Oxetane amino acids: synthesis of tetrameric and hexameric carbopeptoids derived from l-ribo 4-(aminomethyl)-oxetan-2-carboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2008.03.030

The synthesis of methyl 2,4-anhydro-5-azido-3-O-benzyl-5-deoxy-l-ribonate, a δ-2,4-cis-oxetane-azido ester scaffold derived from l-arabinose, is reported. Iterative coupling methods were utilised to form homo-oligomers up to the hexamer in order to investigate the secondary structural preferences of these systems.

Full text of DOI:10.1016/j.tetasy.2008.03.030

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 976–983
Oxetane amino acids: synthesis of tetrameric and hexameric
carbopeptoids derived from L-ribo 4-(aminomethyl)-oxetan-
2-carboxylic acid
Beatrice Lopez-Ortega, Sarah F. Jenkinson, Timothy D. W. Claridge and George W. J. Fleet*
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Received 25 February 2008; accepted 27 March 2008
Abstract—The synthesis of methyl 2,4-anhydro-5-azido-3-O-benzyl-5-deoxy-L-ribonate, a d-2,4-cis-oxetane-azido ester scaffold derived
from L-arabinose, is reported. Iterative coupling methods were utilised to form homo-oligomers up to the hexamer in order to investigate
the secondary structural preferences of these systems.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
to the formation of several biologically active peptidomi-
metics with much improved metabolic stability.10
Peptides and proteins are involved in a vast array of bio-
logical processes and are therefore attractive targets for
drug design.1 Poor bioavailability and metabolic stability
of peptidic drugs, however, have resulted in significant lim-
itations. Sugar amino acids (SAA’s) are versatile building
blocks for the formation of foldamers and peptidomimet-
ics; hence there has been much interest in their synthesis.2
SAA’s have many advantages in the design of peptidomi-
metics as they are conformationally restricted by their ring
size; the backbone functionality can readily be modified to
give, for example, chain branching3 unsaturation4 and
deoxygenation.5 Many different stereochemistries can be
accessed and the acid and amino groups can be introduced
at different positions on the ring to allow access to a-, b-, c-
and d-amino acids (Fig. 1).
Foldamers are molecules which display a predisposition to-
wards the formation of well-defined secondary structure in
short sequences. Investigations into the synthesis and sec-
ondary structure of homo-oligomers of conformationally
restricted11,12 THF and THP SAA’s provide many exam-
ples of predisposition towards secondary structures in rela-
tively small molecules.13–15 Ring contraction to the more
conformationally stable 4-membered oxetane system may
confer more rigidity upon the SAA and hence increase
the potential for their oligomers to adopt stable secondary
structures. In the case of the cis b-amino acid oxetane
oligomers derived from D-xylose and L-rhamnose these
were seen to adopt helical structures stabilised by 10-mem-
bered hydrogen bonds.16 Investigations into the 2,4-trans-
oxetane d-amino acid scaffolds have been reported,
however, the oligomers did not appear to adopt well-
defined secondary structures stabilised by hydrogen bond-
ing.17 Here the synthesis of the 2,4-cis-oxetane amino acid
building blocks and coupling to form homo-oligomers is
reported.
The use of d-SAA’s as peptidomimetics was demonstrated
by Kessler et al. who investigated the conformational influ-
ences of several tetrahydropyran (THP) SAA’s on peptide
chains by replacing them with the Gly-Gly fragment of
Leu-enkephalin.6 The d-SAA dipeptide isosteres 1 and 2
(Fig. 2) were seen to induce different secondary structures
with 1 inducing a b-turn type structure and 2 inducing a
c-turn type structure. Further investigation into THP7
and tetrahydrofuran (THF)8,9 dipeptide isosteres has led
2. Synthesis of oxetane amino acid oligomers
Two strategies could be envisaged for the formation of the
desired 2,4-cis-oxetane amino acid monomers, with the
introduction of the azide functionality either before or after
*
Corresponding author. E-mail: george.fleet@chem.ox.ac.uk
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.030

B. Lopez-Ortega et al. / Tetrahedron: Asymmetry 19 (2008) 976–983
977
R
O
O
O
γ
α
δ
H
N α
δ
H2N
OH
H2N
β
OH
OH
O
R
oxetane
O
O
δ
δ
δ
O
O
O
O
α
α
O
O
α
OH
O
H2N
OH
H2N
OH
H2N
furanoses
pyranoses
α
HO
HO
OH
HO
OH
O
O
O
δ
δ
α
α
H2N
OH
HO
OH
H2N
OH
δ
HO
OH
H2N
OH
HO
OH
OH
OH
Figure 1. Stereochemically constrained SAA’s: examples of the diversity of d-SAA dipeptide isosteres available.
tions of the oxetane ring formed.4,18 Thus the initial oxe-
tane target was azido ester 9.
OH
O
OH
O
HO
H2N
OH
OH
H2N
MeO
OH
OH
The protected L-arabinose 3 (Scheme 1) with only the C-3
hydroxyl unprotected was the common intermediate for
the two routes.19 Deprotection of the silyl group, benzyl-
ation of the two free hydroxyls, followed by acetonide
deprotection and bromine oxidation gave the arabinono-
lactone 5 in good yield. Activation of the free hydroxyl
group as a trifluoromethanesulfonyl ester followed by
treatment with basic methanol yielded the desired oxetane
ring 6 and provided the desired masked acid functionality,
the ester group at C-1.20 Protection of both the C-3 and C-
5 hydroxyl groups prior to the ring closure prevented com-
petitive formation of 3 or 5-membered rings. Deprotection
O
O
1
2
β-turn
γ-turn
Figure 2.
the ring contraction (Scheme 1). The key step, the ring clo-
sure of an a-triflate of a c-lactone in basic methanol, is
known to form oxetane rings in good yields provided that
there is a trans relationship between the C-2 and C-3 posi-
TBDPSO
O
OH
OH
HO
N3
O
O
O
i), ii)
37%
iii), iv)
68%
v), vi)
90%
Route B
O
O
O
HO
O
O
O
OH
HO
BnO
BnO
3
11
12
L-arabinose
vii), viii)
90%
iv), iii)
Route A
BnO
75%
OBn
OH
O
BnO
N3
O
O
O
ix), x)
O
vii), viii)
75%
O
xi)
quant
O
O
O
78%
CO2Me
BnO
HO
CO2Me
BnO
OH
BnO
OH
BnO
7
6
13
5
4
v)
O
ix)
OTs
N3
OTs
N3
N3
O
vi)
O
x)
O
O
O
71%
(over 2
steps)
O
HO
HO
BnO
CO2Me
CO2Me
CO2Me
CO2Me
BnO
OTf
8
9
10
14
15
Scheme 1. Reagents and conditions: (i) TBDPSCl, imidazole, DMF, 60 °C, 2 h; (ii) CuSO4, acetone, ( )-camphor sulfonic acid, rt, 4 h; (iii) NaH, BnBr,
nBu4NI, DMF, ꢀ10 to 5 °C, 3 h; (iv) nBu4NF, THF, rt, 2 h; (v) TsCl, pyridine; (vi) NaN3, DMF; (vii) TFA/H2O 3:2, rt, 30 min; (viii) Br2, BaCO3,
dioxane–H2O, 0 °C to rt, 18 h; (ix) Tf2O, DCM, pyridine, ꢀ30 °C, 30 min; (x) MeOH, K2CO3, ꢀ30 to ꢀ10 °C, 1 h; (xi) Pd/C, H2, MeOH, rt, 45 min.

978
B. Lopez-Ortega et al. / Tetrahedron: Asymmetry 19 (2008) 976–983
of the benzyl ether protecting groups by hydrogenation
proceeded smoothly to give oxetane 7 in good yield (16%
over 9 steps). In order to introduce an azide group, to serve
as the masked amine, selective activation of the primary
alcohol followed by azide displacement was required.
Although selective tosylation to give tosylate 8 was success-
ful, subsequent azide displacement did not yield any of the
desired azido-ester 9. The reason for this was unclear; how-
ever, b-hydroxy oxetanes are prone to retro-aldol ring
opening in basic conditions17 and it may be that the open
chain product 10 (Scheme 1) might have been formed pref-
erentially. The alternative route in which the azide func-
tionality was introduced prior to the ring contraction was
therefore investigated. Thus, reaction of 3 with benzyl bro-
mide and sodium hydride in DMF followed by deprotec-
tion of the silyl protecting group gave the furanose 11 in
which only the C-5 hydroxyl group is free for further
manipulation. Activation of the alcohol with tosyl chloride
in pyridine at low temperature and subsequent displace-
ment with sodium azide afforded 12 in excellent yield
(90% over two steps). Acidic hydrolysis to the lactol and
oxidation with bromine gave lactone 13 which on triflation
of the free hydroxyl group followed by treatment with
potassium carbonate in methanol yielded the desired oxe-
tane monomer unit 15 in 15% over 10 steps.
The synthesis of dimer 19 was accomplished by an iterative
coupling procedure in which the amine derived from azido
ester 15 was coupled with the acid also derived from azido
ester 15 (Scheme 2). For the synthesis of amine 18,
however, transesterification of 15 to 17 was first carried
out to avoid intramolecular lactamisation and oligo-
merisation. The azido ester 15 was therefore treated with
potassium carbonate in isopropanol to afford isopropyl
ester 17 and then reacted with palladium on carbon under
an atmosphere of hydrogen to give the desired amine 18.
The azido ester 15 was also treated with sodium hydroxide
in a mixture of tetrahydrofuran and water and then sub-
sequently acidified to yield acid 16. The acid and amine
were used without further purification in the coupling
reaction, with O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyl-
uronium tetrafluoroborate (TBTU) and triethylamine
in N,N-dimethylformamide to give dimer 19 in 89% yield
calculated from 17.
Tetramer 22 was obtained in a similar manner from the
coupling of dimer amine 20 and dimer acid 21 with TBTU
and triethylamine in 54% yield from the dimer. Finally,
hexamer 24 was successfully prepared by treating dimer
amine 20 and tetramer acid 23 with TBTU and triethyl-
amine giving hexamer 24 in 64% yield from the dimer.
N3
N3
O
O
ii)
CO2Me
CO2H
OBn
OBn
R2
15
16
O
O
O
iv)
CO2R1
i)
N
H
OBn
OBn
19 R1 = iPr, R2 = N3
N3
H2N
O
O
iii)
i
i
v)
vi)
CO2 Pr
CO2 Pr
OBn
OBn
21
R1 = H, R2 = N3
20
R1 = iPr, R2 = NH2
18
17
vii)
R2
O
O
O
O
O
O
O
viii)
CO2R1
23
R1 = H, R2 = N3
N
H
N
N
H
H
OBn
OBn
OBn
OBn
20
R1 = iPr, R2 = NH2
R1 = iPr, R2 = N3
22
ix)
R2
O
O
O
O
O
O
O
O
O
O
O
CO2R1
N
H
N
N
N
N
H
H
H
H
OBn
OBn
OBn
OBn
R1 = iPr, R2 = N3
OBn
OBn
24
i
Scheme 2. Reagents and conditions: (i) PrOH, K2CO3, rt, 19 h, 85%; (ii) NaOH, H2O, THF, rt, 6 h; (iii) Pd/C, H2, AcOEt, rt, 5 h; (iv) TBTU, Et3N,
DMF, rt, 16 h, 89% (from 17); (v) Pd/C, H2, AcOEt, rt, 22 h, 87%; (vi) NaOH, H2O, THF, rt, 5 h; (vii) TBTU, Et3N, DMF, rt, 2.5 h, 54% (from 19); (viii)
NaOH, H2O, THF, rt, 3 h; (ix) TBTU, Et3N, DMF, rt, 18 h, 64% (from 19).

B. Lopez-Ortega et al. / Tetrahedron: Asymmetry 19 (2008) 976–983
979
3. Conclusion
trometer by electrospray ionisation (ES) as stated. For
ES mass spectra the spectrometer was operated at a resolu-
tion of 5000 full width half height. Positive ion spectra were
calibrated relative to PEG with tetraoctylammonium bro-
mide as the internal lock mass. Negative ion spectra were
calibrated relative to poly-DL-alanine with Leu-enkephalin
as the internal lock mass. Optical rotations were recorded
on a Perkin–Elmer 241 polarimeter with a path length of
1 dm. Concentrations are quoted in g/100 mL.
The synthesis of the 2,4-cis oxetane azido ester monomer
unit 15 was successfully achieved in an overall yield of
15% over 10 steps. This was then subsequently used to
form homo-oligomers up to the hexamer, via solution
phase iterative coupling, in good yields. The investigations
into the secondary structural preferences of these oligomers
are described in the following paper.21
4.2. 5-O-tert-Butyldiphenylsilyl-1,2-O-isopropylidene-b-L-
arabinofuranose 3
4. Experimental
4.1. General
L-Arabinose (20 g, 133.3 mmol) was added to a solution of
tert-butyldiphenylsilylchloride (34.6 mL, 133.3 mmol) and
imidazole (18.1 g, 266 mmol) in N,N-dimethylformam-
ide (265 mL). The mixture was heated to 60 °C for 2 h
after which time the resulting solution was poured over
HCl (1 M, 280 mL) and extracted with dichloromethane
(3 ꢁ 150 mL). The organic extracts were washed with water
(100 mL) and sodium bicarbonate (satd aq 100 mL), dried
over MgSO4 and concentrated under reduced pressure. The
crude product was purified by flash column chromatogra-
phy to give the lactol as a colourless oil (25 g, 47%). The
lactol was subsequently dissolved in acetone (260 mL)
and anhydrous copper sulfate (32 g) added. ( )-Cam-
phor-10-sulfonic acid was added until the solution reached
pH 2. The mixture was stirred at room temperature for 4 h
when TLC (1:1, ethyl acetate/hexane) showed the forma-
tion of one major product (R f 0.51). A further portion
of copper sulfate (15 g) was added and after a further 2 h
TLC showed full consumption of the starting material.
The mixture was neutralised by careful addition of sodium
carbonate(s) and filtered through CeliteÒ. The solvent was
removed in vacuo and the resulting residue was dissolved in
dichloromethane (500 mL), extracted with water (100 mL)
and brine (100 mL), dried over MgSO4 and concentrated
in vacuo. The residue was purified by column chromato-
Tetrahydrofuran was distilled under an atmosphere of dry
nitrogen from sodium benzophenone ketyl or purchased
dry from the Aldrich Chemical Company in Sure/SealTM
bottles; dichloromethane was distilled from calcium hy-
dride; 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/SealTM bottles. All other sol-
vents were used as supplied (analytical or HPLC grade)
without prior purification. Reactions performed under an
atmosphere of nitrogen or hydrogen gas were maintained
by an inflated balloon. A pH 7 buffer was prepared by dis-
solving KH2PO4 (85 g) and NaOH (14.5 g) in distilled
water (950 mL). Imidazole was recrystallised from dichlo-
romethane. All other reagents were used as supplied, with-
out prior purification. Thin layer chromatography (TLC)
was performed on aluminium sheets coated with 60 F254 sil-
ica. Sheets were visualised using a spray of 0.2% w/v cer-
ium (IV) sulfate and 5% ammonium molybdate in 2 M
sulfuric acid. Flash column chromatography was per-
formed on Sorbsil C60 40/60 silica. Melting points were re-
corded on a Ko¨fler hot block and are uncorrected. 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 (d) are quoted in ppm and cou-
pling constants (J) in Hz. Residual signals from the sol-
vents were used as an internal reference. 13C multiplicities
were assigned using a DEPT sequence. Infrared spectra
were recorded on a Perkin–Elmer 1750 IR Fourier Trans-
form, or Perkin–Elmer Paragon 1000 spectrophotometer
using thin films on NaCl plates (thin film) or as KBr disks
as stated. Only the characteristic peaks are quoted. Low
resolution mass spectra (m/z) were recorded using the fol-
lowing techniques: electrospray ionisation (ES), chemical
ionisation (CI, NH3), or atmospheric pressure chemical
ionisation (APCI). ES mass spectra were measured on a
Micromass BioQ II-ZS mass spectrometer. CI mass spectra
were recorded on a Micromass 500 OAT spectrometer.
APCI mass spectra were recorded on a Micromass Plat-
form 1 mass spectrometer via an ‘Openlynx’ system. High
resolution mass spectra (HRMS) were recorded on a
Micromass 500 OAT spectrometer by chemical ionisation
(CI, NH3) or a Waters 2790-Micromass LCT mass spec-
graphy and the protected arabinose 3 was obtained as an
23
oil (21.9 g, 78%). ½aꢂD ¼ ꢀ5:0 (c 1.8, CHCl3) {lit.22 [a] D
=
ꢀ5 (c 1.2, CHCl3)}; mmax (thin film): 3450 (s, OH); dH
(CDCl3, 200 MHz): 1.08 (9H, s, OSiPh2C(CH3)3), 1.29
(3H, s, CCH3), 1.34 (3H, s, CCH3), 2.16 (1H, br s, OH),
3.80–3.91 (2H, m, H5), 4.08 (1H, dt, H4, J 2.4, 6.5), 4.43
(1H, d, H3, J 2.2), 4.55 (1H, d, H2, J 4.1), 5.89 (1H, d,
H1, J 4.0), 7.34–7.48 (6H, m, ArH), 7.66–7.72 (4H, m,
ArH); dC (CDCl3, 50 MHz): 19.7 (OSiPh2C(CH3)), 26.6
(CH3), 27.3 (CH3), 64.1 (CH2), 76.7 (CH), 87.5 (CH),
87.9 (CH), 106.0 (C1), 113.0 (C(CH3)2), 128.2, 130.3
(2 ꢁ ArH), 133.6, 133.7 (ArC), 136.1 (ArH).
4.3. 3-O-Benzyl-1,2-O-isopropylidene-b-L-arabinofuranose
11
Sodium hydride (295 mg, 7.28 mmol) was suspended in
N,N-dimethylformamide (5 mL) and cooled to ꢀ20 °C. A
solution of 5-O-tert-butyldiphenylsilyl-1,2-O-isopropyli-
dene-b-L-arabinofuranose 3 (2.07 g, 4.85 mmol) in N,N-
dimethylformamide (10 mL) was added dropwise and the
mixture allowed to warm to room temperature over
30 min. The resulting suspension was cooled to ꢀ20 °C
and nBu4NI (215 mg, 0.58 mmol) and BnBr (750 lL,

980
B. Lopez-Ortega et al. / Tetrahedron: Asymmetry 19 (2008) 976–983
6.309 mmol) were added. The mixture was stirred for
15 min at ꢀ17 °C and then was allowed to warm to room
temperature over a period of 30 min. After this time,
TLC (1:3, ethyl acetate/hexane) showed no starting mate-
rial (Rf 0.23) but the formation of one major product
(Rf 0.65). The reaction was quenched with ammonium
chloride (satd aq 15 mL) and the aqueous layer was
extracted with ethyl acetate (3 ꢁ 100 mL). The combined
organic extracts were washed with brine (20 mL), dried
over MgSO4 and concentrated under reduced pressure.
The residue was dissolved in tetrahydrofuran (51 mL)
and a solution of tetrabutylammoniumfluoride 1.0 M in
tetrahydrofuran (9.7 mL, 9.7 mmol) was added. After 2 h
at room temperature, TLC (1:3, ethyl acetate/hexane)
showed complete consumption of the starting material
and the formation of one product (Rf 0.25). Water
(25 mL) was added and the mixture was extracted with
ether (3 ꢁ 100 mL). The combined organic extracts were
washed with brine (5 mL), dried over MgSO4 and concen-
trated in vacuo. A residue was obtained which was purified
by column chromatography to give the title compound 11
as a white solid (990 mg, 73%). Found: C, 64.23; H, 7.19;
C15H20O5 requires: C, 64.27; H, 7.19; mp: 80–82 °C {lit.23
mp: 77–78 °C; lit.24 (for D-enantiomer) mp: 79–80 °C}; mmax
(KBr): 3492 (m, OH), 1379 (C(CH3)2); dH (CDCl3,
(CDCl3, 50 MHz): 21.5 (ArCH3), 25.8 (CCH3), 26.6
(CCH3), 68.4 (CH2), 71.6 (CH2), 81.9 (CH), 82.1 (CH),
84.3 (CH), 105.9 (C1), 112.6 (C(CH3)2), 127.7, 127.9,
127.9, 128.4, 129.8 (5 ꢁ ArH), 132.4, 136.7, 144.9
(3 ꢁ ArC); m/z (APCI+): 418 (MꢀCH4þ, 70%), 187
(100%).
4.5. 5-Azido-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-b-L-
arabinofuranose 12
3-O-Benzyl-5-(p-toluenesulfonyl)-1,2-O -isopropylidene-b-
L-arabinofuranose (6.41 g, 14.7 mmol) was dissolved in
N,N-dimethylformamide (37 mL) and NaN3 (1.43 g,
14.7 mmol) was added. The reaction mixture was heated
to 90 °C and after 16 h, TLC (1:4, ethyl acetate/hexane)
showed the formation of one product (R 0.42). The mix-
f
ture was cooled to room temperature and water (30 mL)
was added. The solvents were evaporated and the resulting
residue was dissolved in water (50 mL) and ethyl acetate
(200 mL). The aqueous phase was extracted with ethyl ace-
tate (2 ꢁ 100 mL) and the combined organic extracts were
washed with brine (10 mL), dried over MgSO4 and concen-
trated. The resulting residue was purified by flash chroma-
tography to give azide 12 as a white solid (4.01 g, 91%).
Found: C, 59.23; H, 6.21; N, 13.53; C15H19N3O4 requires:
23
200 MHz): 1.34, 1.53 (6H, 2 ꢁ s, C(CH3)2); 2.39–2.55
(1H, m, OH), 3.73 (2H, a-t, H5, J 5.7), 3.97 (1H, dd, H3,
J 0.9, 3.3), 4.20 (1H, dt, H4, J 3.3, 5.5), 4.60 (2H, AB
C, 59.01; H, 6.27; N, 13.76; mp 47–49 °C; ½aꢂ ¼ ꢀ55:8
(c 1.1, CHCl3); mmax (KBr): 2092 (s, N3); dHD (CDCl3,
200 MHz): 1.35, 1.55 (6 H, 2 ꢁ s, C(CH3)2), 3.39 (1H,
dd, H5, J 6.1, 12.6), 3.55 (1H, dd, H50, J 6.6, 12.6), 3.94
(1H, dd, H3, J 0.5, 3.1), 4.18 (1H, dt, H4, J 3.1, 6.4),
4.56 (1H, d, OCHPh, J 11.8), 4.65 (1H, d, OCHPh, J
11.8), 4.66 (1H, a-d, H2, J 4.6), 5.91 (1H, d, H1, J 4.0),
7.28–7.43 (5H, m, ArH); dC (CDCl3, 50 MHz): 26.2, 27.0
(2 ꢁ C(CH3)2), 52.3 (C5), 71.9 (OCH2Ph), 83.0 (CH),
83.2 (CH), 84.8 (CH), 105.7 (C1), 113.0 (C(CH3)2), 127.8,
128.0, 128.5 (3 ꢁ ArH), 136.9 (ArC); m/z (APCI+): 278
(M+H+ꢀN2, 45%), 112 (100%).
0
system d5 4.55, d5 4.64, OCH2Ph, J 11.5); 4.68 (1H,
dd, H2, J 0.9, 4.1), 5.91 (1H, d, H1, J 4.1), 7.29–
7.37 (5H, m, ArH); dC (CDCl3, 50 MHz): 26.2 (CCH3),
27.0 (CCH3), 62.6 (CH2), 71.7 (CH2), 82.6 (CH), 85.1
(CH), 85.5 (CH), 105.1 (C1), 112.8 (C(CH3)2), 127.7,
127.9, 128.4 (3 ꢁ ArH), 137.1 (ArC); m/z (APCI+): 303
(M+Na+, 5%), 121 (100%).
4.4. 3-O-Benzyl-5-(p-toluenesulfonyl)-1,2-O-isopropylidene-
b-L-arabinofuranose
4.6. 5-Azido-3-O-benzyl-5-deoxy-L-arabinono-1,4-lactone 13
˚
p-Toluenesulfonyl chloride (670 mg, 3.51 mmol) and 4 A
molecular sieves (900 mg) were added to a solution of 11
(656 mg, 2.34 mmol) in pyridine (5.3 mL) at ꢀ10 °C. The
mixture was allowed to reach room temperature and after
24 h, TLC (1:2, ethyl acetate/hexane) showed one product
(Rf 0.49). The mixture was filtered through CeliteÒ and
eluted with dichloromethane (200 mL) and the resulting
solution was washed with pH 7 buffer (10 mL). The aque-
ous layer was extracted with ethyl acetate (2 ꢁ 100 mL)
and the combined organic extracts were dried over MgSO4
and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography
to give 3-O-benzyl-5-(p-toluenesulfonyl)-1,2-O-isopropyl-
idene-b- L-arabinofuranose as a white solid (1.01 g, 99%).
Found: C, 60.69; H, 5.98; C22H26O7S requires: C, 60.81;
Azide 12 (2.65 g, 8.67 mmol), was dissolved in TFA:H2O,
3:2 (40 mL) and the mixture was stirred at room tempera-
ture for 30 min, when TLC (2.5:1, ethyl acetate/hexane)
showed no starting material and one product on the base-
line. The solvents were removed in vacuo and the resulting
residue was co-evaporated with toluene (3 ꢁ 100 mL) and
dried in vacuo. The crude lactol was dissolved in 1,4-diox-
ane:water, 2:1 (40 mL) and barium carbonate (5.13 g,
26.01 mmol) was added. The mixture was cooled to 0 °C
and bromine (1.34 mL, 26.01 mmol) was added dropwise
after which the reaction allowed to warm to room temper-
ature. After 16 h, TLC (1:2.5, ethyl acetate/hexane) showed
one product (Rf 0.21). Sodium thiosulfate (satd aq) was
added to quench the reaction and the mixture was
extracted with ethyl acetate (3 ꢁ 150 mL). The combined
organic extracts were washed with brine (10 mL), dried
over MgSO4 and concentrated under reduced pressure.
The crude product was purified by flash chromatography
to give lactone 13 as a white solid (2.04 g, 90%). Found:
23
26
22
H, 6.03; ½aꢂD ¼ ꢀ15:0 (c 1.1, CHCl3) {lit.
½aꢂD
¼
ꢀ22:5 ꢃ 0:9 (c 1.2, CHCl3), lit.23 (for D-enantiomer)
25
½aꢂD ¼ þ20:2 (c 0.5, CHCl3)}; dH (CDCl3, 200 MHz):
1.28, 1.35 (6H, 2 ꢁ s, C(CH3)2), 2.43 (3H, s, ArCH3),
3.95 (1H, a-d, H3, J 2.1), 4.13 (1H, d, H5, J 7.0), 4.13
(1H, d, H50, J 5.8), 4.28 (1H, ddd, H4, J 2.1, 5.8, 7.0),
4.54 (2H, AB system, OCH2Ph), 4.60 (1H, a-d, H2, J
3.9), 5.86 (1H, d, H1, J 3.9), 7.30–7.40 (7H, m, ArH); dC
C, 54.66; H, 4.96; N, 15.67; C12H13N3O4 requires: C,
23
54.75; H, 4.98; N, 15.96; mp 49–50 °C; ½aꢂD ¼ ꢀ158 (c
1.16, CHCl3); mmax (thin film): 3433 (m, br, OH), 2105 (s,

B. Lopez-Ortega et al. / Tetrahedron: Asymmetry 19 (2008) 976–983
981
N3), 1787 (s, C@O); dH (CDCl3, 200 MHz): 3.40 (1H, dd,
H5, J 4.9, 13.8), 3.65 (1H, dd, H50, J 2.8, 13.8), 3.98 (1H, br
s, OH), 4.18 (1H, t, H3, J 7.9), 4.36 (1H, ddd, H4, J 2.8,
4.9, 8.0), 4.63 (1H, d, H2, J 8.0), 4.64 (1H, d, OCHPh, J
11.7), 4.87 (1H, d, OCHPh, J 11.7), 7.29–7.44 (5H, m,
ArH); dC (CDCl3, 50 MHz): 51.3 (C5), 73.2 (OCH2Ph),
75.0 (CH), 78.6 (CH), 80.7 (CH), 128.6, 128.8, 129.1
(3 ꢁ ArH), 137.3 (ArC), 174.8 (C1); m/z (APCI+): 236
(M+H+ꢀN2, 20%), 122 (100%).
400 MHz): 1.29, 1.31 (6H, 2 ꢁ d, CH(CH3)2), 3.19 (1H,
dd, H5, J 4.0, 13.7), 3.46 (1H, dd, H50, J 3.8, 13.7), 4.41
(1H, a-t, H3, J 5.1), 4.47 (1H, d, OCHPh, J 11.7), 4.69
(1H, d, OCHPh, J 11.7), 4.71 (1H, a-dd, H4, J 4.5, 8.1),
4.96 (1H, d, H2, J 5.2), 5.14 (1H, septet, CH(CH3)2, J
6.3), 7.30–7.38 (5H, m, ArH); dC (CDCl3, 100 MHz):
21.6, 21.6 (2 ꢁ C, CH(CH3)2), 52.4 (C5), 69.2
(OCH(CH3)2), 71.7 (OCH2Ph), 76.3 (CH), 81.9 (CH),
84.3 (CH), 127.9, 128.2, 128.5 (3 ꢁ ArH), 136.7 (ArC),
169.1 (C1); m/z (APCI+): 306 (M+H+, 20%), 170 (100%).
4.7. Methyl 2,4-anhydro-5-azido-3-O-benzyl-5-deoxy-L-
ribonate 15
4.9. Isopropyl 2,4-anhydro-5-(2,4-anhydro-5-azido-3-O-
benzyl-5-deoxy-L-ribononamido)-3-O-benzyl-5-deoxy-L-
ribonate 19
Lactone 13 (1.93 g, 7.46 mmol) was dissolved in dichloro-
methane (100 mL) and pyridine (1.81 mL, 22.38 mmol).
The solution was cooled to ꢀ40 °C and triflic anhydride
(1.88 mL, 11.19 mmol) was added dropwise. After
30 min, TLC (1:1, ethyl acetate/hexane) showed no starting
Azido ester 15 (367 mg, 1.33 mmol) was dissolved in THF
(6 mL) and water (1.05 mL) and sodium hydroxide (1 M,
1.5 mL, 1.5 mmol) was added. The mixture was stirred at
room temperature for 6 h after which TLC (2:3, ethyl ace-
tate/hexane) showed no starting material (Rf 0.82) but one
product on the baseline. The mixture was concentrated in
vacuo and the residue was dissolved in water (6 mL) and
treated with amberlite resin (IR 120 H+) for 30 min. The
solution was filtered and concentrated to give the crude
acid 16 as an oil (399 mg) which was used without further
purification.
material (R 0.38) but the formation of one product (Rf
f
0.66). The reaction mixture was diluted with dichlorometh-
ane (200 mL) and extracted with HCl (1 M, 100 mL). The
aqueous layer was washed with dichloromethane (200 mL)
and the combined organic extracts were washed with water
(100 mL), dried over MgSO4 and concentrated under
reduced pressure. The resulting residue was used in the
following step without further purification. The crude tri-
flate 14 was dissolved in methanol (420 mL) and cooled
to ꢀ25 °C. Potassium carbonate (3.09 g, 22.38 mmol) was
added and the mixture was kept between ꢀ25 and
ꢀ10 °C for 30 min and then allowed to warm to 0 °C over
30 min. After this time, TLC (1:1 ethyl acetate/hexane)
showed the formation of one product (Rf 0.4). The mixture
was filtered through silica and eluted with methanol and
concentrated in vacuo. The resulting residue was purified
by flash chromatography to give oxetane 15 as a colourless
oil (1.47 g, 71% over 2 steps). Found: C, 56.21; H, 5.34; N,
Azido ester 17 (393 mg, 1.29 mmol) was dissolved in ethyl
acetate (17.7 mL) and palladium on carbon (19 mg) was
added. The mixture was flushed with hydrogen and after
5 h, TLC (3:7, ethyl acetate/hexane) showed the formation
of a single baseline product. The mixture was filtered
through CeliteÒ, eluted, ethyl acetate and concentrated
in vacuo to give the crude amine 18 (357 mg, 99%) which
was used without further purification.
14.84; C13H15N3O4 requires C, 56.31; H, 5.45; N, 15.15;
Crude acid 16 and crude amine 18 were dissolved in N,N-
dimethylformamide (9.25 mL) and triethylamine (25 lL,
1.79 mmol) and TBTU (493 mg, 1.54 mmol) was added.
The mixture was stirred at room temperature for 16 h after
which time the solution was concentrated in vacuo and the
resulting residue was purified by column chromatography
to give dimer 19 (600 mg, 89% from the isopropyl azide)
23
½aꢂD ¼ ꢀ169 (c 1.25, CHCl3); mmax (thin film): 2105
(s, N3), 1755 (s, C@O); dH (CDCl3, 400 MHz): 3.17 (1H,
dd, H5, J 3.9, 13.8), 3.47 (1H, dd, H50, J 3.9, 13.8), 3.83
(3H, s, CO2CH3), 4.46 (1H, t, H3, J 5.2), 4.49 (1H, d,
OCHPh, J 11.7), 5.02 (1H, d, H2, J 5.3), 7.33–7.38 (5H,
m, ArH); dC (CDCl3, 100 MHz): 52.4 (CO2CH3), 52.5
(C5), 72.0 (OCH2Ph), 76.3 (CH), 81.7 (CH), 84.6 (CH),
128.1, 128.3, 128.6 (3 ꢁ ArC), 136.7 (ArC), 170.0
(CO2CH3); m/z (APCI+): 158 (M+ꢀCH3ꢀN2).
as a glassy oil. Found: C, 61.73; H, 6.11; N, 10.65;
23
C27H32N4O7 requires: C, 61.82; H, 6.15; N, 10.68; ½aꢂD
¼
ꢀ87:7 (c 0.71, CHCl3); mmax (thin film): 2100 (s, N3), 1740
(s, HNC@O, I), 1673 (m, HNC@O, II); dH (CDCl3,
4.8. Isopropyl 2,4-anhydro-5-azido-3-O-benzyl-5-deoxy-L-
ribonate 17
400 MHz): 1.25, 1.29 (6H, 2 ꢁ d, CH(CH3)2, J 6.3), 3.29
(1H, dd, H5A, J 4.9, 13.7), 3.47 (1H, dd, H50A, J 3.8,
13.7), 3.53–3.64 (2H, m, H5B), 4.31 (1H, t, H3, J 5.3),
4.31 (1H, t, H3, J 5.4), 4.45 (1H, d, OCHPh, J 11.7),
4.46 (1H, d, OCHPh, J 11.8), 4.61 (1H, d, OCHPh, J
11.8), 4.72–4.79 (2H, m, H4A, H4B), 4.76 (1H, d, OCHPh,
J 11.7), 4.93 (1H, d, H2B, J 5.3), 4.94 (1H, d, H2A, J 5.2),
5.08 (1H, septet, OCH(CH3)2, J 6.3), 7.14 (1H, a-t, CONH,
J 5.7), 7.29–7.38 (10H, m, ArH); dC (CDCl3, 100 MHz):
21.6, 21.7 (2 ꢁ CH(CH3)2), 41.4 (C5B), 52.5 (C5A), 69.2
(CH(CH3)2), 71.6, 71.7 (2 ꢁ OCH2Ph), 76.6 (C3),
76.7 (C3), 81.7 (C2B), 83.5 (C2A), 84.1 (C4), 84.5 (C4),
127.8, 128.1, 128.1, 128.5, 128.5 (5 ꢁ ArH), 136.7, 136.9
(2 ꢁ ArC), 169.4 (C1), 170.2 (C1); m/z (APCI+): 525.4
(M+H+, 100%).
Azido ester 15 (370 mg, 1.33 mmol) was dissolved in iso-
propanol (3.5 mL) and potassium carbonate (250 mg,
1.81 mmol) was added. The mixture was stirred at room
temperature for 19 h when TLC (3:7, ethyl acetate/hexane)
showed no starting material (Rf 0.26) but one major prod-
uct (Rf 0.53). The reaction mixture was filtered through
Celite eluted with ether and concentrated in vacuo. The res-
idue was purified by flash column chromatography to give
isopropyl azido ester 17 as a colourless oil (347 mg, 85%).
Found : C, 58.93; H, 6.49; N, 13.69; C15H19N3O4 requires:
23
C, 59.01; H, 6.27; N, 13.76; ½aꢂD ¼ ꢀ160 (c 1.5, CHCl3);
mmax (thin film): 2104 (s, N3), 1749 (s, C@O); dH (CDCl3,

982
B. Lopez-Ortega et al. / Tetrahedron: Asymmetry 19 (2008) 976–983
4.10. Isopropyl 2,4-anhydro-5-[2,4-anhydro-5-azido-3-O-
benxyl-5-deoxy-L-ribononamido-(N?5)-2,4-anhydro-5-
azido-3-O-benzyl-5-deoxy-L-ribononamido-(N?5)-2,4-
anhydro-5-azido-3-O-benzyl-5-deoxy-L-ribononamido-
(N?5)]-3-O-benzyl-5-deoxy-L-ribonate 22
4.11. Isopropyl 2,4-anhydro-5-[2,4-anhydro-5-azido-3-O-
benxyl-5-deoxy-L-ribononamido-(N?5)-2,4-anhydro-5-
azido-3-O-benzyl-5-deoxy-L-ribononamido-(N?5)-2,4-
anhydro-5-azido-3-O-benzyl-5-deoxy-L-ribononamido-
(N?5)-2,4-anhydro-5-azido-3-O-benzyl-5-deoxy-L-ribono-
namido-(N?5)-2,4-anhydro-5-azido-3-O-benzyl-5-deoxy-L-
ribononamido-(N?5)]-3-O-benzyl-5-deoxy-L-ribonate 24
Dimer 19 (130 mg, 0.25 mmol) was dissolved in ethyl ace-
tate (3.2 mL) and palladium on carbon (9 mg) was added.
The reaction was flushed with H2 and stirred at room tem-
perature for 22 h, after which TLC (3:2, ethyl acetate/hex-
ane) showed the complete conversion of the starting
material to one baseline product. The reaction mixture
was filtered through Celite, eluted ethyl acetate and concen-
trated in vacuo. The residue was purified by flash chroma-
tography to yield amine 20 as a colourless oil (107 mg,
87%).
Tetramer 22 (107 mg, 0.11 mmol) was dissolved in tetrahy-
drofuran (524 lL) and water (90 lL). Sodium hydroxide
(1 M, 120 lL, 0.12 mmol) was added and the mixture
was stirred for 3 h at room temperature, when TLC (3:2,
ethyl acetate/hexane) showed the complete conversion of
the starting material to one baseline product. The mixture
was concentrated under reduced pressure and the residue
was dissolved in water (600 lL) and treated with amberlite
resin (IR 120 H+). After 30 min, the mixture was filtered
and concentrated under reduced pressure to give acid 23,
which was used without further purification.
Dimer 19 (125 mg, 0.24 mmol) was dissolved in THF
(1.14 mL) and water (200 lL) and sodium hydroxide
(1 M, 270 lL, 0.27 mmol) was added. The mixture was
stirred at room temperature for 5 h after which TLC (3:2,
ethyl acetate/hexane) showed the complete conversion of
the starting material to one baseline product. The mixture
was concentrated and the residue was dissolved in water
(1.1 mL). Amberlite resin (IR120 H+) was added and the
mixture stirred for 30 min, filtered and concentrated in
vacuo to give acid 21 which was used without further
purification.
Dimer 19 (57 mg, 0.11 mmol) was dissolved in ethyl acetate
(1.4 mL) and palladium on carbon (5 mg) was added. The
mixture was flushed with hydrogen and the mixture was
stirred at room temperature for 16 h when TLC (3:2, ethyl
acetate/hexane) showed complete conversion of the
starting material to one baseline product. The mixture
was filtered through Celite, eluted ethyl acetate, and con-
centrated under reduced pressure to give amine 20 which
was used without further purification.
Dimer acid 21 and dimer amine 20 were dissolved in DMF
(1.59 mL) and triethylamine (42 lL, 0.30 mmol) and
TBTU (83 mg, 0.26 mmol) were added. The mixture was
stirred at room temperature for 2.5 h when TLC (3:2, ethyl
acetate/hexane) showed the formation of one major prod-
uct (Rf 0.3). The solution was concentrated under reduced
pressure and purified by flash chromatography to give tet-
Amine dimer 20 and tetramer acid 23 were dissolved in
DMF (800 lL) and triethylamine (21 lL, 0.15 mmol) and
TBTU (41 mg, 0.13 mmol) were added. After 18 h TLC
(4:1, ethyl acetate/hexane) showed the formation of one
major product (R f 0.3). The mixture was concentrated
under reduced pressure and the residue was purified by
ramer 22 as a colourless oil (130 mg, 62% from the amine).
½aꢂD ¼ ꢀ176 (c 0.2, CHCl3); mmax (thin film): 3302 (NH),
flash column chromatography to give hexamer 24 (100 mg,
64%) as a colourless oil. ½aꢂD ¼ ꢀ158 (c 0.3, CHCl3); mmax
22
23
2105 (N3), 1744 (HNC@O, I), 1667 (HNC@O, II); dH
(CDCl3, 500 MHz): 1.24, 1.27 (6 H, 2 ꢁ d, CH(CH3)2, J
6.2), 3.01 (1H, dt, H50B , J 3.8, 14.1), 3.06 (1H, dd, H50A,
J 3.4, 14.1), 3.46 0 (1H, dd, H5A, J 3.0, 14.1), 3.55–3.65
(4H, m, H5C, H5 C, H5D, H50D), 3.90 (1H, ddd, H5B, J
9.3, 10.7, 14.1), 4.05 (1H, t, H3B, J 4.3), 4.11 (1H, t,
H3C, J 4.1), 4.37 (1H, d, OCHPh, J 11.8), 4.44 (2H,
2 ꢁ d, OCHPh, J 11.7), 4.49 (1H, d, OCHPh, J 11.8),
4.56–4.62 (1H, m, H4B), 4.61 (1H, d, OCHPh, J 11.9),
4.61 (1H, d, OCHPh, J 11.7),4.69 (1H, m, H4A), 4.70
(1H, d, OCHPh, J 11.6), 4.71 (1H, m, H4C), 4.72 (1H, d,
OCHPh, J 11.8), 4.76 (1H, m, H4D), 4.81 (1H, d, H2C, J
4.4), 4.92 (1H, d, H2B, J 3.8), 4.93 (1H, d, H2D, J 5.6),
5.03 (1H, d, H2A, J 5.3), 5.07 (1H, septet, OCH(CH3)2, J
6.2), 6.99 (1H, t, NHB, J 4.4), 7.26–7.36 (20H, m, ArH),
8.24 (1H, t, NH, J 6.3), 8.34 (2H, t, NHD, J 6.1); dC
(CDCl3, 125 MHz): 21.7 (1 ꢁ OCH(C H)), 41.7 (CH2),
41.8 (CH2), 52.3 (CH2), 69.0 (CH), 71.2 (CH2), 71.4
(CH2), 71.9 (CH), 77.6 (CH), 77.9 (CH), 78.1 (CH), 81.7
(CH), 83.3 (CH), 83.4 (CH), 83.4 (CH), 84.2 (CH), 84.2
(CH), 84.3 (CH), 84.6 (CH), 127.7, 1278.0, 128.0, 128.1,
128.2, 128.2, 128.5, 238.5 (9 ꢁ ArH), 136.6 136.8, 136.9,
136.9 (4 ꢁ ArC), 169.5 (HNC@O A), 170.9, 171.1, 171.7
(3 ꢁ HNC@O).
(thin film): 3297 (m, NH), 2105 (s, N3), 1743 (s, HNC@O,
I), 1660 (m, HNC@O, II); dH (CDCl3, 500 MHz): 1.23,
1.25 (6H, 2 ꢁ d, CH(CH3)2, J 6.2), 2.99 (1H, dd, H50A, J
3.2, 14.2), 2.94 (1H, a-dt, H50B, J 3.7, 14.0), 3.27 (1H,
ddd, H50D, J 4.0, 4.5, 14.0), 3.36 (1H, ddd, H50C, J 3.0,
5.0, 14.0), 3.45 (1H, m, H50E), 3.45 (1H, dd, H5A, J 2.7,
14.2), 3.60 (2H, m, H5F,H50F), 3.68 (1H, ddd, H5E, J 6.5,
10.5, 14.2), 3.75 (1H, ddd, H5C, J 7.5, 11.5, 14.0), 3.81
(1H, ddd, H5D, J 8.0, 11.0, 14.0), 3.92 (1H, ddd, H5B, J
9.2, 11.5, 14.0), 4.04–4.06 (3H, m, H3B, H3C, H3D), 4.10
(1H, t, H3E, J 4.2), 4.34 (1H, t, H3A, J 5.5), 4.36 (1H, t,
H3F, J 5.2), 4.39 (1H, d, OCHPh, J 12.0), 4.42 (1H, d,
OCHPh, J 11.5), 4.43 (1H, d, OCHPh, J 12.0), 4.45 (1H,
d, OCHPh, J 10.0), 4.48 (1H, d, OCHPh, J 10.0), 4.50
(1H, d, OCHPh, J 12.0), 4.56 (1H, a-dt, H4B, J 3.5,
11.5), 4.62 (1H, d, OCHPh, J 12.0), 4.70 (1H, d, OCHPh,
J 11.5), 4.70–4.80 (9H, m, 4 ꢁ OCHPh, H4A, H4C, H4D,
H4E, H4F), 4.83 (1H, d, H2E, J 4.0), 4.86 (1H, d, H2A, J
5.0), 4.88 (1H, d, H2D, J 4.0), 4.88 (1H, d, H2B, J 4.5),
4.90 (1H, d, H2F, J 5.0), 4.94 (1H, d, H2C, J 4.5), 5.05
(1H, septet, CH(CH3)2, J 6.2), 6.99 (1H, dd, NHB, J 4.5,
9.0), 8.43 (1H, a-t, NHC, J 6.5), 8.49 (1H, a-t, NHF, J
6.2), 8.55 (1H, a-t, NHE, J 6.2), 8.62 (1H, dd, NHD, J
5.5, 7.5); dC (CDCl3, 125 MHz): 21.7 (ꢁ2) (2 ꢁ CH(CH3)2),

B. Lopez-Ortega et al. / Tetrahedron: Asymmetry 19 (2008) 976–983
983
41.7, 41.8, 41.9 (5 ꢁ C5), 52.3 (C5A), 68.9 (CH(CH3)2), 71.3
(ꢁ2), 71.4, 71.6, 72.1 (6 ꢁ OCHPh), 76.5, 78.0, 78.3, 78.4
(ꢁ2), 78.6, 81.7, 83.3, 83.4, 83.5, 84.2, 84.3 (ꢁ2), 84.5,
84.6, 84.9 (16 ꢁ CH), 127.7, 127.9, 128.0 (ꢁ3), 128.2
(ꢁ3), 128.4, 128.5 (ꢁ2), 128.6 (13 ꢁ ArH), 136.6,
136.8, 136.9, 137.0 (6 ꢁ ArC), 169.5 (HNC@OA), 171.2
(HNC@OF), 171.5 (HNC@OE), 171.7 (HNC@OB), 171.8
(HNC@OC), 172.3 (HNC@OD).
11. van Well, R. M.; Meijer, M. E. A.; Overkleeft, H. S.; van
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