Towards hydroxylated nylon 6: Oligomers from a protected 6-amino-6-deoxy-D-allonate

Article abstract of DOI:10.1016/j.tetasy.2003.10.008

The first synthesis of linear oligomers (a dimer, tetramer, hexamer and octamer) of fully hydroxylated analogues of nylon 6 by iterative formation of peptide bonds from a protected 6-amino-6-deoxy-D-allonate monomer is reported.

Full text of DOI:10.1016/j.tetasy.2003.10.008

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3831–3839
Towards hydroxylated nylon 6: oligomers from a protected
6-amino-6-deoxy- -allonate
D
Darren F. A. Hunter and George W. J. Fleet*
Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 14 August 2003; accepted 14 October 2003
Abstract—The first synthesis of linear oligomers (a dimer, tetramer, hexamer and octamer) of fully hydroxylated analogues of
nylon 6 by iterative formation of peptide bonds from a protected 6-amino-6-deoxy-
© 2003 Elsevier Ltd. All rights reserved.
D-allonate monomer is reported.
1. Introduction
essentially no reports of the coupling of sugar 1,6-
diacids with sugar 1,6-diamines. Recent studies also
include the synthesis of stereoregular polymers derived
from glucaric acid and a series of alkylene diamines,17
Although in the past the majority of commercially
available synthetic biodegradable polymers have been
limited to polyesters, several different types of
biodegradable polymers are currently being evaluated
for a wide range of practical uses.1 Biodegradability is
sought after in many applications, above all in the
preparation of environmentally friendly polymers2 and
biomedical materials for temporary surgical use and in
drug delivery.3 For example, polyhydroxyalkanonate
derivatives have been developed as biodegradable
suture strings4 and as polymeric scaffolds for the con-
trolled release of drugs such as dexamethasone.5
polyurethanes from
L-gulonic acid-derived diols and
diisocyanates,18 and investigation of the properties of
polymers formed from 1,6-diamino alditols with alkyl
dioic acids.19 Similar condensations of diamines with
other hydroxyacids have been reported.20 A synthesis of
a monomer for the formation of polymers derived from
a sugar b-amino acid has been reported21 but there
have been no subsequent reports of either oligomers or
polymers of such compounds.
In contrast to the extensive literature on polyhydroxy-
lated nylon 6,6, there have been no reports of the
synthesis of oligomeric or polymeric sugar analogues of
polyhydroxylated nylon 6. Recently a synthesis of 6-
Polyhydroxylated nylon 6,66 and related compounds
constitute a class of biodegradable polymers which has
attracted considerable attention with respect to their
synthesis and structure. Such materials, formed by con-
densation of diamines and aldaric acid derivatives, have
been extensively studied7,8 and are exemplified by the
reactions of diethyl galactarate with a range of
diamines.9,10
amino-6-deoxy-2,3,4,5-tetra-O-methyl-D-galactonic acid
as a precursor of a stereoregular polyamide has been
reported but no oligomers or polymers were
described.22 Undoubtedly one reason for this is that
access to polyhydroxylated 6-aminohexanoic acid
monomers usually requires longer synthetic sequences.
Additionally, such monomers are prone to the forma-
tion of lactams;23 whereas polymerisation of capro-
Even though synthetic11–14 and structural15,16 studies on
such [6,6] nylon analogues are extensive, there are
* Corresponding author. E-mail: george.fleet@chem.ox.ac.uk
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.10.008

3832
D. F. A. Hunter, G. W. J. Fleet / Tetrahedron: Asymmetry 14 (2003) 3831–3839
lactam is the standard method for the synthesis of nylon
6, tetrahydroxylated lactams undergo other reactions
such as dehydration before polymerisation takes place.
The complex mixtures which result preclude convincing
characterisationofthenovelpolymerswhichareprobably
formed.
This paper reports the synthesis of homogeneous well-
defined oligomers of hydroxylated nylon 6 (Scheme 1)
from
D
-ribose 1 via the key azido-ester intermediate 2;
the dimer 3, tetramer 4, hexamer 5 and octamer 6 are the
first reported examples of oligomers of tetrahydroxylated
6-aminohexanoic acids as polyhydroxylated nylon 6
analogues.
The potential of sugar amino acids24 (SAA) as mono-
mers25 for new biomaterials26 has been recognized.27
Conformationally locked28,29 ring-templated SAA have
provided a rich mine of building blocks for the production
of foldamers,30 short oligomers with a predisposition
towards the generation of secondary structures.31 6-
Amino-6-deoxyaldonic acids constitute a class of SAA
which should provide monomers for hydroxylated nylon
6.
2. Synthesis of the monomeric scaffold 2
Access to the building block 2 requires the synthesis of
the thermodynamic monoacetonide of allono-lactone 11
for the introduction of an azide functionality at C-6
(Scheme 2).
Scheme 1.
Scheme 2. Reagents and conditions: (i) NaCN, H2O, 0°C, 24 h, then 80°C, 8 h; (ii) Me2CO, conc. H2SO4; (iii) 80% AcOH/H2O,
,
45°C; (iv) TsCl, pyridine, 3 A sieves, rt; (v) NaN3, DMF, 65°C; (vi) Me2C(OMe)2, CSA, Me2CO, 50°C.

D. F. A. Hunter, G. W. J. Fleet / Tetrahedron: Asymmetry 14 (2003) 3831–3839
3833
The Kiliani ascension of
D
-ribose 1 was effected using a
for the formation of an open chain derivative from
galactonolactone.33 The overall yield of the key inter-
mediate methyl ester 2 from the diacetonide 10 was
20%; 2 is readily available on a gram scale.
minor modification of a literature procedure.32 Treat-
ment of an aqueous solution of ribose with sodium
cyanide initially at 0°C and subsequently at 80°C
afforded, after lactonisation, a crude mixture of
D-
allono- 9 and
D
-altrono- 7 lactone. This mixture, with-
out any purification, was treated with acetone in the
3. Oligomers-dimer 3, tetramer 4, hexamer 5 and
octamer 6 of aminoallonate 2
presence of concentrated sulfuric acid to give an easily
separable mixture of the diacetonide of
lactone 10 in 30% overall yield together with the more
polar monoacetonide 5,6-O-isopropylidene- -altrono-
D-allono-1,4-
The azidoester 2 is the key building block for the
controlled formation of oligomeric hydroxylated [6]
nylons and requires reduction of the azide function to
give the amino component and hydrolysis of the ester
to give the carboxylic acid component. However,
hydrogenation of 2 produced the corresponding amine
which spontaneously closed to the corresponding lac-
tam. Consequently, this was not a convenient proce-
dure for the synthesis of well-defined oligomers.
D
1,4-lactone 8. Treatment of the allo diacetonide 10 with
aqueous acetic acid resulted in selective hydrolysis of
the 5,6 acetonide to afford the thermodynamic
monoacetonide 11 in 52% with recovery of 35% of
starting material; this is a relatively unselective hydroly-
sis of the terminal acetonide and the best overall yields
were obtained by stopping the reaction before all the
starting material had been consumed. Esterification of
the monoacetonide 11 with toluenesulfonyl chloride in
pyridine gave selective formation of the primary tosyl-
ate 12 in 73% yield. Subsequent reaction of the tosylate
12 with sodium azide in DMF afforded the azidolact-
one 13 in 81% yield. Finally, treatment of 13 with
dimethoxypropane in acetone in the presence of cam-
phor sulfonic acid (CSA) caused concomitant lactone
opening and acetonide protection of the resulting 4,5-
diol to produce the open chain ester 2 in 63% yield; the
conditions for this conversion are similar to those used
Thus it was necessary first to exchange the methyl ester
for the more hindered isopropyl ester; reaction of 2
with isopropanol in the presence of potassium carbon-
ate for 15 h under reflux induced transesterification to
afford the isopropyl ester 15 in 56% yield (Scheme 3).
The methyl ester 2 was hydrolysed by sodium hydrox-
ide in aqueous dioxane to give, after stirring with acid
ion exchange resin, the carboxylic acid 14. Hydrogena-
tion of the azido-isopropyl ester 15 in the presence of
palladium black gave the corresponding amine 16. The
Scheme 3. Reagents and conditions: (i) NaOH (aq.), dioxane, then Amberlite IR-120 H+; (ii) iso-PrOH, K2CO3, 90°C; (iii) H2, Pd
black, EtOAc; (iv) 1.5 equiv. EDCI, 1.5 equiv. HOBt, 1.5 equiv. DIPEA, CH2Cl2.

3834
D. F. A. Hunter, G. W. J. Fleet / Tetrahedron: Asymmetry 14 (2003) 3831–3839
crude acid and amine were then coupled by standard
reagents for the formation of peptide links. Activation
of the carboxylic acid 14 by 1-(3-dimethyl-aminopro-
pyl)-3-ethylcarbodiimide hydrochloride (EDCI), fol-
lowed by reaction with hydroxybenzotriazole (HOBt) in
the presence of diisopropylethylamine (DIPEA), pro-
duced an activated ester; further reaction with the crude
amine 16 formed the dimer 3 in an overall yield of 58%.
calcium hydride; pyridine was distilled from calcium
hydride and stored over dried 3 A molecular sieves;
,
hexane refers to 60–80°C petroleum ether; water was
distilled. N,N-Dimethylformamide was purchased dry
from the Aldrich Chemical Company in Sure/Seal™
bottles. All other solvents were used as supplied (ana-
lytical or HPLC grade) without prior purification.
Reactions performed under an atmosphere of nitrogen
or hydrogen gas were maintained by an inflated bal-
loon. pH 7 Buffer was prepared by dissolving KH2PO4
(85 g) and NaOH (14.5 g) in distilled water (950 ml).
All other reagents were used as supplied, without prior
purification. Thin-layer chromatography (TLC) was
An iterative procedure allowed the formation of the
tetramer 4. Thus hydrolysis of the dimer 3 gave the
crude acid 17 which was coupled with the crude amine
18 to give the tetramer 4 in an isolated yield of 53%.
Further iteration by coupling the acid 17 derived from
the dimer with the amine obtained from reduction of
the tetramer 4 gave the hexamer 5 in 45% yield. The
octamer 6 was obtained in 41% yield by coupling the
dimer acid 17 with the amine formed by reduction of
the hexamer.
performed on aluminium or plastic sheets coated with
60 F254 silica. Products were visualised using a spray of
0.2% w/v cerium(IV) sulphate and 5% ammonium
molybdate in 2 M sulphuric acid or 0.5% ninhydrin in
methanol (particularly for amines). Flash column chro-
matography was performed on Sorbsil C60 40/60 silica,
acidic ion-exchange chromatography was performed on
Amberlite® IR-120 (H+) and basic ion exchange chro-
matography was performed on Dowex® 1X8-400 (basic
form). CMAW refers to the eluent system—chloro-
form:methanol:acetic acid:water (60:30:3:5). Melting
points were recorded on a Ko¨fler hot block and are
corrected. Nuclear magnetic resonance (NMR) spectra
were recorded on a Bruker AM 500 or AMX 500 (1H:
500 MHz and 13C: 125.3 MHz) or where stated on a
Bruker AC 200 (1H: 200 MHz and 13C: 50.3 MHz) or
Bruker DPX 400 (1H: 400 MHz and 13C: 100.6 MHz)
spectrometer in deuterated solvent. Chemical shifts (l)
are quoted in ppm and coupling constants (J) in Hz.
Residual signals from the solvents were used as an
internal reference and 13C NMR spectra in D2O were
referenced to 1,4-dioxane (lC 67.4). 13C multiplicities
were assigned using a DEPT sequence. Infrared spectra
were recorded on a Perkin–Elmer 1750 IR Fourier
Transform, or Perkin–Elmer Paragon 1000 spectropho-
tometer using thin films on NaCl plates (thin film).
Only the characteristic peaks are quoted. Low resolu-
tion mass spectra (m/z) were recorded on VG MassLab
20-250, Micromass BIOQ-II, Micromass Platform 1,
Micromass TofSpec 2E, or Micromass Autospec 500
OAT spectrometers and high-resolution mass spectra
(HRMS m/z) on a Micromass Autospec 500 OAT
spectrometer. Techniques used were electrospray (ES),
matrix-assisted laser desorption ionisation (MALDI),
chemical ionisation (CI, NH3), or atmospheric pressure
Little epimerisation appeared to take place during acti-
vation and coupling; in some cases, small amounts of
possible epimeric products were obtained. However, the
majority of product in all the oligomer preparations
1
was homogeneous material as shown by 13C and H
NMR data reported in Section 5.
4. Structural studies and summary
This paper describes the first synthesis of polyhydroxyl-
ated nylon 6 oligomers derived from a protected 6-
amino-6-deoxy-D-allonic acid monomer. Structural
studies by NMR and by CD experiments on the
oligomers prepared in this paper provided no evidence
for the formation of secondary structures. Analogous
structures will be reported in a following paper34 which
describes the formation of linear oligomers from a
6-amino-6-deoxy-D-galactonic acid monomer, together
with the formation of a cyclic tetramer.
5. Experimental
Tetrahydrofuran was distilled under an atmosphere of
dry nitrogen from sodium benzophenone ketyl or pur-
chased dry from the Aldrich Chemical Company in
Sure/Seal™ bottles; dichloromethane was distilled from

D. F. A. Hunter, G. W. J. Fleet / Tetrahedron: Asymmetry 14 (2003) 3831–3839
3835
chemical ionisation (APCI) using partial purification by
5.3. 2,3-O-Isopropylidene-6-O-p-toluenesulfonyl-
D-
HPLC with 40:40:20 methanol:acetonitrile:water as elu-
ent, as stated. Optical rotations were recorded on a
Perkin–Elmer 241 polarimeter with a path length of 1
dm. Concentrations are quoted in g/100 ml.
allono-1,4-lactone 12
The monoacetonide 11 (2.14 g, 9.84 mmol) was dis-
solved in dry pyridine (100 ml) and stirred under nitro-
gen at room temperature with molecular sieves (3 A,
,
5.1. 2,3:5,6-Di-O-isopropylidene-
D
-allono-1,4-lactone 10
3.2 g) for 1 h. p-Toluenesulfonyl chloride (5.63 g, 29.5
mmol) was added and the mixture stirred for 5 h. TLC
(ethyl acetate:hexane, 3:1) indicated conversion of the
starting material (Rf 0.2) to a major product (Rf 0.8).
The reaction mixture was filtered through Celite, elut-
ing with dichloromethane, and the solvent removed in
vacuo, co-evaporating with toluene. The residue was
dissolved in ethyl acetate (300 ml) and washed with pH
7 buffer (40 ml). The organic phase was dried (MgSO4),
filtered and the solvent removed in vacuo. The residue
was purified by flash chromatography (ethyl acet-
ate:hexane, 1:2.5) to yield 2,3-O-isopropylidene-6-O-p-
and 5,6-O-isopropylidene- -altrono-1,4-lactone 8
D
A solution of sodium cyanide (36 g, 0.73 mol) in water
(300 ml) was added to a stirred solution of aqueous
D
-ribose 1 (79 g, 0.53 mol) at 0°C. The reaction mixture
was stirred for 20 h then heated at 80°C for 2 days.
After cooling, the mixture was passed down a column
of Amberlite IR-120 (H+) (approx. 1 kg), and eluted
with water (approx. 3 l). The eluent was concentrated in
vacuo affording
D
-allono-1,4-lactone 9 and
D-altrono-
1,4-lactone 7 as a dark brown viscous oil (94 g crude),
used without further purification. Concentrated sulfuric
acid (1.5 ml) was added dropwise to a stirred suspen-
toluenesulfonyl- -allono-1,4-lactone 12 (2.68 g, 73%) as
D
a yellow oil; [h]D25=−41.2 (c 0.69 in CHCl3); lH (400
MHz, (CD3)2CO): 1.35, 1.39 (2×3H, 2×s, C(CH3)2),
sion of
D
-allono-1,4-lactone 10 and
D-altrono-1,4-lac-
tone 8 (12.0 g, crude) in acetone (400 ml) at room
temperature. After 2 days, TLC (ethyl acetate) indi-
cated conversion of the starting material (Rf 0.0) to a
major product (Rf 0.6) and a minor product (Rf 0.9).
The reaction mixture was neutralised with sodium car-
bonate (15 g, excess), filtered through Celite and
purified by flash chromatography (ethyl acetate:hexane,
2.49 (3H, s, ArCH6 3), 4.13 (1H, ddd, J5,6 6.3 Hz, J5,6% 4.6
Hz, J5,4 3.4 Hz, H-5), 4.22 (1H, m, H-6), 4.29 (1H, m,
H-6%), 4.58 (1H, d, H-4), 4.77 (1H, d, J3,2 5.7 Hz, H-3),
4.92 (1H, d, H-2), 7.53 (2H, d, 2×ArH), 7.87 (2H, d,
2×ArH); m/z (APCI+): 373 (MH+, 100%).
5.4. 6-Azido-6-deoxy-2,3-O-isopropylidene-D-allono-1,4-
lactone 13
2:3) to yield 2,3:5,6-di-O-isopropylidene-
D
-allono-1,4-
lactone 10 (5.26 g, 30.2%) as a white crystalline solid,
mp 68–70°C (ethanol); [h]2D5=−68.2 (c 1.00 in CHCl3)
(lit.35 mp 71–73°C, [h]D23=−67); lH (500 MHz, CDCl3):
1.32, 1.39, 1.45, 1.47 (4×3H, 4×s, 2×C(CH3)2), 3.89 (1H,
dd, J6,6% 9.1 Hz, J6,5 5.1 Hz, H-6), 4.17 (1H, dd, J6%,5 7.5
Hz, H-6%), 4.31 (1H, ddd, J4,5 3.9 Hz, H-5), 4.48 (1H, d,
H-4), 4.72 (1H, d, J3,2 5.7 Hz, H-3), 4.76 (1H, d, H-2).
Sodium azide (702 mg, 10.8 mmol) was added to a
stirred solution of the tosylate 12 (2.68 g, 7.2 mmol) in
DMF (15 ml). The mixture was heated to 65°C and
stirred under nitrogen for 3.5 h. TLC (ethyl acet-
ate:hexane, 1:2) indicated conversion of the starting
material (Rf 0.3) to a major product (Rf 0.7). The
solvent was removed in vacuo (co-evaporation with
toluene), the residue dissolved in ethyl acetate (150 ml)
and washed with water (60 ml). The aqueous phase was
washed with ethyl acetate (3×30 ml), the organic layers
combined, dried (MgSO4) and the solvent removed in
vacuo. The residue was purified by flash chromatogra-
phy (ethyl acetate:hexane, 1:3) to yield 6-azido-6-deoxy-
Continued elution gave a mixture of products contain-
ing 5,6-O-isopropylidene-
monoacetonides of -allono-1,4-lactone.
D
-altrono-1,4-lactone 8 and
D
5.2. 2,3-O-Isopropylidene-D-allono-1,4-lactone 11
The fully protected allono-lactone 10 (5.22 g, 20.2
mmol) was dissolved in aqueous acetic acid (125 ml,
80% v/v) and stirred under nitrogen at 45°C. After 3 h,
TLC (ethyl acetate:hexane, 3:1) indicated partial con-
version of the starting material (Rf 0.7) to a major (Rf
0.2) and a minor (Rf 0.0) product. The solvent was
removed in vacuo (co-evaporation with toluene) and
the residue purified by flash chromatography (ethyl
2,3-O-isopropylidene-D-allono-1,4-lactone 13 (1.42 g,
81.4%) as a white crystalline solid; mp 51°C; [h]2D5=
−68.8 (c 0.95 in CHCl3); wmax(KBr): 2108 (N3), 1784
(CꢀO) cm−1; lH (400 MHz, (CD3)2CO): 1.39, 1.42 (2×
3H, 2×s, C(CH3)2), 3.60 (2H, m, H-6, H-6%), 4.09 (1H,
m, H-5), 4.58 (1H, d, J4,5 3.5 Hz, H-4), 4.83, 5.03
(2×1H, 2×d, J2,3 5.7 Hz, H-2, H-3), 5.37 (1H, d, JOH,5
5.5 Hz, OH); m/z (APCI+): 216 (M−N2+H+, 100%).
acetate:hexane, 3:1) to yield 2,3-O-isopropylidene-D-
allono-1,4-lactone 11 (2.31 g, 52.4%) as a white crys-
talline solid, mp 116–118°C; [h]2D5=−72.7 (c 1.1 in
(CH3)2CO); wmax(KBr): 3368 (b, OH), 1766 (CꢀO lac-
tone) cm−1; lH (400 MHz, (CD3)2CO): 1.36, 1.40 (2×
3H, 2×s, C(CH3)2), 3.70 (1H, dd, J6,6% 11.0 Hz, J6,5 6.3
Hz, H-6), 3.75 (1H, dd, J6%,5 5.4 Hz, H-6%), 3.93 (1H,
ddd, J5,4 2.6 Hz, H-5), 4.67 (1H, d, H-4), 4.76 (1H, d,
J3,2 5.6 Hz, H-3), 4.98 (1H, d, H-2); m/z (APCI+): 219
(MH+, 100%). A significant amount of recovered start-
ing material (1.82 g, 34.9%) was recycled through this
procedure.
5.5. Methyl 6-azido-6-deoxy-2,3:4,5-di-O-isopropyli-
dene-D-allonate 2
DL-Camphor sulfonic acid (380 mg, 1.64 mmol) was
added to a stirred solution of the azide 13 (1.00 g, 4.12
mmol) in 2,2-dimethoxypropane (12 ml) and acetone
(0.9 ml). The reaction mixture was stirred at 50°C for
15 h under an atmosphere of nitrogen. TLC (ethyl
acetate:hexane 1:2) indicated partial conversion of the
starting material (Rf 0.3) to a major product (Rf 0.7).
Sodium hydrogencarbonate (1 g, excess) was added, the

3836
D. F. A. Hunter, G. W. J. Fleet / Tetrahedron: Asymmetry 14 (2003) 3831–3839
reaction mixture stirred for 1 h and then filtered
through Celite. The solvent was removed in vacuo and
the residue purified by flash chromatography (ethyl
acetate:hexane, 1:8) to yield methyl 6-azido-6-deoxy-
propylidene- -allonic acid 14, used without further
D
purification.
A solution of the isopropyl ester 15 (250 mg, 0.73
mmol) in isopropyl alcohol was stirred under an atmo-
sphere of hydrogen in the presence of palladium black
(15 mg). After 6 h, TLC (ethyl acetate:hexane 1:4)
indicated complete conversion of the starting material
(Rf 0.7) to a major product (Rf 0.0). The reaction
mixture was filtered through Celite eluting with isopro-
pyl alcohol and the solvent removed in vacuo to yield
isopropyl amine 16, used without further purification.
2,3:4,5-di-O-isopropylidene- -allonate 2 (815 mg, 63%)
D
as a yellow oil; (HRMS: M−N2+H+: 288.144713.
C13H22NO6 requires: 288.144699); [h]2D5=+31.9 (c 0.95
in CHCl3); wmax(thin film): 2102 (N3), 1755 (CꢀO, ester)
cm−1; lH (400 MHz, CDCl3): 1.29, 1.34, 1.45, 1.54
(12H, 4×s, 2×C(CH
6 3)2), 3.47 (2H, m, H-6, H-6%), 3.72
(3H, s, CO2CH3), 4.13 (1H, dd, J4,5 6.0 Hz, J4,3 9.97 Hz,
6
H-4), 4.30 (1H, m, H-5), 4.34 (1H, dd, J3,2 6.3 Hz, H-3),
4.71 (1H, d, H-2); lC (100.6 MHz, CDCl3): 25.2, 25.5,
27.2, 27.7 (4×q, 2×C(C
6
H3)2), 50.7 (t, C-6), 52.0 (q,
CO2CH3), 74.2, 74.9, 76.2, 76,7 (4×d, C-2, C-3, C-4,
1-(3-Dimethyl-aminopropyl)-3-ethylcarbodiimide hydro-
chloride (EDCI) (239 mg, 1.24 mmol) was added to a
stirred solution of the acid 14, 1-hydroxybenzotriazole
(HOBt) (170 mg, 1.24 mmol) and diisopropylethyl-
amine (0.22 ml, 1.24 mmol) in dichloromethane (2 ml)
at 0°C. The mixture was stirred for 30 min, then a
solution of the crude amine 16 in dichloromethane (1.5
ml) added. The reaction mixture was stirred at room
temperature for 17 h. TLC (ethyl acetate:hexane 1:1)
indicated conversion of the starting materials to a
major product (Rf 0.5). The reaction mixture was
diluted with dichloromethane (25 ml) and washed with
dilute hydrochloric acid (2 M, 15 ml) and pH 7 buffer
(15 ml). The organic phase was dried (MgSO4), filtered,
concentrated in vacuo and the residue purified by flash
chromatography (ethyl acetate:hexane 1:2) to yield the
dimer 3 (256 mg, 58%) as an amorphous white solid;
(HRMS: M+H+: 601.308484. C27H45N4O11 requires:
601.308455); [h]D25=+19.2 (c 0.6 in CHCl3); wmax(thin
film): 2101 (N3), 1742 (b, CꢀO ester, amide I), 1686
(amide II), cm−1; lH (400 MHz, CDCl3): 1.27, 1.29
6
C-5), 109.7, 111.3 (2×s, 2×C6 (CH3)2), 168.7 (s, C-1); m/z
(APCI+ve): 288 (M−N2+H+, 100%).
5.6. Isopropyl 6-azido-6-deoxy-2,3:4,5-di-O-isopropyl-
idene-D-allonate 15
Potassium carbonate (217 mg, 1.57 mmol) was added to
a stirred solution of the methyl ester 2 (413 mg, 1.31
mmol) in isopropyl alcohol (3 ml). The reaction was
refluxed at 90°C under an atmosphere of nitrogen for
15 h. TLC (ethyl acetate:hexane 1:6) indicated partial
conversion of the starting material (Rf 0.3) to a major
product (Rf 0.5). The mixture was cooled, filtered
through Celite and the solvent removed in vacuo. The
residue was purified by flash chromatography (ethyl
acetate:hexane, 1:10) to yield isopropyl 6-azido-6-
deoxy-2,3:4,5-di-O-isopropylidene- -allonate 15 (252
D
mg, 56%) as
a
clear oil; (HRMS: M−N2+H+:
316.176013. C15H26NO6 requires: 316.175997); [h]2D5=
+36.9 (c 0.84 in CHCl3); wmax(thin film): 2103 (N3), 1744
(CꢀO ester) cm−1; lH (400 MHz, CDCl3): 1.28, 1.30
(2×3H, 2×d, Jvicinal 2.7 Hz, OCH(CH3 2
6 ) ), 1.31, 1.35,
1.36, 1.39, 1.44, 1.48, 1.50, 1.52 (8×3H, 8×s, 4×
C(CH6 3 2
) ), 3.44 (1H, dd, J6,6% 12.9 Hz, J6,5 3.6 Hz, H-6A),
(2×3H, 2×d, Jvicinal 1.9 Hz, OCH(CH6 3)2), 1.37, 1.43,
3.51 (2H, m, H-6%A, H-6B), 3.77 (1H, a-quin, Japp 6.8
Hz, H-6%B), 4.01 (1H, dd, J4,3 9.4 Hz, J4,5 5.4 Hz, H-4B),
4.17 (1H, dd, J4,3 9.3 Hz, J4,5 5.8 Hz, H-4A), 4.30 (2H,
m, H-5A, H-5B), 4.40 (3H, m, H-2B, H-3A, H-3B), 4.61
(1H, d, J2,3 6.2 Hz, H-2A), 5.07 (1H, septet, J 6.3 Hz,
1.45, 1.46 (4×3H, 4×s, 2×C(CH3)2), 3.58 (2H, m, H-6,
H-6%), 4.06 (1H, dd, J4,3 9.6 Hz, J4,5 5.9 Hz, H-4), 4.35
(1H, dd, J3,2 5.3 Hz, H-3), 4.48 (1H, m, H-5), 4.44 (1H,
d, H-2), 5.09 (1H, sep, J 6.3 Hz, OCH
(100.6 MHz, CDCl3): 21.6 (2×q, OCH(C
26.3, 27.5, 27.6 (4×q, 2×C(C
6
(CH3)2); lC
H3)2), 25.4,
6
OCH
MHz, CDCl3): 21.6 (2×q, OCH(C
26.1, 27.5, 27.5, 27.6, 28.0 (8×q, 4×C(C
6
(CH3)2), 6.84 (1H, t, J6%,NH 6.1 Hz, NH); lC (100.6
H3)2), 25.2, 25.5, 25.6,
H3)2), 37.8 (t,
H(CH3)2), 74.1, 75.1,
6
H3)2), 50.3 (t, C-6), 69.3 (d,
6
OC
6
H(CH3)2), 76.5, 77.2, 77.6, 78.7 (4×d, C-2, C-3, C-4,
6
C-5), 109.7, 112.5 (2×s, 2×C
6
(CH3)2), 170.2 (s, C-1); m/z
C-6B), 50.9 (t, C-6A), 69.3 (d, OC
6
(APCI+ve): 316 (M−N2+H+, 100%).
75.2, 76.2, 77.0, 77.3, 78.0, 78.7 (8×d, C-2A, C-3A, C-4A,
C-5A, C-2B, C-3B, C-4B, C-5B), 109.2, 109.7, 110.1,
112.3 (4×s, 4×C(CH3)2), 167.3, 170.1 (2×s, C-1A, C-1B);
m/z (APCI+ve): 601 (MH+, 100%), 623 (MNa+, 65%).
5.7. Isopropyl 6-deoxy-2,3:4,5-di-O-isopropylidene-6-N-
(6-azido-6-deoxy-2,3:4,5-di-O-isopropylidene-D-allonyl)-
amino-D-allonate (dimer) 3
5.8. Isopropyl 6-deoxy-2,3:4,5-di-O-isopropylidene-6-N-
(6-deoxy-2,3:4,5-di-O-isopropylidene-6-N-(6-deoxy-
2,3:4,5-di-O-isopropylidene-6-N-(6-azido-6-deoxy-2,3:4,5-
Aqueous sodium hydroxide (1 ml, 1 M) was added to a
stirred solution of the methyl ester 2 (260 mg, 0.83
mmol) in dioxane (4 ml). The reaction mixture was
stirred under nitrogen for 16 h at room temperature.
TLC (ethyl acetate:hexane 1:6) indicated complete con-
version of the starting material (Rf 0.6) to a major
product (Rf 0.0). The solvent was removed in vacuo
and the residue dissolved in water (2 ml) and stirred
with Amberlite IR-120(H+) resin for 1 min. The resin
was removed by filtration and the solvent removed in
vacuo to yield crude 6-azido-6-deoxy-2,3:4,5-di-O-iso-
di-O-isopropylidene-
D-allonyl)-amino-D-allonyl)-amino-
D
-allonyl)-amino- -allonate (tetramer) 4
D
Aqueous sodium hydroxide (0.11 ml, 1 M) was added
to a stirred solution of the dimer 3 (57 mg, 0.095 mmol)
in dioxane (1 ml). The reaction mixture was stirred
under nitrogen for 24 h at room temperature. TLC
(ethyl acetate:hexane 1:2) indicated complete conver-
sion of the starting material (Rf 0.2) to a major product

D. F. A. Hunter, G. W. J. Fleet / Tetrahedron: Asymmetry 14 (2003) 3831–3839
3837
5.9. Isopropyl 6-deoxy-2,3:4,5-di-O-isopropylidene-6-N-
(6-deoxy-2,3:4,5-di-O-isopropylidene-6-N-(6-deoxy-
2,3:4,5-di-O-isopropylidene-6-N-(6-deoxy-2,3:4,5-di-O-
isopropylidene-6-N-(6-deoxy-2,3:4,5-di-O-isopropyli-
dene-6-N-(6-azido-6-deoxy-2,3:4,5-di-O-isopropylidene-
(Rf 0.0). The solvent was removed in vacuo, the residue
dissolved in water (1 ml) and stirred with Amberlite
IR-120(H+) resin for 1 min. The resin was removed by
filtration and the solvent removed in vacuo to yield the
crude dimer acid acid 17, used without further
purification.
D
-allonyl)-amino-
D
-allonyl)-amino-
D-allonyl)-amino-D-
allonyl)-amino- -allonyl)-amino-
D
D
-allonate (hexamer) 5
A solution of the dimer 3 (51 mg, 0.085 mmol) in isopropyl
alcohol (2 ml) was stirred under an atmosphere of
hydrogen in the presence of palladium black (5 mg). After
24 h, TLC (ethyl acetate:hexane 1:2) indicated complete
conversion of the starting material (Rf 0.2) to a major
product (Rf 0.0). The reaction mixture was filtered
through Celite, and the solvent removed in vacuo to yield
the crude dimer amine 18, used without further purifica-
tion.
Aqueous sodium hydroxide (0.1 ml, 1 M) was added to
a stirred solution of the dimer 3 (41 mg, 0.068 mmol) in
dioxane (1 ml). The reaction mixture was stirred under
nitrogen for 24 h at room temperature. TLC (ethyl
acetate:hexane 1:1) indicated complete conversion of
the starting material (Rf 0.5) to a major product (Rf
0.0). The solvent was removed in vacuo, the residue
dissolved in water (1 ml) and stirred with Amberlite
IR-120(H+) resin for 1 min. The resin was removed by
filtration and the solvent removed in vacuo to yield the
crude dimer acid, used without further purification.
EDCI (29 mg, 0.15 mmol) was added to a stirred solution
of the dimer acid 17, HOBt (20 mg, 0.15 mmol) and
diisopropylethylamine (0.026 ml, 0.15 mmol) in
dichloromethane (0.5 ml) at 0°C. The mixture was stirred
for 30 min, then a solution of the dimer amine 3 in
dichloromethane (0.5 ml) added. The reaction mixture
was stirred at room temperature for 17 h. TLC (ethyl
acetate:hexane 3:2) indicated conversion of the starting
materials to a major product (Rf 0.15). The reaction
mixture was diluted with dichloromethane (10 ml) and
washed with dilute hydrochloric acid (2 M, 8 ml) and pH
7 buffer (8 ml). The organic phase was dried (MgSO4),
filtered, concentrated in vacuo and the residue purified
by flash chromatography (ethyl acetate:hexane 1:2) to
yield the tetramer 4 (50 mg, 53%) as an amorphous solid;
m/z (ES+ve), (MeCN:H2O, 1:1; CV=+50 V): 1137.54
(M+Na+; 100%), 1138.54 (60%), 1139.50 (20%), 1140.50
(4%). [C51H82N6O21Na]+ requires: 1137.54 (M+Na+;
100%), 1138.55 (60%), 1139.55 (20%), 1140.50 (4%).
[h]2D5=+25.9 (c 0.8 in CHCl3); wmax(thin film): 2102 (N3),
1743 (b, CꢀO ester), 1688 (amide), cm−1; lC (100.6 MHz,
A solution of the tetramer 4 (76 mg, 0.07 mmol) in
isopropyl alcohol (2 ml) was stirred under an atmo-
sphere of hydrogen in the presence of palladium black
(5 mg). After 24 h, TLC (ethyl acetate:hexane 3:2)
indicated complete conversion of the starting material
(Rf 0.2) to a major product (Rf 0.0). The reaction
mixture was filtered through Celite, and the solvent
removed in vacuo to yield the tetramer amine, used
without further purification.
EDCI (20 mg, 0.10 mmol) was added to a stirred
solution of the crude dimer acid, 17 HOBt (14 mg, 0.10
mmol) and diisopropylethylamine (0.018 ml, 0.10
mmol) in dichloromethane (0.5 ml) at 0°C. The mixture
was stirred for 30 min, then a solution of the crude
tetramer amine in dichloromethane (0.5 ml) added. The
reaction mixture was stirred at room temperature for 17
h. TLC (ethyl acetate:hexane 3:1) indicated conversion
of the starting materials to a major product (Rf 0.2).
The reaction mixture was diluted with dichloromethane
(10 ml) and washed with dilute hydrochloric acid (2 M,
8 ml) and pH 7 buffer (8 ml). The organic phase was
dried (MgSO4), filtered, concentrated in vacuo and the
residue purified by flash chromatography (ethyl ace-
tate:hexane 3:1) to yield the hexamer 5 (50 mg, 45%) as
an amorphous solid; m/z (ES+ve), (MeCN:H2O, 1:1;
CV=+70 V): 1651.85 (M+Na+; 100%), 1652.85 (87%),
1653.85 (40%), 1654.84 (15%), 1655.83 (3%).
[C75H120N8O31Na]+ requires: 1651.80 (M+Na+; 100%),
1652.80 (87%), 1653.80 (40%), 1654.80 (15%), 1655.83
(3%); [h]2D5=+34.5 (c 0.65 in CHCl3); wmax(thin film):
2103 (N3), 1739 (b, CꢀO ester), 1682 (amide), cm−1; lC
CDCl3): 21.6, 21.8 (2×q, OCH(C
25.6, 25.6, 26.1, 26.4 (8×q, 4×C(C
27.7, 27.8, 28.0, 28.1, (8×q, 4×C(C
(3×t, C-6B, C-6C, C-6D), 50.9 (t, C-6A), 69.3 (d,
CO2CH(CH3)2), 74.1, 74.4, 74.9, 75.0, 75.0, 75.1, 75.4,
6
H3)2), 25.2, 25.4, 25.5,
6
H3)2), 27.4, 27.6, 27.6,
6
H3)2), 37.7, 38.1, 38.5
6
76.0, 76.2, 77.0, 77.2, 77.3, 77.4, 78.0, 78.0, 78.8 (16×d,
C-2A, -3A, -4A, -5A, -2B, -3B, -4B, -5B, -2C, -3C, -4C, -5C,
-2D, -3D, -4D, -5D), 109.1, 109.2, 109.3, 109.7, 110.1, 110.2,
111.9, 112.2 (8×s, 8×C
(4×s, C-1A, -1B, -1C, -1D);lH (400MHz, CDCl3):1.28–1.55
(54H, m, 8×C(CH3)2, OCH(CH3)2), 8×C(CH3)2), 5.07
(1H, sept, J 6.3 Hz, CO2CH(CH3)2).
6 (CH3)2), 167.0, 167.3, 170.1, 170.7
6
6
6
(100.6 MHz, CDCl3): 21.6, 21.6 (2×q, OCH(C
25.2, 25.4, 25.5, 25.6, 25.6, 25.7, 26.1 26.4 (12×q, 6×
C(CH3)2), 27.4, 27.6, 27.6, 27.7, 27.7, 27.8, 28.0, 28.1
(12×q, 6×C(CH3)2), 37.7, 38.1, 38.1 38.5, 38.5 (5×t,
C-6B, C-6C, C-6D, C-6E, C-6F), 50.9 (t, C-6A), 69.3 (d,
OCH(CH3)2), 74.1, 74.4, 75.0, 75.1, 75.4, 75.9, 76.0,
6 H3)2),
Unit
A
NH
-
H-2 H-3 H-4 H-5 H-6/H-6%
6
6
4.61 4.41 4.19 4.29 3.44, 3.51
B, C or D 6.84 or4.39 4.39 4.00 4.33 3.80, 3.48
6.83
6
76.2, 77.0, 77.3, 77.4, 77.5, 78.0, 78.1, 78.1, 78.8 (16×d,
C-2A, -3A, -4A, -5A, -2B, -3B, -4B, -5B, -2C, -3C, -4C, -5C,
-2D, -3D, -4D, -5D, -2E, -3E, -4E, -5E, -2F, -3F, -4F, -5F),
109.1, 109.2, 109.2, 109.3, 109.7, 110.1, 110.2, 111.9,
B, C or D 6.90
4.63 4.35 4.08 4.19 3.76, 3.40
B, C or D 6.84 or4.48 4.48 4.03 4.31 3.63, 3.63
6.83
111.9, 112.2, (10×s, 12×C6 (CH3)2), 167.0, 167.1, 167.3,

3838
D. F. A. Hunter, G. W. J. Fleet / Tetrahedron: Asymmetry 14 (2003) 3831–3839
170.1, 170.7, 170.7 (6×s, C-1A, -1B, -1C, -1D, -1E, -1F);
lH (400 MHz, CDCl3): 1.25–1.55 (78H, m,
h. TLC (ethyl acetate:hexane 3:1) indicated conversion
of the starting materials to a major product (Rf 0.1).
The reaction mixture was diluted with dichloromethane
(10 ml) and washed with dilute hydrochloric acid (2 M,
8 ml) and pH 7 buffer (8 ml). The organic phase was
dried (MgSO4), filtered, concentrated in vacuo and the
residue purified by flash chromatography (ethyl ace-
tate:hexane 3:1) to yield the octamer 6 (41%) as an
amorphous solid; m/z (ES+ve), (MeCN:H2O, 1:1; CV=
+30 V): 2161.34 (M+NH+4; 80%), 2162.29 (100%),
2163.33 (70%), 2164.36 (45%). [C99H158N10O41Na]+
requires: 2161.09 (M+NH+4; 80%), 2162.10 (100%),
2163.10 (70%), 2164.10 (40%); [h]2D3=+33.0 (c 0.37 in
CHCl3); wmax(thin film): 2102 (N3), 1736 (b, CꢀO ester),
1684 (amide), cm−1; lC (100.6 MHz, CDCl3): 21.6, 21.6
CO2CH(CH6 3)2), 12×C(CH3)2), 3.37–3.44 (2H, m), 3.46–
3.53 (3H, m), 3.55–3.68 (3H, m), 3.73–3.83 (4H, m),
3.99–4.05 (3H, m), 4.08–4.13 (2H, m), 4.17–4.21 (3H,
m), 4.29–4.43 (9H, m), 4.46–4.51 (4H, m), 4.61–4.63
(3H, m), 5.07 (1H, sept, J 6.3 Hz, CO2CH6 (CH3)2),
6.81–6.85 (3H, m, 3×NH), 6.90 (2H, m, 2×NH). Only
partial assignment of the proton spectrum was possible
and is recorded in the table below.
Unit NH H-2 H-3 H-4 H-5 H-6/H-6%
A
4.62 4.41 4.19 4.29 3.43, 3.52
6.83 4.44 4.44 4.00 4.33 3.80, 3.48
6.89 4.63 4.36 4.10 4.20 3.76, 3.39
(2×q, CO2CH(C
26.4 (7×q, 8×C(C
27.8, 28.0, 28.1 (9×q, 8×C(C
38.5 (5×t, C-6B, C-6C, C-6D, C-6E, C-6F, C-6G, C-6H),
50.9 (t, C-6A), 69.4 (d, CO2C
H(CH3)2), 74.1, 74.4, 75.0,
6
H3)2), 25.2, 25.4, 25.5, 25.6, 25.7, 26.1
H3)2), 27.4, 27.6, 27.6, 27.7, 27.7, 27.8,
H3)2), 37.7, 38.1, 38.1 38.5,
6
6
Unambiguous assignment of the further three monomer
units was impossible due to the significant signal
overlap.
6
75.2, 75.4, 75.9, 76.2, 77.0, 77.3, 77.4, 78.1, 78.8 (12×d,
C-2A, -3A, -4A, -5A, -2B, -3B, -4B, -5B, -2C, -3C, -4C, -5C,
-2D, -3D, -4D, -5D, -2E, -3E, -4E, -5E, -2F, -3F, -4F, -5F,
-2G, -3G, -4G, -5G, -2H, -3H, -4H, -5H), 109.2, 109.2,
109.3, 109.3, 109.7, 110.1, 110.2, 111.9, 111.9, 112.2,
5.10. Isopropyl 6-deoxy-2,3:4,5-di-O-isopropylidene-6-
N-(6-deoxy-2,3:4,5-di-O-isopropylidene-6-N-(6-deoxy-
2,3:4,5-di-O-isopropylidene-6-N-(6-deoxy-2,3:4,5-di-O-
isopropylidene-6-N-(6-deoxy-2,3:4,5-di-O-isopropyli-
dene-6-N-(6-deoxy-2,3:4,5-di-O-isopropylidene-6-N-(6-
deoxy-2,3:4,5-di-O-isopropylidene-6-N-(6-azido-6-deoxy-
(10×s, 16×C
(5×s, C-1A, -1B, -1C, -1D, -1E, -1F, -1G, -1H); lH (400
MHz, CDCl3): 1.24–1.55 (102H, m, CO2CH(CH3)2),
16×C(CH3)2), 3.35–3.84 (16H, m), 3.99–4.21 (12H, m),
4.27–4.44 (11H, m), 4.46–4.51 (5H, m), 4.61–4.63 (4H,
m), 5.07 (1H, sept, J 6.3 Hz, CO2CH(CH3)2), 6.82–6.86
6 (CH3)2), 167.0, 167.1, 167.3, 170.1, 170.7
6
6
2,3:4,5-di-O-isopropylidene-
D
-allonyl)-amino-
D
-allonyl)-
amino-
D
-allonyl)-amino-
D
-allonyl)-amino-
D
-allonyl)-
-allonate
6
amino-
D
-allonyl)-amino-
D
-allonyl)-amino-
D
(4H, m, 4×NH), 6.91 (3H, m, 3×NH). Further assign-
ment of the octamer proton NMR was not possible in
view of the complex signal overlap.
(octamer) 6
Aqueous sodium hydroxide (0.04 ml, 1 M) was added
to a stirred solution of the dimer 3 (17 mg, 0.028 mmol)
in dioxane (0.5 ml). The reaction mixture was stirred
under nitrogen for 24 h at room temperature. TLC
(ethyl acetate:hexane 1:1) indicated complete conver-
sion of the starting material (Rf 0.5) to a major product
(Rf 0.0). The solvent was removed in vacuo, the residue
dissolved in water (1 ml) and stirred with Amberlite
IR-120(H+) resin for 1 min. The resin was removed by
filtration and the solvent removed in vacuo to yield the
crude dimer acid 17, used without further purification.
Acknowledgements
This work has been supported by a BBSRC graduate
award (to D.F.A.H.).
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mixture was filtered through Celite, and the solvent
removed in vacuo to yield the hexamer amine, used
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