A simple enantioselective preparation of (2S,5S)-2,5-diphenylpyrrolidine and related diaryl amines

Article abstract of DOI:10.1016/S0957-4166(00)00208-1

A short efficient catalytic asymmetric route to the preparation of C₂-symmetric diaryl cyclic amines is described. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00208-1

Tetrahedron: Asymmetry 11 (2000) 2455±2462
A simple enantioselective preparation of
(2S,5S)-2,5-diphenylpyrrolidine and related diaryl amines
David J. Aldous,b William M. Duttona and Patrick G. Steela,*
aDepartment of Chemistry, University of Durham, Science Laboratories, South Road, Durham DH1 3LE, UK
bAventis, Rhainham Road, Dagenham, Essex RM10 7XS, UK
Received 8 April 2000; accepted 24 May 2000
Abstract
A short ecient catalytic asymmetric route to the preparation of C2-symmetric diaryl cyclic amines is
described. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The use of C2-symmetric chiral auxiliaries is an area of considerable importance in current
asymmetric synthesis.1 One of the most popular and useful classes of these reagents are the trans
2,5-disubstituted pyrrolidines pioneered by Whitesell2 and subsequently by many others. When,
in the course of another project, we sought to examine the use of a C2-symmetric diamine chiral
auxiliary we explored the preparation of the 2,5-dimethyl derivative 4 using the enantioselective
deprotonation strategy developed by Beak, Scheme 1.3
Scheme 1.
* Corresponding author. E-mail: p.g.steel@durham.ac.uk
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00208-1

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Whilst this approach was successful we had diculties in scaling up the procedure and in the
recovery and recycling of the chiral auxiliary. This problem can be overcome through the use of
the corresponding diphenyl analogue 5; a non-volatile, stable crystalline compound which can be
prepared following a strategy of enantioselective reduction of 1,4-diphenyl-1,4-butanedione and
cyclisation of the resultant diol, Scheme 2.4,5
Scheme 2.
Partly due to the need to generate such C2-symmetric species there has been considerable e€ort
directed towards the stereoselective reduction of diketones.6 12 With a view towards the pre-
paration of the diphenylpyrrolidine, two procedures involving either the asymmetric reduction
with diisopinocampheylchloroborane4 or the reduction with borane and an oxazaborolidine
catalyst, have been reported.5 However, neither process is ideal. Although the former can be
easily adapted to prepare either enantiomer, the reagent must be prepared (or purchased) and the
removal of the chiral auxiliary from the product mixture is non-trivial and requires considerable
time. The oxazaborolidine method requires considerable care and time in the preparation of the
chiral catalyst to achieve good selectivities.13 Although this is simpli®ed through the in situ pro-
cedure developed by Quallich et al.14 it is still necessary to premix the chiral auxiliary and borane
for 18 h to generate the catalyst. Furthermore, good diastereoselectivity (84:16) and enantio-
selectivity (>99:<1) is only obtained with the use of stoichiometric amounts of oxazaborolidine.
We sought a simpler more e€ective protocol and were attracted by a report from Masui and
Shioiri that indicated that extremely e€ective oxazaborolidine catalysts can be easily and rapidly
generated in situ from an aminoalcohol and trimethyl borate (1 h at room temperature).15 They
reported that these catalysts were e€ective in the reduction of simple arylketones. In this paper we
report that they also represent an extremely attractive option for the selective reduction of related
diketones and hence the preparation of 2,5-diarylpyrrolidines.
2. Results and discussion
The required diphenylbutanedione 6 can be easily prepared following established protocols by
Friedel±Crafts acylation of benzene with fumaroyl chloride and subsequent reduction of the
alkene with sodium dithionate.16,17 The use of benzene may be avoided by an equally ecient
procedure involving ceric ammonium nitrate mediated oxidative coupling of the silylenol ether of
acetophenone.18
Following the procedure of Masui, slow addition of this dione to a solution of in situ prepared
B-methoxy oxazaborolidine (0.1 equiv.) derived from diphenylprolinol 7 and borane dimethyl-
sul®de complex (1 equiv.) a€orded, after a further 1 h at room temperature and aqueous work up,
the desired diol in excellent yield (96%) and stereoselectivity (>95% de and 99% ee), Scheme 3.

D. J. Aldous et al. / Tetrahedron: Asymmetry 11 (2000) 2455±2462
2457
The process is simple and amenable to scale upÐwe have repeated the procedure using up to 10 g
of dione without any loss in yield or selectivity. With the diol in hand we were able to convert this
to the desired pyrrolidine using the ecient methodology reported by Chong.
Scheme 3.
The diastereoselectivity is noteworthy in that it is considerably higher than that obtained with
the related oxazaborolidines used by other workers in the reduction of diones (B-H, B-alkyl, B-aryl).
This can possibly be attributed to the increased Lewis acidity of the boron centre allowing the
catalyst to more e€ectively overcome substrate controlled selectivity which leads to the meso isomer.19
We were curious to see if this would provide a general method for the prepartion of these C2-
symmetric diamines and examined the reduction of a number of other simple diones varying the
nature of the substituents. Those substrates which are not readily available were prepared in an
analogous fashion to that described above. All the reductions were carried out in an identical
fashion and we have made no attempt to signi®cantly optimise the yields of these reactions, Table 1.
As can be seen from Table 1, 2,5-hexanedione (R=Me) 9 is not a viable substrate for selective
reduction. This is consistent with Quallich's observations for the B-H oxazaborolidines although in
this case the opposite sense of asymmetric induction is observed as ascertained by a comparison
Table 1
Catalytic enantioselective reduction of diones 9±12

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D. J. Aldous et al. / Tetrahedron: Asymmetry 11 (2000) 2455±2462
of [ꢀ]D values. The reason for this change is not obvious at the present time. As with these earlier
reports, increasing the tether length has little e€ect on the selectivity; 1,5-diphenylpentane-1,5-
diol 16 being produced with both good de and ee.
Interestingly, 1,4-di-20-naphthylbutane-1,4-dione 11 proved to be resistant to reduction. Given
that 2-acetonaphthone is an excellent substrate for asymmetric reduction (>99% ee) with this
procedure, we attribute this to interactions (p-stacking) between the aromatic nucleus and the
carbonyl group which inhibits binding of the catalyst and shields the carbonyl group from attack
by the borane. Evidence for this arises from the 13C NMR spectra in which the carbonyl carbon
appears at ꢁ=198 for acetonapthone and ꢁ=209 for the dione 11.
With the exception of the bis tert butyl diol 15, which proved resitant to nucleophilic dis-
placement, all the diols could be eciently converted to the C2-symmetric cyclic diamines by the
same sequence of mesylation, double displacement with allylamine and ®nal deprotection using
Wilkinson's catalyst. In the case of the piperidine derivative a small amount of the corresponding
meso isomer was detected after the cyclisation step. We presume that this arises through the
intermediacy of a benzylic cation.
In conclusion, the catalytic enantioselective reduction of a,o-diaryldiones to the corresponding
diol can be simply and rapidly achieved using the Masui protocol. This allows an ecient catalytic
asymmetric synthesis of C2-symmetric diaryl cyclic amines to be easily realised. Aliphatic ketones
are less satisfactory substrates and the corresponding diols are best accessed via the reduction of
the corresponding unsaturated species20 or via enzymatic reduction.21
3. Experimental
All air and/or moisture sensitive reactions were carried out under an argon atmosphere. Solvents
were puri®ed following established protocols.22 Petrol refers to petroleum spirit boiling in the 40±
60ꢀC range. Ether refers to diethyl ether. Commercially available reagents were used as received
unless otherwise stated. Diones were prepared following established literature procedures. Yields
refer to isolated yields of products of greater than 95% purity as determined by 1H and 13C NMR
spectroscopy or elemental analysis (Durham University, Microanalytical Laboratory).
Infrared (IR) spectra were recorded on a Perkin±Elmer FT-IR 1720X spectrophotometer, in a
liquid ®lm (NaCl plates), solution cell (CHCl3), KBr disk, or on the above machine ®tted with
Graseby Specac Single Re¯ection Diamond ATR (10500 series) `Golden Gate' accessory, as speci®ed
in the text. Nuclear magnetic resonance (NMR) spectra were obtained on a Varian VXR-400 (1H
at 399.968 MHz, 13C at 100.572 MHz), Varian Oxford Unity 300 (1H at 299.908 MHz, 13C at
75.412 MHz) and a Varian Oxford Mercury 200 (1H at 199.975 MHz, 13C at 50.289 MHz)
spectrometer with deuterochloroform as solvent. Chemical shifts are recorded in ppm (ꢁ units)
relative to residual CHCl3 (ꢁ(1H)=7.26, ꢁ(13C)=77.0), unless otherwise stated. Splitting patterns
are described as singlet (s), doublet (d), triplet (t), quartet (q), or multiplet (m). Coupling constants
were recorded in hertz. All 13C spectra were proton decoupled. Mass spectra (EI and CI) were
recorded on either a VG Analytical 7070E or a Micromass Autospec mass spectrometer. GC±MS
was performed using a Hewlett±Packard 5890 Series II GC, equipped with a 25 m SE30 column,
connected to a VG Mass Lab Trio 1000. Chiral HPLC was carried out using a Varian Star HPLC
system using a Chiracel OD column. Optical rotations were measured on an Optical Activity
LTD AA-10 Automatic Polarimeter. Melting points were determined using a Gallenkamp melting
point apparatus and are uncorrected.

D. J. Aldous et al. / Tetrahedron: Asymmetry 11 (2000) 2455±2462
2459
Reactions were followed by gas chromatography (GC) using Perkin±Elmer 8410 GC with a SA50
column or by thin-layer chromatography (TLC). Flash column chromatography was performed
according to the method of Still et al. using 200±400 mesh silica.23
3.1. General dione reduction procedure
3.1.1. (1R,4R)-1,4-Diphenylbutan-1,4-diol 8
To a stirred solution of a,a-diphenyl-2-pyrrolidine methanol 7 (2 g, 8 mmol) in THF (50 ml) at
room temperature, trimethyl borate (B(OMe)3) (1.15 ml, 10 mmol) was added and stirred for 1 h.
After borane±dimethyl sul®de complex (9.27 ml, 98 mmol) was added, a solution of the diketone
1,2-dibenzoylethane 6 (11 g, 46.2 mmol) in THF (100 ml) was added over an hour. After a further
hour, the resulting mixture was slowly quenched with 2N HCl (69 ml). The aqueous layer was
extracted with ether (3Â100 ml) before the combined organic extracts were washed with H2O and
brine, dried (MgSO4) and concentrated in vacuo. The resulting oil was puri®ed by ¯ash chroma-
tography (eluting with 35% ethyl acetate in petrol) to give the title diol 8, as a colourless oil
(10.7 g, 96%). ‰ꢀŠ2D5=+58 (c 1.02, CHCl3) (lit.4 ^58.5 (c 1.01, CHCl3, >98% ee) for S,S isomer).
ꢂ
max (thin ®lm); 3339 (OH), 3025 (Ar), 1207 (CH), 990 cm^1. ꢁH (300 MHz); 7.3±7.1 (10H, m, Ph),
4.58 (2H, br s, CHOH), 3.0 (2H, br s, OH), 1.84±1.6 (4H, m, CH2). ꢁC (75 MHz); 144.6, 128.1,
127.0, 125.6 (Ar), 74.3 (HCOH), 35.1 (CH2). m/z (EI); 242 (M+), 224, 118 (100%), 107, 79.
3.1.2. (2R,5R)-Hexan-2,5-diol 13
In an identical fashion to that described above hexan-2,5-dione 9 (3 g, 26 mmol) was reduced
to give, following ¯ash chromatography (eluting with 40% ethyl acetate in petrol), hexandiol 13,
as a colourless oil which solidi®ed on standing (2.27 g, 74%). dl:meso 61:39 (GC/13C NMR). Mp
(48±51ꢀC, lit.21 53.0±53.3ꢀC). ‰ꢀŠ2D5=^7 (c 1, CHCl3) (lit.21 +34.9 (c 9.48, CHCl3 for (2S,5S)-
hexan-2,5-diol >98% ee). ꢂmax (thin ®lm); 3346 (OH), 3003 (CH), 1378, 1307, 1052 cm^1. ꢁH (400
MHz); 3.77 (2H, m, CHOH), 2.58 (2H, br, OH), 1.48 (4H, m, CH2), 1.13 (6H, d, 2 Hz, CH3). ꢁC
(75 MHz); 68.37 (0.39C, meso-HCOH), 67.87 (0.61C, dl-HCOH), 35.97 (0.78C, meso-CH2), 34.98
(1.22C, dl-CH2), 23.80 (0.39C, meso-CH3), 23.46 (0.61C, dl-CH3).
3.1.3. (3R,6R)-2,2,7,7-Tetramethyloctan-3,6-diol 14
In an identical fashion to that described above 2,2,7,7-tetramethyloctan-3,6-dione 10 (396 mg,
0.2 mmol) was reduced to give, following ¯ash chromatography (eluting with 40% ethyl acetate
in petrol), diol 14, as a white crystalline solid (230 mg, 57%). dl:meso 86:14 (13C NMR). Mp 142±
143ꢀC. ‰ꢀŠD25=+37 (c 1, CH3OH) (lit.5 ^34.3 (c 1, CH3OH, 97% ee), lit.20 ^44.4 (c 0.94, CH3OH,
99% ee) for the (S,S) isomer). CHN: (found: C, 71.29; H, 13.01; C12H26O2 requires: C, 71.23; H,
12.95). ꢂmax (solution); 3417 (OH), 2962, 2869 (CH), 1478, 1383, 928 cm^1. ꢁH (300 MHz); 3.20
(2H, d, 10 Hz, CHOH), 2.35 (2H, br, OH), 1.7±1.3 (4H, m, CH2), 0.90 (18H, s, CH3). ꢁC (75 MHz,
CD3OD); 81.4 (0.14C, meso-HCOH), 80.2 (0.86C, dl-HCOH), 36.0 (CMe3), 30.4 (0.14C, meso-
CH2), 29.3 (0.86C, dl-CH2), 26.4 (CH3). m/z (CI); 203 (M++H), 185, 167, 127, 111, 97 (100%), 83.
3.1.4. (1R,5R)-1,5-Diphenylpentan-1,5-diol 16
In an identical fashion to that described above 1,2-dibenzoylpropane 12 (5 g, 20 mmol) was
reduced to give, following ¯ash chromatography (eluting with 35% ethyl acetate in petrol), the
title diol 16, as a crystalline solid (4.6 g, 91%). dl:meso 98:2 (HPLC). Mp 101±102ꢀC. ‰ꢀŠD25=+18
(c 1.0, methanol), +20 (c 2.0, methanol) (lit.5 ^22.8 (c 1.0, CH3OH, 99% ee)). CHN: (found: C,

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D. J. Aldous et al. / Tetrahedron: Asymmetry 11 (2000) 2455±2462
79.63; H, 7.94; C17H20O2 requires: C, 79.56; H, 7.86). ꢂmax (thin ®lm); 3321 (OH), 2935 (Ar), 2855
(CH), 1454, 1013 cm^1. ꢁH (400 MHz); 7.3±7.1 (10H, m, Ph), 4.59 (2H, m, CHOH), 2.1 (2H, br,
OH), 1.84±1.6 (4H, m, 2-H2, 4-H2), 1.4 (2H, m, 3-H2). ꢁC (100 MHz); 144.7, 128.4, 127.5, 125.8
(Ar), 74.4 (HCOH), 38.8 (C(2), C(4)), 22.2 (C(3)). m/z (CI); 239 (M+-OH), 221, 161, 117 (100%).
3.2. General procedure for cyclic amine synthesis
3.2.1. (2S,5S)-N-Allyl-2,5-diphenylpyrrolidine
To a solution of methanesulfonyl chloride (400 ml, 5.3 mmol) in DCM (20 ml) at ^20ꢀC was
added a solution of (1R,4R)-1,4-diphenylbutan-1,4-diol 8 (500 mg, 2.06 mmol) and triethylamine
(870 ml, 6.2 mmol) in DCM (20 ml). The mixture was stirred for 105 min at ^20ꢀC and then
quenched with satd NH4Cl (2 ml). The mixture was warmed to room temperature and solvent
removed in vacuo to approximately 17 ml. The solution was then diluted with ethyl acetate (80
ml) and washed with water:brine:satd NaHCO3 (1:2:1) (4Â20 ml), and satd NaHCO3 (2Â20 ml),
before being dried (MgSO4), ®ltered through Celite and concentrated in vacuo to approximately 8
ml. The solution was then cooled to 0ꢀC, set to stir and the crude dimesylate was precipitated out
by dropwise addition of hexane (80 ml). The resulting solid was recrystallized from ethyl acetate by
addition of hexane at 0ꢀC to yield the desired dimesylate, (1R,4R)-1,4-bis(methanesulfonyloxy)-
1,4-diphenylbutane, (680 mg, 82%) as a moderately unstable compound which was used directly
in the next step. ꢁH (200 MHz, C6D6); 7.21±7.00 (10H, m, Ph), 5.74±5.70 (2H, m, CHOMs), 2.05±
1.84 (4H, m, CH2), 2.01 (6H, s, SO2CH3).
Allyl amine (25 ml, 0.33 mol) was added to a cooled ¯ask (0ꢀC) containing the dimesylate (670
mg, 1.68 mmol) and the resultant solution stirred at this temperature for 14 h. After warming to
room temperature, the excess allyl amine was removed in vacuo and the residue dissolved in ether
(70 ml) and washed with satd NaHCO3 (2Â25 ml) and brine (25 ml), dried (MgSO4) and con-
centrated to a€ord the crude product as a yellow oil. Flash chromatography (eluting with 3%
ether/petrol) yielded the diastereomerically pure title amine as a colourless oil (330 mg, 75%
yield). [ꢀ]D=^115 (c 0.56, CHCl3) (lit.4 +115.1 (c 1.40, CHCl3) for (R,R) isomer). CHN: (found:
C, 86.38; H, 7.93; N, 5.57; C19H21N requires: C, 86.65; H, 8.04; N, 5.32). ꢂmax (thin ®lm); 3070,
2967, 2817, 1640, 1071, 916 cm^1. ꢁH (300 MHz); 7.41±7.20 (10H, m, Ph), 5.7±5.55 (1H, m,
CHˆCH2), 4.92±4.87 (2H, m, CHˆCH2), 4.32±4.30 (2H, m, CHPh), 2.95±2.68 (2H, m, NCH2),
2.60±2.45 (2H, br, m, 3,4-CH), 2.01±1.90 (2H, br m, 3,4-CH0). ꢁC (75 MHz); 144.6, 137.2, 128.5,
128.2, 127.1 (Ar, HCˆCH2), 115.9 (HCˆCH2), 65.9 (PhCHN), 50.2 (NCH2CHˆ), 33.5
(CH2CH2). m/z (EI); 263 (M+, 30%), 262, 186 (100%), 91.
3.2.2. (2S,5S)-2,5-Diphenylpyrrolidine 5
(S,S)-N-Allyl-trans-2,5-diphenylpyrrolidine (2.56 g, 9.72 mmol) and (Ph3P)3RhCl (Wilkinson's
catalyst, 44 mg, 0.047 mmol) was dissolved in 25 ml of 84:16 w/w acetonitrile:water mixture and
placed in a 50 ml three-necked ¯ask ®tted with distillation head and dropping funnel. The mixture
was purged with nitrogen gas and heated to boiling. The solvent level was maintained via the drop-
ping funnel and the reaction heated for 5 h. The reaction was then cooled to room temperature
and diluted with 40 ml ether. The layers were separated and the organic layer washed with brine
(2Â20 ml), and the combined aqueous washes were back extracted with ether (10 ml). The combined
organic extracts were dried (MgSO4) and concentrated in vacuo. The resulting oil was puri®ed by
¯ash chromatography (eluting with 33% ethyl acetate in petrol) to yield the desired amine 5 (192
mg, 89%) as a yellow oil which solidi®ed overnight. Mp 43.0ꢀC. [ꢀ]D=^108.2 (c 0.45, CHCl3)

D. J. Aldous et al. / Tetrahedron: Asymmetry 11 (2000) 2455±2462
2461
(lit.4 +104.5 (c 1.00, CHCl3) >98% ee). CHN: (found: C, 86.23; H, 7.63; N, 6.17; C16H17N
requires: C, 86.05; H, 7.67; N, 6.27). ꢂmax (thin ®lm); 3360, 3055, 2962, 2867, 1598, 1489, 1450,
1402 cm^1. ꢁH (200 MHz); 7.5±7.1 (10H, m, Ar), 4.5 (2H, t, PhCHN), 2.4±2.3 (2H, m, 3,4-CH),
2.3 (1H, br NH), 1.9±1.8 (2H, m, 3,4-CH0). ꢁC (75 MHz); 145.7, 128.2, 126.5, 126.1 (Ar), 62.1
(NCHPh), 35.3 (CH2CH2). m/z (EI); 223 (M+, 31%), 222, 195 (100%).
3.2.3. (2S,6S)-N-Allyl-2,6-diphenylpiperidine
In an identical fashion to that described above (1R,5R)-1,5-diphenylpentan-1,5-diol 17 was
converted to (R,R)-1,5-bis(methanesulfonyloxy)-1,5-diphenylpentane, ꢁH (300 MHz); 7.42±7.2
(10H, m, Ph), 5.42 (2H, m, CHOMs), 2.02 (6H, s, SO2CH3), 1.81±1.67 (4H, m, CH2), 1.38 (2H, m,
CH2), and subsequently cyclised with allyl amine to give, following ¯ash chromatography (eluting
with 3% ethyl acetate in petrol), (2S,6S)-N-allyl-2,6-diphenylpiperidine as a colourless oil (2.13 g,
72%) accompanied by a small amount of the meso isomer (R,S/S,R)-N-allyl-2,6-diphenylpiper-
idine (GC ratios, 94.3:5.7%). [ꢀ]D=^80 (c 0.56, CHCl3). CHN: (found: C, 86.45; H, 8.29; N, 4.94;
C20H23N requires: C, 86.59; H, 8.36; N, 5.05). ꢂmax (thin ®lm); 3059, 2932, 2862, 1640, 1600, 1492,
1448, 915 cm^1. ꢁH (400 MHz); 7.4±7.1 (10H, m, Ph), 5.8±5.6 (1H, m, CHˆCH2), 4.98 (1H, d, 6
Hz, CHˆCH2), 4.94 (1H, s, CHˆCH2), 4.10 (2H, dd, 6.5 Hz, 4.5 Hz, CHPh), 3.05±2.8 (2H, m,
NCH2), 1.8±1.6 (2H, m, 4-CH2), 2.01±1.90 (br m, 4H, 3,5-CH2). ꢁC (100 MHz); 144.3, 137.5,
128.3, 128.2, 128.0, 126.3 (Ar, HCˆCH2), 115.8 (HCˆCH2), 58.6 (PhCHN), 50.9 (NCH2CHˆ),
27.7 (C(3)H2), 19.8 (C(4)H2); m/z (GC±MS, EI) (cis: rt 21.48 min; 277 (M+), 200 (100%), 144,
117, 91, 77) (trans: rt 22.28 min; 277 (M+), 200 (100%), 144, 117, 104, 91, 77).
3.2.4. (2S,6S)-trans-2,6-Diphenylpiperidine
In an identical fashion to that described above (2S,6S)-N-allyl-trans-2,6-diphenylpiperidine (1 g,
3.6 mmol) was treated with (Ph3P)3RhCl (166 mg, 0.18 mmol) to give, following ¯ash chroma-
tography (eluting with 33% ethyl acetate in petrol), the title amine (642 mg, 75%) as a yellow
solid. Mp 45±46ꢀC. [ꢀ]D=^81.2 (c 5, EtOH) (lit.24 +70.1 c 4.63, EtOH (c 4.63, EtOH) for the (R,R)
isomer). CHN: (found: C, 85.82; H, 8.97; N, 6.04; C17H19N requires: C, 86.03; H, 9.07; N, 5.90).
ꢂ
max (Golden Gate); 3359, 3058, 2951, 2867, 1486, 1448, 1401 cm^1. ꢁH (300 MHz); 7.3±7.1 (10H,
m, Ar), 3.99 (2H, bt, PhCHN), 2.2 (1H, br NH), 1.9±1.75 (4H, m, 3,5-CH2), 1.6 (2H, m, 4-CH2).
ꢁC (75 MHz); 144.9, 128.1, 126.8, 126.3 (Ar), 59.4 (NCHPh), 28.3 (C(2,4)H2), 18.7 (CH2). m/z
(EI); 237 (M+, 31%), 160, 181 (100%).
Acknowledgements
We thank the EPSRC and Aventis for ®nancial support of this work (CASE studentship to
W.M.D.), Dr. A. M. Kenwright for assistance with NMR experiments, Dr. M. Jones for mass
spectra and Mr. L. Lauchlan for HPLC.
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