Synthesis and application to asymmetric allylic amination of substituted monodonor diazaphospholidine ligands

Article abstract of DOI:10.1016/S0040-4020(03)01062-7

The synthesis of a series of substituted monodonor diazaphospholidine ligands is described. A regioselective lithiation process is a key step in one of these syntheses. The compounds are designed to be incorporated into soluble polymer and other solid pha

Full text of DOI:10.1016/S0040-4020(03)01062-7

Tetrahedron 59 (2003) 6473–6480
Synthesis and application to asymmetric allylic amination of
substituted monodonor diazaphospholidine ligands
Christopher W. Edwards,a Mark R. Shipton,b Nathaniel W. Alcock,a Howard Clasea
and Martin Willsa
,
*
aDepartment of Chemistry, University of Warwick, Gibbit Hill Road, Coventry CV4 7AL, UK
bGlaxoSmithKline Pharmaceuticals PLC, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
Received 9 May 2003; revised 12 June 2003; accepted 3 July 2003
Abstract—The synthesis of a series of substituted monodonor diazaphospholidine ligands is described. A regioselective lithiation process is
a key step in one of these syntheses. The compounds are designed to be incorporated into soluble polymer and other solid phase supports.
Enantiomeric excesses of up to 88% were observed when these compounds were employed in palladium-catalysed asymmetric amination
reactions.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
quantities through the simple reaction of a dichloro- or
bis(dimethyamino)phosphine with a suitable diamine.2 Our
studies of monodonor diazaphospholidine ligands culmi-
nated in the synthesis of SEMI-ESPHOS 2, a robust and
readily-preparable ligand which is capable of generating
high levels of asymmetric induction in reactions such as
allylic amination (Scheme 1, Table 1).5 In this ligand, the
presence of the methoxy group is essential in order for
products of high e.e. to be generated, whilst the C1-
symmetric structure of the compound generates products of
higher e.e. than corresponding ligands generated from C2-
symmetric amines. Although there is a chiral centre at the P
atom, the synthesis of the ligands, carried out at elevated
temperature, results in formation of a single diastereoisomer
of product.
The use of enantiomerically pure phosphorus-donor ligands
in asymmetric catalysis is now well established.1 Although
the majority of international research work has focussed on
the use of phosphines, some dramatic recent breakthroughs
have been achieved with homochiral phosphites and ligands
which contain P–N and P–O bonds.2 Of the many ligands
reported, bidentate ligands have traditionally been regarded
as the most effective and efficient, primarily due to the
stability of their complexes and the well-defined stereo-
chemical environment which they create around metal
centres. However the discovery of the remarkable catalytic
properties of ligands such as MONOPHOS 1,3 and related
compounds,4 has reignited interest in monodonor reagents.
Scheme 1. Reagents and conditions: (i) 10 mol% ligand, 5 mol%
[Pd2(dba)3], 2 equiv. PhCH2NH2, DCM, rt, 2d.
In previous studies in this group, we have reported the
synthesis and applications of a series of ligands containing
the diazaphospholidine ring structure.5 As well as being
stereochemically well-defined P-donor reagents, diaza-
phospholidines are extremely easy to prepare in large
Table 1.
Ligand
Yield%
e.e. (%)
2
5
6
7
8
80
70
82
81
90
86 (R)
76 (R)
82 (R)
75 (R)
88 (R)
Keywords: asymmetric; catalyst; ligand; allylic; substitution; amination.
*
Corresponding author. Tel.: þ44-24-7652-3260; fax: þ44-24-7652-4112;
e-mail: m.wills@warwick.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01062-7

6474
C. W. Edwards et al. / Tetrahedron 59 (2003) 6473–6480
Similar ligands have been reported by other researchers,
most notably Buono, including 36 and, more recently, 4.7
Ligand 3 also gives excellent enantioselectivities in allylic
amination reactions, although both 3 and 4 behave as
bidentate ligands, rather than monodentate, as is the case
with 1 and 2. Buono has also reported the synthesis of 2 as
an intermediate towards some PvO containing ligands for
use in diethylzinc additions to aldehydes.6c,8
It is clear, therefore, that monodonor diazaphospholidine
ligands are valuable tools for asymmetric catalysis.
However, significant further research is still required in
order to define the full scope and limitations of these
materials. In this paper we report the synthesis and
applications to asymmetric allylic amination of a series of
substituted diazaphospholidine ligands which are designed
to act as models for solid-supported derivatives.
In this process the lithiation is selective for the less-hindered
position adjacent to the smaller methoxy group. This
selectivity was confirmed by the isolation of 11, formed
by trapping with Ph2P(O)Cl. The X-ray crystallographic
structure of this compound is shown in Figure 1.
The synthesis of 5 was completed by condensation with
S-(2-phenylaminomethyl)pyrolidine (2 steps from L-gluta-
mic acid) under reflux in toluene. In this process the reaction
is complete when the volatile dimethylamine side-product
has been fully expelled from the reaction mixture, a process
which can be conveniently followed by monitoring of the
pH of the gases emerging from the reaction.
2. Results and discussion
Our objective was to prepare the SEMI-ESPHOS deriva-
tives 5–8, and to evaluate these materials in allylic
amination reactions. The selection of these materials was
made on the basis that the modifications would allow us to
gauge the effect of substitutions at particular positions on
the ability of the ligand to function. Each of the derivatives
has been selected on the basis that the position of
functionalisation is some distance from the phosphorus
atom, and should not therefore interfere with its mode of
action. This prerequisite is essential if the ligands are to be
attached to a solid support through the positions indicated.
Compound 6 was prepared from the cyclic proanilide 12,
which was available in quantity from L-glutamic acid
(Scheme 3). The reaction of 12 with bromine resulted in
para-bromination of the N-aryl ring to give 13 in 68% yield.
The reduction of 13 to diamine 14 was achieved in low yield
through reduction with lithium aluminium hydride at room
temperature overnight. This reaction can be accelerated by
heating the reaction mixture at reflux, but under these
conditions significant debromination is observed. The
condensation of 14 with the bis(dimethylamino)phosphine
intermediate 159 resulted in formation of the target 6 in 57%
yield.
Compound 5 was attractive because the 5-oxygen sub-
stituted provides a remote position for attachment of a
supporting group. The target compound was prepared
through the route illustrated in Scheme 2, pivotal to which
was a regioselective ortho-lithiation of 9 (prepared by TBS
protection of para-methoxyphenol) to give 10.
Scheme 2. Reagents and conditions: (i) nBuLi, THF, 2788C.
(ii) ClP(NMe2)2, THF, 2788C. (iii) S-(2-phenylaminomethyl)pyrolidine
(1 equiv.), toluene, reflux, 2 days.
Figure 1. X-Ray crystallographic structure of 11.

C. W. Edwards et al. / Tetrahedron 59 (2003) 6473–6480
6475
To prepare ligand 8, the sequence of reactions illustrated in
Scheme 4 was employed. N-Benzylcarboxylate protected
L-proline 18 was condensed with para-methoxyaniline to
give 19, which was then converted to diamine 20 in a two-
step process of deprotection followed by reduction with
lithium aluminium hydride. A two-step process was
required here because direct reduction of the N-protecting
group would have resulted in N-methylation. It should also
be noted that we chose not to start from L-glutamic acid in
this instance because of the difficulty of removal of the
unreacted substituted aniline from the reaction; unlike
aniline itself, the para-methoxy derivative cannot be
distilled off. The synthesis of 8 was completed by the
condensation of 20 with 15.
In X-ray crystal structures of all previous examples of
diazaphosphidine ligands such as 2 and its derivatives, the
condensation reaction with the precursor diamine derivative
is always diastereospecific, and results in formation of the
isomer in which the lone pair on P is cis to the three-carbon
bridge in the pyrolidine ring component.5c,6,7 We therefore
assign the relative configuration of compounds 5–8 as
depicted in the schemes on this basis. In order to provide
further evidence, however, the X-ray crystallographic
structure of 8 was also obtained as a representative example
(Fig. 2). As can clearly be seen, the relative configuration at
the P atom matches that observed for other ligands of this
type.
Scheme 3. Reagents and conditions: (i) 2 equiv. Br2, AcOH, 2 days.
(ii) LiAlH4, THF, rt, o/n. (iii) 1 equiv. 15, toluene, reflux, 3 days.
(iv) 5 mol% Pd(OAc)2, 2.5 equiv. phenylboronic acid, 2.5 equiv. K2CO3,
H2O, 1008C, 90 min. (v) LiAlH4, THF, reflux, 3 h.
With ligands 5–8 in hand, we were able to assess the effect
of each substitution on the enantioselectivity of the allylic
amination reaction (Scheme 1), which can be conveniently
followed by chiral HPLC. As can be seen in Table 1, the
modifications do not have a substantially deleterious effect
on the selectivity of the reaction. In all cases, under
conditions modified relative to our earlier publication5c
similar levels of yield and enantioinduction were achieved
relative to those originally obtained with SEMI-ESPHOS 2.
Compound 7 was also formed through a similar sequence
(Scheme 3). For this compound, it was necessary to
introduce the second aromatic ring through a Suzuki
coupling reaction.10 Conditions had to be optimised for
this reaction, which delivered 16 in 42% yield. The
conversion in the Suzuki reaction could be improved with
the addition of a quantity of tetrabutylammonium bromide,
however, the ammonium salt proved difficult to separate
from the product. The success of the Suzuki reaction
effectively permits the introduction of a range of aryl groups
to the ligand. Reduction of 16 provided the diamine 17 in
79% yield, and this was converted to 7 upon condensation
with 15 in 63% yield.
In conclusion, we have been able to demonstrate that the
structure of SEMI-ESPHOS can be modified at several
positions to generate derivatives which are equally effective
at directing allylic amination reactions. We are currently
investigating the use of this chemistry for the attachment of
monodonor diazaphospholidine ligands to solid and poly-
mer supports, and the results of these studies will be
reported in due course.
Scheme 4. Reagents and conditions: (i) 1.2 equiv. para-methoxyaniline,
EtOAc, 1.2 equiv. EtOCOCl, 2158C, 1 h; 08C, 1 h; rt, 48 h. (ii) 20 atm H2,
Pd/C, EtOH. (iii) 2.5 equiv. LiAlH4, THF, reflux, 3 h. (iv) 1 equiv. 15,
toluene, reflux, 3 days.
Figure 2. X-Ray crystallographic structure of 8.

6476
C. W. Edwards et al. / Tetrahedron 59 (2003) 6473–6480
3. Experimental
3.1.3. Phosphine oxide 11. 4-Methoxyphenyl dimethyl-t-
butylsilyl ether, 9, (1.0 g, 4.20 mmol) was dissolved in THF
(20 mL) and cooled to 2788C. n-Butyllithium (2.5 M,
1.76 mL, 4.41 mmol) was added to the cooled reaction
mixture which was then allowed to warm to room
temperature over 3–4 h. Diphenylphosphinic chloride
(0.99 g, 4.20 mmol) was then added to the precooled
reaction mixture and stirred overnight. The reaction mixture
was diluted using DCM (50 mL) and washed using saturated
NaHCO3 solution (200 mL), dried using magnesium
sulphate and concentrated in vacuo to give the crude
product as a white solid. Recrystallisation from toluene gave
the product 11 as a white crystalline solid (0.62 g, 34%
yield), mp 134–1358C; dH (250 MHz, CDCl3) 7.70 (4H, dd,
J¼1.5, 6.7 Hz, Ar), 7.54–7.39 (6H, m, Ar), 7.10 (1H, dd,
J¼2.9, 14.2 Hz, Ar), 6.99 (1H, dd, J¼3.0, 8.9 Hz, Ar), 6.80
(1H, dd, J¼6.1, 8.9 Hz, Ar), 3.49 (3H, s, CH3), 0.93 (9H, s,
CH3), 0.09 (6H, s, CH3); dC (300 MHz, CDCl3) 155.4 (d,
JCP¼3.1 Hz, ipso C), 149.3 (d, JCP¼14.6 Hz, ipso C), 133.6
(ipso C), 132.5 (ipso C), 131.7 (d, JCP¼10.0 Hz, Ar), 131.4
(d, JCP¼2.3 Hz, Ar), 128.0 (d, JCP¼13.0 Hz, Ar), 125.7 (d,
JCP¼7.7 Hz, Ar), 125.1 (d, JCP¼3.1 Hz, Ar), 121.2 (ipso C),
112.7 (d, JCP¼8.4 Hz, Ar), 55.7 (CH3), 26.0 (CH3), 18.5
(C), 24.2 (CH3); dP (300 MHz, CDCl3) 27.97; nmax (nujol)/
cm21 1287, 1216, 1179, 1155, 1118, 1016, 960; m/z (EI)
438 (Mþ), 420 (Mþ2H2O), 381 (Mþ2C(CH3)3), 365
(Mþ2C(CH3)3O), 347 (Mþ2C6H5OH2), 201, 183, 135,
91, 77, 73, 57, 41; HRMS found [M]þ 438.1777, requires
438.1780.
3.1. General
General experimental conditions have been described in a
previous publication.11 Compounds 9,14 1816,17 and 159
were prepared following literature procedures. The method
for the allylic amination reaction has been described in a
previous publication.9
3.1.1. Synthesis of 5-oxo-prolin-anilide. L-Glutamic acid
(40.0 g, 0.27 mol) was dissolved in aniline (300 mL,
3.29 mol) and the reaction mixture heated to 2008C for
45–50 min. The deep orange/red coloured solution was
allowed to cool before being placed under vacuum. Excess
aniline was removed from the reaction mixture using
vacuum distillation. The reaction mixture was allowed to
cool before adding acetone (100 mL) to the remaining
red/brown oil. The resulting cloudy solution was filtered
using a sinter funnel to give a white/brown solid, which was
washed with further acetone whilst on the sinter. The filtrate
was concentrated in vacuo and acetone was again added to
give further crude product. The combined crude product
was crushed using a pestle mortar and allowed to dry
further. The crude product was recrystallised from hot
methanol (,250 mL) to give the pure product as a white
crystalline solid (16.79 g, 30% yield), mp 183–1858C, lit.
mp 189–1918C;12 dH (250 MHz, d-DMSO) 10.05 (1H, bs,
NH), 7.91 (1H, bs, NH), 7.65 (2H, dd, J¼1.2, 8.7 Hz, CH),
7.35 (2H, t, J¼7.8 Hz, CH), 7.15 (1H, t, J¼7.4 Hz, CH), 4.37
(1H, dd, J¼4.4, 4.9 Hz, CH), 2.63–2.14 (4H, m, CH2); dC
(300 MHz, d-DMSO)177.8(CvO), 171.6 (CvO), 139.2(C),
129.1 (CH), 123.8 (CH), 119.7 (CH), 56.7 (CH), 29.6 (CH2),
25.7 (CH2); m/z (EI) 204 (Mþ), 149 (Mþ2C3H3O), 84
(Mþ2C7H6NO), 71 (C3H5NO), 57 (C2H3NO), 41 (C2HO);
[a]2D2¼þ19.6 (c¼1, methanol), lit. [a]2D2¼þ18.5 (c¼1,
methanol) corresponding to (S)-isomer.12
Crystal data. Crystal character: colourless prism. Crystal
dimensions 0.46£0.25£0.20 mm3, C25H31O3PSi, M¼
438.56, monoclinic, a¼10.989(2), b¼16.162(3),
˚
c¼13.431(3) A, a¼908, b¼92.114(5)8, g¼908, U¼
3
˚
2383.8(8) A , T¼180(2) K, space group P21/n, Z¼4,
m(Mo Ka)¼0.222 mm21, least squares refinement on
˚
5599 reflection positions, l¼0.71073 A, D(cal)¼1.222
mg/m3, F(000)¼936, R1¼0.0402, wR2¼0.1150.
3.1.2. (S)-2-(Phenylaminomethyl) pyrrolidine. THF
(150 mL) was added to lithium aluminium hydride
(7.49 g, 197 mmol) and the resulting suspension was
allowed to stir whilst being cooled to 08C. 5-Oxo-prolin-
anilide (16.08 g, 78.82 mmol) was added carefully as a solid
to the suspension of lithium aluminium hydride and then
heated to reflux for 2 h. The reaction mixture was allowed to
cool before the addition of sodium sulphate decahydrate
(30.0 g), which was then allowed to stir for 1 h. The grey
coloured reaction mixture was filtered through a plug of
celite and the filtrate concentrated in vacuo to give the crude
product as a pale green oil. The crude product was purified
by vacuum distillation (1228C, 0.5 Torr), (lit. bp 117–
1208C/0.4 Torr)12 to give the product as a clear oil (11.80 g,
85% yield). Following experimental data was in accordance
with published data;12,13 dH (250 MHz, CDCl3) 7.19 (2H,
dd, J¼7.4, 8.5 Hz, CH), 6.71–6.61 (3H, m, CH), 4.11 (1H,
bs, NH), 3.42–3.32 (1H, m, CH), 3.17 (1H, dd, J¼4.6,
12.0 Hz, NH), 2.98–2.90 (3H, m, 2CH2), 1.97–1.64 (4H, m,
2CH2), 1.51–1.39 (1H, m, CH2); dC (300 MHz, CDCl3)
148.6 (C), 129.2 (CH), 117.3 (CH), 113.0 (CH), 57.7 (CH4,
48.5 (CH2), 47.2 (CH2), 30.3 (CH2), 25.8 (CH2); m/z (EI)
176 (Mþ), 107 (Mþ2C4H9N), 93 (C6H7N), 70 (C4H8N);
[a]2D2¼þ22.2 (c¼1, ethanol), lit. [a]2D2¼þ19.1 (c¼1,
ethanol) corresponding to (S)-isomer.12
3.1.4. Formation of 3-[(bis(dimethylamino)-phosphino]-
4-methoxyphenyldimethyl-t-butylsilyl ether 10. 4-Meth-
oxyphenyl dimethyl-t-butylsilyl ether, 9, (12.0 g,
50.40 mmol) was dissolved in THF (60 mL) and cooled to
2788C. n-BuLi (21.18 mL, 52.94 mmol) was added to the
cooled reaction mixture and allowed to warm to room
temperature. In a separate flask hexamethylphosphorus
triamide (5.42 g, 6.04 mL, 33.28 mmol) was added to
phosphorus trichloride (2.28 g, 1.45 mL, 16.64 mmol) and
the mixture was heated at 808C for 30 min. The contents of
the second flask were diluted using THF (2£15 mL),
transferred via cannula to the ortho-lithiated substrate and
the reaction mixture allowed to stir overnight. The reaction
mixture was diluted using DCM (80 mL) and washed with
saturated NaHCO3 solution (4£100 mL). The NaHCO3
layer was extracted using DCM (200 mL) and the combined
organic layers were dried using magnesium sulphate. The
solvent was removed in vacuo to give the crude product as a
red oil which was purified by vacuum distillation (0.02 Torr,
1368C) to give the product 10 as a clear oil (8.13 g, 45%
yield); dH (250 MHz, CDCl3) 7.37 (1H, t, J¼3.7 Hz, Ar),
6.94–6.89 (1H, m, Ar), 6.56 (1H, dd, J¼4.7, 8.7 Hz, Ar),
3.77 (3H, s, CH3), 2.80 (12H, d, JPH¼9.5 Hz, CH3), 0.98
(9H, s, CH3), 0.17 (6H, s, CH3); dC (300 MHz, CDCl3)

C. W. Edwards et al. / Tetrahedron 59 (2003) 6473–6480
6477
155.1 (d, JCP¼14.9 Hz, ipso C), 149.2 (ipso C), 130.1 (d,
JCP¼13.2 Hz, ipso C), 123.8 (JCP¼5.8 Hz, Ar), 120.0 (Ar),
111.0 (Ar), 56.2 (CH31), 41.7 (d, JCP¼18.4 Hz, CH3), 25.7
(CH3), 18.2 (C), 24.4 (CH3); dP (300 MHz, CDCl3) 96.35;
(CvO, amide band 1), 1660 (CvO, amide band 1), 1607,
1546 (NH bend, amide band 2); m/z (CI) 285 (Br81, Mþþ1,
25%), 283 (Br79, Mþþ1, 25%), 205, 84; HRMS found [M]þ
282.0003, requires 282.0004; [a]2D2¼þ30.5 (c¼1, acetic
acid).
n
max (nujol)/cm21 1270, 1213, 1034, 979, 957; m/z (CI) 357
(MHþ), 325 (MHþ2MeO), 312 (MHþ2NMe2), 267
(MHþ2(NMe2)2), 238 (MHþ2P(NMe2)2), 224 (MHþ2
C6H15OSi); HRMS found [M]þ 356.2052, requires
356.2049.
3.1.7. (S)-(40-Bromophenylaminomethyl)pyrrolidine 14.
Lithium aluminium hydride (3.06 g, 80.53 mmol) was
added to THF (70 mL) and the resulting suspension cooled
in an ice bath. 5-Oxo-prolin-(4-bromo-anilide), 13, (9.12 g,
32.21 mmol) was added carefully as a solid to the cooled
suspension and the reaction mixture allowed to stir at room
temperature overnight. Sodium sulphate decahydrate
(26.0 g) was added as a solid to the reaction mixture and
allowed to stir for 1 h. The grey coloured reaction mixture
was filtered through a plug of celite and washed with DCM
(60 mL). The filtrate was concentrated in vacuo to give the
crude product as an oil which was purified by Kugelrohr
distillation (0.5 Torr, ,2258C) to give, on standing, the
product 14 as a pale yellow solid (2.63 g, 33% yield), mp
110–1118C; dH (250 MHz, CDCl3) 7.24 (2H, d, J¼8.9 Hz,
Ar), 6.47 (2H, d, J¼8.9 Hz, Ar), 3.38–3.31 (1H, m, CH),
3.12 (1H, dd, J¼4.6, 12.0 Hz, NH), 2.94–2.85 (3H, m, CH2,
NH), 1.96–1.69 (4H, m, CH2), 1.46 (2H, m, CH2); dC
(300 MHz, CDCl3) 147.6 (ipso C), 131.8 (CH), 114.5 (CH),
108.7 (ipso C), 57.4 (CH), 48.5 (CH2), 46.5 (CH2), 29.5
(CH2), 25.8 (CH2); nmax (nujol)/cm21 3281 (NH stretch),
1596 (NH bend), 1550 (NH bend), 1404, 1319, 1257, 815;
m/z (EI) 257 (Br81, 25%, Mþ), 255 (Br79, 25%, Mþ), 187
(MþBr812C4H8N, 65%), 185 (MþBr792C4H8N, 65%), 70;
HRMS found [M]þ 254.0419, requires 254.0419;
[a]2D2¼þ29.7 (c¼0.5, chloroform).
3.1.5. Diazaphospholidine 5. (S)-2-(Phenylaminomethyl)-
pyrrolidine, (3.15 g, 0.02 mol) was dissolved in toluene
(50 mL) and added to the 3-[(bis(dimethylamino)-phos-
phino]-4-methoxyphenyl dimethyl-t-butylsilyl ether, 10
(6.35 g, 0.02 mol). The reaction mixture was then heated
at reflux for 3 days, the release of dimethylamine was
monitored using damp litmus paper. The pale yellow
coloured reaction mixture was concentrated in vacuo to
give the crude product as a yellow solid. This was
transferred to a sinter funnel and washed with diethyl
ether to give the product 5 as a pale yellow solid (4.75 g,
60% yield), mp 108–1098C; dH (250 MHz, C6D6) 7.25–
7.20 (1H, m, Ar), 7.09–7.00 (3H, m, Ar), 6.89–6.79 (3H, m,
Ar), 6.48 (1H, dd, J¼4.1, 8.7 Hz, Ar), 3.91–3.81 (1H, m,
CH), 3.37 (3H, s, CH3), 3.32–3.15 (3H, m, CH2), 2.85–2.77
(1H, m, CH2), 1.69–1.60 (1H, m, CH2), 1.58–1.43 (2H, m,
CH2), 1.33–1.25 (1H, m, CH2), 1.00 (9H, s, CH3), 0.10 (6H,
s, CH3); dC (300 MHz, C6D6) 156.5 (d, JCP¼14.9 Hz, ipso
C), 149.6 (ipso C), 147.5 (d, JCP¼14.4 Hz, ipso C), 131.1 (d,
JCP¼28.7 Hz, ipso C), 129.3 (d, JCP¼1.2 Hz, Ar), 122.1 (d,
JCP¼3.4 Hz, Ar), 121.5 (Ar), 117.9 (d, JCP¼3.4 Hz, Ar),
115.8 (d, JCP¼12.6 Hz, Ar), 112.1 (d, JCP¼1.2 Hz, Ar), 64.4
(d, JCP¼8.0 Hz, CH), 55.6 (CH3), 53.4 (d, JCP¼5.2 Hz,
CH2), 52.5 (d, JCP¼29.9 Hz, CH2), 31.2 (CH2), 26.0 (d,
JCP¼5.8 Hz, CH2), 25.1 (CH3), 18.4 (C), 24.4 (CH3); dP
(300 MHz, C6D6) 108.08; nmax (nujol)/cm21 1597 (NH),
1572 (NH), 1323, 1272, 1218, 1172, 1025, 944, 837; m/z
(EI) 442 (Mþ), 373 (Mþ2C4NH7), 337 (Mþ2C7H7N), 311
(Mþ2OSi(CH3)2C(CH3)3), 296, 268 (Mþ2C11H14N2),
211, 205 (C11H14 PN2), 181 (CH3OC6H4OSi(CH3)2), 149
(C6H4OSi(CH3)2), 119 (C6H4OSi); HRMS found [M]þ
442.2215, requires 442.2205; [a]2D2¼2366.5 (c¼1,
benzene).
3.1.8. Synthesis of 5-oxo-prolin-(4-phenyl-anilide) 16.
Phenylboronic acid (4.50 g, 36.88 mmol) was added to a
suspension of 5-oxo-prolin-(4-bromo-anilide), 13, (4.20 g,
14.84 mmol) in water (60 mL). A solution of palladium
diacetate (0.17 g, 0.74 mmol) and potassium carbonate
(5.12 g, 37.10 mmol) in water (60 mL) was added to the
reaction mixture and heated at reflux for 1 h.15 The reaction
mixture was allowed to cool before being extracted with
EtOAc (300 mL), dried using magnesium sulphate, filtered
and concentrated in vacuo to give the crude product as an
off-white solid. Recrystallisation from methanol gave the
pure product 16 as a white solid (1.80 g, 42% yield), mp
227–2298C; dH (250 MHz, d-DMSO) 10.17 (1H, s, NH),
7.94 (1H, s, NH), 7.73 (2H, d, J¼8.8 Hz, Ar), 7.64 (4H, d,
J¼7.9 Hz, Ar), 7.44 (2H, t, J¼7.5 Hz, Ar), 7.35–7.29 (1H,
m, Ar), 4.22 (1H, dd, J¼4.0, 8.2 Hz, CH), 2.44–1.95 (4H,
m, CH2); dC (300 MHz, d-DMSO) 177.5 (CvO), 171.4
(CvO), 139.6 (ipso C), 138.3 (ipso C), 135.1 (ipso C),
128.9 (Ar), 127.0 (Ar), 126.9 (Ar), 126.2 (Ar), 119.7 (Ar),
56.4 (CH), 29.2 (CH2), 25.4 (CH2); nmax (solid state)/cm21
3203 (NH stretch), 1660 (CvO, amide band 1), 1594 (NH
bend, amide band 2), 1519, 1486, 1402, 1105; m/z (FABþ)
281 (MHþ), 154 (C12H10), 111 (C5H6NO2), 83 (C4H5NO);
HRMS found [MþH]þ 281.1294, requires 281.1290;
[a]2D2¼þ29 (c¼1, chloroform).
3.1.6. Synthesis of 5-oxo-prolin-(4-bromo-anilide) 13.
Bromine (29.40 g, 9.48 mL, 183.75 mmol) was added to a
solution
containing
5-oxo-prolin-anilide,
(19.75 g,
96.84 mmol) dissolved in acetic acid (120 mL) and the
reaction mixture allowed to stir for 2 days. Sodium
metathiosulphate solution (200 mL) was added to the deep
red coloured reaction mixture and allowed to stir for 30 min.
The resulting thick white coloured suspension was filtered
using a sinter funnel, and whilst on the sinter, washed with
sodium metathiosulphate solution (100 mL), water
(100 mL) and methanol (200 mL) to give the pure product
13 as a white solid (18.50 g, 68% yield), mp 225–2278C; dH
(250 MHz, d-DMSO) 10.20 (1H, bs, NH), 7.90 (1H, bs,
NH), 7.60 (2H, d, J¼9.0 Hz, Ar), 7.50 (2H, J¼9.0 Hz, Ar),
4.18 (1H, dd, J¼4.4, 8.4 Hz, CH), 2.41–1.94 (4H, m, CH2);
dC (300 MHz, d-DMSO) 177.8 (CvO), 171.8 (CvO),
138.5 (C), 131.9 (CH), 121.6 (CH), 115.5 (C), 56.8 (CH),
29.6 (CH2), 25.6 (CH2); nmax (solid state)/cm21 3305 (NH
asymmetric stretch), 3275 (NH asymmetric stretch), 1687
3.1.9. Synthesis of (S)-2-(Biphenylaminomethyl)pyrroli-
dine 17. 5-Oxo-prolin-(4-phenyl-anilide), 16, (1.70 g,
6.44 mmol) was added as a solid to a cooled suspension
of lithium aluminium hydride (0.62 g, 16.31 mmol) in THF

6478
C. W. Edwards et al. / Tetrahedron 59 (2003) 6473–6480
(40 mL) and the reaction mixture heated at reflux for 2 h.
The reaction mixture was cooled before solid sodium
sulphate decahydrate (6.20 g) was added to the reaction
mixture and allowed to stir for 1 h. The reaction mixture
was filtered through a plug of celite and concentrated in
vacuo to give the crude product as a green oil. This was
dissolved in hot cyclohexane, filtered to remove any
impurities and concentrated in vacuo to give the product
17 as a pale yellow solid (1.21 g, 79% yield), mp 72–738C;
dH (250 MHz, CDCl3) 7.55–7.51 (2H, m, Ar), 7.46–7.35
(3H, m, Ar), 7.27–7.21 (2H, m, Ar), 6.69 (2H, d, J¼8.5 Hz,
Ar), 4.26 (1H, br s, NH), 3.46–3.36 (1H, m, CH), 3.25–3.18
(1H, dd, J¼4.3, 11.6 Hz, NH), 3.03–2.91 (2H, m, CH2),
2.00–1.69 (4H, m, CH2), 1.67–1.43 (2H, m, CH2); dC
(300 MHz, CDCl3) 147.9 (ipso C), 141.2 (ipso C), 130.0
(ipso C), 128.5 (Ar), 127.8 (Ar), 126.2 (Ar), 125.9 (Ar),
113.1 (Ar), 57.6 (CH4), 48.5 (CH2), 46.3 (CH2), 29.5 (CH2),
1595 (NH bend), 1531, 1310, 1273, 1210, 1092; m/z (CI)
253 (MHþ), 183 (C13H13N), 170 (C12H12N), 154 (C12H10),
84 (C5H10N), 70 (C4H8N); HRMS found [M]þ 252.1619,
requires 252.1626; [a]D22¼þ27.2 (c¼0.5, chloroform).
3.1.10. Synthesis of N-(benzyloxycarbonyl)prolin[(40-
methoxy)-anilide] 19.16,17 N-Benzyloxycarbonyl proline,
18, (10.0 g, 40.16 mmol) was dissolved in EtOAc (100 mL)
and cooled to 2158C. N-Methylmorpholine (4.87 g,
5.30 mL, 48.19 mmol) and ethyl chloroformate (5.23 g,
4.61 mL, 48.19 mmol) were added to the precooled reaction
mixture which was stirred for 20 min. Methoxyaniline
(5.93 g, 48.19 mmol) was then added to the reaction mixture
which was kept at 2158C for 1 h, at 208C for a further 1 h
before being allowed to stir at room temperature for 48 h.
The brown coloured reaction mixture was diluted with
EtOAc (200 mL) and washed with water (200 mL),
saturated NaHCO3 solution (200 mL), NaCl solution
(200 mL), 3% HCl (200 mL), NaCl solution (200 mL),
dried with magnesium sulphate and concentrated in vacuo to
give the crude product as a pale pink coloured solid. The
crude product was transferred to a sinter funnel and washed
with diethyl ether (200 mL) and recrystallised from toluene
to give the pure product 19 as a white solid (9.69 g, 68%
yield), mp 124–1258C; dH (250 MHz, CDCl3) 9.02 (1H, br,
NH), 7.40–7.20 (7H, br, Ar), 6.80 (2H, d, J¼9.0 Hz, CH),
5.20 (2H, br, CH2), 4.48 (1H, br, CH), 3.77 (3H, s, CH3),
3.50 (2H, br, CH2), 2.28 (4H, br, CH2); dC (300 MHz,
CDCl3) 169.1 (CvO), 163.7 (CvO), 156.7 (ipso C), 156.1
(ipso C), 136.2 (ipso C), 128.5 (Ar), 128.2 (Ar), 127.9 (Ar),
121.3 (Ar), 113.9 (Ar), 67.5 (CH2), 60.9 (CH), 55.4 (CH3),
47.1 (CH2), 27.5 (CH2), 24.6 (CH2); nmax (nujol)/cm21 3279
(NH stretch), 3137 (NH stretch), 1698 (CvO, amide band
1), 1670 (CvO, amide band 1), 1606 (NH bend, amide band
2), 1552 (NH bend, amide band 2), 1317, 1245, 1167, 1119,
1035; m/z (EI) 354 (Mþ), 204 (C12H14NO2), 149
(C8H7NO2), 122 (C7H8NO), 91 (C7H7), 70 (C4H8N);
HRMS found [M]þ 354.1581, requires 354.1580;
[a]2D2¼229.9 (c¼1, chloroform).
gauge remained constant). The reaction mixture was filtered
through a plug of celite, washed with diethyl ether and
concentrated in vacuo to give the crude product as an oil.
This oil was dissolved in hot cyclohexane and allowed to
cool. The cyclohexane was filtered using a sinter funnel and
the solid on the sinter was washed with cold cyclohexane to
give the product as a white solid (3.88 g, 64% yield), mp
80–818C; dH (250 MHz, CDCl3) 9.62 (1H, s, NH), 7.51
(2H, d, J¼9.0 Hz, CH), 6.86 (2H, d, J¼8.9 Hz, CH), 3.84
(1H, dd, J¼5.3, 9.2 Hz, CH), 3.78 (3H, s, CH3), 3.14–2.95
(2H, m, CH2), 2.63 (1H, s, NH), 2.27–2.00 (2H, m, CH2),
1.82–1.70 (2H, m, CH2); dC (300 MHz, CDCl3) 173.0
(CvO), 155.9 (ipso C), 131.1 (ipso C), 120.7 (CH), 114.0
(CH), 60.8 (CH), 55.4 (CH3), 47.2 (CH2), 30.6 (CH2), 26.8
(CH2); nmax (nujol)/cm21 3340 (NH stretch), 3238 (NH
stretch), 1660 (CvO, amide band 1), 1590 (NH bend, amide
band 2), 1519 (NH bend), 1298, 1263, 1178, 1099, 1032;
m/z (EI) 220 (Mþ), 149 (C8H7NO2), 123 (C7H8NO), 108
(C7H8O), 70 (C4H8N); HRMS found [MþH]þ 221.1291,
requires 221.1290; [a]2D2¼227.7 (c¼1, chloroform).
3.1.12. Synthesis of (S)-2-[N-(40-methoxyphenyl)-amino-
methyl]pyrrolidine 20. THF (50 mL) was added to lithium
aluminium hydride (1.66 g, 43.76 mmol) and the resultin0g
suspension cooled to 08C for 30 min. (S)-Prolin-[(4 -
methoxy)-anilide], (3.85 g, 17.50 mmol) was added care-
fully as a solid to the cooled suspension of lithium
aluminium hydride and the reaction mixture then heated
to reflux for 3 h. The reaction mixture was allowed to cool
before the addition of sodium sulphate decahydrate (8.0 g)
as a solid and allowed to stir for 1 h. The resulting grey
coloured reaction mixture was then filtered through a plug
of celite and washed with diethyl ether. The combined
organic layer was concentrated in vacuo to give the crude
product as a pale yellow liquid and purified using Kugelrohr
distillation (0.5 mm, 2208C) to give the product 20 as a pale
green liquid (3.10 g, 86% yield); dH (250 MHz, CDCl3) 6.77
(2H, d, J¼9.0 Hz, CH), 6.60 (2H, d, J¼9.0 Hz, CH), 3.74
(3H, s, CH3), 3.40–3.31 (1H, m, CH), 3.10 (1H, dd, J¼4.7,
11.9 Hz, NH), 2.94–2.86 (3H, m, CH2, NH), 1.96–1.63
(4H, m, 2CH2), 1.50–1.40 (2H, m, CH2); dC (300 MHz,
CDCl3) 151.9 (ipso C), 142.8 (ipso C), 114.8 (CH), 114.2
(CH), 57.6 (CH), 55.7 (CH3), 49.7 (CH2), 46.4 (CH2), 29.5
(CH2), 25.8 (CH2); nmax (liquid film)/cm21 3346 (NH
stretch), 2952 (CH stretch), 2870 (CH stretch), 1618 (NH
bend), 1514 (CH), 1464 (CH), 1408, 1306, 1235, 1180,
1127, 1102, 1038; m/z (EI) 206 (Mþ), 137 (Mþ2C4H7N),
122 (C7H8NO), 83 (C5H10N), 70 (C4H8N); HRMS found
[M]þ 206.1419, requires 206.1419; [a]2D2¼þ27.7 (c¼1,
chloroform).
3.1.13. Diazaphospholidine ligand 6. (S)-(40-Bromo-
phenylaminomethyl)pyrrolidine, 14 (2.51 g, 9.86 mmol)
was dissolved in toluene (40 mL) and added to ortho-
[bis(dimethylamino)]-phosphino-anisole,
15,
(2.24 g,
9.86 mmol). The reagents were allowed to dissolve fully
before heating the reaction mixture at reflux for 3 days. The
reaction mixture was allowed to cool before the reaction
mixture was concentrated in vacuo to give the crude product
as a pale brown oil. Diethyl ether and hexane were added to
the crude product and the solid formed was isolated by
filtration. This solid was dissolved in hot cyclohexane and
undissolved solid was filtered off. The cyclohexane layer
3.1.11. Synthesis of (S)-prolin-[(40-methoxy)-anilide.
N-(Benzyloxycarbonyl)-prolin[(40-methoxy)-anilide], 19,
(9.69 g, 9.89 mmol) was dissolved in methanol (80 mL)
within a hydrogenation vessel and 5% Pd/charcoal (0.90 g)
added. The reaction mixture was placed on a hydrogenation
machine and hydrogenated for 3–4 days (until pressure

C. W. Edwards et al. / Tetrahedron 59 (2003) 6473–6480
6479
was concentrated in vacuo to give the product 6 as a yellow
solid (2.18 g, 57% yield), mp 80–818C; dH (250 MHz,
C6D6) 7.36 (1H, ddd, J¼1.7, 4.0, 7.3 Hz, Ar), 7.27 (2H, dd,
J¼2.2, 6.9 Hz, Ar), 7.12–7.02 (1H, m, Ar), 6.83 (1H, t,
J¼7.3 Hz, Ar), 6.69 (2H, dd, J¼2.2, 6.8 Hz, Ar), 6.44 (1H,
dd, J¼2.3, 6.8 Hz, Ar), 3.73–3.69 (1H, m, CH), 3.20 (3H, s,
CH3), 3.33–3.01 (2H, m, CH2), 2.91 (1H, dd, J¼7.5,
9.0 Hz, CH2), 2.57–2.51 (1H, m, CH2), 1.58–1.37 (3H, m,
CH2), 1.21–1.13 (1H, m, CH2); dC (300 MHz, C6D6) 161.8
(JCP¼15.5 Hz, ipso C), 146.6 (JCP¼15.5 Hz, ipso C), 131.8
(Ar), 130.9 (JCP¼2.9 Hz, Ar), 130.8 (Ar), 129.8 (ipso C),
120.5 (Ar), 117.6 (JCP¼12.7 Hz, Ar), 110.7 (Ar), 109.9
(ipso C), 64.6 (JCP¼8.6 Hz, CH3), 54.8 (CH), 53.2
(JCP¼5.2 Hz, CH2), 52.5 (JCP¼29.8 Hz, CH2), 31.4 (CH2),
26.1 (JCP¼6.3 Hz, CH2); dP (300 MHz, C6D6) 109.11; nmax
(solid state)/cm21 2918 (CH), 2837 (CH), 1586 (NH), 1488,
1470, 1314, 1270, 1235, 1180; m/z (EI) 392 (Mþ Br81), 390
(Mþ Br79), 285 (C11H13Br81N2P), 283 (C11H13Br79N2P),
207 (C11H14NOP), 185 (C7H6Br81N), 183 (C7H6Br79N), 84
(C5H10N), 70 (C4H8N); HRMS found [M]þ 390.0497,
requires 390.0497; [a]2D2¼2381 (c¼1, benzene).
from toluene (5 mL) and the solid product filtered off and
washed with cold toluene to give the product 8 as a
crystalline solid (2.07 g, 46% yield), mp 159–1608C; dH
(250 MHz, C6D6) 7.48 (1H, ddd, J¼1.9, 3.8, 7.2 Hz, Ar),
7.13–7.10 (1H, m, Ar), 6.95 (2H, dd, J¼1.9, 9.0 Hz, Ar),
6.87–6.82 (3H, m, Ar), 6.48 (1H, dd, J¼3.8, 8.1 Hz, Ar),
3.84–3.76 (1H, m, CH), 3.41–3.13 (3H, m, CH2), 3.38 (3H,
s, CH3), 3.27 (3H, s, CH3), 2.83–2.77 (1H, m, CH2), 1.66–
1.43 (3H, m CH2), 1.31–1.22 (1H, m, CH2); dC (300 MHz,
C6D6) 161.9 (JCP¼14.9 Hz, ipso C), 152.8 (ipso C), 141.8
(JCP¼14.9 Hz, ipso C), 131.1 (JCP¼2.9 Hz, Ar), 130.5 (Ar),
130.5 (JCP¼28.2 Hz, ipso C), 120.5 (Ar), 116.7 (JCP
¼
12.1 Hz, Ar), 114.9 (Ar), 110.7 (Ar), 64.7 (JCP¼8.0 Hz,
CH3), 55.3 (CH3), 54.9 (CH3), 53.7 (JCP¼5.7 Hz, CH2),
52.7 (JCP¼29.9 Hz, CH2), 31.4 (CH2), 26.2 (JCP¼6.3 Hz,
CH2); dP (300 MHz, C6D6) 109.61; nmax (nujol)/cm21 1613
(NH), 1583 (NH), 1509, 1310, 1270, 1236, 1024; m/z (EI)
342 (Mþ), 235 (Mþ2C7H7O), 207 (C11H14NOP), 152
(C7H7NOP), 108 (C7H8O), 70 (C4H8N); HRMS found
[MþH]þ 342.1504, requires 342.1497; [a]2D2¼2466 (c¼1,
benzene).
3.1.14. Diazaphospholidine ligand 7. (S)-2-(Biphenyl-
aminomethyl)pyrrolidine, 17, (1.14 g, 4.52 mmol) was
dissolved in toluene (30 mL) and added to ortho-[bis(di-
methylamino)]-phosphino-anisole, 15, (1.03 g, 4.52 mmol).
The reagents were allowed to dissolve fully before heating
the reaction mixture at reflux for 3 days. The reaction
mixture was allowed to cool before removing the solvent in
vacuo to give the crude product as a white solid. The crude
product was dissolved in hot toluene (18 mL) and the
precipitate that formed was filtered off and washed with cold
toluene to give the product 7 as a white solid (1.13 g, 63%
yield), mp 212–2148C; dH (250 MHz, CDCl3) 7.57–7.21
(9H, m, Ar), 6.95–6.84 (4H, m, Ar), 4.09–4.01 (1H, m,
CH), 3.82 (3H, s, CH3), 3.62–3.57 (1H, m, CH2), 3.47–3.41
(1H, m, CH2), 3.32–3.14 (2H, m, CH2), 2.15–2.05 (1H, m,
CH2), 1.95–1.75 (3H, m, CH2); dC (300 MHz, CDCl3)
161.3 (JCP¼16.1 Hz, ipso C), 146.5 (JCP¼15.5 Hz, ipso C),
141.2 (ipso C), 130.7 (Ar), 130.4 (ipso C), 130.3
(JCP¼2.9 Hz, Ar), 129.0 (ipso C), 128.7 (Ar), 127.6 (Ar),
126.4 (Ar), 126.1 (Ar), 120.4 (Ar), 115.6 (JCP¼13.2 Hz,
Ar), 110.8 (Ar), 64.3 (JCP¼8.6 Hz, CH3), 55.7 (CH3), 53.5
(JCP¼4.6 Hz, CH2), 52.5 (JCP¼29.9 Hz, CH2), 31.0 (CH2),
25.7 (JCP¼10.3 Hz, CH2); dP (300 MHz, CDCl3) 96.51;
Crystal data. Crystal character: colourless prism. Crystal
dimensions 0.40£0.40£0.10 mm3, C19H23N2O2P, M¼
342.36, orthorhombic, a¼7.1825(6), b¼7.9276(6),
3
˚
˚
c¼31.138(2) A, a¼908, b¼908, g¼908, U¼784.38(8) A ,
T¼180(2) K, space group P2(1)2(1)2(1), Z¼4,
m(Mo Ka)¼0.222 mm21, least squares refinement on
˚
3124 reflection positions, l¼0.71073 A, D(cal)¼1.283
mg/m3, F(000)¼728, R1¼0.0788 wR 2¼0.1986.
Crystallographic data (excluding structure factors) for the
structures in this paper have been depostited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 209695 (compound 11) and
CCDC 209696 (compound 8). Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [fax: þ44-1223-336033 or
email: deposit@ccdc.cam.ac.uk].
Acknowledgements
We thank the EPSRC and GlaxoSmithKline for CASE
funding of this project (to C. W. E.) and Professor D. Games
and Dr B. Stein of the EPSRC National Mass Spectroscopic
service (Swansea) for HRMS analysis of certain com-
pounds. H. J. C. (X-ray structure determiantion of 8) thanks
the Memorial Univeristy of Newfoundland for sabbatical
leave. We wish to acknowledge the use of the EPSRC’s
Chemical Database Service at Daresbury.18
n
max (nujol)/cm21 3362 (NH), 1602 (NH), 1571 (NH), 1519,
1327, 1270, 1234, 1021; m/z (EI) 388 (Mþ), 281
(Mþ2C7H7O), 207 (C11H13NOP), 181 (C8H10N2OP), 149
(C7H5N2P), 83 (C5H9N), 70 (C4H8N); HRMS found
[MþH]þ 388.1702, requires 388.1704; [a]2D2¼2488 (c¼1,
benzene).
3.1.15. Diazaphospholidine ligand 8. (S)-2-[N-(40-
Methoxyphenyl)aminomethyl]pyrrolidine, 20, (2.70 g,
13.1 mmol) was dissolved in toluene (60 mL) and added
References
to
ortho-[bis(dimethylamino)]-phosphino-anisole
15,
(2.96 g, 13.11 mmol). The reagents were allowed to
dissolve fully before being heated at reflux for 3 days.
The reaction mixture was allowed to cool before removing
the solvent in vacuo to give the crude product as a green
solid. The crude product was transferred to a sinter funnel
and washed with diethyl ether to give the crude product as a
white crystalline solid. The crude product was recrystallised
1. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: NY, 1994. (b) Ojima, I. Catalytic Asymmetric
Synthesis; VCH: Berlin, 1993. (c) Jacobsen, E. N.; Pfaltz,
A.; Yamamoto, H. Handbook of Asymmetric Catalysis;
Springer: Heidelberg, 1999.
2. Ansell, J. A.; Wills, M. Chem. Soc. Rev. 2002, 31, 259.
3. (a) van den Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman,

6480
C. W. Edwards et al. / Tetrahedron 59 (2003) 6473–6480
M.; Schudde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries,
B.; Buono, G. Tetrahedron Lett. 1998, 39, 9663. (f) Muchow,
G.; Brunel, J. M.; Maffei, M.; Pardigon, O.; Buono, G.
Tetrahedron 1998, 54, 10435. (g) Constantieux, T.; Brunel,
J. M.; Labande, A.; Buono, G. Synlett 1998, 49. (h) Brunel,
J. M.; Constantieux, T.; Labande, A.; Lubatti, F.; Buono, G.
Tetrahedron Lett. 1997, 38, 5971. (i) Bondarev, O. G.;
Gavrilov, K. N.; Tsarev, V. N.; Davankov, V. A.; Lebedev,
R. V.; Moiseev, S. K.; Kalinin, V. N. Russ. Chem. Bull. 2002,
51, 521. (j) lithiation: Ngono, C. J.; Constantieux, T.; Buono,
G. J. Organomet. Chem. 2002, 643–644, 237.
A. H. M.; Maljaars, C. E. P.; Willans, C. E.; Hyett, D.;
Boogers, J. A. F.; Henderickx, H. J. W.; de Vries, J. G. Adv.
Synth. Catal. 2003, 345, 308. (b) Pena, D.; Minnaard, A. J.; de
Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Org. Lett. 2003,
5, 475. (c) Pena, D.; Minnaard, A. J.; de Vries, J. G.; Feringa,
B. L. J. Am. Chem. Soc. 2002, 124, 14552. (d) van den Berg,
M.; Haak, R. M.; Minnaard, A. J.; de Vries, A. H. M.; de Vries,
J. G.; Feringa, B. L. Adv. Synth. Catal. 2002, 344, 1003.
(e) Minnaard, A. J.; Van den Berg, M.; Schudde, E. P.; Van
Esch, J.; De Vries, A. H. M.; De Vries, J. G.; Feringa, B. L.
Chim. Oggi-Chem. Today 2001, 19, 12. (f) Lopez, F.; Ohmura,
T.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125. asap article.
7. Delapierre, G.; Achard, M.; Buono, G. Tetrahedron Lett. 2002,
43, 4025.
8. (a) Brunel, J. M.; Constantieux, T.; Legrand, O.; Buono, G.
Tetrahedron Lett. 1998, 39, 2961. (b) Legrand, O.; Brunel,
J. M.; Buono, G. Angew. Chem., Int. Ed. 1999, 38, 1479.
9. Smyth, D.; Tye, H.; Eldred, C.; Alcock, N. W.; Wills, M.
J. Chem. Soc., Perkin Trans. 1 2001, 2840.
4. (a) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew.
Chem., Int. Ed. 2003, 42, 790. (b) Reetz, M. T.; Sell, T.
Tetrahedron Lett. 2000, 41, 6333. (c) Reetz, M. T.; Gosberg,
A. Tetrahedron: Asymmetry 1999, 10, 2129. (d) Claver, C.;
Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.; Martorell,
A.; Open, A. G.; Pringle, P. G. Chem. Commun. 2000, 961.
(e) Martorell, A.; Naasz, R.; Feringa, B. L.; Pringle, P. G.
Tetrahedron: Asymmetry 2001, 12, 2499.
10. Diederich, F. Metal Catalysed Cross Coupling Reactions; 2nd
ed. Wiley: London, 1998.
11. Kawamoto, A. M.; Wills, M. J. Chem. Soc., Perkin Trans. 1
2001, 1916.
12. Iriuchijima, S. Synthesis 1978, 684.
5. (a) Tye, H.; Smyth, D.; Eldred, C.; Wills, M. Chem. Commun.
1997, 1053. (b) Smyth, D.; Tye, H.; Eldred, C.; Alcock, N. W.;
Wills, M. J. Chem. Soc., Perkin Trans. 1 2001, 2840.
(c) Breeden, S.; Wills, M. J. Org. Chem. 1999, 64, 9735.
(d) Breeden, S.; Cole-Hamilton, D. J.; Foster, D. F.; Schwarz,
G. J.; Wills, M. Angew. Chem., Int. Ed. 2000, 39, 4106.
6. (a) Delapierre, G.; Brunel, J. M.; Constantieux, T.; Buono, G.
Tetrahedron: Asymmetry 2001, 12, 1345. (b) Brunel, J. M.;
Tenaglia, A.; Buono, G. Tetrahedron: Asymmetry 2000, 11,
3585. (c) Legrand, O.; Brunel, J. M.; Buono, G. Tetrahedron
2000, 56, 595. (d) Brunel, J. M.; Constantieux, T.; Buono, G.
J. Org. Chem. 1999, 64, 8940. (e) Brunel, J. M.; Del Campo,
13. Mukaiyama, T. Tetrahedron 1981, 37, 4111.
14. Stern, A. S.; Swenton, J. S. J. Org. Chem. 1987, 52, 2763.
15. Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U.
J. Org. Chem. 1997, 62, 7170.
16. Asami, M.; Ohno, H.; Kobayashi, S.; Mukayama, T. Bull.
Chem. Soc. Jpn 1978, 51, 1869.
17. O’Brien, P.; Warren, S. J. Chem. Soc., Perkin Trans. 1 1996,
2117.
18. Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf.
Comput. Sci. 1996, 36, 746.