A novel series of oligomers from 4-aminomethyl-tetrahydrofuran-2-carboxylates with 2,4-cis and 2,4-trans stereochemistry

Article abstract of DOI:10.1016/j.tet.2006.05.067

Two tetrahydrofuran-based γ-amino acids [2,4-cis and 2,4-trans] were subjected to iterative peptide-coupling procedures to afford dimeric, tetrameric and hexameric carbopeptoids in good yield. These homooligomers were prepared for secondary structural stu

Full text of DOI:10.1016/j.tet.2006.05.067

Tetrahedron 62 (2006) 7718–7725
A novel series of oligomers from 4-aminomethyl-tetrahydrofuran-
2-carboxylates with 2,4-cis and 2,4-trans stereochemistry
b
c
Alison A. Edwards,a, Gangadharar J. Sanjayan, Shuji Hachisu,
*
George E. Trantera and George W. J. Fleetc
aBiological Chemistry, Division of Biomedical Sciences, Imperial College, London SW7 2AZ, UK
bDivision of Organic Synthesis, National Chemical Laboratory, Pune 411 008, India
cChemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Received 22 March 2006; revised 9 May 2006; accepted 25 May 2006
Available online 16 June 2006
Abstract—Two tetrahydrofuran-based g-amino acids [2,4-cis and 2,4-trans] were subjected to iterative peptide-coupling procedures to afford
dimeric, tetrameric and hexameric carbopeptoids in good yield. These homooligomers were prepared for secondary structural study—to
ascertain the conformational preference inherent in the monomer units. The L-xylo oligomers were protected with triethylsilyl ethers to
increase the range of solvents suitable for structural investigation. Initial secondary structure data indicate the presence of hydrogen-bonded
conformations in the L-ribo series.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Numerous b-amino acids, homologues of a-amino acids
have been prepared and their oligomers extensively studied.
These have been found to be stable to proteolytic enzymes
and adopt an array of secondary structures akin to those
observed in a-peptides (see Fig. 1a).4–10 This concept has
been expanded to include g- and d-amino acids; d-amino
acids may be regarded as dipeptide isosteres.11,12 g-Amino
acids are found in nature, e.g., g-aminobutyric acid
(GABA) is an inhibitory neurotransmitter and tubulysins
are potent antimitotic agents.13,14
Peptides and proteins are coded by sequences of a-amino
acids but efforts to decipher this complexity has only been
partially successful.1 Peptides are key to the development
of new drugs however the low oral bioavailability of peptides
has been a long-standing issue.2,3 Initial synthetic efforts to
circumvent this issue focused on the chemical modification
of peptide libraries; more recent synthetic endeavours have
led to an ever-expanding catalogue of peptidomimetics.
(a)
(b)
O
R
O
R
H
H
N
N
α-peptide
N
H
N
H
R
R
O
O
R
O
n
n
vinylogous peptides
O
O
R
β-peptide
O
N
H
N
H
OR
OR
R
R
R
R
H
N
H
N
n
O
O
R
O
n
n
H
N
2,4-cis (1)
2,4-trans (2)
γ-peptide
N
H
γ-amino acid carbopeptoids
R
O
R
R
n
reported herein
Figure 1. (a) From a-peptides to g-peptides and (b) examples of g-peptides.
Keywords: Sugar amino acids; Peptidomimetics; Gamma amino acids; Foldamers.
* Corresponding author. Tel.: +44 20 7594 3143; fax: +44 20 7594 3226; e-mail: alison.edwards@imperial.ac.uk
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.067

A. A. Edwards et al. / Tetrahedron 62 (2006) 7718–7725
7719
Acyclic g-amino acids of vinylogous systems and their
corresponding saturated analogues, have been prepared
employing various side chains and substitution patterns to
achieve structural diversity.15–18,10,11 In addition to the adop-
tion of an array of peptide-like secondary structures and
resistance to proteolytic degradation,19–21,9,10 a g-dipeptide
was found to exhibit affinity for human somatostatin recep-
tors.22 Oligomers of ureas, carbamates, phosphodiesters and
vinylogous sulfonamidopeptides have also been prepared
as g-peptide analogues.23 The first cyclically constrained
g-amino acids were prepared as GABA analogues and based
upon a cyclopentane scaffold; the enantiomer was employed
by Woll et al. to prepare a parallel sheet secondary struc-
ture.24,25 Furanose-based and sugar-fused GABA analogues
have since been prepared.24,26 More recent synthetic efforts
have included cyclic scaffolds, which are (poly)hydroxy-
lated cyclohexanes,27,28 contain a lactam29 or are based on
proline, cyclopropane or bicylic scaffolds.30–32
shown to adopt a g-turn type conformation in solid phase.
g-Turns in a-peptides require three residues and are stabi-
lised by a hydrogen bond from COi to NHi+2 50,51
they exist
;
as two possible enantiomers with respect to the main chain
structure, the inverse turn being more common than the
classic turn. Studies of existing protein data52 and prediction
attempts53,54 have been conducted in an attempt to under-
stand the features that govern such turns. Mimics of g-turns
have been prepared55–60 and analogues of bradykinin,61
the peptide hormone vasopressin62 and angiotensin receptor
ligands63 based on g-turn mimics. Several different
strategies have been reported in the attempt to prepare
g-turns.64,65
2. Results and discussion
2.1. Strategy
Sugar scaffolds with amine and carboxylic acid moieties,
aka sugar amino acids (SAAs), have been used to create
cyclically constrained a-, b-, g-, d- and 3-amino acids.33–36
SAAs have been employed as peptidomimetics37–39 and
library scaffolds and their oligomers (carbopeptoids) exam-
ined as foldamers, which can adopt an array of secondary
structures such as helices and b-turns.40–43 Kessler et al.
have reported a pyranose-based g-SAA, which predeter-
minesab-turnconformationinsyntheticpeptides36 andahet-
erooligomer composed of a furanose g-SAA and GABA,
with no stable conformation in solution.44 Furanose- and
pyranose-based g-SAAs have been utilised to prepare 99-
member and 384-member libraries, respectively.45,46
g-Azido esters 1 and 2 have been prepared as part of the
ongoing search for peptidomimetics with secondary struc-
tural preferences.49,47 To investigate the conformational
preferences of the g-azido esters, they require to be coupled
to form homooligomers. These homooligomers can be stud-
ied using solution- and solid-phase techniques to ascertain
whether the oligomers adopt compact secondary structures
in relatively short sequences, i.e., are foldamers.40
The L-ribo g-azido ester 1 and L-xylo g-azido ester 2 are
available in seven steps starting from the acetonide of
L-arabinose 5 and D-ribose 6, respectively (Fig. 2).47,49 The
homooligomers of THF g-azido esters 1 and 2 were prepared
using established solution-phase coupling procedures with
O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium tetra-
fluoroborate (TBTU) as the coupling agent.66 The formation
of the tetrameric and hexameric homooligomers was
achieved via an iterative approach.
Recently, our group has reported the synthesis of two new
furanose g-SAA scaffolds,47–49 herein we report the prepa-
ration of the oligomers of b-hydroxy g-azido esters (see
Fig. 1b). The dimer arising from the 2,4-cis-SAA (3) was
OH
OH
HO
HO
OH
HO
HO
OH
O
O
D-ribose 6
L-arabinose 5
ref.46, 48 7 steps
TBDPSO N3
6 steps to 4
7 steps to 2
46, 48
ref.
HO
N3
RO
IPrO
O
O
O
O
4 R = Me
1
i
2 R = Pr
RO
TBDPSO
RO
RO
TBDPSO
IPrO
TBDPSO
H
N
H
N
H
N
H
N
IPrO
N3
N3
O
O
O
O
O
O
O
O
O
O
O
O
n
n
3: n = 0
9: n = 2
14: n = 0, R = H
15: n = 2, R = H
20: n = 2, R = TES
18: n = 4, R = H
Figure 2. Homooligomers from the 2,4-cis and 2,4-trans g-azido esters (1 and 2, respectively).

7720
A. A. Edwards et al. / Tetrahedron 62 (2006) 7718–7725
2.2. Synthesis of homooligomers from the L-ribo g-azido
ester 1
presence of 10% palladium on carbon to afford the N-termi-
nal amine 10. Treatment of dimer 3 with aqueous methanolic
potassium hydroxide followed by short exposure to Amber-
lite H+ resin gave access to acid 11, which was coupled to
amine 10 with TBTU/DIPEA in DMF. Purification of the
crude product by flash chromatography afforded tetramer
9, albeit in poor yield (26%).
Hydrogenation of the azido group in isopropyl L-ribo
g-azide 1 with 10% palladium on carbon in propan-2-ol pro-
ceeded smoothly to afford amine 7, which was used without
further purification (Scheme 1). Hydrolysis of the ester func-
tionality in 1 with aqueous methanolic potassium hydroxide
followed by short exposure to Amberlite H+ resin generated
the desired acid 8. Acid 8 was coupled to amine 7 using
standard peptide-coupling conditions with TBTU and N,N-
diisopropylethylamine (DIPEA) in N,N-dimethylformamide
(DMF) to yield dimer 3 in 80% yield from azide 1.
The structure of dimer 3 was confirmed by X-ray crystallo-
graphy.67
2.3. Synthesis of homooligomers from the L-xylo g-azido
ester 2
Amine 12 was afforded by hydrogenation of the azido group
in the isopropyl L-xylo g-azide 2 with 10% palladium on car-
bon in propan-2-ol and was used without further purification
(Scheme 2). Hydrolysis of the ester functionality in the
methyl L-xylo g-azide 4 was achieved with aqueous sodium
hydroxide in dioxane with subsequent treatment with
Amberlite H+ resin to give the desired acid 13. Acid 13
was coupled to amine 12 with TBTU and triethylamine
An iterative approach was adopted to synthesise the tetra-
meric carbopeptoid 9; thus the azide function of dimer 3
was reduced by hydrogenation in propan-2-ol in the
R1 = OH
R
2 = N3
8
(i)
[Si]O
[Si]O
H
R2
[Si]O
R2
R1
O
N
(iii)
R1
O
O
O
(ii)
O
I
R
1 = O Pr
R
3
O
I
R1 = O Pr
2 = NH2
7
(ii)
(i)
R
2 = N3
1
i
R1 = OH
[Si] = TBDPS
R1 = O Pr
2 = N3
11
R
2 = NH2
10
R
(iii)
[Si]O
[Si]O
[Si]O
[Si]O
H
N
H
N
H
N
IPrO
N3
O
O
O
O
O
O
O
O
9
Scheme 1. Reagents and conditions: (i) KOH, MeOH, H2O, rt then Amberlite IR-120 (H+) resin; (ii) 10% Pd/C, propan-2-ol, H2, rt; (iii) DIPEA, TBTU, DMF, rt.
R1 = OMe
R2 = N3
4
R1 = OH
(i)
R
2 = N3
OH
OH
R2
H
N
R2
HO
R1
O
13
(iii)
R1
O
O
O
O
14
R1 = OIPr
R2 = N3
2
R
1 = OIPr
(ii)
O
R2 = NH2
(i)
(ii)
12
R
1 = OIPr
R1 = OH
R2 = NH2
R
2 = N3
(iii)
16
17
R1 = OIPr, R2 = NH2, R3 = H
(iii)
19
OR3
OR3
OR3
H
H
N
IPrO
N3
N
OR3
(v)
OR3
O
OR3
O
H
N
H
N
R1
R2
O
O
O
O
4
O
O
O
O
O
O
2
R3 = H; 18
X
R1 = OIPr, R2 = N3, R3 = H; 15
R3 = TES; 21
(iv)
R1 = OIPr, R2 = N3, R3 = TES; 20
Scheme 2. Reagents and conditions: (i) NaOH, dioxane, H2O, rt then Amberlite IR-120 (H+) resin; (ii) 10% Pd/C, propan-2-ol, H2, rt; (iii) TEA, TBTU, DMF, rt;
(iv) TES-OTf, pyridine, ꢀ20 ꢁC to rt, 14 h; (v) 10% Pd/C, DMF, H2, rt.

A. A. Edwards et al. / Tetrahedron 62 (2006) 7718–7725
7721
O2
(TEA) in DMF to yield the desired dimer 14 in 61% yield
from the azide (2 or 4).
(a)
Tetramer 15 was prepared from the amine and acid derived
from dimer 14. The azide function of dimer 14 was reduced
by hydrogenation in propan-2-ol in the presence of 10%
palladium on carbon to afford the N-terminal amine 16.
Treatment of dimer 14 with aqueous sodium hydroxide in
dioxane followed by short exposure to Amberlite H+ resin
gave access to acid 17, which was coupled to amine 16 using
TBTU/TEA in DMF. Purification of the crude product by
flash chromatography and size exclusion chromatography
afforded tetramer 15 in good yield (60%).
O17
Hexamer 18 was prepared from the amine derived from tet-
ramer 15 and acid 17 derived from dimer 14. The azide func-
tion of tetramer 15 was reduced by hydrogenation in DMF
(15 was not soluble in propan-2-ol) in the presence of 10%
palladium on carbon to afford the N-terminal amine 19.
Acid 17 was coupled to amine 19 with TBTU/TEA in
DMF. Purification of the crude product by flash chromato-
graphy and size exclusion chromatography afforded hexa-
mer 18, albeit in poor yield (25%).
H
O
(b)
H
N
α
O
N
β
γ
α
β
NH
O
[Si]O
O
γ
R
Figure 3. (a) The solid-state conformation of dimer 3, as revealed by single
crystal X-ray diffraction, clearly showing a seven-membered ring hydrogen-
bonded g-turn like structure. The hydrogen bonds are shown as dotted lines.
TBDPS groups attached to O2 and O17 have been omitted for clarity. Note
that the azide group (N3) is not fully refined; (b) g-Turns in an a-peptide and
SAA dimer 3.
2.4. Protection of the free hydroxyls of the
homooligomers (from 2)
Protection of the free hydroxyls of tetramer 15 and hexamer
18 would enable further investigation of the secondary struc-
tural preference of the systems. The hydroxyl derivatisation
would enable solubilisation of the homooligomers in sol-
vents such as chloroform and would enable solution-state
IR spectra to be recorded. Triethylsilyl ethers were chosen
for hydroxyl protection as they are related to the protection
used in the L-ribo homooligomers. More importantly, they
do not contain the phenyl residues, which complicate obser-
vation of amide protons by 1H NMR spectroscopy and study
of the amide chromophores by circular dichroism.
hydrogen-bonded conformation. In contrast to the L-ribo
series, the L-xylo oligomers have relatively low dNH suggest-
ing the absence of a hydrogen-bonded conformation. A
full secondary structural study of these oligomers will be
reported in due course.
3. Conclusion
Tetrahydrofuran-based g-amino acids (2,4-cis
1 and
2,4-trans 2) were subjected to iterative peptide-coupling
procedures to afford dimeric, tetrameric and hexameric
carbopeptoids in good yield. These homooligomers were
prepared to enable secondary structural study—to ascertain
the conformational preference inherent in the monomer
units 1 and 2. Such information is of great significance for
the design of compounds with predisposed conformation,
e.g., peptidomimetics and nanomaterials.
The silyl protection of tetramer 15 was achieved by treat-
ment of 15 with a large excess of triethylsilyl trifluorometh-
anesulfonate in pyridine (Scheme 2). Purification via flash
chromatography on basic alumina afforded the silylated
tetramer 20 in 13% yield. Attempts to protect hexamer 18
in a similar manner were unsuccessful—no silylated prod-
ucts were observed by electrospray mass spectrometry.
The poor yields achieved for the silylation of the homo-
oligomers may be related to steric hindrance due to the bulki-
ness of the triethylsilyl group. Sufficient material was
isolated from the silylated tetramer 20 to allow secondary
structure investigation.
4. Experimental
4.1. General
The general methods used have been described previously49
although there are several further comments. Reactions were
performed under an atmosphere of nitrogen or argon, unless
stated otherwise. Sheets were visualised using a spray of
0.2% w/v cerium(IV) sulfate and 5% ammonium molybdate
in 2 M sulfuric acid or 0.5% ninhydrin in methanol (particu-
larly for amines). Flash chromatography was performed on
Sorbsil C60 40/60 silica and, where stated, on basic alumina
[Actal UGI (aluminium oxide—activated) from Rockwood
Additives Ltd.]. Size exclusion chromatography was per-
formed using Sephadex LH-20. For NMR assignment of the
furanose residues, the residues were labelled sequentially
from the N to C terminus, e.g., in a tetramer, residue A
2.5. Secondary structure
Initial examination of 1H NMR spectroscopic and crystallo-
graphic data provided important secondary structural evi-
dence. The X-ray crystal structure of dimer 3 revealed a
hydrogen-bonded turn conformation akin to that of a g-turn
(see Fig. 3).67 The high dNH of 3 by 1H NMR spectroscopy
(CDCl3, 500 MHz) indicated that this conformation may
also be present in solution. Further to this, the corresponding
tetramer 9 has similar high dNH (benzene-d6, 500 MHz)
for NHB and NHC suggesting that it may adopt a related

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A. A. Edwards et al. / Tetrahedron 62 (2006) 7718–7725
contains the azide and residue D contains the ester. Residual
signals from the solvents were used as an internal reference.
1H and 13C spectral assignments were achieved using a com-
bination of COSY, TOCSY, HSQC, Tr-ROESY and HMBC.
13C data have been quoted to two decimal places for several
oligomers to clarify the assignment given.
4.1.2. Isopropyl 4-amino-2,5-anhydro-3-O-tert-butyldi-
phenylsilyl-4-N-(4-amino-2,5-anhydro-3-O-tert-butyl-
diphenylsilyl-4-N-(4-amino-2,5-anhydro-3-O-tert-butyl-
diphenylsilyl-4-N-(2,5-anhydro-4-azido-3-O-tert-butyldi-
phenylsilyl-4-deoxy-L-ribonyl)-4-deoxy-L-ribonyl)-4-
deoxy-L-ribonyl)-4-deoxy-L-ribonate 9. A solution of
dimer 3 (0.16 g, 0.19 mmol) in propan-2-ol (10 mL) con-
taining palladium (10 wt % on carbon, 50 mg) was vigor-
ously stirred under an atmosphere of hydrogen. After 15 h,
TLC (dichloromethane) showed the absence of the starting
material (Rf 0.40) and the presence of a major product (Rf
0.10). The reaction mixture was degassed, purged with nitro-
gen and filtered through Celite (eluent: propan-2-ol). The fil-
trate was concentrated in vacuo to afford dimer-amine 10 as
colourless oil, which was used without further purification.
4.1.1. Isopropyl 4-amino-2,5-anhydro-3-O-tert-butyl-
diphenylsilyl-4-N-(2,5-anhydro-4-azido-3-O-tert-butyl-
diphenylsilyl-4-deoxy-L-ribonyl)-4-deoxy-L-ribonate 3. A
solution of isopropyl 2,5-anhydro-4-azido-3-O-tert-butyl-
diphenylsilyl-4-deoxy-L-ribonate 1 (0.39 g, 0.86 mmol) in
propan-2-ol (10 mL) containing palladium (10 wt % on car-
bon, 50 mg) was vigorously stirred under an atmosphere of
hydrogen. After 13 h, TLC (dichloromethane) showed the
absence of the starting material (Rf 0.42) and the presence
of a major product (Rf 0.12). The reaction mixture was
degassed, purged with nitrogen and filtered through Celite
(eluent: propan-2-ol). The filtrate was concentrated in vacuo
to afford amine 7 as a colourless oil, which was used without
further purification.
Potassium hydroxide (0.014 g, 0.25 mmol) was added to
a stirred solution of dimer 3 (0.16 g, 0.19 mmol) in methanol
(5 mL) containing water (1 mL). After 20 h, TLC (dichloro-
methane) showed the absence of the starting material (Rf
0.40). The reaction mixture was stirred with excess Amber-
lite IR-120 (H+) resin for 2 min and filtered. The filtrate was
concentrated in vacuo to afford dimer-acid 11 as colourless
oil, which was used without further purification.
Potassium hydroxide (0.063 g, 1.1 mmol) was added to a
stirred solution of isopropyl azido ester 1 (0.39 g, 0.86 mmol)
in methanol (5 mL) containing water (1 mL). After 16 h,
TLC (dichloromethane) showed the absence of the starting
material (Rf 0.42). The reaction mixture was stirred with
excess Amberlite IR-120 (H+) resin for 2 min and filtered.
The filtrate was concentrated in vacuo to afford acid 8 as a
colourless oil, which was used without further purification.
DIPEA (0.043 mL, 0.25 mmol) and TBTU (0.08 g, 0.25
mmol) were added to dimer-amine 10 and dimer-acid 11
in dry DMF (1 mL). After 28 h, TLC (ethyl acetate–pet.
ether, 3:1) revealed the formation of a major product
(Rf 0.56). The mixture was concentrated in vacuo and
purified by flash chromatography (ethyl acetate–pet. ether,
1:9) to yield tetramer 9 as a white solid (0.056 g, 26%);
mp 74–75 ꢁC (MeOH); [a]D23 +70.8 (c 0.5 in CHCl3); Iso-
tope distribution m/z (ES+ve) found: 1555.74 (70),
1556.63 (90) 1557.68 (70), 1558.58 (35), 1559.19 (20%).
C87H106N6O13Si4Na (M+Na+) requires: 1555 (76), 1556
(90) 1557 (65), 1558 (32), 1559 (15%); nmax (thin film):
3386 (NH, amide), 2106 (N3), 1727 (C]O, ester), 1668,
1679, 1692 (C]O, amide) cmꢀ1; dH (C6D6, 500 MHz)
0.73 (3H, d, J 6.2, CH(CH3)2), 0.82 (3H, d, J 6.2,
CH(CH3)2), 1.13 (9H, s, SiC(CH3)3), 1.15 (9H, s,
SiC(CH3)3), 1.18 (9H, s, SiC(CH3)3), 1.19 (9H, s,
SiC(CH3)3), 3.14 (1H, d, J 3.8, H-4A), 3.56 (1H, d, J 9.8,
H-5A), 3.64 (1H, d, J 9.2, H-5D), 3.68 (1H, dd, J 3.7, 6.1,
DIPEA (0.31 mL, 1.8 mmol) and TBTU (0.57 g, 1.71 mmol)
were added to a stirred solution of acid 8 and amine 7 in DMF
(2 mL). After 23 h, TLC (dichloromethane) revealed the
formation of a major product (Rf 0.42). The mixture was con-
centrated in vacuo and purified by flash chromatography
(ethyl acetate–pet. ether, 1:9) to yield dimer 3 as a white solid
(0.58 g, 80%): mp 127–128 ꢁC (MeOH); [a]D23 +91.0 (c
0.51 in CHCl3); (HRMS (ESI+ve): Found 843.3572.
C45H56N4O7Si2Na (M+Na+) requires m/z, 843.3580); Iso-
tope distribution m/z (ES+ve) found: 843.36 (100), 844.29
(60), 845.31 (20%). C45H56N4O7Si2Na (M+Na+) requires:
843 (100), 844 (61), 845 (26%); nmax (thin film): 3360
(NH, amide), 2106 (N3), 1738 (C]O, ester), 1681 (C]O,
amide) cmꢀ1; dH (CDCl3, 500 MHz) 0.97 (3H, d, J 6.3,
CH(CH3)2), 1.10 (9H, s, SiC(CH3)3), 1.15 (9H, s,
SiC(CH3)3), 1.16 (3H, d, J 6.3, CH(CH3)2), 3.51 (1H, d,
A
H-50 ), 3.70 (1H, br s, H-5C), 3.81 (1H, d, J 8.9, H-5B),
B
C
4.10–4.14 (2H, m, H-50 and H-50 ), 4.17 (1H, dd, J 4.2,
9.2, H-50 ), 4.25 (1H, d, J 1.15, H-2C), 4.35 (1H, q, J 4.1,
D
J 3.9, H-4A), 3.89 (1H, d, J5A,5 A 9.7, H-5A), 4.04 (1H, d,
H-4D), 4.40 (1H, br s, H-2B), 4.42 (1H, br s, H-2D), 4.51
(1H, br s, H-3C), 4.55 (1H, br s, H-3D), 4.59–4.64 (2H, m,
H-4B and H-3C), 4.65 (1H, br s, H-2A), 4.72 (1H, sept,
J 6.2, CH(CH3)2), 4.78 (1H, m, H-4B), 4.80 (1H, br s,
H-3A), 6.50 (1H, d, J 8.3, NHD), 7.20–7.36 (24H, m,
24ꢂArH), 7.49 (1H, d, J 9.1, NHC), 7.69 (2H, m, 2ꢂArH),
7.73 (2H, m, 2ꢂArH), 7.78–7.85 (13H, m, NHB and
12ꢂArH); dC (C6D6, 125.7 MHz) 19.62, 19.62, 19.69,
19.73 (4ꢂSiC(CH3)3), 21.70 (CH(CH3)2), 27.34, 27.39,
27.48, 27.52 (4ꢂSiC(CH3)3), 57.93, 58.13, 58.2 (C-4B,
C-4C and C-4D), 67.22 (C-4A), 69.49 (CH(CH3)2), 71.99
(C-5A), 73.39 (C-5D), 73.99 (C-5C), 74.26 (C-5B), 81.57
(C-3A and C-3D), 81.87 (C-3C), 82.50 (C-3B), 85.31
(C-2D), 86.70 (C-2A), 87.10, 87.32 (C-2B and C-2C),
128.52, 128.56, 128.61, 128.68, 128.70, 128.76, 128.80
(16ꢂArCH), 130.49, 130.53, 130.69, 130.75, 130.85,
0
J 9.0, H-5B), 4.15 (1H, dd, J5 A,4A 3.9, J5A,5 A 9.7, H-50 ),
A
0
0
4.18 (1H, br s, H-3B), 4.32 (1H, br s, H-2B), 4.36 (1H, dd,
B
J 4.4, J 9.1, H-50 ), 4.45 (1H, br s, H-2A), 4.56 (1H, br s,
H-3A), 4.60 (1H, a-dd, J 4.2, J 10.0, H-4B), 4.87 (1H, sept,
J 6.3, CH(CH3)2), 7.26–7.41 (6H, m, 6ꢂArH), 7.42–7.48
(7H, m, NHB and 6ꢂArH), 7.60–7.80 (8H, m, 8ꢂArH); dC
(CDCl3, 125.7 MHz) 19.0 (SiC(CH3)3), 19.1 (SiC(CH3)3),
21.3 (CH(CH3)), 21.7 (CH(CH3)), 26.7 (SiC(CH3)3), 26.8
(SiC(CH3)3), 56.7 (C-4B), 66.7 (C-4A), 69.1 (CH(CH3)2),
71.7 (C-5A), 73.8 (C-5B), 80.4 (C-3A), 81.3 (C-3B), 84.8
(C-2B), 85.2 (C-2A), 127.6, 127.7, 127.8, 128.0 (8ꢂArCH),
129.8, 129.9, 130.2, 130.2 (4ꢂArCH), 132.1, 132.2, 132.9,
133.1 (4ꢂArC), 135.6, 135.7, 135.9 (8ꢂArCH), 168.4
(C]OA), 171.1 (C]OB); m/z (ESI+ve): 879 (100%,
M+MeCN+NH+4).

A. A. Edwards et al. / Tetrahedron 62 (2006) 7718–7725
7723
130.89 (8ꢂArCH), 133.06, 133.29, 133.41, 133.44 133.84,
133.88, 134.06, 134.18 (8ꢂArC), 136.43, 136.50, 136.53,
136.60, 136.65, 136.68, 136.71 (16ꢂArCH), 169.01
(C]OB), 170.05 (C]OC), 170.12 (C]OD), 171.91
(C]OA).
(10 wt % on carbon, 21 mg) was vigorously stirred under
an atmosphere of hydrogen. After 23 h, TLC (ethyl acetate)
showed the absence of the starting material (Rf 0.2) and the
presence of a major product (Rf 0.0). The reaction mixture
was degassed, purged with nitrogen and filtered through
Celite (eluent: propan-2-ol). The filtrate was concentrated
in vacuo to afford dimer-amine 16 as a colourless oil, which
was used without further purification.
4.1.3. Isopropyl 2,5-anhydro-4-N-(2,5-anhydro-4-azido-
4-deoxy-L-xylonamido)-4-deoxy-L-xylonate 14. A solution
of isopropyl 2,5-anhydro-4-azido-4-deoxy-L-xylonate 2
(221 mg, 1.03 mmol) in propan-2-ol (11 mL) containing
palladium (10 wt % on carbon, 23 mg) was vigorously
stirred under an atmosphere of hydrogen. After 5 h, TLC
(ethyl acetate–pet. ether, 2:1) showed the absence of the
starting material (Rf 0.5) and the presence of a major product
(Rf 0.0). The reaction mixture was degassed, purged with
nitrogen and filtered through Celite (eluent: propan-2-ol).
The filtrate was concentrated in vacuo to afford amine 12 as
a colourless oil, which was used without further purification.
Sodium hydroxide (1 M aq, 344 mL) was added to dimer
14 (100 mg, 0.29 mmol) in dioxane (0.4 mL) and water
(0.7 mL). After 3 h, TLC (ethyl acetate) showed the absence
of the starting material (Rf 0.2) and the formation of a major
product (Rf 0.0). The reaction mixture was concentrated in
vacuo and the resulting residue was redissolved in water.
The reaction mixture was stirred with excess Amberlite
IR-120 (H+) resin for 30 min and filtered. The filtrate was
concentrated in vacuo to afford dimer-acid 17 as a colourless
oil, which was used without further purification.
Sodium hydroxide (1 M aq, 1.2 mL) was added to a stirred
solution of methyl 2,5-anhydro-4-azido-4-deoxy-L-xylonate
4 (192 mg, 1.03 mmol) in dioxane (1.2 mL) and water
(2.4 mL). After 3 h, TLC (ethyl acetate–pet. ether, 2:1)
showed the absence of the starting material (Rf 0.3) and
the formation of a major product (Rf 0.0). The reaction mix-
ture was concentrated in vacuo and the resulting residue was
redissolved in water. The reaction mixture was stirred with
excess Amberlite IR-120 (H+) resin for 30 min and filtered.
The filtrate was concentrated in vacuo to afford acid 13 as
a colourless oil, which was used without further purification.
Triethylamine (56 mL, 0.40 mmol) and TBTU (112 mg,
0.35 mmol) were added to a stirred solution of dimer-amine
16 and dimer-acid 17 in DMF (3 mL). After 19 h, TLC (ethyl
acetate–methanol, 7:3) revealed the formation of a major
product (Rf 0.5). The reaction mixture was concentrated in
vacuo and purified by flash chromatography (ethyl ace-
tate–methanol–water, 4:6:3). The resulting residue was fur-
ther purified by size exclusion chromatography (methanol),
to yield tetramer 15 (105 mg, 60%) as a white solid: mp 170–
171 ꢁC (decomp.); [a]2D4 ꢀ13.4 (c 1.06 in MeOH); (HRMS
(CI+ve): Found 603.2262. C23H35N6O13 (M+H+) requires
m/z, 603.2262); Isotope distribution m/z (ES+ve) found:
625.28 (100), 626.23 (28), 627.25 (7%). C23H34N6O13Na
(M+Na+) requires: 625.20 (100), 626.21 (25), 627.21
(2%); nmax (KBr): 3400 (OH), 2111 (N3), 1736 (C]O),
1655, 1541 (C]O, amide) cmꢀ1; dH (C5D5N, 500 MHz)
1.17 (3H, d, J 6.3, CH(CH3)2), 1.20 (3H, d, J 6.3,
Triethylamine (204 mL, 1.45 mmol) and TBTU (406 mg,
1.26 mmol) were added to a stirred solution of amine 12
and acid 13 in DMF (11 mL). After 12 h, TLC (ethyl acetate)
revealedthe formation of a major product (Rf 0.2) and a minor
product (Rf 0.3). The reaction mixture was concentrated in
vacuo and redissolved in water (30 mL). Chloroform was
added to the solution and the organic layer was extracted
with water. The combined aqueous extracts were concen-
trated in vacuo and purified by flash chromatography (ethyl
acetate–pet. ether, 1:1) to yield dimer 14 (216 mg, 61%) as
a white solid: mp 48–49 ꢁC; [a]D24 ꢀ25.9 (c 1.03 in CHCl3);
(HRMS (CI+ve): Found 345.1410. C13H21N4O7 (M+H+) re-
quires m/z, 345.1410); nmax (thin film): 3392 (OH), 2108
(N3), 1739 (C]O) 1652, 1538 (C]O, amide) cmꢀ1; dH
(CDCl3, 500 MHz) 1.26 (3H, d, J 6.2, CH(CH3)2), 1.27
CH(CH3)2), 3.93 (1H, d, J5A,5 A 9.2, H-5A), 4.03–4.05 (2H,
0
m, H-5B and H-5D), 4.12 (1H, dd, J4C,5C 2.2, J5C,5 C 9.0,
0
H-5C), 4.31–4.36 (2H, m, H-4A and H-50 ), 4.39–4.42
A
B
D
(2H, m, H-50 and H-50 ), 4.60 (1H, dd, J4C,5 C 5.3, J5C,5 C
0
0
C
9.0, H-50 ), 4.85–4.91 (5H, m, H-2A H-3A, H-4B, H-4C
and H-4D), 4.97–5.00 (3H, m, H-2B, H-2D and H-3C), 5.11
(1H, m, H-2C), 5.13–5.15 (2H, m, H-3B and H-3D), 5.20
(1H, sept, J 6.3, CH(CH3)2), 8.45 (1H, d, J 7.2, NHC),
8.47 (1H, d, J 7.1, NHB), 8.53 (1H, d, J 6.7, NHD); dC
(C5D5N, 125.7 MHz) 22.2, 22.3 (CH(CH3)2), 59.2, 59.2,
59.3 (C-4B, C-4C and C-4D), 68.3 (C-4A), 68.5
(CH(CH3)2), 71.9 (C-5A), 72.3 (C-5C), 72.4, 72.5 (C-5B
and C-5D), 76.4 (C-3), 77.2 (C-3A), 77.3 (C-3), 77.8
(C-2C), 82.0 (C-3C), 83.5, 83.5, 83.5 (C-2B, C-2A and
C-2D), 170.4 (C]OC), 170.5 (C]OD), 170.9 (C]OA),
171.0 (C]OB).
0
(3H, d, J 6.2, CH(CH3)2), 3.84 (1H, dd, J4B,5B 1.7, J5B,5 B
0
9.8, H-5B), 3.94 (1H, d, J5A,5 A 9.8, H-5A), 4.13 (1H, d,
A
J4A,5 A 4.5, H-4 ), 4.24–4.27 (2H, m, H-50A and H-4B) 4.37
0
B
(1H, dd, J4B,5 B 4.8, J5B,5 B 9.8, H-50 ), 4.48 (2H, m, H-2
and OH), 4.53–4.57 (3H, m, H-2, H-3A and H-3B), 4.64
(1H, d, J 2.5, OH), 5.11 (1H, sept, J 6.2, CH(CH3)2), 7.03
(1H, d, J 6.4, NHB); dC (CDCl3, 125.7 MHz) 22.0, 22.1
(CH(CH3)2), 58.3 (C-4B), 66.9 (C-4A), 69.4 (CH(CH3)2),
71.4 (C-5B), 71.8 (C-5A), 75.9, 77.0 (C-3A and C-3B), 80.6,
82.3 (C-2A and C-2B), 169.4 (C]OB), 170.9 (C]OA);
m/z (APCI+ve) 303 (100), 345 (M+H+, 64%).
0
0
4.1.5. Isopropyl 2,5-anhydro-4-N-(2,5-anhydro-4-N-(2,5-
anhydro-4-N-(2,5-anhydro-4-N-(2,5-anhydro-4-N-(2,5-
anhydro-4-azido-4-deoxy-L-xylonamido)-4-deoxy-L-
xylonamido)-4-deoxy-L-xylonamido)-4-deoxy-L-xylon-
amido)-4-deoxy-L-xylonamido)-4-deoxy-L-xylonate 18.
A solution of tetramer 15 (43 mg, 0.07 mmol) in DMF
(5 mL) containing palladium (10 wt % on carbon, 8 mg)
was vigorously stirred under an atmosphere of hydrogen.
After 3 h, TLC (ethyl acetate–methanol, 7:3) showed the
4.1.4. Isopropyl 2,5-anhydro-4-N-(2,5-anhydro-4-N-(2,5-
anhydro-4-N-(2,5-anhydro-4-azido-4-deoxy-L-xylon-
amido)-4-deoxy-L-xylonamido)-4-deoxy-L-xylonamido)-
4-deoxy-L-xylonate 15. A solution of dimer 14 (100 mg,
0.29 mmol) in propan-2-ol (3 mL) containing palladium

7724
A. A. Edwards et al. / Tetrahedron 62 (2006) 7718–7725
absence of the starting material (Rf 0.5) and the presence of
a major product (Rf 0.0). The reaction mixture was
degassed, purged with nitrogen and filtered through Celite
(eluent: DMF). The filtrate was concentrated in vacuo to
afford tetramer-amine 19 as a colourless oil, which was
used without further purification.
CHCl3); Isotope distribution m/z (ES+ve) found: 1059.53
(100), 1060.48 (80), 1061.55 (43), 1062.44 (18), 1063.38
(9%). C47H91N6O13Si4 (M+H+) requires: 1059 (100),
1060 (75), 1061 (44), 1062 (18), 1063 (6%); nmax (thin
film): 3410 (NH), 2105 (N3), 1740 (C]O), 1637, 1540
(C]O, amide) cmꢀ1; dH (CDCl3, 500 MHz) 0.61–0.71
(24H, m, 4ꢂSi(CH2CH3)3), 0.92–0.98 (36H, m, 4ꢂ
Si(CH2CH3)3), 1.26–1.30 (6H, m, CH(CH3)2), 3.78–3.80
(3H, m, H-5B, H-5C and H-5D), 3.92–3.96 (2H, m, H-4A
Sodium hydroxide (1 M aq, 85 mL) was added to a stirred
solution of dimer 14 (100 mg, 0.29 mmol) in dioxane
(85 mL) and water (171 mL). After 3 h, TLC (ethyl acetate)
showed the absence of the starting material (Rf 0.2) and
the formation of a major product (Rf 0.0). The reaction
mixture was concentrated in vacuo and the resulting residue
was redissolved in water. The reaction mixture was stirred
with excess Amberlite IR-120 (H+) resin for 30 min and
filtered. The filtrate was concentrated in vacuo to afford
dimer-acid 17 as colourless oil, which was used without
further purification.
and H-5A), 4.16–4.21 (3H, m, H-4B, H-4C and H-4D),
A
4.27 (1H, dd, J5 A,4A 4.1, J5A,5 A 9.5, H-50 ), 4.30–4.40
0
0
B
C
D
(5H, m, H-2C, H-2D, H-50 , H-50 and H-50 ), 4.43–4.46
(2H, m, H-2B and H-3A), 4.48–4.49 (2H, m, H-3C and
H-3D), 4.52–4.55 (2H, m, H-2A and H-3B), 5.07 (1H,
sept, J 6.2, CH(CH3)2), 6.52 (1H, d, J 6.7, NHD), 6.55
(1H, d, J 6.7, NHC), 6.60 (1H, d, J 6.4, NHB); dC (CDCl3,
125.7 MHz) 4.66, 4.68, 4.76 (4ꢂSi(CH2CH3)3), 6.83,
6.90 (4ꢂSi(CH2CH3)3), 22.10, 22.17 (CH(CH3)2), 57.71,
57.74 (3ꢂC-4), 67.53 (C-4A), 68.99 (CH(CH3)2), 71.59,
71.86, 72.33, 72.45 (4ꢂC-5), 76.78, 77.43, 77.88 (4ꢂC-3),
81.47, 82.54, 82.56, 82.64 (4ꢂC-2), 168.60 (C]OA),
168.77 (C]OB), 169.00, 169.02 (C]OD and C]OC); m/z
(APCI+ve) 156 (100), 1059 (M+H+, 95%).
Triethylamine (14 mL, 0.10 mmol) and TBTU (28 mg,
0.09 mmol) were added to a stirred solution of tetramer-
amine 19 and dimer-acid 17 in DMF (0.5 mL). After 13 h,
TLC (acetonitrile–water, 9:1) revealed the formation of
a major product (Rf 0.2). The reaction mixture was con-
centrated in vacuo and purified by flash chromatography
(acetonitrile–water, 9:1). The resulting residue was further
purified by size exclusion chromatography (methanol)
to yield hexamer 18 (15 mg, 25%) as a white solid: mp
159–160 ꢁC; [a]2D4 ꢀ33.8 (c 0.24 in MeOH); (HRMS
(CI+ve): Found 883.2933. C33H48N8O19Na (M+Na+) re-
quires m/z, 883.2933); Isotope distribution m/z (ES+ve)
found: 883.36 (100), 884.28 (39), 885.28 (8%).
C23H34N6O13Na (M+Na+) requires: 883 (100), 884 (40),
885 (12%); nmax (KBr): 3394 (OH), 2111 (N3), 1737
(C]O), 1661, 1534 (C]O, amide) cmꢀ1; dH (C5D5N,
500 MHz) 1.18 (3H, d, J 6.5, CH(CH3)2), 1.21 (3H, d,
Acknowledgements
Support from the EPSRC (A.A.E.) and DST, New Delhi, for a
BOYCAST Fellowship (G.J.S.) is gratefully acknowledged.
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