Synthesis of a novel diarylphosphinic acid: A distorted ground state mimic and transition state analogue for amide hydrolysis

Article abstract of DOI:10.1016/S0040-4020(01)01048-1

We describe herein the synthesis of a new unsymmetrical diarylphosphinic acid, a hapten aimed to produce catalytic antibodies for the hydrolysis of heterocyclic amides. The phosphinate functionality was selected as a mimic both of the tetrahedral intermed

Full text of DOI:10.1016/S0040-4020(01)01048-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 10299±10307
Synthesis of a novel diarylphosphinic acid: a distorted ground
state mimic and transition state analogue for amide hydrolysis
a,p
Marc Schuman,a Xabier Lopez,b Martin Karplusa,c,d and Veronique Gouverneur
Â
aNew Chemistry Laboratory, The Dyson Perrins Laboratory, University of Oxford, South Parks Road, OX13QY Oxford, UK
bKimika Fakultatea, Euskal Herriko Unibertsitatea, P.K. 1072, 20080 San Sebastian, Spain
cDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
Â
Laboratoire de Chimie Biophysique, Institut le Bel, Universite Louis Pasteur, 67000 Strasbourg, France
d
Received 17 August 2001; revised 2 October 2001; accepted 25 October 2001
AbstractÐWe describe herein the synthesis of a new unsymmetrical diarylphosphinic acid, a hapten aimed to produce catalytic antibodies
for the hydrolysis of heterocyclic amides. The phosphinate functionality was selected as a mimic both of the tetrahedral intermediate and the
transition state of higher energy along the reaction pro®le. The phenyl and 2,4,6-(trimethyl)-phenyl groups ¯anking the phosphinate were
chosen in order to impose rotation around the P±C bond, a choice supported by ab initio calculations. This new hapten should elicit catalytic
antibodies whose binding site could affect the distortion at nitrogen as well as the twist along the N±C(O) bond for heterocyclic amides. This
hapten along with a series of new sterically hindered unsymmetrical phosphinic acid derivatives was prepared by a key palladium-catalysed
step. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
on eliciting antibodies against haptens mimicking both a
distorted ground state and a transition state.3 This strategy
was previously explored by Hansen et al. as a new approach
to sequence-speci®c protease antibodies.4 Haptens such as
2-cis-amino-3-cis-hydroxycyclobutane carboxylic acid and
endo-(3-amino-2-hydroxy)bicyclo-[2.2.1]-heptane-7-anti-
carboxylic acid in which the targeted glycyl±glycyl peptide
bond was replaced by a ring-strained or torsionally-strained
The generation of amidase-like antibodies has been and is
still an extremely challenging task that bears high thera-
peutical potential.1 Afew studies have shown promising
results, but this area of research still remains a testing
ground for new hapten strategies.2 This work is directed
towards the generation of amidase antibodies and is focused
Scheme 1. Design of hapten 4 for the hydrolysis of compounds 1-3.
Keywords: antibodies; phosphinic acids and derivatives; palladium; coupling reactions.
Corresponding author. Fax: 144-1865-275-644; e-mail: veronique.gouverneur@chem.ox.ac.uk
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01048-1

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M. Schuman et al. / Tetrahedron 57 (2001) 10299±10307
hydrolysis of such substrates would need to exhibit lower
rate accelerations for detectable hydrolysis. We therefore
chose the hydrolysis of the heterocyclic amides 1±3,
which contain amine portions of reduced basicity, as
model reactions to test a novel hapten that can mimic both
the transition state and a distorted ground state. We report
herein the design and the synthesis of a new hapten 4
aimed to elicit amidase antibodies for the hydrolysis of
the heterocyclic amides 1±3 (Scheme 1). The conformation
of a close model of compound 4 was determined by ab initio
calculations.
2. Results and discussion
2.1. Hapten design
It was shown that the base catalysed hydrolysis of aroyl
pyrrole derivatives proceeds via rate determining decompo-
sition of the tetrahedral intermediate from which the leaving
group departs as an anion.9 This step could be spontaneous
or catalysed by 2OH and calculations suggested that the
transition state for the spontaneous decomposition of the
intermediate is similar to the tetrahedral intermediate
itself.10 The unsymmetrical diarylphosphinic acid derivative
4 (Scheme 1) was therefore selected based on the following
criteria. We selected the phosphinate functionality as a
mimic both of the tetrahedral intermediate and of the tran-
sition state, a choice supported by the recent computational
and ab initio analysis reported by Tantillo and Houk.11 It is
interesting to note that, in contrast to phosphonate and phos-
phonamidate functions,1,12 the phosphinate group has not
often been selected as a transition state analogue for hydro-
lytic reaction. However, Benkovic and coworkers described
the successful use of a cyclic phosphinate in the generation
of catalytic antibodies for the deamidation of a model dipep-
tide through an intermediate succinimide.13 The phos-
phinate functionality in compound 4 was ¯anked by two
phenyl groups, one of them being substituted on positions
2, 4 and 6 by methyl groups. It is anticipated that the
presence of the ortho methyls at position 2 and 6 will
impose rotation around the P±C bond. To determine the
conformation of the phosphinate compound 4 (Scheme 1),
calculations were performed for a diarylphosphinate in
which one of the phenyl groups presents no substituents
Figure 1. Preferential conformation of (2,6-dimethylphenyl)phenyl phos-
phinic acid.
moiety were made. In pursuit of sequence-speci®c antibody
proteases, these entities were ¯anked by additional amino
acid residues. Also, a series of b-lactam-containing dipep-
tide analogues mimicking only a ring-strained ground state
was prepared.4,5 The same group of workers also synthe-
sised 7-trans-amino-6-trans-hydroxy-spiro-[4.4]-nonane-
carboxylic acid, a dipeptide analogue mimicking both
torsionally-strained glycyl-proline and glycyl-glycine.6 To
our knowledge, no catalytic antibodies raised against these
molecules have been reported.
Uncatalysed peptide bond hydrolysis is extremely slow at
physiological pH and temperature (t1/2 approximately 9
years).7 In contrast to peptide bond hydrolysis, the hydro-
lytic cleavage of N-acylpyrrole, N-acylimidazole and some
activated N-acylpyrrolidine derivatives is a much faster
process.8 Consequently, antibodies for the catalysis of the
Scheme 2. Synthetic approaches to the synthesis of unsymmetrical diarylphosphinic acid derivatives 5a and 5b.

M. Schuman et al. / Tetrahedron 57 (2001) 10299±10307
Table 1. Synthesis of a series of unsymmetrical diarylphosphinic acid derivatives
10301
Entry
Products
Method
Yielda,b (%)
1
A64
2
3
A49
A
B
5a 18
5b 80, 92c, 62d
4
A
B
10a 18
10b 38e
5
A
B
11a 20
11b 45f, 48c
6
B
74
7
B
33, 55d
a
Isolated yields after silica gel chromatography.
Yield for the Pd cross-coupling step.
Pd (OAc)2 (3 mol%) combined with 13 mol% dppf was used instead of Pd(PPh3)4.
K3PO4 (1.5 mol%) was added to Pd(PPh3)4 as an additive.
Pd2(dba)3 (5 mol%) was used instead of Pd(PPh3)4.
b
c
d
e
f
Compound 5b (25%) was isolated as a side product.
and the other shows methyl substituents at the 2 and 6
positions (Fig. 1). The B3LYP function14 with a 6-311Gp
basis set was used to describe the electronic structure of the
molecule. All calculations were done with the Jaguar
program.15 The optimised geometry is shown in Fig. 1.
The most important result concerns the orientation of the
two phenyl groups. For the 2,6-(dimethyl)-phenyl group, the
O2±P±C1±C2 dihedral angle is 1.88, O1±P±C1±C2 angle
is 242.88 and C2±C1±P±C10 is 70.08. For the unsubstituted
phenyl group, we get values of 250.78 for O2±P±C10 ±C20,
25.38 for O2±P±C10 ±C20 and 2118.98 for C20 ±C10 ±P±C1
dihedral. Thus the 2,6-(dimethyl)-phenyl group is oriented
to be almost coplanar with the O2±P±C1 plane, whereas
the unsubstituted phenyl group is almost coplanar with the
O1±P±C10 plane. Amore detailed description of these
calculations including solvent effects will be the subject of

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M. Schuman et al. / Tetrahedron 57 (2001) 10299±10307
Scheme 3. Synthesis of hapten 4.
a future publication. With these results in hand, it seems to
us that hapten 4 should elicit catalytic antibodies whose
binding site could affect distorsion at nitrogen as well as
the twist along the N±C(O) bond for substrates 1±3. The
hapten 4 could therefore be regarded both as a distorted
ground state mimic of compounds 1±3 and a transition
state analogue for their hydrolysis.
might decompose at the temperature required for the palla-
dium cross-coupling process.17 After several unsuccessful
attempts to optimise this reaction, we concentrated our
efforts on the preparation of compound 5b having an ethyl
instead of the more sensitive methyl phosphinate function-
ality. Compound 5b was successfully prepared in three steps
according to the methodology of Xu16b,c (Scheme 2,
Method B and Table 1, entry 3). Diethylmesitylenephos-
phonite was ®rst prepared in 93% yield by the reaction of
mesitylenemagnesium bromide with diethyl phosphoro-
chloridite in re¯uxing THF. It was subsequently smoothly
converted into the corresponding key intermediate 9 in 95%
yield by treatment with 0.1 M hydrochloric acid at 508C.
Interestingly, the palladium-catalysed coupling of com-
pound 9 with iodobenzene furnished compound 5b in 80%
yield after 2 h at 1008C in toluene. Under these conditions, it
seems that the coupling occurs faster than the decompo-
sition of the phosphinate 9. Using Xu's methodology,
compound 5b could thus be prepared with an overall yield
of 70% from the commmercially available diethyl phos-
phorochloridite. The same methodology was successfully
applied to the synthesis of compounds 10±12 including
functional groups, however at the expense of reduced yields
(Table 1, entries 4±6). For compound 11b, a side-product
was isolated in 25% yield and identi®ed as compound 5b.
Presumably, the unsubstituted phenyl group is derived from
triphenylphosphine. Such exchange of aryl groups on Pd
with those of a phosphine ligand is known.18 The use of
Pd2(dba)3 instead of Pd(PPh3)4 for the coupling process
prevented the formation of the side-product but did not
allow us to obtain better yields except for the preparation
of compound 10b (Table 1, entry 4). Compound 13,
exemplifying a more sterically demanding system, was
prepared in 33% yield supporting the hypothesis that this
methodology is also sensitive to steric effects but to a lesser
extent than the methodology developed by Schwabacher. In
order to maximise the yield of 13, the addition of K3PO4
proved to be bene®cial, however this modi®cation is not of
general scope (Table 1, entries 3 and 7).
2.2. Synthesis
In the retrosynthetic analysis of compound 4, the diaryl-
phosphinate would derive from a palladium-catalysed key
step. Several reports have described the synthesis of unsym-
metrical diarylphosphinic acid derivatives16 but, to our
knowledge, the preparation of unsymmetrical diarylphos-
phinic acid derivatives for which one of the phenyl groups
is substituted on both ortho-positions has not been reported.
In a preliminary experiment, we ®rst applied the strategy
developed by Schwabacher et al.16a to the synthesis of the
model compound 5a (Scheme 2, Method Aand Table 1,
entry 3). The procedure relies on a sequential palladium-
catalysed cross-coupling of the two different aryl iodides
with methylphosphinate. In a typical procedure, a solution
of methylphosphinate prepared in situ by the reaction of
anhydrous phosphinic acid with an excess of trimethyl
orthoformate was treated with iodobenzene in acetonitrile
in the presence of excess propylene oxide (as HI scavenger)
and a catalytic amount of Pd(PPh3)2Cl2. One hour re¯ux at
758C provided phenylphosphinic acid methyl ester 6 which
was not puri®ed but was freed of the excess of methyl phos-
phinate and other side products by treatment with NaHCO3.
Subjection of this material to iodomesitylene under palla-
dium catalysis in the presence of propylene oxide led to the
formation of the expected product 5a albeit in only 18%
yield. When the above sequence of reactions was reversed,
coupling ®rst the more sterically hindered iodomesitylene
followed by iodobenzene, no improvements were observed.
Subsequently, in a series of control experiments using the
same procedure, we prepared compounds 7 and 8 in 64 and
49% chemical yield, respectively (entries 1 and 2, Table 1).
These results suggest that under these conditions the palla-
dium-catalysed cross-coupling is sensitive to steric effects
as re¯ected by the decrease in the chemical yields as the
second aryl iodide is more heavily substituted. In addition, it
is likely that the methylphosphinate or the ®rst intermediate
Application of the methodology of Xu to the synthesis of
compound 4 was straighforward as detailed in Scheme 3.
Compound 14 was ®rst prepared in 87% yield from methyl
5-phenylvalerate using thallium tri¯uoroacetate followed by
sodium iodide.19 The key palladium-catalysed coupling

M. Schuman et al. / Tetrahedron 57 (2001) 10299±10307
10303
4
proceeded smoothly in the presence of 10 mol% Pd(PPh3)4
in 45% yield. Deprotection of both the ethyl phosphinate
ester and the methyl carboxylate ester using TMSBr
followed by LiOH yielded compound 4 as a white solid.
11.20 Hz, 3H), 6.90 (d, JH±Pˆ4.00 Hz, 2H), 7.37±7.42
3
(m, 2H), 7.44±7.49 (m, 1H), 7.64±7.67 (dm, JH±Pˆ6.00
Hz, 2H); 13C NMR (100.62 MHz, CDCl3): dˆ21.07, 23.33
(d, 3JCPˆ3.12 Hz), 50.55 (d, 2JCPˆ6.04 Hz), 123.28 (d, 1JCPˆ
3
2
130.61 Hz), 128.39 (d, JCPˆ13.08 Hz), 130.42 (d, JCPˆ
3
4
11.27 Hz), 130.78 (d, JCPˆ13.68 Hz), 131.64 (d, JCPˆ
1
4
2.31 Hz), 133.93 (d, JCPˆ136.04 Hz), 142.11 (d, JCPˆ
2.72 Hz), 143.85 (d, 2JCPˆ11.17 Hz); 31P NMR (101.25 MHz,
CDCl3): dˆ38.47; IR (®lm): nˆ2973, 2944, 1606, 1438, 1220,
1123, 1033, 852, 794, 751, 730, 711, 696, 629, 576, 521 cm21;
APCI-MS: m/z (%): 275.18 (100) [M1H]1; HRMS:
(C16H19O2P: [M1H]1) calcd: 275.1201, found: 275.1213.
3. Conclusion
The design and the synthesis of a new transition state
analogue aimed at eliciting catalytic antibodies for the
hydrolysis of heterocyclic amides has been reported. An
ef®cient synthesis using a palladium cross-coupling reaction
as the key step has been developed for compound 4. The
methodology used for the synthesis of compound 4 has been
applied to a series of sterically hindered unsymmetrical
diarylphosphinic acid derivatives thereby demonstrating
the scope and limitations of this palladium coupling pro-
cess. The production of monoclonal antibodies and their
characterisation for catalysis will be described separately.
4.1.2. Phenyl-(2,4,6-trimethylphenyl)-phosphinic acid
ethyl ester (5b). Method B. Step 1: diethyl-(2,4,6-
trimethylphenyl)phosphonite. Freshly prepared 2,4,6-
trimethylphenyl magnesium bromide (prepared from
2-bromomesitylene (4.79 g, 24.05 mmol), magnesium
(0.72 g, 30.07 mmol) and THF (30 ml)) was added to a
solution of diethyl phosphorochloridite (3.17 g, 20.05
mmol) in THF (30 ml) at rt. After re¯uxing the mixture
for 2 h, dioxane (43 ml) was added at rt and the mixture
®ltered. Evaporation in vacuo, and puri®cation by
Kugelrohr distillation gave the product (4.49 g, 93%) as a
colourless oil; bp 130±1328C (0.3 mbar); 1H NMR
4. Experimental
4.1. General aspects
3
(400 MHz, CDCl3): dˆ1.33 (t, JH±Hˆ7.03 Hz, 6H), 2.30
All reactions were performed in ¯ame-dried glassware in an
3
3
1
atmosphere of argon unless noted otherwise. H and 13C
(s, 3H), 2.65 (s, 6H), 3.99 (dq, JH±Pˆ9.14 Hz, JH±H
ˆ
4
7.02 Hz, 2H), 6.86 (d, JH±Pˆ1.93 Hz, 2H); 13C NMR
(100.6 MHz, CDCl3): dˆ17.37 (d, JCPˆ6.0 Hz), 21.07,
21.65 (d, JCPˆ20.1 Hz), 64.24 (d, JCPˆ21.1 Hz), 129.66
(d, JCPˆ4.0 Hz), 134.74 (d, JCPˆ19.1 Hz), 139.92, 141.74
(d, JCPˆ19.1 Hz); 31P NMR (101.26 MHz, CDCl3): dˆ
25.23; IR (®lm): nˆ2974, 2927, 2875, 1605, 1442, 1385,
1097, 1056, 912, 743 cm21; APCI-MS: m/z (%): 241.2 (100)
[M1H]1, 213.1 (28) [M2C2H4]1; HRMS: (C13H22O2P:
[M1H]1) calcd: 241.1357, found: 241.1361.
NMR spectra were recorded on Bruker DPX-400 and
Bruker AM-500 spectrometers. 31P NMR spectra were
recorded on a Bruker AM-500 spectrometer at 202 MHz
and were referenced externally to phosphoric acid. Infrared
spectra were recorded using a Perkin±Elmer Paragon 1000
FT-IR spectrometer. Mass spectra (m/z) were recorded on a
Micromass Platform-I APCI spectrometer. HRMS were
performed on a Micromass Autospec 5000 OATof. Thin
layer chromatography was performed using Merck alu-
minium foil backed sheets precoated with Kieselgel 60
F254. Plates were visualised using UV light or KMnO4.
Column chromatography was performed using Sorbsile
C60 H(40±60) silica gel.
Step 2: 2,4,6-trimethylphenylphosphinic acid ethyl ester (9).
Diethyl 2,4,6-trimethylphenylphosphonite (4.3 g, 17.9
mmol) in THF (16 ml) was treated with 0.1 M HCl
(35 ml), stirred at rt for 5 min, then heated to 508C for
2.5 h. The reaction mixture was cooled to rt and extracted
with CH2Cl2 (4£50 ml). The combined organic layers were
dried over MgSO4 and the solvents evaporated in vacuo to
4.1.1. Phenyl-(2,4,6-trimethylphenyl)-phosphinic acid
methyl ester (5a). Method A. Anhydrous H3PO2
(455 mg, 6.9 mmol) was allowed to react with 5 equiv. of
trimethyl orthoformate (3.8 ml, 34.5 mmol) for 1 h at rt.
This mixture was added to a solution of iodobenzene
(260 ml, 2.3 mmol), Pd(PPh3)2Cl2 (80 mg, 0.11 mmol) and
propylene oxide (1.6 ml, 23 mmol) in CH3CN at 508C. The
reaction mixture was stirred for 6 h at re¯ux. After cooling
to rt, the reaction mixture was diluted with EtOAc (100 ml)
and washed with sat. NaHCO3 (5£5 ml), H2O (50 ml) and
brine (50 ml). The organic layers were dried over MgSO4
and the solvents evaporated. The crude product was
dissolved in CH3CN (18 ml) and added to a solution of
Pd(PPh3)4 (prepared in situ by adding NaBH4 (8 mg,
0.2 mmol) to a solution of Pd(PPh3)2Cl2 (140 mg, 0.2
mmol) and PPh3 (105 mg, 0.4 mmol) in CH3CN (10 ml)),
propylene oxide (1.8 ml, 26 mmol) and 2-iodomesitylene
(490 mg, 2.0 mmol). The mixture was heated at re¯ux for
28 h. Cooling to rt, evaporation in vacuo and puri®cation by
silica gel chromatography (EtOAc/hexane: 7/3) gave 5a
give 9 (3.62 g, 95%) as a colourless oil; 1H NMR (400 MHz,
3
CDCl3): dˆ1.31 (part A3 of A3FGX system: dd, JA±F
ˆ
3JA±Gˆ7.06 Hz, 3H), 2.21 (s, 3H), 2.49 (s, 6H), 4.06 (part
3
3
F of A3FGX system: dqd, JF±Pˆ8.88 Hz, JF±Aˆ7.00 Hz,
2JF±Gˆ10.08 Hz, 1H), 4.12 (part F of A3FGX system: dqd,
3JG±Pˆ8.88 Hz, 3JG±Aˆ7.06 Hz, 2JF±Gˆ10.08 Hz, 1H), 6.80
4
(d, JH±Pˆ1.93 Hz, 2H), 7.86 (part G of A3FGX system: d,
1JH±Pˆ551.5 Hz, 1H); 13C NMR (100.6 MHz, CDCl3): dˆ
3
3
16.16 (d, JCPˆ6.0 Hz), 20.83, 20.96 (d, JCPˆ34.2 Hz),
2
1
62.08 (d, JCPˆ6.0 Hz), 123.08 (d, JCPˆ67.4 Hz), 130.07
3
2
(d, JCPˆ13.1 Hz), 141.71 (d, JCPˆ11.1 Hz), 142.66 (d,
4JCPˆ3.0 Hz); 31P NMR (101.26 MHz, CDCl3): dˆ25.22;
IR (®lm): nˆ3469, 2978, 2926, 2366, 1606, 1453, 1222,
1089, 1035, 949, 633 cm21; APCI-MS: m/z (%): 213.15
(100) [M1H]1; HRMS: (C11H18O2P: [M1H]1) calcd:
213.1044, found: 213.1046.
(97 mg, 18%) as a colourless oil; 1H NMR (400 MHz,
Step 3: phenyl-(2,4,6-trimethylphenyl)-phosphinic acid
ethyl ester (5b). Iodobenzene (112 ml, 1 mmol), compound
3
CDCl3): dˆ2.29 (s, 3H), 2.49 (s, 6H), 3.73 (d, JH±P
ˆ

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M. Schuman et al. / Tetrahedron 57 (2001) 10299±10307
9 (212 mg, 1 mmol), Pd(PPh3)4 (115 mg, 0.1 mmol), Et3N
(0.45 ml, 3 mmol) and toluene (1.5 ml) were placed in a
capped thick wall tube under Ar and heated to 1008C for
3.5 h. The mixture was allowed to cool to rt, diluted with
EtOAc (20 ml) and ®ltered through celite. Evaporation in
vacuo and puri®cation by silica gel chromatography
(EtOAc/petroleum spirit (40±60) 5/5) gave 5b (231 mg,
cation by silica gel chromatography (EtOAc/hexane: 80/20)
gave 8 (77 mg, 49%) as a colourless oil; 1H NMR
3
(400 MHz, CDCl3): dˆ2.38 (s, 3H) 3.73 (d, 3H, JH±P
ˆ
5
11.20 Hz), 7.15±7.18 (m, 1H), 7.25 (dt, 1H, JH±P
ˆ
3
2.80 Hz, JH±Hˆ7.60 Hz), 7.37±7.43 (m, 3H), 7.47±7.51
3
(m, 1H), 7.71 (dm, 2H, JH±Pˆ12.40 Hz) 7.78 (ddd, 1H,
3
4
3JH±Pˆ12.80 Hz, JH±Hˆ7.60 Hz, JH±Hˆ0.80 Hz); 13C
1
3
80%) as a colourless oil; H NMR (250 MHz, CDCl3):
NMR (100.62 MHz, CDCl3): dˆ21.18 (d, JCPˆ4.43 Hz),
3
dˆ1.34 (part A3 of A3FGX system: dd, JA±Fˆ7.09 Hz,
51.22 (d, 2JCPˆ5.23 Hz), 125.49 (d, 4JCPˆ12.28 Hz), 128.47
4
3JA±Gˆ7.23 Hz, 3H), 2.26 (s, 3H), 2.49 (d, 6H, JH±P
ˆ
ˆ
(d, 3JCPˆ12.58 Hz), 128.82 (d, 1JCPˆ135.44 Hz), 131.31 (d,
3
0.67 Hz), 4.04 (part F of A3FGX system: dqd, JF±P
3
1JCPˆ134.63 Hz), 131.45 (d, JCPˆ13.38 Hz), 131.57 (d,
3
2
4
7.06 Hz, JF±Aˆ7.09 Hz, JF±Gˆ10.11 Hz, 1H), 4.13 (part
2JCPˆ10.06 Hz), 132.08 (d, JCPˆ2.62 Hz), 132.43 (d,
3
3
3
G of A3FGX system: dqd, JG±Pˆ7.22 Hz, JG±Aˆ7.23 Hz,
3JCPˆ3.52 Hz), 133.18 (d, JCPˆ9.36 Hz), 141.90 (d,
2JF±Gˆ10.11 Hz, 1H), 6.87 (d, JH±Pˆ3.97 Hz, 2H), 7.32±
2JCPˆ11.32 Hz); 31P NMR (101.25 MHz, CDCl3): dˆ
36.36; APCI-MS: m/z (%): 247.12 (100) [M1H]1;
HRMS: (C13H24O2P: [M1H]1) calcd: 247.0888, found:
247.0896.
4
7.41 (m, 3H), 7.61±7.71 (dm, JH±Pˆ12.88 Hz, 2H); 13C
3
3
NMR (62.9 MHz, CDCl3): dˆ16.84 (d, JCPˆ6.8 Hz),
3
2
21.47, 23.86 (d, JCPˆ3.1 Hz), 60.66 (d, JCPˆ5.8 Hz),
1
3
124.43 (d, JCPˆ131.1 Hz), 128.76 (d, JCPˆ13.3 Hz),
2
3
130.84 (d, JCPˆ11.0 Hz), 131.18 (d, JCPˆ13.1 Hz),
4.1.5. [4-(1,1-Dimethylethoxycarbonylamino)-phenyl]-
(2,4,6-trimethyl phenyl)-phosphinic acid methyl ester
(10a). Method A. H3PO2 (1.5 g, 22.7 mmol), trimethyl
orthoformate (8.3 ml, 76 mmol), (4-iodophenyl)-carbamic
acid tert-butyl ester (2.4 g, 7.6 mmol), Pd(PPh3)2Cl2
(266 mg, 0.038 mmol), propylene oxide (5.3 ml, 76
mmol), acetonitrile/dioxane (16:4) then Pd(PPh3)4 (530
mg, 0.46 mmol), 2-iodomesitylene (1.1 g, 4.6 mmol),
CH3CN/benzene (15/7.5), Et3N (6.5 ml, 46 mmol); puri®-
cation by silica gel column chromatography (EtOAc/
hexane: 7/3); yield: 320 mg (18%) as a white solid; mp
4
1
131.94 (d, JCPˆ2.6 Hz), 134.89 (d, JCPˆ134.5 Hz),
142.35 (d, JCPˆ2.6 Hz), 144.09 (d, JCPˆ11.3 Hz); 31P
NMR (101.25 MHz, CDCl3): dˆ36.36; IR (®lm): nˆ
2979, 2932, 1606, 1438, 1219, 1122, 1032, 950, 852, 750,
730, 710, 692, 630 cm21; APCI-MS: m/z (%): 289.21 (100)
[M1H]1; HRMS: (C17H22O2P: [M1H]1) calcd: 289.1357,
found: 289.1347.
4
2
Alternative procedure using Pd(OAc)2 and dppf: iodo-
benzene (112 ml, 1 mmol), compound
9
(212 mg,
1
1 mmol), Pd(OAc)2 (7 mg, 0.03 mmol), dppf (74 mg,
0.13 mmol), Et3N (0.28 ml, 2 mmol), acetonitrile (4.0 ml),
658C for 21 h. Yield: 92% (265 mg).
1858C; H NMR (400 MHz, CDCl3): dˆ1.49 (s, 9H), 2.28
(s, 3H), 2.47 (s, 6H), 3.70 (d, 3H, 3JP±Hˆ11.20 Hz), 6.89 (d,
4
4JH±Pˆ3.60 Hz, 2H), 7.09 (s br, 1H), 7.42 (dd, 2H, JH±P
ˆ
3
3
2.40 Hz, JH±Hˆ8.40 Hz), 7.55 (dd, 2H, JH±Pˆ12.40 Hz,
Alternative procedure using K3PO4: Iodobenzene (112 ml,
1 mmol), compound 9 (212 mg, 1 mmol), Pd(PPh3)4
(23 mg, 0.02 mmol), K3PO4 (320 mg, 1.5 mmol), DMF
(6.0 ml), 1008C for 22 h. Yield: 60% (180 mg).
3JH±Hˆ8.80 Hz); 13C NMR (100.61 MHz, CDCl3): dˆ
3
2
21.07, 23.39 (d, JCPˆ3.12 Hz), 28.24, 50.48 (d, JCPˆ
3
6.54 Hz), 80.90, 117.74 (d, JCPˆ13.88 Hz), 123.55 (d,
1JCPˆ131.90 Hz), 127.17 (d, JCPˆ141.16 Hz), 130.75 (d,
1
3JCPˆ12.98 Hz), 131.67 (d, JCPˆ12.58 Hz), 141.81 (d,
2
4
4.1.3. Diphenylphosphinic acid methyl ester (7). Method
A. H3PO2 (1 g, 15.15 mmol), trimethyl orthoformate
(8.3 ml, 75.76 mmol), iodobenzene (3.4 ml, 30.5 mmol),
Pd(PPh3)2Cl2 (533 mg, 0.76 mmol), propylene oxide
(10.5 ml, 150 mmol) and CH3CN; puri®cation by column
chromatography (EtOAc/hexane: 8/2); yield: 2.25 g (64%)
as colourless crystals; mp 508C; 1H NMR (250 MHz,
4JCPˆ2.82 Hz), 141.97 (d, JCPˆ2.82 Hz), 143.71 (d,
2JCPˆ10.46 Hz), 152.41; 31P NMR (101.25 MHz, CDCl3):
dˆ38.48; IR (®lm): nˆ3234, 2979, 2937, 1726, 1594, 1527,
1401, 1367, 1319, 1240, 1205, 1159, 1125, 1033, 909, 836,
796, 732, 684, 625, 576, 535 cm21; APCI-MS: m/z (%):
290.2 (100) [M2C5H7O2]1, 344.2 (31) [M2C4H7]1, 390.2
(42) [M1H]1; HRMS: (C17H22O2P: [M1H]1) calcd:
390.1834, found: 390.1830.
3
CDCl3): dˆ3.78 (d, 3H, JHP3ˆ11.01 Hz), 7.41±7.56 (m,
6H), 7.80±7.84 (dm, 2H, JHPˆ12.26 Hz); 13C NMR
2
(62.89 MHz, CDCl3): dˆ51.95 (d, JCPˆ5.9 Hz), 128.99
4.1.6. [4-(1,1-Dimethylethoxycarbonylamino)-phenyl]-
(2,4,6-trimethyl phenyl)-phosphinic acid ethyl ester
(10b). Method B. Step 3. (4-Iodo-phenyl)-carbamic acid
tert-butyl ester (638 mg, 2 mmol), compound 9 (424 mg,
2 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), Et3N (0.85 ml,
6 mmol), CH3CN (3 ml); puri®cation by silica gel chroma-
tography (EtOAc/petroleum spirit: 40/60) gave compound
3
1
(d, JCPˆ13.1 Hz), 131.42 (d, JCPˆ137.1 Hz), 132.07 (d,
2JCPˆ10.1 Hz), 132.64 (d, JCPˆ2.8 Hz); 31P NMR
4
(101.25 MHz, CDCl3): dˆ34.45; IR (®lm): nˆ3058,
2949, 159, 1438, 1220, 1131, 1035, 998, 800, 753, 731,
696, 659, 561, 527 cm21; APCI-MS: m/z (%): 233.09
(100) [M1H]1; HRMS: (C13H24O2P: [M1H]1) calcd:
233.0731, found: 233.0724.
1
10b (302 mg, 38%) as a white solid; mp 1838C; H NMR
(500 MHz, CDCl3): dˆ1.37 (part Aof A FGX system: dd,
3
3
4.1.4. Phenyl-2-tolyl-phosphinic acid methyl ester (8).
Method A. 2-Iodotoluene (100 ml, 0.77 mmol), propylene
oxide (670 ml, 9.6 mmol), crude phenylphosphinic acid
methyl ester (100 mg, 0.64 mmol), Pd(PPh3)4 (prepared
with sodium borohydride (3 mg, 0.08 mmol), triphenyl-
phosphine (40 mg, 0.15 mmol) and Pd(PPh3)2Cl2 (54 mg,
0.08 mmol), acetonitrile (3 ml) and benzene (3 ml)); puri®-
3JA±Fˆ7.12 Hz, JA±Gˆ7.16 Hz 3H), 1.53 (s, 9H), 2.32 (s,
3H), 2.52 (s, 6H), 4.07 (part F of A3FGX system: dqd,
3JF±Pˆ7.12 Hz, JF±Aˆ7.12 Hz, JF±3Gˆ10.15 Hz, 1H), 4.13
3
2
3
(part G of A3FGX system: dqd, JG±Pˆ7.19 Hz, JG±A
ˆ
2
4
7.16 Hz, JG±Fˆ10.15 Hz, 1H), 6.92 (d, JH±Pˆ3.50 Hz,
4
3
2H), 7.28 (s br, 1H), 7.47 (dd, 2H, JH±Pˆ2.50 Hz, JH±H
ˆ
3
3
8.50 Hz), 7.60 (dd, 2H, JH±Pˆ12.50 Hz, JH±Hˆ8.50 Hz);

M. Schuman et al. / Tetrahedron 57 (2001) 10299±10307
10305
3
13C NMR (125.72 MHz, CDCl3): dˆ16.86 (d, JCPˆ
(®lm): nˆ2978, 2935, 1737, 1605, 1438, 1220, 1120,
1033, 950, 852, 781, 680, 659, 626, 576, 514 cm21
;
3
7.17 Hz), 21.50, 23.96 (d, JCPˆ3.20 Hz), 28.72, 60.62 (d,
2JCPˆ6.03 Hz), 81.25, 118.24 (d, JCPˆ12.57 Hz), 124.82
APCI-MS: m/z (%): 403.29 (100) [M1H]1; HRMS:
(C17H22O2P: [M1H]1) calcd: 403.2038, found: 403.2038;
second product, identi®ed as phenyl-(2,4,6-trimethyl-
phenyl)-phosphinic acid ethyl ester 5b was also isolated in
25% (217 mg, 0.75 mmol).
3
1
1
(d, JCPˆ132.76 Hz), 128.14 (d, JCPˆ137.91 Hz), 131.17
3
2
(d, JCPˆ12.57 Hz), 132.13 (d, JCPˆ12.45 Hz), 142.24,
144.01 (d, JCPˆ11.69 Hz), 152.96; 31P NMR (202.39
2
MHz, CDCl3): dˆ36.41; IR (®lm): nˆ2982, 2930, 1718,
1604, 1518, 1401, 1368, 1318, 1242, 1159, 1032, 909, 835,
733, 683, 649, 576 cm21; APCI-MS: m/z (%): 304.2 (100)
[M2C5H8O2]1, 404.2 (29) [M1H]1; HRMS: (C17H22O2P:
[M1H]1) calcd: 404.1991, found: 404.2000.
For an alternative procedure using using Pd(OAc)2 and
dppf: compound 14 (318 mg, 1.0 mmol), compound 9
(212 mg, 1.0 mmol), Pd(OAc)2 (17 mg, 0.07 mmol), DPPF
(74 mg, 0.13 mmol), Et3N (0.28 ml, 2.0 mmol) acetonitrile
(4.0 ml), 658C for 19 h. Yield: 48% (193 mg).
4.1.7. 4-(4-Methoxycarbonylbutyl)-phenyl-(2,4,6-trimethyl-
phenyl)-phosphinic acid methyl ester (11a). Method A.
H3PO2 (360 mg, 5.5 mmol), trimethyl orthoformate (2.0 ml,
18.4 mmol), compound 15 (0.58 g, 1.8 mmol), Pd(PPh3)2Cl2
(580 mg, 0.092 mmol), propylene oxide (1.3 ml, 18.4
mmol), CH3CN (5 ml) then Pd(PPh3)4 (0.21 g, 0.18
mmol), 2-iodomesitylene (450 mg, 1.8 mmol), CH3CN
(5 ml), propylene oxide (1.3 ml, 18.4 mmol); puri®cation
by silica gel column chromatography (EtOAc/hexane:
4.1.9. Phenyl-(2,4,6-trimethoxyphenyl)-phosphinic acid
ethyl ester (12). Method B. Step 1: diethyl(2,4,6-tri-
methoxyphenyl)phosphonite: 2.1 M nBuLi in n-hexane
(7 ml, 14.8 mmol) was added dropwise to a suspension of
1,3,5-trimethoxybenzene (5 g, 29.7 mmol) and TMEDA
(2.2 ml, 14.8 mmol) in pentane (30 ml) and the resulting
mixture stirred at rt overnight. The formed precipitate was
®ltered and washed with pentane (20 ml), and solubilised in
Et2O (10 ml). Asolution of diethylchlorophosphite (2.1 ml,
14.8 mmol) in Et2O (5 ml) was added dropwise at 08C. The
mixture stirred at rt for 24 h. Dioxane (30 ml) was added to
the solution, which was ®ltered. Evaporation in vacuo and
puri®cation by Kugelrohr distillation gave 1.86 g of product
(43%) as a colourless oil; bp: 158±1608C (0.3 mbar).
1
7/3); yield: 143 mg (20%) as a colourless oil; H NMR
(500 MHz, CDCl3): dˆ1.66±1.68 (m, 4H), 2.32 (s, 3H),
3
2.35 (t, 3H, JH±Hˆ7.00 Hz), 2.52 (s, 6H), 2.67 (t, 2H,
3JH±Hˆ7.25 Hz), 3.69 (s, 3H), 3.75 (d, JP±Hˆ11.00 Hz,
3
4
4
3H), 6.93 (d, JH±Pˆ4.00 Hz, 2H), 7.24 (dd, 2H, JH±P
ˆ
3
3
3.50 Hz, JH±Hˆ8.00 Hz), 7.60 (dd, 2H, JH±Pˆ12.50 Hz,
3JH±Hˆ8.00 Hz); 13C NMR (125.72 MHz, CDCl3): dˆ
21.52, 23.80, 24.89, 30.92, 34.25, 35.98, 50.96 (d,
2JCP3ˆ5.78 Hz), 51.94, 123.99 (d, JCPˆ129.36 Hz), 128.93
Step 2: (2,4,6-trimethoxyphenyl)-phosphinic acid ethyl
ester: diethyl(2,4,6-trimethoxyphenyl)phosphonite (1.57 g,
5.45 mmol), THF (5 ml), 0.1 M HCl (10 ml), 508C for
2.5 h. The reaction mixture was cooled to rt and extracted
with CH2Cl2 (4£20 ml); yield: 1.39 g (98%) as a white
1
2
(d, JCPˆ12.07 Hz), 131.03 (d, JCPˆ10.56 Hz), 131.21 (d,
3JCPˆ10.69 Hz), 131.63 (d, JCPˆ138.79 Hz), 142.44,
1
144.26 (d, JCPˆ12.95 Hz), 146.65, 174.3; 31P NMR
2
(202.39 MHz, CDCl3): dˆ38.80; IR (®lm): nˆ2946,
2869, 1737, 1605, 1438, 1220, 1120, 1032, 852, 786, 681,
661, 624, 575 cm21; APCI-MS: m/z (%): 389.20 (100)
[M1H]1; HRMS: (C22H29O4P: [M1H]1) calcd: 389.1882,
found: 389.1868.
1
solid; mp 528C; H NMR (500 MHz, CDCl3): dˆ1.36 (t,
3JH±Hˆ7.25 Hz, 3H), 3.83 (s, 9H), 4.16 (dq, 3JP±Hˆ9.00 Hz,
4
3JH±Hˆ7.12 Hz, 2H), 6.08 (d, JH±Pˆ4.50 Hz, 2H), 7.85 (d,
1
1H, JH±Pˆ592.48 Hz); 13C NMR (125.72 MHz, CDCl3):
3
2
dˆ16.77 (d, JCPˆ6.91 Hz), 56.35, 62.24 (d, JCPˆ
3
1
4.1.8. 4-(4-Methoxycarbonylbutyl)-phenyl-(2,4,6-trimethyl-
phenyl)-phosphinic acid ethyl ester (11b). Method B.
Step 3. With compound 15 (950 mg, 3.0 mmol), compound
9 (635 mg, 3.0 mmol), Pd(PPh3)4 (345 mg, 0.3 mmol), Et3N
(1.3 ml, 9.0 mmol) and toluene (4.5 ml); puri®cation by
silica gel chromatography (EtOAc/petroleum spirit: 40/60)
5.78 Hz), 90.99 (d, JCPˆ4.90 Hz), 99.79 (d, JCPˆ
137.79 Hz), 164.55, 165.98; 31P NMR (101.25 MHz,
CDCl3): dˆ20.57; IR (®lm): nˆ2979, 2942, 2403, 1600,
1579, 1459, 1437, 1413, 1340, 1230, 1208, 1161, 1131,
1111, 1047, 953, 815, 730, 644 cm21; APCI-MS: m/z (%):
261.11 (100) [M1H]1; HRMS: (C11H18O5P: [M1H]1)
calcd: 261.0892, found: 261.0900.
1
gave 11b (546 mg, 45%) as a colourless oil; H NMR
(400 MHz, CDCl3): dˆ1.35 (part Aof A FGX system:
3
3
3
dd, JA±Fˆ7.10 Hz, JA±Gˆ7.17 Hz, 3H), 1.63 (m, 4H),
Step 3: phenyl-(2,4,6-trimethoxyphenyl)-phosphinic acid
ethyl ester (12): iodobenzene (204 mg, 1 mmol), (2,4,6-
trimethoxyphenyl)-phosphinic acid ethyl ester (260 mg,
1 mmol), Pd(PPh3)4 (115 mg, 0.1 mmol), Et3N (0.45 ml,
3 mmol), toluene (2.5 ml); 1008C overnight; puri®cation
by silica gel chromatography (EtOAc/MeOH: 96/4); yield:
3
2.27 (s, 3H), 2.31 (t, 3H, JH±Hˆ7.20 Hz), 2.49 (s, 6H),
3
2.63 (t, 2H, JH±Hˆ7.20 Hz), 3.64 (s, 3H), 4.03 (part F of
3
3
A3FGX system: dqd, JF±Pˆ7.05 Hz, JF±Aˆ7.10 Hz,
2JF±Gˆ10.05 Hz), 4.12 (part G of A3FGX system: dqd,
3JG±Pˆ7.15 Hz, JG±Aˆ7.17 Hz, JG±Fˆ10.05 Hz, 1H),
3
2
4
4
1
6.88 (d, JH±Pˆ4.00 Hz, 2H), 7.19 (dd, 2H, JH±P
ˆ
249 mg (74%) as a colourless oil; H NMR (400 MHz,
ˆ
3
3
3
3.30 Hz, JH±Hˆ8.20 Hz), 7.56 (dd, 2H, JH±Pˆ12.60 Hz,
CDCl3): dˆ1.29 (part Aof A FGX system: dd, JA±F
3
3JH±Hˆ7.40 Hz); 13C NMR (100.62 MHz, CDCl3): dˆ
7.15 Hz, JA±Gˆ7.15 Hz, 3H), 3.60 (s, 6H), 3.76 (s, 3H),
3
3
3
3
16.43 (d, JCPˆ6.8 Hz), 21.05, 23.46 (d, JCPˆ3.2 Hz),
4.06 (part F of A3FGX system: dqd, JF±Pˆ7.15 Hz,
2
2
24.43, 30.47, 33.79, 35.52, 51.47, 60.17 (d, JCPˆ5.6 Hz),
3JF±Aˆ7.15 Hz, JF±Gˆ10.10 Hz, 1H), 4.13 (part G of
1
3
3
3
124.24 (d, JCPˆ131.5 Hz), 128.41 (d, JCPˆ13.7 Hz),
A3FGX system: dqd, JG±Pˆ7.05 Hz, JG±Aˆ7.15 Hz,
2
3
4
130.57 (d, JCPˆ11.9 Hz), 130.70 (d, JCPˆ13.4 Hz),
2JG±Fˆ10.10 Hz, 1H), 6.01 (d, JH±Pˆ4.40 Hz, 2H), 7.31±
1
4
3
131.67 (d, JCPˆ137.3 Hz), 141.78 (d, JCPˆ3.3 Hz),
7.41 (m, 3H), 7.73±7.76 (dm, JH±Pˆ12.80 Hz, 2H); 13C
2
4
3
143.64 (d, JCPˆ11.64 Hz), 146.00 (d, JCPˆ2.4 Hz),
NMR (100.62 MHz, CDCl3): dˆ16.51 (d, JCPˆ7.04 Hz),
173.89; 31P NMR (101.25 MHz, CDCl3): dˆ36.72; IR
55.28, 55.73, 60.57 (d, JCPˆ6.04 Hz), 91.02 (d, JCPˆ
2
3

10306
M. Schuman et al. / Tetrahedron 57 (2001) 10299±10307
1
3
8.05 Hz), 100.22 (d, JCPˆ139.86 Hz), 127.59 (d, JCPˆ
8.5 ml) was added to a solution of 11b (471 mg, 1.17 mmol) in
CH2Cl2 (4.5 ml). The mixture was stirred for 2 h at rt then
methanol (5 ml) was added. The solvents were evaporated
and the crude dissolved in dioxane (4.5 ml). Asolution of
1 M aq. LiOH (8.5 ml) was added, and the mixture stirred
for 5 h at rt. The aqueous phase was acidi®ed (pHˆ1) with a
1 M HCl solution, extracted with chloroform and the combined
organic layers dried (Na2SO4). Evaporation in vacuo and puri-
®cation by silica gel column chromatography (EtOAc
100%!EtOAc/CH2Cl2/MeOH: 5/5/0.5) gave 4 (265 mg,
63%) as a white solid; mp 858C; Rfˆ0.1 (EtOAc/CH2Cl2:
50/50); 1H NMR (500 MHz, MeOH-d4, TFA-d): dˆ7.57
2
4
13.08 Hz), 130.57 (d, JCPˆ10.06 Hz), 130.72 (d, JCPˆ
1
2
3.02 Hz), 135.76 (d, JCPˆ146.91 Hz), 164.29 (d, JCPˆ
2.01 Hz), 164.97; 31P NMR (101.25 MHz, CDCl3): dˆ
31.29; FT-IR (®lm): nˆ2979, 2940, 1600,1577, 1467 (s),
1438, 1410, 1340, 1230, 1208, 1162, 1123, 1100, 1038, 955,
815, 750, 736, 718, 697, 545, 526 cm21; APCI-MS: m/z (%):
337.16 (100) [M1H]1; HRMS: (C17H22O5P: [M1H]1)
calcd: 337.1205, found: 337.1201.
4.1.10. (2-Methylphenyl)-(2,4,6-trimethylphenyl)-phos-
phinic acid ethyl ester (13). Method B. 2-Iodotoluene
(114 ml, 1.1 mmol), compound 9 (212 mg, 1 mmol),
Pd(PPh3)3 (115 mg, 0.05 mmol), Et3N (0.42 ml, 3 mmol)
and toluene (3 ml); 1108C for 3 days; puri®cation by silica
gel chromatography (EtOAc/petroleum spirit (40±60) 5/5);
yield: 100 mg (33%) as a colourless oil; 1H NMR
(dd, 2H, JH±Hˆ7.6 Hz, JP±Hˆ12.8 Hz), 7.29 (dd, 2H, JH±H
ˆ
7.5 Hz, JP±Hˆ2.7 Hz), 6.94 (d, 2H, JP±Hˆ3.5 Hz), 2.68 (t, 2H,
JH±Hˆ6 Hz), 2.48 (s, 6H), 2.34 (t, 2H, JH±Hˆ7 Hz), 2.28 (s,
3H), 1.64 (m, 4H); 13C NMR (125.7 MHz, MeOH-d4, TFA-d):
dˆ174.9, 146.8, 143.4 (d, JCPˆ10.3 Hz), 142.4, 132.3 (d,
JCPˆ136.2 Hz), 130.7 (d, JCPˆ15.72 Hz), 130.3 (d, JCPˆ
13.1 Hz), 128.6 (d, JCPˆ11.2 Hz), 125.5 (d, JCPˆ135.2 Hz),
35.4, 33.5, 30.6, 24.5, 22.8, 20.1; 31P NMR (202.4 MHz,
MeOH-d4, TFA-d): dˆ34.94; FT-IR (®lm): nˆ2979, 2942,
2403, 1600, 1579, 1459, 1437, 1413, 1340, 1230, 1208,
1161, 1131, 1111, 1047, 953, 815, 730, 644 cm21; A PCI-
MS: m/z (%): 361.21 (100) [M1H]1; HRMS: (C20H26O4P:
[M1H]1) calcd: 361.1569, found: 361.1566.
(500 MHz, CDCl3): dˆ1.40 (part Aof A FGX system:
3
3
3
dd, JA±Fˆ7.06 Hz, JA±Gˆ7.08 Hz, 3H), 2.33 (s, 3H),
2.42 (s, 3H), 2.50 (s, 6H), 4.02 (part F of A3FGX system:
3
3
2
dqd, JF±Pˆ7.06 Hz, JF±Aˆ7.06 Hz, JF±Gˆ9.97 Hz, 1H),
4.18 (part G of A3FGX system: dqd, 3JG±Pˆ7.12 Hz, 3JG±A
ˆ
7.08 Hz, 2JG±Fˆ9.97 Hz, 1H), 6.92 (d, 4JH±Pˆ3.50 Hz, 2H),
7.20±7.26 (m, 2H), 7.39 (t, 3JH±Hˆ7.50 Hz, 1H), 7.76 (ddd,
3JH±Pˆ14.00 Hz, JH±Hˆ7.50 Hz, JH±Hˆ1.00 Hz, 1H); 13C
3
4
3
NMR (125.72 MHz, CDCl3): dˆ16.85 (d, JCPˆ5.40 Hz),
3
3
21.06 (d, JCPˆ3.52 Hz), 21.51, 23.76 (d, JCPˆ1.76 Hz),
2
1
60.44 (d, JCPˆ6.35 Hz), 125.15 (d, JCPˆ131.26 Hz),
Acknowledgements
3
3
125.74 (d, JCPˆ15.09 Hz), 131.26 (d, JCPˆ11.69 Hz),
2
2
131.79 (d, JCPˆ12.19 Hz), 132.05, 132.61 (d, JCPˆ
This work was supported by the European Community
Training and Mobility Research Programme (COSSAC,
ERBFMRXCT 980193 to M. S. and X. L.). We thank Dr
R. Procter for recording the HRMS spectra and Professor G.
M. Blackburn (University of Shef®eld) for very helpful
suggestions regarding this manuscript.
1
2
11.06 Hz), 132.92 (d, JCPˆ131.16 Hz), 141.56 (d, JCPˆ
10.94 Hz) 142.21, 144.02 (d, JCPˆ13.07 Hz); 31P NMR
2
(202.40 MHz, CDCl3): dˆ36.58; FT-IR (®lm): nˆ2979,
2932, 1606, 1454, 1218, 1029, 949, 852, 755, 691, 629,
581 cm21; APCI-MS: m/z (%): 303.2 (100) [M1H]1;
HRMS: (C18H23O2P: [M1H]1) calcd: 303.1514, found:
303.1524.
References
4.1.11. Methyl 5-(4-iodophenyl) pentanoate (14). Methyl
5-phenylvalerate(1.7 g, 8.8 mmol) was dissolved in tri-
¯uoroacetic acid (35 ml) containing Tl(OOCCF3)3 (4.8 g,
8.8 mmol) and stirred for 5 days at rt in the dark. Potassium
iodide (7.3 g, 12.9 mmol) in water (55 ml) was added and
the mixture stirred for 15 min, sodium thiosulfate (1.4 g)
was then added and the mixture stirred for 15 min. The
mixture was poured into water (250 ml) and extracted
with ether. The combined organic layers were washed
with aqueous HCl (0.1N, 3£250 ml), water (4£250 ml)
and dried (MgSO4). Evaporation in vacuo and puri®cation
by column chromatography (petroleum spirit (40±60)/
1. For reviews on catalytic antibodies see: (a) Lerner, R. A.;
Benkovic, S. J.; Schultz, P. G. Science 1991, 252, 659±667.
(b) Schultz, P. G.; Lerner, R. A. Acc. Chem. Res. 1993, 26,
391±395. (c) Schultz, P. G.; Lerner, R. A. Science 1995, 269,
1835±1842. (d) MacBeath, G.; Hilvert, D. Chem. Biol. 1996, 3
(6), 433±445. (e) Wentworth, P.; Datta, A.; Blakey, D.; Boyle,
T.; Partridge, L. J.; Blackburn, G. M. Proc. Natl. Acad. Sci.
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Nat. Prod. Rep. 2000, 535±577. (g) Blackburn, G. M.;
Garcon, A. 2nd ed., Biotechnology; Kelly, D. R., Ed.;
Wiley-VCH: Weinheim, 2000; Vol. 8b, pp 403±490.
1
EtOAc: 9/1) gave 15 (2.6 g, 93%) as a colourless oil; H
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3
3
2H, Jˆ6.50 Hz), 2.62 (t, 2H, Jˆ7.25 Hz), 3.71 (s, 3H),
6.98 (d, 2H, Jˆ8.00 Hz), 7.64 (d, 2H, Jˆ8.00 Hz); 13C
NMR (125.7 MHz, CDCl3): dˆ24.9, 31.1, 34.3, 35.5,
52.0, 91.2, 131.0, 137.8, 142.2, 174.4 (CO); FT-IR (®lm):
3
3
nˆ2946, 2859, 1737, 1485, 1435, 1200, 1173, 1006 cm21
;
GC±MS (CI1): m/z (%): 336.0 (100) [M1NH4]1; HRMS:
(C12H15IO2): [M1NH4]1) calcd: 336.0461, found:
336.0469.
4.1.12. 4-(4-Hydroxycarbonylbutylphenyl)-2,4,6-trimethyl-
phenyl-phosphinic acid (4b). Bromotrimethylsilane (1.1 ml,

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