61 (1H, s,
]CHa), 5.43 (1H, s, ]CHb), 4.03 (1H, dd, NCH J¼6.0,
7.7 Hz), 3.21 (1H, dd, NCCH, J¼6.0, 15.4 Hz), 3.11 (1H,
dd, NCCH, J¼7.7, 15.4 Hz); dC (75 MHz, D2O): 174.32
(CO), 142.57 (H2C]C), 138.76 (Ar), 129.28 (Ar), 128.55
(Ar), 126.72 (Ar), 125.77 (Ar), 117.75 (]CH2), 52.97
(NC), 36.87 (NCC); m/z (ES+): 227 (35Cl MH+), 229 (37Cl
MH+).
2.3.7. 2-(S)-2-Amino-4-(3-methoxy-phenyl)-pent-4-enoic
acid (S-5e).
5
4
6
NH2
CO2H
O
2
Ha
Hb
Obtained as colourless prisms (0.088 g, 97%) after ion
exchange chromatography. Mp 144–147 ꢀC; [a]D20 +10.9
(c 0.2, MeOH); Found: 222.1126, C12H15NO3 requires:
222.1125; nmax/cmꢁ1: 3009 (br, OH), 2593, 2288, 2085,
1843, 1576 (CO), 1491, 1457, 1398; dH (500 MHz, D2O):
7.22 (1H, dd, Ar-5H, J¼7.7, 8.1 Hz), 6.99 (1H, d, Ar-4H,
J¼7.7 Hz), 6.94 (1H, s, Ar-2H), 6.84 (1H, d, Ar-6H,
J¼8.1 Hz), 5.45 (1H, s, ]CHa), 5.20 (1H, s, ]CHb),
3.93 (1H, dd, NCH, J¼5.1, 8.1 Hz), 3.69 (3H, s, OCH3),
3.18 (1H, dd, NCCH, J¼5.1, 15.4 Hz), 2.96 (1H, dd,
NCCH, J¼8.1, 15.4 Hz); dC (75 MHz, D2O): 171.57
(CO), 159.40 (H2C]C), 141.21 (Ar), 140.10 (Ar), 130.41
(Ar), 119.67 (Ar), 119.05 (]CH2), 114.96 (Ar), 112.57
(Ar), 55.70 (OCH3), 51.70 (NC), 36.09 (NCC); m/z
(ES+): 222 (MH+).
2.3.10. 2-(R)-2-Amino-4-(6-chloro-pyridin-2-yl)-pent-4-
enoic acid (R-5f).
4
3
5
NH2
CO2H
Cl
N
Ha
Hb
Obtained as colourless prisms (0.123 g, 79%) after ion
exchange chromatography. Mp 196–198 ꢀC; [a]D20 ꢁ32.1

12168
R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
(c 0.3, MeOH); Found: 227.0583, C10H11ClN2O2 requires:
227.0587; nmax/cmꢁ1: 3051 (br, OH), 2093, 1893, 1607
(CO), 1555, 1474, 1454, 1410; dH (500 MHz, D2O): 8.17
(1H, d, pyridyl-5H, J¼2.4 Hz), 7.89 (1H, dd, pyridyl-4H,
J¼2.4, 8.8 Hz), 7.89 (1H, d, pyridyl-3H, J¼8.8 Hz), 5.23
(1H, s, ]CHa), 5.09 (1H, s, ]CHb), 3.54 (1H, dd, NCH,
J¼6.2, 7.7 Hz), 2.74 (1H, dd, NCCH, J¼6.2, 15.5 Hz),
2.64 (1H, dd, NCCH, J¼7.7, 15.5 Hz); dC (75 MHz, D2O):
174.19 (CO), 150.06 (H2C]C), 147.16 (Ar), 138.55 (Ar),
138.20 (Ar), 134.25 (Ar), 124.83 (Ar), 120.16 (]CH2),
53.47 (NC), 36.45 (NCC); m/z (ES+): 227 (35Cl MH+), 229
(37Cl MH+).
2.3.13. 2-(S)-2-Amino-4-(3,5-bis-trifluoromethyl-phen-
yl)-pent-4-enoic acid (S-5h).
CF3
4
2
NH2
CO2H
F3C
6
Ha
Hb
Obtained as colourless prisms (0.178 g, 89%) after ion
exchange chromatography. Mp 152–155 ꢀC; [a]D20 +10.9
(c 0.5, MeOH); Found: C, 47.65; H, 3.30; N, 4.05,
C13H11F6NO2 requires: C, 47.72; H, 3.39; N, 4.28%; Found:
328.0765, C13H11F6NO2 requires: 328.0767; nmax/cmꢁ1
:
2.3.11. 2-(S)-2-Amino-4-(3,4-dichloro-phenyl)-pent-4-
enoic acid (S-5g).
3456 (NH), 3049 (br, OH), 2929, 1854, 1622 (CO), 1524,
1398, 1334, 1277; dH (500 MHz, CD3OD): 8.01 (2H, s,
Ar-2H, Ar-6H), 7.83 (1H, s, Ar-4H), 5.55 (1H, s, ]CHa),
5.40 (1H, s, ]CHb), 3.40 (1H, dd, NCH, J¼4.1, 9.7 Hz),
3.33 (1H, dd, NCCH, J¼4.1, 15.4 Hz), 2.79 (1H, dd,
NCCH, J¼9.7, 15.4 Hz); dC (75 MHz, CD3OD): 173.70
(CO), 143.83 (H2C]C), 143.11 (Ar), 133.42 (q, F3CC,
J¼33.25 Hz), 128.64 (Ar), 125.14 (q, CF3, J¼271.82 Hz),
122.96 (Ar), 121.14 (]CH2), 54.63 (NC), 38.29 (NCC);
m/z (ES+): 328 (MH+).
5
Cl
6
NH2
Cl
2
CO2H
Ha
Hb
Obtained as colourless prisms (0.107 g, 82%) after ion
exchange chromatography. Mp 147–148 ꢀC; [a]D20 +33.1
(c 0.4, MeOH); Found: C, 50.80; H, 4.50; Cl, 27.40; N,
5.30, C11H11Cl2NO2 requires: C, 50.79; H, 4.26; Cl, 27.26;
N, 5.38%; nmax/cmꢁ1: 3025 (br OH), 2064, 1899, 1840,
1761, 1670, 1579, 1517; dH (500 MHz, D2O): 7.54 (1H, s,
Ar-2H), 7.40 (1H, d, Ar-5H, J¼8.4 Hz), 7.26 (1H, d, Ar-
6H, J¼8.4 Hz), 5.48 (1H, s, ]CHa), 5.26 (1H, s, ]CHb),
3.96 (1H, dd, NCH, J¼5.1, 5.5 Hz), 3.15 (1H, dd, NCCH,
J¼5.5, 13.2 Hz), 2.98 (1H, dd, NCCH, J¼5.1, 13.2 Hz);
dC (75 MHz, D2O): 165.14 (CO), 142.0 (H2C]C), 141.14
(Ar), 134.78 (Ar), 134.39 (Ar), 133.30 (Ar), 131.07 (Ar),
128.91 (Ar), 120.84 (]CH2), 54.02 (NC), 38.21 (NCC);
m/z (ES+): 260 (35/35Cl MH+), 262 (35/37Cl MH+), 264
2.3.14. 2-(R)-2-Amino-4-(3,5-bis-trifluoromethyl-phen-
yl)-pent-4-enoic acid (R-5h).
CF3
4
2
NH2
CO2H
F3C
6
Ha
Hb
Obtained as colourless prisms (0.167 g, 68%) after ion
exchange chromatography. Mp 153–156 ꢀC; [a]D20 ꢁ9.5
(c 0.6, MeOH); Found: C, 47.50; H, 3.30; N, 4.20,
(
37/37Cl MH+).
2.3.12. 2-(R)-2-Amino-4-(3,4-dichloro-phenyl)-pent-4-
enoic acid (R-5g).
C13H11F6NO2 requires: C, 47.72; H, 3.39; N, 4.28%; nmax/
cmꢁ1: 3683, 2929 (br, OH), 2065, 1832, 1634 (CO), 1510,
1444; dH (500 MHz, D2O): 7.40 (2H, s, Ar-2H, Ar-6H),
7.36 (1H, s, Ar-4H), 5.12 (1H, s, ]CHa), 4.95 (1H, s,
]CHb), 3.48 (1H, dd, NCH, J¼5.5, 8.0 Hz), 2.78 (1H, dd,
NCCH, J¼5.5, 15.3 Hz), 2.79 (1H, dd, NCCH, J¼8.0,
15.4 Hz); dC (75 MHz, CD3OD): 173.65 (CO), 143.64
(H2C]C), 142.96 (Ar), 133.22 (q, F3CC, J¼33.25 Hz),
128.56 (Ar), 125.14 (q, CF3, J¼271.82 Hz), 122.94 (Ar),
121.15 (]CH2), 54.46 (NC), 38.17 (NCC); m/z (ES+): 328
(MH+).
5
Cl
6
NH2
Cl
2
CO2H
Ha
Hb
Obtained as colourless prisms (0.094 g, 73%) after ion
exchange chromatography. Mp 146–148 ꢀC [a]D20 ꢁ31.4
(c 0.1, MeOH); Found: C, 49.30; H, 4.60; N, 4.70,
C11H11Cl2NO2$0.5 M H2O requires: C, 49.09; H, 4.49;
N, 5.20%; Found: 259.0164, C11H11Cl2NO2 requires:
259.0161; nmax/cmꢁ1: 3033 (br, OH), 1669, 1576, 1516;
dH (500 MHz, D2O): 7.54 (1H, s, Ar-2H), 7.40 (1H, d,
Ar-5H, J¼8.4 Hz), 7.26 (1H, d, Ar-6H, J¼8.4 Hz), 5.48
(1H, s, ]CHa), 5.26 (1H, s, ]CHb), 3.96 (1H, dd, NCH,
J¼5.1, 5.5 Hz), 3.15 (1H, dd, NCCH, J¼5.5, 13.2 Hz),
2.98 (1H, dd, NCCH, J¼5.1, 13.2 Hz); dC (75 MHz,
D2O): 171.48 (CO), 142.0 (H2C]C), 141.14 (Ar),
134.78 (Ar), 134.39 (Ar), 133.30 (Ar), 131.07 (Ar),
128.91 (Ar), 120.84 (]CH2), 54.02 (NC), 38.21 (NCC);
m/z (ES+): 260 (35/35Cl MH+), 262 (35/37Cl MH+), 264
2.4. General procedure for the synthesis of N-sulfinyl-
a-amino esters 17–20
Bifunctional aryl iodide/allene (0.75 mmol) was added to
a suspension of chiral a-imino ester (0.5 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 piperidine (0.05 ml,
0.5 mmol) in DMF (10 ml) in a Schlenk tube. The mixture
was stirred and heated to 60 ꢀC (oil bath temperature)
for 24 h, left to cool and vented. Ethyl acetate (20 ml)
and 5% HCl solution (10 ml) was added and the mixture
(
37/37Cl MH+).

R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
12169
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
(3ꢂ100 ml), dried over magnesium sulfate, filtered and
the filtrate concentrated in vacuo. The residue was purified
by flash chromatography to give the N-sulfinylamino
esters.
2.4.3. Ethyl 2S,5S,6R-(1-benzenesulfonyl-3-methylene-
2,3-dihydro-1H-indol-2-yl)-(2-methyl-propane-2-sulfinyl-
amino)acetate (S,S,R-18).
Ha
Hb
H
3
N
S+
4
5
–
O
N
S
CO2Et
O
6
2.4.1. Ethyl 2S,5S,6R-(3-methylene-2,3-dihydro-benzofu-
ran-2-yl)-(2-methyl-propane-2-sulfinylamino)acetate
(S,S,R-17).
O
2'
3'
6'
4'
5'
Ha
Hb
Obtained as colourless prisms (0.110 g, 46%) after flash
chromatography (Et2O). Mp 149–151 ꢀC; Rf 0.14 (Et2O);
[a]2D0 ꢁ16.3 (c 0.6); Found: C, 57.85; H, 5.65; N, 5.80; S,
13.35, C23H28N2O5S2 requires: C, 57.96; H, 5.92; N, 5.88;
S, 13.45%; nmax/cmꢁ1: 3294 (NH), 3085, 3014, 2985,
1732 (CO), 1648, 1600, 1584; dH (500 MHz, CDCl3): 7.71
(1H, d, Ar-6H, J¼8.1 Hz), 7.55 (2H, d, Ar-20H, Ar-60H,
J¼7.7 Hz), 7.49 (1H, d, Ar-3H, J¼7.5 Hz), 7.34 (2H, t,
Ar-30H, Ar-50H, J¼7.7 Hz), 7.27–7.23 (2H, m, Ar-4H, Ar-
5H), 7.05 (1H, t, Ar-40H, J¼7.7 Hz), 5.44 (1H, s, ]CHa),
5.08 (1H, s, ]CHb), 4.97 (1H, d, NH, J¼1.6 Hz), 4.37
(1H, d, PhSO2NCH, J¼7.6 Hz), 4.33 (2H, m, OCH2), 4.15
(1H, dd, SNCH, J¼1.6, 7.6 Hz), 1.32 (3H, t, OCH2CH3,
J¼7.2 Hz), 0.91 (9H, s, C(CH3)3); dC (75 MHz, CDCl3):
170.09 (CO), 144.73 (H2C]C), 143.14 (Ar), 136.75 (Ar),
133.91 (Ar), 131.61 (Ar), 130.57 (Ar), 129.44 (Ar), 127.61
(Ar), 121.19 (Ar), 118.02 (H2C]C), 68.14 (SO2NC),
64.46 (SC), 62.90 (SNC), 56.45 (OCH2), 22.50 (C(CH3)3),
14.41 (OCH2CH3); m/z (ES+): 477 (MH+).
H
N
3
6
S+
4
5
–
O
O
O
EtO
Obtained as a pale yellow oil (0.110 g, 64%) after flash chro-
matography (Et2O); Rf 0.11 (Et2O); [a]2D0 ꢁ42.2 (c 1.1);
Found: C, 58.60; H, 7.20; N, 4.10, C17H23NO4S$0.5 M
H2O requires: C, 58.94; H, 6.98; N, 4.04%; nmax/cmꢁ1
:
3286, 3078, 2984, 2968, 2869, 2836, 1739 (CO), 1634; dH
(500 MHz, CDCl3): 7.33 (1H, d, Ar-6H, J¼7.6 Hz), 7.19
(1H, t, Ar-5H, J¼7.6 Hz), 6.87 (1H, t, Ar-4H, J¼7.6 Hz),
6.84 (1H, d, Ar-3H, J¼7.6 Hz), 5.54 (2H, m, NCH,
]CHa), 5.09 (1H, s, ]CHb), 4.32 (2H, q, OCH2,
J¼7.3 Hz), 4.21 (2H, m, NCH, OCH), 1.32 (3H, t,
OCH2CH3, J¼7.3 Hz); dC (75 MHz, CDCl3): 170.45 (CO),
163.13 (Ar), 144.48 (Ar), 131.14 (Ar), 126.52 (Ar), 124.27
(Ar), 121.39 (Ar), 121.11 (Ar), 110.67 (Ar), 102.69
(]CH2), 85.78 (OCH), 62.99 (OCH2), 62.65 (NC), 56.73
(SC), 22.57 (C(CH3)3), 14.50 (OCH2CH3); m/z (ES+): 338
(MH+).
2.4.4. Ethyl 2R,5R,6S-(1-benzenesulfonyl-3-methylene-
2,3-dihydro-1H-indol-2-yl)-(2-methyl-propane-2-sulfinyl-
amino)acetate (R,R,S-18).
2.4.2. Ethyl 2R,5R,6S-(3-methylene-2,3-dihydro-benzo-
furan-2-yl)-(2-methyl-propane-2-sulfinylamino)acetate
(R,R,S-17).
Ha
Hb
H
N
3
6
S+
4
5
O–
Ha
Hb
N
S
CO2Et
O
H
3
S+
N
O
2'
3'
4
–
O
6'
5
O
O
6
4'
5'
EtO
Obtained as colourless prisms (0.231 g, 48%) after flash
chromatography (Et2O). Mp 149–151 ꢀC; Rf 0.14 (Et2O);
[a]2D0 +15.7 (c 0.8); Found: C, 58.0; H, 5.90; N, 5.90; S,
13.60, C23H28N2O5S2 requires: C, 57.96; H, 5.92; N, 5.88;
S, 13.45%; nmax/cmꢁ1: 3294 (NH), 3085, 3014, 2985,
1732 (CO), 1648, 1600, 1584; dH (500 MHz, CDCl3): 7.71
(1H, d, Ar-6H, J¼8.1 Hz), 7.55 (2H, d, Ar-20H, Ar-60H,
J¼8.2 Hz), 7.49 (1H, d, Ar-3H, J¼7.5 Hz), 7.34 (2H, t,
Ar-30H, Ar-50H, J¼7.9 Hz), 7.27–7.23 (2H, m, Ar-4H, Ar-
5H), 7.05 (1H, t, Ar-40H, J¼7.5 Hz), 5.44 (1H, s, ]CHa),
5.08 (1H, s, ]CHb), 4.97 (1H, d, NH, J¼1.6 Hz), 4.37
(1H, d, SO2NCH, J¼7.6 Hz), 4.33 (2H, m, OCH2), 4.15
(1H, dd, NCH, J¼1.6, 7.6 Hz), 1.32 (3H, t, OCH2CH3,
J¼7.2 Hz), 0.91 (9H, s, C(CH3)3); dC (75 MHz, CDCl3):
170.09 (CO), 144.73 (H2C]C), 143.14 (Ar), 136.75 (Ar),
133.91 (Ar), 131.61 (Ar), 130.57 (Ar), 129.44 (Ar), 127.61
(Ar), 121.19 (Ar), 118.02 (H2C]C), 68.14 (SO2NC),
Obtained as a pale yellow oil (0.108 g, 64%) after flash
chromatography (Et2O); Rf 0.11 (Et2O); [a]2D0 +39.7
(c 0.5); Found: C, 59.60; H, 6.85; N, 4.25,
C17H23NO4S$0.25 M H2O requires: C, 59.71; H, 6.93; N,
4.10%; nmax/cmꢁ1: 3281, 3077, 2959, 2869, 2836, 1737
(CO), 1634; dH (500 MHz, CDCl3): 7.33 (1H, d, Ar-6H,
J¼7.6 Hz), 7.19 (1H, t, Ar-5H, J¼7.6 Hz), 6.87 (1H, t,
Ar-4H, J¼7.6 Hz), 6.84 (1H, d, Ar-3H, J¼7.6 Hz), 5.54
(2H, m, NCH, ]CHa), 5.09 (1H, s, ]CHb), 4.32 (2H, q,
OCH2, J¼7.3 Hz), 4.21 (2H, m, NCH, OCH), 1.32 (3H, t,
OCH2CH3, J¼7.3 Hz); dC (75 MHz, CDCl3): 170.43
(CO), 163.12 (ArC), 144.46 (Ar), 131.12 (Ar), 126.51 (Ar),
121.37 (Ar), 121.10 (Ar), 110.67 (Ar), 102.64 (]CH2),
85.76 (OCH), 62.94 (OCH2), 62.62 (NC), 56.68 (SC),
22.65 (C(CH3)3), 14.49 (OCH2CH3); m/z (ES+): 338
(MH+).

12170
R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
64.46 (SC), 62.90 (SNC), 56.45 (OC), 22.50 (C(CH3)3),
14.41 (OCH2CH3); m/z (ES+): 477 (MH+).
Obtained as a pale yellow oil (0.052 mg, 28%) after flash
chromatography (EtOAc); Rf 0.10 (EtOAc); [a]2D0 ꢁ7.3 (c
0.4); Found: C, 60.20; H, 6.90; N, 7.10; S, 8.40,
C19H26N2O4S requires: C, 60.29; H, 6.92; N, 7.40; S, 8.47%;
nmax/cmꢁ1: 3459 (NH), 3274, 2961, 2239, 1739 (CO), 1648
(CO), 1602, 1573; dH (500 MHz, CDCl3): 8.09 (1H, d, Ar-
6H, J¼7.7 Hz), 7.51 (1H, d, Ar-3H, J¼7.7 Hz), 7.47 (1H,
td, Ar-4H, J¼0.9, 7.7 Hz), 7.40 (1H, td, Ar-5H, J¼0.9,
7.7 Hz), 5.74 (1H, s, ]CHa), 5.31 (1H, s, ]CHb), 4.38
(1H, d, MeNCH, J¼4.7 Hz), 4.27 (1H, d, NH, J¼8.1 Hz),
4.11 (1H, dd, NCH, J¼4.7, 8.1 Hz), 3.90 (1H, dq, OCH,
J¼7.3, 10.7 Hz), 3.54 (1H, dq, OCH, J¼7.3, 10.7 Hz), 3.22
(3H, s, NCH3), 1.15 (9H, s, C(CH3)3), 1.13 (3H, t, OCH2CH3,
J¼7.3 Hz); dC (75 MHz, CDCl3): 170.53 (CO), 163.29
(NCO), 136.20 (]C), 134.46 (Ar), 132.19 (Ar), 128.10
(Ar), 127.83 (Ar), 127.27 (Ar), 123.68 (Ar), 115.76
(]CH2), 68.33 (MeNC), 62.34 (OC), 59.54 (SNC), 56.22
(SC), 35.14 (NCH3), 22.53 (C(CH3)3), 10.97 (OCH2CH3);
m/z (ES+): 379 (MH+).
2.4.5. Ethyl 2S,5S,6R-(4-methylene-isochroman-3-yl)-(2-
methyl-propane-2-sulfinylamino)acetate (S,S,R-19).
Ha Hb
–
O
CO2Et
S+
3
4
N
H
O
5
6
Obtained as a pale yellow oil (0.108 g, 62%) after flash chro-
matography (Et2O); Rf 0.14 (Et2O); [a]2D0 ꢁ41.0 (c 0.7);
Found: C, 61.80; H, 7.00; N, 3.70; S, 9.20, C18H25NO4S
requires: C, 61.51; H, 7.17; N, 3.99; S, 9.12%; nmax/cmꢁ1
:
3296 (NH), 3126, 2980, 2960, 2905, 2868, 2841, 1738
(CO), 1628; dH (500 MHz, CDCl3): 7.57 (1H, d, Ar-6H,
J¼2.5 Hz), 7.25–7.22 (2H, m, Ar-4H, Ar-5H), 7.03 (1H,
m, Ar-3H), 5.72 (1H, s, ]CHa), 5.11 (1H, s, ]CHb), 4.89
(1H, dd, OCH, J¼1.7, 3.8 Hz), 4.75 (1H, d, ArCH,
J¼14.5 Hz), 4.62 (1H, d, ArCH, J¼14.5 Hz), 4.32 (1H,
dd, NCH, J¼3.8, 8.6 Hz), 4.27 (2H, dq, CO2CH2, J¼1.3,
7.3 Hz), 1.29 (3H, t, OCH2CH3, J¼7.1 Hz), 1.09 (9H, s,
C(CH3)3); dC (75 MHz, CDCl3): 171.49 (CO), 138.88
(]C), 134.58 (Ar), 132.32 (Ar), 128.33 (Ar), 127.83 (Ar),
124.89 (Ar), 124.14 (Ar), 110.09 (]CH2), 79.17 (NCC),
66.91 (OCH2), 62.40 (CO2C), 62.06 (NC), 56.84 (SC),
22.96 (C(CH3)3), 14.51 (OCH2CH3); m/z (ES+): 352 (MH+).
2.4.8. Ethyl (R)-((S)-2-methyl-4-methylene-1-oxo-1,2,3,4-
tetrahydro-isoquinolin-3-yl)-((R)-2-methyl-propane-2-
sulfinylamino)acetate (R,R,S-20).
Ha
H
bCO2Et
O–
S+
3
6
4
5
N
H
N
2.4.6. Ethyl 2R,5R,6S-(4-methylene-isochroman-3-yl)-(2-
methyl-propane-2-sulfinylamino)acetate (R,R,S-19).
O
Obtained as a pale yellow oil (0.130 g, 69%) after flash chro-
matography (EtOAc); Rf 0.10 (EtOAc); [a]2D0 +9.2 (c 0.6);
Found: C, 60.50; H, 7.20; N, 7.40; S, 8.40, C19H26N2O4S
Ha Hb
O–
S+
CO2Et
3
requires: C, 60.29; H, 6.92; N, 7.40; S, 8.47%; nmax/cmꢁ1
:
4
5
N
H
3459 (NH), 3274, 2964, 2239, 1744 (CO), 1658 (CO),
1602; dH (500 MHz, CDCl3): 8.09 (1H, d, Ar-6H,
J¼7.8 Hz), 7.51 (1H, d, Ar-3H, J¼7.7 Hz), 7.47 (1H, td,
Ar-4H, J¼0.9, 7.7 Hz), 7.40 (1H, td, Ar-4H, J¼0.9,
7.7 Hz), 5.74 (1H, s, ]CHa), 5.31 (1H, s, ]CHb), 4.39
(1H, d, MeNCH, J¼4.7 Hz), 4.27 (1H, d, NH, J¼8.1 Hz),
4.14 (1H, dd, NCH, J¼4.5, 8.1 Hz), 3.90 (1H, dq, OCH,
J¼7.3, 10.7 Hz), 3.54 (1H, dq, OCH, J¼7.3, 10.7 Hz),
3.23 (3H, s, NCH3), 1.15 (9H, s, C(CH3)3), 1.13 (3H, t,
OCH2CH3, J¼7.3 Hz); dC (75 MHz, CDCl3): 170.53 (CO),
163.29 (NCO), 136.20 (]C), 134.46 (Ar), 132.19 (Ar),
128.10 (Ar), 127.83 (Ar), 127.27 (Ar), 123.68 (Ar), 115.76
(]CH2), 68.33 (MeNC), 62.34 (OC), 59.54 (SNC), 56.22
(SC), 35.14 (NCH3), 22.53 (C(CH3)3), 10.97 (OCH2CH3);
m/z (ES+): 379 (MH+).
O
6
Obtained as a pale yellow oil (0.101 g, 58%) after flash chro-
matography (Et2O); Rf 0.14 (Et2O); [a]2D0 +41.5 (c 1.3);
Found: 374.1402, C18H25NO4S$Na requires: 374.1402;
nmax/cmꢁ1: 3450, 3297 (NH), 2959, 2868, 1738 (CO),
1628, 1576; dH (500 MHz, CDCl3): 7.57 (1H, dd, Ar-6H,
J¼4.3, 9.0 Hz), 7.23 (2H, m, Ar-4H, Ar-5H), 7.03 (1H, dd,
Ar-3H, J¼4.3, 6.0 Hz), 5.72 (1H, s, ]CHa), 5.11 (1H, s,
]CHb), 4.89 (1H, m, NH), 4.75 (1H, d, OCH,
J¼14.5 Hz), 4.62 (1H, d, OCH, J¼14.5 Hz), 4.32 (1H, dd,
NCH, J¼3.8, 8.6 Hz), 4.29–4.24 (3H, m, CO2CH2, OCH),
1.30 (3H, t, OCH2CH3, J¼7.1 Hz), 1.09 (9H, s, C(CH3)3);
dC (75 MHz, CDCl3): 170.08 (CO), 137.44 (]C), 133.15
(Ar), 130.89 (Ar), 126.90 (Ar), 126.40 (Ar), 123.46 (Ar),
122.71 (Ar), 108.66 (]CH2), 77.74 (NCC), 65.48
(OCH2), 60.98 (CO2C), 60.92 (NC), 55.39 (SC), 21.53
(C(CH3)3), 13.09 (OCH2CH3); m/z (ES+): 352 (MH+).
Acknowledgements
We thank Leeds University, the EPSRC and Avecia for sup-
port.
2.4.7. Ethyl 2S,5S,6R-(2-methyl-4-methylene-1-oxo-
1,2,3,4-tetrahydro-isoquinolin-3-yl)-(2-methyl-propane-
2-sulfinylamino)acetate (S,S,R-20).
Ha
Hb
CO2Et
O–
S+
References and notes
3
6
4
5
N
H
1. Najera, C. Synlett 2002, 1388–1403.
2. Hohsaka, T.; Sisido, M. Curr. Opin. Chem. Biol. 2002, 6,
809–815.
N
O

R. Grigg et al. / Tetrahedron 62 (2006) 12159–12171
12171
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12. Davis, F. A.; Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem.
2000, 65, 8704–8708.
4. Anwar, U.; Grigg, R.; Sridharan, V. Chem. Commun. 2000,
933–934.
5. Anwar, U.; Grigg, R.; Rasparini, M.; Savic, V.; Sridharan, V.
Chem. Commun. 2000, 645–646.
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MacLachlan, W. S.; Rasparini, M.; Sridharan, V. J. Organomet.
Chem. 2003, 687, 483–493.
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7973.
8. Cooper, I. R.; Grigg, R.; MacLachlan, W. S.; Sridharan, V.;
Thornton-Pett, M. Tetrahedron Lett. 2002, 44, 403–405.
9. Cooper, I. R.; Grigg, R.; MacLachlan, W. S.; Thornton-Pett,
M.; Sridharan, V. Chem. Commun. 2002, 1372–1373.
10. Cooper, I. R.; Grigg, R.; Hardie, M. J.; MacLachlan, W. S.;
Sridharan, V.; Thomas, W. A. Tetrahedron Lett. 2003, 44,
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11. (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
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14. Supplementary crystallographic data for S,S-6 (CCDC
277090), R,R-6 (CCDC 277091) and R,R,S-18 (CCDC
277092) can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/datare-
quest/cif.
15. Semi-empirical calculations were performed using MOPAC v7
by J. J. P. Stewart and the PM3 Hamiltonian. Approximate tran-
sition structures were located using the SADDLE routine
within MOPAC following full conformational optimisation of
the attached sub-structures (MM2). Transition structures were
then fully optimised using the TS routine within MOPAC and
these then characterised by observing them to have a single
negative vibrational frequency following use of the FORCE
calculation within MOPAC.
16. Grigg, R.; Sridharan, V. Transition Metal Catalysed Reactions;
Davies, S. G., Murahashi, S.-I., Eds.; IUPAC Monograph;
Blackwell Science: 1999; pp 81–97; Grigg, R.; Sridharan, V.
Perspectives in Organopalladium Chemistry for the 21st
Century; Tsuji, J., Ed.; Elsevier: 1989; pp 65–87.