Enantiodivergent synthesis of cytotoxic styryl lactones from d-xylose. The first total synthesis of (+)- and (-)-crassalactone C

Article abstract of DOI:10.1016/j.tet.2009.10.079

Enantiodivergent total syntheses of both (+)- and (-)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C have been accomplished starting from d-xylose. The key steps of the synthesis of 7-epi-(+)-goniofufurone were a stereo-selective ad

Full text of DOI:10.1016/j.tet.2009.10.079

Tetrahedron 65 (2009) 10596–10607
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Tetrahedron
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Enantiodivergent synthesis of cytotoxic styryl lactones from
D-xylose. The first
total synthesis of (þ)- and (ꢀ)-crassalactone C
,
a
a
a
a
Velimir Popsavin a , Goran Benedekovic , Bojana Sreco , Jovana Francuz , Mirjana Popsavin ,
*
´
´
b
b
c
´
´
´
Vesna Kojic , Gordana Bogdanovic , Vladimir Divjakovic
a
´
Department of Chemistry, Faculty of Sciences, University of Novi Sad, Trg D. Obradovica 3, 21000 Novi Sad, Serbia
b Oncology Institute of Vojvodina, Institutski put 4, 21204 Sremska Kamenica, Serbia
c Department of Physics, Faculty of Sciences, University of Novi Sad, Trg D. Obradovi´ca 4, 21000 Novi Sad, Serbia
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiodivergent total syntheses of both (þ)- and (ꢀ)-enantiomers of goniofufurone, 7-epi-goniofufur-
Received 21 May 2009
Received in revised form
6 October 2009
Accepted 22 October 2009
Available online 25 October 2009
one and crassalactone C have been accomplished starting from D-xylose. The key steps of the synthesis of
7-epi-(þ)-goniofufurone were a stereo-selective addition of phenyl magnesium bromide to a protected
dialdose, and a stereospecific furano–lactone ring formation by reaction of a related hemiacetal de-
rivative with Meldrum’s acid. Synthesis of both (þ)-goniofufurone and (þ)-crassalactone C required
a configurational inversion at C-5 in the common intermediate that was efficiently achieved under the
standard Mitsunobu conditions, or alternatively through a sequential oxidation of the benzylic hydroxyl
group followed by a stereo-selective reduction with borohydride. A similar approach was then applied to
the synthesis of the unnatural (ꢀ)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone
C, as well as two novel, conformationally constrained analogues of both (þ)- and (ꢀ)-goniofufurone.
Their in vitro antiproliferative activities against a number of human tumour cell lines were recorded and
compared with those observed for the parent natural products.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
The styryl lactones are a group of secondary metabolites mainly
isolated from the genus Goniothalamus of the plant family Anno-
naceae.1 A number styryl lactones that have been isolated from
Goniothalamus species or synthesized exhibited a notable cytotoxic
activity against certain human tumour cell lines.2 The cytotoxicity
of styryl lactones appears to be specific on neoplastic cells since
negligible effects of these compounds on normal cells are reported.
(þ)-Goniofufurone (1; Fig. 1) and 7-epi-(þ)-goniofufurone3 (2) are
naturally occurring styryl lactones that have attracted considerable
attention since their isolation from the stem bark of Goniothalamus
giganteus (Annonaceae).4,5 Their structures were elucidated by
spectroscopic methods, and the relative configurations were de-
termined by X-ray crystallography. The absolute stereochemistry of
both natural products was established by Shing et al.6 through the
total synthesis of their opposite enantiomers (ent-1, and ent-2)
Figure 1. Structures of (þ)-goniofufurone (1), 7-epi-(þ)-goniofufurone (2) and
(þ)-crassalactone C (3), and the corresponding unnatural enantiomers ent-1, ent-2 and
ent-2.
a number of their analogues been the targets of many total syn-
theses.7,8 (þ)-Crassalactone C (3) is a natural 7-O-cinnamoyl de-
rivative of (þ)-goniofufurone that was recently isolated from the
leaves and twigs of Polyalthia crassa.9 Its structure was determined
on the basis of standard spectroscopic methods. The absolute ste-
reochemistry of 3 was established by treatment of the isolated
(þ)-1 with cinnamoyl chloride. Apart from this non-selective and
low-yielding single step route, no total synthesis of 3 has been
hitherto reported. As a part of our continuing interest in the syn-
thesis of biologically active natural products from abundant
monosaccharides, we have planned to develop a new approach to
starting from
D-glycero-D-gulo-heptano-1,4-lactone as a chiral
source. Due to their unique structural features and promising
antitumour activities, both natural products 1 and 2, along with
* Corresponding author. Tel.: þ381 21 485 27 68; fax: þ381 21 454 065.
E-mail address: velimir.popsavin@dh.uns.ac.rs (V. Popsavin).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.079

V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
10597
1–3 by chirality transfer from D-xylose. Apart from these natural
products, we were especially keen to prepare and evaluate their
opposite enantiomers (ent-1, ent-2 and ent-3), since it is well
known that enantiomers of certain bioactive compounds may ex-
hibit improved potencies10 or completely different biological ac-
tivities altogether.11 Several syntheses of ent-1 and ent-2 were
reported,6,12 but there was no record in the literature about their
antiproliferative activities. Neither the synthesis nor biological ac-
tivity of ent-3 was reported in the literature. Herein, we disclose
a new enantiodivergent synthesis of both enantiomeric forms of 1,
2 and 3 starting from D-xylose. We also disclose the preparation of
novel styryl lactones 4 and ent-4 that are designed as conforma-
tionally locked analogues of 1 and ent-1, respectively. The rationale
underlying the preparation of 4 and ent-4 arises from fact that both
parent compounds 1 and ent-1 (Scheme 1) have a restricted ge-
ometry of the C5–C7 segment, due to an intramolecular H-bond
formed between the 5-OH and the 7-OH, as established by X-ray
analysis.4 Comparison of antiproliferative activities of synthesized
styryl lactones 1–4 from both (þ)- and (ꢀ)-series against a panel of
human tumour cells is also provided.13
Scheme 2. Retrosynthetic analysis of (þ)-goniofufurone (1), 7-epi-(þ)-goniofufurone
(2) and (þ)-crassalactone C (3).
In order to synthesize natural products 1–3, we first focused
on the preparation of the key building block 9 from
D-xylose
(Scheme 3). In terms of its stereochemical and topological fea-
tures, molecule 9 completely corresponds to the intermediate 2a
designed by retrosynthetic analysis. The synthetic sequence
commenced with the formation of the protected dialdose 8 from
D
-xylose derivative 518 by a slight modification of a literature
Scheme 1. Design of structurally constrained goniofufurone analogues 4 and ent-4.
method.16 Thus, compound 5 was first di-O-benzylated under
standard conditions (BnBr, NaH, DMF) to give 6 that was con-
verted to the corresponding primary alcohol 7 (72% from 5) by
using KBrO3/Na2S2O5 reagent system.19 A slightly more efficient
regioselective C-5 deprotection of 6 was achieved under the
hydrogenolytic conditions in the presence of 0.05 M equiv of Pd.
This method provided the desired intermediate 7 in 80% yield
(from two steps). Oxidation of 9 was carried out under the
conditions similar to that previously reported,16 to give
the protected dialdose 8 in 71% overall yield (from three steps).
The preceding preparation of 8 was accomplished in 62% overall
yield over four linear steps.16 Addition of phenyl magnesium
bromide to 8 preferentially gave the key divergent intermediate
9 (69%) as a result of 1,2-chelation control. A minor amount of
2. Results and discussion
All three target compounds 1–3 contain five contiguous ster-
eocenters and display a clear structural similarity. We thus wanted
to design a unified synthesis for all three compounds from a com-
mon intermediate. Among other methods, the required [3.3.0] bi-
cyclic lactone core could be formed through condensation of
Meldrum’s acid with a protected sugar lactol derivative.14 Accord-
ingly, we envisaged the retrosynthetic concept depicted in
Scheme 2. For both 1 and 2, lactone ring-removal would give rise to
the epimeric alcohols 1a and 2a (R2,R2¼alkylidene), respectively. It
was assumed that intermediate of type 2a can be prepared from the
aldehyde 8 by stereo-selective addition of phenyl magnesium
bromide under the 1,2-chelation control.15 The intermediate 1a
however could be prepared after epimerization of 2a at C-5. Syn-
D
-gluco stereoisomer 10 (13%) was also obtained from this re-
action. The key building block 9 was thus successfully synthe-
sized in facile stereo-selective route from the partially
a
thesis of 8 itself is visualized from
D
-xylose by established chemical
protected D-xylose derivative 5.
reactions.16 Disconnection of 3 shows that it can be derived from
the diol of type 3a by a number of successive transformations that
involve regioselective Mitsunobu reaction in the presence of cin-
namic acid and hydrolytic removal of the 1,2-O-alkylidene pro-
With the requisite intermediate 9 in hand, we next focused on
its further transformations to (þ)-goniofufurone (1). For the syn-
thesis of target 1, it was necessary first to invert the stereochem-
istry at C-5 of the major isomer 9 from the Grignard reaction. To
prepare compound 10, an efficient two-step route was developed
that involved configurational inversion at C-5 in 9 under the
standard Mitsunobu conditions20 (Scheme 4). Accordingly, treat-
ment of 9 with diethyl azodicarboxylate, triphenyl phosphine, and
benzoic acid gave the expected 5-O-benzoyl derivative 11, which
tective group, followed by g-lactone formation. Intermediate 3a in
turn, should be accessible from 2a by removal of benzyl protective
group from C-3. Accordingly, the protected benzylic alcohol of type
2a was selected as a convenient common intermediate in the di-
vergent synthesis of all three targets 1–3.

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V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
Scheme 3. Reagents and conditions: (a) BnBr, NaH, DMF, 0 ꢁC for 0.5 h, then rt for 1 h; (b) KBrO3, Na2S2O5, CH2Cl2, H2O, 12 ꢁC for 15 min, then rt for 3 h, 72% from 5; (c) H2-Pd/C
(0.05 equiv of Pd), 2:1 EtOH/EtOAc, rt, 1.5 h, 80% from 5; (d) DCC, anh. H3PO4, Py, DMSO, rt, 3.5 h, 89%; (e) PhMgBr, Et2O, 0 ꢁC, 3.5 h, 69% of 9, 13% of 10.
Scheme 4. Reagents and conditions: (a) PhCO2H, Ph3P, DEAD, THF, 0 ꢁC for 1 h, then rt for 2 h, 82%; (b) NaOMe/MeOH, CH2Cl2, 0 ꢁC for 1 h, then rt for 23 h, 99%; (c) PCC, CH2Cl2,
reflux, 2 h, 98%; (d) NaBH4, MeOH, rt, 2 h, 87% of 10, 12% of 9; (e) NaBH4, L-tartaric acid, THF, ꢀ7 ꢁC for 1 h, then 0 ꢁC for 2 h, 97% of 10, (f) 70% aq AcOH, reflux, 4 h, 87%; (g)
Meldrum’s acid, Et3N, DMF, 46 ꢁC, 76 h, 52%; (h) H2-Pd/C, MeOH, rt, 46 h, 97%.
upon deprotection with methanolic sodium methoxide formed 10.
Compound 10 was also prepared by using an alternative two-step
sequence that involved oxidation of 9 with PCC whereupon the
corresponding ketone 12 was obtained in an almost quantitative
yield. Reduction of the keto group in 12 with NaBH4 afforded a 7:1
mixture of diastereomers, which after chromatographic separation
furnished the alcohol 10 as the major product in 87% yield. How-
ever, when the reduction with NaBH4 was carried out in the pres-
furnished the target 2. This synthetic sequence produced
7-epi-(þ)-goniofufurone (2) in 15% overall yield in seven steps
from 5. All physical constants and spectroscopic data of thus
prepared natural product 2 were in good agreement with those
reported.22,25
The synthesis of (þ)-crassalactone C (3) also started from the
L
-ido stereoisomer 9. Thus, removal of the benzyl protective group
in 9 gave the corresponding diol 17 (70%), that was further
allowed to react with cinnamic acid under the standard Mitsu-
nobu conditions. The corresponding cinnamic ester 18 was thus
obtained (63%) accompanied by a minor amount of 3,5-anhydro
derivative 21 (16%). Hydrolytic removal of the cyclohexylidene
protective group in 18 gave the expected lactol 19 (67%), which
upon treatment with Meldrum’s acid in the presence of triethyl-
amine gave (þ)-crassalactone C (3), with physical and spectro-
scopic properties in reasonable agreement with those reported in
the literature.9
Our initial plan was to utilize oxetane 21 for the prepara-
tion of analogue 4 (5,7-anhydro-goniofufurone). In order to
increase the yield of 21, the Mitsunobu reaction of 17 was
carried out in absence of cinnamic acid (Ph3P, DEAD, refluxing
toluene, 1.5 h). Under these reaction conditions, the oxetane 21
was isolated as a main reaction product in 77% yield. The
assignment of stereochemistry at the C-5 in product 21 was
confirmed by an NOE interaction between H-1 and H-5, in-
dicating that these protons are in close proximity on the same
side of the ring. It was assumed that the synthesis of 4 can be
accomplished by a two-step sequence consisting of hydrolytic
removal of the cyclohexylidene protective group in 21, fol-
lowed by subsequent lactonisation. However, attempted
selective removal of the cyclohexylidene moiety under a vari-
ety of hydrolytic conditions failed to afford the desired lactol
21a. The products of oxetane ring opening always dominated
in reaction mixtures. We have therefore decided to prepare
the target 4 directly from 7-epi-(þ)-goniofufurone (2). Thus,
ence of L
-tartaric acid21 alcohol 10 was obtained as the only
stereoisomer in 97% yield. The last two-step sequence appeared to
be a more convenient route to the intermediate 10, since it pro-
vided a considerably higher overall yield (95% from 9) compared to
the former route via the 5-O-benzoyl derivative 11 (81% from 9).
Hydrolytic removal of the cyclohexylidene protective group in 10
with aqueous acetic acid gave an 87% yield of the corresponding
lactol 13. Attempted condensation of 13 with Meldrum’s acid in the
presence of tert-butylamine22 failed to give the expected
14. However, when the last reaction was carried out in the presence
of triethylamine as a catalyst,23 the desired
-lactone 14 was
g-lactone
g
obtained in 52% yield. Final cleavage of benzyl protecting group in
14 gave (þ)-goniofufurone (1). The physical and spectroscopic data
of thus obtained sample 1 were identical to those reported in the
literature.8h
According to our retrosynthetic plan, the L-ido isomer 9 also
represents a divergent intermediate for the preparation of both
7-epi-(þ)-goniofufurone (2) and (þ)-Crassalactone C (3). It was also
assumed that 9 might serve as an intermediate in the synthesis of
conformationally locked (þ)-goniofufurone analogue 4 (Scheme 2).
The synthesis of targets 2–4 is presented in Scheme 5.
The stereoisomer 9 was converted to 7-epi-(þ)-goniofufurone
(2) by using the same methodology as that already applied for
the conversion of 10–1 (Scheme 4). Treatment of 9 with aqueous
acetic acid gave 15 (73%) along with a minor amount of 1,5-
anhydride 20 (5%).24 Subsequent treatment of 15 with Mel-
drum’s acid, followed by final hydrogenolytic 5-O-deprotection

V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
10599
Scheme 5. Reagents and conditions: (a) 70% aq AcOH, reflux, 6.5 h for 9, 73% of 15, 5% of 20, 4 h for 18, 67% of 19; (b) Meldrum’s acid, Et3N, DMF, 46 ꢁC, 70 h for 15, 48% of 16, 72 h
for 19, 62% of 3; (c) H2-Pd/C, MeOH, rt, 72 h for 16, 87% of 2, 4 h for 9, 70% of 17; (d) PhCH:CHCO2H, Ph3P, DEAD, THF, 0 ꢁC for 1 h, then rt for 2 h, 63% of 18, 16% of 21; (e) Ph3P, DEAD,
toluene, reflux, 1.5 h for 17, 77% of 21, 3 h for 2, 35% of 4.
compound 2 was subjected to the intramolecular Mitsunobu
reaction, under reaction conditions similar to that already
applied for the conversion of 17–21 (Ph3P, DEAD, toluene,
reflux). Target 4 was thus obtained as a main reaction product
in 35% yield.
Retrosynthetic analysis of ent-1, ent-2 and ent-3 is outlined in
Scheme 6. As their natural counterparts, the opposite enantiomers
ent-1, ent-2 and ent-3 contain five contiguous stereocentres but
differ in stereochemistry and functionality at C-7. The presence of
the cinnamoyl moiety in ent-3 implies that this molecule could be
obtained from ent-2 through a regioselective Mitsunobu reaction
with cinnamic acid. Further disconnection of ent-1 and ent-2 shows
that they can be derived from the protected aldehyde 4a by several
successive transformations that involve a hydrolysis of the acetal
functionality, stereo-selective addition of phenyl magnesium
bromide to the liberated aldehyde group, followed by removal of
benzyl protective group. The intermediate 4a should be accessible
through an adopted literature procedure,17 which involves a
Z-selective Wittig olefination of 8, followed by an acid-catalyzed
methanolysis of the intermediate 4b. In such a way we identified
the protected aldehydo lactone 24 (Scheme 7) as a possible com-
mon building block for the synthesis of all three targets (ent-1, ent-
2, and ent-3). In the light of its stereochemical features compound
24 fully corresponds to the intermediate 4a from the retrosynthetic
analysis.
The synthesis of enantiomers ent-1, ent-2, ent-3 and ent-4 is
outlined in Scheme 7. The sequence started with the Z-selective
Wittig olefination26 of aldehyde 8 with methyl (triphenylphos-
phoranylidene)-acetate, whereupon the Z-unsaturated ester 22
was obtained as a dominant reaction product, in 83% yield. A minor
amount (12%) of the corresponding E-isomer (not shown in the
reaction scheme) was also isolated from the reaction mixture. It
was expected that the key intermediate 24 could be obtained by an
acid-catalyzed methanolysis of 22. The procedure followed here is
analogous to that previously developed by Prakash and Rao17 for
the conversion of the isopropylidene analogue of 22 into the lac-
tone 24. Accordingly, compound 22 was refluxed in dry methanol in
the presence of a catalytic amount of sulfuric acid (2%). Although
complete conversion of starting compound was observed after
4.5 h, only traces of the desired lactone 24 were detected in the
reaction mixture. The unsaturated lactone 23 was formed as a ma-
jor reaction product under these reaction conditions. However,
when the reaction solution was alkalized to pH 9 (NaHCO3) and
stirred for 1 h at 35 ꢁC, the bicyclic lactone 24 was predominantly
formed as a result of the stereospecific Michael ring closure in 23.
The key building block 24 was isolated in 74% yield, along with
a minor amount of 23 (4%). These results are in accord with Prakash
and Rao’s assumption that lactonisation precedes Michael attack in
Scheme 6. Retrosynthetic analysis of (ꢀ)-goniofufurone (ent-1), 7-epi-(ꢀ)-goniofu-
furone (ent-2) and (ꢀ)-crassalactone C (ent-3).

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V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
Scheme 7. Reagents and conditions: (a) Ph3P:CHCO2Me, MeOH, 0 ꢁC for 0.5 h, then rt for 1.5 h, 83%; (b) (i) H2SO4 (cat.), MeOH, reflux, 4.5 h, (ii) NaHCO3 (pH¼9), 35 ꢁC, 1 h, 74% of 24,
4% of 23; (c) 9:1 TFA/H2O, 0 ꢁ for 0.5 h, then rt for 0.5 h; (d) PhMgBr/THF, Et2O, ꢀ7 ꢁC, 3h, 3% of ent-14, 56% of ent-16 (from 24); (e) H2-Pd/C, MeOH, rt, 46 h, 70% of ent-1, 64% of ent-2;
(f) PCC, CH2Cl2, reflux, 2 h, 84%; (g) NaBH4, MeOH, rt, 3.5 h, 54% of ent-14, 26% of ent-16; (h) PhCH:CHCO2H, Ph3P, DEAD, THF, 0 ꢁC for 1 h, then rt for 2 h, 53% of ent-3, 16% of ent-4; (i)
Ph3P, DEAD, toluene, reflux, 3 h, 40%.
this process, but contradicts their hypothesis that the tetrahydro-
furan ring closure in 23 occurs under the acidic conditions.17
Hydrolytic removal of the dimethyl acetal protection in 24
afforded the corresponding aldehyde 25, which was subsequently
treated with phenyl magnesium bromide to give two di-
astereomeric alcohols ent-16 and ent-14 in a 19:1 ratio and 59%
combined yield (calculated to 24). Major isomer ent-16 was con-
verted to target ent-2 after removal of the benzyl protecting group.
The physical and spectroscopic data of thus obtained sample ent-2
were identical to those previously reported.12a This new synthesis
of ent-2 proceeds in seven steps with 16% overall yield calculated to
starting compound 5. Along with the Gracza and Ja¨ger approach,12b
it appears to be one of the most efficient routes to this molecule yet
disclosed.27
above structural elucidation of ent-4 was confirmed by X-ray
crystallographic analysis (Fig. 2). The distance between H-3 and H-
7 (2.56 Å) is consistent with NOE results.
Figure 2. ORTEP presentation of compound ent-4.
The minor stereoisomer from the Grignard reaction of 25 (ent-
14) has the correct stereochemistry for the synthesis of
(ꢀ)-goniofufurone (ent-1). The reaction proceeds under chelation
control and efforts to change the ratio in favour of ent-14 were
unsuccessful. However access to ent-14 was possible by oxidation
of ent-16 followed by reduction of the intermediary ketone 26 to
give a separable 2:1 mixture of ent-14 and ent-16 in 67% overall
yield. Stereoisomer ent-14 was converted to (ꢀ)-goniofufurone
(ent-1) after removal of benzyl protecting group. All physical con-
stants and spectroscopic data of thus prepared product ent-1 were
in good agreement with those already reported.12a
Compound ent-2 was converted to (ꢀ)-crassalactone C (ent-3)
upon treatment with cinnamic acid, under the standard Mitsunobu
conditions20 (PhCH:CHCO2H, Ph3P, DEAD, THF, 0 ꢁC/rt, 3.5 h). The
target ent-3 that was isolated in 53% yield, displayed physical and
spectroscopic properties in reasonable agreement with those pre-
viously reported for the natural (þ)-crassalactone C.9
2.1. Evaluation of antiproliferative activity
A side-by-side comparison of the synthesized (þ)- and (ꢀ)-en-
antiomers in a range of cytotoxic assays28 is presented in Table 1.
The commercial antitumour agent doxorubicin (DOX) served as
a reference compound.
In general, all synthesized styryl lactones showed diverse anti-
proliferative activities against human malignant cell lines
Table 1
Antiproliferative activities of synthesized compounds and DOX
Compound
IC50, m
Ma
K562
HL-60
Jurkat
Raji
18.45
23.42
1.25
MRC-5
1
0.41
2.96
0.028
3.35
3.56
3.67
0.39
2.05
0.25
>100
>100
22.02
13.93
>100
32.45
2.49
>100
>100
>100
>100
>100
>100
>100
>100
ent-1
2
ent-2
3
ent-3
4
ent-4
DOX
18.64
0.054
25.45
15.67
0.03
A minor amount of oxetane ent-4 (16%) was also obtained from
the last Mitsunobu reaction. However, compound ent-2 was more
efficiently converted to ent-4 (40%) under the reaction conditions
similar to those already used for the conversion of 2–4. Spectro-
scopic data and physical constants of ent-4 thus obtained were in
full agreement with values recorded for the opposite enantiomer 4.
Additionally, an NOE interaction between H-3 and H-7 was
>100
15.46
0.57
3.65
0.45
2.98
1.87
0.11
0.025
0.92
28.45
0.03
0.10
a
IC50 is the concentration of compound required to inhibit the cell growth by 50%
compared to an untreated control.
consistent with L-glycero-L-ido stereochemistry of ent-4. Finally, the

V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
10601
(myelogenous leukaemia K562, promyelocytic leukaemia HL-60, T
cells leukaemia Jurkat, and Burkitt’s lymphoma Raji cell line), but
were devoid of any significant cytotoxicity towards the normal
foetal lung fibroblasts (MRC-5). The natural product 2 and the un-
natural enantiomer of crassalactone C (ent-3), as well as both
structurally constrained analogues (4 and ent-4) exhibited anti-
proliferative activities towards the all tested cell lines, while com-
pounds 1, ent-1 and 3 showed potent to moderate activities against
K562, Jurkat and Raji cells, but were completely inactive against the
HL-60 cell line. The unnatural enantiomer of 7-epi-(þ)-goniofu-
furone (ent-2) however, was completely inactive against Raji cells,
but demonstrated a notable antiproliferative activity against K562,
HL-60 and Jurkat cell lines. It is noteworthy that both 5,7-anhydro-
goniofufurone enantiomers (4 and ent-4) displayed higher potency
against HL-60 cell line than the commercial cytotoxic agent doxo-
rubicin (DOX).
A comparison of IC50 values for (þ)- and (ꢀ)- enantiomers re-
veals that both unnatural enantiomers ent-1 and ent-2 had more
profound effect only against Jurkat cells being 13- and 345-fold
more potent than the natural products 1 and 2, respectively. At the
same time, the growth inhibitory effect of ent-2 on the Jurkat cell
line was of the same order of magnitude as that recorded for the
standard antitumour agent doxorubicin (DOX). Remarkably, the
unnatural enantiomer of crassalactone C (ent-3) showed a potent
antiproliferative activity towards HL-60 cells, while the corre-
sponding natural enantiomer 3 was completely inactive against
this cell line. This molecule demonstrated a 27- and 5-fold greater
cytotoxicity in Raji cells, when compared to the natural product 3
and DOX, respectively. These results indicate that the unnatural 3S,
4R, 5R and 6S absolute configurations may be beneficial for the
activity of these styryl lactones.
The results obtained from the treatment of cancer cells with 4
and ent-4 demonstrated that the introduction of a new 5,7-anhydro
ring increases the potency originally displayed by 1 and ent-1.
Analogue 4 exhibited a submicromolar antiproliferative activity
towards HL-60 cells, while the corresponding parent compound 1
was completely inactive against this cell line. At the same time,
molecule 4 showed over 8-fold stronger cytotoxicity in the same
cell line when compared to the reference compound (DOX).
Remarkably, this analogue demonstrated a 1082- and 5-fold greater
cytotoxicity in Jurkat and Raji cells, respectively, when compared to
the natural product 1. Along with DOX, analogue 4 was the most
active compound towards Jurkat cell line. On the contrary to 4, its
opposite enantiomer ent-4 exhibited a lower activity against Jurkat
cells than the corresponding parent compound ent-1. However, this
analogue demonstrated powerful cytotoxicity in HL-60 cells, on the
contrary to the parent compound ent-1 that was completely in-
active against this cell line. At the same time, analogue ent-4
exhibited the highest activity against the HL-60 cell line, being
approximately 37-fold more potent than DOX. Finally, ent-4 dem-
onstrated over 50- and 6-fold stronger cytotoxicity in Raji cell line
when compared to the parent compound ent-1 and DOX,
respectively.
enantiomeric series for biological evaluation. In a preliminary
bioassay, doxorubicin (DOX, a standard anticancer drug used as
a positive control) displayed lower activity against Raji malignant
cells (IC50¼2.98
(IC50¼0.57 M), and ent-4 (IC50¼0.45
exhibited one order of magnitude lower antiproliferative effect
against the K562 cells (IC50¼0.25 M) when compared with the
natural product 2 (IC50¼0.028 M). On HL-60 cells, the analogues 4
(IC50¼0.11 M) and ent-4 (IC50¼0.025 M) were more potent than
DOX (IC50¼0.92 M), while approximately the same values were
observed for DOX (IC50¼0.03 M), ent-2 (IC50¼0.054 M) and 4
(IC50¼0.03 M) in Jurkat cell line. Based upon the potent anti-
mM) than lactones
2
(IC50¼1.25
mM), ent-3
m
mM). Additionally, DOX
m
m
m
m
m
m
m
m
tumour activities of 2, ent-2, ent-3, 4 and ent-4, as well as upon their
non-toxicity against normal MRC-5 cells, we believe that these
compounds may serve as convenient leads in the synthesis of more
potent and selective antitumour agents. Finally, from a synthetic
perspective, the fact that both enantiomers efficiently inhibit
tumour cells growth also means that both are equally valuable
synthetic targets. In this sense, an additional advantage of this new
enantiodivergent approach is that it provides the opportunity to
access the cytotoxic properties of not only the natural products, but
also (for the first time) their unnatural enantiomers.
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 KRUSS
P3002 polarimeter at room temperature. IR spectra were recorded
with an FTIR/NIR Nexus 670 spectrophotometer (Thermo-Nicolet).
NMR spectra were recorded on a Bruker AC 250 E instrument and
chemical shifts are expressed in ppm downfield from TMS. Low
resolution mass spectra were recorded on Finnigan-MAT 8230 (CI)
and on an Agilent Technologies HPLC/MS 3Q system, series 1200/
6410 (ESI). High resolution mass spectra were taken on a 6210
Time-of-Flight LC/MS Agilent Technologies instrument (ESI). Flash
column chromatography was performed using ICN silica 32–63. TLC
was performed on DC Alufolien Kieselgel 60 F254 (E. Merck). All
organic extracts were dried with anhydrous Na2SO4. Organic so-
lutions were concentrated in a rotary evaporator under diminished
pressure at a bath temperature below 30 ꢁC.
4.1.1. 3-O-Benzyl-1,2-O-cyclohexylidene-a-D-xylofuranose
(7). 4.1.1.1. Procedure A. To a cooled (0 ꢁC) and stirred solution of 5
(1.0 g, 4.34 mmol) in dry DMF (20 mL), were added successively
NaH (0.625 g, 26.06 mmol) and BnBr (1.5 mL, 12.64 mmol). The
mixture was stirred at 0 ꢁC for 0.5 h and then at room temperature
for 1 h. Methanol (7 mL) was then added, and the mixture was
stirred at room temperature for the next 20 min. The mixture
was neutralised with glacial AcOH and evaporated. The residue was
suspended in water (200 mL) and extracted with CH2Cl2
(2ꢂ40 mL). The combined organic solutions were dried and evap-
orated. The remaining crude 6 (1.97 g) was dissolved in CH2Cl2
(50 mL) and the solution was cooled to þ12 ꢁC. To the mixture was
added dropwise a solution of KBrO3 (1.46 g, 8.68 mmol) in water
(30 mL) followed by a solution of Na2S2O5 (1.65 g, 8.68 mmol) in
water (20 mL) and the temperature maintained at þ12 ꢁC for
15 min and then at room temperature for 3 h. The mixture was
diluted with CH2Cl2 (30 mL) and poured into 5% aq NaHCO3
(100 mL), washed with EtOH. Organic layer was separated and the
aqueous solution was extracted with CH2Cl2 (3ꢂ60 mL). The com-
bined organic solutions were dried and evaporated. Flash column
3. Conclusions
In conclusion, we have completed a new enantiodivergent
synthesis of both (þ)- and (ꢀ)-enantiomers of styryl lactones
goniofufurone (1 and ent-1), 7-epi-goniofufurone (2 and ent-2),
crassalactone
C (3 and ent-3), and novel conformationally
constrained goniofufurone analogues (4 and ent-4) starting from
D-
xylose. In addition to providing access to both enantiomers of 1–4
this enantiodivergent approach is flexible and straightforward. It
uses non-expensive reagents and a readily available starting ma-
terial. These advantages make the synthetic methodology suitable
for easy preparation of a variety of styryl lactone analogues in both
chromatography of the residue (3:2 hexane/Et2O) gave pure 7
20
(1.01 g, 72%), isolated as a colourless syrup, [
CHCl3); Rf¼0.37 (2:3 hexane/Et2O).
a
]
¼ꢀ57.7 (c 0.99,
D

10602
V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
4.1.1.2. Procedure B. To a cooled (0 ꢁC) and stirred solution of 5
with 10% aq NaHCO3 (150 mL), and extracted with CH2Cl2
(2ꢂ40 mL). The combined extracts were dried and evaporated and
the residue purified on a column of flash silica (17:3 light petro-
leum/Et2O), to give pure 11 (0.559 g, 82%) as a colourless solid.
(1.0 g, 4.34 mmol) in dry DMF (20 mL), were added successively
NaH (0.5 g, 16.67 mmol) and BnBr (1.34 mL, 11.29 mmol). The
mixture was stirred at 0 ꢁC for 0.5 h and then at room temperature
for 1 h. The mixture was quenched as described above to give crude
6 as a yellow oil. Crude product 6 was dissolved in a 2:1 mixture
EtOH/EtOAc (30 mL) and the solution was added to a suspension of
10% Pd/C (0.46 g, 0.43 mmol) in aps. EtOH (30 mL), which was
previously saturated with hydrogen (at room temperature for 1 h).
The mixture hydrogenated for 1.5 h at room temperature. The
catalyst was filtered off and washed with EtOH. The combined or-
ganic solutions were evaporated and the residue was purified by
flash column chromatography (3:2 hexane/Et2O). Eluted first was
Recrystallization from CH2Cl2/hexane gave colourless needles, mp
20
135–138 ꢁC, [
a
]
¼ꢀ4.5 (c 1.01, CHCl3); Rf¼0.46 (4:1 light petro-
D
leum/Et2O). IR (CHCl3): nmax 1725 (C]O). 1H NMR (CDCl3):
d 1.2–
1.86 (m, 10H, C6H10), 4.19 (d, 1H, J3,4¼3.0 Hz, H-3), 4.42 (d, 1H,
Jgem¼11.5 Hz, PhCHa), 4.59–4.74 (m, 3H, H-2, H-4 and PhCHb), 5.97
(d, 1H, J1,2¼3.6 Hz, H-1), 6.26 (d, 1H, J4,5¼9.6 Hz, H-5), 7.2–8.11 (m,
15H, 3ꢂPh). 13C NMR (CDCl3):
d 23.5, 23.8, 24.8, 35.6 and 36.4
(5ꢂCH2), 72.2 (PhCH2), 72.8 (C-5), 81.1 (C-3), 81.3 (C-2), 81.5 (C-4),
104.8 (C-1), 112.4 (Cq from C6H10), 127.4, 127.8, 128.0, 128.2, 128.3,
128.4, 129.6, 130.0, 132.9, 136.7 and 138.2 (3ꢂPh), 164.5 (PhCO).
LRMS (CI): m/z 501 (MþþH). Anal. Found: C, 74.11; H, 6.67. Calcd for
C31H32O6: C, 74.38; H, 6.44.
unreacted intermediate 6 (0.25 g, 14%). Eluted second was pure 7
20
(1.11 g, 80%), isolated as a colourless syrup, [
a]
¼ꢀ57.7 (c 0.99,
D
CHCl3); Rf¼0.37 (2:3 hexane/Et2O). Spectroscopic data of thus
prepared sample 7 matched those previously reported by us.16
4.1.5. 3-O-Benzyl-1,2-O-cyclohexylidene-5-C-phenyl-a-D-xylo-pento-
4.1.2. 3-O-Benzyl-1,2-O-cyclohexylidene-
a
-
D
-xylo-pentodialdo-1,4-
furano-5-ulose (12). A solution of 9 (0.42 g, 1.05 mmol) and PCC
(0.58 g, 2.67 mmol) in dry CH2Cl2 (40 mL) was heated to reflux for
2 h. The mixture was evaporated, and the residue purified by flash
furanose (8). To a stirred solution of 7 (2.20 g, 6.87 mmol) and DCC
(4.250 g, 20.60 mmol) in anhydrous DMSO (11 mL), was added dry
pyridine (0.28 mL, 3.43 mmol) and 1 M solution of anhydrous
H3PO4 in DMSO (3.4 mL). The resulting reaction mixture was stirred
at room temperature for 3.5 h, then diluted with Et2O (20 mL) and
cooled to 0 ꢁC. A solution of oxalic acid (1.73 g, 13.7 mmol) in MeOH
(6 mL) was added in two portions every 5 min. The mixture was
stirred at room temperature for 10 min, then poured into 10% aq
NaCl (100 mL) and extracted with EtOAc (2ꢂ40 mL). The combined
extracts were washed with 10% aq NaHCO3 (100 mL), dried and
evaporated. Flash column chromatography (4:1 hexane/EtOAc) of
column chromatography (17:3 toluene/Et2O). Pure 12 (0.41 g, 98%)
20
was isolated as colourless syrup, [
a]
¼ꢀ59.3 (c 1.72, CHCl3),
D
Rf¼0.38 (3:2 hexane/Et2O). IR (film): nmax 1704 (C]O). 1H NMR
(CDCl3):
d
1.20–1.80 (m, 10H, C6H10), 4.27 and 4.49 (2ꢂd, 2H,
Jgem¼12.1 Hz, PhCH2), 4.42 (d, 1H, J3,4¼3.7 Hz, H-3), 4.67 (d, 1H,
J1,2¼3.6 Hz, H-2), 5.56 (d, 1H, J3,4¼3.7 Hz, H-4), 6.19 (d, 1H,
J1,2¼3.6 Hz, H-1), 6.88–7.96 (m, 10H, 2ꢂPh). 13C NMR (CDCl3):
d
23.5, 23.8, 24.8, 35.8 and 36.6 (C6H10), 71.8 (PhCH2), 81.6 (C-2),
83.4 (C-3), 83.5 (C-4),105.0 (C-1),112.9 (Cq from C6H10),127.5,127.7,
128.1, 128.3, 128.4, 133.1, 135.8, 136.3 and 136.8 (2ꢂPh), 193.9 (C-5).
LRMS (CI): m/z 395 (MþþH). HRMS (ESI): Found: 395.1845 (MþþH),
calcd for C24H27O5: 395.1853.
the residue (2.70 g) gave pure 8 (1.94 g, 89%) as an unstable pale
20
yellow syrup, [
a]
¼ꢀ41.4 (c 0.95, CHCl3); Rf¼0.27 (9:1 toluene/
D
EtOAc). Spectroscopic data of thus prepared sample 8 matched
those previously reported by us.16
4.1.6. 3-O-Benzyl-1,2-O-cyclohexylidene-5-C-phenyl-a-D-gluco-pen-
4.1.3. 3-O-Benzyl-1,2-O-cyclohexylidene-5-C-phenyl-
a
-
L
-ido-pento-
tofuranose (10). 4.1.6.1. Procedure A. To a cooled (0 ꢁC) and stirred
solution of 11 (0.31 g, 0.62 mmol) in dry CH2Cl2 (1 mL) and MeOH
(4 mL), was added 1 M NaOMe in MeOH (1 mL, 1.0 mmol). The
solution was stirred at 0 ꢁC for 1 h, and then at room temperature
for additional 1 h. An additional amount of 1 M NaOMe in MeOH
(1.1 mL, 1.1 mmol) was added to the reaction mixture and stirring
was continued for the next 22 h at room temperature. The mixture
was neutralised with glac. AcOH and the volatiles were removed by
co-distillation with toluene. Flash column chromatography of the
furanose (9). To a cooled (0 ꢁC) and stirred solution of freshly pre-
pared 8 (1.34 g, 4.20 mmol) in dry Et2O (42 mL) was added 1 M
solution of PhMgBr in Et2O (1.70 mL, 5.10 mmol). The mixture was
stirred at 0 ꢁC under atmosphere of nitrogen for 3.5 h, then neu-
tralised with 10% aq NH4Cl (105 mL) and extracted with CH2Cl2
(2ꢂ60 mL). The combined extracts were washed with aq 10% NaCl
(90 mL), dried and evaporated, and the residue purified by flash
column chromatography (9:1 light petroleum/EtOAc). The minor
stereoisomer 10 (0.22 g,13%) was first eluted, followed by the major
residue (4:1 hexane/Et2O), gave pure 10 (0.24 g, 99%) as a colourless
20
product 9 (1.15 g, 69%). Pure 9 was isolated as a colourless oil,
oil, [
a
]
¼ꢀ57.0 (c 1.0, CHCl3); Rf¼0.46 (3:2 hexane/Et2O).
D
20
[
a]
¼ꢀ21.6 (c 0.88, CHCl3), Rf¼0.26 (3:2 hexane/Et2O). IR (neat):
D
nmax 3477 (OH). 1H NMR (CDCl3):
d
1.20–1.80 (m, 10H, C6H10), 3.01
4.1.6.2. Procedure B. To a solution of 12 (0.41 g, 1.03 mmol) in
MeOH (10 mL) was added NaBH4 (0.08 g, 2.26 mmol) and the
mixture was stirred at room temperature for 2 h. The mixture was
evaporated, and the residue purified by flash column chromatog-
(br s, 1H, exchangeable with D2O, OH), 3.65 (d, 1H, J3,4¼3.0 Hz, H-3),
4.32 and 4.58 (2ꢂd, 1H each, Jgem¼11.7 Hz, PhCH2), 4.34 (dd, 1H,
J3,4¼3.0, J4,5¼7.6 Hz, H-4), 4.62 (d, 1H, J1,2¼3.8 Hz, H-2), 5.08 (d, 1H,
J4,5¼7.6 Hz, H-5), 6.04 (d, 1H, J1,2¼3.8 Hz, H-1), 7.28–7.46 (m, 10H,
raphy (9:1 toluene/Et2O). The major stereoisomer 10 (0.35 g, 87%)
2ꢂPh). 13C NMR (CDCl3):
d
23.5, 23.8, 24.8, 35.6 and 36.3 (5ꢂCH2),
was first isolated as a colourless oil, [
a
]
¼ꢀ57.0 (c 1.0, CHCl3),
20
D
71.7 (PhCH2), 72.3 (C-5), 81.6 (C-2), 82.2 (C-3), 84.4 (C-4), 104.6
(C-1), 112.5 (Cq from C6H10), 127.0, 127.5, 127.87, 127.91, 128.16,
128.22, 128.3, 128.4 and 139.7 (2ꢂPh). LRMS (CI): m/z 397 (MþþH),
379 (MþþH–H2O). Anal. Found: C, 73.00; H, 7.49. Calcd for
C24H28O5: C, 72.70; H, 7.12.
Rf¼0.46 (3:2 hexane/Et2O). Eluted second was pure 9 (0.050 g, 12%),
20
D
isolated as a colourless syrup, [
a
]
¼ꢀ21.6 (c 0.88, CHCl3), Rf¼0.26
(3:2 hexane/Et2O). For spectroscopic data of 9 see Section 4.1.3.
4.1.6.3. Procedure C. To a suspension of L-tartaric acid (0.51 g,
3.41 mmol) in dry THF (5 mL) was added NaBH4 (0.13 g, 3.41 mmol)
portionwise and the suspension was heated at reflux for 2 h before
being cooled to ꢀ7 ꢁC. A solution of 12 (0.22 g, 0.57 mmol) in dry
THF (5 mL) was added dropwise and the temperature maintained
at ꢀ7 ꢁC for 1 h and then at 0 ꢁC for the next 2 h. The mixture was
evaporated with silica gel (1 g) and the residue was purified on
4.1.4. 5-O-Benzoyl-3-O-benzyl-1,2-O-cyclohexylidene-5-C-phenyl-
D
a-
-gluco-pentofuranose (11). To a cooled (0 ꢁC) and stirred solution
of 9 (0.54 g, 1.34 mmol), benzoic acid (0.22 g, 1.76 mmol) and Ph3P
(0.68 g, 2.58 mmol) in dry THF (5 mL), was added dropwise over
a period of 5 min a solution of DEAD (0.34 mL, 2.16 mmol) in dry
THF (5 mL). The solution was stirred at 0 ꢁC for 1 h, and then at
room temperature for additional 2 h. The mixture was quenched
a column of flash silica (7:3 light petroleum/Et2O). Pure 10 (0.219 g,
20
97%) was isolated as a colourless syrup, [
a
]
¼ꢀ57.0 (c 1.0, CHCl3);
D

V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
10603
Rf¼0.46 (3:2 hexane/Et2O). IR (neat): nmax 3480 (OH). 1H NMR
82.9 (C-6), 87.4 (C-4), 125.8, 128.5, 128.8 and 138.8 (Ph), 175.4 (C-1).
LRMS (CI): m/z 501 (2 MþþH), 251 (MþþH), 233 (MþþHꢀH2O).
HRMS (ESI): Found: 251.0912 (MþþH), calcd for C13H15O5:
251.0914.
(CDCl3): d 1.17–1.85 (m, 10H, C6H10), 3.39 (d, 1H, exchangeable with
D2O, J¼6.1 Hz, OH), 4.03 (d, 1H, J3,4¼3.2 Hz, H-3), 4.34 (dd, 1H,
J3,4¼3.2, J4,5¼6.1 Hz, H-4), 4.48 and 4.71 (2ꢂd, 1H each,
Jgem¼11.4 Hz, PhCH2), 4.63 (d, 1H, J1,2¼3.8 Hz, H-2), 5.11 (t, 1H,
J5,OH¼J4,5¼6.1 Hz, H-5), 6.05 (d, 1H, J1,2¼3.8 Hz, H-1), 7.12–7.60 (m,
4.1.10. 3-O-Benzyl-5-C-phenyl-L-ido-pentopyranose (15). A solution
10H, 2ꢂPh). 13C NMR (CDCl3):
d
23.5, 23.8, 24.8, 35.6 and 36.3
of 9 (0.87 g, 2.2 mmol) in 70% aq AcOH (26 mL) was stirred for 4.5 h
at reflux. After the mixture cooled to room temperature it was
concentrated by co-distillation with toluene and the residue
(0.79 g) purified by flash column chromatography (7:3 light pe-
troleum/Et2O). The minor product 20 (0.06 g, 9%) was first isolated
(5ꢂCH2), 72.0 (C-5), 72.2 (PhCH2), 81.2 (C-2), 82.4 (C-4), 82.9 (C-3),
104.7 (C-1), 112.3 (Cq from C6H10), 126.0, 127.5, 127.9, 128.3, 128.34,
128.4, 128.7, 136.7, 141.3 (2ꢂPh). LRMS (CI): m/z 397 (MþþH). Anal.
Found: C, 73.05; H, 7.52. Calcd for C24H28O5: C, 72.70; H, 7.12.
as a colourless solid. Recrystallization from CH2Cl2/hexane gave
20
4.1.7. 3-O-Benzyl-5-C-phenyl-
D
-gluco-pentopyranose (13). A solu-
colourless needles, mp 116 ꢁC, [
a]
¼ꢀ3.2 (c 1.15, CHCl3), Rf¼0.33
D
tion of 10 (0.24 g, 0.61 mmol) in 70% aq AcOH (12 mL) was stirred
for 4 h at reflux. After the mixture cooled to room temperature it
was concentrated by co-distillation with toluene and the residue
purified by flash chromatography (7:3 CH2Cl2/EtOAc), to afford pure
13 (0.17 g, 87%) as a colourless solid. Recrystallization from MeOH/
(7:3 light petroleum/Et2O). IR (film): nmax 3285 (OH). 1H NMR
(CDCl3):
d
2.10 (d, 1H, exchangeable with D2O, J¼7.8 Hz, OH), 3.82
(ddd, 1H, J2,3¼1.4, J1,3¼0.9, J3,4¼4.8 Hz, H-3), 3.97 (ddd, 1H, J1,2¼1.1,
J2,3¼1.4, J2,OH¼7.8 Hz, H-2), 4.53 (d, 1H, J3,4¼4.8 Hz, H-4), 4.63 and
4.76 (2ꢂd, 1H each, Jgem¼11.8 Hz, PhCH2), 5.23 (s, 1H, H-5), 5.56 (d,
1H, J1,2¼1.1 Hz, H-1), 7.28–7.55 (m, 10H, 2ꢂPh). 13C NMR (CDCl3):
CH2Cl2 gave an analytical sample 13, as colourless needles, mp 153–
20
155 ꢁC, [
a]
¼þ23.7 (c 0.94, Py), after 77 h mutarotated to þ39.6;
d 73.2 (PhCH2), 73.5 (C-5), 77.9 (C-2), 81.4 (C-4), 86.1 (C-3), 104.9 (C-
D
Rf¼0.34 (7:3 CH2Cl2/EtOAc). IR (KBr): nmax 3396 (OH). 1H NMR
1), 126.4, 127.8, 128.0, 128.2, 128.6, 137.3 and 140.0 (2ꢂPh). LRMS
(CI): m/z 338 (MþþC4H10–H2O), 301 (MþþH). Anal. Found: C, 72.47;
H, 6.08. Calcd for C18H18O4: C, 72.28; H, 6.19. Eluted second was the
major product 15 slightly contaminated with unreacted starting
material 9. Repeated purification on a column of flash silica (3:1
(methanol-d4):
d
3.39–3.62 (m, 2.4H), 3.68 (dd, 0.3H, J¼3.6, 9.5 Hz),
3.81 (t, 0.3H, J¼9.5 Hz), 4.22 (d, 0.7H, J¼9.0 Hz), 4.66 (d, 0.7H,
J¼7.3 Hz), 4.76 (d, 0.3H, J¼9.8 Hz), 4.90–5.00 (m, 2H), 5.20 (d, 0.3H,
J¼3.6 Hz), 7.20–7.52 (m, 10H, 2ꢂPh). 13C NMR (methanol-d4):
d 74.1,
75.0, 76.1, 76.4, 76.5, 76.8, 79.9, 83.6, 86.2, 94.4, 98.6, 128.5, 128.9,
129.1, 140.4, 140.9. MS (CI): m/z 317 (MþþH), 299 (MþþHꢀH2O).
Anal. Found: C, 68.11; H, 6.57. Calcd for C18H20O5: C, 68.34; H, 6.37.
toluene/Et2O) gave pure 15 (0.443 g, 64%) as a colourless syrup,
20
[a
]
¼þ15.7 (c 1.65, CHCl3), Rf¼0.19 (3:1 toluene/Et2O). IR (CHCl3):
D
nmax 3396 (OH). 1H NMR (CDCl3þD2O):
d 3.78 (m, 2H), 4.02 (t, 1H,
J¼3.0 Hz), 4.61 and 4.69 (2ꢂd, 1H each, Jgem¼11.5 Hz, PhCH2), 4.99
4.1.8. 3,6-Anhydro-5-O-benzyl-2-deoxy-7-C-phenyl-D-glycero-D-ido-
(br s,1H), 5.11 (br s,1H), 7.22–7.47 (m,10H, 2ꢂPh). 13C NMR (CDCl3):
heptono-1,4-lactone (14). To a solution of 13 (0.37 g, 1.17 mmol) in
dry DMF (4 mL) was added Meldrum’s acid (0.49 g, 3.39 mmol) and
dry Et3N (0.48 mL, 3.44 mmol). The mixture was stirred for 76 h at
46 ꢁC and then evaporated. The residue was purified by flash col-
umn chromatography (1:1/3:2 Et2O/light petroleum) to afford
pure 14 (0.165 g, 52% calculated to reacted starting compound 13)
b-anomer: d 67.9, 69.6, 72.4, 75.1, 76.0, 93.0, 126.1, 127.4, 127.6, 127.7,
127.9, 128.0, 128.5, 137.3; a-anomer: d 65.9, 67.6, 69.4, 73.3, 75.6,
96.0. LRMS (ESI): m/z 598 (2 MþþH–2H2O), 300 (MþþHꢀH2O).
Anal. Found: C, 67.98; H, 6.52. Calcd for C18H20O5: C, 68.34; H, 6.37.
4.1.11. 3,6-Anhydro-5-O-benzyl-2-deoxy-7-C-phenyl-L-glicero-D-ido-
as a colourless solid. Recrystallization from Et2O/EtOAc/hexane
heptono-1,4-lactone (16). To a solution of 15 (0.89 g, 2.82 mmol) in
dry DMF (12 mL) was added Meldrum’s acid (1.28 g, 8.88 mmol)
and dry Et3N (1.2 mL, 8.61 mmol). The mixture was stirred for 70 h
at 46 ꢁC and then evaporated. The residue was purified by flash
column chromatography (4:1 Et2O/light petroleum) to afford
slightly impure 16 (0.55 g) as a colourless solid. Recrystallization
from CH2Cl2/hexane gave colourless needles of pure 16 (0.29 g).
Mother liquor was purified by flash column chromatography (9:1
20
gave colourless crystals, mp 40–42 ꢁC, [
a
]
¼ꢀ4.34 (c 1.06, CHCl3),
D
Rf¼0.30 (3:2 Et2O/light petroleum). IR (CHCl3): nmax 3476 (OH),
1785 (C]O). 1H NMR (CDCl3þD2O):
d
2.61 (dd, 1H, J2a,2b¼18.8,
J2a,3¼1.5 Hz, H-2a), 2.71 (dd, 1H, J2a,2b¼18.8, J2b,3¼5.4 Hz, H-2b),
2.87 (d, 1H, exchangeable with D2O, J¼5.7 Hz, OH), 4.21 (dd, 1H,
J5,6¼3.6, J6,7¼7.2 Hz, H-6), 4.30 (d, 1H, J5,6¼3.6 Hz, H-5), 4.61 and
4.71 (2ꢂd, 1H each, Jgem¼11.6 Hz, PhCH2), 4.92 (d, 1H, J3,4¼4.4 Hz,
H-4), 5.01 (m, 2H, H-3 and H-7), 7.30–7.47 (m, 10H, 2ꢂPh). 13C NMR
CH2Cl2/EtOAc) to give an additional amount of pure 16 (0.16 g).
20
(CDCl3):
d
35.9 (C-2), 71.7 (C-7), 73.1 (PhCH2), 77.2 (C-3), 81.7 (C-5),
Total yield of pure 16 was 0.45 g (47%). Mp 146–147 ꢁC, [
a
]
¼þ40.0
D
83.2 (C-6), 84.7 (C-4), 126.2, 127.9, 128.1, 128.5, 128.6, 128.8, 136.4
and 140.9 (2ꢂPh), 175.3 (C-1). LRMS (CI): m/z 341 (MþþH). Anal.
Found: C, 70.19; H, 6.11. Calcd for C20H20O5: C, 70.57; H, 5.92. Eluted
second was unchanged 13 (0.077 g, 21%).
(c 0.67, CHCl3), Rf¼0.26 (1:1 toluene/Et2O); lit.8a mp 146–148 ꢁC,
[a
]D¼þ25.5 (c 0.67, CHCl3). IR (KBr): nmax 3469 (OH), 1754 (C]O). 1H
NMR (CDCl3):
d
2.75 (m, 3H, 2ꢂH-2 and OH), 3.93 (d, 1H,
J5,6¼3.9 Hz, H-5), 4.26 (dd, 1H, J5,6¼3.9, J6,7¼6.6 Hz, H-6), 4.45 and
4.55 (2ꢂd, 1H each, Jgem¼11.5 Hz, PhCH2), 4.92 (d, 1H, J3,4¼4.7 Hz,
H-4), 5.09 (d, 1H, J6,7¼6.6 Hz, H-7), 5.11 (m, 1H, H-3), 7.28–7.45 (m,
4.1.9. (þ)-Goniofufurone (1). A solution of 14 (0.082 g, 0.24 mmol)
in MeOH (4 mL) was hydrogenated over 10% Pd/C (0.02 g) for 46 h
at room temperature. The mixture was filtered and the catalyst
washed with EtOAc. The combined organic solutions were evapo-
rated and the residue was purified by flash chromatography (7:3
CH2Cl2/EtOAc), to afford pure 1 (0.058 g, 97%) as a colourless solid.
10H, 2ꢂPh). 13C NMR (CDCl3):
d 36.0 (C-2), 72.7 (C-7), 72.8 (PhCH2),
77.4 (C-3), 81.8 (C-5), 84.6 (C-6), 85.1 (C-4),126.9,127.8,128.3,128.4,
128.5, 128.7, 136.5 and 139.5 (2ꢂPh), 175.2 (C-1). LRMS (ESI): m/z
341 (MþþH).
Recrystallization from EtOAc/hexane gave colourless prisms, mp
4.1.12. 7-epi-(þ)-Goniofufurone (2). A solution of 16 (0.08 g,
0.24 mmol) in MeOH (3.6 mL) was hydrogenated over 10% Pd/C
(0.02 g, 0.015 mmol) for 72 h at room temperature. The mixture was
filtered and the catalyst washed with MeOH. The combined organic
solutions were evaporated and the residue (0.074 g) was purified by
flash chromatography (49:1/24:1/19:1 CH2Cl2/MeOH), to afford
pure 2 (0.051 g, 87%) asa colourless crystalline mass. Recrystallization
20
154–155 ꢁC, [
a
]
¼þ39.2 (c 0.94, CHCl3), Rf¼0.19 (7:3 CH2Cl2/
20
D
D
EtOAc); lit.8h mp 154–156 ꢁC, [
a
]
¼þ39.5 (c 1.0, CHCl3). IR (KBr):
nmax 3410 (OH), 1755 (C]O). 1H NMR (CDCl3):
d
2.61 (d, 1H,
J2a,2b¼18.7 Hz, H-2a), 2.74 (dd, 1H, J2a,2b¼18.7, J2b,3¼5.6 Hz, H-2b),
4.05 (dd, 1H, J5,6¼2.7, J6,7¼5.3 Hz, H-6), 4.43 (d, 1H, J5,6¼2.7 Hz, H-
5), 4.87 (d, 1H, Hz J3,4¼4.2 Hz, H-4), 5.08 (dd, 1H, J2b,3¼5.6,
J3,4¼4.2 Hz, H-3), 5.12 (d, 1H, J6,7¼5.3 Hz, H-7), 7.30–7.44 (m, 5H,
fromMe2CO/lightpetroleumgavecolourlessneedles,mp197–200 ꢁC,
Ph). 13C NMR (CDCl3):
d
36.1 (C-2), 73.5 (C-7), 74.4 (C-5), 77.3 (C-3),
[a]
¼þ108.5 (c 0.75, EtOH), Rf¼0.40 (7:3 hexane/EtOAc); lit.8a mp
20
D

10604
V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
15
20
200–203 ꢁC,[
a]
¼þ102.0 (c0.5,EtOH);IR(KBr):nmax 3368and3283
[
a
]
¼þ68.8 (c 0.5, EtOAc), Rf¼0.26 (7:3 EtOAc/hexane). IR (KBr):
D
D
(OH), 1755 (C]O). 1H NMR (DMSO-d6þD2O):
d
2.50 (d, 1H,
nmax 3403 (OH), 1702 (C]O), 1629 (C]C). 1H NMR (acetone-d6):
J2a,2b¼18.6 Hz, H-2a), 2.85 (dd, 1H, J2a,2b¼18.6, J2b,3¼6.4 Hz, H-2b),
3.59 (d, 1H, J5,6¼2.8 Hz, H-5), 3.82 (dd, 1H, J5,6¼2.8, J6,7¼7.9 Hz, H-6),
4.73 (d, 1H, J6,7¼7.9 Hz, H-7), 4.78 (d, 1H, J3,4¼4.6 Hz, H-4), 4.93 (dd,
1H, J3,4¼4.6, J2b,3¼6.4 Hz, H-3), 7.20–7.38 (m, 5H, Ph). 13C NMR
d
3.92 (dd, 0.3H, J¼3.8, 2.4 Hz), 4.10–4.40 (m, 1.7H), 4.40–4.56 (m,
1H), 4.99 (s, 0.7H), 5.35 (d, 0.3H, J¼3.8 Hz), 5.87 (d, 0.3H, J¼9.0 Hz),
6.00 (d, 0.7H, J¼9.8 Hz), 6.52 (d, 0.3H, J¼16 Hz), 6.52 (d, 0.7H,
J¼16.0 Hz), 7.31–7.59 (m,11H).13C NMR (acetone-d6):
d 73.79, 74.26,
(DMSO-d6):
d
36.7 (C-2), 72.6 (C-7), 73.6 (C-5), 77.8 (C-3), 85.5 (C-6),
75.98, 76.49, 77.12, 81.10, 81.31, 84.08, 98.04, 104.33, 119.01, 128.52,
128.75, 128.96, 129.72, 131.16, 135.20, 140.43, 140.51, 145.46, 165.79,
165.86. LRMS (ESI): m/z 379 (MþþNa), 339 (MþþH–H2O). HRMS
(ESI): Found: 379.1150 (MþþNa), calcd for C13H13NaO4: 379.1152.
88.8(C-4),127.9,129.0,129.4and 142.3 (Ph),178.3 (C-1). LRMS (CI): m/
z 501 (2 MþþH), 251 (MþþH), 233 (MþþH–H2O).
4.1.13. 1,2-O-Cyclohexylidene-5-C-phenyl-b-L-ido-pentofuranose
(17). A solution of 9 (0.45 g, 1.13 mmol) in MeOH (11 mL), was hy-
drogenated over 10% Pd/C (0.09 g, 0.09 mmol) for 4 h at room
temperature. The mixture was filtered and the catalyst washed with
MeOH. The combined organic solutions were evaporated and the
residue was purified by flash chromatography (3:7 hexane/Et2O) to
afford pure 17 (0.24 g, 70%) as colourless solid. Recrystallization
4.1.16. 3,5-Anhydro-1,2-O-cyclohexylidene-5-C-phenyl-a-D-gluco-
pentofuranose (21). To a cooled (0 ꢁC) and stirred solution of 17
(0.184 g, 0.60 mmol) and Ph3P (0.392 g, 1.50 mmol) in dry toluene
(5 mL), was added DEAD (0.24 mL, 1.5 mmol) dropwise over a pe-
riod of 2–3 min. The solution was stirred at reflux temperature for
1.5 h and then evaporated. Flash column chromatography of the
residue gave pure 21 (0.133 g, 77%) as a colourless solid. Re-
from CH2Cl2/hexane, gave colourless needles, mp 178–179 ꢁC,
20
[
a]
¼þ20.3 (c 1.0, CHCl3), Rf¼0.25 (7:3 Et2O/hexane). IR (KBr): nmax
crystallization from CH2Cl2/hexane afforded colourless needles, mp
D
20
3427 (OH). 1H NMR (CDCl3):
d
1.16–1.80 (m, 10H, C6H10), 3.00 (d, 1H,
88–89 ꢁC, [
a]
¼ꢀ43.6 (c 1.0, CHCl3), Rf¼0.71 (1:1 hexane/Et2O). 1H
D
exchangeable with D2O, J5,OH¼5.1 Hz, OH-5), 3.27 (d, 1H, ex-
changeable with D2O, J3,OH¼4.9 Hz, OH-3), 4.10 (dd, 1H, J3,OH¼4.9,
J3,4¼2.8 Hz, H-3), 4.32 (dd,1H, J3,4¼2.8, J4,5¼4.9 Hz, H-4), 4.49 (d,1H,
J1,2¼3.6 Hz, H-2), 5.06 (t, 1H, J4,5¼4.9, J5,OH¼5.1 Hz, H-5), 6.03 (d, 1H,
NMR (CDCl3):
d
1.32–1.76 (m, 10H, C6H10), 4.85 (dd, 1H, J3,4¼4.1,
J4,5¼2.1 Hz, H-4), 4.89 (d, 1H, J1,2¼3.6 Hz, H-2), 5.31 (d, 1H,
J3,4¼4.1 Hz, H-3), 5.34 (d, 1H, J4,5¼2.1 Hz, H-5), 6.39 (d, 1H,
J1,2¼3.6 Hz, H-1), 7.29–7.50 (m, 5H, Ph); NOE contact: H-1 and H-5.
J1,2¼3.6 Hz, H-1), 7.29–7.56 (m, 5H, Ph). 13C NMR (CDCl3):
d
23.5,
13C NMR (CDCl3):
d
23.7, 23.8, 24.8, 36.6 and 37.5 (5ꢂCH2), 84.0 (C-
23.8, 24.8, 35.6 and 36.3 (5ꢂCH2), 72.6 (C-5), 76.0 (C-3), 82.6 (C-4),
84.9 (C-2), 104.5 (C-1), 112.6 (Cq from C6H10), 126.7, 128.2, 128.6 and
140.0 (Ph). LRMS (ESI): m/z 329 (MþþNa), 307 (MþþH). Anal. Found:
C, 66.25; H, 7.44. Calcd for C17H22O5: C, 66.65; H, 7.24.
4), 84.1 (C-2), 85.0 (C-3), 90.0 (C-5), 108.0 (C-1), 114.8 (Cq from
C6H10), 125.0, 128.2, 128.7 and 138.9 (Ph). LRMS (ESI): m/z 311
(MþþNa), 289 (MþþH). Anal. Found: C, 70.56; H, 7.12. Calcd for
C17H20O4: C, 70.81; H, 6.99.
4.1.14. 1,2-O-Cyclohexylidene-5-O-cinnamoyl-5-C-phenyl-
a
-
D
-gluco-
4.1.17. (þ)-Crassalactone
C (3). To a solution of 19 (0.034 g,
pentofuranose (18). To a cooled (0 ꢁC) and stirred solution of 17
(0.16 g, 0.52 mmol), cinnamic acid (0.1 g, 0.68 mmol) and Ph3P
(0.29 g, 1.1 mmol) in dry THF (5 mL), was added DEAD (0.15 mL,
0.94 mmol) dropwise over a period of 5 min. The solution was
stirred at 0 ꢁC for 1 h, and then at room temperature for additional
2 h. The mixture was quenched with 10% aq NaHCO3 (50 mL), and
extracted with EtOAc (2ꢂ20 mL). The combined extracts were dried
and evaporated and the residue purified on a column of flash silica
(4:1/1:1 hexane/Et2O). The minor product 21 (0.037 g, 16%) was
first eluted, followed by the major product 18 (0.144 g, 63%). Re-
0.095 mmol) in dry DMF (1 mL) was added Meldrum’s acid (0.03 g,
0.19 mmol) and dry Et3N (0.03 mL, 0.19 mmol). The mixture was
stirred for 72 h at 46 ꢁC and then evaporated. The residue was
purified by flash column chromatography (17:3 Et2O/hexane) to
afford pure 3 (0.022 g, 62%) as a colourless solid. Recrystallization
from CH2Cl2/hexane gave colourless needles, mp 147–150 ꢁC,
20
[a
]
¼þ111.6 (c 0.5, EtOH), Rf¼0.46 (1:1 light petroleum/EtOAc);
D
lit.9 mp 147–150 ꢁC, [
(OH), 1784 (C]O, lactone), 1695 (C]O, cinnamoyl), 1635 (C]C,
cinnamoyl). 1H NMR (CDCl3):
a]
¼þ98.4 (c 0.5, EtOH). IR (KBr): nmax 3459
30
D
d
2.56 (d, 1H, J2a,2b¼18.6 Hz, H-2a),
crystallization from CH2Cl2/hexane gave pure 18 as colourless
2.70 (dd, 1H, J2a,2b¼18.6, J2b,3¼5.8 Hz, H-2b), 4.19 (br s, 1H, ex-
changeable with D2O, OH), 4.26 (dd, 1H, J6,7¼9.2, J5,6¼2.4 Hz, H-6),
4.43 (br s, 1H, H-5), 5.00 (m, 2H, H-3 and H-4), 6.00 (d, 1H,
20
needles, mp 127 ꢁC, [
a
]
¼þ52.5 (c 1.0, CHCl3), Rf¼0.25 (1:1 hex-
D
ane/Et2O). IR (KBr): nmax 3463 (OH), 1715 (C]O), 1636 (C]C). 1H
NMR (CDCl3): 1.20–1.80 (m, 10H, C6H10), 3.89 (d, 1H, exchangeable
0
0
0
d
J6,7¼9.2 Hz, H-7), 6.47 (d,1H, J2 ,3 ¼15.90Hz, H-2 ), 7.36–7.59 (m,10H,
2ꢂPh), 7.78 (d, 1H, J2 ,3 ¼15.9 Hz, H-3 ). 13C NMR (CDCl3):
d 35.8
0
0
with D2O, J3,OH¼2.9 Hz, OH-3), 4.23 (br s, 1H, H-3), 4.42 (dd, 1H,
J3,4¼2.1, J4,5¼9.2 Hz, H-4), 4.60 (d, 1H, J1,2¼3.6 Hz, H-2), 5.94 (d, 1H,
J1,2¼3.6 Hz, H-1), 6.07 (d, 1H, J4,5¼9.2 Hz, H-5), 6.48 (d, 1H,
(C-2), 72.8 (C-7), 73.1 (C-5), 77.1 (C-3), 82.4 (C-6), 87.0 (C-4), 116.4
(C-20), 127.6, 128.3, 128.6, 128.9, 130.9, 133.6 and 136.6 (2ꢂPh), 147.5
(C-30), 167.5 (C-10), 175.5 (C-1). LRMS (ESI): m/z 403 (MþþNa), 363
(MþþHꢀH2O).
J2 ,3 ¼16.0 Hz, H-20), 7.31–7.59 (m, 10H, 2ꢂPh), 7.76 (d, 1H,
0
0
J2 ,3 ¼16.0 Hz, H-3 ). 13C NMR (CDCl3):
d
23.5, 23.8, 24.8, 35.5 and
0
0
0
36.4 (5ꢂCH2), 72.9 (C-5), 74.0 (C-3), 81.6 (C-4), 84.0 (C-2), 104.4
(C-1), 112.3 (Cq from C6H10), 116.8 (C-20), 127.7, 128.3, 128.4, 128.6,
128.7, 128.8, 128.9, 130.8, 133.8 and 136.9 (2ꢂPh), 146.9 (C-30), 167.2
(C-10). LRMS (ESI): m/z 459 (MþþNa), 437 (MþþH). Anal. Found: C,
69.26; H, 6.39. Calcd for C26H28O6ꢂH2O: C, 68.71; H, 6.65.
4.1.18. 3,6:5,7-Dianhydro-2-deoxy-7-C-phenyl-D-glycero-D-ido-hep-
tono-1,4-lactone (4). A solution of 2 (0.036 g, 0.14 mmol) in dry
toluene (1 mL), was reacted with Ph3P (0.098 g, 0.37 mmol) and
DEAD (0.06 mL, 0.38 mmol) following the same methodology as
described above (procedure in Section 4.1.15). The mixture was
refluxed for 3 h and then evaporated. Flash column chromatogra-
phy (4:1 Et2O/light petroleum) of the residue gave slightly con-
taminated 4. Repeated purification on a column of flash silica
(CH2Cl2) gave pure 4 (0.012 g, 35%), as white solid. Recrystallization
4.1.15. 5-O-Cinnamoyl-5-C-phenyl-
D
-gluco-pentofuranose
(19). A
solution of 18 (0.21 g, 0.48 mmol) in 70% aq AcOH (7 mL) was stirred
for 4 h at reflux. After the mixture cooled to room temperature it
was concentrated by co-distillation with toluene and the residue
(0.19 g) purified by flash chromatography (7:3 EtOAc/hexane).
A minor amount of starting compound 19 (0.02 g, 15%) was first
eluted, followed by slightly contaminated diol 19. Repeated chro-
matographic purification (4:1 hexane/EtOAc) gave pure 19 (0.10 g,
59%; 67% calculated to reacted 18) as a colourless syrup. Crystalli-
zation from EtOAc/hexane gave colourless needles, mp 171 ꢁC,
from CH2Cl2/hexane afforded colourless needles, mp 145–147 ꢁC,
20
[a
]
¼þ46.0 (c 0.5, CHCl3), Rf¼0.39 CH2Cl2. IR (KBr): nmax 1730
D
(C]O). 1H NMR (CDCl3):
d
2.83 (d, 1H, J2a,2b¼18.0 Hz, H-2a), 2.92
(dd, 1H, J2a,2b¼18.0, J2b,3¼4.1 Hz, H-2b), 4.83 (dd, 1H, J5,6¼4.2,
J6,7¼2.5 Hz, H-6), 5.08 (d, 1H, J3,4¼3.6 Hz, H-4), 5.37 (dd, 1H,
J2b,3¼4.1, J3,4¼3.6 Hz, H-3), 5.49 (d, 1H, J5,6¼4.2 Hz, H-5), 5.52 (d, 1H,

V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
10605
J6,7¼2.5 Hz, H-7), 7.30–7.49 (m, 5H, Ph); NOE contact: H-3 and H-7.
13C NMR (CDCl3):
36.0 (C-2), 79.2 (C-3), 84.9 (C-4), 85.1 (C-6), 85.3
(C-5), 89.1 (C-7), 125.0, 128.5, 128.8 and 138.6 (Ph), 174.1 (C-1).
HRMS (ESI): Found: 233.0813 (MþþH), calcd for C13H13O4:
233.0808.
(CDCl3):
d
2.64 (d, 1H, exchangeable with D2O, J2,OH¼5.1 Hz, OH),
d
3.30 and 3.43 (2ꢂs, 3H each, 2ꢂOCH3), 3.56 (br s, after treatment
with D2O, dd, 1H, J1,2¼6.4, J2,3¼2.2 Hz, H-2), 3.75 (dd, 1H, J2,3¼2.2,
J3,4¼6.2 Hz, H-3), 4.40 (d, 1H, J1,2¼6.4 Hz, H-1), 4.63 and 4.86 (2ꢂd,
2H, Jgem¼11.3 Hz, PhCH2), 5.29 (dd, 1H, J3,4¼6.2, J4,5¼1.6, J4,6¼2.1 Hz,
H-4), 6.16 (dd, 1H, J5,6¼5.8, J4,6¼2.1, Hz, H-6), 7.31–7.37 (m, 5H, Ph),
4.1.19. Methyl (Z)-3-O-benzyl-5,6-dideoxy-1,2-O-cyclohexylidene-
D
a
-
7.57 (dd, 1H, J4,5¼1.6, J5,6¼5.8 Hz, H-5). 13C NMR (CDCl3):
d 54.5 and
-xylo-hept-5-enofuranuronate (22). To a cooled (0 ꢁC) and stirred
55.4 (2ꢂOCH3), 70.4 (C-2), 74.2 (PhCH2), 78.3 (C-3), 84.6 (C-4),103.8
(C-1), 122.0 (C-6), 128.1, 128.3, 128.4 and 137.3 (Ph), 153.9 (C-5),
172.8 (C]O). LRMS (CI): m/z 584 (2 Mþ–MeOH), 309 (MþþH), 277
(MHþ–MeOH).
solution of aldehyde 8 (1.38 g, 4.33 mmol) in dry MeOH (35 mL)
was added Ph3P¼CHCO2Me (1.812 g, 5.42 mmol). The mixture was
stirred at 0 ꢁC for 0.5 h and then at room temperature for 1.5 h. The
solvent was evaporated and the residue purified by flash column
chromatography (4:1 light petroleum/Et2O), to give pure (Z)-iso-
4.1.21. 2,5-Anhydro-3-O-benzyl-6-deoxy-L-ido-hepturono-4,7-lac-
20
mer 22 (1.35 g, 83%) as a colourless syrup, [
a
]
¼ꢀ262.1 (c 1.04,
tone (25). A solution of 24 (0.66 g, 2.16 mmol) in a mixture of TFA/
H2O (9:1, 4.2 mL) was first stirred at 0 ꢁC for 0.5 h and then at room
temperature for 0.5 h. The volatiles were removed by co-distillation
with toluene and the residue purified by flash column chroma-
D
CHCl3); Rf¼0.28 (17:3 light petroleum/Et2O). IR (neat): nmax 1721
(C]O), 1652 (C]C). 1H NMR (CDCl3):
d
1.33–1.81 (m, 10H, C6H10),
3.68 (s, 3H, CO2CH3), 4.31 (d, 1H, J3,4¼3.3 Hz, H-3), 4.57 and 4.62
(2ꢂd, 2H, Jgem¼12.0 Hz, PhCH2), 4.64 (d, 1H, J1,2¼3.8 Hz, H-2), 5.65
(ddd, 1H, J3,4¼3.3, J4,5¼6.7, J4,6¼1.7 Hz, H-4), 5.93 (dd, 1H, J4,6¼1.7,
J5,6¼11.7 Hz, H-6), 6.02 (d, 1H, J1,2¼3.8 Hz, H-1), 6.41 (dd, 1H,
J4,5¼6.7, J5,6¼11.7 Hz, H-5), 7.22–7.37 (m, 5H, Ph). 13C NMR (CDCl3):
tography (1:1 light petroleum/EtOAc). Eluted first was pure 25
20
(0.508 g, 90%) as a colourless syrup, [
a]
¼ꢀ21.3 (c 1.05, CHCl3);
D
Rf¼0.20 (1:1 light petroleum/EtOAc). Eluted second was the mix-
ture of 24 and 25 (0.07 g), which was again subjected to hydrolysis
and chromatographic purification by using the same procedure as
described above, to afford an additional amount of pure 25
(0.025 g). Total yield of pure 25 was 0.533 g (94%). IR (neat): nmax
d
23.6, 23.9, 24.9, 35.9 and 36.6 (5ꢂCH2), 51.3 (CO2CH3), 72.2
(PhCH2), 78.0 (C-4), 82.7 (C-2), 84.0 (C-3), 104.7 (C-1), 112.5 (Cq
from C6H10), 120.5 (C-6), 127.6, 127.8, 128.3 and 137.5 (Ph), 145.8 (C-
5),165.9 (C-7). LRMS (CI): m/z 375 (MþþH). Anal. Found: C, 67.10; H,
7.17. Calcd for C21H26O6: C, 67.36; H, 7.00. Further elution of the
1788 (C]O). 1H NMR (CDCl3):
d
2.75 (d, 2H, J5,6¼3.4 Hz, 2ꢂH-6),
4.49–4.69 (m, 4H, H-2, H-3 and PhCH2), 4.91 (d, 1H, J4,5¼4.0 Hz, H-
4), 5.14 (dd, 1H, J4,5¼4.0, J5,6¼3.4 Hz, H-5), 7.23–7.40 (m, 5H, Ph),
column gave pure (E)-isomer 22a (0.193 g, 12%) as a colourless
20
syrup, [
a
]
D
¼ꢀ45.0 (c 1.09, CHCl3); Rf¼0.22 (17:3 light petroleum/
9.61 (d, 1H, J1,2¼1.2 Hz, CHO). 13C NMR (CDCl3):
d 35.9 (C-6), 73.0
Et2O). IR (neat): nmax 1724 (C]O), 1665 (C]C). 1H NMR (CDCl3):
1.30–1.79 (m, 10H, C6H10), 3.76 (s, 3H, CO2CH3), 4.00 (d, 1H,
(PhCH2), 78.8 (C-5), 82.9 (C-3), 84.7 (C-4), 84.9 (C-2), 127.8, 128.4,
128.6 and 136.1 (Ph), 174.3 (C-7), 198.6 (C-1). LRMS (CI): m/z 263
(MþþH). HRMS (ESI): Found: 263.0917 (MþþH), calcd for C14H15O5:
263.0914.
d
J3,4¼3.3 Hz, H-3), 4.50 and 4.63 (2ꢂd, 2H, Jgem¼12.1 Hz, PhCH2),
4.64 (d, 1H, J1,2¼3.7 Hz, H-2), 4.80 (ddd, 1H, J3,4¼3.3, J4,5¼4.9,
J4,6¼1.7 Hz, H-4), 6.00 (d, 1H, J1,2¼3.7 Hz, H-1), 6.19 (dd, 1H, J4,6¼1.7,
J5,6¼15.8 Hz, H-6), 6.98 (dd, 1H, J4,5¼4.9, J5,6¼15.8 Hz, H-5),
4.1.22. 3,6-Anhydro-5-O-benzyl-2-deoxy-7-C-phenyl-D-glicero-L-
7.24–7.39 (m, 5H, Ph). 13C NMR (CDCl3):
d
23.5, 23.8, 24.8, 35.7 and
ido-heptono-1,4-lactone (ent-16). A solution of 24 (0.66 g,
2.16 mmol) in a mixture of 9:1 TFA/H2O (4.2 mL) was first stirred
at 0 ꢁC for 0.5 h and then at room temperature for 0.5 h. The
volatiles were removed by co-distillation with toluene, and the
remaining crude 25 (0.19 g) was dissolved in dry THF (10 mL) and
cooled to ꢀ7 ꢁC. To this solution was added a 3 M solution of
PhMgBr in Et2O (0.26 mL, 0.78 mmol). The mixture was stirred at
ꢀ7 ꢁC, under an atmosphere of nitrogen for 3 h, and then neu-
tralised with 5% AcOH in THF (to pH 7). The mixture was poured to
10% aq NaCl (100 mL) and extracted with CH2Cl2 (2ꢂ40 mL). The
combined extracts were washed with 10% aq NaCl (100 mL), dried
and evaporated, and the residue purified by flash column chro-
matography (5:1 Et2O/light petroleum). The pure minor stereo-
isomer ent-14 (0.008 g, 3%) was first eluted that crystallized from
36.5 (5ꢂCH2), 51.5 (CO2CH3), 72.2 (PhCH2), 79.4 (C-4), 82.4 (C-2),
83.1 (C-3), 104.6 (C-1), 112.6 (Cq from C6H10), 122.7 (C-6), 127.7,
127.9, 128.4 and 137.1 (Ph), 141.8 (C-5), 166.4 (C-7). LRMS (CI): m/z
375 (MþþH). Anal. Found: C, 66.97; H, 7.00. Calcd for C21H26O6: C,
67.36; H, 7.00.
4.1.20. 2,5-Anhydro-3-O-benzyl-6-deoxy-L-ido-hepturono-4,7-lac-
tone dimethyl acetal (24). A solution containing 2.5% H2SO4 in dry
MeOH (60 mL) and 22 (1.7 g, 4.54 mmol) was stirred under reflux
for 4.5 h. The mixture was cooled to 35 ꢁC, then rendered alkaline
(to pH¼9) by addition of NaHCO3 (5.5 g, 65.48 mmol) in portions
(1.0 g) every 5 min. The resulting suspension was stirred at 35 ꢁC for
1 h, then filtered and evaporated. The residue was purified by flash
column chromatography (1:3 light petroleum/EtOAc). Eluted first
was pure 24 (1.04 g, 74%), isolated as a colourless solid. Re-
a mixture Me2CO/hexane as colourless needles, mp 43–44 ꢁC,
20
[
a
]
¼þ6.1 (c 0.5, CHCl3); Rf¼0.63 (1:1 EtOAc/light petroleum). IR,
D
crystallization from EtOAc/light petroleum gave an analytical
1H and 13C NMR spectroscopic data of ent-14 were consistent with
those recorded for the opposite enantiomer 14 (Section 4.1.8).
HRMS (ESI): Found: 363.1191 (MþþNa), calcd for C22H20NaO6:
363.1203. Eluted second was the major stereoisomer ent-16
20
sample 24 as colourless needles, mp 90 ꢁC, [
a]
¼ꢀ20.7 (c 1.04,
D
CHCl3); Rf¼0.44 (7:3 light petroleum/Et2O). IR (KBr): nmax 1790
(C]O). 1H NMR (acetone-d6):
d
2.50 (d, 1H, J6a,6b¼18.8 Hz, H-6a),
2.87 (dd, 1H, J6a,6b¼18.8, J5,6b¼6.5 Hz, H-6b), 3.35 and 3.36 (2ꢂs, 3H
each, 2ꢂOCH3), 4.01 (dd, 1H, J1,2¼7.5, J2,3¼3.5 Hz, H-2), 4.19 (d, 1H,
J2,3¼3.5 Hz, H-3), 4.59 (d, 1H, J1,2¼7.5 Hz, H-1), 4.63 and 4.76 (2ꢂd,
2H, Jgem¼11.6 Hz, PhCH2), 4.97 (dd, 1H, J4,5¼4.4, J5,6b¼6.5 Hz, H-5),
5.09 (d, 1H, J4,5¼4.4 Hz, H-4), 7.26–7.45 (m, 5H, Ph). 13C NMR (ac-
(0.15 g, 56%) that crystallized from CH2Cl2/hexane as colourless
20
needles, mp 145–147 ꢁC, [
a
]
¼ꢀ34.0 (c 0.95, CHCl3); Rf¼0.25
D
(9:11 EtOAc/light petroleum). IR, 1H and 13C NMR spectroscopic
data of ent-16 were consistent with those recorded for the op-
posite enantiomer 16 (Section 4.1.11). HRMS (ESI): Found:
363.1193 (MþþNa), calcd for C22H20NaO6: 363.1203.
etone-d6):
d
36.4 (C-6), 53.1 and 55.1 (2ꢂOCH3), 73.0 (PhCH2), 78.4
(C-5), 80.4 (C-2), 82.4 (C-3), 85.4 (C-4), 102.9 (C-1), 128.6, 128.7,
129.1 and 138.8 (Ph), 176.0 (C-7). LRMS (CI): m/z 309 (MþþH).
HRMS (ESI): Found: 347.0891 (MþþK), calcd for C16H20KO6:
4.1.23. 3,6-Anhydro-5-O-benzyl-2-deoxy-7-C-phenyl-L-ido-hept-7-
ulosono-1,4-lactone (26). A solution of ent-17 (0.06 g, 0.18 mmol)
and PCC (0.1 g, 0.44 mmol) in dry CH2Cl2 (10 mL) was heated to
reflux for 2 h. The mixture was evaporated and the residue was
purified by flash column chromatography (3:2 cyclohexane/EtOAc),
347.0891. Eluted second was pure 23 (0.056 g, 4%) as a colourless
20
syrup, [
a
]
¼þ63.0 (c 1.85, CHCl3); Rf¼0.25 (3:2 toluene/EtOAc). IR
D
(neat): nmax 3465 (OH), 1785 and 1755 (C]O), 1600 (C]C). 1H NMR

10606
V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
to give pure 26 (0.05 g, 84%) as a colourless syrup. Crystallization
(Section 4.1.18). HRMS (ESI): Found: 233.0805 (MþþH), calcd for
from CH2Cl2/hexane gave colourless needles, mp 119–121 ꢁC,
C13H13O4: 233.0808.
20
[
a]
¼ꢀ3.8 (c 0.5, CHCl3); Rf¼0.33 (3:2 cyclohexane/EtOAc). IR
D
(CHCl3): nmax 1788 (C1]O), 1701 (C7]O). 1H NMR (CDCl3):
d 2.79
4.2. X-ray crystal structure determination29
(d, 2H, J2,3¼3.2 Hz, 2ꢂH-2), 4.27 and 4.45 (2ꢂd, 2H, Jgem¼12.0 Hz,
PhCH2), 4.66 (d, 1H, J5,6¼5.1 Hz, H-5), 4.95 (d, 1H, J3,4¼4.1 Hz, H-4),
5.26 (m, 1H, H-3), 5.61 (d, 1H, J5,6¼5.1 Hz, H-6), 6.80–7.93 (m, 10H,
A single colourless crystal of ent-4 was selected and glued on
glass fibber. Diffraction data were collected on an Oxford Diffraction
KM4 four-circle goniometer equipped with Sapphire CCD detector.
The crystal to detector distance was 45.0 mm and a graphite
2ꢂPh). 13C NMR (CDCl3):
d 35.9 (C-2), 72.4 (PhCH2), 78.3 (C-3), 82.4
(C-5), 83.2 (C-6), 84.9 (C-4), 127.7, 127.8, 128.0, 128.3, 128.6, 133.3,
135.5, and 135.6 (2ꢂPh), 174.8 (C-1), 194.1 (C-7). HRMS (ESI):
Found: 339.1238 (MþþH), calcd for C20H19O5: 339.1233.
monochromated MoKa (l¼0.71073 Å) X-radiation was employed in
the measurement. The frame widths of 0.3ꢁ and 2ꢁ in
u
, with 10 and
200 s were used to acquire each frame. More than a hemisphere of
three-dimensional data was collected. The data were reduced using
4.1.24. 3,6-Anhydro-5-O-benzyl-2-deoxy-7-C-phenyl-
L-glycero-L-
ido-heptono-1,4-lactone (ent-14). To solution of 26 (0.05 g,
a
the Oxford Diffraction program CrysAlisPro.
A semiempirical
0.15 mmol) in MeOH (10 mL) was added NaBH4 (0.006 g, 0.16 mmol)
in six equal portions and the mixture was stirred at ꢀ7 ꢁC for 3.5 h.
The mixture was neutralised with glac AcOH and evaporated. The
residue was purified by flash column chromatography (3:2 cyclo-
hexane/EtOAc). Pure ent-14 (0.023 g, 54%) was first eluted that
absorption-correction based upon the intensities of equivalent re-
flections was applied, and the data were corrected for Lorentz,
polarization, and background effects. Scattering curves for neutral
atoms, together with anomalous-dispersion corrections, were
taken from International Tables for X-ray Crystallography.30 The
structure was solved by direct methods (SHELXS-97).31 Refinement
was based on F2 values and done by full-matrix least-squares
(SHELXL-97)32 with all non-H atoms anisotropic. 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 final refinement included atomic positional and
displacement parameters for all non-H atoms. The non-H atoms
were refined anisotropically, while H sites were refined with iso-
tropic displacement parameters. However, at the final stage of the
refinement, H atoms were positioned geometrically (N–H¼0.86, O–
H¼0.82 and C–H¼0.93–0.97 Å) and refined using a riding model
with fixed isotropic displacement parameters. The crystal data and
refinement parameters are listed in Table 2.
crystallized from a mixture Me2CO/hexane as colourless needles, mp
20
43–44 ꢁC, [
a]
D
¼þ6.1 (c 0.5, CHCl3); Rf¼0.63 (1:1 EtOAc/light petro-
leum). IR, 1H and 13C NMR spectroscopic data of ent-14 were consis-
tent with those recorded for the opposite enantiomer 14 (Section
4.1.8). HRMS (ESI): Found: 363.1191 (MþþNa), calcd for C22H20NaO6:
363.1203. Eluted second was the minor stereoisomer ent-16 (0.013 g,
26%). For physical and spectroscopic data of ent-16 see Section 4.1.23.
4.1.25. (ꢀ)-Goniofufurone (ent-1). A solution of ent-14 (0.04 g,
0.13 mmol) in MeOH (3 mL) was hydrogenated over 10% Pd/C
(0.02 g) following the same methodology as described above
(procedure in Section 4.1.9), to afford pure ent-1 (0.02 g, 70% cal-
20
culated to reacted ent-14), mp 155 ꢁC, [
a]
¼ꢀ10.2 (c 0.44, EtOH);
D
30
lit.6 mp 152–154 ꢁC, [
a]
¼ꢀ8.0 (c 0.79, EtOH). IR, 1H and 13C NMR
D
spectroscopic data of ent-1 were consistent with those recorded for
(þ)-enantiomer 1 (Section 4.1.9).
Table 2
Crystallographic data and structure refinement of ent-4
4.1.26. 7-epi-(ꢀ)-Goniofufurone (ent-2). A solution of ent-16
(0.03 g, 0.1 mmol) in MeOH (2 mL), was hydrogenated over 10% Pd/
C (0.01 g) following the same methodology as described above
(procedure in Section 4.1.12) to afford pure ent-2 (0.02 g, 64%) as
Crystallographic parameter
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
C13H12O4
232.23
293
0.71073
Triclinic
P1
a
colourless solid. Recrystallization from EtOAc/hexane gave
20
colourless plates, mp 205–206 ꢁC, [
a
]
¼ꢀ98.3 (c 0.47, Me2CO); lit.6
D
Space group
Unit cell dimensions
20
mp 208–209 ꢁC, [
spectroscopic data of ent-2 were consistent with those recorded for
(þ)-enantiomer 2 (Section 4.1.12).
a
]
¼ꢀ92.5 (c 1.1, Me2CO). IR, 1H and 13C NMR
D
a¼5.7553(3)
a
¼98.611(4)
¼90.003(4)
¼90.004(4)
b¼11.7910(7)
c¼16.2110(8)
1087.7(1)
4
b
g
Volume (Å3)
Z
4.1.27. (ꢀ)-Crassalactone C (ent-3). A cooled (0 ꢁC) and stirred so-
lution of ent-2 (0.05 g, 0.20 mmol), cinnamic acid (0.04 g, 0.27 mmol)
and Ph3P (0.11 g, 0.42 mmol) in dry THF (5 mL), was treated with
DEAD (0.06 mL, 0.38 mmol) following the same methodology as
described above (procedure in Section 4.1.14) to afford pure ent-3
Density (calculated, g/cm3)
Absorption coefficient (mmꢀ1
F(000)
1.418
0.11
488
)
Crystal size (mm)
0.16ꢂ0.18ꢂ0.25
2
qmax for data collection (deg)
29.03
Index ranges
ꢀ14ꢃhꢃ14, ꢀ7ꢃkꢃ4, ꢀ20ꢃlꢃ21
(0.04 g, 53%), which crystallized from Et2O as colourless needles, mp
Reflections collected
Independent reflections
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
6539
20
147–150 ꢁC, [
a]
D
¼ꢀ110.1 (c 0.5, EtOH), Rf¼0.5 (Et2O); (þ)-enantio-
4917 [R(int)¼0.0900]
Full-matrix l.s. on F2
2572/2/615
0.807
mer: lit.9 mp 147–150 ꢁC, [
a]
¼þ98.4 (c 0.5, EtOH). IR, 1H and 13
C
30
D
NMR spectroscopic data of ent-3 were consistent with those recorded
for (þ)-enantiomer 3 (Section 4.1.17). HRMS (ESI): Found: 403.1133
(MþþNa), calcd for C22H20NaO6: 403.1152.
Final R indices [I>2
s(I)]
R1¼0.0350
R indices (all data)
Maximum shift/esd
R1¼0.0965, wR2¼0.0551
0.05
4.1.28. 3,6:5,7-Dianhydro-2-deoxy-7-C-phenyl-L-glycero-L-ido-hep-
Extinction coefficient
No
Largest diff. peak and hole (e/Å3)
0.12 and ꢀ0.16
tono-1,4-lactone (ent-4). A cooled (0 ꢁC) and stirred solution of
ent-2 (0.05 g, 0.20 mmol) in dry toluene (3 mL) was treated with
Ph3P (0.13 g, 0.49 mmol) and DEAD (0.08 mL, 0.51 mmol) following
the same methodology as described above (procedure in Section
4.1.18) to afford pure ent-4 (0.02 g, 40%) as colourless needles, mp
4.3. In vitro antitumour assay
Exponentially growing cells were harvested, counted by trypan
blue exclusion and plated into 96-well microtitar plates (Costar) at
optimal seeding density of 104 (K562, HL-60, Jurkat and Raji) cells per
well to assure logarithmic growth rate throughout the assay period.
146 ꢁC; [
a
]D¼ꢀ48.1 (c 0.5, CHCl3); Rf¼0.17 (CH2Cl2). Absolute value
of optical rotation, mp, IR, 1H and 13C NMR spectroscopic data of
ent-4 were consistent with those recorded for (þ)-enantiomer 4

V. Popsavin et al. / Tetrahedron 65 (2009) 10596–10607
10607
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Antiproliferative activity was evaluated by the tetrazolium colouri-
metric MTT assay following the recently reported procedure.16
Acknowledgements
13. For preliminary accounts of this work see: (a) Popsavin, V.; Benedekovic´, G.;
´
´
´
Sreco, B.; Popsavin, M.; Francuz, J.; Kojic, V.; Bogdanovic, G. Bioorg. Med. Chem.
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This work was supported by a research grant from the Ministry
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8. For recent syntheses of styryl lactones related to (þ)-goniofufurone, see: (a)
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28. Cytotoxic activities were evaluated by using standard MTT assay after exposure
of cells to the tested compounds for 72 h. Results are presented as mean values
of three independent experiments done in quadruplicates. Coefficients of
variation were <10%.
29. Crystallographic data (excluding structure factors) for the structure ent-4 have
been deposited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 730191. 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].
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