Enantiodivergent synthesis of muricatacin related lactones from d-xylose based on the latent symmetry concept: preparation of two?novel cytotoxic (+)- and (-)-muricatacin 7-oxa analogs

Article abstract of DOI:10.1016/j.tet.2006.09.054

Enantiodivergent formal synthesis of (+)- and (-)-muricatacins from d-xylose has been accomplished through utilization of the?latent plane of symmetry present in the starting monosaccharide. This approach was extended to the preparation of two novel (+)-

Full text of DOI:10.1016/j.tet.2006.09.054

Tetrahedron 62 (2006) 11044–11053
Enantiodivergent synthesis of muricatacin related lactones from
D-xylose based on the latent symmetry concept: preparation of
two novel cytotoxic (D)- and (L)-muricatacin 7-oxa analogs
a
a
a
a
Velimir Popsavin,a, Ivana Krstic, Mirjana Popsavin, Bojana Sreco, Goran Benedekovic,
*
´
Vesna Kojic and Gordana Bogdanovic
´
´
b
b
´
´
a
´
Department of Chemistry, Faculty of Sciences, University of Novi Sad, Trg D. Obradovica 3, 21000 Novi Sad, Serbia
bInstitute of Oncology Sremska Kamenica, Institutski put 4, 21204 Sremska Kamenica, Serbia
Received 3 July 2006; revised 1 September 2006; accepted 15 September 2006
Available online 11 October 2006
Abstract—Enantiodivergent formal synthesis of (+)- and (ꢀ)-muricatacins from D-xylose has been accomplished through utilization of
the latent plane of symmetry present in the starting monosaccharide. This approach was extended to the preparation of two novel (+)- and
(ꢀ)-muricatacin 7-oxa analogs (2 and ent-2, respectively), which showed in vitro antitumor activity toward some human malignant cells.
The analog ent-2 showed a powerful antiproliferative activity against the K562 cell line, being 36-fold more potent than the standard cytotoxic
agent, doxorubicin. Compound 2, however, showed a powerful cytotoxic activity against HL-60 cells, being more than 17-fold more potent
with respect to the reference compound.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
them were found to be too toxic for general clinical applica-
tions. On the contrary, the corresponding L-configuration
counterparts are not recognized by normal cellular enzymes
and are less toxic to normal cells.2 A number of biologically
active natural products comprised of both (+)- and (ꢀ)-enan-
tiomers have been described.3,4 One such molecule that has
attracted considerable attention since its isolation from the
seeds of the tropical plant Anona muricata4 is muricatacin
(5-hydroxy-4-heptadecanolide), an acetogenin derivative
that shows strong cytotoxic activity against certain human
tumor cell lines. The isolated sample was a mixture of enan-
tiomers 1 and ent-1 (Scheme 1) with the (ꢀ)-(R,R)-isomer
Development of efficient chemical pathways that allow the
preparation of both enantiomers of compounds of biomedi-
cinal interest is an important goal in the synthetic organic
chemistry. Enantiomers of biologically active natural prod-
ucts often exhibit improved potencies or even novel activi-
ties altogether. For example, the unnatural (ꢀ)-enantiomer
of the antitumor, antibiotic roseophilin is 2–10 times more
potent than the natural (+)-isomer in cytotoxicity assays.1
Numerous nucleoside analogs of natural D-configuration dis-
played a potent antitumor or antiviral activity, but most of
OR1
OR1
1
OH
5
4
2
3
1
5
3
R
R
2
4
3
OH
O
O
O
i, ii
iii, iv
OH
OH
O
O
ent-1 R = C12H25; R1 = H
1 R = C12H25; R1 = H
2 R = CH2OC10H21;R1 = H
3 R = CHO; R1 = Bn
D-Xylose
(Latent plane of symmetry)
ent-2 R = CH2OC10H21; R1 = H
ent-3 R = CHO; R1 = Bn
ent-4 R = CH2OH; R1 = H
4 R = CH2OH; R1 = H
Scheme 1. Enantiodivergent strategy for the preparation of (+)- and (ꢀ)-muricatacin related lactones by chirality transfer from D-xylose (sugar numbering). (i)
‘CH2CO2R’—introduction at C-1 followed by g-lactonization, (ii) oxidative glycol cleavage of the C4–C5 bond, (iii) ‘CH2CO2R’—elongation at C-5 followed
by g-lactonization, (iv) C1–C2 glycol cleavage.
* Corresponding author. Tel.: +381 21 485 27 68; fax: +381 21 454 065; e-mail: popsavin@ih.ns.ac.yu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.054

V. Popsavin et al. / Tetrahedron 62 (2006) 11044–11053
11045
ent-1 being predominant (ee, ca. 25%). Both (+)- and
(ꢀ)-muricatacins show similar antitumor potency,4,5 and
not surprisingly were the object of numerous synthetic ef-
forts. Syntheses of (+)- and/or (ꢀ)-muricatacin from various
non-carbohydrate precursors have been reported,5,6 along
with a number of carbohydrate based approaches,7,8 most
being target oriented. Hence, development of new and flex-
ible strategy that would enable the preparation of not only
both enantiomers 1 and ent-1, but also a variety of their iso-
steric analogs is still demanded. A number of muricatacin
stereoisomers and analogs have also been synthesized,9,10
but only a few have been evaluated for their antitumor activ-
ity.10 Herein we report a novel general approach to the enan-
tiodivergent formal synthesis of (+)- and (ꢀ)-muricatacins
from D-xylose11 based on the latent symmetry concept,12
as well as the preparation and antitumor screening of two
novel (+)- and (ꢀ)-muricatacin 7-oxa analogs 2 and ent-2.
D-xylose derivative, should provide access to the aldehydo-
lactone ent-3 bearing the C3–C4 chiral segment of D-xylose.
It was further assumed that both intermediates 3 and ent-3
could be converted to the targets 1 and ent-1 by a Wittig
elongation/catalytic reduction process. Alternatively, the
chiral synthons 3 and ent-3 may be first converted to the di-
hydroxylactones 4 and ent-4 and finally to the targets 1 and
ent-1 via a known two-step sequence.8 Moreover, we have
also planned to adopt this enantiodivergent strategy for the
preparation of both enantiomeric forms of hitherto unknown
muricatacin 7-oxa analogs 2 and ent-2 via the hydroxyl-
actones 12 (Scheme 2) and ent-12 (Scheme 3).
The formal synthesis of 1, along with the preparation of
corresponding 7-oxa-analog 2 is summarized in Scheme 2.
The sequence started from 5-O-benzoyl-3-O-benzyl-1,2-O-
cyclohexylidene-a-D-xylofuranose (5), which is prepared
from D-xylose in four steps.13 Hydrolytic removal of the
cyclohexylidene protective group in 5 with aq acetic acid,
gave the corresponding lactol 6. Wittig olefination of 6
with methyl(triphenylphosphoranylidene)-acetate in DMF
took place stereoselectively to afford the (E)-unsaturated es-
ter 7 (83%) as the only isolable product. The E-selectivity of
this step was essential, because it is well known that similar
(Z)-a,b-unsaturated esters rapidly undergo a sequential
lactonization/Michael ring-closure process.16 Catalytic
hydrogenation of 7 over PtO2 in ethanol yielded the corre-
sponding saturated ester 8, which upon treatment with aq
trifluoroacetic acid gave hydroxylactone 9 in excellent
yield. Sodium methoxide O-debenzoylation of 9 furnished
a moderate yield of dihydroxylactone 10. By using the last
two-step sequence ester 8 was converted to lactone 10 in
51% overall yield. However, we found that direct treatment
of 8 with sodium methoxide in methanol provides the de-
sired intermediate 10 in significantly higher yield (82%).
2. Results and discussion
Our enantiodivergent strategy relies on the synthesis of both
enantiomeric forms of aldehydo-lactone 3 from D-xylose. As
outlined in Scheme 1, (+)-muricatacin (1) might be prepared
by a sequence that will ensure the introduction of the C-2 and
C-3 stereocenters of D-xylose into the target structure 1 via
the aldehydo-lactone 3. It was further assumed that the inter-
mediate 3 should be available from a suitably protected
D-xylose derivative through the following several key steps:
(i) ‘CH2CO2R’—introduction at C-1 followed by g-lactoni-
zation and (ii) oxidative glycol cleavage of the C4–C5 bond.
Due to the latent plane of symmetry present in the starting
monosaccharide an alternative sequence, which involves
(iii) ‘CH2CO2R’—elongation at C-5 followed by g-lactoni-
zation and (iv) C1–C2 glycol cleavage in a suitably protected
BzO
BzO
OMe
OBn OBz
OMe
OBn OBz
O
a
b
c
O
OH
OH
O
O
O
OH OH
OH OH
BnO
O
BnO
7
5
6
8
d or e
OBn
OBn
OBn OR
OH
OBn
3
O
(CH2)8Me
OH
4
j
h
f
5
CHO
2
1
O
O
O
O
O
O
O
O
14
12
3
9 R = Bz
10 R = H
e
g
i
i
(CH2)8Me
OH
OH
OBn
OMe
OBn
O
(CH2)8Me
OH
O
O
O
O
OH OH
13
O
O
O
2
4
11
Scheme 2. (a) 7:3 AcOH/H2O, reflux, 5.5 h, 85%; (b) Ph3P/CHCO2Me, DMF, 60–70 ꢁC, 3.5 h, 84%; (c) H2/PtO2, EtOH, rt, 16 h, 75%; (d) 2:1 TFA/H2O, rt,
2.5 h, 92%; (e) NaOMe, MeOH, rt, 1.5 h, 55% from 9, 82% from 8; (f) aq NaIO4, silica gel, CH2Cl2, rt, 1 h, 89%; (g) [Ph3PCH2(CH2)9Me]+Brꢀ, LiHMDS, THF,
ꢀ78 ꢁC/rt, 72 h, 7%; (h) (i) NaBH4, MeOH, 0 ꢁC/rt, 1.5 h, (ii) TFA, 2 h, 73%; (i) H2-Pd/C, EtOAc, rt, 19 h, 69% of 4, 82% of 2; (j) C10H21Br, Ag2O, AgOTf,
Et2O, reflux, 7.5 h, 80%.

11046
V. Popsavin et al. / Tetrahedron 62 (2006) 11044–11053
R1O
CO2Me
O
CO2Me
O
O
O
O
c
b
d
O
O
O
O
O
O
BnO
RO
O
O
BnO
BnO
15 R = H; R1 = Bz
16 R = Bn; R1 = H
17
18
a
19
e
OH
OBn
CHO
CO2Me
O
OBn
O
OH
g
h
f
O
5
3
OH
OH
6
4
2
1
OCHO
MeO
O
O
O
O
BnO
ent-4
ent-3
22
20
i
OBn
OBn
OH
CO2H
O
OH
O
(CH2)8Me
O
(CH2)8Me
j
k
OH
OH
O
O
O
O
O
O
BnO
ent-12
ent-14
ent-2
21
Scheme 3. (a) (i) BnBr, NaH, DMF, 0 ꢁC/rt, 2.5 h, (ii) NaOMe, MeOH, rt, 2 h, 89%; (b) DCC, anhyd H3PO4, Py, DMSO, rt, 3.5 h, 83%; (c) Ph3P/CHCO2Me,
CH2Cl2, N2, rt, 2 h, 97%; (d) H2/PtO2, EtOH, rt, 19 h, 92%; (e) 1:1 AcOH/H2O, reflux, 1.5 h, 64% of 20, 7% of 21; (f) aq NaIO4, silica gel, CH2Cl2, rt, 1.5 h,
98%; (g) 2:1 TFA/H2O, rt, 1.5 h, 77% from 20; (h) (i) NaBH4, MeOH, 0 ꢁC/rt, 2.5 h, (ii) TFA, 1 h, (iii) H2-Pd/C, 19 h, 71%; (i) (i) NaBH4, MeOH, 0 ꢁC/rt,
2 h, (ii) TFA, 1 h, 68% from 20; (j) C10H21Br, Ag2O, AgOTf, Et2O, reflux, 5.5 h, 71%; (k) H2/PtO2, EtOH, rt, 19 h, 87%.
1
Oxidative cleavage of the diol functionality in 10 was
achieved by treatment with NaIO4-impregnated wet silica
in dichloromethane, whereby the aldehydo-lactone 3 was
obtained. In the light of its stereochemical features the
molecule 3 fully corresponds to the chiral lactone core of
(+)-muricatacin (1).
ester 13, as established from H NMR of crude reaction
mixture.18 The mixture was not separated, but was further
treated with aq trifluoroacetic acid to complete the lactoniza-
tion of ester 13 into lactone 12. The intermediate 12 was thus
obtained in a 73% overall yield with respect to the starting
compound 10 (based on recovered intermediate 3). Catalytic
hydrogenolysis of 12 (10% Pd/C) furnished the known diol
4, which was recently used a convenient intermediate for the
preparation of conformationally constrained analogs of di-
With the requisite intermediate 3 in hand, we next focused
on its C11-elongation in order to elaborate the muricatacin
side chain. According to the initial plan, Wittig olefination
of aldehyde 3 with the appropriate C11-ylide should enable
us to resolve this problem. However, reaction of 3 with
Ph3P]CH(CH2)Me results in complex mixtures of products
under a variety of experimental conditions, possibly because
of the electrophilic nature of the lactone moiety. The best
experimental protocol, which provides a poor yield (7%) of
the desired olefin 11, involved a reaction of aldehyde 3 with
the Wittig reagent generated in situ from undecyltriphenyl-
phosphonium bromide and LiHMDS in THF at ꢀ78 ꢁC.17
Disappointingly, all attempts to improve the outcome of
this transformation were unsuccessful. We were therefore
forced to find an alternative methodology for elaboration of
the muricatacin side chain. According to the plan presented
in Scheme 1, conversion of aldehyde 3 to the corresponding
diol 4 represents a possible alternative route for completion
of the synthesis.
acylglycerol.19 The H and 13C NMR spectral data and the
optical rotation of diol 4 thus obtained were in full agree-
ment with reported values.19 Compound 4 can be converted
to (+)-muricatacin according to the reported procedure.8
1
Hydroxylactone 12 also represents a divergent intermediate
for the preparation of (+)-muricatacin 7-oxa analog 2. Thus,
O-alkylation of 12 with decyl bromide gave the correspond-
ing 7-O-decyl derivative 14 (80%), which was subsequently
O-debenzylated, under the conditions similar to those al-
ready used for the conversion of 12 to 4. (+)-Muricatacin
7-oxa-analog 2 was thus obtained in 82% yield.
The 5-O-benzoyl-1,2-O-cyclohexylidene-a-D-xylofuranose
(15), readily available from D-xylose,14,15 was used as a start-
ing material for the formal synthesis of (ꢀ)-muricatacin
(ent-1), as well as for the preparation of its 7-oxa-analog
ent-2 (Scheme 3). Compound 15 was converted to the pri-
mary alcohol 16 through a simple one-pot procedure, which
involved 3-O-benzylation of 15 (BnBr, NaH, DMF) fol-
lowed by 5-O-debenzoylation of 5 (NaOMe, MeOH). The
intermediate 16 was thus obtained in 89% overall yield
with respect to 15. Oxidation of the primary hydroxyl group
in 16 gave the unstable20 aldehyde 17 (83%), which upon
treatment with methyl(triphenylphosphoranylidene)-acetate
The preparation of 4 began with the synthesis of the primary
alcohol 12 from dihydroxylactone 10. Oxidative cleavage of
the terminal diol in 10 provided the aldehydo-lactone 3,
which was isolated in pure form after the usual work-up
and used in the next step without further purification. Subse-
quent reduction of crude 3 with sodium borohydride gave the
expected primary alcohol 12 along with an equal amount of

V. Popsavin et al. / Tetrahedron 62 (2006) 11044–11053
Table 1. In vitro cytotoxicity of 2, ent-2, and DOX
11047
in dry dichloromethane afforded the expected unsaturated
ester 18 as a 2:1 mixture of the corresponding Z- and E-iso-
mers. Catalytic hydrogenation of 18, followed by hydrolytic
removal of the cyclohexylidene protective group in 19, gave
a 64% yield of the corresponding lactol 20 (based on recov-
ered 19), accompanied with a small amount of the carboxylic
acid 21 (7%). In an alternative procedure the crude mixture
obtained after hydrolysis of 19 was treated with an ethereal
solution of diazomethane to convert the carboxylic acid 21 to
the ester 20. In this way, the required intermediate 20 was
obtained in 81% yield. Oxidative cleavage of purified diol
20 with sodium periodate on silica gel afforded the formate
22, which upon treatment with aq trifluoroacetic acid yielded
the g-lactone ent-3, with absolute configuration of both
stereocenters corresponding to (ꢀ)-muricatacin (ent-1).
Spectral data (1H and 13C NMR) and physical constants
([a]D and Rf) of ent-3 thus obtained were in full agreement
with values recorded for the opposite enantiomer 3.
Compds
IC50, mMa
K562
HL-60
JURKAT
HeLa
MCF-7
2
1.96
0.01
0.36
0.26
2.96
4.62
4.89
1.06
0.39
>100
>100
ent-2
DOX
23.58
1.17
31.55
0.75
a
IC50 is the concentration of compound required to inhibit the cell growth
by 50% compared to an untreated control.
respect to those observed for the reference compound,
DOX. The opposite enantiomer ent-2 showed a powerful
cytotoxic activity against K562 cells being 36-fold more
potent than doxorubicin. Against the HL-60 cell line, this
compound exhibited a significant antiproliferative activity,
which was 35% higher than that observed for doxorubicin.
This analog was also active against the JURKAT, HeLa,
and MCF-7 cells but with respective IC50 values being
over 2-, 20- and 40-fold higher than those observed for the
reference compound.
The intermediate ent-3 was converted to dihydroxylactone
ent-4 by the newly developed one-pot procedure comprised
of previous sodium borohydride reduction of ent-3 to the
corresponding primary alcohol (not shown in the reaction
scheme), followed by a subsequent hydrogenolytic removal
of benzyl ether protective group in the intermediate under
the acidic conditions (10% Pd/C, 2:1 TFA/MeOH). This pro-
cedure provided the desired intermediate ent-4 in 71% over-
all yield. The 1H and 13C NMR spectral data, as well as the
value of optical rotation for ent-4 were fully consistent with
those reported previously.8 Since the conversion of diol ent-4
to (ꢀ)-muricatacin through a three-step sequence has been
previously reported by Saniere et al.,8 the preparation of
ent-4 formally represents a novel synthesis of (ꢀ)-muricata-
cin (ent-1) from D-xylose.
3. Conclusions
In conclusion, a new and general strategy for the synthesis of
enantiopure 5-hydroxyalkylbutan-4-olides by chirality
transfer from D-xylose has been developed. The synthetic
pathway that furnished with the preparation of (+)- and
(ꢀ)-5,6-dihydroxy-4-hexanolides 4 and ent-4 formally rep-
resents a new enantiodivergent synthesis of (+)- and (ꢀ)-
muricatacins from D-xylose. This approach has been applied
for the preparation of hitherto unknown (+)- and (ꢀ)-muri-
catacin 7-oxa analogs 2 and ent-2, which showed powerful
antiproliferative activities against some malignant cells. In
addition to providing access to both enantiomers of 1 and
2, this enantiodivergent approach is flexible and straightfor-
ward. It uses non-expensive reagents and a readily available
starting material. These advantages make the synthetic
methodology suitable for easy preparation of a variety of
muricatacin analogs in both enantiomeric series for biologi-
cal evaluation.
Moreover, the aldehydo-lactone ent-3 was converted to the
(ꢀ)-muricatacin 7-oxa-analog (ent-2) through a three-step
sequence similar to that already used for the conversion of
3 to 2. Thus, sodium borohydride reduction of the aldehyde
group in ent-3 gave the primary alcohol ent-12, which was
subsequently converted to the 7-O-decyl derivative ent-14
after reaction with decyl bromide in refluxing ether, in pres-
ence of Ag2O and AgOTf as catalysts. Hydrogenolytic re-
moval of benzyl ether protective group in ent-14 furnished
the target ent-2 to be ready for biological testing.
4. Experimental
4.1. General methods
€
Melting points were determined on a Buchi 510 apparatus
and were not corrected. Optical rotations were measured on
2.1. Evaluation of cytotoxic activity
€
Compounds 2 and ent-2 were evaluated for their in vitro
cytotoxicity against human myelogenous leukemia K562,
promyelocytic leukemia HL-60, human T-cell leukemia
(JURKAT), cervix carcinoma HeLa, and estrogen receptor
positive breast adenocarcinoma MCF-7 cell line. Cytotoxic
activity was evaluated by using MTT assay,21 after exposure
of cells to the tested compounds for 48 h. Standard cytotoxic
agent doxorubicin (DOX) was used as a positive control in
this assay. The results are presented in Table 1.
P 3002 (Kruss) and Polamat A (Zeiss, Jena) polarimeters in
chloroform solutions at room temperature. IR spectra were
recorded with Specord 75 (Carl–Zeiss) and Nexus 670
(Thermo Nicolet, DTGS-detector) IR spectrophotometers.
NMR spectra were recorded on a Bruker AC 250 E instru-
ment and the chemical shifts (d-scale) are expressed in parts
per million values downfield from tetramethylsilane. Chem-
ical ionization mass spectra were recorded on Finnigan-MAT
8230 spectrometer with isobutane as a reagent gas. TLC was
performed on DC Alufolien Kieselgel 60 F254 (E. Merck).
Flash column chromatography was performed using Kiesel-
gel 60 (0.040–0.063 mm, E. Merck). All organic extracts
were dried with anhydrous Na2SO4. Organic solutions were
concentrated in a rotary evaporator under diminished pres-
sure at a bath temperature below 35 ꢁC.
Compound 2 showed a powerful antiproliferative activity
against the HL-60 cell line, being over 17-fold more potent
with respect to doxorubicin. This analog was also active
against the K562 and JURKAT cells, but the respective
IC50 values were more than 5- and 12-fold higher with

11048
V. Popsavin et al. / Tetrahedron 62 (2006) 11044–11053
4.1.1. 5-O-Benzoyl-3-O-benzyl-D-xylofuranose (6).
A
2ꢂH-3), 2.49 (m, 2H, 2ꢂH-2), 2.72 (d, 1H, J4,OH¼6.5 Hz,
exchangeable with D2O, OH-4), 3.06 (d, 1H, J6,OH¼5.9 Hz,
exchangeable with D2O, OH-6), 3.48 (dd, 1H, J4,5¼4.0,
J5,6¼3.1 Hz, H-5), 3.67 (s, 3H, CO2Me), 3.88 (m, 1H,
solution of 5 (3.644 g, 8.58 mmol) in 70% aq AcOH was
stirred for 5.5 h at reflux. After the mixture cooled to room
temperature it was concentrated by co-distillation with tolu-
ene and the residue purified by flash column chromato-
graphy (3:2 toluene/EtOAc), to afford pure 6 (2.517 g,
85%) as a colorless solid. Recrystallization from CH2Cl2/
hexane gave an analytical sample 6 as colorless needles,
mp 59–60 ꢁC, [a]D23 ꢀ18.1/+4.2 (24 h, c 1.0, CHCl3),
H-4), 4.17 (m, 1H, H-6), 4.41 (dd, 1H, J6,7a¼5.0, J7a,7b
¼
11.5 Hz, H-7a), 4.47 (dd, 1H, J6,7b¼6.7, J7a,7b¼11.5 Hz,
H-7b), 4.73 (s, 2H, PhCH2), 7.28–8.09 (m, 10H, 2ꢂPh).
13C NMR (CDCl3): d 29.0 (C-3), 30.49 (C-2), 51.65
(CO2Me), 66.12 (C-7), 70.22 (C-6), 71.15 (C-4), 75.11
(PhCH2), 80.9 (C-5), 128.16, 128.38, 128.42, 128.47,
128.56, 129.63, 133.15 and 137.39 (2ꢂPh), 166.56
(PhCO), 174.27 (CO2Me). MS (CI): m/z 403 (MH+), 371
(M+ꢀOMe). Anal. Found: C, 66.02; H, 6.21. Calcd for
C22H26O7: C, 65.66; H, 6.51.
1
Rf ¼0.68 (Et2O), anomeric ratio: a/b¼3:1 (from H NMR
spectrum recorded immediately after dissolution of the sam-
ple). IR (KBr): nmax 3420 (OH), 1720 (C]O), 1600 (Ph). 1H
NMR (CDCl3+D2O): d 4.05 (br s, 0.25H, J2,3¼1.3, J3,4
¼
3.5 Hz, H-3b), 4.09 (dd, 0.75H, J2,3¼2.9, J3,4¼4.8 Hz,
H-3a), 4.24 (dd, 0.75H, J1,2¼3.8 Hz, H-2a), 4.33 (br s,
0.25H, H-2b), 4.41–4.78 (m, 4H, PhCH2, H-4b, H-4a,
H-5b and H-5a), 5.27 (br s, 0.25H, H-1b), 5.56 (d, 0.75H,
J1,2¼3.8 Hz, H-1a), 7.18–8.09 (m, 10H, 2ꢂPh). 13C NMR
(CDCl3): d 63.61 (C-5a), 64.12 (C-5b), 71.94 (PhCH2-a),
72.51 (PhCH2-b), 75.02 (C-2a), 76.35 (C-4a), 77.50
(C-2b), 79.08 (C-4b), 82.07 (C-3b), 82.85 (C-3a), 96.26
(C-1a), 103.36 (C-1b), 127.49, 127.59, 127.73, 127.82,
127.89, 128.19, 128.28, 128.39, 128.46, 128.56, 129.61,
129.72, 129.98, 133.05 and 137.34 (2ꢂPh), 166.49
(C]O). MS (CI): m/z 401 (M+ꢀH+C4H10), 383
(M+ꢀOH+C4H10), 345 (MH+), 327 (M+ꢀOH), 237
(M+ꢀOBn). Anal. Found: C, 66.53; H, 6.06. Calcd for
C19H20O6: C, 66.27; H, 5.85.
4.1.4. 7-O-Benzoyl-5-O-benzyl-2,3-dideoxy-D-xylo-hep-
tono-1,4-lactone (9). A solution of 8 (0.127 g, 0.31 mmol)
in a mixture of TFA (2 mL) and water (1 mL) was stirred
at room temperature for 2.5 h. The volatiles were removed
by co-distillation with toluene and the residue purified by
flash column chromatography (4:1 CH2Cl2/EtOAc) to give
pure 9 (0.106 g, 92%) as a colorless oil, [a]2D3 ꢀ19.3
(c 0.99, CHCl3), Rf ¼0.46 (4:1 CH2Cl2/EtOAc). IR (film):
nmax 3450 (OH), 1780 (C]O, lactone), 1710 (C]O, Bz),
1
1600 (Ph). H NMR (CDCl3): d 1.82–2.41 (m, 2H, 2ꢂ
H-3), 2.61 (m, 2H, 2ꢂH-2), 3.15 (s, 1H, exchangeable
with D2O, OH), 3.60 (dd, 1H, J4,5¼5.8, J5,6¼3.1 Hz, H-5),
4.11 (m, 1H, H-6), 4.37 (dd, 1H, J6,7a¼5.2, J7a,7b¼11.5 Hz,
H-7a), 4.49 (dd, 1H, J6,7b¼6.7, J7a,7b¼11.5 Hz, H-7b), 4.73
and 4.85 (2ꢂd, 2H, Jgem¼11.6 Hz, PhCH2), 4.82 (m, 1H,
H-4), 7.29–8.05 (m, 10H, 2ꢂPh). 13C NMR (CDCl3):
d 24.52 (C-3), 28.24 (C-2), 65.85 (C-7), 69.06 (C-6), 74.18
(PhCH2), 79.73 (C-5), 80.83 (C-4), 127.91, 128.0, 128.15,
128.25, 128.32, 129.46, 133.08 and 137.21 (2ꢂPh), 166.4
(PhCO), 176.89 (C-1). MS (CI): m/z 371 (MH+).
4.1.2. Methyl 7-O-benzoyl-5-O-benzyl-2,3-dideoxy-D-xylo-
hept-2-enonate (7). To a solution of 6 (1.985 g, 5.76 mmol)
in dry DMF (37 mL) was added Ph3P]CHCO2Me (2.508 g,
7.5 mmol). The mixture was stirred for 3.5 h at 60–70 ꢁC
and then evaporated. The residue was purified by flash
column chromatography (Et2O) to afford pure 7 (1.948 g,
84%) as a colorless syrup, [a]2D3 ꢀ13.8 (c 1.0, CHCl3),
i
Rf ¼0.5 (4:1 Pr2O/EtOAc). IR (KBr): nmax 3450 (OH),
4.1.5. 5-O-Benzyl-2,3-dideoxy-D-xylo-heptono-1,4-
lactone (10). Procedure A: a solution of 9 (0.107 g,
0.29 mmol) in 0.09 M methanolic NaOMe (0.6 mL,
0.06 mmol) was stirred for 1 h at room temperature. An addi-
tional amount of 0.09 M NaOMe in MeOH (0.3 mL,
0.03 mmol) was added to the reaction mixture and stirring
was continued for the next 1 h at room temperature. The mix-
ture was neutralized with 1 M AcOH in MeOH (0.09 mL,
0.09 mmol) and evaporated. Flash column chromatography
(4:1/1:4 CH2Cl2/EtOAc) of the residue gave pure 10
(0.043 g, 55%) as a colorless syrup, Rf ¼0.31 (EtOAc).
1
1700 (C]O), 1620 (C]C), 1600 (Ph). H NMR (CDCl3):
d 3.33 (br s, 2H, exchangeable with D2O, 2ꢂOH), 3.63 (t,
1H, J4,5¼J5,6¼3.8 Hz, H-5), 3.74 (s, 3H, CO2Me), 4.15
(m, 1H, H-6), 4.36 (dd, 1H, J6,7a¼4.8, J7a,7b¼11.5 Hz, H-
7a), 4.46 (dd, 1H, J6,7b¼6.8, J7a,7b¼11.5 Hz, H-7b), 4.62
(m, 1H, H-4), 4.64 and 4.72 (2ꢂd, 2H, Jgem¼11.2 Hz,
PhCH2), 6.20 (dd, 1H, J2,4¼1.9, J2,3¼15.6 Hz, H-2), 7.07
(dd, 1H, J3,4¼4.4, J2,3¼15.6 Hz, H-3), 7.22–8.06 (m, 10H,
2ꢂPh). 13C NMR (CDCl3): d 51.68 (CO2Me), 65.82 (C-7),
70.23 (C-6), 71.19 (C-4), 74.75 (PhCH2), 79.96 (C-5),
121.25 (C-2), 128.21, 128.29, 128.37, 128.52, 129.49,
129.61, 133.22 and 136.97 (2ꢂPh), 147.39 (C-3), 166.63
and 166.81 (C-1 and PhC]O). MS (CI): m/z 401 (MH+),
369 (M+ꢀOMe). Anal. Found: C, 66.25; H, 5.88. Calcd
for C22H24O7: C, 65.99; H, 6.04.
Procedure B: a solution of 8 (1.458 g, 3.62 mmol) in 0.09 M
methanolic NaOMe (6.9 mL, 0.63 mmol) was stirred for
1.5 h at room temperature, then acidified with 2:1 aq TFA
(0.08 mL) and concentrated by co-distillation with toluene.
Flash column chromatography (EtOAc) of the residue gave
pure 10 (0.7932 g, 82%) as a colorless oil, [a]2D3 +3.0 (c
1.06, CHCl3), Rf ¼0.31 (EtOAc). IR (film): nmax 3400
4.1.3. Methyl 7-O-benzoyl-5-O-benzyl-2,3-dideoxy-D-xylo-
heptonate (8). A solution of 7 (0.554 g, 1.38 mmol) in EtOH
(11 mL) was hydrogenated over PtO2 (8 mg) for 16 h at
room temperature. The mixture was filtered and the catalyst
washed with EtOH. The organic solution was evaporated
and the residue was purified by flash column chromato-
1
(OH), 1750 (C]O), 1610 (Ph). H NMR (CDCl3+D2O):
d 1.91 and 2.25 (2ꢂm, 2H, 2ꢂH-3), 2.35 (m, 2H, 2ꢂH-2),
3.49 (t, 1H, J4,5¼J5,6¼4.9 Hz, H-5), 3.60 (dd, 1H,
J6,7a¼5.2, J7a,7b¼11.6 Hz, H-7a), 3.67 (dd, 1H, J6,7b¼5.2,
J7a,7b¼11.6 Hz, H-7b), 3.81 (m, 1H, H-6), 4.62–4.83 (m,
3H, PhCH2 and H-4), 7.24–7.4 (m, 5H, Ph). 13C NMR
(CDCl3): d 24.49 (C-3), 28.24 (C-2), 63.54 (C-7), 70.98
(C-6), 74.41 (PhCH2), 80.70 (C-5), 80.73 (C-4), 128.09,
i
graphy (9:1 Pr2O/EtOAc) to afford pure 8 (0.419 g, 75%)
as a colorless syrup, [a]2D3 ꢀ12.8 (c 1.0, CHCl3), Rf ¼0.36
(4:1 iPr2O/EtOAc). IR (film): nmax 3470 (OH), 1720
(C]O), 1600 (Ph). 1H NMR (CDCl3): d 1.89 (m, 2H,

V. Popsavin et al. / Tetrahedron 62 (2006) 11044–11053
11049
128.17, 128.5 and 137.43 (Ph), 177.32 (C-1). MS (CI): m/z
267 (MH+). Anal. Found: C, 63.43; H, 6.63. Calcd for
C14H18O5: C, 63.15; H, 6.81.
and the residue purified by flash column chromatography
(4:1 CH2Cl2/EtOAc). The unchanged aldehyde 3 (0.015 g,
12%) was first eluted, followed by pure 12 (0.082 g, 73%
on the basis of the recovered intermediate 3) that was
isolated as a colorless oil, [a]2D3 +22.9 (c 1.09, CHCl3),
Rf ¼0.24 (4:1 CH2Cl2/EtOAc). IR (film): nmax 3450 (OH),
1770 (C]O). 1H NMR (CDCl3): d 1.87–2.32 (m, 2H,
2ꢂH-3), 2.36–2.85 (m, 3H, 2ꢂH-2 and OH), 3.50 (m, 1H,
H-5), 3.70 (dd, 1H, J5,6a¼4.9, J6a,6b¼11.6 Hz, H-6a), 3.79
(dd, 1H, J5,6b¼5.3, J6a,6b¼11.6 Hz, H-6b), 4.65 and 4.73
(2ꢂd, 2H, Jgem¼11.6 Hz, PhCH2), 4.70 (m, 1H, H-4),
7.28–7.45 (m, 5H, Ph). 13C NMR (CDCl3): d 24.08 (C-3),
28.22 (C-2), 60.93 (C-6), 72.99 (PhCH2), 80.22 (C-4),
80.51 (C-5), 127.79, 127.86, 128.4 and 137.71 (Ph),
177.36 (C]O). MS (CI): m/z 473 (2M++H), 237 (MH+).
4.1.6. 6-Aldehydo-5-O-benzyl-2,3-dideoxy-L-threo-hex-
ono-1,4-lactone (3). To a solution of 10 (0.793 g,
2.98 mmol) in CH2Cl2 (11 mL) was added Kieselgel 60
(6.0 g, 0.063–0.2 nm) and 0.65 M aq NaIO4 (6.0 mL,
3.90 mmol). The resulting heterogeneous mixture was vigor-
ously stirred for 1 h at room temperature then filtered and
evaporated. Flash column chromatography (2:1 toluene/
EtOAc), followed by crystallization from CH2Cl2/hexane
gave an analytical sample 3 (0.621 g, 89%) as colorless nee-
dles, mp 93–94 ꢁC, [a]D23 +135.8 (c 1.08, CHCl3), Rf ¼0.3
(2:1 toluene/EtOAc). IR (film): nmax 1770 (C]O, lactone),
1
1720 (CH]O). H NMR (CDCl3): d 1.92–2.68 (m, 4H,
2ꢂH-2 and 2ꢂH-3), 3.78 (dd, 1H, J4,5¼2.7, J5,6¼1.5 Hz,
H-5), 4.58 (d, 1H, Jgem¼11.9 Hz, PhCHa), 4.74–4.85 (m,
2H, H-4 and PhCHb), 7.33 (m, 5H, Ph), 9.68 (d, 1H, H-6).
13C NMR (CDCl3): d 23.38 (C-3), 27.61 (C-2), 73.33
(PhCH2), 78.69 (C-4), 83.88 (C-5), 128.2, 128.52, 128.69
and 136.76 (Ph), 176.57 (C-1), 201.57 (C-6). MS (CI): m/z
469 (2M++H), 235 (MH+). Anal. Found: C, 66.30; H, 6.00.
Calcd for C13H14O4: C, 66.66; H, 6.02.
4.1.9. 2,3-Dideoxy-L-threo-hexono-1,4-lactone (4). A solu-
tion of 12 (0.082 g, 0.35 mmol) in EtOAc (1.7 mL) was
hydrogenated over 10% Pd/C (0.041 g) for 18 h at room
temperature. The mixture was filtered and the catalyst
washed successively with EtOAc and MeOH. The combined
organic solutions were evaporated and the residue was puri-
fied by flash column chromatography (EtOAc) to afford pure
4 (0.035 g, 69%) as a colorless syrup, [a]D +58.0 (c 2.01,
MeOH), lit.19 [a]D +58.18 (c 2.03, MeOH), Rf ¼0.22
(EtOAc). IR (film): nmax 3384 (OH), 1759 (C]O). 1H
NMR (CDCl3): d 2.26 (m, 2H, 2ꢂH-3), 2.57 (m, 2H,
2ꢂH-2), 3.46–3.84 (m, 4H, H-5, 2ꢂH-6 and OH), 4.14 (br
s, 1H, OH), 4.59 (m, 1H, H-4). 13C NMR (CDCl3): d 23.9
(C-3), 28.45 (C-2), 63.27 (C-6), 73.56 (C-5), 80.77 (C-4),
178.21 (C-1).
4.1.7. (Z)-6-C-Decylidene-5-O-benzyl-2,3-dideoxy-L-threo-
hexono-1,4-lactone (11). To a stirred suspension of undecyl-
triphenylphosphonium bromide (0.716 g, 1.44 mmol) in dry
THF (5 mL) was added a 1 M solution of LiHMDS in dry
THF (1.44 mL, 1.44 mmol) dropwise over a period of
5 min at 0 ꢁC under N2. The bright red solution was stirred
for another 15 min, cooled to ꢀ78 ꢁC, and a solution of
the aldehyde 3 (0.1698 g, 0.72 mmol) in dry THF (1.5 mL)
was instantly added. The mixture was stirred for 3 h at
ꢀ78 ꢁC, while it was allowed to warm to room temperature.
The light yellow mixture was stirred at room temperature for
72 h, then quenched with 10% aq NH4Cl (5 mL), and
extracted with Et2O. The combined organic phases were
washed with brine, dried, and evaporated. Flash column
chromatography of the residue (2:1 toluene/EtOAc) gave
pure (Z)-olefin 11 (0.0175 g, 7%) as a colorless oil, [a]D23
+40.2 (c 0.74, CHCl3), Rf ¼0.45 (9:1 toluene/EtOAc). IR
4.1.10. 5-O-Benzyl-6-O-decyl-2,3-dideoxy-L-threo-hex-
ono-1,4-lactone (14). To a solution of 12 (0.101 g,
0.43 mmol) in dry Et2O (2 mL) were added successively
Ag2O (0.249 g, 1.07 mmol), AgOTf (0.028 g, 0.11 mmol),
and C10H21Br (0.44 mL, 2.13 mmol). The mixture was
stirred under reflux for 7.5 h, then diluted with CH2Cl2
(10 mL), filtered, and evaporated. The residue was purified
by flash column chromatography (CH2Cl2) to give pure 14
(0.129 g, 80%) a colorless oil, [a]2D3 +30.2 (c 1.05, CHCl3),
1
Rf¼0.24 (CH2Cl2). IR (film): nmax 1779 (C]O). H NMR
1
(film): nmax 1780 (C]O). H NMR (CDCl3): d 0.89 (t,
(CDCl3): d 0.88 (t, 3H, Me), 1.16–1.65 (m, 16H, 8ꢂCH2),
1.93–2.31 (m, 2H, 2ꢂH-3), 2.32–2.67 (m, 2H, 2ꢂH-2),
3.44 (t, 2H, J¼6.6 Hz, 2ꢂH-8), 3.60 (m, 3H, H-5 and
2ꢂH-6), 4.60 and 4.77 (2ꢂd, 2H, Jgem¼11.8 Hz, PhCH2),
4.70 (m, 1H, H-4), 7.24–7.41 (m, 5H, Ph). 13C NMR
(CDCl3): d 13.97 (Me), 22.52, 23.89, 25.98, 28.18, 29.17,
29.29, 29.41, 29.45, 29.49 and 31.74 (8ꢂCH2, C-2 and
C-3), 69.61 (C-6), 71.64 (C-8), 72.77 (PhCH2), 78.9 (C-5),
79.67 (C-4), 127.65, 127.70, 128.26 and 137.90 (Ph),
177.34 (C-1). MS (CI): m/z 377 (MH+). Anal. Found: C,
73.18; H, 9.50. Calcd for C23H36O4: C, 73.37; H, 9.64.
3H, J¼6.4 Hz, Me), 1.07–1.60 (m, 16H, 8ꢂCH2), 1.95–
2.67 (m, 6H, H-2, H-3 and H-8), 4.24 (dd, 1H, J4,5¼5.4,
J5,6¼9.4 Hz, H-5), 4.38 and 4.66 (2ꢂd, 2H, Jgem¼12.0 Hz,
PhCH2), 4.55 (m, 1H, H-4), 5.41 (m, 1H, J5,6¼9.4,
J6,7¼11.4 Hz, H-6), 5.80 (m, 1H, J6,7¼11.4, J7,8¼7.8 Hz,
1
H-7), 7.25–7.43 (m, 5H, Ph). H NOE contact: H-6 and
H-7. 13C NMR (CDCl3): d 14.07 (Me), 22.65, 23.80,
28.07, 28.30, 28.31, 29.45, 29.52, 29.58 and 31.88
(9ꢂCH2, C-2 and C-3), 70.05 (PhCH2), 75.25 (C-5), 81.77
(C-4), 124.81 (C-6), 127.66, 128.36 and 138.09 (Ph),
137.39 (C-7), 177.20 (C-1). MS (CI): m/z 373 (MH+).
4.1.11. 6-O-Decyl-2,3-dideoxy-L-threo-hexono-1,4-lac-
tone (2). A solution of 14 (0.084 g, 0.22 mmol) in EtOAc
(1.7 mL) was hydrogenated over 10% Pd/C (0.042 g) for
19 h at room temperature. The suspension was filtered
through a Celite pad and washed with EtOAc. The combined
filtrates were evaporated and the residue purified by flash
column chromatography (CH2Cl2/9:1 CH2Cl2/EtOAc) to
afford pure 2 (0.051 g, 82%) as a colorless solid. Recrystal-
lization from CHCl3/hexane gave an analytical sample 2, mp
4.1.8. 5-O-Benzyl-2,3-dideoxy-L-threo-hexono-1,4-lac-
tone (12). To a cooled (0 ꢁC) and stirred solution of 3
(0.122 g, 0.52 mmol) in MeOH (1.2 mL) was added
NaBH4 (0.0197 g, 0.52 mmol) in two portions, and the re-
sulting suspension was stirred at 0 ꢁC for 1.5 h. TFA
(2 mL) was then added and the mixture was stirred for addi-
tional 2 h while it was allowed to warm to room temperature.
The volatiles were removed by co-distillation with toluene

11050
V. Popsavin et al. / Tetrahedron 62 (2006) 11044–11053
42 ꢁC, [a]D23 +33.0 (c 0.83, CHCl3), Rf¼0.21 (9:1 CH2Cl2/
EtOAc). IR (film): nmax 3427 (OH), 1737 (C]O). 1H
NMR (CDCl3): d 0.85 (t, 3H, J¼6.4 Hz, Me), 1.13–1.63
(m, 16H, 8ꢂCH2), 2.24 (m, 2H, 2ꢂH-3), 2.39–2.72 (m,
2H, 2ꢂH-2), 2.87 (br s, 1H, exchangeable with D2O, OH),
3.44 (t, 2H, J¼6.6 Hz, 2ꢂH-8), 3.51 (d, 2H, J5,6¼5.8 Hz,
2ꢂH-6), 3.78 (br s, 1H, H-5), 4.56 (td, 1H, J4,5¼3.4,
J3,4¼7.0 Hz, H-4). 13C NMR (CDCl3): d 13.99 (Me),
22.56, 23.74, 25.96, 28.27, 29.2, 29.45, 29.47 and 31.78
(8ꢂCH2, C-2 and C-3), 71.12 (C-6), 71.69 (C-8), 71.94
(C-5), 79.79 (C-4), 177.53 (C-1). MS (CI): m/z 573
(2M++H), 287 (MH+). Anal. Found: C, 66.99; H, 10.74.
Calcd for C16H30O4: C, 67.10; H, 10.56.
J4,5¼1.5 Hz, H-4), 4.66 (d, 1H, J1,2¼3.5 Hz, H-2), 6.14
(d, 1H, J1,2¼3.5 Hz, H-1), 7.27–7.41 (m, 5H, Ph), 9.69 (d,
1H, CHO). 13C NMR (CDCl3): d 23.53, 23.81, 24.75,
35.85 and 36.67 (5ꢂCH2 from C6H10), 72.36 (PhCH2),
81.76 (C-2), 83.92 (C-3), 84.58 (C-4), 105.8 (C-1), 113.31
(Cq from C6H10), 127.66, 128.11, 128.51 and 136.69 (Ph),
200.07 (CH]O). MS (CI): m/z 637 (2M++H), 319 (MH+).
4.1.14. Methyl 3-O-benzyl-5,6-dideoxy-1,2-O-cyclohexyl-
idene-a-D-xylo-heptofuranuronate (19). A mixture of 17
(2.429 g, 7.63 mmol) and Ph3P]CHCO2Me (6.412 g,
19.18 mmol) in anhydrous CH2Cl2 (92 mL) was stirred un-
der N2 at room temperature for 2 h and then evaporated.
The residue was purified by flash column chromatography
(9:1 toluene/EtOAc) to give 18 (2.767 g, 97%) as a 2:1 mix-
ture of corresponding Z- and E-isomers. A solution of 18
(2.767 g, 7.39 mmol) in EtOH (55 mL) was hydrogenated
over PtO2 (0.029 g) for 19 h at room temperature. The mix-
ture was filtered and the catalyst washed with EtOH. The
organic solution was evaporated and the residue was purified
by flash column chromatography (15:1 toluene/EtOAc) to
afford pure 19 (2.571 g, 92%) as a colorless oil, [a]2D3 ꢀ38.6
(c 1.02, CHCl3), Rf¼0.31 (15:1 toluene/EtOAc), IR (film):
nmax 1740 (C]O). 1H NMR (CDCl3): d 1.33–1.77 (m,
5ꢂCH2 from C6H10), 2.04 (m, 2H, 2ꢂH-5), 2.40 (m, 2H,
2ꢂH-6), 3.66 (s, 3H, CO2Me), 3.82 (d, 1H, J3,4¼3.1 Hz,
H-3), 4.18 (ddd, 1H, J3,4¼3.1 Hz, J4,5a¼5.6, J4,5b¼8.4 Hz,
H-4), 4.50 and 4.71 (2ꢂd, 2H, Jgem¼12.0 Hz, PhCH2), 4.61
(d, 1H, J1,2¼3.9 Hz, H-2), 5.91 (d, 1H, J1,2¼3.9 Hz, H-1),
7.25–7.37 (m, 5H, Ph). 13C NMR (CDCl3): d 23.51 (C-5),
23.81, 23.82, 24.86, 35.68 and 36.29 (5ꢂCH2 from C6H10),
30.56 (C-6), 51.41 (CO2Me), 71.67 (PhCH2), 79.12 (C-4),
81.82 (C-2), 82.19 (C-3), 104.22 (C-1), 111.97 (Cq from
C6H10), 127.57, 127.80, 128.38 and 137.50 (Ph), 173.57
(C-7). MS (CI): m/z 377 (MH+), 345 (M+ꢀOMe).
4.1.12. 3-O-Benzyl-1,2-O-cyclohexylidene-a-D-xylofura-
nose (16). To a cooled (0 ꢁC) and stirred solution of 15
(2.603 g, 7.78 mmol) in anhydrous DMF (39 mL) were
added successively NaH (0.403 g, 13.4 mmol) and BnBr
(1.4 mL, 11.77 mmol), and the mixture was stirred for
2.5 h at room temperature. The mixture was cooled to 0 ꢁC
and treated with 0.1 M NaOMe in MeOH (15.6 mL,
1.56 mmol) while stirring for 2 h at room temperature.
The mixture was neutralized with 1 M AcOH in MeOH
(1.56 mL, 1.56 mmol), evaporated by co-distillation with
toluene, and the residue purified by flash column chromato-
graphy (9:1 CH2Cl2/EtOAc) to afford pure 16 (2.22 g, 89%)
as a colorless oil, [a]D23 ꢀ57.7 (c 0.99, CHCl3), Rf ¼0.32 (9:1
CH2Cl2/EtOAc). IR (film): nmax 3450 (OH). 1H NMR
(CDCl3): d 1.32–1.77 (m, 10H, 5ꢂCH2 from C6H10), 2.33
(br s, 1H, exchangeable with D2O, OH), 3.84 (dd, 1H, J4,5a
¼
4.6, J5a,5b¼11.8 Hz, H-5a), 3.96 (dd, 1H, J4,5b¼5.0 Hz,
J5a,5b¼11.8 Hz, H-5b), 4.03 (d, 1H, J3,4¼3.4 Hz, H-3),
4.28 (m, 1H, H-4), 4.50 and 4.73 (2ꢂd, 2H, Jgem¼12.0 Hz,
PhCH2), 4.65 (d, 1H, J1,2¼3.8 Hz, H-2), 6.00 (d, 1H,
J1,2¼3.8 Hz, H-1), 7.28–7.44 (m, 5H, Ph). 13C NMR
(CDCl3): d 23.53, 23.81, 24.83, 35.78 and 36.42 (5ꢂCH2
from C6H10), 60.92 (C-5), 71.86 (PhCH2), 80.0 (C-4),
81.99 (C-2), 82.86 (C-3), 104.61 (C-1), 112.44 (Cq from
C6H10), 127.63, 128.09, 128.59 and 137.11 (Ph). MS (CI):
m/z 642 (2M++H), 321 (MH+). Anal. Found: C, 65.01; H,
6.61. Calcd for C18H22O6: C, 64.66; H, 6.63.
4.1.15. Methyl 3-O-benzyl-5,6-dideoxy-D-xylo-heptofura-
nuronate (20) and 3-O-benzyl-5,6-dideoxy-D-xylo-hepto-
furanuronic acid (21). Procedure A: a solution of 19
(1.322 g, 3.51 mmol) in 50% aq AcOH (38 mL) was heated
under reflux for 2 h and then concentrated by co-distillation
with toluene. The residue was purified by flash column
chromatography (1:1 toluene/EtOAc). Eluted first was the
unchanged starting compound 19 (0.142 g, 11%). Eluted
second was the pure 20 (0.596 g, 64% on the basis of the re-
covered starting material 19) as a colorless syrup, Rf ¼0.24
(1:1 toluene/EtOAc). Final eluting of the column with
EtOAc gave pure 21 (0.074 g, 7%) as a colorless syrup,
[a]2D3 ꢀ4.1 (c 0.9, EtOH), Rf¼0.44 (999:1 EtOAc/AcOH).
4.1.13. 3-O-Benzyl-1,2-O-cyclohexylidene-a-D-xylo-pen-
tadialdo-1,4-furanose (17). To a stirred solution of 16
(2.935 g, 9.16 mmol) and DCC (5.67 g, 27.48 mmol) in
anhydrous DMSO (14.6 mL), were added dry pyridine
(0.36 mL; 5 mmol) and 0.82 M solution of anhydrous
H3PO4 in DMSO (5.5 mL, 4.5 mmol). The resulting reaction
mixture was stirred at room temperature for 3.5 h and then
diluted with EtOAc (50 mL). A solution of oxalic acid
(2.31 g, 10.15 mmol) in MeOH (7 mL) was added and the
resulting suspension was washed successively with 10% aq
NaCl (100 mL) and 10% aq NaHCO3 (50 mL). The organic
layer was separated and the aqueous solution extracted with
EtOAc (2ꢂ30 mL). The combined organic solution was
washed with brine, dried, and concentrated by co-distillation
with toluene. Flash column chromatography (9:1 toluene/
EtOAc) of the residue gave pure 17 (2.429 g, 83%) as an
unstable pale yellow syrup, [a]2D3 ꢀ41.4 (c 0.95, CHCl3),
Rf ¼0.27 (9:1 toluene/EtOAc). IR (film): nmax 1720
(CH]O). 1H NMR (CDCl3): d 1.34–1.76 (m, 5ꢂCH2 from
C6H10), 4.37 (d, 1H, J3,4¼3.7 Hz, H-3), 4.49 and 4.62
(2ꢂd, 2H, Jgem¼11.9 Hz, PhCH2), 4.58 (dd, 1H, J3,4¼3.7,
1
IR (film): nmax 3395 (OH), 1713 (C]O). H NMR (ace-
tone-d6): d 1.84–2.60 (m, CH2-5, CH2-6a and b), 3.87–
3.92 (m, H-3a and b), 4.14–4.32 (m, H-2 and H-4a and
b), 4.50 and 4.83 (2ꢂd, 2H, PhCH2), 5.05 (s, H-1b), 5.34
(d, J1,2¼4.3 Hz, H-1a), 7.21–7.48 (m, 5H, Ph). 13C NMR
(acetone-d6): d 25.62, 26.39, 30.72 and 30.91 (C-5, C-6a
and b), 72.02 and 72.23 (PhCH2 a and b), 76.23, 77.70,
80.03 and 80.22 (C-2 and C-4a and b), 84.66 (C-3b),
85.01 (C-3a), 96.63 (C-1a), 104.14 (C-1b), 128.22,
128.33, 128.34, 128.46, 129.02, 129.07, 139.28 and 139.51
(Ph), 174.73 and 174.82 (C]O, a and b).
Procedure B: a solution of 19 (1.103 g, 2.9 mmol) in 50% aq
AcOH (31 mL) was heated under reflux for 2 h and then

V. Popsavin et al. / Tetrahedron 62 (2006) 11044–11053
11051
concentrated by co-distillation with toluene. The residue
was dissolved in ether (9 mL) and treated for 1.5 h at room
temperature with an ethereal solution of diazomethane
(9 mL), generated from N-methyl-N0-nitro-N-nitroso guani-
dine (0.532 g) and 5 M NaOH (2.4 mL). The mixture was
evaporated and the residue purified by flash column chro-
matography (1:1 toluene/EtOAc). Eluted first was the un-
changed starting compound 19 (0.149 g, 13%). Eluted
second was the pure 20 (0.607 g, 81% on the basis of the re-
covered starting material 19) as a colorless syrup, Rf ¼0.24
(1:1 toluene/EtOAc), [a]2D3 +2.0 (c 1.08, CHCl3), anomeric
ratio: a/b¼3:1 (from 1H NMR). IR (film): nmax 3400
product ent-3 were consistent with those recorded for the
(+)-enantiomer 3 (Section 4.1.6). Anal. Found: C, 66.23;
H, 6.03. Calcd for C13H14O4: C, 66.66; H, 6.02.
4.1.17. 2,3-Dideoxy-D-threo-hexono-1,4-lactone (ent-4).
To a solution of ent-3 (0.111 g; 0.47 mmol) in MeOH
(1.1 mL) was added NaBH4 (0.02 g; 0.52 mmol) in portions
at 0 ꢁC. The reaction mixture was stirred for 1.5 h at 0 ꢁC and
then for 1 h at room temperature. One more equivalent of
NaBH4 (0.02 g; 0.52 mmol) was added and stirring was con-
tinued for an additional 1 h at room temperature. After cool-
ing to 0 ꢁC, TFA (2 mL) was added and the reaction mixture
was stirred for an additional 1 h. To the mixture was finally
added 10% Pd/C (0.056 g) and the resulting suspension was
hydrogenated for 19 h at room temperature. The mixture was
filtered and the catalyst washed with methanol. The organic
solution was concentrated by co-distillation with toluene and
methanol. The residue was purified by flash column chroma-
tography (4:1 CH2Cl2/EtOAc) to afford pure ent-4 (0.048 g;
71%) as a colorless syrup, [a]D ꢀ40.0 (c 2.07, MeOH), lit.8
[a]D ꢀ43.3 (c 0.9, MeOH), Rf¼0.22 (EtOAc). Spectral data
of ent-4 were consistent with those recorded for the opposite
enantiomer 4 (Section 4.1.9), as well as with the reported
values.8
1
(OH), 1720 (C]O). H NMR (CDCl3+D2O): d 1.96 (m,
2H, 2ꢂH-5a and b), 2.41 (m, 2H, 2ꢂH-6), 3.66 (s, 2.25H,
CO2Me-a), 3.71 (s, 0.75H, CO2Me-b), 3.84 (dd, 0.25H,
J2,3¼1.2, J3,4¼4.3 Hz, H-3b), 3.88 (dd, 0.75H, J2,3¼2.6,
J3,4¼4.6 Hz, H-3a), 4.16–4.32 (m, 2H, H-2 and H-4), 4.54
and 4.71 (2ꢂd, 1.5H, Jgem¼12.0 Hz, PhCH2-a), 4.55 and
4.70 (2ꢂd, 0.5H, Jgem¼11.7 Hz, PhCH2-b), 5.30 (s, 0.25H,
H-1b), 5.44 (d, 0.75H, J1,2¼4.3 Hz, H-1a), 7.30–7.41 (m,
5H, Ph). 13C NMR (CDCl3): d 24.6 (C-5a), 25.51 (C-5b),
30.53 (C-6a), 30.7 (C-6b), 51.62 (CO2Me-a), 51.65
(CO2Me-b), 71.79 (PhCH2-a), 72.47 (PhCH2-b), 75.57
(C-2b), 77.63 (C-2a), 77.89 (C-4b), 80.45 (C-4a), 82.56
(C-3b), 83.67 (C-3a), 95.59 (C-1a), 102.9 (C-1b), 127.61,
127.78, 127.87, 128.19, 128.4, 128.59, 136.94 and 137.74
(Ph), 174.06 (C-7). MS (CI): m/z 557 (2M+ꢀOHꢀH2O),
297 (MH+), 279 (M+ꢀOH). Anal. Found: C, 61.08; H,
6.66. Calcd for C15H20O6: C, 60.80; H, 6.80.
4.1.18. 5-O-Benzyl-2,3-dideoxy-D-threo-hexono-1,4-lac-
tone (ent-12). To a solution of 20 (0.699 g, 2.36 mmol) in
CH2Cl2 (9.5 mL) were added Kieselgel 60 (4.72 g, 0.063–
0.2 nm) and 0.65 M aq NaIO4 (4.7 mL, 3.06 mmol). The
mixture was vigorously stirred at room temperature for
45 min, filtered, and the precipitate washed with CH2Cl2.
The combined organic solutions were dried and evaporated
to give chromatographically homogenous sample 22. A so-
lution of crude 22 (0.665 g) in a mixture of TFA (10.8 mL)
and water (5.4 mL) was stirred at room temperature for
1.5 h. The mixture was concentrated by co-distillation with
toluene to give chromatographically homogenous lactone
ent-3 (0.598 g) as a colorless solid. To a cooled (0 ꢁC) and
stirred solution of crude ent-3 (0.598 g) in MeOH (5.6 mL)
was added NaBH4 (0.095 g, 2.52 mmol) and the mixture
was stirred for 1.5 h at 0 ꢁC. One more equivalent of
NaBH4 (0.095 g, 2.52 mmol) was added and stirring was
continued for an additional 1 h at room temperature. After
cooling to 0 ꢁC, TFA (11.2 mL) was added and the reaction
mixture was stirred for an additional 1 h while it was allowed
to warm to room temperature. The mixture was concentrated
by co-distillation with toluene and the residue was purified
by flash column chromatography (4:1 CH2Cl2/EtOAc).
Eluted first was the unchanged intermediate ent-3 (0.092 g,
17% with respect to 20). Eluted second was the pure product
ent-12 (0.314 g, 68% from 20, on the basis of the recovered
ent-3), [a]2D3 ꢀ23.1 (c 1.05, CHCl3), Rf¼0.24 (4:1 CH2Cl2/
EtOAc). Spectral data of ent-12 were consistent with those
recorded for the opposite enantiomer 12 (Section 4.1.8).
4.1.16. Methyl 2-O-benzyl-4,5-dideoxy-3-O-formyl-
D-threo-hexuronate (22) and 6-aldehydo-5-O-benzyl-2,3-
dideoxy-D-threo-hexono-1,4-lactone (ent-3). To a solution
of 20 (0.576 g, 1.94 mmol) in CH2Cl2 (7.8 mL) were added
Kieselgel 60 (3.88 g, 0.063–0.2 nm) and 0.65 M aq NaIO4
(3.9 mL, 2.53 mmol). The resulting heterogeneous mixture
was vigorously stirred for 1.5 h at room temperature, then
filtered, and evaporated by co-distillation with toluene to
afford crude 22 (0.561 g, 98%) as a yellow oil, which was
used in the next step without further purification. A minor
part of crude 22 was purified by flash column chromato-
graphy (49:1 CH2Cl2/EtOAc) to afford pure 22 as a colorless
syrup, [a]2D3 ꢀ15.1 (c 1.13, CHCl3), Rf¼0.28 (49:1 CH2Cl2/
EtOAc). IR (film): nmax 3460 (OH), 1740–1720 (C]O).
1H NMR (CDCl3): d 2.06 (m, 2H, 2ꢂH-4), 2.30 (m, 2H,
2ꢂH-5), 3.65 (s, 3H, CO2Me), 3.90 (dd, 1H, J1,2¼1.0,
J2,3¼3.7 Hz, H-2), 4.58 and 4.80 (2ꢂd, 2H, Jgem¼11.8 Hz,
PhCH2), 5.36 (td, 1H, J2,3¼3.7, J3,4a¼J3,4b¼7.0 Hz, H-3),
7.25–7.40 (m, 5H, Ph), 8.03 (s, 1H, OCHO), 9.60 (d, 1H,
J1,2¼1.0 Hz, H-1). 13C NMR (CDCl3): d 25.56 (C-4),
29.58 (C-5), 51.76 (CO2Me), 71.07 (C-3), 73.42 (PhCH2),
82.87 (C-2), 128.32, 128.45, 128.64 and 136.34 (Ph),
160.11 (OCHO), 172.67 (C-6), 200.37 (C-1). MS (CI): m/z
295 (MH+), 267 (MH+ꢀCO). A solution of crude ester
22 (0.561 g) in a mixture of TFA (9.1 mL) and water
(4.55 mL) was stirred for 1.5 h at room temperature and
then concentrated by co-distillation with toluene. The resi-
due was chromatographed on a column of flash silica (2:1
toluene/EtOAc) to give pure ent-3 (0.35 g, 77% from 20)
as a white solid. Recrystallization from CH2Cl2/hexane
gave an analytical sample as colorless needles, mp 93–
94 ꢁC, [a]D23 ꢀ129.8 (c 1.0, CHCl3), Rf¼0.3 (2:1 toluene/
EtOAc). IR, NMR, and mass spectral data of thus obtained
4.1.19. 5-O-Benzyl-6-O-decyl-2,3-dideoxy-D-threo-hex-
ono-1,4-lactone (ent-14). A mixture of ent-12 (0.054 g,
0.23 mmol), Ag2O (0.133 g, 0.57 mmol), AgOTf (0.015 g,
0.06 mmol), and C10H21Br (0.24 mL, 1.15 mmol) in anhy-
drous Et2O (0.55 mL) was heated under reflux for 5.5 h.
After the mixture cooled to room temperature it was diluted
with CH2Cl2 (5 mL), filtered, and evaporated. Flash column
chromatography (CH2Cl2/EtOAc) of the residue gave pure

11052
V. Popsavin et al. / Tetrahedron 62 (2006) 11044–11053
ent-14 (0.061 g, 71%) as a colorless oil, [a]2D3 ꢀ35.1 (c 0.92,
CHCl3), Rf ¼0.24 (CH2Cl2). Spectral data of ent-14 were
consistent with those recorded for (+)-enantiomer 14 (Sec-
tion 4.1.10). Anal. Found: C, 73.03; H, 9.38. Calcd for
C23H36O4: C, 73.37; H, 9.64.
2. For recent reviews see: (a) Chen, S. H. Curr. Med. Chem. 2002,
9, 899–912; (b) Gumina, G.; Song, G. Y.; Chu, C. K. FEMS
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4.1.20. 6-O-Decyl-2,3-dideoxy-D-threo-hexono-1,4-lac-
tone (ent-2). A solution of ent-14 (0.061 g; 0.16 mmol)
in EtOAc (1.25 mL) was hydrogenated over 10% Pd/C
(0.031 g) following the same methodology as described
above (procedure in Section 4.1.11), to afford pure ent-2
(0.040 g, 87%), mp 42 ꢁC, [a]D ꢀ33.0 (c 0.83, CHCl3),
Rf ¼0.21 (9:1 CH2Cl2/EtOAc). Spectral data of ent-2 were
consistent with those recorded for (+)-enantiomer 2 (Section
4.1.11). Anal. Found: C, 67.01; H, 10.67. Calcd for
C16H30O4: C, 67.10; H, 10.56.
3. For some recent examples see: (a) Lee, S. T.; Molyneux, R. J.;
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5. Cave, A.; Chaboche, C.; Figadere, B.; Haramange, J. C.;
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4.2. In vitro antitumor assay
Antitumor activity was evaluated by the tetrazolium colori-
metric MTT assay. The assay is based on cleavage of the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bro-
mide (MTT) to formazan by mitochondrial dehydrogenases
in viable cells. Exponentially growing cells were harvested,
counted by trypan blue exclusion, and plated into 96-well
microtiter plates (Costar) at optimal seeding density of 104
(K562, HL-60, JURKAT) or 5ꢂ103 (HeLa, MCF-7) cells
per well to assure logarithmic growth rate throughout the as-
say period. Viable cells were plated in a volume of 90 mL per
well, and preincubated in complete medium at 37ꢁ C for 24 h
to allow cell stabilization prior to the addition of substances.
Tested compounds, at ten the required final concentration, in
growth medium (10 mL/well) were added to all wells except
to the control ones and microplates were incubated for 24 h.
The wells containing cells without tested compounds were
used as control. Three hours before the end of incubation pe-
riod, 10 mL of MTT solution was added to each well. MTT
was dissolved in the medium at 5 mg/mL and filtered to ster-
ilize and remove a small amount of insoluble residue present
in some batches of MTT. Acidified 2-propanol (100 mL of
0.04 M HCl in 2-propanol) was added to each well and mixed
thoroughly to dissolve the dark blue crystals. After a few
minutes at room temperature to ensure that all crystals were
dissolved, the plates were read on a spectrophotometer plate
reader (Multiscan MCC340, Labsystems) at 540/690 nm.
The wells without cells containing complete medium and
MTT only acted as blank. The compound cytotoxicity was
expressed as the IC50 (50% inhibitory concentration).
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Acknowledgements
This work was supported by a research grant from the Min-
istry of Science and Environment Protection of the Republic
of Serbia (Project No. 142005). The authors are grateful to
´
Mr. Dejan Djokovic (Faculty of Chemistry, University of
Belgrade, Serbia and Montenegro) for recording the CI
mass spectra.
´
M.; Petrovic, J. Carbohydr. Lett. 2000, 3, 411–418; (e) Yoon,
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