Heteroannelated (+)-muricatacin mimics: Synthesis, antiproliferative properties and structure-activity relationships

Article abstract of DOI:10.1016/j.tet.2011.09.132

Six new (+)-muricatacin mimics bearing a furano-furanone core have been synthesized and their in vitro antiproliferative activity was evaluated against a panel of human tumour cell lines. A straightforward total synthesis of (+)-muricatacin (1) from d-xyl

Full text of DOI:10.1016/j.tet.2011.09.132

Tetrahedron 67 (2011) 9358e9367
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Heteroannelated (þ)-muricatacin mimics: synthesis, antiproliferative properties
and structureeactivity relationships
a
a
ꢀ
ꢀ a
ꢁ ꢀ b
ꢀ c
Bojana Sreco , Goran Benedekovic , Mirjana Popsavin , Pavle Hadzic , Vesna Kojic ,
a,
ꢀ c
ꢀ d
*
Gordana Bogdanovic , Vladimir Divjakovic , Velimir Popsavin
Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica 3, 21000 Novi Sad, Serbia
a
ꢀ
b
ꢁ
ꢀ
Gosa Institute, Milana Rakica 35, 11000 Belgrade, Serbia
c Oncology Institute of Vojvodina, Institutski put 4, 21204 Sremska Kamenica, Serbia
d
ꢀ
Department of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovica 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:
Received 20 July 2011
Received in revised form 6 September 2011
Accepted 26 September 2011
Available online 5 October 2011
Six new (þ)-muricatacin mimics bearing a furano-furanone core have been synthesized and their in vitro
antiproliferative activity was evaluated against a panel of human tumour cell lines. A straightforward
total synthesis of (þ)-muricatacin (1) from
D-xylose is disclosed providing a sample of 1 that served as
a positive control in antitumour assays. All new compounds showed diverse antiproliferative effects
against human malignant cell lines, but were devoid of any significant cytotoxicity towards the normal
foetal lung fibroblasts (MRC-5). Additionally, the most of (þ)-muricatacin analogues show selective cy-
totoxicities towards certain cancer cell lines, whereas only two of six analogues are broadly toxic against
all cell lines under evaluation. A SAR study reveals the structural features that may be beneficial for the
antiproliferative activity of these lactones. These include the absolute stereochemistry, introduction of
a THF ring, interchange of the O8 ether functionality and the C8 methylene group in the side chain of
muricatacin oxa analogues, as well as the one- or two-carbon homologation of the side chain in both
3 and 6.
Keywords:
Muricatacin
Annonaceous acetogenins
Heteroannelated muricatacin mimics
Isostere
Antitumour activity
SAR
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Muricatacin, a naturally occurring acetogenin derivative has
been isolated by McLaughlin and co-workers from the seeds of
Annona muricata.1 The isolated material was found to be a mixture
of (þ)-(4S,5S)-5-hydroxyheptadecan-4-olide (1, Fig. 1) and its
(ꢀ)-(4R,5R)-enantiomer (ent-1), with a slight predominance of the
later. Both (þ)- and (ꢀ)-muricatacin have demonstrated a remark-
able antiproliferative activity towards several human tumour cell
lines. These findings have stimulated a significant interest in the
synthesis of this type of compounds. Accordingly, many syntheses
of (þ)- and (ꢀ)-muricatacin and congeners from various precursors
have been reported.2e4 In addition, these molecules have been used
as starting materials for the synthesis of other complex biologically
relevant natural products.5 A number of muricatacin analogues and
stereoisomers have also been synthesized,6 and some of them were
evaluated for their antitumour activity.6h,7,8
Previous studies in our laboratory revealed that a mimic of
(ꢀ)-muricatacin in which a methylene group from the side chain
* Corresponding author. Tel.: þ381 21 485 27 68; fax: þ381 21 454 065; e-mail
Fig. 1. Structures of (þ)-muricatacin (1), (ꢀ)-muricatacin (ent-1) and the related
address: velimir.popsavin@dh.uns.ac.rs (V. Popsavin).
analogues.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.132

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9359
has been replaced by an ether function (compound ent-2) exhibited
in vitro antitumour activity against several human cancer cell
lines.9 We have also found that introduction of a THF ring increases
the activity of heteroannelated (ꢀ)-muricatacin mimic ent-3
against the HeLa malignant cells, and that one-carbon homologa-
tion of the side chain in ent-3 increases the activity of resulting
homologue ent-4 against the K562, HL-60 and HeLa cell lines.10
As part of our continuing efforts to further optimize the anti-
tumour potency of leads of type ent-1, ent-2, ent-3 and ent-4, we
have investigated the corresponding opposite enantiomers, as
conformationally constrained analogues of (þ)-muricatacin (1).
The target compounds 3e8 were designed to restrict the rotation
around the C4eC5 and C5eC6 bonds through incorporation of
a condensed THF ring as shown in Fig. 1, providing a number of
heteroannelated (þ)-muricatacin mimics. Thus, compounds 3 and
4 are the opposite enantiomers of ent-3 and ent-4, while the mol-
ecule 5 represents a one-carbon higher homologue of 4. Analogues
6e8 represent classical isosteres of 3e5 designed by replacement of
an ether function from the side chain with a methylene group.
Analogues 3 and 6 represent one-carbon lower homologues of 4
and 7, while lactones 5 and 8 represent one-carbon higher homo-
logues of 4 and 7. In addition to the synthesis of analogues 3e8,
a novel route to (þ)-muricatacin (1) was developed in order to
provide a sample of the lead that would serve as a positive control
in antitumour assays.
þ22.3 (c 0.43, CHCl3)}, were found to be in reasonable agreement
with those previously reported {lit.3 mp 68e70 ꢁC, [
þ22.4
(c 0.42, CHCl3); lit.4 mp 68e70 ꢁC, [
a
]
D
a
]
D þ19.6 (c 1.0, CHCl3)}.
Syntheses of conformationally restricted (þ)-muricatacin oxa
analogues 3e5 are outlined in Scheme 2.
2. Results and discussion
2.1. Chemical synthesis
The synthesis of (þ)-muricatacin (1) is shown in Scheme 1. The
starting hydroxy lactone 9 was prepared from D-xylose in eight
steps as reported earlier by us.9
Scheme 2. Reagents and conditions: (a) two steps, 50%, Ref. 12; (b) Meldrum’s acid,
Et3N, DMF, 46e48 ꢁC, 48 h, 82%; (c) H2, 10% Pd/C (0.1 equiv of Pd), abs EtOH, rt,
105 min, 87%; (d) C9H19Br, Ag2O, AgOTf, Et2O, reflux, 30 h, 61%; (e) H2, 10% Pd/C, EtOH,
rt, 18 h for 16, 96% of 3, 20 h for 17, 86% of 4, 3.5 h for 18, 83% of 5; (f) C10H21Br, Ag2O,
AgOTf, Et2O, reflux, 31 h, 51%; (g) C11H23Br, Ag2O, AgOTf, Et2O, reflux, 48 h, 56%.
The sequence started with the preparation of the protected pri-
mary alcohol 15 from the known12
-xylose derivative 13. Com-
D
pound13 was treatedwith Meldrum’s acidin DMF, in the presence of
Et3N, whereupon the protected lactone 14 was obtained in 82% yield.
Compound 14 was previously prepared in our laboratory by Z-se-
lective Wittig olefination of lactol 13 with Ph3P]CHCO2Me but only
in 61% yield. Catalytic reduction of 14 over 10% Pd/C (0.1 mol equiv of
Pd) for 105 min at room temperature effected selective removal of
the benzyl group from the primary position to afford the alcohol 15
in 87% yield.13 Alcohol 15 readily reacted with an excess of nonyl
bromide and silver oxide in ether, in the presence of a catalytic
amount of silver triflate, to give the corresponding 7-O-nonyl de-
rivative 16 in 61% yield. The 5-O-benzyl protecting group from 16
was removed bycatalytic hydrogenolysis over 10% Pd/C in methanol,
to give a 96% yield of 3. Treatment of 15 with decyl bromide, under
the reaction conditions similar to those applied for the preparation
of 16, gave the expected 7-O-decyl derivative 17 in 51% yield. In-
termediate 17 was earlier synthesized in our laboratory in 18%
overall yield from starting compound 12.14 This new synthesis of 4
proceeds in five steps with 24% overall yield based on the same
starting compound. Hydrogenolytic removal of the benzyl ether
protective group in 17 under the same reaction conditions as re-
ported earlier by us,14 afforded 4 in 86% yield. Moreover, by using the
undecyl bromide as an alkylation agent, compound 15 was first
converted to the protected lactone 18 (56%) and finally to target 5
(83%), after removal of the benzyl protecting group.
Scheme 1. Reagents and conditions: (a) eight steps, 23.6%, Ref. 9; (b) I2, ImdH, Ph3P,
MeCN, N2, 90 ꢁC, 1.5 h, 96%; (c) dodec-1-ene, Grubbs catalyst II generation, CH2Cl2, rt,
27.5 h, 61%; (d) H2, 10% Pd/C, MeOH, rt, 4 h, 90%.
Reaction of 9 with iodine, triphenylphosphine and imidazole,
according to the methodology developed by Garegg and Samuels-
son,11 gave the corresponding terminal alkene 10 in 96% yield. The
cross metathesis reaction of 10 with dodec-1-ene (5 mol equiv) in
the presence of Grubbs second generation catalyst (10 mol %)
afforded the corresponding disubstituted olefin 11 in 61% yield with
exclusively E-selectivity (J6,7¼15.5 Hz). Catalytic hydrogenation of
11 over 10% Pd/C in methanol gave (þ)-muricatacin (1) in 90% yield.
The physical data of thus obtained product 1 {mp 68e69 ꢁC, [
a]
D

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B. Sreco et al. / Tetrahedron 67 (2011) 9358e9367
9360
Syntheses of (þ)-muricatacin mimics 6 and 7 are presented in
Scheme 3.
Scheme 4. Reagents and conditions: (a) four steps, 40%, Ref. 17; (b) C12H25MgBr, THF,
reflux, 4 h, 56%; (c) 70% aq AcOH, reflux, 3.5 h, 57%; (d) Meldrum’s acid, Et3N, DMF,
46 ꢁC, 48 h, 66%.
2.2. X-ray analysis
The complete structure and relative stereochemistry of 7 and 8
were established by X-ray diffraction analysis.18 The absolute con-
figuration was determined by the use of D-xylose or D-glucose as the
enantiomerically pure starting materials. A view of the molecular
structures is provided in Fig. 2a and b. Additional details of crys-
tallographic data are given in Supplementary data.
Scheme 3. Reagents and conditions: (a) three steps, 56%, Ref. 15a; (b) Meldrum’s acid,
Et3N, DMF, 46e48 ꢁC, 70 h, 43%; (c) I2, ImdH, Ph3P, MeCN, N2, 90 ꢁC, 1.5 h, 93%; (d)
undec-1-ene, Grubbs catalyst II generation, CH2Cl2, rt, 24 h, 68%; (e) dodec-1-ene,
Grubbs catalyst II generation, CH2Cl2, Ar, rt, 68 h, 69%; (f) H2, 10% Pd/C, MeOH, rt, 3 h for
22, 82% of 6, 4.5 h for 23, 57% of 7.
3-O-Benzyl-
D
-glucose (19), readily available from D
-glucose,15
was used as a convenient starting compound in this part of the
work. Thus, compound 19 was allowed to react with Meldrum’s
acid in DMF, in the presence of Et3N, to afford the expected lactone
20 in 43% yield. Reaction of 20 with iodine, imidazole and triphe-
nylphosphine gave the corresponding terminal olefin 21 in 93%
Fig. 2. ORTEP drawing of (a) analogue 7 and (b) analogue 8.
ꢀ
yield. Preparation of (ꢂ)-21 has been recently disclosed by Kapitan
and Gracza.16 The authors have described this product as a colour-
less oil, but we have isolated it in the form of colourless needles, mp
62e63 ꢁC. However, the 1H and 13C NMR data of thus obtained
furanolactone 21 were in full agreement with reported values. The
cross metathesis between 21 and undec-1-ene or dodec-1-ene, in
presence of Grubbs second generation catalyst (10 mol %) produced
the desired long-chain olefins 22 (68%) and 23 (69%), respectively,
both with exclusively E-selectivity (J7,8¼15.5 Hz). In the final step,
the hydrogenation of double bond simultaneously with the re-
moval of the benzyl ether protection in 22 and 23 were carried out
smoothly by hydrogenation over 10% Pd/C in MeOH, to afford the
target molecules 6 (82%) and 7 (57%) as white solids.
2.3. In vitro antitumour activity
The human cancer cell lines used in this study represent several
common types of solid cancer and leukaemia. These include the
myelogenous leukaemia (K562), promyelocytic leukaemia (HL-60),
Jurkat T cell leukaemia, Burkitt’s lymphoma (Raji), colon carcinoma
(HT-29), oestrogen receptor negative breast carcinoma (MDA-MB-
231), and cervix carcinoma (HeLa) cells. The use of human foetal
lung fibroblasts (MRC-5) serves to evaluate the toxicity of the an-
alogues towards normal cells. Cytotoxic activity was evaluated by
using the standard MTT assay, after exposure of cells to the tested
compounds for 72 h. (þ)-Muricatacin (1), the corresponding 7-oxa
analogue 2,19 and the commercial antitumour agent doxorubicin
(DOX) were used as reference compounds.
The 3,5-anhydro-
D
-xylose derivative 24, readily available from
D
-xylose,17 was used as a convenient starting material for the syn-
thesis of target 8 (Scheme 4).
According to the resulting IC50 values of the cytotoxic assay
(Table 1), all synthesized compounds demonstrated diverse anti-
proliferative effects against human malignant cell lines but were
devoid of any significant cytotoxicity towards the normal foetal
lung fibroblasts (MRC-5). Additionally, the most of (þ)-muricatacin
analogues show selective cytotoxicities towards certain cancer cell
Treatment of 24 with dodecylmagnesium bromide produced the
expected alcohol 25 in 56% yield. Hydrolytic removal of the cyclo-
hexylidene protective group (7:3 H2O/AcOH) gave the expected
lactol 26 (57%), which was finally converted to the furanolactone 8
(66%) after treatment with Meldrum’s acid and Et3N in DMF.

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B. Sreco et al. / Tetrahedron 67 (2011) 9358e9367
9361
Table 1
In vitro cytotoxicity of (þ)-muricatacin (1), analogues 3e8 and DOX
a
Compd
IC50
(
m
M)
K562
HL-60
0.06
17.36
>100
Jurkat
0.14
1.16
25.46
Raji
HT-29
MDA-MB-231
HeLa
1.09
>100
9.17
>100
10.19
MRC-5
1
2
3
4
5
6
7
8
0.03
1.01
1.95
3.91
7.71
1.55
2.02
0.36
0.25
1.32
>100
13.25
>100
>100
>100
>100
45.32
5.58
>100
>100
3.56
>100
>100
>100
>100
>100
>100
>100
>100
0.02
1.69
>100
35.71
>100
>100
15.45
0.15
0.06
1.64
5.31
4.44
0.89
0.92
>100
0.99
5.33
0.95
1.01
1.23
2.98
2.03
2.54
3.87
0.05
0.03
1.01
0.22
2.24
0.07
DOX
0.09
0.10
a
IC50 is the concentration of compound required to inhibit the cell growth by 50% compared to an untreated control. Values are means of three independent experiments.
Coefficients of variation were less than 10%.
lines, whereas only 5 and 8 are broadly toxic against all cell lines
under evaluation.
control compound 1. Lead 2 and analogue 4 were inactive against
these cells.
Remarkably all analogues 3e8, as well as both parent com-
pounds 1 and 2 exhibit potent in vitro anticancer activity towards
the K562 cell line, with IC50 values in the low-micromolar range.
The most active compound against this cell line was lead 1
2.4. SAR studies
In an early attempt to correlate the structures of muricatacin
(IC50¼0.03
antitumour agent doxorubicin. Only analogue 8 exhibited a sub-
M) against the
K562 cells, being essentially as potent as the commercial anti-
tumour agent doxorubicin.
Most of synthesized analogues demonstrated potent cytotoxic-
ities against HL-60 cell line. The only exception is the analogue 3,
which was inactive towards HL-60 cells, as well as 2 that showed
m
M), being 8-fold more potent than the commercial
and congeners with their cytotoxic activities against KB and VERO
7
ꢂ
cell lines, Figadere and co-workers have found that cytotoxicity
micromolar antiproliferative activity (IC50¼0.36
m
was dependent on the length of the alkyl chain. A shorter chain
dramatically decreased the activity, whereas a longer chain did not
influence to the activity. Introduction of unsaturation in the lactone
ring improved the activity of the analogues with a short chain but
had no effect on muricatacin itself. When other functionalities were
present, such as an oxo function, the activity was about the same as
for the parent compound. Addition of a tetrahydrofuran ring did not
change the activity of the analogues as long as the length of the
alkyl chain was not changed. In the cases of the pyrrolidones (aza-
muricatacins), the activity was either identical to that of mur-
icatacin or even better, independent of the relative or absolute
stereochemistry of the analogues.
a moderate cytotoxicity (IC50¼17.36
mM) in the same cell line. The
7-O-decyl derivative 4 is the most potent cytotoxic agent in this cell
line, showing exactly the same antiproliferative activity as the
natural product 1 (IC50¼0.06
mM).
Analogues 5e8 including parent compounds 1 and 2 exhibited
strong antiproliferative activities against the Jurkat cells with IC50
values in the range of 0.05e3.87
towards these cells, while analogue 3 showed a moderate cyto-
M) in the same cell line. The most active
molecule in the culture of Jurkat cells is analogue 8 that exhibited
over 2- and 20-fold higher potency than both control compounds 1
and 2, respectively. In the same time, this molecule showed a sim-
ilar activity as DOX in the same cell line.
Parent compound 2 was inactive against Raji cells. However,
analogues 4, 6, 7 and 8 exhibited notable cytotoxic effects towards
this cell line with IC50 values in the range of 0.95e1.23 mM. These
molecules are the most active compounds against the Raji cells,
being essentially 2e3-fold more active than the commercial anti-
tumour agent doxorubicin.
HT-29 cell line appears to be much less sensitive to the syn-
thesized (þ)-muricatacin analogues, including the parent com-
pound 1 that was inactive against these cells. However, 7-oxa
analogue 2 demonstrated the most potent activity against the HT-
m
M. Compound 4 was inactive
Our previous findings9 observed with (ꢀ)-muricatacin de-
rivatives have prompted us to execute a more comprehensive SAR
investigation of the analogues of both (þ)- and (ꢀ)-muricatacin
series. The first structural element considered was the absolute
stereochemistry of analogues. The importance of this structural
feature for the cytotoxic activities of these compounds was studied
by comparing the IC50 values of (þ)- (1) and (ꢀ)-muricatacin (ent-
1), as well as of 3 pairs of analogues (2 and ent-2, 3 and ent-3, 4 and
ent-4), each of which contains exactly the same substituents and
differs only in their absolute stereochemistry. As shown in Fig. 3a,
the results indicate that, in most cases, the (ꢀ)-muricatacin mimics
show a more potent cytotoxicity than the opposite enantiomers of
(þ)-muricatacin series. A comparison of biological data of 1 with 6,
7, and 8 (Fig. 3b), revealed that introduction of a THF ring may only
slightly affect the cytotoxic activities of the corresponding
(þ)-muricatacin mimics (6e8). Interestingly, the effect is signifi-
cantly more pronounced if the side chain of (þ)-muricatacin is
extended for two carbon atoms. However, it is difficult to evaluate
any trend conclusively in this case, as only three pairs of analogues
were available for comparison. As shown in Fig. 3c, hetero-
annelation of lead 1 followed by replacement of the C7 atom with
an ether group significantly decreases the activities of (þ)-mur-
icatacin mimics (3e5). However, the same structural changes in
lead ent-1 increases the cytotoxicities of the resulting (ꢀ)-mur-
icatacin mimics (ent-3 and ent-4). As observed in (þ)-muricatacin
series the effect is significantly more pronounced in the analogue
with the extended side chain for one carbon atom (ent-4). As shown
in Fig. 3d, interchange of the O8 ether functionality and C8 meth-
ylene groups in the side chain of muricatacin oxa analogues results
toxicity (IC50¼25.46
m
29 cells (IC50¼0.02
mM) being 7.5-fold more cytotoxic than the
standard antitumour agent doxorubicin.
MDA-MB-231 cells are even less sensitive to the synthesized
(þ)-muricatacin analogues. Both parent molecules 1 and 2, as well
as analogues 3, 6 and 8 were inactive towards this cell line, while
analogue 4 showed a weak cytotoxicity (IC50¼45.32
same cell line. The most active molecule in the culture of MDA-MB-
M).
mM) in the
231 cells is analogue 8 (IC50¼3.56
m
The majority of synthesized analogues exhibited notable anti-
proliferative effects on HeLa cells, with IC50 values in the range of
0.22e10.19
mM. The most active compound against this cell line was
8 (IC50¼0.22
mM), being approximately 5-fold more potent than the

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B. Sreco et al. / Tetrahedron 67 (2011) 9358e9367
9362
Fig. 3. Contributions of selected structural features to the cytotoxic activities: (a) influence of absolute stereochemistry, (b) influence of an additional THF ring, (c) influence of
introduction of a THF ring followed by CH2/O isosteric replacement, (d) influence of O/CH2 interchange, (e) influence of one- or two-carbon homologation of the side chain. The
IC50 values of two structures differing in one given position were compared, and the Δlog IC50 was subsequently calculated (Δlog IC50 is a difference between the IC50 values of an
analogue and the corresponding control compound). Positive Δlog IC50 values indicate a decrease of cytotoxic activity, whereas negative values show an increase in the activity upon
the structural modification being considered.
in a substantial increase in cytotoxic activity against most of the cell
lines tested in this study. The most pronounced activities were
observed with analogues 2, 3 and 5. These findings indicated that-
introduction of an oxygen atom in the side chain increases the
antiproliferative activity of the analogues against most tumour cell
lines under evaluation. The final structural element considered was
the length of the alkyl chain (Fig. 3e). Thus, one-or two-carbon
homologation of the side chain in 3 (to give analogues 4 and 5),
as well as in 6 (to afford analogues 7 and 8) increases the activity of
the resulting homologues against most of the cell lines tested.
These results are in good agreement with previous findings that the
length of the side chain is crucial for antitumour activity of mur-
icatacin analogues.7 However, the mechanism of action is still not
understood. Since it has been proposed that acetogenins of Anno-
naceae act as an inhibitor of complex I in the mitochondrial re-
spiratory system,20 it is possible that muricatacin and analogues act
via an identical mechanism. The observed differences in the anti-
proliferative potencies in respect to the cancer cell lines used may
mitochondrial complex I (NADH-ubiquinone oxidoreductase), but
more work is needed before any conclusion can be made.
3. Conclusion
In conclusion, we have developed a straightforward synthesis of
antitumour acetogenin derivative (þ)-muricatacin, as well as a di-
vergent route to several new (þ)-muricatacin mimics (3e8) and
evaluated them for in vitro cytotoxic activities against seven human
tumour cell lines. All synthesized compounds demonstrated di-
verse antiproliferative effects against human malignant cell lines
but were devoid of any significant cytotoxicity towards the normal
foetal lung fibroblasts (MRC-5). Additionally, the most of
(þ)-muricatacin analogues show selective cytotoxicities towards
certain cancer cell lines, whereas only two of six are broadly toxic
against all cell lines under evaluation. A SAR study reveals that the
following structural features are beneficial for the antiproliferative
activity of these lactones: the absolute stereochemistry, presence of
an additional tetrahydrofuran ring, interchange of the O8 ether
then be explained by
a specificity difference in the hosts’

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B. Sreco et al. / Tetrahedron 67 (2011) 9358e9367
9363
functionality and C8 methylene groups in the side chain of mur-
icatacin oxa analogues, as well as the one- and two-carbon ho-
mologation of the side chain in both 3 and 6. It was found that
cytotoxicity is dependent on the length of the alkyl chain, whereby
the C2 homologation has the most pronounced effects on inhibition
of cells growth. The results of MTTassay along with the SAR analysis
enabled us to identify the (þ)-muricatacin mimic 8 as the most
promising antitumour agent, since it exhibited a potent anti-
proliferative activity against all malignant cell lines under evalua-
tion, but was completely inactive against the normal human cells
(MRC-5). Hence, we believe that this approach may be of use in the
search for new, more potent and selective anticancer agents de-
rived from the natural product 1.
(0.12 g, 61%) as a bright yellow syrup, [
a
]
þ58.2 (c 1.03, CHCl3),
D
Rf¼0.19 (19:1 light petroleum/EtOAc). IR (neat): nmax 1779 (C]O).1H
NMR (250 MHz, CDCl3):
d
0.89 (t, 3H, J¼6.8 Hz, Me), 1.13e1.48 (m,
16H, 8ꢃCH2), 1.97e2.28 (m, 4H, CH2e3, CH2e8), 2.35e2.66 (m, 2H,
CH2e2), 3.81 (dd, 1H, J4,5¼4.6 Hz, J5,6¼8.4 Hz, H-5), 4.38 and 4.66
(2ꢃd, 2H, Jgem¼12.0 Hz, PhCH2), 4.54 (m, 1H, J3,4¼7.8 Hz, J3,4¼5.8 Hz,
J4,5¼4.6 Hz, H-4), 5.44 (m, 1H, J5,6¼8.4 Hz, J6,7¼15.5 Hz, J6,8¼1.3 Hz,
H-6), 5.78 (dt, 1H, J6,7¼15.5 Hz, J7,8¼6.6 Hz, H-7), 7.28e7.40 (m, 5H,
Ph). 13C NMR (62.9 MHz, CDCl3):
d 14.1 (Me), 22.6, 23.8, 23.9, 28.3,
29.0, 29.1, 29.3, 29.4, 29.6, 31.9, 32.3, (9ꢃCH2, C-2 and C-3), 69.9
(PhCH2), 81.2, 81.8 (C-4 and C-5), 125.0 (C-6), 127.6, 127.7, 128.4 (Ph),
138.1 (C-7),177.4 (C-1). HRMS (ESI): m/z 373.2728 (MþþH), calcd for
C24H37O3: 373.2737.
4. Experimental section
4.1. Chemistry
4.1.4. (þ)-Muricatacin (1). To a stirred solution of 11 (59 mg,
0.2 mmol) in MeOH (1.2 mL) was added 10% Pd/C (83 mg,
0.08 mmol). The suspension was hydrogenated at room tempera-
ture and normal pressure of H2 for 4 h, then filtered through a Celite
pad, washed with 1:1 CH2Cl2/EtOAc and evaporated. Silica gel flash
column chromatography (7:3 light petroleum/EtOAc) of the residue
gave pure 1 (39 mg, 90%) as a white solid that was recrystallized
from a mixture of Et2O/pentane to afford colourless needles, mp
€
4.1.1. General methods. Melting points were determined on a Buchi
510 apparatus and were not corrected. Optical rotations were mea-
€
sured on P 3002 (Kruss) and Autopol IV (Rudolph Research) polar-
imeters at 24 ꢁC. NMR spectra were recorded on a Bruker AC 250 E
instrument and chemical shifts are expressed in parts per million
downfield from TMS. IR spectra were recorded with an FTIR Nexus
670 spectrophotometer (Thermo-Nicolet). Low resolution mass
spectra (CI) were recorded on Finnigan-MAT 8230 and on an Agilent
Technologies HPLC/MS 3Q system (ESI), series 1200/6410. High
resolution mass spectra (ESI) of synthesized compounds were ac-
quired on an Agilent Technologies 1200 series instrument equipped
68e69 ꢁC, [
EtOAc); lit.3 mp 68e70 ꢁC, [
68e70 ꢁC, [
a
]
D þ22.3 (c 0.43, CHCl3), Rf¼0.21 (7:3 light petroleum/
a
]
þ22.4 (c 0.42, CHCl3); lit.4 mp
D
a
]
D þ19.6 (c 1.0, CHCl3). IR (CHCl3): nmax 3360 and 2447
(OH), 1742 (C]O). 1H NMR (250 MHz, CDCl3):
d 0.87 (t, 3H,
J¼6.7 Hz, Me),1.13e1.64 (m, 22H, 11ꢃCH2), 1.90 (d, 1H, J5,OH¼5.9 Hz,
OH), 2.01e2.33 (m, 2H, 2ꢃH-3), 2.50 (dd, 1H, J2a,2b¼17.8 Hz,
J2a,3¼9.0 Hz, H-2a), 2.63 (ddd, 1H, J2a,2b¼17.8 Hz, J3,2b¼9.5 Hz,
J3,2b¼5.2 Hz, H-2b), 3.56 (m, 1H, J4,5¼4.6 Hz, H-5), 4.41 (td, 1H,
with Zorbax Eclipse Plus C18 (100 mmꢃ2.1 mm i.d. 1.8
mm) column
and DAD detector (190e450 nm) in combination with a 6210 time-
of-flight LC/MS instrument (ESI) in the positive ion mode. Flash
column chromatography was performed using Kieselgel 60
(0.040e0.063, E. Merck). All organic extracts were dried with an-
hydrous Na2SO4. Organic solutions were concentrated in a rotary
evaporator under reduced pressure at a bath temperature below
35 ꢁC.
J3,4¼7.4 Hz, J4,5¼4.6 Hz, H-4). 13C NMR (62.9 MHz, CDCl3):
d 14.1
(Me), 24.1 (C-3), 28.7 (C-2), 22.7, 25.4, 29.3, 29.5, 29.6, 29.63, 29.65,
31.9 and 33.0 (9ꢃCH2), 73.7 (C-5), 82.9 (C-4), 177.1 (C-1). HRMS
(ESI): m/z 285.2420 (MþþH), calcd for C17H33O3: 285.2424.
4.1.5. 3,6-Anhydro-5,7-di-O-benzyl-2-deoxy-D-ido-heptono-1,4-
lactone (14). To a solution of 13 (0.95 g, 2.89 mmol) in dry DMF
(9.4 mL), was added anhydrous Et3N (0.81 mL, 5.81 mmol) and
Meldrum’s acid (0.83 g, 5.78 mmol). The mixture was stirred for
48 h at 46e48 ꢁC and then evaporated. The residue was purified by
flash column chromatography on silica gel (49:1 CH2Cl2/EtOAc) to
afford pure 14 (0.84 g, 82%), as a colourless solid. Recrystallization
from a mixture of CH2Cl2/Et2O/light petroleum gave colourless
needles, mp 90e91 ꢁC, Rf¼0.50 (3:2 Et2O/toluene); lit.21 mp 90 ꢁC.
Spectroscopic data of thus prepared sample 14 matched those
previously reported by us.21
4.1.2. 5-O-Benzyl-2,3,6,7-tetradeoxy-L-threo-hept-6-enono-1,4-
lactone (10). To a mixture of iodine (0.98 g, 3.84 mmol), imidazole
(1.08 g, 15.94 mmol) and triphenylphosphine (1 g, 3.79 mmol) in
dry MeCN (6 mL) was added a solution of 9 (0.25 g, 0.95 mmol) in
dry MeCN (6 mL). The mixture was vigorously stirred at 90 ꢁC (bath
temperature) for 1.5 h, in an atmosphere of N2, then evaporated and
purified by flash column chromatography (9:1/4:1/1:1 light
petroleum/EtOAc), to yield unsaturated lactone 10 (0.21 g, 96%) as
a pale yellow oil, [
troleum/EtOAc). IR (neat): nmax 1777 (C]O). 1H NMR (250 MHz,
CDCl3): 1.96e2.26 (m, 2H, H-3), 2.33e2.64 (m, 2H, H-2), 3.84 (dd,
a
]
þ51.5 (c 2.04, CHCl3), Rf¼0.63 (1:1 light pe-
D
4.1.6. 3,6-Anhydro-5-O-benzyl-2-deoxy-D-ido-heptono-1,4-lactone
d
(15). A solution of 14 (0.56 g, 1.58 mmol) in a mixture of EtOAc
(4 mL) and abs EtOH (4 mL) was added to a stirred suspension of
10% Pd/C (0.17 g, 0.16 mmol, 0.1 equiv Pd) in abs EtOH (8 mL), which
was pre-saturated with H2 for 1 h. The suspension was hydroge-
nated at room temperature and normal pressure of H2 for 105 min,
then filtered through a Celite pad, washed with EtOH, and evapo-
rated. Flash column chromatography (9:1 Et2O/light petroleum) of
1H, J4,5¼4.5 Hz, J5,6¼7.8 Hz, H-5), 4.39 (d, 1H, Jgem¼12.0 Hz, PhCH2),
4.53 (ddd, 1H, J3,4¼6.1 Hz, J3,4¼7.9 Hz, J4,5¼4.5 Hz, H-4), 4.66 (d, 1H,
Jgem¼12.0 Hz, PhCH2), 5.38 (d, 1H, J6,7a¼18.5 Hz, H-7a), 5.40 (d, 1H,
J6,7b¼10.5 Hz, H-7b), 5.82 (m, 1H, H-6), 7.22e7.41 (m, 5H, Ph). 13C
NMR (62.9 MHz, CDCl3):
d 23.6 (C-2), 28.0 (C-3), 70.2 (PhCH2), 81.2
and 81.24 (C-4 and C-5), 120.4 (C-7), 127.5, 128.2, 137.6 (Ph), 133.4
(C-6), 177.2 (C-1). HRMS (ESI): m/z 233.1165 (MþþH), calcd for
C14H17O3: 233.1172.
the residue gave pure 15 (0.36 g, 87%), as a colourless syrup, [
þ4.3 (c 1.0, CHCl3), Rf¼0.31 (Et2O). IR (CHCl3): nmax 3467 (OH), 1789
(C]O). 1H NMR (250 MHz, CDCl3):
2.52 (br s, 1H, OH), 2.58e2.78
a]
D
d
4.1.3. (E)-5-O-Benzyl-7-C-decyl-2,3,6,7-tetradeoxy-
L
-threo-hept-6-
(m, 2H, 2ꢃH-2), 3.76 (dd, 1H, J6,7a¼4.3 Hz, J7a,7b¼12.0 Hz, H-7a),
3.84 (dd, 1H, J6,7b¼5.1 Hz, J7a,7b¼12.0 Hz, H-7b), 4.17 (m, 1H,
J5,6¼4.9 Hz, H-6), 4.25 (d, 1H, J5,6¼4.9 Hz, H-5), 4.56 and 4.71 (2ꢃd,
Jgem¼11.9 Hz, CH2Ph), 4.91e5.01 (m, 2H, H-3 and H-4), 7.26e7.42
enono-1,4-lactone (11). To a stirred solution of olefin 10 (0.12 g,
0.50 mmol) and dodec-1-ene (1.1 mL, 5.0 mmol) in dry CH2Cl2
(2.3 mL) was added the second generation Grubbs catalyst (42 mg,
0.05 mmol). The reaction mixture was stirred in an argon atmo-
sphere for 27.5 h at room temperature. The solvent was evaporated
and the remaining crude product was purified by flash column
chromatography (19:1/9:1/4:1 light petroleum/EtOAc), to give 11
(m, 5H, Ph). 13C NMR (62.9 MHz, CDCl3):
d 35.8 (C-2), 61.1 (C-7), 72.7
(CH2Ph), 76.7 (C-3), 80.7 (C-6), 82.1 (C-5), 85.7 (C-4), 127.6, 128.2,
128.6, 136.7 (Ph), 175.2 (C-1). LRMS (ESI): m/e 265 (MþþH), 529
(2 MþþH). HRMS (ESI): m/z 265.1066 (MþþH), calcd for C14H17O5:

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B. Sreco et al. / Tetrahedron 67 (2011) 9358e9367
9364
265.1070; m/z 287.0885 (MþþNa), calcd for C14H16NaO5: 287.0890;
m/z 303.0625 (MþþK), calcd for C14H16KO5: 303.0629.
analytical sample 4, as colourless needles, mp 59e60 ꢁC, [
(c 0.45, CHCl3), Rf¼0.24 (4:1 Et2O/hexane). Anal. Found: C, 64.66; H,
9.86. Calcd for C17H30O5: C, 64.94; H, 9.62. Spectroscopic data of
thus prepared sample 4 matched those previously reported by us.14
a]
D þ35.4
4.1.7. 3,6-Anhydro-5-O-benzyl-2-deoxy-7-O-nonyl-D-ido-heptono-
1,4-lactone (16). To a solution of 15 (0.25 g, 0.95 mmol) in dry Et2O
(5 mL) were added successively Ag2O (0.55 g, 2.36 mmol), AgOTf
(61 mg, 0.24 mmol) and C9H19Br (0.45 mL, 2.35 mmol). The mix-
ture was stirred under reflux for 30 h, then diluted with CH2Cl2
(10 mL), filtered, and evaporated. The residue was purified on
a column of flash silica (3:2 light petroleum/Et2O) to give pure 16
(0.23 g, 61%), a colourless oil that crystallized from cooled (ꢀ10 ꢁC)
4.1.11. 3,6-Anhydro-5-O-benzyl-2-deoxy-7-O-undecyl-D-ido-hep-
tono-1,4-lactone (18). A mixture of 15 (84 mg, 0.32 mmol), Ag2O
(0.2 g, 0.85 mmol), AgOTf (17 mg, 0.07 mmol) and C11H23Br
(0.18 mL, 0.81 mmol) in anhydrous Et2O (2 mL) was heated under
reflux for 48 h. After the mixture cooled to room temperature it was
diluted with CH2Cl2 (5 mL), filtered, and evaporated. Flash column
chromatography (3:2 light petroleum/Et2O) of the residue gave
CH2Cl2/hexane as colourless needles, mp 31e32 ꢁC, [
a
]
þ11.6 (c
D
1.8, CHCl3), Rf¼0.33 (1:1 Et2O/light petroleum). IR (neat): nmax
pure lactone 18 (74 mg, 56%) as a colourless oil, [
CHCl3), Rf¼0.23 (3:2 light petroleum/Et2O). IR (neat): nmax 1790
(C]O). 1H NMR (250 MHz, CDCl3):
a]
þ10.9 (c 0.19,
D
1790 (C]O). 1H NMR (250 MHz, CDCl3):
d
0.88 (t, 3H, J¼6.7 Hz,
Me), 1.18e1.49 (m, 12H, 6ꢃCH2), 1.58 (m, 2H, CH2), 2.72 (d, 2H,
2ꢃH-2), 3.46 (m, 2H, OCH2CH2), 3.65 (d, 2H, J6,7¼5.4 Hz, H-7), 4.20
(d, 1H, J5,6¼4.0 Hz, H-5), 4.25 (m, 1H, H-6), 4.60 and 4.70 (2ꢃd, 2H,
Jgem¼11.9 Hz, CH2Ph), 4.93 (d, 1H, J3,4¼4.8 Hz, H-4), 4.99 (m, 1H, H-
d
0.89 (t, 3H, J¼6.8 Hz, Me),
1.12e1.41 (m, 16H, 8ꢃCH2), 1.58 (m, 2H, OCH2CH2CH2), 2.70 (m, 2H,
2ꢃH-2), 3.46 (m, 2H, OCH2CH2), 3.64 (d, 2H, J6,7¼5.3 Hz, H-7), 4.20
(d, 1H, J5,6¼4.0 Hz, H-5), 4.24 (m, 1H, H-6), 4.59 and 4.70 (2ꢃd, 2H,
Jgem¼11.9 Hz, CH2Ph), 4.92 (d, 1H, J3,4¼4.7 Hz, H-4), 4.97 (m, 1H, H-
3), 7.29e7.46 (m, 5H, Ph). 13C NMR (62.9 MHz, CDCl3):
d 14.0 (Me),
22.6, 26.0, 29.2, 29.4, 29.45, 29.5, 31.8 (7ꢃCH2) 35.9 (C-2), 68.5
(2ꢃH-7), 71.7 (OCH2CH2), 72.6 (PhCH2), 76.7 (C-3), 79.5 (C-6), 81.3
(C-5), 85.3 (C-4), 127.6, 128.1, 128.5, 137.0 (Ph), 175.3 (C-1). LRMS
(ESI): m/z 391 (MþþH). Anal. Found: C, 70.47; H, 8.70. Calcd for
C23H34O5: C, 70.74; H, 8.78.
3), 7.29e7.40 (m, 5H, Ph). 13C NMR (62.9 MHz, CDCl3):
d 14.1 (Me),
22.7, 26.1, 29.3, 29.4, 29.6, 31.9 (9ꢃCH2), 36.0 (C-2), 68.5 (C-7), 71.8
(OCH2CH2), 72.7 (CH2Ph), 76.8 (C-3), 79.6 (C-6), 81.4 (C-5), 85.5 (C-
4), 127.7, 128.1, 128.6, 137.2 (Ph), 175.4 (C-1). HRMS (ESI): m/z
441.2625 (MþþNa), calcd for C25H38NaO5: 441.2612; m/z 457.2370
(MþþK), calcd for C25H38KO5: 457.2351.
4.1.8. 3,6-Anhydro-2-deoxy-7-O-nonyl-D-ido-heptono-1,4-lactone
(3). A solution of 16 (0.11 g, 0.28 mmol) in MeOH (4 mL) was hy-
drogenated over 10% Pd/C (21 mg, 0.02 mmol) at room temperature
and normal pressure of H2 for 18 h, then filtered through a Celite
pad, washed with MeOH, and evaporated. The residue was purified
by flash column chromatography (7:3 CH2Cl2/EtOAc), to afford pure
3 (81 mg, 96%) as a colourless syrup oil that crystallized from
4.1.12. 3,6-Anhydro-2-deoxy-7-O-undecyl-D-ido-heptono-1,4-lactone
(5). A solution of benzyl ether 18 (59 mg, 0.14 mmol) in MeOH
(1.5 mL) was hydrogenated over 10% Pd/C (30 mg, 0.03 mmol) at
room temperature and normal pressure of H2 for 3.5 h. The sus-
pension was filtered through a Celite pad and washed with MeOH.
The combined filtrates were evaporated and the residue purified by
flash column chromatography (24:1 CH2Cl2/MeOH) to afford pure 5
(38 mg, 83%) as a colourless solid. Recrystallization from CH2Cl2/
CH2Cl2/hexane, as transparent needles, mp 51e52 ꢁC, [
1.9, CHCl3), Rf¼0.40 (7:3 CH2Cl2/EtOAc). IR (neat): nmax 3286 (OH),
1776 (C]O). 1H NMR (250 MHz, CDCl3):
0.85 (t, 3H, J¼6.8 Hz, Me),
a
]
D þ29.7 (c
d
hexane gave transparent needles, mp 60 ꢁC, [
CHCl3), Rf¼0.49 (19:1 CH2Cl2/MeOH). IR (neat): nmax 3484e3275
(OH), 1790 (C]O). 1H NMR (250 MHz, CDCl3):
0.87 (t, 3H,
a
]
þ27.3 (c 0.98,
D
1.11e1.39 (m, 12H, 6ꢃCH2), 1.57 (m, 2H, CH2), 2.65 (dd, 1H,
J2a,2b¼18.7 Hz, J2a,3¼1.0 Hz, H-2a), 2.76 (dd, 1H, J2a,2b¼18.7 Hz,
J2b,3¼5.4 Hz, H-2b), 3.49 (m, 2H, OCH2CH2), 3.85 (m, 2H, 2ꢃH-7),
4.10 (m, 1H, H-6), 4.28 (d, 1H, J5,OH¼3.8 Hz, OH), 4.50 (dd, 1H,
J5,6¼3.1 Hz, J5,OH¼3.8 Hz, H-5), 4.86 (d, 1H, J3,4¼4.2 Hz, H-4), 5.01
(ddd, 1H, J2a,3¼1.0 Hz, J2b,3¼5.4 Hz, J3,4¼4.2 Hz, H-3). 13C NMR
d
J¼6.7 Hz, Me), 1.12e1.39 (m, 16H, 8ꢃCH2), 1.57 (m, 2H, CH2), 2.65
(dd,1H, J2a,3¼1.2 Hz, J2a,2b¼18.6 Hz, H-2a), 2.76 (dd,1H, J2b,3¼5.3 Hz,
J2a,2b¼18.7 Hz, H-2b), 3.51 (m, 2H, OCH2CH2), 3.84 (dd, 1H,
J6,7a¼3.2 Hz, J7a,7b¼11.0 Hz, H-7a), 3.90 (dd, 1H, J6,7b¼3.3 Hz,
J7a,7b¼11.2 Hz, H-7b), 4.11 (m, 1H, H-6), 4.52 (d, 1H, J5,6¼3.2 Hz, H-
5), 4.86 (d, 1H, J3,4¼4.2 Hz, H-4), 5.02 (m, 1H, H-3). 13C NMR
(62.9 MHz, CDCl3):
d 14.0 (Me), 22.6, 25.8, 29.1, 29.26, 29.3, 29.4,
31.7 (7ꢃCH2) 36.0 (C-2), 69.4 (C-7), 72.5 (OCH2CH2), 75.8 (C-5), 76.8
(C-3), 78.5 (C-6), 88.2 (C-4), 175.5 (C-1). LRMS (ESI): m/z 301
(MþþH), 601 (2 MþþH).
(62.9 MHz, CDCl3):
d 14.0 (Me), 22.6, 25.9, 29.2, 29.3, 29.36, 29.4,
29.5, 31.8 (9ꢃCH2), 36.0 (C-2), 69.5 (C-7), 72.6 (OCH2CH2), 76.0 (C-
5), 76.8 (C-3), 78.6 (C-6), 88.2 (C-4), 175.4 (C-1). HRMS (ESI): m/z
329.2317 (MþþH), calcd for C18H33O5: 329.2322; m/z 351.2146
(MþþNa), calcd for C18H32NaO5: 351.2142.
4.1.9. 3,6-Anhydro-5-O-benzyl-7-O-decyl-2-deoxy-D-ido-heptono-
1,4-lactone (17). To a solution of 15 (0.18 g, 0.66 mmol) in dry Et2O
(3.5 mL) were added successively Ag2O (0.39 g, 1.66 mmol), AgOTf
(43 mg, 0.17 mmol) and C10H21Br (0.35 mL, 1.66 mmol). The mix-
ture was heated under reflux for 31 h, then cooled to room tem-
perature, diluted with CH2Cl2 (5 mL), filtered, and evaporated. Flash
column chromatography (4:1/7:3 hexane/Et2O) of the residue
4.1.13. 3,6-Anhydro-5-O-benzyl-2-deoxy-D-glycero-D-ido-octono-
1,4-lactone (20). To a solution of 19 (0.25 g, 0.94 mmol) in dry DMF
(2.5 mL) were added anhydrous Et3N (0.52 mL, 3.73 mmol) and
Meldrum’s acid (0.55 g, 3.85 mmol). The resulting reaction mixture
was stirred at 46e48 ꢁC for 70 h, and then evaporated. Purification
by flash column chromatography (4:1 EtOAc/light petroleum) gave
20 (0.12 g, 43%) as a white solid. Recrystallization from a mixture of
gave pure 17 (0.14 g, 51%) as a colourless oil, [
a
]
þ13.1 (c 1.0,
D
CHCl3), Rf¼0.25 (1:1 hexane/Et2O). Anal. Found: C, 71.14; H, 8.72.
Calcd for C24H36O5: C, 71.26; H, 8.97. Spectroscopic data of thus
prepared sample 17 matched those previously reported by us.14
CH2Cl2/hexane gave pure 20 as
104e105 ꢁC, [
þ32.2 (c 0.5, EtOH); Rf¼0.2 (Et2O). IR (KBr): nmax
3444 (OH), 1784 (C]O). 1H NMR (250 MHz, CDCl3):
d 2.64 (d, 1H,
a colourless powder, mp
a]
D
4.1.10. 3,6-Anhydro-7-O-decyl-2-deoxy-
D
-ido-heptono-1,4-lactone
(4). A solution of 17 (0.15 g, 0.37 mmol) in EtOH (3 mL) was hy-
drogenated over 10% Pd/C (76 mg, 0.07 mmol) at room temperature
and normal pressure of H2 for 20 h. The suspension was filtered
through a Celite pad and washed with ether. The combined filtrates
were evaporated and the residue purified by flash column chro-
matography (4:1 Et2O/hexane/Et2O), to afford pure 4 (0.1 g, 86%)
as a colourless solid. Recrystallization from CH2Cl2/hexane gave an
J2a,2b¼18.5 Hz, H-2a), 2.74 (dd, 1H, J2a,2b¼18.5 Hz, J3,2b¼4.5 Hz, H-
2b), 3.66 (dd, 1H, J7,8a¼4.7 Hz, J8a,8b¼12.7 Hz, H-8a), 3.79 (dd, 1H,
J7,8b¼2.7 Hz, J8a,8b¼12.7 Hz, H-8b), 3.94e4.04 (m, 2H, H-5 and H-7),
4.35 (d, 1H, J¼2.5 Hz, H-6), 4.65 and 4.75 (2ꢃd, 2H, Jgem¼11.7 Hz,
PhCH2), 4.91e4.98 (m, 2H, H-3 and H-4), 7.31e7.43 (m, 5H, Ph). 13
C
NMR (62.9 MHz, CDCl3):
d 36.0 (C-2), 64.2 (C-8), 69.2 (C-7), 72.9
(PhCH2), 77.1 (C-3), 80.2 (C-5), 81.4 (C-6), 85.0 (C-4), 128.0, 128.5,

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B. Sreco et al. / Tetrahedron 67 (2011) 9358e9367
9365
128.8, 136.8 (Ph), 175.4 (C-1). HRMS (ESI): m/z 317.0999 (MþþNa),
calcd for C17H34NO4: 316.2482; m/z 337.1772 (MþþK), calcd for
calcd for C15H18NaO6: 317.0996.
C17H30KO4: 337.1776.
4.1.14. 3,6-Anhydro-5-O-benzyl-2,7,8-trideoxy-
D
-ido-oct-7-enono-
4.1.17. (E)-3,6-Anhydro-5-O-benzyl-8-C-decyl-2,7,8-trideoxy-D-ido-
1,4-lactone (21). To a mixture of iodine (0.55 g, 2.18 mmol), imid-
azole (0.26 g, 4.40 mmol) and Ph3P (0.56 g, 2.14 mmol) in dry MeCN
(4.0 mL) was added a solution of 20 (0.16 g, 0.53 mmol) in dry
MeCN (4 mL). The mixture was stirred at 90 ꢁC (bath temperature)
for 1.5 h, in an atmosphere of N2, and then evaporated. Flash col-
umn chromatography (1:1 Et2O/light petroleum) of the residue
yielded pure 21 (0.13 g, 93%) as a white solid. Recrystallization from
oct-7-enono-1,4-lactone (23). To a solution of 21 (32 mg, 0.12 mmol)
in dry CH2Cl2 (0.65 mL) was added dodec-1-ene (0.27 mL,
1.22 mmol) and the second generation Grubbs catalyst (8 mg,
0.01 mmol). The mixture was stirred in an argon atmosphere for 68 h
at room temperature. The solvent was removed in vacuum and the
mixture purified by flash column chromatography (CH2Cl2) to afford
pure 23 (34 mg, 69%) as a pale yellow oil, [
a
]
D þ11.2 (c 0.52, CHCl3),
CH2Cl2/hexane/Et2O afforded colourless needles, mp 62e63 ꢁC, [
þ11.2 (c 1.0, CHCl3), Rf¼0.29 (1:1 Et2O/light petroleum). IR (CHCl3):
nmax 1789 (C]O). 1H NMR (250 MHz, CDCl3):
2.66 (dd, 1H,
a
]
Rf¼0.38 (1:1 Et2O/light petroleum). IR (neat): nmax 1790 (C]O). 1H
D
NMR (250 MHz, CDCl3):
d
0.89 (t, 3H, J¼6.8 Hz, Me), 1.02e1.49 (m,
d
16H, 8ꢃCH2), 2.09 (m, 2H, 2ꢃH-9), 2.64 (d, 1H, J2a,2b¼17.6 Hz, H-2a),
2.74 (dd, 1H, J2b,3¼4.6 Hz, J2a,2b¼17.6 Hz, H-2b), 4.01 (d, 1H,
J5,6¼3.4 Hz, H-5), 4.45 (dd,1H, J5,6¼3.4 Hz, J6,7¼7.7 Hz, H-6), 4.61 and
4.67(2ꢃd, 2H, Jgem¼12.1 Hz, CH2Ph), 4.89e4.99 (m, 2H, H-3 andH-4),
5.65 (dd,1H, J6,7¼7.8 Hz, J7,8¼15.5 Hz, H-7), 5.84 (dt,1H, J7,8¼15.5 Hz,
J8,9¼6.6 Hz, H-8), 7.29e7.43 (m, 5H, Ph). 13C NMR (62.9 MHz, CDCl3):
J2a,2b¼18.9 Hz, J2a,3¼1.7 Hz, H-2a), 2.76 (dd, 1H, J2b,3¼4.8 Hz,
J2a,2b¼18.9 Hz, H-2b), 4.14 (d, 1H, J5,6¼3.6 Hz, H-5), 4.51 (dd, 1H,
J5,6¼3.7 Hz, J6,7¼7.0 Hz, H-6), 4.62 and 4.68 (2ꢃd, 2H, Jgem¼12.1 Hz,
CH2Ph), 4.80e5.00 (m, 2H, H-3 and H-4), 5.35 (dd, 1H, J7,8a¼10.4 Hz,
J8a,8b¼1.0 Hz, H-8a), 5.42 (dd, 1H, J7,8b¼17.3 Hz, J8a,8b¼1.0 Hz, H-8b),
6.01 (ddd, 1H, J6,7¼7.0 Hz, J7,8a¼10.4 Hz, J7,8b¼17.3 Hz, H-7),
d
14.0 (Me), 22.6, 28.8, 29.1, 29.2, 29.4, 29.5, 31.8, 32.8 (9ꢃCH2), 36.0
7.27e7.42 (m, 5H, Ph). 13C NMR (62.9 MHz, CDCl3):
d
35.9 (C-2), 72.7
(C-2), 72.7 (CH2Ph), 76.2 (C-3), 81.9 (C-5), 82.6 (C-6), 85.9 (C-4),123.3
(C-7), 127.6, 128.0, 128.4, 136.6 (Ph), 137.2 (C-8), 175.5 (C-1). HRMS
(ESI):m/z 383.2572 (MþþHꢀH2O), calcd for C25H35O3: 383.2581; m/z
423.2486 (MþþNa), calcd for C25H36NaO4: 423.2506.
(CH2Ph), 76.4 (C-3), 81.9 (C-6), 82.6 (C-5), 85.8 (C-4), 119.4 (C-8),
127.6, 128.0, 128.5, 137.0 (Ph), 132.0 (C-7), 175.3 (C-1). HRMS (ESI):
m/z 261.1112 (MþþH), calcd for C15H17O4: 261.1121.
4.1.15. (E)-3,6-Anhydro-5-O-benzyl-2,7,8-trideoxy-8-C-nonyl-
D
-ido-
4.1.18. 3,6-Anhydro-2-deoxy-6-C-dodecyl-D-ido-hexono-1,4-lactone
oct-7-enono-1,4-lactone (22). To a solution of 21 (79 mg, 0.30 mmol)
in dry CH2Cl2 (1.6 mL) were added undec-1-ene (0.5 mL, 2.43 mmol)
and the second generation Grubbs catalyst (25 mg, 0.03 mmol). The
mixture was stirred in an argon atmosphere for 24 h at room tem-
perature. The solvent was removed under vacuum and the mixture
purified by flash column chromatography (CH2Cl2). Eluted first was
(7). To a stirred solution of 23 (54 mg, 0.13 mmol) in dry MeOH
(1 mL) was added 10% Pd/C (61 mg, 0.06 mmol). The suspension
was hydrogenated at room temperature and normal pressure of H2
for 4.5 h, then filtered through a Celite pad, washed with 1:1
CH2Cl2/EtOAc, and evaporated. Flash chromatography (3:2 Et2O/
light petroleum) of the residue gave pure 7 (24 mg, 57%) as a white
solid. Recrystallization from CH2Cl2/hexane gave colourless nee-
pure 22 (80 mg, 68%), isolated as a colourless oil, [
a
]
D þ7.5 (c 0.99,
CHCl3), Rf¼0.35 (CH2Cl2). IR (neat): nmax 1790 (C]O). 1H NMR
dles, mp 88e89 ꢁC, [
light petroleum). IR (neat): nmax 1779 (C]O), 3394 (OH). 1H NMR
(250 MHz, CDCl3):
a
]
þ19.3 (c 0.52, CHCl3), Rf¼0.32 (1:1 Et2O/
D
(250 MHz, CDCl3):
d
0.9 (t, 3H, J¼7.0 Hz, Me), 1.06e1.49 (m, 14H,
7ꢃCH2), 2.10 (m, 2H, 2ꢃH-9), 2.63 (d, 1H, J2a,2b¼17.8 Hz, H-2a), 2.75
(dd, 1H, J2a,2b¼17.8 Hz, J2b,3¼4.7 Hz, H-2b), 4.07 (d, 1H, J5,6¼3.4 Hz,
H-5), 4.46 (dd, 1H, J5,6¼3.4 Hz, J6,7¼7.7 Hz, H-6), 4.61 and 4.67 (2ꢃd,
2H, Jgem¼12.1 Hz, CH2Ph), 4.90e4.98 (m, 2H, H-3 and H-4), 5.66 (dd,
1H, J6,7¼7.8 Hz, J7,8¼15.5 Hz, H-7), 5.85 (dt, 1H, J7,8¼15.5 Hz,
J8,9¼6.5 Hz, H-8), 7.29e7.42 (m, 5H, Ph).13C NMR (62.9 MHz, CDCl3):
d
0.88 (t, 3H, J¼6.7 Hz, Me), 1.12e1.73 (m, 22H,
11ꢃCH2), 2.34 (br s, 1H, OH), 2.62 (d, 1H, J2a,2b¼18.9 Hz, H-2a), 2.78
(dd, 1H, J2a,2b¼18.9 Hz, J2b,3¼5.9 Hz, H-2b), 3.91 (td, 1H, J5,6¼2.6 Hz,
J6,7¼6.8 Hz, H-6), 4.27 (d,1H, J5,6¼2.5 Hz, H-5), 4.87e4.99 (m, 2H, H-
3 and H-4). 13C NMR (62.9 MHz, CDCl3):
d 14.1 (Me), 22.6, 26.1, 27.8,
29.3, 29.4, 29.5, 29.6, 29.62, 31.9 (11ꢃCH2), 35.8 (C-2), 74.4 (C-5),
75.6 (C-3), 80.5 (C-6), 87.8 (C-4), 175.8 (C-1). HRMS (ESI): m/z
313.2373 (MþþH), calcd for C18H33O4: 313.2373; m/z 330.2634
(MþþNH4), calcd for C18H36NO4: 330.2639.
d
14.0 (Me), 22.6, 28.8, 29.1, 29.2, 29.4, 29.6, 31.8, 32.3 (8ꢃCH2), 36.0
(C-2), 72.6 (CH2Ph), 76.1 (C-3), 81.8 (C-5), 82.5 (C-6), 85.9 (C-4),123.2
(C-7),127.5,127.9,128.4 (Ph),137.2 (C-8),175.4 (C-1). HRMS (ESI): m/
z 387.2517 (MþþH), calcd for C24H35O4: 387.2530; m/z 425.2077
(MþþK), calcd for C24H34KO4: 425.2089. Eluted second was un-
changed starting compound 21 (0.019 g, 25%).
4.1.19. 1,2-O-Cyclohexylidene-5-deoxy-5-C-dodecyl-a-D-xylo-pento-
furanose (25). A crystal of iodine was added to a suspension of
magnesium turnings (0.75 g, 30 mmol) in dry THF (15 mL) and then
dodecylbromide (7.5 g, 30 mmol) was added while stirring, in one
portion at room temperature. The reaction started spontaneously
and was completed after 1 h at reflux, whereupon the complete
dissolution of magnesium was observed. To this mixture was added
a solution of 24 (6.3 g, 30 mmol) in dry THF (15 mL) and the stirring
under reflux was continued for the next 4 h. The mixture was
quenched by the addition of 10% aq hydrochloric acid (100 mL) and
products were extracted with light petroleum (3ꢃ50 mL). The
combined organic layers were washed with 20% aq NaHCO3
(50 mL), dried, discoloured with activated carbon and evaporated.
Flash column chromatography (C6H6) of the residue (9.6 g) gave
4.1.16. 3,6-Anhydro-2-deoxy-6-C-undecyl-D-ido-hexono-1,4-lactone
(6). To a stirred solution of 22 (57 mg, 0.15 mmol) in dry MeOH
(1.13 mL) was added 10% Pd/C (78 mg, 0.07 mmol). The suspension
was hydrogenated at room temperature and normal pressure of H2
for 3 h, then filtered through a Celite pad, washed with 1:1 CH2Cl2/
EtOAc, and evaporated. Flash chromatography (7:3 Et2O/light pe-
troleum) of the residue gave pure 6 (36 mg, 82%) as a white solid.
Recrystallization from CH2Cl2/hexane gave colourless needles, mp
74ꢀ75 ꢁC, [
a]
þ23.9 (c 0.51, CHCl3), Rf¼0.18 (7:3 Et2O/light petro-
D
leum). IR (CHCl3): nmax 1779 (C]O), 3389 (OH). 1H NMR (250 MHz,
CDCl3):
d
0.87 (t, 3H, J¼6.9 Hz, Me), 1.16e1.72 (m, 20H, 10ꢃCH2),
2.32 (br s, 1H, OH), 2.62 (d, 1H, J2a,2b¼18.9 Hz, H-2a), 2.77 (dd, 1H,
J2a,2b¼18.9 Hz, J2b,3¼5.9 Hz, H-2b), 3.91 (td, 1H, J5,6¼2.6 Hz,
J6,7¼6.7 Hz, H-6), 4.27 (d,1H, J5,6¼2.6 Hz, H-5), 4.87e4.98 (m, 2H, H-
pure 25 (6.4 g, 56%) as a white waxy solid, [
a
]
ꢀ9.5 (c 1.1, CHCl3),
D
Rf¼0.69 (1:1 Et2O/light petroleum). IR (neat): nmax 3409 (OH). 1H
NMR (250 MHz, CDCl3):
d
0.85 (t, 3H, J¼6.8 Hz, Me), 1.18e1.77 (m,
3 and H-4). 13C NMR (62.9 MHz, CDCl3):
d
14.1 (Me), 22.6, 26.1, 27.8,
34H, 17ꢃCH2), 2.54 (br s, 1H, OH), 4.00 (d, 1H, J3,4¼2.4 Hz, H-3), 4.07
(dt, 1H, J3,4¼2.2 Hz, J4,5¼6.7 Hz, H-4), 4.46 (d, 1H, J1,2¼3.8 Hz, H-2),
29.4, 29.5, 29.6, 29.62, 31.8 (10ꢃCH2), 35.9 (C-2), 74.4 (C-5), 75.6 (C-
3), 80.5 (C-6), 87.8 (C-4), 175.9 (C-1). HRMS (ESI): m/z 299.2213
(MþþH), calcd for C17H31O4: 299.2217; m/z 316.2475 (MþþNH4),
5.86 (d, 1H, J1,2¼3.8 Hz, H-1). 13C NMR (CDCl3):
d 14.0 (Me), 22.6,
23.4, 23.8, 24.8, 26.0, 27.5, 29.3, 29.46, 29.5, 29.6, 29.7, 31.8, 35.5,

ꢀ
B. Sreco et al. / Tetrahedron 67 (2011) 9358e9367
9366
36.1 (17ꢃCH2), 60.7 (C-7), 75.2 (C-3), 80.3 (C-4), 84.7 (C-2),103.6 (C-
1), 111.9 (qC). LRMS (ESI): m/z 383 (MþþH), 382 (Mþ). HRMS (ESI):
m/z 421.2711 (MþþK), calcd for C23H42KO4: 421.2715.
parameters. The crystal data and refinement parameters are listed
in Table S1 in Supplementary data.
4.3. In vitro antitumour assay
4.1.20. 5-Deoxy-5-C-dodecyl- -xylo-pentofuranose (26). A solution
D
of 25 (0.26 g, 0.68 mmol) in 70% aq AcOH (10 mL) was stirred for
3.5 h at reflux. After the mixture cooled to room temperature it was
concentrated by co-distillation with toluene and the residue puri-
fied by flash chromatography (EtOAc), to afford pure 26 (0.12 g,
57%) as a colourless solid. Recrystallization from a mixture of
MeOH/H2O gave an analytical sample 26, as transparent needles,
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) or
5ꢃ103 (HT-29, MDA-MB-231, HeLa, and MRC-5) cells per well to
assure logarithmic growth rate throughout the assay period. Anti-
proliferative activity was evaluated by the tetrazolium colorimetric
MTT assay, after exposure of cells to the tested compounds for 72 h,
following the recently reported procedure.14
mp 115e117 ꢁC, [
mutarotated to þ4.2 after equilibration for 71 h, Rf¼0.32 (EtOAc). IR
(KBr): nmax 3381 (OH). 1H NMR (250 MHz, acetone-d6):
0.81 (t, 6H,
J¼6.8 Hz, Me and ), 1.11e1.67 (m, 48H, 12ꢃCH2 and ),
3.82e4.21 (m, 6H, H-2, H-3, H-4 and ), 4.97 (s, 1H, H-1 ), 5.30 (d,
1H, J1,2¼3.7 Hz, H-1 14.5
). 13C NMR (62.9 MHz, methanol-d4):
a]
D þ12.4 (c 0.50, MeOH) the initial [a]D value that
d
a
b
a
b
Acknowledgements
a
b
b
a
d
This work was supported by a research grant from the Ministry
of Science and Technological Development of the Republic of Serbia
(Grant No. 172006).
(Me), 23.8, 27.1, 27.3, 30.0, 30.5, 30.76, 30.8, 30.9, 33.1 (13ꢃCH2
a
and
b
), 77.2, 77.9, 78.4, 80.3, 82.6 and 83.4 (C-2, C-3 and C-4,
a
and
b
), 97.3 (C-1a), 104.0 (C-1b). HRMS (ESI): m/z 347.2444
(MþHCOOꢀ), calcd for C18H35O6: 347.2439.
Supplementary data
4.1.21. 3,6-Anhydro-2-deoxy-6-C-tridecyl-D-ido-hexono-1,4-lactone
More detailed description of the crystallographic results. Sup-
plementary data associated with this article can be found in online
version, at doi:10.1016/j.tet.2011.09.132.
(8). To a solution of 26 (76 mg, 0.25 mmol) in dry DMF (1 mL) were
added Meldrum’s acid (80 mg, 0.56 mmol) and dry Et3N (0.07 mL,
0.51 mmol). The mixture was stirred for 48 h at 46 ꢁC and then
evaporated. The residue was purified by flash chromatography (4:1
Et2O/light petroleum) to afford pure 8 (54 mg, 66%) as a colourless
solid. Recrystallization from CH2Cl2/hexane, gave colourless needles,
References and notes
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a]
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OH), 2.62 (d, 1H, J2a,2b¼18.9 Hz, H-2a), 2.77 (dd, 1H, J2a,2b¼18.9 Hz,
J2b,3¼5.8 Hz, H-2b), 3.91 (td,1H, J5,6¼2.7 Hz, J6,7¼6.8 Hz, H-6), 4.27 (d,
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2367e2374.
ꢀ €
31.9 (12ꢃCH2), 35.9 (C-2), 74.3 (C-5), 75.6 (C-3), 80.5 (C-6), 87.8 (C-4),
175.9 (C-1). HRMS (ESI): m/z 327.2525 (MþþH), calcd for C19H35O4:
327.2530; m/z 349.2347 (MþþNa), calcd for C19H34NaO4: 349.2349;
m/z 365.2084 (MþþK), calcd for C19H34KO4: 365.2089.
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45.0 mm and a graphite monochromated MoK
a
(l
¼0.71073 A) X-
radiation was employed in both measurements. The frame width
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u
, with 40 and 154 s were used to acquire each frame for
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alent reflections was applied, and the data were corrected for
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solved by direct methods23 and the figures were drawn using
Mercury v. 2.4.24 Refinements were based on F2 values and done
by full-matrix least-squares25 with all non-H atoms anisotropic.
The positions of all non-H atoms were located by direct methods.
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of the difference Fourier maps. The final refinement included
atomic positional and displacement parameters for all non-H
atoms. At the final stage of the refinement H atoms were posi-
ꢀ
ꢀ
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ꢀ
ꢀ
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18. Crystallographic data (excluding structure factors) for the structures 7 and 8
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publications number CCDC 832453 and 832454, respectively.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
ꢃ
tioned geometrically (OeH¼0.82 and CeH¼0.96e0.98 A) and re-
fined using a riding model with fixed isotropic displacement

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B. Sreco et al. / Tetrahedron 67 (2011) 9358e9367
9367
Union Road, Cambridge CB2 1EZ, UK [fax: þ44 (0)1223 336033 or e-mail: de-
posit@ccdc.cam.ac.uk].
22. Data collection and processing software CrysAlisPro, v. 1; Oxford Diffraction
Ltd: Oxford, 2006.
19. The synthesis of 2 was previously reported by us, along with preliminary results of
its antiproliferative effects against K562, HL-60, Jurkat, HeLa and MCF-7 tumour
cell lines, but after exposure of cells to the tested compound for 48 h (see Ref. 9).
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