Synthesis of heterodisaccharide-containing peptides, fragments of actinoidin antibiotics

Article abstract of DOI:10.1039/a802053a

Prototypes corresponding to glycopeptide fragments of actinoidin antibiotics have been synthesized using an L-acosaminyl-D-glucose-containing heterodisaccharide linked to 4-hydroxyphenylglycine as pivotal synthon. This latter compound has been obtained by coupling of a suitably protected D-glucopyranosyl bromide with the blocked amino acid, followed by selective deprotection of the glucopyranosyl moiety at C-2 and subsequent stereospecific attachment of the acosaminyl unit.

Full text of DOI:10.1039/a802053a

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Synthesis of heterodisaccharide-containing peptides, fragments of
actinoidin antibiotics
Carole Mouton,a François Tillequin,a Elisabeth Seguinb and Claude Monneretc
a Laboratoire de Pharmacognosie de l’Université René Descartes, URA-CNRS 1310,
Faculté de Pharmacie, 4 Avenue de l’Observatoire, 75270 Paris cedex 06, France
b Laboratoire de Pharmacognosie UFR Médecine-Pharmacie, Université de Rouen,
Avenue de l’Université, BP 97, 76800 St Etienne du Rouvray, France
c UMR 176, CNRS-Institut Curie, Section Recherche, F-75248 Paris cedex 05, France
Prototypes corresponding to glycopeptide fragments of actinoidin antibiotics have been synthesized using
an L-acosaminyl-D-glucose-containing heterodisaccharide linked to 4-hydroxyphenylglycine as pivotal
synthon. This latter compound has been obtained by coupling of a suitably protected D-glucopyranosyl
bromide with the blocked amino acid, followed by selective deprotection of the glucopyranosyl moiety at
C-2 and subsequent stereospecific attachment of the acosaminyl unit.
OH
R
R
Introduction
OBn
O
O
Glycopeptide antibiotics such as vancomycin1 and, more
recently, teicoplanin1 are widely used in the treatment of
staphylococcal infections and considerable interest has been
devoted to their structural elucidation and synthesis.2,3
Although improvements have been registered4 in recent years
in the total synthesis of the peptide-antibiotic aglycons, total
syntheses of the carbohydrate portion are rather scarce. Many
of these representative antibiotics present a common structural
feature which is a heterodisaccharide side-chain. Thus, the
central phenolic ring of the peptide-based aglycons is bound
through a β-linkage to a glucosyl residue which is, in turn,
attached through a (2→1) α-linkage to an aminodeoxy sugar.
However the aminodeoxy sugar varies in the individual anti-
biotics, mainly in the stereochemistry and substitution at C-3
and C-4.
HO
HO
O
BnO
BnO
O
O
O
R1
CH3
H3C
HO
O
O
H3C
R2
NHBz
OBz
1 R1 = NH2, R2 = H
2 R1 = H, R2 = NH2
3 R = H
4 R = OCH3
OAc
OBn
O
O
AcO
AcO
O
BnO
BnO
O
O
O
A first paper appeared in 1986 from Bognar’s group,5 related
to the synthesis of phenyl β-acobioside 1, a derivative which
simulated the aryloxycarbohydrate domain of actinoidins.
More recently, in collaboration with this group, but using a
different strategy, we achieved the synthesis6 of a prototype
corresponding to avoparcins, namely phenyl β-avobioside 2.
Simultaneously, Dushin and Danishefsky published7 a stereo-
specific synthesis of fully protected aryl β-glucosides such as
compounds 3 and 4 simulating the heterodisaccharide part of
vancomycin. Closely related, these two last syntheses were
based upon the formation of an aryl β-glucoside selectively
deprotected at C-2 and upon a subsequent attachment of a
ristosamine- (for compound 2) or a vancosamine-based glycal
(for compounds 3 and 4) as glycosyl donors, in the presence of
trimethylsilyl triflate and camphorsulfonic acid as catalyst,
respectively.
The purpose of the present investigation was to attempt pro-
gress in the synthesis of prototypes corresponding to more
complex glycopeptide fragments of these antibiotics, in order to
examine subsequently their interaction with the model peptide-
ligand (diacetyl--lysyl--alanyl--alanine, DALAA) which
correlated8 with the antibacterial potency of close analogues of
vancomycin.
Me
Me
OMe
OMe
5
6
of the protecting groups or of the 1,2-trans-di-O-acetyl-
glucopyranoside 711 with a phenol. However, whereas we suc-
ceeded in coupling both glucose derivatives with phenol itself,
no glycosidation occurred with the aryloxyhydroxy moiety as
present in the glycine derivative 9. Therefore diacetate 7 was
converted into the glucopyranosyl bromide 8 by a known pro-
cedure12 and identified with literature data.13 Glycosylation
of compounds 8 with 9 was achieved in acceptable yield
(47%) under phase-transfer conditions (BnEt3NBr, aq. KOH,
CHCl3)14 to give compound 10.
Next, in order to obtain access to the heterodisaccharide
unit, selective 2-O-deprotection of compound 10 was realized
under Zemplen conditions (NaOMe–MeOH). This led to ester
11 in 83% yield, resulting from concomitant replacement of the
benzyl ester as present in 10 by methyl ester. At the same time,
the acosamine-based glycal 13 was obtained from the trifluoro-
acetamido precursor 12, which was synthesized in a few steps
from di-O-acetyl--rhamnal by our own procedure.15 Glyco-
sylation of alcohol 11 with compound 13 [trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf), CH2Cl2 and then Et3N]
afforded the glycopeptide 14 in 85% yield, having the amino
function of the amino acid moiety selectively deprotected in the
course of the reaction. Coupling of compound 14 with N-Boc-
-phenylalanine 15 was effected by 2-chloro-4,6-dimethoxy-
1,3,5-triazine (CDMT) and N-methylmorpholine activation,16
using one molar equivalent of each component. This led to
Results and discussion
We decided first to use the same successful strategy we
developed in our previous approach, i.e. coupling of the
orthoester 69 readily prepared from triacetate 510 by exchange
J. Chem. Soc., Perkin Trans. 1, 1998
2055

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RHN
compound 17 in 86% yield, isolated as a crystalline compound.
However, since cleavage of the tert-butylcarbamate protection
of the terminal amino acid proved to be relatively difficult and
led to side-products when drastic conditions were attempted,
repetitive coupling of compound 14 was carried out with the
corresponding N-Z--phenylalanine 16. This coupling was
performed in the presence of 1-hydroxybenzotriazole (HOBT)
and 3-ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydro-
chloride (EDCI) to give the disaccharide-dipeptide 18 in high
yield (84%).
RHN
O
OBn
HO2C
NH
O
BnO
BnO
O
15 R = Boc
16 R = Z
CO2CH3
O
14
H3C
AcO
O
17 R = Boc
18 R = Z
NHCOCF3
Access to more complex glycopeptides was then attempted in
experiments using the glycopeptide 14 as pivotal synthon. For
instance, compound 14 was first condensed with N-Z--phenyl-
alanyl--phenylalanine17 19 in the presence of HOBT and
EDCI, to afford the glycopeptide 20 in 78% yield.
14
N-Z-L-Phe-L-Phe
19
OBn
O
NHZ
BnO
BnO
R1
AcO
R2
O
HN
7 R1 = OAc, R2 = H
8 R1 = H, R2 = Br
O
OBn
O
NH
BnO
BnO
O
CO2CH3
O
NHBoc
HO
H3C
AcO
CO2Bn
9
O
20
NHCOCF3
OBn
NHBoc
O
BnO
O
ZHN
BnO
COR2
OR1
L-Phe-L-Phe-OBut 21
Z-D-(Ph)Gly-L-Phe-L-Phe-OBu
N-Z-D-ph-Gly-L-Phe-L-Phe
O
10 R1 = Ac, R2 = Bn
11 R1 = H, R2 = CH3
NH
NH
t 22
23
O
H3C
HN
O
14
RO
O
OBn
NHCOCF3
12 R = H
13 R = Ac
O
BnO
BnO
O
CO2CH3
O
13
11
H3C
AcO
O
24
NHCOCF3
OBn
NH2
example of a glycopeptide synthesis involving an aminodeoxy
sugar unit. This strategy based upon the stereospecific glyco-
sylation of an acosamine derivative with a suitably protected
-4-hydroxyphenylglycyl glucoside may allow access to a large
series of glycopeptide-containing heterodisaccharides.
O
BnO
BnO
O
CO2CH3
O
O
H3C
AcO
NHCOCF3
14
Experimental
The second target 24 was a tetrapeptide derivative of the
heterodisaccharide. This compound was obtained in good yield
(83%) by coupling of compound 14 with the tripeptide N-Z-
-phenylglycyl--phenylalanyl--phenylalanine 23 under the
same conditions as above. For its part, free acid 23 was syn-
thesized in three steps and 73% overall yield from N-Z--
phenylalanyl--phenylalanine tert-butyl ester:18 (i) hydro-
genolysis; (ii) condensation of the resulting dipeptide 21 with
N-Z--phenylglycine19 (EDCI, HOBT); (iii) acid hydrolysis of
N-Z--phenylglycyl--phenylalanyl--phenylalanine tert-butyl
ester 22.
Mps were taken on a hot plate Reichert microscope. Optical
rotations were measured on a Perkin-Elmer 241 polarimeter
and values ([α]D20) are given in units of 10Ϫ1 deg cm2 gϪ1. IR were
recorded on a Perkin-Elmer 1600 FT-IR spectrometer. 13C
NMR spectra were recorded at 75 MHz and 1H NMR spectra
were recorded at 300 MHz using a Bruker AC 300 spectrometer.
Coupling constants (J) are given in Hz. Protons and carbons of
phenylglycine, 4-hydroxyphenylglycine and phenylalanine of
compounds 10, 11, 14, 17, 18, 20 and 24 are referred to as P, PЈ,
F1 and F2, respectively in the NMR descriptions of those com-
pounds. Chemical ionization mass spectra (CI-MS; NH3,
positive-ion mode) were recorded on a Nermag R 10-10C spec-
trometer. Electrospray ionization mass spectra (ESI-MS) were
acquired with a quadrapole instrument with a mass of charge
In summary, an efficient synthesis of a prototype of an
actinoidin fragment of a glycopeptide antibiotic has been
achieved. So far, this represents, to our knowledge, the first
2056
J. Chem. Soc., Perkin Trans. 1, 1998

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(m/z) range of 2000. The Nermag R 10-10 mass spectrometer
used was equipped with an analytical atmospheric pressure
electrospray source. Microanalyses were performed by the
‘Service de Microanalyse ICSN-CNRS-91198 Gif sur Yvette’
(France).
phenylglycine benzyl ester 9 (629 mg, 1.76 mmol) and 2-O-
acetyl-3,4,6-tri-O-benzyl-α--glucopyranosyl bromide 8 (940
mg, 1.76 mmol) in chloroform (10 cm3) was added a solution
of benzyltriethylammonium bromide (480 mg, 1.76 mmol) in
1.25  aq. potassium hydroxide (6 cm3). The reaction mixture
was vigorously stirred under reflux for 15 h. After cooling to rt
it was diluted with water (80 cm3) and extracted with chloro-
form (100 cm3). The organic layer was washed with 1.25  aq.
potassium hydroxide (2 × 90 cm3), dried (MgSO4), and evapor-
ated under reduced pressure. The residue was purified by
column chromatography on silica gel (20–45 µm) with cyclo-
hexane–ethyl acetate (85:15 v/v) as eluent to give the benzyl
ester 10 as a pale yellow oil (693 mg, 47%), [α]D20 Ϫ9 (c 0.9,
3,4,6-Tri-O-acetyl-1,2-O-(1-methoxyethylidene)-á-D-gluco-
pyranose10
5
To a solution of α-acetobromoglucose (6.2 g, 15 mmol) and
TBAB (7.3 g, 22.5 mmol) in anhydrous dichloromethane was
added, under argon, DMF dimethyl acetal (3 cm3, 22.5 mmol).
After being stirred at 40 ЊC for 24 h, the reaction mixture was
diluted with chloroform (100 cm3) and washed with a mixture
of water–triethylamine (99:1 v/v) (50 cm3). The organic layer
was dried (MgSO4), evaporated under reduced pressure, and the
residue was purified by column chromatography on silica gel
(35–70 µm) using cyclohexane–ethyl acetate–triethylamine
(60:40:1 v/v/v) as eluent to give 3,4,6-tri-O-acetyl-1,2-O-(1-
methoxyethylidene)-α--glucopyranose 5 as 6:1 (NMR) exo/
endo mixture, as a pale yellow oil (5.3 g, 96%), νmax(film)/cmϪ1
CHCl3); νmax(film)/cmϪ1 3429 (NH), 2944, 1748 (C᎐O), 1509,
᎐
1222 and 1162 and 1068 (C᎐O); δH(CDCl3) 1.46 (9 H, s, But),
2.00 (3 H, s, OCOCH3), 3.64–3.86 (5 H, m, 3-, 4- and 5-H,
6-H2), 4.50–4.90 (6 H, m, 3 × CH2Ph), 4.96 (1 H, d, J1,2 8, 1-H),
5.17 [1 H, d, JA,B 12, HA(CO2CH2)], 5.27 (2 H, m, 2-H and
CHP), 5.36 [1 H, d, JA,B 12, HB(CO2CH2)], 5.61 (1 H, d, JNH,CHP
7, NH), 7.00 (2 H, d, J5Ј,2Ј = J3Ј,6Ј = 8, 3Ј- and 5Ј-HP) and 7.20–
7.40 (22 H, m, ArH); δC(CDCl3) 20.7 (OCOCH3), 28.2
[(CH3)3C], 57.0 (CHP), 67.1 (CO2CH2), 68.5 (6-C), 72.7 (2-C),
73.4 (CH2Ph), 75.0 (2 × CH2Ph), 75.3 (5-C), 77.7 (4-C), 80.0
[(CH3)3C], 82.6 (3-C), 99.1 (1-C), 117.0 (3Ј- and 5Ј-CP), 127.6–
128.3 (Ar-C), 131.1 (1Ј-CP), 135.0 (1Љ-CP), 137.3 and 137.6
[Cq(Ph)], 154.6 (4Ј-CP), 157.2 (OCONH) and 169.3 and 170.9
(OCOMe and CO2Bn); m/z (ES) 854 (M ϩ Na)ϩ.
2952, 1747 (C᎐O), 1436, 1370, 1228 and 1041 (C᎐O); δ (CDCl )
᎐
H
3
1.55 (3 H, s, endo-CH3), 1.70 (3 H, s, exo-CH3), 2.08 (9 H, 3s,
3 × OCOCH3), 3.27 (3 H, s, exo-OCH3), 3.44 (3 H, s, endo-
OCH3), 3.93 (1 H, dt, J5,4 9, J5,6 4.5, 5-H), 4.18 (2 H, d, J6,5 4.5,
6-H2), 4.31 (1 H, ddd, J2,1 5, J2,3 3, J2,4 1, 2-H), 4.88 (1 H, ddd,
J4,5 9, J4,3 3, J4,2 1, 4-H), 5.18 (1 H, t, J3,4 = J3,2 = 3, 3-H), 5.65
(1 H, d, J1,2 5, endo-1-H) and 5.70 (1 H, d, J1,2 5, exo-1-H);
δC(CDCl3) 20.0 (CH3), 20.7 (OCOCH3), 50.9 (OCH3), 63.0
(6-C), 66.9 (5-C), 68.1 (4-C), 70.0 (3-C), 73.0 (2-C), 96.8 (1-C),
121.5 (C-Me), 169.1 and 169.6 and 170.6 (3 × OCOCH3); m/z
(CI) 363 (M ϩ H)ϩ and 380 (M ϩ NH4)ϩ.
N-Boc-4-(3,4,6-tri-O-benzyl-â-D-glucopyranosyloxy)-D-phenyl-
glycine methyl ester 11
A solution of benzyl ester 10 (692 mg, 0.83 mmol) in dry
methanol was treated with anhydrous sodium methoxide (67
mg, 1.25 mmol) at rt for 16 h. The reaction mixture was neutral-
ized by addition of Amberlite IRC 50Hϩ resin. The solution
was filtered and the filtrate was evaporated under reduced pres-
sure. The residue was purified by column chromatography on
silica gel (20–45 µm) with cyclohexane–ethyl acetate (80:20 v/v)
as eluent to give the methyl ester 11 as a powder (493 mg, 83%),
which was recrystallized from cyclohexane, mp 64–65 ЊC; [α]D20
Ϫ2 (c 1, CHCl3) (Found: C, 68.8; H, 6.7. Calc. for C41H47NO10:
C, 68.97; H, 6.64%); νmax(film)/cmϪ1 3432 (NH), 2869, 1740 and
3,4,6-Tri-O-benzyl-1,2-O-(1-methoxyethylidene)-á-D-gluco-
pyranose (exo-orthoester)9 6
A solution of 3,4,6-tri-O-acetyl-1,2-O-methoxyethylidene-α--
glucopyranose 5 (5.3 g, 14.5 mmol) in dry methanol was treated
with anhydrous sodium methoxide (2.4 g, 43.5 mmol) at rt for
1 h. The reaction mixture was then concentrated under reduced
pressure. To a solution of the residue in DMF (200 cm3) was
added portionwise sodium hydride (1.75 g, 72.5 mmol). After
complete liberation of hydrogen, benzyl bromide (6.9 cm3, 58
mmol) was added dropwise and the reaction mixture was stirred
at rt for 3 h. The excess of reagents was destroyed by careful
treatment with methanol (60 cm3). After being stirred at rt
for 16 h, the reaction mixture was concentrated under reduced
pressure and the residue was diluted with water (400 cm3) and
extracted with diethyl ether (3 × 200 cm3). The combined
extracts were successively washed with saturated aq. sodium
hydrogen carbonate (200 cm3) and water (200 cm3), dried
(MgSO4), and evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel (35–70
µm) with cyclohexane–ethyl acetate–triethylamine (85:15:1
v/v/v) as eluent to give 3,4,6-tri-O-benzyl-1,2-O-(1-methoxy-
ethylidene)-α--glucopyranose 6 as a pale yellow oil (6.0 g,
82%), [α]D20 ϩ38 (c 1, CHCl3) {lit.,9 [α]D20 ϩ36 (c 1, CHCl3)};
1714 (C᎐O), 1610, 1509, 1454, 1234 and 1163 and 1067 (C᎐O);
᎐
δH(CDCl3) 1.44 (9 H, s, But), 3.71 (3 H, s, OCH3), 3.60–3.89
(6 H, m, 2-, 3-, 4- and 5-H, 6-H2), 4.49–4.63 (4 H, m,
2 × CH2Ph), 4.84–5.01 (3 H, m, CH2Ph and 1-H), 5.29 (1 H,
d, J2P,NH 7, CHP), 5.55 (1 H, d, JNH,CHP 7, NH), 7.05 (2 H, d,
J5Ј,6Ј = J3Ј,2Ј = 8, 3Ј- and 5Ј-HP), 7.20–7.43 (17 H, m, ArH);
δC(CDCl3) 28.3 [(CH3)3C], 52.6 (OCH3), 56.9 (CHP), 68.7
(6-C), 73.4 and 75.0 and 75.2 (3 × CH2Ph), 74.3 and 75.3 and
77.3 (2-, 4- and 5-C), 80.1 [(CH3)3C], 84.3 (3-C), 100.7 (1-C),
117.2 (3Ј- and 5Ј-CP), 127.7–128.4 (Ar-C), 131.1 (1Ј-CP), 137.9
and 138.4 [Cq(Ph)], 152.7 (4Ј-CP), 157.2 (OCONH) and 167.0
(CO2Me); m/z (ES) 736 (M ϩ Na)ϩ.
4-O-Acetyl-1,5-anhydro-2,3,6-trideoxy-3-trifluoroacetamido-L-
arabino-hex-1-enitol 13
νmax(film)/cmϪ1 3030, 2869, 1758 (C᎐O), 1496, 1453, 1366, 1236
᎐
and 1059 (C᎐O); δH(CDCl3) 1.70 (3 H, s, CH3), 3.31 (3 H, s,
OCH3), 3.69 (2 H, d, J6,5 3, 6-H2), 3.75 (1 H, dd, J4.5 9, J4,3 4, 4-
H), 3.84 (1 H, dt, J5,4 9, J5,6 3, 5-H), 3.92 (1 H, t, J3,4 = J3,2 = 4,
3-H), 4.47 (1 H, dd, J2,1 5, J2,3 4, 2-H), 4.40–4.80 (6 H, m,
3 × CH2Ph), 5.82 (1 H, d, J1,2 5, 1-H) and 7.20–7.40 (15 H, m,
ArH); δC(CDCl3) 21.2 (CH3), 50.5 (OCH3), 69.1 (6-C), 70.4
(5-C), 71.8 and 72.9 and 73.3 (3 × CH2Ph), 74.8 (4-C), 75.8
(2-C), 78.6 (3-C), 97.7 (1-C), 121.3 (CMe), 127.6–128.3 (Ar-C),
137.6 and 137.8 and 137.9 (Ar-C); m/z (CI) 475, 492 and 524
(M ϩ NH4)ϩ.
1,5-Anhydro-2,3,6-trideoxy-3-trifluoroacetamido--arabino-
hex-1-enitol15 12 (344 mg, 1.60 mmol) was treated with acetic
anhydride (2 cm3) in pyridine at rt for 16 h. The reaction mix-
ture was concentrated under reduced pressure and the residue
was dissolved in ethyl acetate (25 cm3). The organic layer was
washed successively with cold 1  sulfuric acid (25 cm3), water
(25 cm3) and saturated aq. sodium hydrogen carbonate (25
cm3). The solvent was removed under reduced pressure to give
4-O-acetyl-1,5-anhydro-2,3,6-trideoxy-3-trifluoroacetamido--
arabino-hex-1-enitol 13 (366 mg, 85%) as a powder, which was
recrystallized from cyclohexane–ethyl acetate (85:15 v/v), mp
169–170 ЊC; [α]D20 Ϫ81 (c 0.5, CHCl3) (Found: C, 45.05; H, 4.5.
Calc. for C10H12F3NO4: C, 44.95; H, 4.53%); νmax(film)/cmϪ1
N-Boc-4-(2-O-acetyl-3,4,6-tri-O-benzyl-â-D-glucopyranosyl-
oxy)-D-phenylglycine benzyl ester 10
To a stirred solution of N-(tert-butoxycarbonyl)-4-hydroxy--
3290 (NH), 1729 (C᎐O), 1650 and 1455; δ (CDCl ) 1.30 (3 H, d,
᎐
H 3
J. Chem. Soc., Perkin Trans. 1, 1998
2057

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J6,5 6, 6-H), 2.12 (3 H, s, OCOCH3), 4.07 (1 H, dq, J5,4 9, J5,6 6,
5-H), 4.66 (1 H, dd, J2,1 6, J2,3 2, 2-H), 4.78 (1 H, ddt, J3,4 9,
J3,NH 7, J3,2 = J3,1 = 2, 3-H), 4.91 (1 H, t, J4,5 = J4,3 = 9, 4-H), 6.42
(1 H, dd, J1,2 6, J1,3 2, 1-H) and 6.85 (1 H, d, J 7, NH);
δC(CDCl3), 16.9 (6-C), 20.5 (OCOCH3), 49.2 (3-C), 72.8 and
73.0 (4- and 5-C), 99.0 (2-C), 115.6 (q, J 279, CF3), 146.0 (1-C),
152.7 (NHCO) and 171.1 (OCOMe); m/z (CI) 285 (M ϩ NH4)ϩ.
C60H68F3NO15: C, 63.87; H, 6.08%); νmax(film)/cmϪ1 3341 (NH),
1725 and 1670 (C᎐O), 1509, 1239 and 1165 and 1065 (C᎐O);
᎐
δH(CDCl3) 1.22 (3 H, d, J6Ј,5Ј 6, 6Ј-H3), 1.38 and 1.41 and 1.44 (9
H, s, But), 1.62 (1 H, m, 2Ј-Heq), 1.74 (1 H, s, NH), 1.91 (1 H, s,
NH), 2.02 (3 H, s, OCOCH3), 2.08 (1 H, m, 2Ј-Hax), 3.09 (2 H,
m, CH2F1), 3.70 (3 H, s, OCH3), 3.58–3.82 (5 H, m, 3-, 4- and
5-H, 6-H2), 3.93 (1 H, t, J2,1 = J2,3 = 8, 2-H), 4.27–4.42 (2 H, m,
3Ј- and 5Ј-H), 4.53 (1 H, d, J1,2 2, CHF1), 4.96 (1 H, d, J1,2 8,
1-H), 4.47–5.04 (7 H, m, 3 × CH2Ph and 4Ј-H), 5.34 (1 H, m,
1Ј-H), 5.47 (1 H, m, CHP), 6.84 (1 H, d, J 8, NH), 6.94–7.40
(24 H, m, ArH); δC(CDCl3) 17.5 (6Ј-C), 20.6 (OCOCH3), 28.2
[(CH3)3C], 35.4 (2Ј-C), 38.5 (CH2F1), 47.8 (3Ј-C), 52.7 (OCH3),
55.7 (CHP), 65.7 (5Ј-C), 68.4 (6-C), 74.9 and 73.4 (2 × CH2Ph),
75.2 (4Ј-C and CHF1), 75.6 (CH2Ph), 76.5 (2-C), 76.1 and 78.1
(4- and 5-C), 80.5 [(CH3)3C], 85.7 (3-C), 96.4 (1Ј-C), 98.9 (1-C),
116.9 (3Ј- and 5Ј-CP), 126.9–130.0 (Ar-C), 136.4 and 137.6 and
137.9 [Cq(Ph)], 157.0 (OCONH) and 170.5 and 170.7 and 172.1
(CO2Me, OCOMe and NHCO); m/z (ES) 1150 (M ϩ Na)ϩ.
4-[2-O-(4-O-Acetyl-2,3,6-trideoxy-3-trifluoroacetamido-á-L-
arabino-hexopyranosyl)-3,4,6-tri-O-benzyl-â-D-glucopyranosyl-
oxy]-D-phenylglycine methyl ester 14
A solution of N-Boc-4-(3,4,6-tri-O-benzyl-β--glucopyrano-
syloxy)--phenylglycine methyl ester 11 (929 mg, 1.30 mmol)
and
4-O-acetyl-1,5-anhydro-2,3,6-trideoxy-3-trifluoroacet-
amido--arabino-hex-1-enitol 13 (348 mg, 1.30 mmol) in
anhydrous dichloromethane (5 cm3) containing powdered
molecular sieves 4 Å was stirred under argon for 1 h at rt. The
reaction mixture was then cooled to Ϫ45 ЊC and stirred for 15
min, and then TMSOTf (252 mm3, 1.30 mmol) was added
dropwise. The mixture was stirred at Ϫ45 ЊC for 45 min and
allowed to warm to rt gradually overnight. After the reaction
had been quenched by addition of triethylamine (500 mm3), the
solution was filtered and the filtrate was evaporated under
reduced pressure. The residue was purified by column chrom-
atography on silica gel (35–70 µm) with dichloromethane–
methanol (97:3 v/v) as eluent to give title compound 14 as
a powder (980 mg, 85%), which was recrystallized from di-
chloromethane, mp 174–175 ЊC; [α]D20 Ϫ56 (c 0.1, CHCl3)
(Found: C, 62.55; H, 5.8. Calc. for C46H51F3NO12: C, 62.72; H,
N-(N-Z-L-phenylalanyl)-4-[2-O-(4-O-acetyl-2,3,6-trideoxy-3-
trifluoroacetamido-á-L-arabino-hexopyranosyl)-3,4,6-tri-O-
benzyl-â-D-glucopyranosyloxy]-D-phenylglycine methyl ester 18
To an ice-cooled solution of compound 14 (300 mg, 0.34
mmol), 1-hydroxybenzotriazole (HOBT) (51 mg, 0.37 mmol),
N-Z--phenylalanine 16 (102 mg, 0.34 mmol) and triethylamine
(57 mm3, 0.41 mmol) in dry DMF (20 cm3) was added EDCI
(78 mg, 0.41 mmol). The reaction mixture was stirred for 1.5 h
at 0 ЊC then for 16 h at rt. The solvent was removed under
reduced pressure and the residue was suspended in dichloro-
methane (50 cm3). The suspension was washed successively
with 1  hydrochloric acid (40 cm3), saturated aq. sodium
hydrogen carbonate (40 cm3) and brine (40 cm3). The organic
layer was dried (MgSO4), and evaporated under reduced pres-
sure. The residue was purified by column chromatography on
silica gel (35–70 µm) with dichloromethane–methanol (99:1
v/v) as eluent to give title compound 18 (333 mg, 84%) as a
powder, which was recrystallized from methanol, mp 217–
219 ЊC; [α]D20 Ϫ45 (c 0.5, CHCl3) (Found: C, 65.0; H, 5.7. Calc.
for C63H66F3N3O15: C, 65.11; H, 5.72%); νmax(film)/cmϪ1 3314
5.83%); νmax(film)/cmϪ1 3315 (NH), 2927, 2857, 1737 (C᎐O),
᎐
1509, 1454, 1376, 1238 and 1162 and 1066 (C᎐O); δH(CDCl3)
1.21 (3 H, d, J6Ј,5Ј 6, 6Ј-H3), 1.58 (1 H, m, 2Ј-Heq), 1.91 (2 H, s,
NH2), 2.06 (3 H, s, OCOCH3), 2.09 (1 H, m, 2Ј-Hax), 3.72 (3 H,
s, OCH3), 3.61–3.83 (5 H, m, 3-, 4- and 5-H, 6-H2), 3.93 (1 H, t,
J2,1 = J2,3 = 8, 2-H), 4.27–4.44 (2 H, m, 3Ј- and 5Ј-H), 4.61 (1 H,
s, CHP), 4.49–5.02 (7 H, m, 3 × CH2Ph and 4Ј-H), 4.99 (1 H, d,
J1,2 8, 1-H), 5.34 (1 H, dd, J1Ј,2Јax 3, J1Ј,2Јeq 1, 1Ј-H), 6.79 (1 H,
d, J 8, NH), 7.01 (2 H, d, J5ЈP,6ЈP = J3ЈP,2ЈP = 9, 3Ј- and 5Ј-HP)
and 7.16–7.40 (17 H, m, ArH); δC(CDCl3) 17.5 (6Ј-C), 20.6
(OCOCH3), 35.5 (2Ј-C), 48.0 (3Ј-C), 52.4 (OCH3), 58.1 (CHP),
65.7 (5Ј-C), 68.5 (6-C), 73.5 (4Ј-C), 75.0 and 75.2 (3 × CH2Ph),
76.6 (2-C), 75.6 and 78.2 (4- and 5-C), 85.8 (3-C), 96.6 (1Ј-C),
99.0 (1-C), 116.7 (3Ј- and 5Ј-CP), 127.4–128.5 (Ar-C), 134.4
and 137.6 and 137.9 [Cq(Ph)], 156.7 (4Ј-CP) and 172.1 and
174.5 (CO2Me and OCOMe); m/z (ES) 881 (M ϩ Na)ϩ.
(NH), 3064, 2948, 1742–1708 and 1678 (C᎐O), 1530, 1511,
᎐
1376, 1241–1166 and 1060 (C᎐O); δC(CDCl3) 1.22 (3 H, d, J6Ј,5Ј
6, 6Ј-H3), 1.62 (1 H, m, 2Ј-Heq), 1.94 (1 H, s, NH), 2.02 (3 H, s,
OCOCH3), 2.08 (1 H, m, 2Ј-Hax), 3.08 (2 H, m, CH2F1), 3.70 (3
H, s, OCH3), 3.59–3.83 (5 H, m, 3-, 4- and 5-H, 6-H2), 3.93 (1 H,
t, J2,1 = J2,3 = 8, 2-H), 4.27–4.43 (2 H, m, 3Ј- and 5Ј-H), 4.53
(1 H, m, CHF1), 4.97 (1 H, d, J1,2 8, 1-H), 4.47–5.05 (9 H, m,
3 × CH2Ph, 4Ј-H and CH2OCO), 5.34 (1 H, m, 1Ј-H), 5.43 (1 H,
d, J2P,NH 7, CHP), 6.83 (1 H, d, J 8, NH), 6.94 (1 H, m, NH),
6.90–7.40 (29 H, m, ArH); δC(CDCl3) 17.6 (6Ј-C), 20.6
(OCOCH3), 35.5 (2Ј-C), 38.8 (CH2F1), 47.9 (3Ј-C), 52.8
(OCH3), 55.8 (CHP and CHF1), 65.7 (5Ј-C), 67.0 (CH2OCO),
68.4 (6-C), 73.4 and 74.9 (2 × CH2Ph), 75.2 (4Ј-C), 76.6 (2-C),
75.6 and 78.1 (4- and 5-C), 85.8 (3-C), 96.7 (1Ј-C), 98.9 (1-C),
116.8 (3Ј- and 5Ј-CP), 126.9–129.9 (Ar-C), 136.5 and 137.6 and
137.9 [Cq(Ph)], 157.0 (OCONH) and 170.1 and 170.8 and 172.2
(CO2Me, OCOMe and NHCO); m/z (ES) 1184 (M ϩ Na)ϩ.
N-(N-Boc-L-phenylalanyl)-4-[2-O-(4-O-acetyl-2,3,6-trideoxy-
3-trifluoroacetamido-á-L-arabino-hexopyranosyl)-3,4,6-tri-O-
benzyl-â-D-glucopyranosyloxy]-D-phenylglycine methyl ester 17
Activation. N-Methylmorpholine (NMM) (12.8 mm3, 0.11
mmol) was added dropwise to a stirred solution of CDMT (20
mg, 0.11 mmol) and N-Boc--phenylalanine 15 (31 mg, 0.11
mmol) in dichloromethane (10 cm3) at Ϫ5 to 0 ЊC. The reaction
mixture was stirred for 2.5 h at 0 ЊC until complete consump-
tion of CDMT (checked by TLC).
Coupling. A solution of compound 14 (100 mg, 0.11 mmol)
and NMM (12.5 mm3, 0.11 mmol) in dichloromethane (5 cm3)
was added to the crude solution obtained as described above at
Ϫ5 to 0 ЊC. The reaction mixture was stirred for 3 h at 0 ЊC,
then for 16 h at rt. The solvent was removed under reduced
pressure and the residue was suspended in ethyl acetate (30
cm3). The suspension was washed successively with water (10
cm3), 1  hydrochloric acid (10 cm3), saturated aq. sodium
hydrogen carbonate (10 cm3) and water (10 cm3). The organic
layer was dried (MgSO4), and evaporated under reduced pres-
sure. The residue was purified by column chromatography on
silica gel (35–70 µm) with dichloromethane–methanol (99:1
v/v) as eluent to give title compound 17 (110 mg, 86%) as a
powder, which was recrystallized from methanol, mp 203 ЊC,
[α]D20 Ϫ44 (c 0.9, CHCl3) (Found: C, 63.8; H, 6.1. Calc. for
N-(N-Z-L-phenylalanyl-L-phenylalanyl)-4-[2-O-(4-O-acetyl-
2,3,6-trideoxy-3-trifluoroacetamido-á-L-arabino-hexopyrano-
syl)-3,4,6-tri-O-benzyl-â-D-glucopyranosyloxy]-D-phenylglycine
methyl ester 20
Synthesized by a procedure essentially similar to that described
for the synthesis of compound 18. To an ice-cooled solution
of compound 14 (350 mg, 0.40 mmol), HOBT (65 mg, 0.44
mmol), N-Z--phenylalanyl--phenylalanine16 19 (177 mg, 0.40
mmol) and triethylamine (66 mm3, 0.48 mmol) in dry DMF (30
cm3) was added EDCI (91 mg, 0.48 mmol). The reaction mix-
ture was stirred for 1.5 h at 0 ЊC then for 16 h at rt. The solvent
was removed under reduced pressure and the residue was sus-
pended in dichloromethane (50 cm3). The suspension was
2058
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
washed successively with 1  hydrochloric acid (40 cm3), satur-
ated aq. sodium hydrogen carbonate (40 cm3) and brine (40
cm3). The organic layer was dried (MgSO4), and evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel (35–70 µm) with dichloro-
methane–methanol (99:1 v/v) as eluent to give title compound
20 (406 mg, 78%) as a powder, which was recrystallized from
methanol, mp 196–197 ЊC; [α]D20 Ϫ47 (c 0.5, CHCl3–MeOH 1:1
v/v) (Found: C, 66.2; H, 5.8. Calc. for C72H75F3N4O16: C, 66.04;
H, 5.77%); νmax(film)/cmϪ1 3401 and 3307 (NH), 3060, 3031,
J(CH2,CHF) 7, CH2F], 4.64 [1 H, td, J(CH,CH2F) = J(CH,
NHF) = 7, CHF], 4.79 (1 H, m, CHF), 5.06 (2 H, s, CH2OCO),
5.30 [1 H, d, J(CH,NHPЈ) 6, CHPЈ], 6.46 (1 H, s, NH),
6.62 (1 H, s, NH), 6.77 [1 H, d, J(NH,CHF) 7, NH] and 6.98–
7.40 (20 H, m, ArH); δC(CDCl3) 27.8 [(CH3)3C], 38.0
(2 × CH2F), 53.7 and 54.0 (2 × CHF), 58.7 (CHPЈ), 66.9
(CH2OCO), 82.3 [(CH3)3C], 126.8–129.4 (Ar-C), 135.6, 135.8,
136.2 and 138.0 [Cq(Ph)], 155.6 (OCONH), 169.6 and 170.1
(COO2But and NHCO); m/z (CI) 636 (M ϩ H)ϩ, 653
(M ϩ NH4)ϩ.
2925, 1734 and 1719 and 1653 (C᎐O), 1537, 1508, 1374, 1238
᎐
and 1162 and 1061 (C᎐O); δH(CDCl3) 1.22 (3 H, d, J6Ј,5Ј 6, 6Ј-
H3), 1.59 (1 H, m, 2Ј-Heq), 1.98 (1 H, s, NH), 2.02 (3 H, s,
OCOCH3), 2.08 (1 H, m, 2Ј-Hax), 3.05 (4 H, m, CH2F1 and
CH2F2), 3.70 (3 H, s, OCH3), 3.54–3.81 (5 H, m, 3-, 4- and 5-H,
6-H2), 3.92 (1 H, t, J2,1 = J2,3 = 8, 2-H), 4.25–4.43 (3 H, m,
3Ј- and 5Ј-H and CHF1), 4.95 (1 H, d, J1,2 8, 1-H), 4.45–5.08 (10
H, m, 3 × CH2Ph, 4Ј-H, CHF2 and CH2OCO), 5.34 (1 H, m,
1Ј-H), 5.41 (1 H, d, J 7, CHP), 5.46 (1 H, d, J 7, NH), 6.50 (1 H,
d, J 8, NH), 6.57 (1 H, d, J 7, NH), 6.87–7.40 (34 H, m, ArH);
δC(CDCl3) 17.6 (6Ј-C), 20.6 (OCOCH3), 35.5 (2Ј-C), 38.1
(CH2F1 and CH2F2), 48.0 (3Ј-C), 52.8 (OCH3), 54.1 (CHF2),
56.1 (CHP and CHF1), 65.7 (5Ј-C), 67.2 (CH2OCO), 68.3 (6-C),
73.4 (CH2Ph), 75.0 (2 × CH2Ph and 4Ј-C), 76.6 (2-C), 75.6 and
78.1 (4- and 5-C), 85.7 (3-C), 96.5 (1Ј-C), 99.2 (1-C), 116.7
(3Ј- and 5Ј-CP), 127.1–129.7 (Ar-C), 135.9 and 137.6 and 137.9
[Cq(Ph)], 157.0 (OCONH) and 169.5, 170.9 and 172.2 (CO2Me,
OCOMe and NHCO); m/z (ES) 1331 (M ϩ Na)ϩ.
N-Z-D-phenylglycyl-L-phenylalanyl-L-phenylalanine 23
To a solution of dry dichloromethane (50 cm3) and TFA (20
cm3) was added N-Z--phenylglycyl--phenylalanyl--phenyl-
alanine tert-butyl ester 22 (1.42 g, 2.24 mmol). The reaction
mixture was stirred for 5 h at rt, then was evaporated under
reduced pressure to eliminate excess of TFA to give title acid 23
(1.23 g, 95%) as a powder, which was recrystallized from ethyl
acetate, mp 220 ЊC; [α]D20 Ϫ33 (c 0.5, DMF) (Found: C, 70.5; H,
5.7; N, 7.2. Calc. for C34H33N3O6: C, 70.75; H, 5.74; N, 7.25%);
δH(CDCl3) 2.69–3.13 (4 H, m, 2 × CH2F), 4.48 (2 H, m,
2 × CHF), 5.03 (2 H, s, CH2OCO), 5.32 [1 H, d, J(CH,NHPЈ)
9, CHPЈ], 6.46 (1 H, s, NH), 6.62 (1 H, s, NH), 6.77 [1 H, d,
J(NH,CHF) 7, NH] and 6.98–7.40 (20 H, m, Ar-H); δC(CDCl3)
27.8 [(CH3)3C], 37.9 (2 × CH2F), 53.7 and 54.0 (2 × CHF), 58.7
(CHPЈ), 66.9 (CH2OCO), 82.3 [(CH3)3C], 126.8–129.4 (Ar-C),
135.6, 135.8, 136.2 and 138.0 [Cq(Ph)], 155.6 (OCONH) and
169.6 and 170.1 (CO2But and NHCO); m/z (CI) 636 (M ϩ H)ϩ
and 653 (M ϩ NH4)ϩ.
L-Phenylalanyl-L-phenylalanine tert-butyl ester 21
Palladium on activated carbon (10%; 242 mg) was added to a
solution of N-Z--phenylalanyl--phenylalanine tert-butyl
ester17 (2.42 g, 4.82 mmol) in methanol (25 cm3). After the
reaction mixture had been stirred for 5 h under hydrogen (1
atm.), it was filtered through a Celite pad and the filtrate was
evaporated under reduced pressure to give title ester 21 as a
powder (1.75 g, 81%), which was recrystallized from cyclo-
hexane, mp 68 ЊC; [α]D20 ϩ4 (c 1, CHCl3) (Found: C, 71.8; H, 7.65;
N, 7.6. Calc. for C22H28N2O3: C, 71.71; H, 7.66; N, 7.60%);
νmax(film)/cmϪ1 3356 (NH), 3025, 2965, 2917, 1733 and 1668
N-(N-Z-D-phenylglycyl-L-phenylalanyl-L-phenylalanyl)-4-[2-O-
(4-O-acetyl-2,3,6-trideoxy-3-trifluoroacetamido-á-L-arabino-
hexopyranosyl)-3,4,6-tri-O-benzyl-â-D-glucopyranosyloxy]-D-
phenylglycine methyl ester 24
Synthesized by a procedure essentially similar to that described
for the synthesis of compound 18. To an ice-cooled solution
of compound 14 (500 mg, 0.57 mmol), HOBT (85 mg, 0.63
mmol), N-Z--phenylglycyl--phenylylalanyl--phenylylalanine
23 (329 mg, 0.57 mmol) and triethylamine (95 mm3, 0.68 mmol)
in dry DMF (40 cm3) was added EDCI (131 mg, 0.68 mmol).
The reaction mixture was stirred for 2 h at 0 ЊC then for 16 h at
rt. The solvent was removed under reduced pressure and the
residue was dissolved in dichloromethane (80 cm3). The solu-
tion was washed successively with 1  hydrochloric acid (50
cm3), saturated aq. sodium hydrogen carbonate (50 cm3) and
brine (50 cm3). The organic layer was dried (MgSO4), and
evaporated under reduced pressure. The residue was purified by
column chromatography on silica (35–70 µm) with dichloro-
methane–methanol (99:1 v/v) as eluent to give title compound
24 (681 mg, 83%) as a powder, which was recrystallized from
methanol, mp 220–222 ЊC; [α]D20 Ϫ38 (c 0.5, DMF) (Found: C,
66.5; H, 5.7. Calc. for C80H82F3N5O17: C, 66.61; H, 5.73%);
νmax(film)/cmϪ1 3302 (NH), 3060, 3025, 2931, 1740–1706 and
(C᎐O) and 1497; δ (CDCl ) 1.40 (9 H, s, But), 1.47 (2 H, s, NH ),
᎐
H
3
2
2.61 {1 H, dd, J[Hb,Ha(CH2F2)] 13.5, J(Hb,CH2F2) 9, Hb/
CH2F2}, 3.07 [2 H, d, J(Ha,CH2F2) 6, CH2F1], 3.17 {1 H, dd,
J[Ha,Hb(CH2F2)] 13.5, J(CH,HbF2) 4, Ha/CH2F2}, 3.61 {1 H,
dd, J(CH,HaF2) 9, J[CH,Hb(F2)] 4, CHF2}, 4.77 [1 H, td,
J(CH,NHF1) 8, J(CH,CH2F1) 6, CHF1], 7.06–7.36 (10 H,
m, ArH) and 7.77 [1 H, d, J(NH,CHF1) 8, NH]; δC(CDCl3)
27.8 [(CH3)3C], 38.1 and 40.6 (2 × CH2F), 53.0 and 56.0
(2 × CHF), 82.2 [(CH3)3C], 126.8–129.4 (Ar-C), 136.1 and
137.5 [Cq(Ph)], 170.6 (NHCO) and 173.9 (CO2But); m/z (CI)
369 (M ϩ H)ϩ and 386 (M ϩ NH4)ϩ.
N-Z-D-phenylglycyl-L-phenylalanyl-L-phenylalanine tert-butyl
ester 22
1642 (C᎐O), 1543, 1509, 1376, 1239–1164 and 1064 (C᎐O);
᎐
To an ice-cooled solution of -phenylalanyl--phenylalanine
tert-butyl ester 21 (1 g, 2.62 mmol), N-Z--phenylglycine18 (746
mg, 2.62 mmol) and HOBT (354 mg, 2.62 mmol) in anhydrous
DMF containing Et3N (375 mm3, 2.62 mmol) was added EDCI
(502 mg, 2.62 mmol) portionwise. The reaction mixture was
stirred for 1.5 h at 0 ЊC and then for 16 h at rt. The solvent was
removed under reduced pressure and the residue was dissolved
in ethyl acetate (100 cm3). The solution was washed successively
with 1  hydrochloric acid (2 × 50 dm3) and brine (50 cm3).
The organic layer was dried (MgSO4), and evaporated under
reduced pressure to give title compound 22 (1.57 g, 95%) as a
powder, which was recrystallized from cyclohexane, mp 188 ЊC;
[α]D20 Ϫ18 (c 0.5, CHCl3) (Found: C, 71.8; H, 6.5; N, 6.6. Calc. for
C38H41N3O6: C, 71.79; H, 6.50; N, 6.61%); νmax(KBr)/cmϪ1 3288
δH(CD3OD) 1.02 (3 H, d, J6Ј,5Ј 6, 6Ј-H3), 1.59 (1 H, m, 2Ј-Heq),
1.74 (1 H, m, 2Ј-Hax), 1.80 (3 H, s, OCOCH3), 2.80 (4 H, m,
CH2F1 and CH2F2), 3.50 (3 H, s, OCH3), 3.39–3.65 (5 H,
m, 3-, 4- and 5-H, 6-H2), 3.73 (1 H, m, 2-H), 4.10–4.27 (2
H, m, 3Ј- and 5Ј-H), 4.31–5.05 (13 H, m, 3 × CH2Ph, 4Ј-H,
CHF1, CHF2, CHPЈ, 1-H and CH2OCO), 5.17 (1 H, m, 1Ј-H),
5.28 (1 H, d, J 3, CHP) and 6.78–7.22 (39 H, m, ArH);
δC(CD3OD) 17.1 (6Ј-C), 20.0 (OCOCH3), 34.6 (2Ј-C), 37.6
(CH2F1 and CH2F2), 46.4 (3Ј-C), 52.2 (OCH3), 54.0 (CHF1 and
CHF2), 55.6 (CHP), 58.3 (CHPЈ), 65.7 (5Ј-C), 66.7 (CH2OCO),
68.0 (6-C), 73.1 (CH2Ph), 74.7 (2 × CH2Ph and 4Ј-C), 76.6
(2-C), 75.3 and 77.4 (4- and 5-C), 85.3 (3-C), 96.6 (1Ј-C), 98.5
(1-C), 116.4 and 116.6 (3Ј- and 5Ј-CP), 126.4–128.9 (Ar-C),
135.7, 137.3 and 137.6 [Cq(Ph)], 156.9 (OCONH) and 170.3,
171.1, 170.7 and 171.0 (CO2Me, OCOMe and NHCO); m/z
(ES) 1464 (M ϩ Na)ϩ.
(NH), 3061, 2989, 1735 and 1694 and 1644 (C᎐O) and 1532;
᎐
δH(CDCl3) 1.45 (9 H, s, But), 2.95 (2 H, m, CH2F), 2.98 [2 H, d,
J. Chem. Soc., Perkin Trans. 1, 1998
2059

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9 H. B. Borén, G. Ekborg, K. Eklind, P. J. Garegg, A. Pilotti and
Acknowledgements
We thank the French Ministry of Education and Research for a
Ph.D. fellowship (to Carole Mouton).
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133; J. P. Mackay, U. Gerhard, D. A. Beauregard, R. A. Maplestone
and D. H. Williams, J. Am. Chem. Soc., 1994, 116, 4573; J. P.
Mackay, U. Gerhard, D. A. Beauregard, M. S. Westwell, M. S.
Searle and D. H. Williams, ibid., 1994, 116, 4581.
Paper 8/02053A
Received 13th March 1998
Accepted 16th April 1998
2060
J. Chem. Soc., Perkin Trans. 1, 1998