Novel goniofufurone and 7-epi-goniofufurone mimics from an unexpected titanium-mediated displacement process

Article abstract of DOI:10.1016/j.tetlet.2012.01.121

Treatment of 7-O-benzoyl-5-O-benzyl derivatives of (+)-goniofufurone or 7-epi-(+)-goniofufurone with titanium(IV) chloride or titanium(IV) bromide gave 7-chloro and 7-bromo-7-deoxy-goniofufurone mimics as the main reaction products along with minor amounts of the corresponding C-7 epimers. An unexpected cyclized product, benzoxepane 8 was isolated in some cases.

Full text of DOI:10.1016/j.tetlet.2012.01.121

Tetrahedron Letters 53 (2012) 1819–1822
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel goniofufurone and 7-epi-goniofufurone mimics from an unexpected
titanium-mediated displacement process
a
a
a
a
b
´
´
´
Jovana Francuz , Bojana Sreco , Mirjana Popsavin , Goran Benedekovic , Vladimir Divjakovic ,
c
c
b
a,
⇑
´
´
Vesna Kojic , Gordana Bogdanovic , Agneš Kapor , Velimir Popsavin
a Department of Chemistry, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovic´a 3, 21000 Novi Sad, Serbia
b Department of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovi´ca 4, 21000 Novi Sad, Serbia
c Oncology Institute of Vojvodina, Institutski put 4, 21204 Sremska Kamenica, Serbia
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of 7-O-benzoyl-5-O-benzyl derivatives of (+)-goniofufurone or 7-epi-(+)-goniofufurone with
titanium(IV) chloride or titanium(IV) bromide gave 7-chloro and 7-bromo-7-deoxy-goniofufurone mim-
ics as the main reaction products along with minor amounts of the corresponding C-7 epimers. An unex-
pected cyclized product, benzoxepane 8 was isolated in some cases.
Received 6 December 2011
Revised 17 January 2012
Accepted 27 January 2012
Available online 4 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Styryl lactones
Goniofufurone mimics
7-epi-Goniofufurone mimics
Antitumour agents
Titanium(IV)-mediated halogenation
(+)-Goniofufurone and 7-epi-(+)-goniofufurone (1 and 2, Fig. 1)
are naturally occurring styryl lactones that exhibit significant cyto-
toxic activities against several human tumour cell lines.1 Their
cytotoxicity appears to be specific to neoplastic cells since no
effects of these compounds on the growth of normal cells were
reported. Due to their unique structural features and promising
antitumour activities, both natural products 1 and 2, along with
a number of their analogues have been the targets of many total
syntheses.2,3 We have also been involved in the synthesis of these
natural products, their derivatives and analogues. Thus, during the
synthesis of 7-O-benzoyl-(+)-goniofufurone (Scheme 1) we faced
the problem of de-O-benzylation of 3 at C-5. Since it has been
shown that the standard de-O-benzylation reaction catalysed with
palladium on carbon always gives certain amounts of 7-deoxy
derivatives,4 we wanted to explore an alternative de-O-benzyla-
tion of 3, by using Lewis acids (TiCl4 or TiBr4) and an adapted liter-
ature procedure.5
Figure 1. Structures of natural products 1 and 2.
the same reaction conditions (TiCl4, CH2Cl2, 1 h at 0 °C, 3 h at rt).
This points to a possible SN1 mechanism for the reaction, presum-
ably via the stabilized benzylic carbocation 3a and 3-O-benzyl
derivatives 4 or 5 (isolated in small quantities from some experi-
ments). Preferential attack of the chloride from the less hindered
re-face (path b) leads to (7R)-epimer 4 as the major reaction
product, while the minor (7S)-epimer 5 is formed as a result of
carbocation capture from the more hindered si-face (path c). Sub-
sequent titanium-mediated 5-O-debenzylation of intermediates 4
and 5 gave the final products 6 and 7. The cyclized product 8
was presumably formed by an intramolecular Friedel–Crafts alkyl-
ation process (path d).
In order to gain a better insight into the mechanism of the pro-
cess, we planned to synthesize the postulated intermediates 4 and
5, and then to explore their chemical behaviour in the presence of
TiCl4 in dichloromethane. Benzylic alcohols 10 and 12 (Scheme 2),
previously synthesized in our laboratory starting from
were used as convenient starting compounds for this work.
However, treatment of 3 with TiCl4 in dry CH2Cl2 (Scheme 1) did
not afford the expected O-debenzylated product, but resulted in
the formation of 7-chloro-7-deoxy derivative 6 (33%), the corre-
sponding C-7 epimer 7 (19%), and the benzoxepane 8 (17%).
Essentially the same product distribution (33% of 6, 16% of 7 and
18% of 8) was obtained after the treatment of compound 9 under
D
-xylose,6
⇑
Corresponding author. Tel.: +381 21 485 27 68; fax: +381 21 454 065.
E-mail address: velimir.popsavin@dh.uns.ac.rs (V. Popsavin).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.121

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J. Francuz et al. / Tetrahedron Letters 53 (2012) 1819–1822
Scheme 2. Reagents and conditions: (a) CCl4, Ph3P, Py, 0 °C, 0.5 h, then rt (6 h for
10, 27 h for 12); (b) TiCl4, CH2Cl2, 0 °C, (0.5 h for 5, 1 h for 4), then rt (6 h for 5, 3 h
for 4); (c) attack from the re-face (less hindered); (d) attack from the si-face (more
hindered).
Since molecules 6 and 7 represent direct isosteres of (+)-gon-
iofufurone and 7-epi-(+)-goniofufurone, we expanded our study
to the synthesis of the corresponding bromide analogues 13 and
14, in order to explore their biological activity. Hence, this study
was continued by investigating the reaction of 3 with titanium(IV)
bromide in CH2Cl2 (Scheme 3).
We were pleased to find that 7-bromo derivative 13 was formed
in a 53% yield accompanied by a minor amount of its C-7 epimer 14
(22%) as the only by-product. The intramolecular Friedel–Crafts
alkylation process did not occur in the presence of this catalyst,
as oxepane 8 was not detected in the reaction mixture. When the
same reaction conditions were applied to epimer 9, compounds
13 and 14 were obtained in 50% and 22% yields, respectively. Obvi-
ously, the major product 13 in this reaction is formed as a result of
Walden inversion at C-7. Moreover, it seems that titanium(IV)
Scheme 1. Reagents and conditions: (a) TiCl4, CH2Cl2, 0 °C, 1 h, then rt, 3 h; (b)
attack from re-face (the less hindered); (c) attack from si-face (the more hindered);
(d) intramolecular Friedel–Crafts alkylation; (e) de-O-benzylation.
Thus, alcohol 10 readily reacted with CCl4 and Ph3P, under the
standard conditions of the Whistler–Anisuzzaman reaction,7 to af-
ford 7-chloro-7-deoxy derivative 5 (44%) as the main product,
accompanied with a minor amount of olefin 11 (23%). Under the
same reaction conditions, compound 12 gave the expected 7-
chloro-7-deoxy derivative 4 in a 41% yield along with a minor
amount of olefin 11 that was isolated in an 8% yield. The Z-geom-
etry of 11 was confirmed by an NOE interaction between H-5 and
H-7, indicating that these protons are in close proximity.
After chromatographic purification, the reactions of 4 and 5
with TiCl4 in CH2Cl2 gave a mixture of 6 (42% from 4, 37% from
5) and 7 (25% from 4, 28% from 5). As in the previous de-O-benzy-
lation reaction (Scheme 1), both starting compounds (4 and 5) on
treatment with TiCl4 gave approximately the same ratio of C-7 epi-
mers 6 and 7, thus indicating that the epimerization of 4 and 5 also
occurs through an SN1 mechanism, presumably via the stabilized
benzylic carbocation 4a. Since the product of the Friedel–Crafts
alkylation process could not be detected in the reaction mixture
it can be concluded that de-O-benzylation of 4 and 5 precedes
the epimerization at C-7.
Scheme 3. Reagents and conditions: (a) TiBr4, CH2Cl2, 0 °C, 1 h, then rt (2 h for 3,
4 h for 9).

J. Francuz et al. / Tetrahedron Letters 53 (2012) 1819–1822
1821
Table 1
bromide is not only a more selective catalyst, but also gives a mod-
In vitro cytotoxicity of 1, 2, 6, 7, 13, 14, and DOX
erate yield of (+)-goniofufurone isostere 13 (50–53%) compared
with the poor chemoselectivity and low yield of 6 (33%) obtained
with TiCl4.
a
Compound
IC50
Jurkat
(lM)
K562
HL-60
Raji
HeLa
MRC-5
For the sake of further comparisons of both catalysts, we
decided to prepare the bromide analogues of 4 and 5 (compounds
15 and 16, Scheme 4), and to explore their reactivity in the pres-
ence of titanium(IV) bromide as the catalyst.
1
6
13
2
7
7.29
4.78
2.15
3.62
2.78
3.52
0.36
>100
10.34
2.01
38.61
11.64
1.95
65.87
50.51
5.64
34.21
0.12
39.27
0.06
21.22
5.93
3.54
16.73
4.09
10.36
7.38
2.31
5.99
5.68
3.33
1.17
>100
>100
>100
>100
>100
>100
0.12
Whistler–Anisuzzaman reaction of 10 with CBr4 and Ph3P gave
a mixture of the expected 7-bromo derivative 15 (49%) and olefin
11 (24%). However, when 12 was allowed to react under the same
reaction conditions the expected product 16 was isolated in a 54%
yield, accompanied with only a small amount of olefin 11 (8%).
To our pleasant surprise, a clean and smooth reaction of 16 oc-
curred in the presence of TiBr4 whereupon (+)-goniofufurone mi-
mic 13 was obtained in an 86% yield, while the opposite 7-
epimer 14 was isolated in only a 1% yield. Moreover, reaction of
5-O-benzyl derivative 15 with TiBr4 under the same conditions
gave a a 60% yield of 7-epi-(+)-goniofufurone mimic 14, along with
a minor amount of epimerized product 13 (14%). Accordingly, the
epimerization at C-7 catalysed with TiBr4 is considerably slower
than that catalysed by TiCl4. The structures of products 6, 7, 8,
13, and 14 were unambiguously confirmed by X-ray diffraction
analyses.8
A side-by-side comparison of the antiproliferative activity of the
synthesized styryl lactone mimics 6, 7, 13, and 14 against a range
of human tumour cell lines9 is presented in Table 1. The commer-
cial anti-tumour agent doxorubicin (DOX), as well as the naturally
occurring styryl lactones (+)-goniofufurone (1) and 7-epi-(+)-gon-
iofufurone (2), served as reference compounds.
As the data from Table 1 reveal, both (+)-goniofufurone mimics
6 and 13 showed stronger in vitro antitumour activity compared to
the parent compound 1 against all the malignant cells under eval-
uation. Analogue 6 exhibited the most powerful activity towards
Raji cells being 654-fold more potent than the commercial cyto-
14
DOX
7.61
0.39
4.62
a
IC50 is the concentration of compound required to inhibit cell growth by 50%
compared to an untreated control.
toxic agent doxorubicin. The bromide analogue 13 showed potent
antiproliferative activity towards HL-60 cells, while the corre-
sponding parent compound 1 was completely inactive against this
cell line. Analogue 13 demonstrated over five and twofold greater
cytotoxicity in HL-60 cells, when compared to the chloro derivative
6 and DOX, respectively. Finally, both 7-epi-(+)-goniofufurone
mimics 7 and 14 showed stronger cytotoxicity compared to the
lead 2 against the most tested malignant cell lines (with the excep-
tion of 14 against Raji cells). Analogue 7 exhibited a strong antipro-
liferative activity against the Jurkat cell line being 285-fold more
potent than the parent compound 2. At the same time, compound
7 demonstrated threefold higher potency than DOX in the same
cell line. Analogue 14 showed the most potent cytotoxicity to-
wards HL-60 cells. This molecule exhibited approximately 20-
and 2-fold higher potency against this cell line with respect to lead
2 and DOX, respectively. Remarkably, both natural products 1 and
2 and analogues 6, 7, 13, and 14 were inactive against normal foe-
tal lung fibroblasts (MRC-5).
The results of this bioassay are consistent with our previous
findings,10 which indicated that 7-epi-(+)-goniofufurone (2) repre-
sents a more potent cytotoxic agent than (+)-goniofufurone (1). In
fact, it appears that 1 showed the weakest activity when compared
to all the other lactones under evaluation. In order to address this
issue, we first compared the structures of natural products 1 and 2,
determined previously by X-ray analysis,11,12 with our X-ray data
of analogues 6, 7, 13, and 14. As the superimposed structures re-
veal (Fig. 2), the geometries of the bicyclic cores in all the lactones
were very similar. The torsion angle between H-6 and H-7 in the
crystal structures of 2, 6, 7, 13, and 14 was in the range of
174.3–178.4°. These values correspond well with the 1H NMR vic-
inal couplings (J6,7 = 7.9–10.3 Hz), thus implying that all the com-
pounds had similar conformations both in solution and in the
solid state. However, the torsion angle between H-6 and H-7 in
the crystal structure of 1 is 72.1° as a result of the intramolecular
H-bond formed between the 5-OH and 7-OH.11 The corresponding
vicinal coupling (J6,7 = 5.3 Hz) again indicates similar geometries of
the acyclic moieties both in solution and in the solid state. The
Scheme 4. Reagents and conditions: (a) CBr4, Ph3P, Py, 0 °C, 0.5 h, then rt (26.5 h for
10, 3.5 h for 12); (b) TiBr4, CH2Cl2, 0 °C, 1 h, then rt (5 h for 15, 4 h for 16).
Figure 2. Superimposed structures of: (A) 1 (turquoise), 6 (pink), 13 (orange) and
(B) 2 (blue), 7 (green), and 14 (brown).

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J. Francuz et al. / Tetrahedron Letters 53 (2012) 1819–1822
structural difference between 1 and all the other molecules might
be a reason for the different antiproliferative activities of com-
pound 1.
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2012.01.121. These data include MOL files
and InChiKeys of the most important compounds described in this
article.
In summary, we have developed a new and facile route to (+)-
goniofufurone (1) and 7-epi-(+)-goniofufurone (2) mimics bearing
chloro (6 and 7), or bromo functions (13 and 14) at C-7. Both tita-
nium(IV) chloride and titanium(IV) bromide were found to cata-
lyse rapid nucleophilic substitution of the benzylic ester
functions at C-7 along with de-O-benzylation at C-5. However,
these transformations were usually accompanied by epimerization
at C-7, which was more pronounced in the presence of TiCl4, but
was much less evident when titanium(IV) bromide was used as
the catalyst. All the synthesized styryl lactone mimics demon-
strated potent to moderate growth-inhibitory effects against a pa-
nel of human malignant cell lines, but were devoid of any
significant cytotoxicity towards normal foetal lung fibroblasts
(MRC-5). Additionally, all of the synthesized analogues were
broadly toxic against most of the cell lines under evaluation. Bro-
mide isosteres 13 and 14 exhibited the most pronounced growth
inhibitory effects when compared to leads 1 and 2, respectively.
These results confirm that the isosteric replacement of hydroxy
functionalities at C-7 with Cl or Br groups improves the antiprolif-
erative effects of the resulting mimics against some human neo-
plastic cells.
References and notes
1. For recent reviews on the cytotoxicity of styryl lactones and their analogues,
see: (a) Wiart, C. Evid. Based Complement Alertern. Med. 2007, 4, 299–311; (b) de
Fatima, A.; Modolo, L. V.; Conegero, L. S.; Pilli, R. A.; Ferreira, C. V.; Kohn, L. K.;
de Carvalho, J. E. Curr. Med. Chem. 2006, 13, 3371–3384; (c) Mereyala, H. B.; Joe,
M. Curr. Med. Chem. Anticancer Agents 2001, 1, 293–300; (d) Blazquez, M. A.;
Bermejo, A.; Zafra-Polo, M. C.; Cortes, D. Phytochem. Anal. 1999, 10, 161–170.
2. For reviews on syntheses of styryl lactones, see: (a) Mondon, M.; Gesson, J.-P.
Curr. Org. Synth. 2006, 3, 41–75; (b) Zhao, G.; Wu, B.; Wu, X. Y.; Zhang, Y. Z.
Mini-Rev. Org. Chem. 2005, 2, 546–564.
3. For recent examples, see: (a) Pal, P.; Shaw, A. K. Tetrahedron 2011, 67, 4036–
4047; (b) Sharma, G. V. M.; Mallesham, S. Tetrahedron: Asymmetry 2010, 21,
2646–2658; (c) Hernández-García, L.; Quintero, L.; Höpfl, H.; Sosa, M.; Sartillo-
Piscil, F. Tetrahedron 2009, 65, 139–144; (d) Prasad, K. R.; Gholap, S. L. J. Org.
Chem. 2008, 73, 2–11; (e) Yadav, V. K.; Agrawal, D. Chem. Commun. 2007, 10,
5232–5234.
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´
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4. Popsavin, V.; Sreco, B.; Benedekovic, G.; Francuz, J.; Popsavin, M.; Kojic, V.;
Bogdanovic´, G. Eur. J. Med. Chem. 2010, 45, 2876–2883.
5. Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989, 54, 1346–1353.
6. Popsavin, V.; Benedekovic´, G.; Srec´o, B.; Francuz, J.; Popsavin, M.; Kojic´, V.;
Bogdanovic´, G.; Divjakovic´, V. Tetrahedron 2009, 65, 10596–10607.
7. Anisuzzaman, A. K. M.; Whistler, R. L. Carbohydr. Res. 1978, 60, 511–518.
8. For details see Supplementary data. Crystallographic data (excluding structure
factors) for the structures 6–8, 13, and 14 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publications
number CCDC 856698, 856699, 856700, 856701, and 856702, respectively.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk].
Acknowledgment
Financial support from the Ministry of Education and Science of
the Republic of Serbia (Grant No. 172006) is gratefully
acknowledged.
9. Cytotoxic activities were evaluated by using the standard MTT assay after
exposure of cells to the tested compounds for 48 h. Results are presented as
mean values of three independent experiments performed in quadruplicate.
Coefficients of variation were <10%.
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10. Popsavin, V.; Benedekovic, G.; Sreco, B.; Popsavin, M.; Francuz, J.; Kojic, V.;
Bogdanovic´, G. Org. Lett. 2007, 9, 4235–4238.
Supplementary data
11. Fang, X. P.; Anderson, J. E.; Chang, C. J.; Mclaughlin, J. L.; Fanwick, P. E. J. Nat.
Prod. 1991, 54, 1034–1043.
12. Su, Y.-L.; Yang, C.-S.; Teng, S.-J.; Zhao, G.; Ding, Y. Tetrahedron 2001, 57, 2147–
2153.
Supplementary data (general experimental procedures, full
characterization data, detailed description of the crystallographic
results and copies of NMR spectra of final products) associated