Carbon-branched δ-tetrahydrofuran sugar amino acids (SAAs) as dipeptide isostere scaffolds

Article abstract of DOI:10.1016/j.tetasy.2008.12.012

The synthesis of the first branched sugar amino acid (SAA) scaffolds [methyl (3R,4R,5R)-5-azidomethyl-3,4-dihydroxy-tetrahydrofuran-3-carboxylate and methyl (3R,4R,5S)-5-azidomethyl-3,4-dihydroxy-tetrahydrofuran-3-carboxylate] by an efficient intramolecular displacement of a highly hindered neopentyl triflate allows access to enantiopure THF derivatives which have carbon substituents.

Full text of DOI:10.1016/j.tetasy.2008.12.012

Tetrahedron: Asymmetry 19 (2008) 2887–2894
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Carbon-branched d-tetrahydrofuran sugar amino acids (SAAs) as dipeptide
isostere scaffolds
Michela I. Simone a, Alison A. Edwards b, George E. Tranter c, George W. J. Fleet a,
*
a Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom
b Medway School of Pharmacy, Universities of Kent and Greenwich at Medway, Kent, ME4 4TB, United Kingdom
c Chiralabs Limited, Begbroke Centre for Innovation and Enterprise, Oxford University Begbroke Science Park, Oxfordshire, OX5 1PF, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the first branched sugar amino acid (SAA) scaffolds [methyl (3R,4R,5R)-5-azidomethyl-
3,4-dihydroxy-tetrahydrofuran-3-carboxylate and methyl (3R,4R,5S)-5-azidomethyl-3,4-dihydroxy-tet-
rahydrofuran-3-carboxylate] by an efficient intramolecular displacement of a highly hindered neopentyl
triflate allows access to enantiopure THF derivatives which have carbon substituents.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 21 October 2008
Accepted 10 December 2008
Available online 20 January 2009
1. Introduction
5 in which the C-5 OH displaces the triflate to give the THF carbox-
ylate 6. The formation of both oxetane and THF rings both involves
Sugar amino acids (SAAs) constitute a major class of peptidom-
imetics providing a set of monomers for both combinatorial syn-
thesis and drug design.1 Oligomers of SAAs frequently adopt
secondary structures in relatively short sequences;2 many have a
predisposition to adopt secondary structural motifs, giving rise to
a large family of foldamers.3 In particular, a number of cyclic d-
amino acids containing an oxygen heterocyclic ring have been
shown to act as dipeptide isosteres (Fig. 1) including saturated4
and unsaturated5 pyranose, furanose6 and oxetanose7 amino acids.
All d-SAAs previously described have linear carbon chains. This pa-
ring closure by intramolecular nucleophilic displacement of a leav-
ing group to the ester carbonyl, where nucleophilic attack is fac-
a
ile—but will only produce linear carbon chains in the THF.
This report extends the range of THF rings that may be formed
by this methodology by the synthesis of the trans- 17 and cis- 18
azidomethyl d-THF carboxylates to provide the first examples of
THF SAAs, which contain a branched carbon chain (Scheme 2).
The epimeric D-ribono-7 and L-lyxono-8 lactones were converted
to the corresponding azidolactoses 9 and 10. The branched carbon
chain was then introduced by a Ho16 crossed aldol reaction be-
tween formaldehyde and the open form of 9 and 10 to afford the
branched azidolactols 11 and 12, which were converted to the cor-
responding triflates 13 and 14. Treatment of 13 and 14 with meth-
anolic hydrogen chloride resulted in removal of the acetonide and
methanolysis of the ring to give the open esters 15 and 16 which
subsequently close by nucleophilic attack of the C-4 OH group onto
the 2C0 triflate to give the branched SAA scaffolds 17 and 18. This
unexpectedly efficient intramolecular displacement of a highly
hindered neopentyl triflate should allow convenient access to com-
plex THF systems which contain quaternary carbons. The synthe-
ses of 17 and 18 reported in this paper are on a suitable scale for
the preparation of their homooligomers; the structure of these
oligomers has been studied by NMR and circular dichroism and
compared with unbranched d-THF SAAs.
per describes the first example of d-SAA furanoses with
a
branched-carbon chain; some of this work has been reported in a
preliminary publication.8
2-O-Triflates of suitably protected 1,4-sugar lactones 1 in meth-
anol give base-catalyzed contraction of the five-membered lactone
ring to an oxetane carboxylic ester 2 in which the substituent at C-
3 is trans to the carboxylate, regardless of the configuration at C-2
of the original
c
-lactone.9 This has allowed the preparation of a
wide range of azidooxetane carboxylates that have shown their va-
lue in inducing secondary structures.10 Thus, 1 undergoes nucleo-
philic ring opening of the lactone to give the open chain ester 2
which closes by displacement of the triflate at C-2 by C-4 OH to
the oxetane 3 (Scheme 1).
2-O-Triflates of both 1,4-sugar lactones 4 and 1,5-sugar lactones
give high yields of tetrahydrofuran (THF) carboxylates under catal-
ysis by either acid or base, and always with inversion of configura-
2. Synthesis
14
tion at C-2 of the original hydroxy lactone;11 many -,12 b-,13
a c-
and d-15 amino acid building blocks have been prepared by this
strategy. In this case, the lactone 4 is opened to the acyclic triflate
2.1. Synthesis of a branched trans-azidomethyl carboxylate -
THF SAA 17
The protected ribonolactone 7, readily available from
D-ribose
* Corresponding author.
E-mail address: george.fleet@chem.ox.ac.uk (G.W.J. Fleet).
by an Organic Syntheses procedure,17 was esterified by triflic anhy-
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.012

2888
M. I. Simone et al. / Tetrahedron: Asymmetry 19 (2008) 2887–2894
O
O
δ
O
δ
R
O
δ
α
O
δ
δ
α
O
α
O
γ
H
α
O
O
O
α
α
H2N
HO
OH
H2N
OH
N
O
H2N
H2N
OH
δ
H2N
OH
β
H2N
OH
HO
OH
O
R
OH
OH
HO OH
HO OH
OH
OH
pyranoses
dipeptide
deoxy unsaturated
pyranose
furanose
oxetane
branched furanose
Figure 1. SAA dipeptide isosteres.
5
5
OH
OH
4
O
O
R
R
CO2Me
OTf
R
OH
CO2Me
O
R
O
O
(i)
(i) or
(ii)
CO2Me
R
R
O
2
CO2Me
2
3
PO OTf
HO OH
HO OH
HO OTf
OP
PO OTf
2
3
4
5
6
1
Scheme 1. (i) K2CO3, MeOH (ii) H+, MeOH.
4
H
O
O
O
O
(ii)
N
steps
3H2C
(i)
N3H2C
N3H2C
O
HOH2C
steps
O
OH
OH
CH2OH
2'
O
O
N3H2C
CH2OTf
N3H2C
CH2OTf
CO2Me
HO OH
O
O
O
O
O
O
CO2Me
HO OH
O
O
9 D-ribo
7 D-ribo
L-lyxo
11 D-ribo
12 L-lyxo
13 D-ribo
14 L-lyxo
17
18
15 D-ribo
D-ribo
L-lyxo
10
8
L-lyxo
16
L-lyxo
Scheme 2. (i) CH2O, HOꢀ (ii) H+, MeOH.
dride in dichloromethane to give the corresponding triflate which
was immediately treated with sodium azide in DMF to afford the
azido lactone 19 in 76% overall yield (Scheme 3). Reduction of the
azidolactone by DIBAL-H in toluene gave the corresponding aldose
9 (93% yield) which underwent a highly efficient Ho16 crossed al-
dol reaction with aqueous formaldehyde to form the branched
azido lactol 11 (94% yield). Oxidation of the lactol 11 with bro-
mine in the presence of barium carbonate gave the lactone 20
(82% yield) which was esterified to the stable triflate 13 (97%
yield).
acetonide 21 would introduce a trans-acetonide protecting group.
When the triflate 13 was treated with benzylamine in dioxane,
the open chain triflate amide 23 was formed—again there was no
indication of cyclization of 23 to the THF benzylamide 24 which
again would require the formation of a strained protecting group.
When the open chain triflate 23 was stirred in THF in the presence
of potassium carbonate, cyclization to the b-lactam 25 was ob-
served; the IR spectrum of 25 shows the appearance of a strong,
sharp peak at 1745 cmꢀ1, consistent with the lactam structure.
The 1H NMR spectrum of 25 shows a free hydroxyl as a doublet
which couples to proton H-4 in the COSY spectrum; the HMBC
spectrum showed some long range correlations (Fig. 2).
Treatment of 13 with methoxide in methanol did not give any
product as the formation of the THF ring 22 from the open chain
O
O
O
O
O
O
(ii)
HOH2C
(i)
N3H2C
N3H2C
N3H2C
N3H2C
N3H2C
O
(iii)
O
O
OH
OH
(iv)
CH2OH
CH2OH
CO2Me
O
O
O
O
O
O
O
O
O
O
O
O
9
11
20
22
7
19
(v)
X
1
O
H
1
O
O
H
N3H2C
O
N3H2C
O
(vi)
N3H2C
CH2OTf
CO2Me
(vii)
3
CH2OTf
CO2Me
N3H2C
CH2OTf
CO2Me
2'
O
O
HO OH
HO OH
O
O
17
13
15
21
(viii)
OH
HO
O
O
HO
N3H2C
O
O
Ph
N3H2C
N3H2C
CH2OTf
CONHBn
Ph
N3H2C
CH2OTf
CONHBn
O
N
(ix)
N3H2C
N
CONHBn
O
X
CH2OTf
O
O
O
O
O
O
O
O
23
24
25
Scheme 3. (i) Tf2O, pyridine, CH2Cl2, ꢀ25 °C; then NaN3, EtOAc, 76% (over two steps); (ii) DIBAL-H, CH2Cl2, ꢀ78 °C, 93%; (iii) 38% aq CH2O, K2CO3, MeOH, 50 °C, 24 h, 94%; (iv)
Br2, BaCO3, H2O, 0 °C, 82%; (v) Tf2O, pyridine, CH2Cl2, ꢀ25 °C, 97%; (vi) MeOH, MeONa; (vii) MeOH/AcCl (1:1), 87%. (viii) BnNH2, 1,4-dioxane; (ix) K2CO3, THF, 8 days, 89%.

M. I. Simone et al. / Tetrahedron: Asymmetry 19 (2008) 2887–2894
2889
tions, the cis-substituted SAA scaffold 18 was isolated in 57% yield.
It is noteworthy that in the synthesis of unbranched carbon chain,
the THF ring is formed under treatment with dilute methanolic
hydrogen chloride with no intermolecular nucleophilic triflate dis-
placement by methanol.11–15 The overall yield of the scaffold 18
HB
HA
N
OH
O
H5
O
Ph
H5'
H2'
N3
H3
from the protected L-lyxonolactone 8 was 37% over 7 steps.
H2
O
3. Summary
Figure 2. 1H–13C Correlations obtained from the 500/125 MHz HMBC spectrum of
lactam 25 in CDCl3 at 298 K.
Both trans-17 and cis-18 azidomethyl-THF carboxylates can be
readily synthesized suitable for incorporation as dipeptide equiva-
lents in amino acid sequences. NMR and circular dichroism studies
on homooligomers of 17 and 18 have allowed the evaluation of
their predisposition to induce secondary structures in short
sequences.22
It was, therefore, evident that it was necessary to remove the
acetonide to allow the THF ring to be formed; when the triflate
13 was treated with methanolic hydrogen chloride (prepared from
a 1:1 mixture of acetyl chloride and methanol), the target THF car-
boxylate was produced in 87% yield. The strong acid conditions
cause ring opening of the lactone to the methyl ester as well as re-
moval of the acetonide; the open chain deprotected triflate 15 can
then cyclize to the THF, even though an SN2 reaction at a very hin-
dered carbon is necessary. It is noteworthy that 15 does not
decompose by any other pathway. The overall yield of the scaffold
17 from the protected ribonolactone 7 is 36% over 6 steps.
4. Experimental
Tetrahydrofuran was purchased dry from the Aldrich Chemical
Company in sure-sealTM bottles. Water was distilled. All other sol-
vents were used as supplied without further purification (Analyti-
cal or HPLC grade). Reactions were performed under an
atmosphere of nitrogen or argon and were maintained by an in-
flated balloon. Thin layer chromatography (TLC.) was performed
on alumnum sheets coated with 60 F254 silica, visualized using a
spray of 0.2% w/v cerium (IV) sulfate and 5% ammonium molyb-
date in 2 M sulfuric acid. Purification via flash column chromatog-
raphy was performed on Sorbsil C60 40/60 silica. Melting points
were recorded on a Kofler hot block. Nuclear magnetic resonance
(NMR) spectra were recorded on Bruker AMX 500, DRX 500, DPX
400 or DQX 400 spectrometers in the deuterated solvent stated.
Chemical shifts (d) are quoted in ppm and coupling constants (J)
in Hertz and residual solvent signals were used as an internal ref-
erence. The assignments of the 1H and 13C NMR spectra were made
using the results obtained from 2D methods such as COSY, HMQC,
HMBC, HSQC and DEPT correlations. Infra red (IR) spectra were re-
corded on a Perkin-Elmer 1750 IR Fourier Transform spectropho-
tometer and on a Bruker Tensor 27 FT-IR spectrophotometer
using thin films. Only the characteristic peaks are quoted and in
units of cmꢀ1. Optical rotations were measured on a Perkin–Elmer
241 polarimeter with a path length of 1.0 dm and concentrations
are quoted in g/100 mL. Low resolution mass spectra were re-
corded using electrospray ionization (ES) or chemical ionization
(CI, NH3), and were measured on Micromass BioQ II-ZS, Micromass
500 OAT, Micromass TofSpec 2E, Micromass GCT, or Micromass
Platform 1 mass spectrometers. High resolution mass spectra
(HRMS) were measured on a Micromass 500 OAT spectrometer
by CI or on a Waters 2790-Micromass LCT by ES. Elemental analy-
ses were performed by the microanalysis service of the Inorganic
Chemistry Laboratory, University of Oxford, Oxford.
2.2. Synthesis of a branched cis-azidomethyl carboxylate -THF
SAA 18
2,3-O-Isopropylidene-L-lyxono-1,4-lactone 8, readily available
from D
-ribono-1,4-lactone,18 has been converted to the azido lac-
tone 27 on a 200 kg scale19 by the method first described to pre-
pare the enantiomer.20 Esterification of the alcohol in 8 with
triflic anhydride in dichloromethane in the presence of pyridine
gave the triflate 26 which on reaction with sodium azide in acetone
gave the azide 27 in 86% yield over the two steps. Reduction of the
lactone 27 with DIBAL-H in dichloromethane afforded the lactol 10
in 99% yield. Monitoring the conversion of the triflate 26 to the
azide 27 by TLC. analysis was difficult as the two compounds co-
spotted. If some of triflate 26 remained in the DIBAL-H reduction,
the tricyclic compound 31 was formed, presumably by initial
reduction of 26 to the lactol 30 and subsequent ring closure; the
structure of 31 was firmly established by X-ray crystallographic
analysis.21
The azidolactol 10 underwent an efficient Ho crossed aldol con-
densation with aqueous formaldehyde to form the branched lactol
12 in 88% yield (based on recovered starting material). Oxidation of
the lactol 12 gave the corresponding lactone 28 (in 87% yield)
which was esterified with triflic anhydride in dichloromethane to
give the stable triflate 14 in 99% yield.
Treatment of the triflate 14 with dilute hydrogen chloride in
methanol provided the methoxymethyl lactone 29; the structure
of which was determined by NMR, IR and high resolution mass
spectroscopy. In the 1H NMR spectrum of lactone 29, the OMe sin-
glet was present at 3.39 ppm; in the HMBC spectrum 3J couplings
arose from H-3 to C@O and C-20, from C-20 to OCH3 and from
C@O to H-2 and H-20; the IR spectrum showed the presence of a
lactone at 1789 cmꢀ1. The exclusive production of 29 was probably
realized due to the difficulty of the removal of the acetonide group
under the milder acidic conditions (MeOH/HCl (99:1)). Specifically,
consistent with our prior observations (Scheme 3), THF formation
through the corresponding open-chain ester of compound 14 failed
due to the presence of the acetonide, and direct intermolecular dis-
placement of the triflate group by methanol was favoured. Under
more aggressive acidic conditions (MeOH/HCl (2:3)), hydrolysis
of the acetonide group occurred faster than nucleophilic displace-
ment of the triflate by methanol; 18 was successfully produced
through the open-chain ester intermediate 16. Under these condi-
The numbering of all compounds for NMR data is in accordance
with carbohydrate nomenclature except the azidomethyl THF SAA
17 and 18 which are numbered as the THF (as indicated in Schemes
3 and 4).
4.1. Synthesis of trans-azidomethyl THF SAA 17
4.1.1. 5-Azido-5-deoxy-2,3-O-isopropylidene-D-ribono-1,
4-lactone 19
Triflic anhydride (10.9 mL, 64.79 mmol) was added dropwise to
a solution of the protected lactone 7 (8.10 g, 43.02 mmol) and pyr-
idine (10 mL) stirring in dichloromethane (325 mL) at ꢀ50 °C un-
der an atmosphere of argon. After 30 min, the reaction
temperature had risen to ꢀ25 °C. TLC. analysis (ethyl acetate/cyclo-
hexane, 1:2) showed the presence of a product (Rf 0.52) and com-

2890
M. I. Simone et al. / Tetrahedron: Asymmetry 19 (2008) 2887–2894
O
O
O
O
O
HOH2C
TfOH2C
N3H2C
N3H2C
N3H2C
OH
O
O
O
OH
(ii)
(iv)
(iii)
(i)
CH2OH
O
O
O
O
O
O
O
O
O
O
10
8
26
27
12
(v)
(iii)
OH
O
O
N3H2C
O
1
O
N3H2C
O
N3H2C
N3H2C
(vi)
O
CO2Me
CH2OTf
O
(viii)
CH2OTf
CH2OMe
O
CH2OH
OH
TfOH2C
O
O
O
O
O
O
O
O
O
29
14
28
30
(vii)
H
1
O
3
O
N3H2C
O
N3H2C
2'CH2OTf
4
O
CO2Me
OH
CO2Me
2
O
HO
16
HO OH
O
18
31
Scheme 4. (i) Tf2O, pyridine, CH2Cl2, ꢀ55 °C; (ii) NaN3, acetone, 60 °C (86% over 2 steps); (iii) DIBAL-H (1.5 M soln in toluene), CH2Cl2, ꢀ80 °C, 99%; (iv) aq CH2O soln (38.5%),
MeOH, K2CO3, 78 °c, 88% (based on recovered starting material); (v) Br2, BaCO3, H2O, 0 °c, 87%; (vi) Tf2O, pyridine, CH2Cl2, ꢀ55 °C, 99%; (vii) MeOH/HCl (34:23), 57%; (viii)
MeOH/HCl (99:1), 24 h, 51% (based on recovered starting material); (ix) DIBAL-H (1.5 M soln in toluene), CH2Cl2, ꢀ80 °C.
plete consumption of starting material (Rf 0.10). The reaction mix-
ture was washed with aqueous hydrochloric acid solution (1 M,
100 mL), brine (25 mL), dried (magnesium sulfate), filtered and
concentrated in vacuo to afford 2,3-O-isopropylidene-5-O-trifluo-
tate/dichloromethane, 1:4) showed the presence of a major prod-
uct (Rf 0.53) and almost complete consumption of the starting
material 19 (Rf 0.76). The reaction mixture was quenched by addi-
tion of water (10 mL), then diluted with dichloromethane (40 mL),
water (30 mL) and extracted with dichloromethane (3 ꢁ 250 mL).
The organic extracts were combined, dried (magnesium sulfate),
filtered and concentrated in vacuo to give a residue, which was
purified by flash column chromatography (ethyl acetate/dichloro-
methane, 1:7) to afford starting material (114 mg) and the lactols
9 (3.80 g, 90%; 93% based on recovered starting material) as a pale
yellow oil. m/z (ESꢀ): 214.1 ([MꢀH]ꢀ, 100%); HRMS (ESꢀ): found
romethanesulfonyl-D-ribono-1,4-lactone (13.50 g, 98%) as an
unstable white solid. mmax (thin film): 2987 (C–H), 1790 (s, C@O)
cmꢀ1; dH (CDCl3, 400 MHz): 1.42, 1.50 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2),
0
4.71 (1H, dd, JH-5,H-5 11.2 Hz, JH-5,H-4 2.3 Hz, H-5), 4.77 (1H, dd,
JH-5 ,H-5 11.2 Hz, JH-5 ,H-4 2.4 Hz, H-50), 4.79 (1H, m, H-4), 4.81–4.84
(2H, m, H-3 and H-2); dC (CDCl3, 100 MHz): 25.5, 26.6 (C(CH3)2),
74.0 (C-5), 74.7 (C-3), 76.8 (C-2), 78.5 (C-4), 114.5 (C(CH3)2),
172.0 (C@O). Sodium azide (8.61 g, 132.47 mmol) was added to a
stirred solution of the triflate (13.50 g, 42.29 mmol) in acetone
(250 mL) and the reaction mixture was stirred at room tempera-
ture under an atmosphere of argon. After 22 h 30 min, a white salt
had precipitated out of solution and TLC analysis (ethyl acetate/
cyclohexane, 1:2) showed the presence of one product (Rf 0.52).
The reaction mixture was filtered through Celite (eluent/acetone),
dried (magnesium sulfate), filtered and concentrated in vacuo to
afford a residue, which was purified by flash column chromatogra-
phy (ethyl acetate/cyclohexane, 1:2) to give the azide 19 (7.07 g,
78%; 76% over 2 steps) as a pale yellow oil which crystallized on
standing. mp 36 °C [Lit.23 mp 39 °C]. m/z (CI+): 231.2 ([M+NH4]+,
100%); HRMS (CI+): found 231.1083 [M+NH4]+ C8H15N4O4 requires
0
0
214.0828 [MꢀH]ꢀ C8H12N3O4 requires 214.0822; ½a D25
¼ ꢀ42:8 (c
ꢂ
0.54, acetonitrile); mmax (thin film): 3434 (br, OH), 2991 (C–H),
2106 (s, N3) cmꢀ1
; dH (CD3CN, 400 MHz), anomeric ratio:
a
:b = 5:4; 1.30, 1.42 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2, b), 1.37, 1.43 (2 ꢁ 3H,
0
2 ꢁ s, C(CH3)2,
a), 3.30 (1H, dd, JH-5,H-5 12.8 Hz, JH-5,H-4 6.0 Hz, H-
5, b), 3.53 (1H, dd, JH-5 ,H-5 12.7 Hz, JH-5 ,H-4 8.2, H-50, b), 3.69 (1H,
0
0
0
0
dd, JH-5,H-5 13.6 Hz, JH-5,H-4 3.5 Hz, H-5,
a), 3.77 (1H, dd, JH-5 ,H-5
13.5 Hz, JH-5 ,H-4 3.4, H-50,
d, JOH-1,H-1 4.4 Hz, OH-1,
a
), 4.16–4.21 (1H, m, H-4, b), 4.51 (1H,
), 4.57 (1H, d, JH-2,H-3 5.9 Hz, H-2, b),
0
a
4.65 (1H, dd, JH-3,H-2 5.9 Hz, JH-3,H-4 1.3 Hz, H-3, b), 4.69 (1H, t, JH-
0
4,H-5 = JH-4,H-5 3.4 Hz, H-4,
a
), 4.74 (1H, d, JH-2,H-3 5.6 Hz, H-2,
), 5.33 (1H, d, JH-1,OH-1 4.4 Hz, H-
); dC (CD3CN, 100 MHz): 24.4, 26.2 (C(CH3)2, b), 24.9, 26.3
(C(CH3)2, ), 52.5 (C-5, ), 54.1 (C-5, b), 75.3 (C-3, ), 78.5 (C-2,
), 80.9 (C-4, ), 82.5 (C-3, b), 85.6 (C-4, b), 86.4 (C-2, b), 97.5 (C-
1, b), 103.2 (C-1, ), 112.5 (C(CH3)2, ), 113.4 (C(CH3)2, b).
a),
4.87 (1H, d, JH-3,H-2 5.6 Hz, H-3,
1,
a
a
231.1093; ½a 2D3
ꢂ
¼ þ18:9 (c 1.66, chloroform) {Lit.23
½
a D
ꢂ
¼ þ15:0 (c
a
a
a
1.00, chloroform)};
m
max (thin film): 2990 (C–H), 2113 (s, N3), 1788
a
a
(s, C@O) cmꢀ1; dH (CDCl3, 400 MHz): 1.38, 1.48 (2 ꢁ 3H, 2 ꢁ s,
a
a
0
C(CH3)2), 3.67 (1H, dd, JH-5,H-5 13.2 Hz, JH-5,H-4 2.4 Hz,H-5), 3.79
(1H, dd, JH-5 ,H-5 13.3 Hz, JH-5 ,H-4 3.1, H-50), 4.64 (1H, a-d, J 5.5, H-
3), 4.67 (1H, m, H-4), 4.86 (1H, d, JH-2,H-3 6.0 Hz, H-2); dC (CDCl3,
100 MHz): 25.5, 26.6 (C(CH3)2), 52.5 (C-5), 75.1 (C-3), 78.0 (C-2),
80.0 (C-4), 113.7 (C(CH3)2), 173.3 (C@O). C8H11N3O4 required C,
45.07; H, 5.20; N 19.71. Found: C, 45.09; H, 5.26; N, 19.58.
4.1.3. 5-Azido-5-deoxy-2-C-hydroxymethyl-2,
3-O-isopropylidene- -ribose 11
0
0
D
Potassium carbonate (1.98 g, 14.35 mmol) was added, followed
by an aqueous solution of formaldehyde (38.5%, 63 mL), to a stirred
solution of the lactols 9 (6.16 g, 28.64 mmol) in methanol (168 mL)
and the mixture was heated to 50 °C. After 24 h, TLC analysis (ethyl
acetate/cyclohexane, 1:1) showed the presence of a product (Rf
0.24) and complete consumption of the starting material (Rf
0.59). The reaction mixture was allowed to cool to room tempera-
ture, water was added (200 mL) and the mixture was concentrated
until the methanol was completely removed. The aqueous solution
was then extracted with diethyl ether (3 ꢁ 250 mL). The organic
extracts were combined, dried (magnesium sulfate), filtered and
4.1.2. 5-Azido-5-deoxy-2,3-O-isopropylidene-D-ribose 9
Diisobutylaluminum hydride solution (1.5 M in toluene,
14.4 mL, 21.60 mmol) was added dropwise over a period of
30 min to a stirred solution of the azidolactone 19 (4.16 g,
19.51 mmol) in dichloromethane (51 mL) under an atmosphere
of argon at ꢀ78 °C. The temperature was kept at ꢀ78 °C for the
duration of the reaction. After 3 h 20 min, TLC analysis (ethyl ace-

M. I. Simone et al. / Tetrahedron: Asymmetry 19 (2008) 2887–2894
2891
concentrated in vacuo to give a residue, which was purified by
flash column chromatography (ethyl acetate/cyclohexane, 1:2 to
1:1) to afford the branched ribose 11 (6.57 g, 94%) as a colourless
oil which crystallized on standing, mp 115–117 °C; m/z (ESꢀ):
244.4 ([MꢀH]ꢀ, 100%); HRMS (ESꢀ): found: 244.0929 [MꢀH]ꢀ
½
a 2D1
ꢂ
¼ þ58:9 (c 0.52, dichloromethane); mmax (thin film): 2997
(C–H), 2120 (s, N3), 1786 (s, C@O) cmꢀ1; dH (CDCl3, 400 MHz):
0
1.46, 1.47 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2), 3.79 (1H, dd, JH-5 ,H-5 13.4 Hz,
JH-5 ,H-4 2.5 Hz, H-50), 3.87 (1H, dd, JH-5,H-5 13.4 Hz, JH-5,H-4 3.2 Hz,
0
0
0
H-5), 4.70 (1H, ddd, JH-4,H-5 3.3 Hz, JH-4,H-5 2.6 Hz, JH-4,H-3 0.8 Hz,
C9H14N3O5 requires 244.0933; ½a D25
ꢂ
¼ þ23:1 (c 0.95, acetonitrile);
H-4), 4.73 (1H, d, JH-3,H-4 0.8 Hz, H-3), 4.83 (1H, d, JH-2,H-2
0
11.2 Hz, H-2), 4.93 (1H, d, JH-2 ,H-2 11.2 Hz, H-20); dC (CDCl3,
0
mmax (thin film): 3436 (br s, OH), 2988, 2938 (C–H), 2105 (s, N3),
1633 (s, CHO) cmꢀ1
;
dH (CD3CN, 400 MHz): anomeric ratio:
100 MHz): 26.3, 27.0 (C(CH3)2), 52.2 (C-5), 71.3 (C-20), 78.9 (C-3),
81.6 (C-4), 83.6 (C-2), 113.7, 116.9, 120.1, 123.3 (1C, q, JC,F
ꢀ318 Hz, CF3), 115.2 (C(CH3)2), 171.1 (C@O). C10H12F3N3O7S re-
quired C, 32.00; H, 3.22; N, 11.20. Found: C, 32.09; H, 3.25; N,
11.18.
b:
a
= 9:11; 1.39, 1.45 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2,
a), 1.42, 1.54
), 3.31 (1H, dd,
(2 ꢁ 3H, 2 ꢁ s, C(CH3)2, b), 3.07 (1H, m, OH-20,
a
0
0
JH-5,H-5 12.8 Hz, JH-5,H-4 6.0, H-5,
20,H-20
a
), 3.34 (1H, a-t, JOH-2 ,H-2 = JOH-
5.8 Hz, OH-20, b), 3.37 (1H, dd, JH-5,H-5 13.2 Hz, JH-5,H-4 4.8,
0
H-5, b), 3.45 (1H, dd, JH-5 ,H-5 13.3 Hz, JH-5 ,H-4 6.6 Hz, H-50, b), 3.55
0
0
(1H, dd, JH-5 ,H-5 12.8 Hz, JH-5 ,H-4 8.3 Hz, H-50,
a
), 3.66 (1H, dd, JH-
0
0
4.1.6. Methyl (3R,4R,5R)-5-azidomethyl-3,4-dihydroxy-tetrahy-
drofuran-3-carboxylate 17
2,H-20
0
0
12.0 Hz, JH-2,OH-2 6.0 Hz, H-2, b), 3.68 (1H, dd, JH-2 ,H-2
12.0 Hz, JH-2 ,OH-2 5.6 Hz, H-20, b), 3.74 (1H, m, H-2,
a
), 3.77 (1H,
), 4.09 (1H, d, JOH-1,H-1
), 4.16–4.21 (2H, m, H-4, b and H-4, ), 4.44–4.46
(2H, m, H-3, b and H-3, ), 4.90 (1H, d, JOH-1,H-1 4.4 Hz, OH-1, b),
5.09 (1H, d, JH-1,OH-1 9.2 Hz, H-1, ), 5.31 (1H, d, JH-1,OH-1 4.4 Hz,
H-1, b); dC (CD3CN, 100 MHz): 26.8, 27.0 (C(CH3)2, b), 27.5 (1 ꢁ s,
C(CH3)2, ), 51.9 (C-5, b), 53.6 (C-5,
), 62.4 (C-20, ), 62.5 (C-20,
b), 80.7 (C-4, b), 83.8 (C-3, b), 84.8 (C-4, ), 85.2 (C-3, ), 91.3 (C-
2, b), 94.3 (C-2, ), 98.3 (C-1, ), 104.8 (C-1, b), 113.6 (C(CH3)2,
), 114.8 (C(CH3)2, b).
0
0
A freshly prepared solution of acetyl chloride/methanol (1:1 v/v,
210 mL) was cooled to 0 °C and was added to the crude triflate 13
(2.17 g, 5.78 mmol) and stirred at room temperature under an
atmosphere of nitrogen. After 19 h, TLC analysis (ethyl acetate/
cyclohexane, 1:1) showed the presence of a major product (Rf
0.18) and complete consumption of the starting material (Rf
0.66). The reaction mixture was diluted in methanol (300 mL), then
quenched with anhydrous sodium bicarbonate and adjusted to pH
7. The mixture was filtered (eluent: methanol) and the filtrate con-
centrated in vacuo to yield a white residue, which was suspended
in water (50 mL) and extracted with dichloromethane (2 ꢁ 400 mL,
4 ꢁ 100 mL). The organic layers were combined, dried (magnesium
sulfate), filtered and concentrated in vacuo to yield the title com-
pound 17 (1.09 g, 87%) as a dark yellow viscous oil. m/z (CI+):
235.1 ([M+NH4]+, 28%); HRMS (CI+): found 235.1048 [M+NH4]+
dd, JH-2 ,H-2 12.0 Hz, JH-2 ,OH-2 5.6 Hz, H-20,
9.2 Hz, OH-1,
a
0
0
0
a
a
a
a
a
a
a
a
a
a
a
a
4.1.4. 5-Azido-5-deoxy-2-C-hydroxymethyl-2,3-O-isopropyli-
dene- -ribono-1,4-lactone 20
D
Bromine (1.4 mL, 27.26 mmol) was added dropwise over a per-
iod of 7 min to the lactol 11 (5.10 g, 20.07 mmol) stirring in water
(540 mL) at 0 °C in the presence of barium carbonate (4.97 g,
25.16 mmol). After 2 h and 15 min, TLC analysis (ethyl acetate/
cyclohexane, 1:1) showed the presence of a product (Rf 0.34) and
almost complete consumption of the starting material (Rf 0.21).
The reaction mixture was quenched with sodium thiosulfate and
extracted with diethyl ether (3 ꢁ 200 mL). The organic extracts
were combined, dried (magnesium sulfate), filtered and concen-
trated in vacuo to afford a residue, which was purified by flash col-
umn chromatography (ethyl acetate/cyclohexane, 1:1) to give the
branched lactone 20 (4.20 g, 82%) as a white crystalline solid. mp
100.5–102 °C. m/z (CI+): 261.0 ([M+NH4]+, 100%); HRMS (CI+):
found 261.1197 [M+NH4]+ C9H17N4O5 requires 261.1199;
C7H15N4O5 requires 235.1042; ½a D21
¼ þ25 (c 4.4, methanol); mmax
ꢂ
(thin film): 3428 (br, OH), 2957 (C–H), 2106 (s, N3), 1735
(C@O) cmꢀ1; dH (CDCl3, 400 MHz): 3.44 (1H, dd, JH-6,H-6 13.1 Hz,
0
0
0
JH-6,H-5 5.0 Hz, H-6), 3.60 (1H, dd, JH-6 ,H-6 13.1 Hz, JH-6 ,H-5 3.6 Hz,
H-60), 3.71 (1H, d, JOH-4,H-4 5.5 Hz, OH-4), 3.86 (3H, s, CO2CH3),
0
3.96 (1H, d, JH-2,H-2 9.7 Hz, H-2), 4.02–4.08 (1H, m, H-5), 4.18
0
(1H, a-t, J 6.3 Hz, H-4), 4.21 (1H, s, OH-3), 4.26 (1H, d, JH-2 ,H-2
9.7 Hz, H-20); dC (CDCl3, 100 MHz): 51.7 (C-6), 53.4 (CO2CH3),
74.5 (C-2), 81.2 (C-4), 82.6 (C-5), 84.0 (C-3), 172.9 (C@O).
4.1.7. N-Benzyl 5-azido-5-deoxy-2-C-hydroxymethyl-2,3-isopro-
pylidene-20-O-trifluoromethanesulfonyl-
D-ribonamide 23
½
a 2D5
ꢂ
¼ þ11:3 (c 0.31, acetonitrile); mmax (thin film): 3430 (s, OH),
2992, 2954 (C–H), 2129 (s, N3), 1782 (s, C@O) cmꢀ1; dH (CDCl3,
400 MHz): 1.45, 1.47 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2), 2.20–2.45 (1H, br s,
Benzylamine (25
lL, 0.23 mmol) was added dropwise to a solu-
tion of the triflate 13 (85 mg, 0.23 mmol) in THF (2 mL) at room
temperature under an atmosphere of argon. After 2 h, TLC analysis
(ethyl acetate/cyclohexane, 1:1) showed the presence of one major
UV-active product (Rf 0.56) and starting material (Rf 0.48). More
OH), 3.6–3.71 (2H, m, H-5 and H-50), 3.94 (1H, d, JH-2,H-2 11.7 Hz,
0
H-2), 4.08 (1H, d, JH-2 ,H-2 11.7 Hz, H-20), 4.66 (1H, a-t, J 5.6 Hz, H-
0
4), 4.64 (1H, a-s, H-3); dC (CDCl3, 100 MHz): 26.7, 26.9 (C(CH3)2),
51.9 (C-5), 61.5 (C-20), 79.7 (C-3), 81.7 (C-4), 85.3 (C-2), 114.0
(C(CH3)2), 174.4 (C@O). C9H13N3O4 required C, 44.44; H, 5.39; N,
17.28. Found: C, 44.39; H, 5.37; N, 17.32.
benzylamine (25 lL) was added and after 3 h and 45 min TLC anal-
ysis (ethyl acetate/cyclohexane, 1003A1) showed complete con-
sumption of the starting material (Rf 0.48). The reaction mixture
was purified by flash column chromatography (ethyl acetate/cyclo-
hexane, 1:3) to afford the open chain triflate amide 23 (60.6 mg,
55%) as a colourless oil. m/z (CI+): 483.1 (M+H+, 100%); HRMS
(CI+): found 483.1154 [M+H]+ C17H22N4O7F3S requires 483.1161;
mmax (thin film): 3417 (s, NH, OH), 3033 (ArC-H), 2993, 2939 (C–
4.1.5. 5-Azido-5-deoxy-2-C-hydroxymethyl-2,3-O-isopropylide
ne-20-C-trifluoromethanesulfonyl-
D-ribono-1,4-lactone 13
Pyridine (1.70 mL) then triflic anhydride (1.50 mL, 8.92 mmol)
was added dropwise to a stirred solution of hydroxymethyl lactone
20 (1.40 g, 5.76 mmol) in dichloromethane (110 mL) at ꢀ25 °C un-
der an atmosphere of argon. After 15 min, TLC (ethyl acetate/cyclo-
hexane, 1:1) showed the presence of one product (Rf 0.53) and
complete consumption of the starting material (Rf 0.32). The reac-
tion mixture was diluted in dichloromethane (70 mL), washed with
an aqueous hydrochloric acid solution (1 M, 40 mL), brine (40 mL)
and dried (magnesium sulfate). The organic layer was then filtered,
concentrated in vacuo to yield the triflate 13 (2.10 g, 97%) as a thick
colourless oil. m/z (ES+): 439.0 ([M+NH4+Na]+, 100%); HRMS (MS+):
found 398.0240 [M+NH4]+ C10H12F3N3NaO7S requires 398.0234;
H), 2106 (s, N3), 1664 (s, C@ONH, I), 1531 (s, C@ONH, II) cmꢀ1
dH (CDCl3, 400 MHz): 1.48, 1.52 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2), 3.40 (1H,
;
dd, JH-5 ,H-5 12.7 Hz, JH-5 ,H-4 5.6 Hz, H-50), 3.52 (1H, dd, JH-5,H-5
0
0
0
12.8 Hz, JH-5,H-4 2.6 Hz, H-5), 3.74–3.81 (1H, m, H-4), 4.06 (1H, d,
JH-3,H-4 9.4 Hz, H-3), 4.51 (1H, dd, JH-A,H-B 15.3 Hz, JH-A,NH 6.2 Hz,
CHAHBNH), 4.57 (1H, dd, JH-B,H-A 15.3 Hz, JH-B,NH 6.3 Hz, CHAHBNH),
0
4.61 (1H, d, JH-2,H-2 10.7 Hz, H-2), 4.96 (1H, a-s, OH-4), 4.98 (1H, d,
JH-2 ,H-2 10.8 Hz, H-20), 7.24–7.42 (6H, m, NH and 5 ꢁ Ar-H); dC
0
(CDCl3, 100 MHz): 25.3, 27.2 (C(CH3)2), 43.8 (NHCH2), 53.5 (C-5),
70.0 (C-4), 77.5 (C-20), 79.4 (C-3), 84.8 (C-2), 111.9 (C(CH3)2),

2892
M. I. Simone et al. / Tetrahedron: Asymmetry 19 (2008) 2887–2894
114.5, 117.1, 119.7, 122.3 (CF3), 127.3, 128.0, 129.0 (5 ꢁ Ar-CH),
136.5 (ArC), 169.5 (CONH).
(C(CH3)2), 49.6 (C-5), 75.6 (C-3), 76.0 (C-2), 77.1 (C-4), 114.2
(C(CH3)2), 172.9 (C@O). C8H11N3O4 requires C, 45.07; H, 5.20; N,
19.71. Found: C, 45.05; H, 5.22; N, 19.32.
4.1.8. N-Benzyl 1,20-anhydro-5-azido-5-deoxy-2-C-hydroxyme-
thyl-2,3-O-isopropylidene-
D-ribonamide 25
4.2.2. 5-Azido-5-deoxy-2,3-O-isopropylidene-L-lyxose 10
Potassium carbonate (96 mg, 0.70 mmol) was added to a solu-
tion of the open chain triflate 23 (63.3 mg, 0.13 mmol) in tetrahy-
drofuran (13 mL) at room temperature under an atmosphere of
argon. After 6 days, TLC (ethyl acetate/cyclohexane, 1:1) showed
the presence of one product (Rf 0.64) and complete consumption
of the starting material (Rf 0.43). The reaction mixture was filtered
through Celite (eluent: ethyl acetate), concentrated in vacuo and
purified by flash chromatography (ethyl acetate/cyclohexane,
1:3) to yield N-benzyl 1,20-anhydro-5-azido-5-deoxy-2-C-hydroxy-
Diisobutylaluminum hydride (1.7 M in toluene, 12.9 mL,
22.03 mmol) was added dropwise over a period of 15 min to a stir-
red solution of the azidolactone 27 (4.05 g, 18.99 mmol) in dichlo-
romethane (51 mL) at 78 °C under an atmosphere of argon. After
2.5 h at ꢀ78 °C, more diisobutylaluminum hydride (10 mL,
17.00 mmol) was added dropwise to the stirring solution. After
45 min, TLC analysis (ethyl acetate/dichloromethane, 1:4) showed
the presence of a major product (Rf 0.47) and complete consump-
tion of the starting material (Rf 0.70). The reaction mixture was
quenched by addition of water (25 mL) and extracted with dichlo-
romethane (3 ꢁ 100 mL). The organic extracts were combined,
dried (magnesium sulfate), filtered and concentrated in vacuo to
give the azidolyxose 10 (4.07 g, 99%) as a pale yellow oil. m/z
(CI+): 233.1 ([M+NH4]+, 100%); HRMS (CI+): found 233.1245
methyl-2,3-O-isopropylidene-D-ribonamide 25 (39 mg, 89%) as a
colourless oil. m/z (CI+): 333.3 ([M+H]+, 100%); HRMS (CI+): found:
333.1572 [M+H]+ C16H21N4O4 requires 333.1563; ½a D23
¼ þ25:2 (c
ꢂ
1.76, acetonitrile); mmax (thin film): 3414 (br, OH), 3032 (ArC-H),
2988, 2935 (C–H), 2105 (s, N3), 1745 (C@O, 4-ring lactam) cmꢀ1
;
dH (CDCl3, 400 MHz): 1.37, 1.52 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2), 3.25 (1H,
[M+NH4]+ C8H17N4O4 requires 233.1250; ½a 2D1
¼ ꢀ36:0 (c 0.90,
ꢂ
0
d, JOH-4,H-4 5.5 Hz, OH-4), 3.40 (1H, d, JH-2,H-2 5.5 Hz, H-2), 3.43
methanol); mmax (thin film): 3423 (br, OH), 2942 (C–H), 2102 (s,
(1H, d, JH-2 ,H-2 5.6 Hz, H-20), 3.44 (1H, dd, JH-5,H-5 12.6 Hz, JH-5,H-4
N3) cmꢀ1; dH (C6D6, 400 MHz): (data for the major anomer
a):
0
0
5.7 Hz, H-5), 3.59 (1H, dd, JH-5 ,H-5 12.7 Hz, JH-5 ,H-4 2.6 Hz, H-50),
4.20 (1H, dddd, JH-4,H-3 9.4 Hz, JH-4,H-5 5.7 Hz, JH-4,OH-4 5.5 Hz, JH-
1.06, 1.35 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2), 2.12 (1H, d, JOH-1,H-1 2.8 Hz,
0
0
0
OH-1), 3.27 (1H, dd, JH-5,H-5 12.8 Hz, JH-5,H-4 4.6 Hz, H-5), 3.50
2.6 Hz, H-4), 4.25 (1H, d, JH-3,H-4 9.4 Hz, H-3), 4.40 (1H, d, JHA,HB
(1H, dd, JH-5 ,H-5 12.8 Hz, JH-5 ,H-4 8.0 Hz, H-50), 4.14 (1H, m, H-4),
4.50 (1H, dd, JH-3,H-2 6.0 Hz, JH-3,H-4 3.6 Hz, OH-1), 4.50 (1H, d, JH-
4,H-50
0
0
15.1 Hz, NCHAHB), 4.47 (1H, d, JH-B,H-A 15.1 Hz, NCHAHB), 7.23–7.39
(5H, m, 5 ꢁ Ar-H); dC (CDCl3, 100 MHz): 26.1, 27.3 (C(CH3)2), 46.0
(NCH2), 54.3 (C-5), 54.5 (C-20), 70.0 (C-4), 79.4 (C-3), 90.4 (C-2),
111.4 (C(CH3)2), 128.0, 128.1, 128.9 (5 ꢁ Ar-CH), 134.5 (ArCCH2),
167.4 (CONH).
5.9 Hz, H-2), 5.30 (1H, d, JH-1,OH-1 2.4 Hz, H-1); dC (C6D6,
2,H-3
100 MHz): 24.5, 26.0 (2 ꢁ C(CH3)2), 50.1 (C-5), 79.0 (C-4), 80.0
(C-3), 85.9 (C-2), 101.4 (C-1), 112.6 (C(CH3)2).
If the azide-triflate displacement reaction was not complete, the
triflate 26 was carried through giving an impurity which was re-
4.2. Synthesis of cis-azidomethyl THF SAA 18
duced to 1,5-anhydro-2,3-O-isopropylidene-L-lyxofuranose 31, a
volatile colourless crystalline solid; Rf 0.57 (ethyl acetate: cyclohex-
ane, 1: 1); mp 65–66 °C (recrystallized from ethyl acetate/cyclohex-
ane); HRMS (FI+): found 172.0732 [M]+ C8H12O4 requires 172.0736;
4.2.1. 5-Azido-5-deoxy-2,3-O-isopropylidene-L-lyxono-1,
4-lactone 27
Pyridine (2.61 mL) followed by trifluoromethanesulfonic anhy-
dride (5.96 mL, 35.45 mmol) was added dropwise to a solution of
the alcohol 8 (6.67 g, 35.45 mmol) stirred in dichloromethane
(445 mL) at ꢀ50 °C under an atmosphere of nitrogen. After
15 min, TLC analysis (ethyl acetate/cyclohexane, 1:1) showed the
presence of one product (Rf 0.57) and complete consumption of
starting material (Rf 0.13). The reaction mixture was washed with
aqueous hydrochloric acid solution (1 M, 150 mL) and brine
(120 mL), dried (magnesium sulfate), filtered and concentrated in
vacuo to afford crude triflate 26 as a white hygroscopic amorphous
solid (13.17 g, 99%). Sodium azide (6.91 g, 106.34 mmol) was
added to a solution of the crude triflate 26 in acetone (54 mL)
and was stirred at 65 °C under an atmosphere of nitrogen. After
15 h, a white precipitate had formed in the stirring reaction mix-
ture and TLC analysis (ethyl acetate/cyclohexane, 1:1) showed
the presence of one product (Rf 0.57). The reaction mixture was fil-
tered through Celite (eluent/acetone), and the filtrate was dried
(magnesium sulfate), filtered and concentrated in vacuo to afford
a residue, which was purified by flash column chromatography
(ethyl acetate/cyclohexane, 1:1 to ethyl acetate) to give the azi-
do-lactone 27 (6.51 g, 86% over two steps) as pale yellow crystals.
mp 72–74 °C [Lit.20 mp 59.7 °C for the enantiomer 5-azido-5-
½
a 2D1
ꢂ
¼ þ106:8 (c 0.72, methanol); mmax (thin film): 2992, 2955,
2906 (s, C–H), 1378 (–O–CO–CH), 1291 (C–O) cmꢀ1; dH (CDCl3,
400 MHz): 1.34, 1.60 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2), 3.55 (1H, ddd, JH-5,H-
50
6.6 Hz, JH-5,H-4 3.5 Hz, JH-5,H-3 1.3 Hz, H-5), 4.31 (1H, a-d, J 6.8 Hz,
H-50), 4.45 (1H, a-dd, J 8.2 Hz, J 2.3, H-2), 4.64 (1H, dd, JH-3,H-2
8.1 Hz, JH-3,H-4 4.6, H-3), 4.72–4.77 (1H, m, H-4), 5.45 (1H, d, JH-1,H-
2.2 Hz, H-1); dC (CDCl3, 100 MHz): 25.6, 26.1 (C(CH3)2), 63.7 (C-
2
5), 76.5 (C-3), 78.8 (C-4), 81.6 (C-2), 100.1 (C-1), 119.7 (C(CH3)2).
4.2.3. 5-Azido-5-deoxy-2-C-hydroxymethyl-2,
3-O-isopropylidene-L-lyxose 12
Potassium carbonate (598 mg, 4.33 mmol), followed by an
aqueous solution of formaldehyde (38.5 wt %, 19 mL), was added
to a solution of lactol 10 (1.86 g, 8.63 mmol) in methanol (51 mL)
and heated at 78 °C. After 22 h, TLC analysis (ethyl acetate/cyclo-
hexane, 1:1) showed the presence of a major product (Rf 0.39)
and almost complete consumption of the starting material (Rf
0.56). The reaction mixture was cooled to room temperature, water
was added (200 mL) and the mixture was concentrated in vacuo;
the
concentrate
was
extracted
with
dichloromethane
(3 ꢁ 250 mL). The organic extracts were combined, dried (magne-
sium sulfate), filtered and concentrated in vacuo to give a residue,
which was purified by flash column chromatography (ethyl ace-
tate/cyclohexane, 1:1) to give the branched lyxose 12 [1.31 g,
62%; 88% based on recovered starting material (551 mg)] as a pale
yellow oil which crystallized on standing, mp 63–65 °C; m/z (CI+):
263.1 ([M+NH4]+, 100%); HRMS (CI+): found: 263.1362 [M+NH4]+
deoxy-2,3-O-isopropylidene-D
-lyxono-1,4-lactone]; HRMS (FI+):
found 213.0757 [M]+ C8H11N3O4 requires 213.0750; ½a D22
¼ ꢀ75:8
ꢂ
(c 0.52, chloroform) {Lit.19
½ ꢂ ¼ ꢀ71:0 (c 2.0, chloroform)}; mmax
a D
(thin film): 2992, 2971 (C–H), 2108 (s, N3), 1790 (C@O) cmꢀ1; dH
(CDCl3, 400 MHz): 1.39, 1.49 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2), 3.66 (1H,
C9H19N4O5 requires 263.1355; ½a D22
¼ ꢀ0:2 (c 0.96, chloroform);
ꢂ
0
0
dd, JH-5,H-5 12.9 Hz, JH-5,H-4 6.3 Hz, H-5), 3.72 (1H, dd, JH-5 ,H-5
13.0 Hz, JH-5 ,H-4 7.1 Hz, H-50), 4.54–4.59 (1H, ddd, JH-4,H-5 7.1 Hz,
JH-4,H-5 6.4, JH-4,H-3 3.6 Hz, H-4), 4.85 (1H, d, JH-2,H-3 10.9 Hz, H-2),
4.85 (1H, a-t, J 10.9 Hz, H-3); dC (CDCl3, 100 MHz): 25.8, 26.7
mmax (thin film): 3423 (br s, OH), 2989, 2939 (s, C–H), 2104 (s,
N3), 1635 (w, CHO) cmꢀ1; C9H15N3O5 requires C, 44.08; H, 6.17;
N, 17.13. Found: C, 44.18; H, 6.14; N, 17.11.
0
0

M. I. Simone et al. / Tetrahedron: Asymmetry 19 (2008) 2887–2894
2893
4.2.4. 5-Azido-5-deoxy-2-C-hydroxymethyl-2,
3-O-isopropylidene- -lyxono-1,4-lactone 28
anhydrous sodium bicarbonate, filtered through Celite (eluent/
methanol) and concentrated in vacuo. The residue was purified
by flash column chromatography (ethyl acetate/cyclohexane, 1:3)
to give starting material 14 (24 mg) and the methyl ether 29
(16 mg, 33%; 51% based on recovered starting material) as a pale
yellow oil. HRMS (FI+): found 257.1010 [M]+ C10H15N3O5 requires
L
Bromine (0.64 mL, 12.49 mmol) was added dropwise at 0 °C to a
solution of the azidolyxose 12 (2.00 g, 8.16 mmol) in water
(250 mL) in the presence of barium carbonate (2.46 g, 12.47 mmol)
over a period of 30 min. After 1 h 30 min, an extra portion of bar-
ium carbonate (0.27 g, 1.35 mmol) was carefully added. After 1 h,
TLC analysis (ethyl acetate/cyclohexane, 1:1) indicated the pres-
ence of a major product (Rf 0.43), and complete consumption of
the starting material (Rf 0.27). The reaction mixture was quenched
with a saturated solution of sodium thiosulfate and the suspension
was extracted with diethyl ether (3 ꢁ 250 mL). The organic ex-
tracts were combined, dried (magnesium sulfate), filtered and con-
centrated in vacuo to give a residue, which was purified by flash
column chromatography (ethyl acetate) to yield the branched lyx-
onolactone 28 (1.73 g, 87%) as pale yellow crystals. mp 98–99 °C;
m/z (CI+): 261.1 ([M+NH4]+, 100%); HRMS (CI+): found 261.1204
257.1012; ½a 2D3
¼ ꢀ32:7 (c 0.22, dichloromethane); mmax (thin
ꢂ
film): 2941 (C–H), 2109 (s, N3), 1789 (s, C@O) cmꢀ1; dH (CDCl3,
400 MHz): 1.39, 1.48 (2 ꢁ 3H, 2 ꢁ s, C(CH3)2), 3.39 (3H, s, COCH3),
0
3.54 (1H, dd, JH-5,H-5 12.8 Hz, JH-5,H-4 6.5 Hz, H-5), 3.69 (1H, m, H-
50), 3.68 (1H, d, JH-2,H-2 8.8 Hz, H-2), 3.77 (1H, d, JH-2 ,H-2 8.8 Hz,
0
0
H-20), 4.53 (1H, ddd, JH-4,H-5 10.2 Hz, JH-4,H-5 6.7 Hz, JH-4,H-3 3.5 Hz,
0
H-4), 4.72 (1H, d, JH-3,H-4 3.5 Hz, H-3); dC (CDCl3, 100 MHz): 26.2,
26.8 (C(CH3)2), 49.4 (COCH3), 60.0 (C-5), 72.3 (C-20), 76.2 (C-4),
79.6 (C-3), 84.5 (C-2), 114.1 (C(CH3)2), 174.8 (C@O).
4.2.7. Methyl (3R,4R,5S)-5-azidomethyl-3,4-dihydroxy-tetrahy-
drofuran-3-carboxylate 18
[M+NH4]+ C9H17N4O5 requires 261.1199; ½a 2D1
¼ ꢀ0:1 (c 0.73, chlo-
ꢂ
roform); mmax (thin film): 3221 (s, OH), 2984, 3040 (C–H), 2101 (s,
N3), 1784 (C@O) cmꢀ1; dH (CDCl3, 400 MHz): 1.43, 1.49 (2 ꢁ 3H,
A freshly prepared solution of acetyl chloride/methanol (1.5/1.0,
160 mL) was carefully added to a solution of the triflate 14 (1.43 g,
3.81 mmol) stirring in methanol (30 mL) at 0 °C under an atmo-
sphere of nitrogen. The reaction solution was allowed to warm
up to room temperature. After 19 h, TLC analysis (ethyl acetate/
cyclohexane, 1:1) showed the presence of a major product (Rf
0.23) and complete consumption of the starting material (Rf
0.76). The reaction mixture was quenched with anhydrous sodium
bicarbonate, filtered through Celite (eluent : methanol) and con-
centrated in vacuo. The residue was dissolved in ethyl acetate, fil-
tered through Celite (ethyl acetate), concentrated in vacuo and
purified by flash column chromatography (ethyl acetate/cyclohex-
ane, 1:2 to 2:1) to give the lyxo-scaffold 18 (470 mg, 57%) as a pale
yellow oil. m/z (ES+): 218.0 ([M+H]+, 100%), 235.0 ([M+NH4]+, 62%);
HRMS (CI+): found 218.0776 [M+H]+ C7H12N3O5 requires 218.0777;
0
2 ꢁ s, C(CH3)2), 2.19–2.25 (1H, dd, JOH,H-2 3.9 Hz, JOH,H-2 7.6 Hz,
0
OH), 3.65 (1H, dd, JH-5,H-5 13.1 Hz, JH-5,H-4 6.1 Hz, H-5), 3.73 (1H,
dd, JH-5 ,H-5 13.0 Hz, JH-5 ,H-4 7.3 Hz, H-50), 3.94 (1H, dd, JH-2,H-2
0
0
0
0
0
11.4 Hz, JH-2,OH 3.8 Hz, H-2), 4.03 (1H, dd, JH-2 ,H-2 11.4 Hz, JH-2 ,OH
7.5 Hz, H-20), 4.58 (1H, ddd, JH-4,H-5 7.2 Hz, JH-4,H-5 6.2 Hz, JH-4,H-3
0
3.5 Hz, H-4), 4.79 (1H, d, JH-3,H-4 3.5 Hz, H-3); dC (CDCl3,
125 MHz): 26.4, 26.9 (C(CH3)2), 49.5 (C-5), 61.4 (C-20), 77.2 (C-4),
78.4 (C-3), 86.0 (C-2), 114.2 (C(CH3)2), 174.7 (C@O). C9H13N3O4 re-
quires C, 44.44; H, 5.39; N, 17.28. Found: C, 44.41; H, 5.39; N,
17.10.
4.2.5. 5-Azido-5-deoxy-2-C-hydroxymethyl-2,3-O-isopropylide-
ne-20-O-trifluoromethanesulfonyl-
L-lyxono-1,4-lactone 14
Pyridine (0.62 mL) then triflic anhydride (1.67 mL, 9.94 mmol)
was added dropwise to a stirred solution of lactone 28 (1.42 g,
5.86 mmol) in dichloromethane (95 mL) at ꢀ25 °C under an atmo-
sphere of nitrogen. After 20 min, TLC analysis (ethyl acetate/cyclo-
hexane, 1:1) showed the presence of one product (Rf 0.76) and
complete consumption of starting material (Rf 0.40). The reaction
mixture was diluted with dichloromethane (100 mL), washed with
an aqueous solution of HCl (1 M, 90 mL) and then with brine
(90 mL). The organic layer was dried (magnesium sulfate), filtered
and concentrated in vacuo to yield the azidotriflate 14 as a colour-
less oil which crystallized on standing (2.17 g, 99%). mp 33–34 °C;
m/z (CI+): 393.0 ([M+NH4]+, 100%); HRMS (CI+) found: 393.0695
½
a 2D1
ꢂ
¼ ꢀ39:5 (c 0.61, methanol); mmax (thin film): 3418 (br, OH),
2959 (s, C–H), 2107 (s, N3), 1732 (C@O) cmꢀ1
; dH (CD3CN,
0
400 MHz): 2.85 (1H, dd, JH-6,H-6 12.8 Hz, JH-6,H-5 5.0 Hz, H-6), 2.92
(1H, dd, JH-6 ,H-6 12.8 Hz, JH-6 ,H-5 7.7 Hz, H-60), 3.18 (1H, d, JH-2,H-2
0
0
0
9.8 Hz, H-2), 3.19 (3H, s, CO2CH3), 3.38 (1H, d, JOH-4,H-4 5.9 Hz,
OH-4), 3.50 (1H, dd, JH-4,OH-4 5.8 Hz, JH-4,H-5 3.5 Hz, H-4), 3.65
(1H, m, H-5), 3.79 (1H, d, JH-2 ,H-2 9.8 Hz, H-20), 3.80 (1H, a-s, OH-
0
3); dC (CD3CN, 100 MHz): 49.8 (C-6), 51.8 (CO2CH3), 73.4 (C-2),
77.9 (C-4), 80.0 (C-5), 84.4 (C-3), 170.9 (C@O).
Acknowledgement
[M+NH4]+ C10H16N4O7F3S requires 393.0692;
½
a 2D1
ꢂ
¼ ꢀ29:4 (c
Financial support [to M.I.S.] provided through the European
Community’s Human Potential Programme under Contract HPRN-
CT-2002-00173 is gratefully acknowledged.
0.70, ethyl acetate); mmax (thin film): 2996 (C-H), 2111 (s, N3),
1790 (C@O) cmꢀ1; dH (CDCl3, 400 MHz): 1.45, 1.51 (2 ꢁ 3H, 2 ꢁ s,
C(CH3)2), 3.68 (1H, dd, JH-5,H-5 13.1 Hz,, JH-5,H-4 6.1 Hz, H-5), 3.76
´
(1H, dd, JH-5,H-5 13.1 Hz, JH-5 ,H-4 7.2 Hz, H-50), 4.56 (1H, ddd, JH-4,
0
´
References and notes
H-50
0
7.2 Hz, JH-4,H-5 6.1 Hz, JH-4,H-3 3.6 Hz, H-4), 4.68 (1H, d, JH-2,H-2
11.2, H-2), 4.78 (1H, d, JH-2 ,H-2 11.2 Hz, H-20), 4.84 (1H, d, JH-3,H-4
3.6 Hz, H-3); dC (CDCl3, 100 MHz): 25.9, 26.7 (C(CH3)2), 49.2 (C-
5), 70.6 (C-20), 77.1 (C-4), 77.4 (C-3), 83.5 (C-2), 113.7, 116.8,
120.0, 123.2 (CF3) 115.5 (C(CH3)2), 171.1 (C@O). C10H12F3N3O7S re-
quires C, 32.00; H, 3.22; N, 11.20. Found: C, 32.41; H, 3.32; N,
11.02.
0
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