Synthesis of 4-aminomethyl-tetrahydrofuran-2-carboxylates with 2,4-cis and 2,4-trans relationships

Article abstract of DOI:10.1016/j.tet.2006.02.007

Templated tetrahydrofuran-based γ-azido esters were prepared with the C-2 and C-4 functionalities in cis and trans relative configurations. This was achieved by ring contraction of the suitably protected 2-O-triflates of pentono-1,5-lactones (d-ribose and

Full text of DOI:10.1016/j.tet.2006.02.007

Tetrahedron 62 (2006) 4110–4119
Synthesis of 4-aminomethyl-tetrahydrofuran-2-carboxylates
with 2,4-cis and 2,4-trans relationships
b
c
d
Alison A. Edwards,a, Gangadharar J. Sanjayan, Shuji Hachisu, Raquel Soengas,
*
Alistair Stewart,c George E. Trantera and George W. J. Fleetc
aBiological Chemistry, Division of Biomedical Sciences, Imperial College, London SW7 2AZ, UK
bDivision of Organic Synthesis, National Chemical Laboratory, Pune 411 008, India
cChemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
dDepartamento de Quimica Fundamental, Facultad de Ciencias, Campus da Zapateira, Universidad de A Corun˜a, 15071 A Corun˜a, Spain
Received 20 December 2005; revised 12 January 2006; accepted 2 February 2006
Available online 28 February 2006
Abstract—Templated tetrahydrofuran-based g-azido esters were prepared with the C-2 and C-4 functionalities in cis and trans relative
configurations. This was achieved by ring contraction of the suitably protected 2-O-triflates of pentono-1,5-lactones (D-ribose and
L-arabinose) with subsequent introduction of the azide via the 4-O-triflate. Access to a corresponding b-azido ester was achieved in good
yield. Little elimination product was observed by introduction of the azide via the 3-O-triflate. These azido esters are scaffolds, which may be
predisposed to adopt secondary structural motifs, for example, for use as peptidomimetics; they may also be utilised for the preparation of
stereodiverse compound libraries.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
14-helices.16–18 The biological importance of such systems
has been highlighted by analogues of a g-dipeptide, which
exhibited submicromolar affinities for human somatostatin
receptors.19 Oligomers of ureas, carbamates, phosphodi-
esters and vinylogous sulfonamidopeptides have also been
prepared as g-peptide analogues.20
Improvement of the pharmacological properties of natural
peptides has focused on the structural modification of the
constituent amino acids.1,2 Both b- and g-peptides (Fig. 1)
have been shown to be stable to common proteases.3
g-Peptides have been less extensively studied than their
b-counterparts.4–8 Nonetheless, g-amino acids (both acyclic
and cyclic) have been found to adopt secondary structures
akin to those observed for a-peptides.
Rigid cyclic g-amino acids have been employed in the
formation of parallel sheet structures21 and in the formation
of potent g-amino butyric acid (GABA) antagonists.22
Several conformationally restricted g-amino acids have
Vinylogous (a,b-unsaturated) g-peptides adopt parallel
sheet structures; with the insertion of a Pro-Gly unit into
the backbone, they also adopt novel helical conformations
with 10- and 12-membered hydrogen bonded rings.9
Conformational searching of a g-hexapeptide and corre-
sponding vinylogous analogue10 have since been reported
and vinylogous peptides identified as a source for g-peptide
foldamers.11,12 Hanessian and Seebach13 have prepared an
extensive set of acyclic g-peptides and related substitution
patterns and stereochemistry to secondary structural
preference for bII0-type turns14,15 and left and right handed
Keywords: Sugar amino acids; Peptidomimetics; Scaffolds; Gamma amino
acids.
*
Corresponding author. Tel.: C44 20 7594 3143; fax: C44 20 7594 3226;
e-mail: alison.edwards@imperial.ac.uk
Figure 1. Homologues of a-amino acids.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.007

A. A. Edwards et al. / Tetrahedron 62 (2006) 4110–4119
4111
been prepared recently.23–28 This paper describes the
synthesis of conformationally restricted g-amino acids
from sugar starting materials. Sugar amino acids
(SAAs) have been frequently employed as peptidomimetic
foldamers29–33 and as library scaffolds with their potential
for host–guest chemistry recently explored.34–38 Compared
to d-SAAs, there are relatively few examples of g-sugar
amino acids (g-SAAs) in literature.22,39–45 A pyranose
based g-SAA, which predetermines a b-turn conformation
in synthetic peptides has been described.41 Additionally, a
heterooligomer composed of a furanose g-SAA and GABA
exhibited no stable conformation in solution.44 Furanose
and pyranose based g-SAAs have been utilised to prepare
99-member and 384-member libraries, respectively.43,46
This paper reports the full synthesis of templated
tetrahydrofuran-based g-azido esters (1 and 2) and b-azido
ester 3 as SAA precursors for subsequent study of foldamer
preference.47
the activated pentono-1,5-lactone 5 (Fig. 2). This paper
reports the synthesis of two g-azido esters (1 and 2) via
strategy 1. The key step in the synthesis of g-azido ester 4
was the ring contraction of a trifluoromethanesulfonyl ester
(triflate), from a suitably protected pentono-1,5-lactone (5),
to form the diol 6. This method of ring contraction, using
either acidic or basic conditions, has been established for the
formation of related tetrahydrofuran-2-carboxylates.48,49
Activation of the C-4 hydroxyl via a sulfonyl ester with
subsequent azide displacement from 6 would yield the
desired g-azido ester 4.
L-Arabinose and D-ribose stereochemistries were employed
to give access to g-azido esters 1 and 2, which were related
at C-2 and C-4 positions by cis and trans stereochemistries,
respectively (Fig. 3). The stereochemical relationship
between the acid and amine functions of related d-azido
esters has been found to be important in subsequent
investigation of conformational preference.29,30,50,51 Poor
selectivity of the C-3 hydroxyl over that at C-4 in 7
generated a suitable precursor (8) for synthesis of the
corresponding b-azido ester 3. The b-azido ester 3 has the
amine and acid functions in a cis configuration. During
synthesis, the methyl ester was converted to the more
hindered isopropyl ester where convenient. This was to
prevent uncontrolled oligomer and/or lactam formation
resulting from nucleophilic attack of the carbonyl group by
2. Results and discussion
2.1. Strategy
Two different synthetic strategies could be employed for the
preparation of g-azido ester 4 as the azide function can be
introduced either before of after ring contraction of
Figure 2. Synthetic strategy for the formation of g-azido ester 4.
Figure 3. Strategy 1 applied to the formation of 1 and 2.

4112
A. A. Edwards et al. / Tetrahedron 62 (2006) 4110–4119
the amine function (by reduction of the azide in later
synthesis).52
deprotection of the acetonide. To achieve complete
deprotection of the acetonide to generate the desired diol
13, hydrochloric acid was added and the reaction mixture
warmed to 70 8C. It was convenient at this point to convert
the methyl ester to the more sterically hindered isopropyl
ester to prevent potential lactone formation. Therefore, the
crude diol 13 was subjected to acid-catalysed trans-
esterification with HCl in propan-2-ol (5% v/v) to afford
the isopropyl ester 7 as a colourless oil in an overall yield of
63% (over four steps from lactone 14). Selective reaction of
the diol 7 would provide an efficient route to both the g- and
b-azido ester (Fig. 2).
2.2. Synthesis of the b- and g-azido esters (1 and 3) from
L-arabinose stereochemistry
The 2-O-trifluoromethanesulfonyl pentono-1,4-lactone (tri-
flate) 9 can be prepared from L-arabinose in three steps using
known literature procedures.53 It was anticipated that the
triflate 9 would smoothly undergo the key ring contraction
reaction to form 10 upon treatment with methanol in the
presence of anhydrous potassium carbonate (K2CO3),
Scheme 1. However, when the triflate 9 was subjected to
basic conditions, the desired product 10 was isolated in 30%
yield and a second product 11 in 17% yield, by the K2CO3-
mediated epimerisation at C-2; in order to confirm this
assumption an independent experiment was carried out by
the treatment of 10 with methanol containing K2CO3. After
13 h, the majority of 10 had been consumed and the more
thermodynamically stable C-2 epimer 11 isolated in 89%
yield. The stereochemistry of 11 was confirmed by
comparison to the physical data of the enantiomer 12
(Scheme 2).
The introduction of azido group at the g-position, with
respect to the carboxyl function on the THF framework, of 7
was investigated. Initial efforts to esterify the C-4 hydroxyl
of 7 met with failure as the desired product was found to be
highly unstable. It was necessary to protect the free
hydroxyls prior to formation of the sulfonyl ester.
Introduction of the silyl protecting group was achieved by
treatment of the diol 7 with a single equivalent of tert-butyl
diphenylsilyl chloride (TBDPS-Cl) with imidazole in
dimethylformamide. Little selectivity was observed for the
hydroxyl at C-3 over that at C-4 giving both the 3-O-TBDPS
ether 15 and the 4-O-TBDPS silyl ether 8 in 34 and 55%
yield, respectively. The regio-isomers were easily distin-
guished from each other by 2D correlated spectroscopy in
DMSO-d6. The formation of the 4-O-TBDPS silyl ether 8,
although not part of the desired synthesis for the g-azido
In contrast to basic conditions, acidic conditions obviated
epimerisation. Analysis of the reaction mixture by TLC
revealed formation of the acetonide 10 (Rf 0.70, ethyl
acetate/pet. ether 1:1) together with a second product (Rf
0.20, ethyl acetate/pet. ether 1:1), the diol 13 formed by the
Scheme 1. Reagents and conditions: (i) Tf2O, pyridine, DCM, K20 8C; (ii) 1.1 equiv K2CO3, MeOH, 0 8C, 1.3 h; (iii) 0.3 equiv K2CO3, MeOH, rt, 14 h; (iv)
1% v/v AcCl in MeOH, rt, 13 h; (v) 2 N HCl, 70 8C, 3 h then 5% v/v AcCl in propan-2-ol, 80 8C, 48 h; (vi) TBDPSCl, imidazole, DMF, 0 8C to rt, 10 h; (vii)
4 equiv NaN3, DMF, rt, 10 h; (viii) 3 equiv TBAF, THF, rt, 14 h.

A. A. Edwards et al. / Tetrahedron 62 (2006) 4110–4119
4113
the unprotected diol 20, the (R)-benzylidene 21 and the
(S)-benzylidene 22 in 84, 7 and 6% yields, respectively. The
stereochemistry of the epimeric centre of the benzylidene
group in 21 and 22 was assigned on the basis of NOESY
cross-peaks between each benzylidine methane proton and
protons of the THF ring (Fig. 4). The diol 20 was treated
with acetone and DL-camphor-10-sulfonic acid to yield the
acetonide 12 in 83% yield. The formation of 12 confirmed
the diol had cis configuration and the physical data is in
agreement with the enantiomer 11 (Scheme 1).
Scheme 2. Reagents and conditions: (i) 5% v/v AcCl in MeOH, rt to 70 8C,
3 h then aq HCl added, 70 8C, 15 h; (ii) CSA, acetone, rt, 24 h; (iii)
1.5 equiv Tf2O, pyridine, DCM, K25 8C, 4 h then rt, 48 h; (iv) 5 equiv
NaN3, DMF, rt then 85 8C for 15 h; (v) p-toluenesulfonic acid, propan-2-ol,
80 8C, 24 h.
Figure 4. Assignment of R and S configurations of 21 and 22.
The preparation of the 4-azido derivative 23 was achieved
via SN2 displacement with sodium azide after selective
activation of the C-4 hydroxyl of 20. The activated ester 24
was obtained in 48% yield by treatment of 20 with
trifluoromethanesulfonic anhydride and pyridine in
dichloromethane at K25 8C although was observed to be
unstable on silica (by 2D TLC). Reaction of the crude
triflate 24 with sodium azide in dimethylformamide
afforded the azide 23 in 46% yield (over two steps from
20). Finally, the methyl azido ester 23 was converted to the
isopropyl ester 2 in 72% yield by treatment with
p-toluenesulfonic acid in propan-2-ol at 80 8C.
ester 1, was advantageous as the ether 8 is an ideal precursor
for the formation of the b-azido ester 3. A small amount of
the disubstituted silyl derivative 16 was isolated (8% yield)
and was easily converted back to the diol 7, albeit in
moderate yield (50%), by treatment with tetrabutylammo-
nium fluoride (TBAF) in tetrahydrofuran. A single crystal
X-ray structure of 16 was obtained,54 confirming that ring
contraction occurred with complete inversion of configur-
ation at C-2 and thus the relative stereochemistry of the diol.
The 3-O-TBDPS ether 15 was esterified using trifluoro-
methanesulfonic anhydride with pyridine in dichloro-
methane and was reacted without purification. The 4-O-
triflate was treated with excess sodium azide in dimethyl-
formamide to yield the g-azido ester 1 in 95% yield (from
15) with inversion of configuration at C-4. Following
similar protocols, the b-azido ester 3 was obtained via the
3-O-triflate in good yield (81% from 8) together with a small
amount (4%) of the b-eliminated product 17. The effective
substitution (with little elimination) is in stark contrast to a
related synthesis previously reported.39
3. Conclusion
This paper reports the efficient preparation of two
diastereomeric g-azido esters (1 and 2) and a b-azido
ester 3. The g-amino acid precursors have been studied for
conformational preference to assess their future role as
peptidomimetic foldamers; these results will be published
shortly. The efficient displacement of the b-triflate by
sodium azide will provide easy access to a range of THF
templated b-amino acid building blocks. Furthermore, these
orthogonally protected g- and b-amino acids may be
employed for the preparation of novel stereodiverse
compound libraries.
2.3. Synthesis of g-azido ester 2 from D-ribose
stereochemistry
The 2-O-triflate of 3,4-O-benzylidene-D-ribono-1,5-lactone
(18) can be prepared using literature procedures, in three
steps starting from D-ribose 19.55,56 The preparation of diol
20 from the triflate 18 was achieved by acid-catalysed ring
contraction with subsequent deprotection (Scheme 2).
Reaction of the crude triflate gave a more complex reaction
mixture. Treatment of the recrystallised triflate 18 with
methanolic hydrogen chloride (5% v/v) gave the desired
ring contraction products and subsequent heating at 70 8C
with further addition of hydrochloric acid afforded
4. Experimental
4.1. General
All commercial reagents were used as supplied. N-N-
Dimethylformamide (DMF) was purchased dry from the
Aldrich chemical company in sure-seal bottles. All other
solvents were used as supplied (Analytical or HPLC grade),

4114
A. A. Edwards et al. / Tetrahedron 62 (2006) 4110–4119
without prior purification. Petroleum ether (pet. ether) refers
to the fraction of petroleum ether that boils in the range
40–60 8C and hexane refers to the fraction of petroleum
ether that boils in the range 60–80 8C. Reactions were
performed under an atmosphere of nitrogen or argon. Thin-
layer chromatography (TLC) was performed on aluminium
or plastic sheets coated with 60 F254 silica. Sheets were
visualised using a spray of 0.2% w/v cerium (IV) sulfate and
5% ammonium molybdate in 2 M sulfuric acid. Flash
chromatography was performed on Sorbsil C60 40/60 silica.
Melting points were recorded on a Kofler hot block and are
uncorrected. Optical rotations were recorded on a Perkin–
Elmer 241 polarimeter with a path length of 1 dm.
Concentrations are quoted in g 100 mLK1. Elemental
analyses were performed by the microanalysis service of
the Dyson Perrins Laboratory, Oxford or the Inorganic
Chemistry Laboratory, Oxford. Infra-red (IR) spectra were
recorded on a Perkin–Elmer 1750 IR Fourier Transform
spectrophotometer using thin films on NaCl plates (film) or
KBr discs. Only the characteristic peaks are quoted and in
units of cmK1. Low resolution 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
chemical ionization (CI NH3), or atmospheric pressure
chemical ionization (APCI). Nuclear magnetic resonance
(NMR) spectra were recorded on Bruker AMX 500 and
DRX 500 spectrometers (1H: 500 MHz and 13C:
125.7 MHz), a Bruker DPX 400 spectrometer (1H:
400 MHz and 13C: 100.6 MHz) and a Bruker DPX 200
spectrometer (1H: 200 MHz and 13C: 50.3 MHz) in the
deuterated solvent stated. All chemical shifts (d) are quoted
in parts per million and coupling constants (J) given in Hz.
Residual signals from the solvents were used as an internal
reference. 13C multiplicities were assigned using a DEPT
sequence. 3,4-Isopropylidene-L-arabinose 25 was provided
by CMS chemicals and the selectively protected lactone 14
prepared according to a literature procedure.53 3,4-O-
Benzylidene-2-O-trifluoromethanesulfonyl-D-ribono-1,5-
lactone 18 was prepared in three steps from D-ribose using
literature procedures.55,56
formation of a major (Rf 0.70) and minor (Rf 0.38) product.
The reaction mixture was filtered and the residue washed
with methanol (2!5 mL). The filtrate was concentrated in
vacuo and purified by flash chromatography (ethyl acetate/
pet. ether, 1:4) to afford the desired product 10 (150 mg,
30%) as a colourless oil and the C-2 epimer 11 (82 mg,
17%) as a solid.
Compound 10. [a]2D3 C64.6 (c 1.2 in CHCl3); (HRMS (CIC):
Found 203.092464. C9H14O5 (MCHC) requires m/z,
203.091949); nmax (thin film)/cmK1 1741 (C]O, ester);
dH (CDCl3, 200 MHz) 1.32 (3H, s, C(CH3)2), 1.50 (3H, s,
C(CH3)2), 3.75 (3H, s, CO2CH3), 4.02 (1H, dd, J5,4
Z
0
0
4.3 Hz, J5,5 Z11.0 Hz, H-5), 4.15 (1H, d, J5 ,5Z11.0 Hz,
H-50), 4.60 (1H, br s, H-2), 4.83 (1H, m, H-4), 4.95 (1H, m,
H-3); dC (CDCl3, 50.3 MHz) 24.8 (q, C(CH3)2), 26.3 (q,
C(CH3)2), 52.2 (q, CO2CH3), 74.0 (t, C-5), 80.7 (d, C-4),
83.2 (d, C-3), 83.9 (d, C-2), 113.1 (s, C(CH3)2), 170.8 (s,
C]O); m/z (APCIC): 203.01 (MCHC, 33), 148.88
(100%).
Compound 11. Mp 61–62 8C; [a]2D3 C88.5 (c 1.1 in CHCl3):
(HRMS (CIC): Found 203.092171. C9H14O5 (MCHC)
requires m/z, 203.091949); nmax (thin film)/cmK1 1765
(C]O, ester); dH (C6D6, 500 MHz) 1.13 (3H, s, C(CH3)2),
0
1.48 (3H, s, C(CH3)2), 2.90 (1H, dd, J5,4Z4.1 Hz, J5,5
10.2 Hz, H-5), 3.45 (3H, s, CO2CH3), 3.73 (1H, d, J2,3
Z
Z
3.9 Hz, H-2), 3.95 (1H, d, J5 ,5Z10.2 Hz, H-50), 4.05 (1H,
m, H-4), 4.43 (1H, m, H-3); dC (C6D6, 50.3 MHz) 25.7 (q,
C(CH3)2), 26.5 (q, C(CH3)2), 51.5 (q, CO2CH3), 73.0 (t, C-
5), 80.9 (d, C-4), 81.9 (d, C-3), 82.2 (d, C-2), 113.30 (s,
C(CH3)2), 168.5 (s, C]O); m/z (APCIC): 203.03 (MC
HC, 100%).
0
4.1.2. Conversion of methyl 2,5-anhydro-3,4-O-isopro-
pylidene-L-ribonate 10 to methyl 2,5-anhydro-3,4-O-
isopropylidene-L-arabinoate 11. A catalytic amount of
anhydrous potassium carbonate (3 mg, 0.025 mmol) was
added to a stirred solution of acetonide 10 (18 mg,
0.089 mmol) in dry methanol (0.5 mL) at room temperature.
After 14 h, TLC (ethyl acetate/pet. ether, 1:1) showed the
formation of a major product (Rf 0.45) and a trace of starting
material (Rf 0.70). The reaction mixture was filtered,
concentrated in vacuo and the residue was purified by
flash chromatography (ethyl acetate/pet. ether, 1:4) to obtain
the C-2 epimer 11 (16 mg, 89%); data given above.
4.1.1. Methyl 2,5-anhydro-3,4-O-isopropylidene-L-ribo-
nate 10 and methyl 2,5-anhydro-3,4-O-isopropylidene-L-
arabinoate 11. Trifluoromethanesulfonic anhydride
(0.6 mL, 3.67 mmol) was added dropwise to a stirred
solution of the lactone 14 (460 mg, 2.40 mmol) in
dichloromethane (5 mL) with freshly distilled pyridine
(0.32 mL, 3.90 mmol) at K20 8C. After 40 min, TLC
(ethyl acetate/pet. ether, 1:1) showed the absence of starting
material (Rf 0.45) and the formation of a single product (Rf
0.73). The reaction mixture was diluted with dichloro-
methane (10 mL), and then washed sequentially with brine
(10 mL), citric acid (1 M aq, 10 mL) and water (10 mL).
The organic layer was concentrated in vacuo at low
temperature (0–5 8C) to obtain a yellow solid (9), which
was used without further purification. The triflate 9 was
dissolved in methanol (10 mL) containing anhydrous
potassium carbonate (360 mg, 2.64 mmol) and stirred at
0–5 8C. After 1.3 h, TLC (ethyl acetate/pet. ether, 1:1)
showed the absence of the triflate 9 (Rf 0.73) and the
4.1.3. Isopropyl 2,5-anhydro-L-ribonate 7. Trifluoro-
methanesulfonic anhydride (11.6 mL, 70.9 mmol) was
added slowly over a period of 15 min to a stirred solution
of the lactone 14 (9.52 g, 50.6 mmol) in freshly distilled dry
dichloromethane (100 mL) containing dry pyridine
(6.13 mL, 75.9 mmol) at K20 8C. After 40 min, TLC
(ethyl acetate/pet. ether, 1:1) showed the absence of starting
material (Rf 0.45) and the formation of a single product (Rf
0.73). The reaction mixture was diluted with dichloro-
methane (100 mL), washed sequentially with brine and
concentrated in vacuo at low temperature (0–5 8C). The
residue (triflate 9) was dissolved in methanolic hydrogen
chloride (1% v/v, 100 mL) and stirred at room temperature.
After 13 h, TLC (ethyl acetate/pet. ether, 1:1) showed the
absence of the triflate 9 (Rf 0.73) and the formation of two
products; Rf 0.70 (10) and Rf 0.20 (13). Hydrochloric acid

A. A. Edwards et al. / Tetrahedron 62 (2006) 4110–4119
4115
(2 N aq, 15 mL) was added and the reaction mixture
warmed to 70 8C. After 3 h, TLC (ethyl acetate/pet. ether,
1:1) indicated the absence of 10 (Rf 0.70). The reaction
mixture was concentrated in vacuo and co-evaporated with
toluene. The residue was dissolved in 5% v/v HCl in
propan-2-ol (100 mL) and heated to 80 8C. After 48 h, TLC
(ethyl acetate) showed the formation of a major product (Rf
0.55). The reaction mixture was neutralised by careful
addition of solid sodium hydrogen carbonate (30 g) until no
more effervescence was observed. The reaction mixture was
filtered and the filtrate concentrated in vacuo to obtain an
oil, which was purified by flash chromatography (ethyl
acetate/pet. ether, 2:3) to afford the title product 7 (6.10 g,
63%) as a colourless oil: [a]2D3 C44.3 (c 1.01 in CHCl3);
(HRMS (CIC): Found 208.118100. C8H14O5 (MCNHC4 )
requires m/z, 208.118498); nmax (thin film)/cmK1 3436 (OH)
and 1724 (C]O, ester); dH (CDCl3, 500 MHz) 1.32 (6H, d,
JZ6.3 Hz, CH(CH3)2), 3.13 (2H, br s, OH), 3.92 (1H, dd,
Compound 8. [a]2D3 C16.5 (c 1.6 in CHCl3); (HRMS (CIC):
Found 446.236835. C24H32O5Si (MCNHC4 ) requires m/z,
446.236277); nmax (thin film)/cmK1 3513 (OH) and 1738
(C]O, ester); dH ((CD3)2SO, 400 MHz) 1.05 (9H, s,
SiC(CH3)3), 1.13 (6H, d, JZ6.2 Hz, CH(CH3)2), 3.53
(1H, m, H-5), 3.72 (1H, m, H-50), 3.95 (1H, m, H-3), 4.12
(1H, m, H-4), 4.20 (1H, d, JZ4.8 Hz, H-2), 4.90 (1H, sept,
JZ6.2 Hz, CH(CH3)2), 5.55 (1H, d, OH), 7.40–7.75 (10H,
m, ArH); dC ((CD3)2SO, 50.3 MHz) 19.8 (s, SiC(CH3)3),
22.2 (q, CH(CH3)2), 27.6 (q, SiC(CH3)3), 68.8 (d,
CH(CH3)2), 72.7 (t, C-5), 73.9 (d, C-4), 75.4 (d, C-3),
82.2 (d, C-2), 128.6, 128.7, 130.7 (3!d, 6!ArCH), 133.8,
134.2 (2!s, 2!ArC), 136.1, 136.2 (2!d, 4!ArCH),
171.3 (s, C]O); m/z (CIC): 446.3 (MCNHC4 , 100%).
Compound 16. Mp 135–136 8C (EtOAc/n-hexane, 1:4);
[a]2D3 C15.1 (c 0.5 in CHCl3); (HRMS (CIC): Found
684.354410. C40H50O5Si2 (MCNHC4 ) requires m/z,
684.354056); nmax (thin film)/cmK1 1743 (C]O, ester);
dH (CDCl3, 200 MHz) 1.00 (6H, d, JZ6.7 Hz, CH(CH3)2),
1.12, 1.15 (18H, 2!s, 2!SiC(CH3)3), 3.62 (1H, m, H-5),
3.85 (1H, m, H-50), 4.13 (1H, m, H-4), 4.22 (1H, d, JZ
1.8 Hz, H-2), 4.35 (1H, m, H-3), 4.75 (1H, sept, JZ6.7 Hz,
CH(CH3)2), 7.23–7.82 (20H, m, ArH); dC (CDCl3,
50.3 MHz) 19.2, 19.4 (2!s, 2!SiC(CH3)3), 21.4 (q,
CH(CH3)2), 26.9, 27.0 (2!q, 2!SiC(CH3)3), 68.3 (d,
CH(CH3)2), 70.5 (t, C-5), 73.2 (d, C-4), 76.5 (d, C-3), 82.7
(d, C-2), 127.6, 127.7, 127.7, 127.7, 129.7, 129.9, 129.9
(7!d, 12!ArCH), 133.0, 133.1, 133.5 (3!s, 4!ArC),
135.6, 135.7, 136.0, 136.1 (4!d, 8!ArCH), 170.3 (s,
C]O); m/z (CIC): 684.4 (MCNHC4 , 35), 589.3 (100%).
0
0
J5,4Z2.7 Hz, J5,5 Z10.0 Hz, H-5), 4.16 (1H, dd, J5 ,4
Z
4.5 Hz, J5 ,5Z10.0 Hz, H-50), 4.10 (2H, m, H-2 and H-3),
4.35 (1H, m, H-4), 5.15 (1H, sept, JZ6.3 Hz, CH(CH3)2);
dC (CDCl3, 125.3 MHz) 21.6 (q, CH(CH3)2), 69.3 (d,
CH(CH3)2), 70.9 (d, C-4), 73.4 (t, C-5), 75.1 (d, C-3), 80.8
(d, C-2), 171.1 (s, C]O); m/z (CIC): 208.3 (MCNHC4 ,
100%).
0
4.1.4. Isopropyl 2,5-anhydro-3-O-tert-butyldiphenylsilyl-
L-ribonate 15, isopropyl 2,5-anhydro-4-O-tert-butyldi-
phenylsilyl-L-ribonate 8 and isopropyl 2,5-anhydro-3,4-
di-O-tert-butyldiphenylsilyl-L-ribonate 16. tert-Butyldi-
phenylsilyl chloride (5.46 mL, 21.0 mmol) was added to a
stirred solution of diol 7 (4.00 g, 21.0 mmol) in dry DMF
(20 mL) containing imidazole (1.71 g, 25.2 mmol) at 0 8C.
The reaction was allowed to warm to room temperature.
After 10 h, TLC (ethyl acetate) showed the absence of
starting material (Rf 0.55). Elution of the TLC (with ethyl
acetate/pet. ether, 1:9) showed the presence of one minor
product (Rf 0.65) and two major products, (Rf 0.32) and (Rf
0.20). The reaction mixture was concentrated in vacuo. The
residue was dissolved in ethyl acetate (100 mL) and
sequentially washed with brine (100 mL), citric acid (1 M
aq, 100 mL), saturated aq sodium hydrogen carbonate
(100 mL) and water (100 mL) and then concentrated in
vacuo. The residue was purified by flash chromatography
(ethyl acetate/pet. ether, 1:19) to afford 3-O-silyl derivative
15 (3.10 g, 34%) as a colourless oil, the 4-O-silyl derivative
8 (5.00 g, 55%) as a colourless oil and the disilylated
derivative 16 (1.12 g, 8%) as a white solid.
4.1.5. Conversion of isopropyl 2,5-anhydro-3,4-di-O-tert-
butyldiphenylsilyl-L-ribonate 16 to isopropyl 2,5-anhy-
dro-L-ribonate 7. Tetrabutylammonium fluoride (1 M
solution in THF, 2.2 mL, 2.2 mmol) was added to a stirred
solution of disilylated derivative 16 (0.50 g, 0.75 mmol) in
dry THF (2 mL) at room temperature. After 14 h, TLC
(ethyl acetate) showed the formation of a major product (Rf
0.55). The reaction mixture was concentrated in vacuo and
the residue purified by flash chromatography (ethyl acetate/
pet. ether, 2:3) to afford the diol 7 (70 mg, 50%) as a
colourless oil; data given above.
4.1.6. Isopropyl 2,5-anhydro-4-azido-3-O-tert-butyldi-
phenylsilyl-4-deoxy-L-ribonate 1. Trifluoromethane-
sulfonic anhydride (1.72 mL, 10.5 mmol) was added
dropwise over a period of 5 min to a stirred solution of 3-
O-silyl derivative 15 (3.00 g, 7.0 mmol) in dichloromethane
(60 mL) containing freshly distilled dry pyridine (0.96 mL,
11.9 mmol) at K20 8C. After 40 min, TLC (ethyl acetate/
pet. ether, 1:9) showed the absence of starting material (Rf
0.20) and the formation of a single product (Rf 0.60). The
reaction mixture was diluted with dichloromethane
(50 mL), then washed sequentially with brine (50 mL),
citric acid (1 M aq, 50 mL) and water (50 mL) and
concentrated in vacuo at low temperature (0–5 8C). The
residue was dissolved in pre-cooled (0 8C) dry DMF
(30 mL) containing sodium azide (1.80 g, 28.0 mmol) and
stirred under an atmosphere of nitrogen. After 1 h, the ice
bath was removed and the reaction mixture stirred at room
temperature. After 10 h, TLC (ethyl acetate/pet. ether, 1:9)
showed the formation of a single product (Rf 0.63).
Compound 15. [a]2D3 C28.9 (c 1.9 in CHCl3); (HRMS (CIC):
Found 446.234455. C24H32O5Si (MCNHC4 ) requires m/z,
446.234934); nmax (thin film)/cmK1 3538 (OH) and 1736
(C]O, ester); dH ((CD3)2SO, 200 MHz) 1.10 (15H, m,
CH(CH3)2 and SiC(CH3)3), 3.72 (1H, m, H-5), 3.92 (2H, m,
H-4 and H-50), 4.25 (2H, m, H-3 and H-2), 4.82 (1H, sept,
JZ6.36 Hz, CH(CH3)2), 5.05 (1H, d, OH), 7.34–7.65 (10H,
m, ArH); dC ((CD3)2SO, 50.3 MHz) 19.9 (s, SiC(CH3)3),
22.1 (q, CH(CH3)2), 27.6 (q, SiC(CH3)3), 68.9 (d,
CH(CH3)2), 71.3 (d, C-4), 73.6 (t, C-5), 77.8 (d, C-3),
82.1 (d, C-2), 128.5, 128.6, 130.8 (3!d, 6!ArCH), 133.6,
133.8 (2!d, 2!ArC), 136.2, 136.4 (2!d, 4!ArCH),
171.3 (s, C]O); m/z (CIC): 446.4 (MCNHC4 , 100%).

4116
A. A. Edwards et al. / Tetrahedron 62 (2006) 4110–4119
The reaction mixture was filtered and the filtrate concen-
trated in vacuo and purified by flash chromatography (ethyl
acetate/pet. ether, 2:23) to yield the g-azido ester 1 (3.02 g,
95%) as a colourless oil: [a]2D3 C11.3 (c 1.15 in CHCl3);
(HRMS (CIC): Found 471.242624. C24H31N3O4Si (MC
NH4C) requires m/z, 471.242759); nmax (thin film)/cmK1
2107 (N3) and 1753 (C]O, ester); dH (CDCl3, 500 MHz)
1.16 (9H, s, SiC(CH3)3), 1.19 (3H, d, JZ6.2 Hz,
CH(CH3)2), 1.23 (3H, d, JZ6.2 Hz, CH(CH3)2), 3.80 (1H,
requires m/z, 410.1913); nmax (thin film)/cmK1 1737
(C]O, ester); dH (CDCl3, 200 MHz) 1.08 (9H, s,
SiC(CH3)3), 1.32 (3H, d, JZ6.3 Hz, CH(CH3)2), 1.35
(3H, d, JZ6.3 Hz, CH(CH3)2), 4.23 (1H, m, H-5), 4.41
(1H, dd, J5 ,4Z3.2 Hz, J5 ,5Z10.8 Hz, H-50), 5.10 (1H, m,
H-4), 5.13 (1H sept, JZ6.3 Hz, CH(CH3)2), 5.82 (1H, d,
J3,4Z2.8 Hz, H-3), 7.40–7.70 (10H, m, 10!ArH); dC
(CDCl3, 50.3 MHz) 19.0 (s, SiC(CH3)3), 21.7 (q,
CH(CH3)2), 26.8 (q, SiC(CH3)3), 69.2 (d, CH(CH3)2), 74.8
(d, C-4), 78.4 (t, C-5), 111.5 (d, C-3), 127.7, 127.9, 129.9
(3!d, 6!ArCH), 133.5 (s, 2!ArC), 135.6 (d, 4!Ar-CH),
151.0 (s, C-2), 159.9 (s, C]O); m/z (TOF MS FIC): 410.19
(MC, 100%).
0
0
0
d, JZ3.5 Hz, H-4), 4.11 (1H, d, J5,5 Z10.0 Hz, H-5), 4.30
(1H, dd, J5 ,4Z4.5 Hz, J5 ,5Z10.0 Hz, H-50), 4.50 (1H, br s,
H-2), 4.58 (1H, br s, H-3), 5.05 (1H, sept, JZ6.2 Hz,
CH(CH3)2), 7.43–7.67 (10H, m, ArH); dC (CDCl3,
50.3 MHz) 19.1 (s, SiC(CH3)3), 21.6 (q, CH(CH3)2), 26.8
(q, SiC(CH3)3), 66.4 (d, CH(CH3)2), 68.9 (d, C-4), 71.5 (t,
C-5), 80.7 (d, C-3), 84.3 (d, C-2), 127.9, 128.0, 130.2, 130.3
(4!d, 6!ArCH), 132.2, 132.7 (2!s, 2!ArC), 135.6,
135.8 (2!d, 4!ArCH), 169.1 (s, C]O); m/z (CIC): 471.4
(MCNHC4 , 65), 376.3 (100%).
0
0
4.1.8. Methyl 2,5-anhydro-D-arabinoate 20, methyl 2,5-
anhydro-3,4-O-(S)-benzylidene-D-arabinoate 22 and
methyl 2,5-anhydro-3,4-O-(R)-benzylidene-D-arabinoate
21. 3,4-O-Benzylidene-2-O-trifluoromethanesulfonyl-D-
ribono-1,5-lactone 18 (2.00 g, 5.43 mmol) was dissolved
in methanolic hydrogen chloride (5% v/v, 42 mL) and
stirred at room temperature. After 1 h, the reaction mixture
was heated to 70 8C for 3 h. The reaction mixture was
cooled to room temperature, hydrochloric acid (1 M aq,
6 mL) was added and the reaction mixture heated to 70 8C.
After 24 h, TLC (chloroform/methanol, 4:1) showed the
absence of the starting material (Rf 0.65), the presence of a
major product (Rf 0.37) and minor products (Rf 0.71 and
0.68). The reaction mixture was cooled to room temperature
and sodium hydrogen carbonate added to neutralize the
solution. The mixture was filtered through Celite (eluent:
methanol), concentrated in vacuo and purified by flash
chromatography (chloroform/methanol, 4:1) to yield the
diol 20 (740 mg, 84%) as a white solid. The minor products
were purified by further flash chromatography (ethyl
acetate/pet. ether, 1:1) to yield the S-benzylidene derivative
22 (95 mg, 7%) and the R-benzylidene derivative 21
(81 mg, 6%).
4.1.7. Isopropyl 2,5-anhydro-3-azido-4-O-tert-butyl-
diphenylsilyl-3-deoxy-L-ribonate
3 and isopropyl
L-glycero-4-O-tert-butyldiphenylsilyl-pent-2-enoate 17.
Trifluoromethanesulfonic anhydride (1.2 mL, 7.35 mmol)
was added dropwise over a period of 5 min to a stirred
solution of 4-O-silyl derivative 8 (2.10 g, 4.9 mmol) in
dichloromethane (60 mL) containing freshly distilled dry
pyridine (0.63 mL, 7.8 mmol) at K20 8C. After 40 min,
TLC (ethyl acetate/pet. ether, 1:9) showed the absence of
starting material (Rf 0.32) and the formation of a single
product (Rf 0.58). The reaction mixture was diluted with
dichloromethane (50 mL), washed sequentially with brine
(50 mL), citric acid (1 M aq, 50 mL) and water (50 mL) and
concentrated in vacuo at low temperature (0–5 8C). The
residue was dissolved in pre-cooled (0 8C) dry DMF
(20 mL) containing sodium azide (1.27 g, 19.6 mmol) and
stirred. After 1 h, the ice bath was removed and the reaction
mixture stirred at room temperature. After 10 h, TLC (ethyl
acetate/pet. ether, 1:9) showed the formation of a minor
product (Rf 0.62) and a major product (Rf 0.56). The
reaction mixture was filtered and the filtrate concentrated in
vacuo and purified by flash chromatography (ethyl acetate/
pet. ether, 1:49) to give the b-azido ester 3 (1.80 g, 81%) and
the b-elimination product 17 (84 mg, 4%) as colourless oils.
Compound 20. Mp 71–73 8C; [a]2D3 C21.7 (c 1.0 in CHCl3);
(HRMS (CICve): Found 163.0614. C6H11O5 (MCHC)
requires m/z, 163.0606); (Found C, 44.15; H, 6.52. C6H10O5
requires C, 44.45; H, 6.22%); nmax (KBr)/cmK1 3491 (OH),
1737 (C]O, ester); dH (CDCl3, 400 MHz) 3.31, 3.48 (2H,
m, 2!OH), 3.81 (3H, s, CO2CH3), 4.04–4.07 (2H, m, H-5
and H-50), 4.26–4.33 (1H, m, H-4), 4.48–4.52 (1H, m, H-3),
4.53 (1H, d, J2,3Z6.4 Hz, H-2); dC (CDCl3, 100 MHz) 53.0
(q, CO2CH3), 71.7 (d, C-4), 72.9 (d, C-3), 73.4 (t, C-5), 80.2
(d, C-2), 172.0 (s, C]O); m/z (APCICve): 163 (MCHC,
80), 103 (100%).
Compound 3. [a]2D3 K12.6 (c 1.04 in CHCl3); (HRMS (CIC):
Found 471.241851. C24H31N3O4Si (MCNHC4 ) requires m/z,
471.240959); nmax (thin film)/cmK1 2111 (N3) and 1759
(C]O, ester); dH (CDCl3, 500 MHz) 1.15 (9H, s, SiC(CH3)3),
1.34 (6H, d, JZ6.3 Hz, CH(CH3)2), 3.90 (1H, dd, J5,4
Z
Compound 22. Mp 125–126 8C; [a]2D4 K71.9 (c 1.0 in
CHCl3): (Found C, 62.55; H, 5.61. C13H14O5 requires C,
62.39; H, 5.64%); nmax (KBr)/cmK1 1756 (C]O, ester); dH
0
0
0.9 Hz, J5,5 Z9.6 Hz, H-5), 4.03 (1H, t, J3,2Z4.6 Hz, H-3),
4.08 (1H, dd, J5 ,4Z3.8 Hz, J5 ,5Z9.6 Hz, H-50), 4.40 (1H, m,
H-4), 4.81 (1H, d, J2,3Z4.6 Hz, H-2), 5.20 (1H, sept, JZ
6.3 Hz, CH(CH3)2), 7.42–7.70 (10H, m, 10!ArH); dC
(CDCl3, 50.3 MHz) 19.0 (s, SiC(CH3)3), 21.7 (q,
CH(CH3)2), 21.8 (q, CH(CH3)2), 26.8 (q, SiC(CH3)3), 69.3
(d, CH(CH3)2), 69.7 (d, C-4), 74.8 (t, C-5), 77.0 (d, C-3), 79.1
(d, C-2), 128.0, 128.1, 130.2, 130.3 (4!d, 6!ArCH), 132.6
(s, 2!ArC), 135.6 (d, 4!ArCH), 168.3 (s, C]O); m/z
(APCIC): 454.33 (MCHC, 20), 127.85 (100%).
0
0
(CDCl3, 200 MHz) 3.76 (1H, dd, J4,5Z4.0 Hz, J5,5
11.3 Hz, H-5), 3.84 (3H, s, CO2CH3), 4.33 (1H, d, J2,3
Z
Z
0
0
4.3 Hz, H-2), 4.41 (1H, dd, J4,5 Z0.6 Hz, J5,5 Z11.3 Hz, H-
50), 4.98 (1H, ddd, J4,5 Z0.6 Hz, J4,5Z4.0 Hz, J3,4
Z
0
5.7 Hz, H-4), 5.08 (1H, dd, J2,3Z4.3 Hz, J3,4Z5.7 Hz, H-
3), 6.07 (1H, s, Ar-CH), 7.35–7.47 (5H, m, 5!ArH); dC
(CDCl3, 50.3 MHz) 52.6 (q, CO2CH3), 74.6 (t, C-5), 80.4 (d,
C-4), 81.3 (d, C-3), 82.6 (d, C-2), 106.3 (d, Ar-CH), 127.0,
128.6, 129.9, 135.5 (5!d and s, 5!ArCH and ArC), 167.9
(s, C]O); m/z (APCICve): 121 (100), 251 (MCHC, 35%).
Compound 17. [a]2D3 K22.3 (c 1.75 in CHCl3); (HRMS
(TOF MS FIC): Found 410.1973. C24H30O4Si (MC)

A. A. Edwards et al. / Tetrahedron 62 (2006) 4110–4119
4117
Compound 21. Mp 79–81 8C: [a]2D3 K162.8 (c 1.02 in
CHCl3): (Found C, 62.19; H, 6.00. C13H14O5 requires C,
62.39; H, 5.64%); nmax (thin film)/cmK1 1764 (C]O,
ester); dH (CDCl3, 400 MHz) 3.66 (1H, dd, J4,5Z3.5 Hz,
CF3), 169.5 (s, C]O); m/z (TOF CICve): 312 (MCNHC4 ,
100%).
4.1.11. Methyl 2,5-anhydro-4-azido-4-deoxy-L-xylonate
23. Pyridine (1.0 mL, 12.3 mmol) and trifluoromethane-
sulfonic anhydride (1.56 mL, 9.23 mmol) were added to a
stirred solution of the diol 20 (1.00 g, 6.17 mmol) in
dichloromethane (50 mL) at K25 8C. The reaction mixture
was warmed to room temperature after being stirred for 4 h.
After 48 h, TLC (ethyl acetate/pet. ether, 1:1) showed traces
of starting material (Rf 0.0) and the presence of a major
product (Rf 0.3). The reaction mixture was diluted with
dichloromethane (125 mL), washed with hydrochloric acid
(1 M aq, 50 mL) and extracted with dichloromethane (3!
30 mL). The combined organic extracts were washed with
aq buffer (pH 7, 100 mL) and brine (100 mL). The organic
layer was dried over magnesium sulfate, filtered and
concentrated in vacuo to afford the triflate 24 as a yellow
solid, which was used without further purification.
0
J5,5 Z10.9 Hz, H-5), 3.78 (3H, s, CO2CH3), 4.31 (1H, d,
0
0
J2,3Z4.3 Hz, H-2), 4.36 (1H, d, J5,5 Z10.9 Hz, H-5 ), 4.89
(1H, dd, J4,5Z3.5 Hz, J3,4Z6.3 Hz, H-4), 5.05 (1H, dd,
J2,3Z4.3 Hz, J3,4Z6.3 Hz, H-3), 5.76 (1H, s, Ar-CH), 7.37–
7.52 (5H, m, 5!ArH); dC (CDCl3, 100 MHz) 52.7 (q,
CO2CH3), 73.0 (t, C-5), 81.6 (d, C-4), 81.9 (d, C-2), 82.3 (d,
C-3), 107.1 (d, Ar-CH), 127.8, 128.8, 130.4, 136.0 (5!d
and s, 5!ArCH and ArC), 168.1 (s, C]O); m/z (APCIC
ve): 251 (MCHC, 100%).
4.1.9. Methyl 2,5-anhydro-3,4-O-isopropylidene-D-ara-
binoate 12. DL-Camphor-10-sulfonic acid (182 mg,
0.78 mmol) was added to a stirred solution of the diol 20
(1.27 g, 7.84 mmol) in acetone (6 mL). After 18 h, a white
solid had precipitated from solution and TLC (ethyl acetate/
hexane, 1:1) showed the absence of starting material (Rf 0.0)
and the presence of a major product (Rf 0.2). Sodium
hydrogen carbonate was added to the reaction mixture to
neutralize the solution and the reaction mixture filtered
through Celite (eluent/acetone). The filtrate was concen-
trated in vacuo and purified by flash chromatography (ethyl
acetate/hexane, 1:1) to yield the acetonide 12 (1.19 g, 75%)
as a white solid. Mp 60–61 8C; [a]2D3 K91.7 (c 1.02 in
CHCl3): (Found C, 53.48; H, 6.99. C9H14O5 requires C,
53.46; H, 6.98%); nmax (thin film)/cmK1 1761 (C]O,
ester); dH (C6D6, 400 MHz) 1.13, 1.50 (2!3H, 2!s,
Sodium azide (2.21 g, 34.0 mmol) was added to a stirred
solution of the triflate 24 in DMF (95 mL). The reaction
mixture was heated to 85 8C after being stirred for 10 h.
After 15 h, TLC (ethyl acetate/pet. ether, 1:1) showed the
absence of the starting material (Rf 0.3, UV active) and the
presence of a major product (Rf 0.3). The reaction mixture
was cooled to room temperature and concentrated in vacuo.
The resulting residue was dissolved in ethyl acetate
(480 mL), washed with water (100 mL) and extracted with
ethyl acetate (3!380 mL). The combined organic extracts
were dried over magnesium sulfate, filtered, then concen-
trated in vacuo and purified by flash chromatography (ethyl
acetate/pet. ether, 1:1) to yield the title product (528 mg,
46% over two steps) as a white solid. Mp 115–116 8C; [a]D23
C35.9 (c 0.99 in CHCl3): (Found C, 38.63; H, 4.82.
C6H9O4N3 requires C, 38.51; H, 4.85%); nmax (thin film)/
cmK1 3449 (OH), 2127 (N3) and 1743 (C]O, ester); dH
(CDCl3, 200 MHz) 2.60 (1H, d, JZ5.0 Hz, OH), 3.84 (3H,
0
C(CH3)2), 2.85 (1H, dd, J4,5Z3.8 Hz, J5,5 Z10.6 Hz, H-5),
3.41 (3H, s, CO2CH3), 3.71 (1H, d, J2,3Z4.3 Hz, H-2), 3.94
0
0
(1H, d, J5,5 Z10.6 Hz, H-5 ), 4.04–4.08 (1H, m, H-4), 4.47–
4.51 (1H, m, H-3); dC (C6D6, 100 MHz) 24.9, 25.9 (2!q,
C(CH3)2), 52.2 (q, CO2CH3), 72.8 (t, C-5), 80.3 (d, C-4),
81.4 (d, C-3), 81.6 (d, C-2), 113.1 (s, C(CH3)2), 167.8 (s,
C]O); m/z (APCICve): 203 (MCHC, 100%).
0
s, CO2CH3), 3.95 (1H, dd, J4,5Z2.0 Hz, J5,5 Z9.8 Hz, H-5),
4.1.10. Methyl 2,5-anhydro-4-O-trifluoromethanesulfonyl-
D-arabinoate 24. Pyridine (374 mL, 4.59 mmol) and
trifluoromethanesulfonic anhydride (0.78 mL, 4.64 mmol)
were added to a stirred solution of the diol 20 (500 mg,
3.09 mmol) in dichloromethane (25 mL) at K25 8C. The
reaction mixture was warmed to room temperature after
being stirred for 4 h. After 48 h, TLC (ethyl acetate/pet.
ether, 1:1) showed traces of starting material (Rf 0.0) and
the presence of a major product (Rf 0.3). The reaction
mixture was diluted with dichloromethane (125 mL),
washed with hydrochloric acid (1 M aq, 50 mL) and
extracted with dichloromethane (3!30 mL). The combined
organic extracts were washed with aq buffer (pH 7, 100 mL)
and brine (100 mL). The organic layer was dried over
magnesium sulfate, filtered, concentrated in vacuo and
purified by flash chromatography (ethyl acetate/pet. ether,
1:1) to give the triflate 24 (432 mg, 48%) as a yellow solid.
Mp 101–102 8C; [a]2D4 K4.6 (c 0.53 in CHCl3): (Found C,
28.53; H, 3.11. C7H9F3O7S requires C, 28.58; H, 3.08%);
nmax (thin film)/cmK1 3426 (OH) and 1755 (C]O, ester);
dH ((CD3)2CO, 400 MHz) 3.69 (3H, s, CO2CH3), 4.22–4.25
(2H, m, H-5 and H-50), 4.63 (1H, d, J2,3Z6.4 Hz, H-2), 4.89
(1H, dd, J2,3Z6.4 Hz, J3,4Z5.4 Hz, H-3), 5.51–5.55 (1H,
m, H-4); dC ((CD3)2CO, 50.3 MHz) 51.6 (q, CO2CH3), 69.9
(t, C-5), 71.5 (d, C-3), 79.5 (d, C-2), 86.7 (d, C-4), 119.8 (q,
0
0
4.10–4.15 (1H, m, H-4), 4.35 (1H, dd, J4,5 Z4.9 Hz, J5,5
Z
9.8 Hz, H-50), 4.52 (1H, m, H-3), 4.65 (1H, d, J2,3Z4.4 Hz,
H-2); dC (CDCl3, 50.3 MHz) 52.7 (q, CO2CH3), 66.8 (d, C-
4), 71.4 (t, C-5), 76.8 (d, C-3), 80.7 (d, C-2), 170.3 (s,
C]O); m/z (APCICve): 160 (MKN2CHC, 100%).
4.1.12. Isopropyl 2,5-anhydro-4-azido-4-deoxy-L-xylo-
nate 2. Method A. Potassium carbonate (30 mg,
0.22 mmol) was added to a stirred solution of the methyl
azido ester 23 (30 mg, 0.16 mmol) in propan-2-ol
(2.42 mL). After 72 h, TLC (ethyl acetate/pet. ether, 2:1)
showed the absence of the starting material (Rf 0.3) and the
presence of a major product (Rf 0.5). The reaction mixture
was filtered through Celite (eluent propan-2-ol), concen-
trated in vacuo and purified by flash chromatography (ethyl
acetate/pet. ether, 2:1) to yield isopropyl azido ester 2
(18 mg, 52%) as a white solid.
Method B. p-Toluenesulfonic acid monohydrate (160 mg,
0.84 mmol) was added to a stirred solution of methyl azido
ester 23 (500 mg, 2.67 mmol) in propan-2-ol (5 mL) at
80 8C. After 24 h, TLC (ethyl acetate/pet. ether, 2:1) showed
the absence of the starting material (Rf 0.3) and the presence
of a major product (Rf 0.5). The reaction mixture was

4118
A. A. Edwards et al. / Tetrahedron 62 (2006) 4110–4119
17. Hintermann, T.; Gademann, K.; Jaun, B.; Seebach, D. Helv.
Chim. Acta 1998, 81, 983–1002.
cooled to room temperature and sodium hydrogen carbonate
added to neutralize the solution. The reaction mixture was
filtered, concentrated in vacuo and purified by flash
chromatography (ethyl acetate/pet. ether, 2:1) to yield
isopropyl azido ester 2 (414 mg, 72%) as a white solid.
18. Seebach, D.; Brenner, M.; Rueping, M.; Jaun, B. Chem. Eur. J.
2002, 8, 573–584.
19. Seebach, D.; Schaeffer, L.; Brenner, M.; Hoyer, D. Angew.
Chem., Int. Ed. 2003, 42, 776–778.
Compound 2. Mp 78–80 8C; [a]2D4 C28.9 (c 1.07 in CHCl3);
(HRMS (CICve): Found 216.0987. C8H14N3O4 (MCHC)
requires m/z, 216.0984); nmax (thin film)/cmK1 3431 (OH),
2088 (N3) and 1728 (C]O, ester); dH (CDCl3, 200 MHz)
1.30 (3H, d, JZ6.3 Hz, CH(CH3)2), 1.31 (3H, d, JZ6.3 Hz,
CH(CH3)2), 2.71 (1H, d, JZ5.3 Hz, OH), 3.92 (1H, dd,
20. Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore,
J. S. Chem. Rev. 2001, 101, 3893–4011.
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11077–11078.
22. Allan, R. D.; Tran, H. W. Aust. J. Chem. 1984, 37, 1123–1126.
23. Xiao, D.; Carroll, P. J.; Mayer, S. C.; Pfizenmayer, A. J.;
Joullie, M. M. Tetrahedron: Asymmetry 1997, 8, 3043–3046.
24. Crisma, M.; Moretto, A.; Toniolo, C.; Kaczmarek, K.;
Zabrocki, J. Macromolecules 2001, 34, 5048–5052.
25. Mouries, C.; Deguin, B.; Lamari, F.; Foglietti, M. J.; Tillequin,
F.; Koch, M. Tetrahedron: Asymmetry 2003, 14, 1083–1086.
26. Carballido, M.; Castedo, L.; Gonzalez-Bello, C. Eur. J. Org.
Chem. 2004, 3663–3668.
0
J4,5Z2.0 Hz, J5,5 Z9.9 Hz, H-5), 4.10–4.13 (1H, m, H-4),
0
0
0
4.34 (1H, dd, J4,5 Z4.7 Hz, J5,5 Z9.9 Hz, H-5 ), 4.49–4.52
(1H, m, H-3), 4.57 (1H, d, J2,3Z4.4 Hz, H-2), 5.17 (1H,
sept, JZ6.3 Hz, CH(CH3)2); dC (CDCl3, 50.3 MHz) 22.0 (q,
CH(CH3)2), 66.9 (d, C-4), 69.8 (d, CH(CH3)2), 71.3 (t, C-5),
76.8 (d, C-3), 80.3 (d, C-2), 169.4 (s, C]O); m/z (APCIC
ve): 188 (MKN2CHC, 24), 233 (MCNHC4 , 100%).
27. Gnad, F.; Poleschak, M.; Reiser, O. Tetrahedron Lett. 2004,
45, 4277–4280.
Acknowledgements
28. Farrera-Sinfreu, J.; Zaccaro, L.; Vidal, D.; Salvatella, X.;
Giralt, E.; Pons, M.; Albericio, F.; Royo, M. J. Am. Chem. Soc.
2004, 126, 6048–6057.
Support from DST, New Delhi for a BOYCAST Fellowship
(G.J.S.), Ministerio de Cieccia y Technologia (R.G.) and
EPSRC (A.A.E.) is gratefully acknowledged. A generous
gift from CMS chemicals of the lactol 25 made this project
possible.
29. Smith, M. D.; Claridge, T. D. W.; Sansom, M. S. P.; Fleet,
G. W. J. Org. Biomol. Chem. 2003, 1, 3647–3655.
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