A total synthesis of (+)-oxybiotin from D-arabinose

Article abstract of DOI:10.1016/j.tet.2004.04.040

A novel ten-step synthesis of (+)-oxybiotin, a biologically active analogue of (+)-biotin, has been achieved starting from D-arabinose.

Full text of DOI:10.1016/j.tet.2004.04.040

Tetrahedron 60 (2004) 5225–5235
A total synthesis of (1)-oxybiotin from D-arabinose
a
a
b
Velimir Popsavin,a Goran Benedekovic, Mirjana Popsavin, Vladimir Divjakovic
,
*
´
´
and Thomas Armbrusterc
a
´
Department of Chemistry, Faculty of Sciences, University of Novi Sad, Trg D. Obradovica 3, 21000 Novi Sad, Serbia and Montenegro
Department of Physics, Faculty of Sciences, University of Novi Sad, Trg D. Obradovica 4, 21000 Novi Sad, Serbia and Montenegro
b
´
cLaboratory for Chemical and Mineralogical Crystallography, Bern University, Freiestr. 3, CH-3012 Bern, Switzerland
Received 11 February 2004; revised 23 March 2004; accepted 14 April 2004
Abstract—A novel ten-step synthesis of (þ)-oxybiotin, a biologically active analogue of (þ)-biotin, has been achieved starting from
D-arabinose.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The oxygenated analogue of biotin in which an oxygen atom
replaces sulphur was synthesized by Hofmann1 and named
oxybiotin.2 The obtained racemic material showed 50% of
biotin like growth-stimulatory activity.3 Such results
implied that the biologically active enantiomer should
have the same absolute configuration as naturally occurring
(þ)-biotin. This assumption was confirmed by a total
synthesis of enantiopure (þ)-oxybiotin (1) that was
achieved in 19 steps starting from D-glucose.4 Recently
we have reported a 14-step synthesis of (þ)-1 from
D-xylose,5 and now we describe a new ten-step synthesis of
(þ)-oxybiotin based on chirality transfer from D-arabinose.6
Retrosynthetic analysis of (þ)-oxybiotin (1) is presented in
Scheme 1. An examination of the target molecule 1 reveals a
chiral tetrahydrofuran system containing three contiguous
substituents including the C-3 and C-4 nitrogen functions
incorporated into a cis-fused imidazolidinone ring. Our
synthetic plan for the assembly of the C3–C4 domain
involved an introduction of two nitrogen functions at C-3
and C-4 in a derivative of type II (with Walden inversion),
Scheme 1. Retrosynthetic analysis (sugar numbering scheme).
followed by a subsequent closure of the imidazolidinone
ring system. Further disconnection of II leads to a protected
2,5-anhydro-D-ribose derivative III, which should be
accessible from an arabinopyranoside 2-triflate IV by a
ring contraction process.
synthetic precursor of II by an intramolecular displacement
of the allylic C-2 mesyloxy function by the C-5 hydroxyl
group. The structure V can be finally correlated with a
partially protected D-arabinose derivative VI via a simple
Wittig reaction. Accordingly, the preparation of the
postulated intermediates of type III and VI was first
attempted.
An alternative disconnection of the retron II leads to the
open-chain intermediate V, which might be converted to a
2. Results and discussion
Keywords: 2,5-Anhydro sugars; D-Arabinose; (þ)-Oxybiotin; Ring
contraction; Triphosgene; Wittig reaction.
*
In 1989, Baer et al.7 reported a facile formation of
2,5-anhydro-6-deoxy-L-talose derivatives by ring contraction
Corresponding author. Tel.: þ381-21-350-122; fax: þ381-21-454-065;
e-mail address: popsavin@ih.ns.ac.yu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.040

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V. Popsavin et al. / Tetrahedron 60 (2004) 5225–5235
Scheme 2. (a) Me2C(OMe)2, TsOH, DMF, rt, 3.5 h, 89%; (b) Imd2CO, C6H6, reflux, 1.5 h, 69%; (c) Tf2O, Py, CH2Cl2, 210 8C, 0.5 h; (d) KOBz, DMF, rt, 20 h
for 5, 99% of 7 (two steps), 60–658, 2 h for 6, 80% of 8 (two steps); (e) NaHCO3, MeOH, 50 8C, 4 h for 5, 12% of 9, 55–60 8C, 3 h for 6, 77% of 10.
in methyl 2-O-trifluoromethanesulfonyl-b-L-fucopyrano-
side under solvolytic conditions (KOBz/DMF, NaHCO3/
MeOH). It was therefore assumed that utilization of similar
methodology in the D-arabinopyranose series would provide
the postulated intermediate III from the retrosynthetic
analysis scheme. The preparation of the 2-triflate esters 5
and 6 was first attempted starting from the 3,4-O-protected
methyl b-D-arabinopyranosides 3 and 4 (Scheme 2). We
adopted the Kiso–Hasegawa acetonation procedure8 for the
conversion of commercially available methyl b-D-arabino-
pyranoside (2) to the known9 3,4-O-isopropylidene deriva-
tive 3. Compound 4, in turn, was conveniently prepared by
treatment of 2 with 1,10-carbonyldiimidazole in boiling
benzene. The melting point and NMR spectral data of
thus obtained intermediate 4 were in reasonable agreement
with those earlier reported for the L-configuration counter-
part of 4, obtained by treatment of the corresponding
3,4-O-thiocarbonyl derivative with bistributyltin oxide.10
Both 3 and 4 readily reacted with triflic anhydride to afford
the corresponding 2-O-triflate esters 5 (74%) and 6 (89%).
Compound 5 was partially characterized from NMR
spectroscopic data, but was rather unstable on storage
similar to its fucopyranoside analogue.7 It should be
therefore used in the next synthetic step immediately after
its brief isolation. On the contrary, the triflate 6 is a stable
crystalline compound, which was fully characterized by the
corresponding spectral (IR, NMR, MS) and analytical data.
Similarly to L-fucopyranoside derivatives,7 both arabino-
pyranosides 5 and 6 smoothly reacted with potassium
benzoate in N,N-dimethylformamide to give the corre-
sponding 2,5-anhydro-D-ribose derivatives 7 (99% from 2;
2:1 mixture of C-1 epimers) and 8 (80% from 2; 1:1 mixture
of C-1 epimers). Compound 5 also reacted with sodium
hydrogen carbonate in methanol (50 8C for 4 h)7 to afford a
low yield of the corresponding dimethyl acetal derivative 9
(12%), as a ring-contracted product. Conversely, the
3,4-O-carbonyl derivative 6, under the similar reaction
conditions, gave the known11 epoxide 10 (77%) as a product
of transesterification of the cyclic carbonate functionality in
6, followed by a subsequent epoxide ring closure process.
The dimethyl acetal derivative 10a, an expected product of
the presumed ring contraction process, could not be detected
in the reaction mixture. In the light of their stereochemical
and topological features, the 2,5-anhydro derivatives 7–9
fully correspond to the intermediate III from our retro-
synthetic analysis. However, further work was continued
with the isopropylidene derivative 7, since only this
intermediate was accessible from the starting material 2 in
an almost quantitative yield.
Preparation of the 2-O-mesyl derivative 13, a postulated
intermediate in the alternative approach to 1, started from
3,4-O-isopropylidene-D-arabinose (11), which was readily
available from D-arabinose through a modified literature
procedure8 (Scheme 3). Treatment of 11 with mesyl
chloride and triethylamine in dry dichloromethane gave
the crystalline glycosyl chloride 12 as the only reaction
product. Small vicinal coupling between H-1 and H-2
(J1,2¼3.7 Hz) is consistent with the cis arrangement of these
protons and convincingly proved a b-configuration at the
anomeric position. Although the compound 12 could be
stored at 220 8C for weeks without change, it tended to
decompose on prolonged standing at room temperature.
Hence, the intermediate 12 was immediately treated with
silver oxide in aqueous acetone, in the presence of a
catalytic amount of silver triflate, to give the stable lactol 13
(94% from 11). The synthesis of product 13 from methyl
3,4-O-isopropylidene-2-O-methanesulfonyl-b-D-arabino-
pyranoside, has already been described in the literature,9 but
in an overall yield of only 18% from two synthetic steps.
Scheme 3. (a) MsCl, Et3N, CH2Cl2, 210 8C, 1 h; (b) Ag2O, AgOTf, aq. Me2CO, rt, 24 h, 95% from 11.

V. Popsavin et al. / Tetrahedron 60 (2004) 5225–5235
5227
Scheme 4. (a) MeONa, MeOH, rt, 2 h; (b) Ph3P:CHCH:CHCO2Me, MeOH, rt, 2 h, 41% from 7; (c) Ph3P:CHCH:CHCO2Me, Na2CO3, DMF, 135 8C, 2 h;
(d) H2, PtO2, MeOH, rt, 24 h, 36% from 3, 67% from 13; (e) 9:1 TFA–H2O, rt, 0.5 h, 95%; (f) Tf2O, Py, CH2Cl2, 0 8C, 1.5 h; (g) NaN3, HMPA, rt, 1.5 h, 68%
from 16.
Our sample 13 displayed a value of optical rotation
{[a]D¼2116.5 (c 1.5)} similar to that reported previously
{[a]D¼2118.0 (c 2.06)},9 but its melting point was
significantly lower (116–117 8C) with respect to the
reported value (130–131 8C).9 However, its IR, NMR (1H
and 13C) and HR MS spectral data were fully consistent with
structure 13. The product 13 was mainly the b anomer since
its chloroform solution mutarotated to a less negative
equilibrium value {[a]D¼2116.5!2106.4 (24 h)}. The 1H
NMR spectral data also proved that the crystalline sample
13 consists of both a- and b-anomers, as established by
integration of the corresponding proton signals [d 3.83
essentially the same signals as the sample 14 prepared
from the 2,5-anhydride 7, but indicated somewhat different
ratio of E- and Z-isomers. Conversely, the reaction of 13
with trimethyl-4-phosphono crotonate, in the presence of
NaH in THF, at room temperature for 0.5 h, gave pure
E,E-14 (48%) as the only stereoisomer (not shown in the
scheme). Finally, catalytic hydrogenation of 14, over the
Adams catalyst, gave the corresponding saturated ester 15
(67% from 13). The four-step sequence based on the Wittig
reaction of lactol 13 with 3-(carbomethoxy-2-propenyl-
idene)triphenylphosphorane represents a more convenient
route towards the key intermediate 15, since it provided a
considerably higher overall yield (63% from 11) compared
to the combined five-step sequence via the 2,5-anhydride 7
(36% from 2). Hydrolytic removal of the isopropylidene
protective group in 15 gave an excellent yield of the
expected diol 16 (95%). Reaction of 16 with triflic
anhydride in pyridine and dichloromethane gave the
corresponding 3,4-ditriflate 17, isolated by flash column
chromatography in 51% yield. Subsequent treatment of 17
with sodium azide in HMPA afforded the corresponding
3,4-diazido derivative 18 as the only reaction product (47%
from 16). However, when the last two-step sequence was
carried out without purification of the intermediate 17, the
desired product 18 was obtained in a considerably higher
overall yield (68% from 16).
(dd, J5a,5b¼14.1 Hz, J4,5a¼2.5 Hz, H-5aa), 3.97 (d, J5a,5b
¼
13.3 Hz, H-5ab). The initial 1:5 a/b anomeric ratio,
recorded immediately after dissolution of the sample in
CDCl3, was changed to 1:3 after storing the solution at room
temperature for 48 h.
Having obtained the key intermediates 7 and 13, we next
focused on their C4-elongation at C-1 in order to elaborate
the carboxybutyl (þ)-oxybiotin side chain (Scheme 4).
O-Debenzoylation of 7 with sodium methoxide in methanol
produced the unstable aldehyde 7a, which was not isolated
but was further treated with 3-(carbomethoxy-2-propenyl-
idene)triphenylphosphorane,12 by using a one-pot pro-
cedure. The expected dienoate 14 was thus obtained as an
inseparable mixture of corresponding E- and Z-isomers.
Catalytic hydrogenation of 14 over PtO2 in methanol finally
furnished the saturated ester 15 in 36% overall yield with
respect to 3. In a different approach, the 3,4-O-isopropyl-
idene-2-O-methanesulfonyl-D-arabinose (13) was treated
with 3-(carbomethoxy-2-propenylidene)triphenylphos-
phorane in dry DMF, in the presence of sodium carbonate
as a proton acceptor, to give directly the dienoates 14 (an
inseparable mixture of E- and Z-isomers), as a result of the
sequential Wittig reaction/intramolecular displacement
process. Neither the acyclic intermediate 13a nor the
products of the competitive Michael addition could be
Diazide 18 represents a final chiral intermediate for the
completion of the synthesis of target 1, since it has the
correct absolute configuration at all the stereocentres.
Therefore we next focused on the conversion of its vicinal
diazido functionality into the imidazolidinone heterocyclic
system. This requires previous conversion of 18 into
the corresponding diamine 18a (Scheme 6), followed by
subsequent cyclization of the intermediate upon treat-
ment with phosgene or its equivalent. However, in
order to avoid wasting of the valuable intermediate 18,
the final imidazolidinone system building was first explored
on the diazido derivative 23 as a model compound
(Scheme 5).
1
detected in the reaction mixture. The H and 13C NMR
spectra of the mixture of 14 thus obtained displayed

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V. Popsavin et al. / Tetrahedron 60 (2004) 5225–5235
Scheme 5. (a) MsCl, Et3N, CH2Cl2, 210 8C, 40 min, 97%; (b) NaN3, DMF, 90–95 8C, 0.5 h, then 110–115 8C, 15 min 56% of 20, 18% of 22; (c) NaN3, DMF,
140–145 8C, 3.5 h, 20, 4% of 21, 51% of 22; (d) TBSCl, imidazole, DMF, rt, 24 h, 97%; (e) Ph3P, THF, rt, 3 h, then aq. NaHCO3, rt, 24 h, 63%;
(f) (Cl3CO)2CO, Et3N, CH2Cl2, 08C, 2 h, 67%; (g) H2, PtO2, CH2Cl2, rt, 24 h, then (Cl3CO)2CO, Et3N, 08C, 2 h, then rt 22 h, 69% from 23.
Methyl 2,3-anhydro-b-D-arabinopyranoside (10) was used
as a convenient starting compound in this part of the work.
Treatment of 10 with mesyl chloride and triethylamine in
dichloromethane gave the corresponding 4-O-mesyl deriva-
tive 19 in an almost quantitative yield. Compound 19
readily reacted with sodium azide in DMF (90–95 8C) to
afford the corresponding 4-azido derivative 20 (56%)
accompanied with a small amount of the 3,4-diazido
derivative 22 (18%). However, when the last reaction was
carried out at an elevated temperature (140–145 8C), the
desired compound 22 was isolated in 51% yield along with
a minor quantity of the 2,4-diazido derivative 21 (4%).
Major regioisomer 22 was treated with tert-butyldimethyl-
silyl chloride and imidazole to give the corresponding silyl
ether 23 (97%), a convenient model-compound for opti-
mising reaction conditions for the conversion of two vicinal
azido functions into the imidazolidinone ring. The
Staudinger reaction13 of 23 provided the corresponding
3,4-diamino derivative 24 (63%), which was subsequently
treated with triphosgene, under the conditions similar to
those recently applied for the conversion of vicinal amino
alcohols to oxazolidinones,14 to give the imidazolidinone 25
in 67% yield (42% from 23). However, the one-pot catalytic
reduction of 23 followed by subsequent triphosgene
treatment provided a significantly higher overall yield of
25 (69% from 23).
mixture was treated with triphosgene, whereby the imida-
zolidinone 26 was obtained in 66% yield. Treatment of 26
with an aqueous solution of sodium hydroxide, followed by
neutralization with Amberlyst 15, gave an almost quanti-
tative yield of (þ)-oxybiotin (1, Scheme 6), with physical
constants (mp and [a]D) in full agreement with those
already reported.4 Spectroscopic data of the final product
thus obtained were consistent with structure 1.
2.1. X-ray analysis
A single crystal X-ray diffraction analysis of compound 26
(Fig. 1) unambiguously confirmed its structure providing a
proof that all intermediates generated by the multistep
sequence 7!18 retained the required (S)-configuration at
the C-2. The values of torsion angles C10 –C2–C3-
N3¼42.4(1)8 and N3–C3–C4–N4¼6.4(2)8 are consistent
with the all-cis geometry of 26. The ureido ring, including
the carbonyl oxygen, is essentially planar. The maximum
deviation from the best plane of the ureido ring atoms is
˚
0.066(2) A for C-4. The bond distances [C6–O6¼1.241(2),
˚
C6–N4¼1.348(2) and C6–N3¼1.350(2) A] are compar-
able to those observed in the ureido system of (þ)-biotin.15
The five membered tetrahydrofuran ring adopts an envelope
˚
conformation, with O-1 above the best plane [0.608(1) A]
that contains the C-2, C-3, C-4 and C-5 ring atoms. The
bicyclic moiety adopts an endo conformation with the O-1
oxygen atom proximal to the ureido ring [the nonbonded
Given this success in the model series, the last one-pot
sequence was applied to 18. The diazide 18 was first
reduced over PtO2 in dichloromethane and after 24 h, when
the TLC indicated complete conversion of 18, the reaction
˚
distance O1· · ·C6¼3.433(2) A; torsion angles: N3–C3–
C2–O1¼279.7(2)8 and N4–C4–C5–O1¼90.6(1)8]. Simi-
lar geometry of the bicyclic moiety was already observed in
Scheme 6. (a) (i) H2, PtO2, CH2Cl2, rt, 22 h, (ii) (Cl3CO)2CO, Et3N, 0 8C, 2 h, then rt, 21 h, 66%; (b) NaOH, H2O, rt, 24 h, then Amberlyst 15, rt, 1 h, 99%.

V. Popsavin et al. / Tetrahedron 60 (2004) 5225–5235
5229
Figure 1. ORTEP drawing of the (þ)-oxybiotin methyl ester (26) with non-H labelling scheme. The displacement ellipsoids were drawn at 50% probability.
the molecular structure of0 biotin.15 The values of0 torsion
angles C2–C10 –C20 –C3 ¼20176.4(1)8,0 C10 –C2 –C30 –
C40¼179.3(2)8 and C20 –C3 –C40 –C5 ¼171.8(2)8 are
consistent with an all-trans extended conformation of
the valeryl side chain.
(FAB) mass spectrometers. High-resolution mass spectra
were taken on a Micromass LCT KA111 spectrometer. TLC
was performed on DC Alufolien Kieselgel 60 F254 (E.
Merck). Flash column chromatography was performed
using ICN silica 32–63. All organic extracts were dried
with anhydrous Na2SO4. Organic solutions were concen-
trated in a rotary evaporator under diminished pressure at a
bath temperature below 35 8C.
3. Conclusions
4.1.1. Methyl 3,4-O-isopropylidene-b-D-arabinopyrano-
side (3). To a solution of 2 (1.37 g, 8.37 mmol) in dry DMF
(12 mL) was added Me2C(OMe)2 (2.22 mL, 18.08 mmol)
and TsOH£H2O (0.015 g, 0.08 mmol). The mixture was
stirred for 3.5 h at room temperature and then neutralized by
stirring with Amberlite IRA-400 resin (3 g) at room
temperature for 1 h. The mixture was filtered and the resin
washed with MeOH. The combined organic solutions were
evaporated to give pure 3 (1.52 g, 89%) as a colorless syrup,
[a]D¼2184.2 (c, 2.0 in CHCl3), lit.9 [a]D¼2197.0 (c, 1.85
in CHCl3), RF¼0.60 (EtOAc). 1H NMR (CDCl3): d 1.35 and
1.52 (2£s, 3H each, Me2C), 3.43 (s, 3H, OMe), 2.41 (d, 1H,
exchangeable with D2O, J2,OH¼7 Hz, OH), 3.74 (td, 1H,
In conclusion, this paper reports a convenient ten-step
synthesis of (þ)-oxybiotin by chirality transfer from
D-arabinose. Two independent routes towards the key
intermediate 15 have been developed. The six-step sequence
that involves the arabinopyranoside 2-triflate ring contrac-
tion process as a key step (Scheme 2) provided 15 in 32%
overall yield with respect to the commercially available
methyl b-D-arabinopyranoside (2). However, the alternative
five-step sequence, based on the lactol 13 as a key
intermediate (Scheme 3) furnished 15 in considerably
higher overall yield (60% from D-arabinose). The inter-
mediate 15 was finally converted to the target 1 by using the
four-step sequence, which included the successive intro-
duction of two azido groups at C-3 and C-4, with inversion
of configuration at these positions, followed by a newly
developed one-pot procedure for construction of the ureido
system by using triphosgene, a safe and stable replacement
of phosgene.16 The overall yield of (þ)-oxybiotin (1) from
D-arabinose achieved via the lactol 13 as an intermediate
was 22%. Finally, an X-ray diffraction analysis of 26
confirmed that its bicyclic moiety adopts an endo con-
formation, which is thought to be crucial for biological
activity of (þ)-biotin and analogues.17
J1,2¼3.7 Hz, J2,3¼6.4 Hz, H-2), 3.92 (pseudo d, 2H, J4,5
1.7 Hz, 2£H-5), 4.16 (t, 1H, J3,4¼6 Hz, H-3), 4.21 (m, 1H,
H-4), 4.71 (d, 1H, H-1); 1H NOE contact: OMe and H-5. 13
¼
C
NMR (CDCl3): d 25.94 and 27.92 (Me2C), 55.61 (OMe),
59.24 (C-5), 70.12 (C-2), 72.95 (C-4), 76.00 (C-3), 98.84
(C-1), 109.14 (Me2C).
4.1.2. Methyl 3,4-O-carbonyl-b-D-arabinopyranoside
(4). A solution of 2 (0.149 g, 0.85 mmol) and 1,10-
carbonyldiimidazole (0.157 g, 0.97 mmol) in dry benzene
(3 mL) was stirred for 1.5 h at reflux. The mixture was
evaporated and the residue was purified by flash column
chromatography (3:2 EtOAc–CH2Cl2). Crystallization
from CH2Cl2–hexane gave pure 4 (0.111 g, 69%) as
colorless needles, mp 113–114 8C; lit.10 mp 115–119 8C
(L-enantiomer), [a]D¼2142.7 (c, 0.79 in CHCl3), RF¼0.31
(Et2O). IR (KBr): nmax 3410 (OH), 1800 (CvO). 1H NMR
(pyridine-d5þD2O): d 3.33 (s, 3H, OMe), 4.18 (dd,
1H, J1,2¼3.7 Hz, J2,3¼7 Hz, H-2), 4.27 (s, 2H, 2£H-5),
5.10 (d, 1H, H-1), 5.28 (m, 2H, H-3 and H-4). 13C NMR
(pyridin-d5): d 55.82 (OMe), 58.30 (C-5), 69.14 (C-2),
76.41 and 78.37 (C-3 and C-4), 99.71 (C-1), 155.38 (CvO).
FAB MS: m/z 191 (MþþH), 173 (Mþ2OH), 159
(Mþ2OMe).
4. Experimental
4.1. General methods
Melting points were determined on a Bu¨chi 510 apparatus
and were not corrected. Optical rotations were measured on
a Polamat A (Zeiss, Jena) polarimeter. IR spectra were
recorded with a Specord 75 IR spectrophotometer. NMR
spectra were recorded on a Bruker AC 250 E instrument and
chemical shifts are expressed in ppm downfield from
tetramethylsilane. Low resolution mass spectra were
recorded on Finnigan-MAT 8230 (CI) and VG AutoSpec

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V. Popsavin et al. / Tetrahedron 60 (2004) 5225–5235
4.1.3. Methyl 3,4-O-isopropylidene-2-O-trifluoromethane-
sulfonyl-b-D-arabinopyranoside (5). To cooled
53.40 mmol) in dry DMF (100 mL) for 20 h at room
temperature, followed by the same workup as described
above (Procedure A) gave 7 (8.20 g, 99%), as an inseparable
2:1 mixture of C-1 epimers, [a]D¼242.6 (c, 0.5 in CHCl3),
RF¼0.44 (CH2Cl2). IR (film): nmax 1730 (CvO, ester), 1600
a
(210 8C) and stirred solution of 3 (1.34 g, 6.65 mmol) in
dry CH2Cl2 (10 mL) and pyridine (2.66 mL, 32.92 mmol)
was added a cooled (210 8C) solution of Tf2O (2.16 mL,
13.17 mmol) in dry CH2Cl2 (10 mL). The mixture was
stirred at 210 8C for 0.5 h, then diluted with CH2Cl2
(20 mL) and washed successively with aq 5% HCl
(2£25 mL) and 1% NaHCO3 (25 mL). The organic solution
was dried and evaporated. Flash column chromatography
of the residue (1:1 CH2Cl2–cyclohexane) gave pure 5
(7.84 g, 70%) as a colorless solid. Recrystallization from
CH2Cl2–hexane gave colorless crystals, mp 121–123 8C,
[a]D¼2176.6 (c, 0.5 in CHCl3), RF¼0.50 (CH2Cl2). IR
(KBr): nmax 1415 (as. SO2), 1225–1210 (sim. SO2), 1125
1
(Ph); H NMR (CDCl3): d 1.38, 1.52 and 1.53 (3£s, 6H,
CMe2), 3.51 and 3.53 (2£s, 3H, OMe), 3.92–4.11 (m, 2H,
2£H-5), 4.21 and 4.29 (partially overlapped 2£dd, 1H, H-2),
4.82–5.05 (m, 2H, H-3 and H-4), 6.00 and 6.09 (2£d, 1H,
H-1), 7.40–8.16 (m, 5H, Ph). FAB MS: m/z 331 (MþþNa),
309 (MþþH). HR MS (ESþ): m/z 331.1157 (MþþNa).
Calcd for C16H20O6Na: 331.1158.
4.1.6. 2,5-Anhydro-1-O-benzoyl-3,4-O-carbonyl-D-
ribose methyl hemiacetal (8). Procedure A. A mixture of
6 (0.203 g, 0.63 mmol) and KOBz (0.20 g, 1.25 mmol) in
dry DMF (5 mL) was stirred for 2 h at 60–65 8C. After
workup as described above (preparation of 7) followed by
chromatographic purification on a column of flash silica (9:1
CH2Cl2–toluene) gave pure 8 (0.161 g, 87%) as a colorless
syrup (an inseparable mixture of C-1 epimers).
1
(CF3). H NMR (CDCl3): d 1.37 and 1.53 (2£s, 3H each,
Me2C), 3.44 (s, 3H, OMe), 3.93 (dd, 1H, J5a,5b¼13.5 Hz,
J4,5a¼2.6 Hz, H-5a), 4.03 (d, 1H, H-5b), 4.31 (dd, 1H,
J3,4¼5.5 Hz, H-4), 4.38 (dd, 1H, J2,3¼7.6 Hz, H-3), 4.73
(dd, 1H, J1,2¼3.4 Hz, H-2), 4.88 (d, 1H, H-1). 13C NMR
(CDCl3): d 26.08 and 27.69 (Me2C), 55.17 (C-5), 72.26
(C-3), 74.22 (C-4), 85.23 (C-2), 97.13 (C-1), 110.05
(Me2C), 118.43 (q, JC,F¼319 Hz, CF3). FAB MS: m/z 359
(MþþNa), 337 (MþþH).
Procedure B. A solution of 4 (0.51 g, 2.68 mmol) in a
mixture of CH2Cl2 (20 mL) and pyridine (2 mL,
24.75 mmol) was allowed to react with a solution of Tf2O
(1.32 mL, 8.05 mmol) in CH2Cl2 (5 mL) according to
procedure B in Section 4.1.5 to afford crude 6. A mixture
of crude 6 and KOBz (0.861 g, 5.38 mmol) in dry DMF
(20 mL), was stirred for 2 h at 60–65 8C. After workup as
described above (preparation of 7) followed by chromato-
graphic purification on a column of flash silica (9:1
CH2Cl2–toluene) oily 8 was obtained (0.63 g, 80%), as a
1:1 mixture of C-1 epimers, [a]D¼216.7 (c, 0.70 in
CHCl3), RF¼0.54 (CH2Cl2). IR (film): nmax 1810 (CvO,
carbonate), 1730 (CvO, BzO), 1600 (Ph). 1H NMR
(CDCl3): d 3.51 and 3.52 (2£s, 3H, OMe), 4.09–4.23 (m,
2H, 2£H-5), 4.40 and 4.51 (2£d, 1H, J1,2¼3 Hz, H-2), 5.29
(m, 1H, H-4), 5.41 and 5.49 (2£d, 1H, J3,4¼7.1, 7 Hz, H-3),
6.06 and 6.13 (2£d, 1H, H-1), 7.40–8.15 (m, 5H, Ph). 13C
NMR (CDCl3): d 57.61 and 57.66 (OMe), 73.76 and 74.04
(C-5), 80.54, 80.66 and 81.00 (C-3 and C-4), 83.91 and
84.04 (C-2), 97.28 and 97.39 (C-1), 128.50, 128.59, 128.71,
129.69, 129.81, 129.94, 133.84 and 133.94 (Ph), 154.00
(CvO, carbonate), 165.42 and 165.58 (CvO, BzO). FAB
MS: m/z 317 (MþþNa), 295 (MþþH). HR MS (ESþ): m/z
317.0640 (MþþNa). Calcd for C14H14O7Na: 317.0637.
4.1.4. Methyl 3,4-O-carbonyl-2-O-trifluoromethane-
sulfonyl-b-D-arabinopyranoside (6). A solution of 4
(0.326 g, 1.71 mmol) in dry CH2Cl2 (15 mL) and pyridine
(0.7 mL, 8.66 mmol) was treated with Tf2O (0.7 mL,
4.27 mmol) in dry CH2Cl2 (3 mL) under the above
described conditions to give crude 6. Flash column
chromatography (CH2Cl2) afforded pure 6 (0.493 g, 89%)
that crystallized from CH2Cl2–hexane in the form of
colorless needles, mp 118–120 8C, [a]D¼2148.2 (c, 0.89
in CHCl3), RF¼0.47 (CH2Cl2). IR (KBr): nmax 1800
(CvO), 1420 (as. SO2), 1230–1210 (sim. SO2), 1140
(CF3). 1H NMR (CDCl3): d 3.51 (s, 3H, OMe), 3.96 (dd, 1H,
J5a,5b¼14.3 Hz, J4,5a¼2.7 Hz, H-5a), 4.17 (d, 1H, H-5b),
4.83 (dd, 1H, J1,2¼3.5 Hz, J2,3¼7.2 Hz, H-2), 4.89 (dd, 1H,
J3,4¼6.9 Hz, H-4), 4.96 (t, 1H, H-3), 5.03 (d, 1H, H-1). 13
C
NMR (CDCl3): d 56.46 (OMe), 56.86 (C-5), 73.12 (C-3),
75.29 (C-4), 81.55 (C-2), 96.03 (C-1), 118.32 (q, JC,F
¼
320.4 Hz, CF3SO2), 152.65 (CvO). FAB MS: m/z 345
(MþþNa), 323 (MþþH). Anal. calcd for C8H9F3O8S: C,
29.82; H, 2.82; S, 9.95. Found: C, 30.06; H, 2.95; S, 10.33.
4.1.5. 2,5-Anhydro-1-O-benzoyl-3,4-O-isopropylidene-D-
ribose methyl hemiacetal (7). Procedure A. To a solution
of 5 (1.80 g, 5.35 mmol) in dry DMF (25 mL) was added
KOBz (2.00 g, 12.49 mmol) and the resulting suspension
was stirred at room temperature for 20 h. The solvent was
evaporated and the residue partitioned between CH2Cl2
(50 mL) and water (50 mL). Organic phase was washed
with water (2£50 mL), dried and evaporated. Flash column
chromatography of the residue (4:1 CH2Cl2–toluene) gave
pure 7 (1.31 g, 79%) as a colorless oil (an inseparable
mixture of C-1 epimers).
4.1.7. 2,5-Anhydro-3,4-O-isopropylidene-D-ribose
dimethyl acetal (9).
A suspension of 5 (3.90 g,
11.60 mmol) and NaHCO3 (1.20 g, 14.29 mmol) in dry
MeOH (35 mL), was stirred for 4 h at 50 8C. The mixture
was cooled to ambient temperature, diluted with Et2O
(15 mL), filtered and evaporated to an oil. Flash column
chromatography (17:3 toluene–Et2O) of the residue gave
pure 9 (0.29 g, 12%) as a colorless oil, [a]D¼221.0 (c, 1.02
in CHCl3), RF¼0.36 (CH2Cl2). IR (film): nmax 1100–1050
1
(C–O–C). H NMR (1:1 CDCl3–benzene-d6): d 1.22 and
1.46 (2£s, 3H each, Me2C), 3.20 and 3.22 (2£s, 3H each,
2£OMe), 3.88 (dd, 1H, J4,5a¼4.2 Hz, J5a,5b¼9.9 Hz, H-5a),
3.94 (dd, 1H, J4,5b¼1.1 Hz, H-5b), 4.09 (bs, 2H, H-1 and
H-2), 4.57 (ddd, 1H, J3,4¼6.3 Hz, H-4), 4.77 (d, 1H, H-3).
13C NMR (1:1 CDCl3–benzene-d6): d 24.60 and 26.42
(Me2C), 54.68 and 55.66 (2£OMe), 74.06 (C-5), 81.32
Procedure B. A solution of 3 (5.50 g, 26.93 mmol) in
CH2Cl2 (70 mL) and pyridine (11 mL, 136.14 mmol) was
treated with Tf2O (10.66 mL, 64.99 mmol) in CH2Cl2
(20 mL) according to procedure given in Section 4.1.4. to
afford crude 5. Treatment of crude 5 with KOBz (8.60 g,

V. Popsavin et al. / Tetrahedron 60 (2004) 5225–5235
5231
(C-4), 81.48 (C-3), 84.46 (C-2), 104.98 (C-1), 112.07
(CMe2). FAB MS: m/z 241 (MþþNa), 225 (MþþNaþH-
Me), 217 (Mþ2H). HR MS (ESþ): m/z 241.1054
(MþþNa). Calcd for C10H18O5Na: 241.1052.
Et2O gave an analytical sample 13, mp 116–117 8C,
[a]D¼2116.5 (c, 1.5 in CHCl3), lit.9 mp 130–131 8C,
[a]D¼2118.0 (c, 2.06 in Me2CO), RF¼0.70 (EtOAc). IR
(KBr): nmax 3420 (OH), 1360 (as. SO2), 1190 (sim. SO2). 1H
NMR (CDCl3): d 1.38 and 1.58 (2£s, 3H each, Me2C), 3.18
(s, 3H, MeSO2), 3.83 (dd, J5a,5b¼14.1 Hz, J4,5a¼2.5 Hz,
H-5aa), 3.97 (d, 1H, J5a,5b¼13.3 Hz, H-5ab), 4.14–4.33 (m,
4.1.8. Methyl 2,3-anhydro-b-D-ribopyranoside (10). To a
solution of 6 (0.218 g, 0.68 mmol) in dry MeOH (5 mL) was
added NaHCO3 (0.07 g, 0.83 mmol) and the resulting
suspension was stirred at 55–60 8C for 3 h, then filtered
and evaporated. Flash column chromatography (9:1
CH2Cl2–EtOAc) of the residue gave pure 10 (0.076 g,
77%). Crystallization from CH2Cl2–hexane furnished
colorless crystals, mp 51 8C, [a]D¼253.2 (c, 0.5 in
CHCl3); lit.11 mp 46 8C, [a]D¼235.8 (c, 0.6 in CHCl3),
RF¼0.47 (Et2O). IR (KBr): nmax 3440–3300 (OH). 1H NMR
2H, H-4ab, H-5bab), 4.40 (dd, 1H, J2,3¼7.8 Hz, J3,4
¼
5.4 Hz, H-2a and H-3b), 4.56 (dd, 1H, J1,2¼3.3 Hz, H-2b),
4.61 (d, 1H, J1,2¼7.9 Hz, H-1a), 5.35 (d, 1H, H-1b). 13C
NMR (CDCl3): d 26.25 and 27.99 (Me2C, a), 26.24 and
27.80 (Me2C, b), 38.66 (MeSO2, b), 39.06 (MeSO2, a), 58.4
(C-5, b), 63.28 (C-5, a), 72.98 (C-3), 73.83 (C-4), 80.01
(C-2, b), 83.42 (C-2, a), 90.94 (C-1, b), 93.91 (C-1, a),
109.84 (Me2C, b), 110.84 (Me2C, a). FAB MS: m/z 518
(2Mþ2H2O), 269 (MþþH), 251 (Mþ2OH). HR MS
(ESþ): m/z 286.0960 (MþþNH4). Calcd for C9H20NO7S:
286.0960.
(CDCl3):
d 2.64 (d, 1H, exchangeable with D2O,
J4,OH¼11.3 Hz, OH), 3.21 (d, 1H, J2,3¼3.8 Hz, H-2), 3.41
(dt, 1H, J5a,5b¼12.5 Hz, J4,5a¼1.3 Hz, J3,5a¼1 Hz, H-5a),
3.46 (s, 3H, OMe), 3.54 (bt, 1H, J3,4¼4.5 Hz, H-3), 3.77 (dd,
1H, J4,5b¼3 Hz, H-5b), 3.90 (m, 1H, H-4), 4.84 (s, 1H, H-1).
13C NMR (CDCl3): d 51.68 (C-2 and C-3), 55.70 (OMe),
61.60 and 61.65 (C-4 and C-5), 95.34 (C-1). FAB MS: m/z
147 (MþþH).
4.1.11. E,E22S-(40-Methoxycarbonyl-10,30-butadienyl)-
3S,4R-O-isopropylidene-tetrahydrofuran (14). To a stir-
red solution of 13 (0.54 g, 2.01 mmol) and trimethyl-4-
phosphonocrotonate (0.46 g, 2.21 mmol) in dry THF
(20 mL) was added NaH (0.136 g, 5.67 mmol) in portions
during 5 min. The mixture was stirred at room temperature
for 20 min then filtered, diluted with Et2O (20 mL) and
evaporated. Flash column chromatography (19:1 CH2Cl2–
EtOAc) of the residue gave pure E,E-isomer 14 (0.246 g,
48%) as a colorless solid. Recrystallization from CH2Cl2–
hexane gave an analytical sample E,E-14 as colorless
needles, mp 75 8C, [a]D¼2108.2 (c, 0.88 in CHCl3),
RF¼0.29 (CH2Cl2). IR (KBr): nmax 1710 (CvO, ester),
1650 and 1630 (CHvCH–CHvCH). 1H NMR (CDCl3): d
1.32 and 1.51 (2£s, 3H each, Me2C), 3.73 (s, 3H, CO2Me),
3.83 (dd, 1H, J5a,5b¼10.7 Hz, J4,5a¼4.2 Hz, H-5a), 3.99 (dd,
4.1.9. 3,4-O-Isopropylidene-2-O-methanesulfonyl-b-D-
arabinopyranosyl chloride (12). To a stirred and cooled
(210 8C) solution of 118 (1.15 g, 6.05 mmol) in a mixture of
dry CH2Cl2 (12 mL) and Et3N (2.53 mL, 18.15 mmol) was
added dropwise a solution of MsCl (1.17 mL, 15.12 mmol)
in CH2Cl2 (3.5 mL). The mixture was stirred for 1 h at
210 8C, then diluted with CH2Cl2 (20 mL), and washed
successively with cold (þ4 8C) aq 5% HCl (2£40 mL) and
1% NaHCO3 (20 mL). Organic phase was dried and
evaporated to a pale yellow solid. Flash column chroma-
tography (CH2Cl2) gave pure 12 (1.52 g, 88%). Recrystalli-
zation from CH2Cl2–hexane gave colorless crystals, mp
129–131 8C (decomposition), [a]D¼2205.3 (c, 1.0 in
CHCl3), RF¼0.40 (CH2Cl2). 1H NMR (CDCl3): d 1.39
and 1.59 (2£s, 3H each, Me2C), 3.19 (s, 3H, MeSO2), 4.18–
4.38 (m, 3H, 2£H-5 and H-4), 4.43 (dd, 1H, J2,3¼7.6 Hz,
J3,4¼4.9 Hz, H-3), 4.75 (dd, 1H, J1,2¼3.7 Hz, H-2), 6.13 (d,
1H, H-1). 13C NMR (CDCl3): d 26.13 and 27.86 (Me2C),
38.75 (MeSO2), 61.12 (C-5), 72.37 (C-3), 73.03 (C-4),
78.11 (C-2), 90.92 (C-1), 110.11 (Me2C). CI MS: m/z 536
(2Mþ2Cl), 287 (MþþH), 251 (Mþ2Cl).
1H, J4,5b¼1 Hz, H-5b), 4.58 (dd, 1H, J2,3¼1.7 Hz, J3,4
¼
0
0
6.2 Hz, H-4), 4.62 (ddd, 1H, J2,2 ¼1.8 Hz, J2,1 ¼4.6 Hz,
0
0
0
H-2), 4.77 (dd, 1H, H-3), 5.88 (d, 1H, J3 ,4 ¼15.4 Hz, H-4 ),
0
0
0
0
0
5.97 (dd, 1H, J1 ,2 ¼15.5 Hz, H-1 ), 6.39 (ddd, 1H, J2 ,3
¼
11 Hz, H-20), 7.24 (dd, 1H, H-30). 13C NMR (CDCl3): d
24.91 and 26.48 (Me2C), 51.53 (CO2Me), 72.53 (C-5), 80.84
(C-4), 83.92 (C-2), 84.76 (C-3), 112.90 (Me2C), 121.75
(C-40), 128.83 (C-20), 138.02 (C-10), 143.23 (C-30), 167.09
(CO2Me). FAB MS: m/z 277 (MþþNa), 255 (MþþH).
HR MS (ESþ): m/z 277.1052 (MþþNa). Calcd for
C13H18O5Na: 277.1052. Anal. calcd for C13H18O5: C,
61.40; H, 7.14. Found: C, 61.52; H, 6.97.
4.1.10. 3,4-O-Isopropylidene-2-O-methanesulfonyl-D-
arabinopiranose (13). To a solution of 11 (3.00 g,
15.77 mmol) in dry CH2Cl2 (25 mL) and Et3N (9.10 mL,
65.29 mmol) was added dropwise a solution of MsCl (4 mL,
51.58 mmol) in dry CH2Cl2 (12 mL). The mixture was
stirred at 210 8C for 1 h. After workup as described above
(procedure in Section 4.1.9), crude 12 was dissolved in
Me2CO (40 mL) and cooled to 0 8C. To the solution were
added Ag2O (3.70 g, 15.97 mmol), AgOTf (0.30 g,
1.17 mmol), and water (2 mL). The mixture was allowed
to warm to room temperature and then stirred for the next
20 h. The reaction mixture was diluted with EtOAc
(20 mL), filtered through a Celite pad and evaporated.
Flash column chromatography (EtOAc) of the residue gave
pure 13 (4.00 g, 95%), as a colorless syrup. Crystallization
from a mixture of EtOAc–light petroleum furnished
colorless crystals, mp 112–114 8C. Recrystallization from
4.1.12. 2S-(40-Methoxycarbonyl-10-butyl)-3S,4R-O-iso-
propylidene-tetrahydrofuran (15). Procedure A. To a
solution of 7 (0.85 g, 2.76 mmol) in anhydrous MeOH
(35 mL) was added 0.15 M NaOMe in MeOH (3.5 mL)
and the mixture was stirred for 2 h at room temperature.
3-(methoxycarbonyl-2-propenylidene)triphenylphosphor-
ane14 (1.49 g, 4.14 mmol) was added to the solution and the
reaction mixture was stirred at room temperature for
additional 2 h and then evaporated. Chromatographic
purification on a column of flash silica (7:3 light
petroleum–Et2O) afforded pure 14 (0.29 g) as an insepar-
able mixture of E- and Z-isomers. A solution of 14 (0.29 g,
1.14 mmol) in MeOH (20 mL) was hydrogenated over PtO2
(0.03 g) for 24 h at room temperature. The mixture was
filtered and the catalyst washed with MeOH. The organic

5232
V. Popsavin et al. / Tetrahedron 60 (2004) 5225–5235
solution was evaporated. and the residue was purified by
flash chromatography (9:1 CH2Cl2–EtOAc) to afford pure
15 (0.26 g, 36%) as a colorless oil.
(CH2Cl2). IR (film): 1730 (CvO, ester), 1420 (as. SO2),
1
1240–1205 (sim. SO2), 1130 (CF3). H NMR (CDCl3): d
1.37–1.83 (m, 6H, 3£CH2), 2.31 (t, 2H, CH2CO2Me), 3.65
(s, 3H, CO2Me), 4.03 (dd, 1H, J5a,5b¼11.2 Hz, J4,5a
¼
Procedure B. To a solution of 13 (0.15 g, 0.56 mmol) in
anhydrous DMF (6 mL) was added 3-(methoxycarbonyl-2-
propenylidene)triphenylphosphorane14 (0.28 g, 0.78 mmol)
and anh Na2CO3 (0.50 g, 4.72 mmol). The mixture was
stirred for 2 h at 110–120 8C, then poured in water
(100 mL) and extracted with Et2O (3£30 mL). The extracts
were combined and evaporated. Flash column chroma-
tography (7:3 light petroleum–ether) of the residue gave an
inseparable mixture of E- and Z-isomers 14 (0.115 g, 81%).
A solution of 14 (0.115 g, 1.14 mmol) in MeOH (6 mL) was
hydrogenated over PtO2 (0.01 g) by using the same
methodology as described in the Procedure A, to afford
pure 15 (0.127 g, 88%) as a colorless oil, [a]D¼230.7 (c,
0.90 in CHCl3), RF¼0.32 (CH2Cl2). IR (KBr): nmax 1735
(CvO, ester). 1H NMR (CDCl3): d 1.24 and 1.41 (2£s, 3H
each, Me2C), 1.28–1.67 (m, 6H, 3£CH2), 2.23 (t, 2H,
CH2CO2Me), 3.58 (s, 3H, CO2Me), 3.72, (dd, 1H,
J5a,5b¼10.6 Hz, J4,5a¼4.2 Hz, H-5a), 3.81 (dd, 1H,
J4,5b¼1.7 Hz, H-5b), 3.89 (m, 1H, J2,3¼1.7 Hz, H-2), 4.32
(dd, 1H, J3,4¼6.3 Hz, H-3), 4.69 (ddd, 1H, H-4). 13C NMR
(CDCl3): d 24.76 and 26.40 (Me2C), 24.44, 25.09 and 30.18
(3£CH2), 33.64 (CH2CO2Me), 51.24 (CO2Me), 71.28 (C-5),
80.71 (C-4), 83.87 (C-2), 84.70 (C-3), 112.50 (Me2C),
173.68 (CO2Me). FAB MS (ESþ): m/z 281 (MþþNa).
HR MS (ESþ): m/z 281.1363 (MþþNa). Calcd for
C13H22O5Na: 281.1365.
4.2 Hz, H-5a), 4.09 (m, 1 H, J¼6.7 Hz, H-2), 4.32 (dd, 1H,
J4,5b¼5.3 Hz, H-5b), 4.88 (t, 1H, J3,4¼6.1 Hz, H-3), 5.34
(m, 1H, H-4). 13C NMR (CDCl3): d 24.40, 24.61 and 31.38
(3£CH2), 33.59 (CH2CO2Me), 51.43 (CO2Me), 69.24 (C-5),
79.23 (C-2), 81.42 (C-4), 83.66 (C-3), 118.19 (q, JC,F
¼
319.5 Hz, 2£CF3SO2), 173.69 (CvO). HR MS (EI): m/z
482.0163 (Mþ). Calcd for C12H16F6O9S2: 482.0140.
4.1.15. 2S-(40-Methoxycarbonyl-10-butyl)-3S,4R-diazido-
tetrahydrofuran (18). Procedure A. To a solution of 17
(0.40 g, 0.83 mmol) in HMPA (4 mL) was added NaN3
(1.50 g, 23.08 mmol) and the resulting suspension was
stirred for 1.5 h at room temperature. The mixture was
poured in water (30 mL) and extracted with 1:1 benzene–
light petroleum (4£20 mL). Organic phase was washed with
H2O (2£20 mL), dried and evaporated to a yellow oil. Flash
column chromatography (CH2Cl2) of the residue gave pure
18 (0.207 g, 93%) as a pale yellow oil.
Procedure B. A solution of 16 (0.56 g, 2.57 mmol) in dry
CH2Cl2 (40 mL) and pyridine (2.08 mL, 25.74 mmol) was
treated with Tf2O (2.53 mL, 15.42 mmol) in dry CH2Cl2
(10 mL) under the same reaction conditions as described in
procedure under Section 4.1.14. The workup as described
above yielded crude 17, which was immediately dissolved
in HMPA (20 mL), and treated with NaN3 (4.70 g,
72.31 mmol) according to the procedure 4.1.15A. Thus
obtained crude mixture was purified by flash chroma-
tography (4:1 light petroleum–EtOAc) to afford pure 18
(0.467 g, 68%) as a bright yellow oil, [a]D¼þ36.0 (c, 1.95
in CHCl3), RF¼0.28 (CH2Cl2). IR (film): nmax 2100 (N3),
1740 (CvO, ester). 1H NMR (CDCl3): d 1.29–1.78 (m, 6H,
3£CH2), 2.33 (t, 2H, CH2CO2Me), 3.66 (s, 3H, CO2Me),
3.78 (dd, 1H, J5a,5b¼9.1 Hz, J4,5a¼7.2 Hz, H-5a), 3.88 (m,
4.1.13. 2S-(40-Methoxycarbonyl-10-butyl)-3S,4R-dihy-
droxy-tetrahydrofuran (16). A solution of 15 (0.316 g,
1.22 mmol) in aq 90% TFA (2 mL) was stirred for 1 h at
room temperature. The mixture was evaporated by co-
distillation with toluene (3£5 mL) to a yellow oil. Flash
column chromatography (EtOAc) of the residue gave pure
16 (0.253 g, 95%) as a colorless oil, [a]D¼239.4 (c, 1.0 in
CHCl3), RF¼0.26 (Et2O). IR (film): nmax 3380 (OH), 1370
(CvO, ester). 1H NMR (CDCl3): d 1.38–1.65 (m, 6H,
3£CH2), 2.35 (t, 2H, CH2CO2Me), 3.62 (s, 3H, CO2Me),
3.6–3.8 (m, 5H, 2£OH, H-2, H-3 and H-5a), 4.04 (dd, 1H,
0
0
1H, J1 a,2¼5.8 Hz, J1 b,2¼7.3 Hz, J2,3¼3.4 Hz, H-2), 3.95–
4.05 (m, 2H, J3,4¼7.7, J4,5b¼4 Hz, H-3 and H-5b), 4.25 (td,
1H, H-4). 13C NMR (CDCl3): d 24.76, 25.47 and 29.68
(3£CH2), 33.72 (CH2CO2Me), 51.46 (CO2Me), 62.96 (C-4),
65.24 (C-3), 68.52 (C-5), 80.78 (C-2), 173.87 (CO2Me). CI
MS: m/z 269 (MþþH). FAB MS (ESþ): m/z 291 (MþþNa).
HR MS (ESþ): m/z 291.1174 (MþþNa). Calcd for
C10H16N6O3Na: 291.1182.
J5a,5b¼9.9 Hz, J4,5b¼5.2 Hz, H-5b), 4.19 (m, 1H, J4,5a
¼
4.6 Hz, H-4). 13C NMR (CDCl3): d 24.67, 25.19 and 32.74
(3£CH2), 33.79 (CH2CO2Me), 51.52 (CO2Me), 70.81 (C-4),
72.44 (C-5), 75.64 (C-2), 81.85 (C-3). CI MS: m/z 219
(MþþH). FAB MS (ESþ): m/z 241 (MþþNa). HR MS
(ESþ): m/z 241.1057 (MþþNa). Calcd for C10H18O5Na:
241.1052.
4.1.16. Methyl 2,3-anhydro-4-O-methanesulfonyl-b-D-
ribopyranoside (19). To a stirred and cooled solution
(210 8C) of 10 (0.97 g, 6.65 mmol) in dry CH2Cl2 (20 mL)
was added Et3N (1.8 mL, 12.91 mmol) and a solution of
MsCl (0.8 mL, 10.32 mmol) in CH2Cl2 (3 mL). Stirring was
continued for 0.5 h at 210 8C and the mixture diluted with
CH2Cl2 (10 mL), washed successively with aq 5% HCl
(2£30 mL), satd aq NaHCO3 (20 mL) and water (20 mL).
The organic solution was dried and evaporated to yellow
syrup. Flash column chromatography (19:1 CH2Cl2–
EtOAc) of the residue gave pure 19 (1.45 g, 97%) as a
solid, which upon crystallization from CH2Cl2–hexane
gave colorless needles, mp 90 8C, [a]D¼219.2 (c, 0.5 in
CHCl3), RF¼0.52 (Et2O). IR (KBr): nmax 1350 (as. SO2),
4.1.14. 2S-(40-Methoxycarbonyl-10-butyl)-3S,4R-bis-tri-
fluoromethanesulfonyloxi-tetrahydrofuran (17). To a
stirred and cooled (210 8C) solution of 16 (0.43 g,
1.97 mmol) in a mixture of dry CH2Cl2 (17 mL) and
pyridine (0.80 mL, 9.9 mmol) was added dropwise a cooled
(210 8C) solution of Tf2O (0.69 mL, 4.21 mmol) in dry
CH2Cl2 (7 mL). The mixture was stirred at 0 8C for 1.5 h,
then diluted with CH2Cl2 (20 mL) and washed successively
with aq 5% HCl (2£25 mL), 1% NaHCO3 (25 mL) and
water (25 mL). The organic solution was separated, dried
and evaporated to a yellow oil. Flash column chromatog-
raphy (CH2Cl2) of the residue gave pure 17 (0.48 g, 51%) as
a colorless oil, [a]D¼235.9 (c, 2.25 in CHCl3), RF¼0.68
1
1190–1170 (sim. SO2). H NMR (CDCl3): d 3.16 (s, 3H,
MeSO2), 3.22 (d, 1H, J2,3¼3.7 Hz, H-2), 3.46 (s, 3H, OMe),

V. Popsavin et al. / Tetrahedron 60 (2004) 5225–5235
5233
3.57–3.67 (m, 2H, J3,4¼4.3 Hz, J4,5a¼2.4 Hz, J5a,5b
¼
4.1.19. Methyl 3,4-diazido-3,4-dideoxy-2-O-tert-butyldi-
methylsilyl-a-L-arabinopyranoside (23). To a stirred
solution of 22 (0.27 g, 1.26 mmol) in dry DMF (11 mL)
were added tert-BuMe2SiCl (0.81 g, 5.37 mmol) and
imidazole (0.373 g, 5.48 mmol). The mixture was stirred
for 24 h at room temperature and then evaporated. Flash
column chromatography (9:1 light petroleum–EtOAc) of
the residue gave pure 23 (0.403 g, 97%) as a colorless syrup,
[a]D¼212.8 (c, 0.5 in CHCl3), RF¼0.76 (CH2Cl2). IR
13.5 Hz, H-3 and H-5a), 3.92 (dd, 1H, J4,5b¼4.1 Hz,
H-5b), 4.87 (s, 1H, H-1), 4.97 (td, 1H, H-4). 13C NMR
(CDCl3): d 38.72 (MeSO2), 48.88 (C-3), 51.19 (C-2), 56.02
(OMe), 58.41 (C-5), 70.71 (C-4), 95.15 (C-1). FAB MS: m/z
247 (MþþNa), 225 (MþþH), 193 (Mþ2OMe). Anal. calcd
for C7H12O6S: C, 37.49; H, 5.39; S, 14.30. Found: C, 37.65;
H, 5.57; S, 14.56.
1
4.1.17. Methyl 2,3-anhydro-4-azido-4-deoxy-a-L-lyxo-
pyranoside (20). To a solution of 19 (0.25 g, 1.12 mmol)
in dry DMF (10 mL) was added NaN3 (0.755 g,
11.62 mmol). The mixture was stirred at 90–95 8C for
0.5 h and then at 110–115 8C for additional 15 min. The
mixture was evaporated and extracted with EtOAc (30 mL).
Organic phase was filtered, washed with water (2£20 mL),
dried and evaporated. The residue was purified by flash
chromatography (3:2 light petroleum–EtOAc) to give pure
20 (0.107 g, 56%) as a colorless oil, [a]D¼291.8 (c, 0.8 in
(film): nmax 2120 (N3). H NMR (CDCl3): d 0.11 and 0.16
(2£s, 3H each, Me3CSiMe2), 0.91 (s, 9H, Me3CSiMe2), 3.47
(s, 3H, OMe), 3.50 (dd, 1H, J2,3¼8.6 Hz, J3,4¼3.6 Hz, H-3),
3.58 (dd, 1H, J4.5a¼1.6 Hz, J5a,5b¼12.5 Hz, H-5a), 3.68 (dd,
1H, J1,2¼6.3 Hz, H-2), 3.88 (m, 1H, J4,5b¼3.3 Hz, H-4),
4.01 (dd, 1H, H-5b), 4.09 (d, 1H, H-1). 13C NMR (CDCl3): d
25.08 and 24.48 (Me3CSiMe2), 18.09 (Me3CSiMe2), 25.64
(Me3CSiMe2), 56.69 (OMe), 59.49 (C-4), 63.20 (C-5),
65.66 (C-3), 70.93 (C-2), 104.58 (C-1). FAB MS (ESþ): m/z
351 (MþþNa). HR MS (ESþ): m/z 351.1593 (MþþNa).
Calcd for C12H24N6O3SiNa: 351.1577.
1
CHCl3), RF¼0.66 (CH2Cl2). IR (film): nmax 2120 (N3). H
NMR (CDCl3): d 3.11 (d, 1H, J2,3¼3.7 Hz, H-3), 3.33 (dd,
1H, J3,5b<0.7 Hz, H-2), 3.46 (s, 3H, OMe), 3.52 (dd, 1H,
4.1.20. Methyl 3,4-diamino-3,4-dideoxy-2-O-tert-butyl-
dimethylsilyl-a-L-arabinopyranoside (24) and the corre-
sponding oxalate (243H2C2O4). To a solution of 23
(0.229 g, 0.70 mmol) in dry THF (4 mL) was added Ph3P
(0.46 g, 1.75 mmol). The mixture was stirred for 3 h at room
temperature. To the reaction mixture was added water
(0.3 mL) and NaHCO3 (0.06 g, 0.71 mmol), and the stirring
at ambient temperature was continued for the next 24 h. The
mixture was evaporated and the residue was purified on a
column of flash silica (4:1 EtOAc–MeOH) to give pure 24
(0.121 g, 63%) as a colorless oil, [a]D¼226.6 (c, 0.4 in
CHCl3), RF¼0.18 (4:1 EtOAc–MeOH). IR (film): nmax
3390–3300 (NH2). 1H NMR (CDCl3): d 0.06 and 0.07 (2£s,
3H each, Me3CSiMe2), 0.86 (s, 9H, Me3CSiMe2) 2.42 (bs,
4H, 2£NH2), 2.76 (dd, 1H, J2,3¼7.7 Hz, J3,4¼3.9 Hz, H-3),
3.05 (m, 1H, J4,5a¼6 Hz, J4,5b¼4.5 Hz, H-4), 3.37 (dd, 1H,
J1,2¼5.7 Hz, H-2), 3.41 (s, 3H, OMe), 3.52 (dd, 1H,
J5a,5b¼11.8 Hz, H-5a), 3.71 (dd, 1H, H-5b), 4.06 (d,
1H, H-1). 13C NMR (CDCl3): d 24.96 and 24.42
(Me3CSiMe2), 18.14 (Me3CSiMe2), 25.82 (Me3CSiMe2),
49.04 (C-4), 55.86 (C-3), 56.22 (OMe), 66.14 (C-5), 73.34
(C-2), 104.44 (C-1). A portion of 24 was converted to the
corresponding oxalic acid salt (24£H2C2O4) by using the
following procedure: To a solution of 24 (0.055 g,
0.2 mmol) in dry EtOH (2 mL) was added a solution of
oxalic acid (0.02 g, 0.22 mmol) in dry EtOH (1 mL). The
mixture was stirred at room temperature for 4 h and then
stored at þ4 8C for 20 h to yield colorless crystals of pure
24£H2C2O4 (0.051 g, 70%). Recrystallization from EtOH
gave an analytical sample as colorless needles, mp 164 8C,
[a]D¼224.2 (c, 0.2 in H2O). IR (KBr): nmax 3450–2320
J4,5a¼9.1 Hz, J5a,5b¼11.4 Hz, H-5a), 3.62 (ddd, 1H, J4,5b
¼
5.8 Hz, H-5b), 3.75 (s, 1H, H-1), 4.79 (s, 1H, H-4). 13C
NMR (CDCl3): d 49.98 (C-3), 52.29 (C-4), 52.56 (C-2),
55.91 (OCH3), 57.44 (C-5), 99.79 (C-1). FAB MS: m/z 194
(MþþNa), 172 (MþþH). Further elution of the column
gave 3,4-diazido derivative 22 (0.042 g, 18%) as a minor
product.
4.1.18. Methyl 3,4-diazido-3,4-dideoxy-a-L-arabino-
pyranoside (22) and methyl 2,4-diazido-2,4-dideoxy-a-
L-xylopyranoside (21). To a solution of 19 (0.63 g,
2.83 mmol) in dry DMF (30 mL) was added NaN3 (1.84 g,
28.31 mmol) and the resulting suspension was stirred at
140–145 8C for 3.5 h. The workup as described above,
followed by flash column chromatography (4:1!3:2 light
petroleum–EtOAc), gave two fractions. The first fraction
contained pure 21 (0.025 g, 4%), which crystallized from
CH2Cl2–hexane as colorless crystals, mp 124 8C, [a]D¼
2202.1 (c, 0.5 in CHCl3), RF¼0.55 (9:1 CH2Cl2–EtOAc).
IR (KBr): nmax 3480 (OH), 2130 (N3). 1H NMR (CDCl3): d
3.01 (bd, 1H, exchangeable with D2O, J3,OH¼2.4 Hz, OH),
3.26 (dd, 1H, J1,2¼3.5 Hz, J2,3¼10.1 Hz, H-2), 3.42 (s, 3H,
OMe), 3.46–3.79 (m, 3H, J3,4¼8.9 Hz, J4,5a¼7 Hz, J4,5b
¼
3.6 Hz, 2£H-5 and H-4), 3.96 (bt, 1H, H-3), 4.78 (d, 1H,
H-1). 13C NMR (CDCl3): d 55.47 (OMe), 59.49 (C-5), 61.90
(C-4), 63.41 (C-2), 71.03 (C-3), 98.76 (C-1). CI MS: m/z
215 (MþþH). Anal. calcd for C6H10N6O3: C, 33.65; H,
4.71; N, 39.24. Found: C, 33.96; H, 5.06; N, 38.89. Pure 22
(0.306 g, 51%) was then eluted, which crystallized from
CH2Cl2–hexane as colorless needless, mp 91 8C, [a]D¼
217.0 (c, 0.5 in CHCl3), RF¼0.37 (9:1 CH2Cl2–EtOAc). IR
1
(NHþ3 ), 1650 (CvO, oxalate). H NMR (D2O): d 0.24 (s,
1
(KBr): nmax 3450 (OH), 2170 and 2120 (N3). H NMR
6H, Me3CSiMe2), 0.97 (s, 9H, Me3CSiMe2), 3.59 (s, 3H,
OMe), 3.73 (m, 1H, H-2), 3.93–4.11 (m, 4H, H-3, H-4, and
2£H-5), 4.62 (d, 1H, J1,2¼4.4 Hz, H-1). Anal. calcd for
C14H30N2O7Si: C, 45.88; H, 8.25, N, 7.64. Found: C, 46.08;
H, 8.26, N, 7.32.
(CDCl3): d 2.90 (bs, 1H, exchangeable with D2O, OH), 3.55
(s, 3H, OMe), 3.60 (dd, 1H, J5a,5b¼12.8 Hz, J4,5a¼1.6 Hz,
H-5a), 3.62 (dd, 1H, J2,3¼9.8 Hz, J3,4¼3.8 Hz, H-3), 3.80
(dd, 1H, J1,2¼7.2 Hz, H-2), 3.81 (m, 1H, J4,5b¼2.2 Hz,
H-4), 4.06 (dd, 1H, H-5b), 4.13 (d, 1H, H-1). 13C NMR
(CDCl3): d 55.47 (OMe), 59.49 (C-5), 61.90 (C-4), 63.41
(C-2), 71.03 (C-3), 98.76 (C-1). FAB MS: m/z 215
(MþþH), 172 (Mþ2N3). Anal. calcd for C6H10N6O3: C,
33.65; H, 4.72; N, 39.24. Found: C, 34.05; H, 4.72; N, 38.88.
4.1.21. Methyl 3,4-dideoxy-3,4-carbonyldiamino-2-
O-tert-butyldimethylsilyl-a-L-arabinopyranoside (25).
Procedure A. To a stirred and cooled solution (0 8C) of 24
(0.051 g, 0.18 mmol) in dry CH2Cl2 (5 mL) was first added

5234
V. Popsavin et al. / Tetrahedron 60 (2004) 5225–5235
Et3N (0.08 mL, 0.57 mmol) and then a cooled solution
(0 8C) of triphosgene (0.018 g, 0.06 mmol) in dry
CH2Cl2 (1 mL) was added in three portions. The mixture
was stirred for 2 h at 0 8C and evaporated. Flash
column chromatography (EtOAc) of the residue,
gave pure 25 (0.038 g, 67%), which crystallized from
CH2Cl2–hexane.
(NHCONH), 174.14 (CO2Me). FAB MS: m/z 243
(MþþH). FAB MS (ESþ): m/z 265 (MþþNa). HR MS
(ESþ): m/z 265.1168 (MþþNa). Calcd for C11H18N2O4Na:
265.1164.
4.1.23. (1)-Oxybiotin (1). A solution of 26 (0.068 g,
0.28 mmol) in 1 M aq NaOH (2 mL) was stirred for 24 h at
room temperature. The mixture was diluted with water
(3 mL) and neutralized by stirring with Amberlist-15 resin
(3 g) at room temperature for 1 h. The mixture was filtered
and the resin washed with water. The combined aqueous
solution was evaporated by co-distillation with a mixture of
1:1 toluene–EtOH to give pure 1 (0.064 g, 99%) as a white
powder. Recrystallization from water gave pure 18 as silky
crystals, mp 187–188 8C, [a]D¼þ57.8 (c, 0.65 in 1 M
NaOH); lit.4 mp 187–188 8C, [a]D¼þ57.7. IR (KBr): nmax
3430–2500 (COOH), 1700 (NHCONH), 1670 (COOH). 1H
NMR (D2O): d 1.41–1.80 (m, 6H, 3£CH2), 2.46 (t, 2H,
CH2CO2H), 3.64–3.76 (m, 2H, J2,3¼4 Hz, J4,5a¼4.4 Hz,
J5a,5b¼10.4 Hz, H-2 and H-5a), 3.94 (d, 1H, H-5b), 4.42 (dd,
1H, J3,4¼8.7 Hz, H-3), 4.45 (dd, 1H, H-4). 1H NMR
(Me2SO-d6): d 1.18–1.58 (m, 6H, 3£CH2), 2.20 (t, 2H,
CH2CO2H), 3.33 (m, 1H, J2,3¼4 Hz, H-2), 3.39 (dd, 1H,
J4,5a¼4.6 Hz, J5a,5b¼9.8 Hz, H-5a), 3.65 (d, 1H, H-5b), 4.07
(dd, 1H, J3,4¼8.7 Hz, H-3), 4.21 (dd, 1H, H-4), 6.36 and
6.40 (2£bs, 1H each, 2£NH). 13C NMR (Me2SO-d6): d
25.29, 25.99 and 28.33 (3£CH2), 34.35 (CH2CO2H), 57.53
(C-4), 59.01 (C-3), 74.34 (C-5), 82.85 (C-2), 163.80
(NHCONH), 176.09 (CO2H). FAB MS: m/z 229 (MþþH),
211 (Mþ2OH). FAB MS (ESþ): m/z 251 (MþþNa). HR
MS (ESþ): m/z 251.1007 (MþþNa). Calcd for
C10H16N2O4Na: 251.1008.
Procedure B. A solution of 23 (0.15 g, 0.46 mmol) in dry
CH2Cl2 (9 mL) was hydrogenated over PtO2 (0.015 g,
0.66 mmol) for 24 h at room temperature, and then to the
stirred and cooled (0 8C) mixture was added Et3N (0.2 mL,
1.47 mmol) in one portion. A solution of triphosgene
(0.047 g, 0.16 mmol) in dry CH2Cl2 (1.5 mL) was added
dropwise while stirring the mixture at 0 8C for 1 h. After
stirring at room temperature for additional 18 h, the
suspension was filtered and the catalyst washed with
CH2Cl2. The combined organic solution was evaporated
and the residue purified by flash chromatography (EtOAc)
to afford pure 25 (0.095 g, 69%) as colorless crystals.
Recrystallization from CH2Cl2–hexane gave an analytical
sample 25, mp 111–112 8C, [a]D¼23.2 (c, 1.65 in CHCl3),
1
RF¼0.25 (EtOAc). IR (KBr): nmax 1710 (CvO). H NMR
(CDCl3): d 0.08 and 0.10 (2£s, 3H each, Me3CSiMe2), 0.88
(s, 9H, Me3CSiMe2), 3.41 (s, 3H, OMe), 3.55 (t, 1H,
J2,3¼J3,4¼8.3 Hz, H-3), 3.6 (dd, 1H, J1,2¼6 Hz, H-2), 3.73
(dd, 1H, J4,5a¼5.7 Hz, J5a,5b¼12.3 Hz, H-5a), 3.81 (dd, 1H,
J4,5b¼6.4 Hz, H-5b), 4.07 (m, 1H, H-4), 4.20 (d, 1H, H-1),
4.92 (bs, 1H, NH-3), 5.50 (bs, 1H, NH-4). 13C NMR
(CDCl3): d 25.04 and 24.42 (Me3CSiMe2), 18.01
(Me3CSiMe2), 25.74 (Me3CSiMe2), 51.45 (C-4), 55.73
(OMe), 56.13 (C-3), 62.22 (C-5), 73.81 (C-2), 103.13
(C-1), 163.56 (CvO). FAB MS (ESþ): m/z 301 (Mþ2H).
HR MS (ESþ): m/z 325.1543 (MþþNa). Calcd
for C13H26N2O4SiNa: 325.1560. Anal. calcd for
C13H26N2O4Si: C, 51.66; H, 8.77; N, 9.27. Found: C,
51.94; H, 8.77; N, 9.88.
4.2. X-ray analysis18
A single transparent crystal of compound 26 selected for
data collection was mounted on a Bruker PLATFORM
three-circle goniometer equipped with SMART 1K CCD
detector mounted at a crystal to detector distance of 5.4 cm.
The data were collected using graphite monochromated
MoKa X-radiation and frame widths of 0.38 in v, with 10 s
used to acquire each frame. More than a hemisphere of
three-dimensional data were collected. Additional infor-
mation regarding data collection and structure refinement is
given in Table 1. The data were reduced using the Bruker
program SAINT.19 A semiempirical absorption-correction
based upon the intensities of equivalent reflections was
applied (program XPREP),20 and the data were corrected for
Lorentz, polarization, and background effects. The Bruker
SHELXTL20 system of programs was used for the
refinement of the crystal structure. The positions of all
non H-atoms were located by direct methods. The positions
of hydrogen atoms were found from the inspection of the
difference Fourier maps. The high value of the Flack
parameter [1.8 (1.0)] indicates that the absolute configu-
ration cannot reliably be resolved. The final refinement
included atomic positional and displacement parameters for
all atoms. The non H-atoms were refined anisotropically,
while all H sites were refined with isotropic displacement
parameters. The refinement converged at a final agreement
index (R1) of 0.0376, calculated for 2143 unique observed
reflections (lFol.4sF) and a goodness-of-fit (S) of 0.945
(226 refined parameters).
4.1.22. (1)-Oxybiotin methyl ester (26). A solution of 18
(0.086 g, 0.32 mmol) in dry CH2Cl2 (5 mL) was hydro-
genated over PtO2 (0.02 g) for 22 h at room temperature.
A solution of triphosgene (0.033 g, 0.11 mmol) in dry
CH2Cl2 (1 mL), was added dropwise while stirring the
mixture at 0 8C for 1 h, and then at room temperature for
3 h. To the solution was added an additional amount of
triphosgene (0.012 g, 0.04 mmol) and the mixture was
stirred for 1 h at 0 8C and then at room temperature for 18 h.
The suspension was filtered and the catalyst washed with
CH2Cl2. The combined organic solution was concentrated
and the residue purified by flash chromatography (9:1
EtOAc–MeOH) to afford pure 26 (0.051 g, 66%) as
colorless solid. Recrystallization from CH2Cl2–hexane
gave colorless crystals, mp 141 8C, [a]D¼þ44.7 (c, 0.5 in
CHCl3), RF¼0.29 (Me2CO). IR (KBr): nmax 3410–3120
(NH), 1750 (COOMe), 1710 (NHCONH). 1H NMR
(CDCl3): d 1.21–1.80 (m, 6H, 3£CH2), 2.23 (t, 2H,
0
CH2CO2Me), 3.40 (m, 1H, J2,3¼3.6 Hz, J1 a,2¼6.4 Hz,
H-2), 3.49 (dd, 1H, J5a,5b¼10.1 Hz, J4,5a¼4.2 Hz, H-5a),
3.63 (s, 3H, CO2Me), 3.86 (d, 1H, H-5b), 4.17 (dd, 1H,
J3,4¼8.4 Hz, H-3), 4.34 (dd, 1H, H-4), 5.98 and 6.18 (2£bs,
1H each, 2£NH). 13C NMR (CDCl3): d 24.81, 25.52 and
28.36 (3£CH2), 33.67 (CH2CO2Me), 51.42 (CO2Me), 57.52
(C-4), 58.98 (C-3), 75.23 (C-5), 82.58 (C-2), 163.62

V. Popsavin et al. / Tetrahedron 60 (2004) 5225–5235
5235
3. Dyke, S. F. Chemistry of Natural Products; Bentley, K. W.,
Ed.; Interscience: London, 1964; Vol. 6, pp 161–181.
4. Ohrui, H.; Kuzuhara, H.; Emoto, S. Agric. Biol. Chem. 1971,
35, 752–755.
Table 1. Crystallographic data and structure refinement of 26
Crystallographic parameter
Empirical formula
Formula weight
Temperature (K)
C11H18N2O4
242.3
293
0.71073
´
5. (a) Miljkovic, D.; Popsavin, V.; Harangi, J. Tetrahedron Lett.
´
1987, 28, 5733–5736. (b) Miljkovic, D.; Popsavin, V.;
Harangi, J.; Batta, G. J. Serb. Chem. Soc. 1989, 54,
´
163–165. (c) Popsavin, V.; Benedekovic, G.; Popsavin, M.;
˚
Wavelength (A)
Crystal system
Space group
Unit cell dimensions
Orthorhombic
P212121
´
Miljkovic, D. Carbohydr. Res. 2002, 337, 459–465.
6. For a preliminary account of this work see: Popsavin, V.;
a¼4.5903
b¼7.517
c¼36.0507
´
Benedekovic, G.; Popsavin, M. Tetrahedron Lett. 2002, 43,
2281–2284.
3
˚
Volume (A )
1243.94
4
Z
Density (calculated)
Absorption coefficient (mm21
F(000)
Crystal size
2Q max for data collection
Index ranges
Reflections collected
Independent reflections
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [Fo.4sFo]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole
1.354 Mg/m3
0.10
7. Baer, H. H.; Mateo, F. H.; Siemsen, L. Carbohydr. Res. 1989,
187, 67–92.
)
520
0.30 mm£0.20 mm£0.20 mm
8. Kiso, M.; Hasegawa, A. Carbohydr. Res. 1976, 52, 95–102.
9. Jones, J. K. N.; Nicholson, W. H. J. Chem. Soc. 1955,
3050–3055.
56.438
h: 26þ5, k: 29þ10, l: 247þ27
7228
10. Tsuda, Y.; Sato, Y.; Kakimoto, K.; Kanemitsu, K. Chem.
Pharm. Bull. 1992, 40, 1033–1036.
2786 [R(int)¼0.0507]
Full matrix l.s. on F 2
2786/0/226
11. Carbohydrates; Collins, P. M., Ed.; Chapman & Hall: London,
1987; p 58.
0.945
R1¼0.0376
12. Buchta, E.; Andree, F. Chem. Ber. 1959, 92, 3111–3115.
13. For a review on the Staudinger reaction, see: Golobov, Y. G.;
Kasukhin, L. F. Tetrahedron 1992, 48, 1353–1406.
14. Mitchell, S. A.; Oates, B. D.; Razavi, H.; Polt, R. J. Org.
Chem. 1998, 63, 8837–8842. Falb, E.; Bechor, Y.; Nudelman,
A.; Hassner, A.; Albreck, A.; Gottlieb, H. E. J. Org. Chem.
1999, 64, 498–506.
R1¼0.0512, wR2¼0.0905
No
0.14 and 20.18 e A23
Acknowledgements
This work was supported by a research grant from the
Ministry of Science, Technologies and Development of
the Republic of Serbia (Grant No. 1896). The authors
are grateful to Mrs T. Marinko-Covell (Department of
Chemistry, University of Leeds, UK) for recording the mass
spectra.
15. DeTitta, G. T.; Edmonds, J. W.; Stallings, W.; Donohue, J.
J. Am. Chem. Soc. 1976, 98, 1920–1926.
16. Eckert, H.; Foster, B. Angew. Chem. Int. Ed. Engl. 1987, 26,
894–895.
17. Kondo, H.; Miura, K.; Uno, S.; Sunamoto, J. J. Inorg.
Biochem. 1984, 21, 93–102. DeTitta, G. T.; Parthasarathy, R.;
Blessing, R. H.; Stallings, W. Proc. Natl. Acad. Sci. U. S. A.
1980, 77, 333–337.
18. Crystallographic data (excluding structure factors) for the
structure 26 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
number CCDC 226377. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: þ44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
References and notes
1. Hofmann, K. J. Am. Chem. Soc. 1945, 67, 1459–1462.
2. In a review related to the chemistry of biotin dependent
enzymes the oxygenated analogue was named O-heterobiotin;
see: Knowles, J. R. Annu. Rev. Biochem. 1989, 58, 195–221.
However, the original name seems to be still in use according
to some more recent references; see for example: De Titta,
G. T.; Blessing, R. H.; Moss, G. R.; King, H. F.; Sukumaran,
D. K.; Roskwitalski, R. L. J. Am. Chem. Soc. 1994, 116,
6485–6493.
19. SAINT, version 6.2.9; Bruker AXS Inc.: Madison, WI, USA,
2001.
20. SHELXTL, version 5.1; Bruker AXS Inc.: Madison, WI, USA,
2001.