Synthesis of (±) debenzoyl analogs of norsampsones as potential anticancer agents

Article abstract of DOI:10.1016/j.tetlet.2015.07.057

Synthesis of (±) debenzoyl analogs of norsampsones 1 and 2 is reported starting from commercially available 1,3-cyclohexadione in six steps with overall yields of 37% and 36%, respectively. Compounds 1 and 2 were tested for their anticancer activity and showed moderate anticancer activity against HeLa cell lines.

Full text of DOI:10.1016/j.tetlet.2015.07.057

Tetrahedron Letters xxx (2015± xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of (± ± debenzoyl analogs of norsampsones as potential
anticancer agents
a
a
b
a,
⇑
Amol R. Jadhav , Raju S. Thombal , Preeti Nigam , Vrushali H. Jadhav
a
Division of Organic Chemistry, National Chemical Laboratory (CSIR-NCL), Pune 411008, India
Combichem Bioresource Centre, National Chemical Laboratory, Pune, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of (± ± debenzoyl analogs of norsampsones 1 and 2 is reported starting from commercially
Received 17 June 2015
Revised 16 July 2015
Accepted 17 July 2015
Available online xxxx
available 1,3-cyclohexadione in six steps with overall yields of 37% and 36%, respectively. Compounds
1
and 2 were tested for their anticancer activity and showed moderate anticancer activity against
HeLa cell lines.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Acylphloroglucinols
Debenzoyl
Norsampsones
Anticancer
The polycyclic polyprenylated acylphloroglucinols (PPAPs± con-
stitute a family of natural products whose antiseptic, antidepres-
sant, and antibiotic properties have been known for centuries.
and spectral data matched with those in the literature.10
Alkylation of enone 5 with LDA and prenyl bromide afforded com-
1
–7
11
pound 6 (trans/cis = 9:1± as reported by Ahmad et al. The major
Hypericum sampsonii belongs to the Clusiaceae family which exhi-
bits anticancer activity and has been used as a promising anti-
cancer herb in Taiwan.8 Very recently, Tian and co-workers
isolated norsampsones A–D (Fig. 1±, four new dicarbonyl
polyprenylated acylphloroglucinols from the plant H. sampsonii.
They have reported structural elucidation, plausible biogenetic
pathway, and biological evaluation of norsampsones A–D. We
herewith report the synthesis of the (± ± debenzoyl analogs of
norsampsones. These analogs were tested for their anticancer
activity against HeLa cell lines using MTT assay and were found
to have moderate cell growth inhibitory activity.
trans-isomer of compound 6 was separated from cis-isomer and
1
13
the H and C NMR spectra were found identical with those of
9
11
the reported. Similarly, enone 5 when treated with geranyl bro-
mide provided the geranylated product 7 (trans/cis = 9:1± in 80%
yield. The major trans-isomer of compound 7 was separated by
column chromatography with 80% yield and its identity was
1
13
confirmed by H, C NMR, and HRMS data.
O
O
O
O
Ph
Ph
We envisioned the synthesis of compounds 1 and 2 as shown in
Scheme 1. Compounds 1 and 2 could be obtained by 1,4-addition of
methyl nucleophile on intermediates 15 and 16, respectively.
Intermediates 15 and 16 could be afforded from dialkylation of
synthon 5, which in turn could be obtained from commercially
available 1,3-cyclohexadione 3.
O
O
A
B
O
O
O
O
1
,3-Cyclohexadione was used as a starting material for synthe-
sis of (± ± debenzoyl analogs of norsampsones. 1,3-Cyclohexadione
Ph
Ph
3
was treated with iodine in methanol to afford the vinyl ether 4 in
O
O
9
2% yield (Scheme 2±. Stork–Danheiser reaction of 4, afforded the
prenylated enone 5 in 89% yield as reported by Shibasaki et al.
C
D
⇑
Corresponding author.
E-mail address: vh.jadhav@ncl.res.in (V.H. Jadhav±.
Figure 1. Structures of norsampsones A–D.
http://dx.doi.org/10.1016/j.tetlet.2015.07.057
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Jadhav, A. R.; et al. Tetrahedron Lett. (2015±, http://dx.doi.org/10.1016/j.tetlet.2015.07.057

2
A. R. Jadhav et al. / Tetrahedron Letters xxx (2015) xxx–xxx
O
O
O
O
R
R
1,4-addition
Dialkylation
Stork-Danheiser
O
O
O
1
2
. R = H
. R =
15. R = H
16. R =
5
3
Scheme 1. Retrosynthesis of debenzoyl analogs 1 and 2 of norsampsone.
O
1
O
O
O
a) LDA, Prenyl bromide,
THF, -78 °C
I
MeOH
,
6
2
LDA, Prenyl bromide,
THF, -78 °C, 82%
2
5
rt, 5 min, 92%
b) MeLi, THF, -78 °C
c) 1M HCl, rt
3
O
O
4
3
4
89%
5
6
(trans/cis = 9:1)
LDA, Geranyl bromide,
THF, -78 °C, 80%
O
7
(
trans/cis = 9:1)
Scheme 2. Synthesis of compounds 6 and 7.
OH
Ethyl Vinyl ether, Hg(OAc)2
H
O
2
MeLi, Et O
O
78 °C, 10 min, 88%
130 °C, sealed tube, 5h, 59%
8
9
10
Scheme 3. Synthesis of aldehyde 10.
O
O
O
O
OH
PCC, DCM
reflux, 20 min, 88%
LiHMDS, 10, THF
8 °C, 75 min, 89%
7
6
11
Scheme 4. Synthesis of 12.
12
2
-Methylbut-3-en-2-ol 9 was prepared from methyl vinyl
ketone 8 by 1,2-addition of MeLi in dry ether at À78 °C for
0 min. Compound 9 was then treated with ethyl vinyl ether in
the presence of catalytic Hg(OAc± in a sealed tube at 130 °C for
h to obtain a rather volatile ,d-unsaturated aldehyde 10 in 59%
Compounds 6 and 7 on reacting with aldehyde 10 in the pres-
ence of LDA at À78 °C afforded alcohol 13 and alcohol 14 in a
1
diastereomeric ratio of 9:1 and 7:3, respectively (Scheme 5±. The
1
2
diastereomeric ratio was confirmed from
H NMR spectra.
5
c
Without separating the diastereomers of compounds 13 and 14,
oxidation of 13 and 14 with PCC afforded compounds 15 and 16,
respectively in good yields (89% and 85%±. Conjugate addition of
the organocuprate derived from methylmagnesium bromide and
CuBr to enone 15 and 16 in THF at 0 °C afforded (± ± debenzoyl ana-
logs of norsampsones 1 and 2, respectively, in excellent yields. The
structures were confirmed using NMR and HRMS data. Thus, we
have reported synthesis of compounds 1 and 2 with overall yields
yield by the aliphatic Claisen rearrangement (Scheme 3±.
In an attempt to introduce the C6-side chain, compound 6 was
alkylated with aldehyde 10 using LiHMDS to generate the enolate
to give compound 11 as a diastereomeric mixture (Scheme 4±.
Since, we generated a mixture of diastereomers, we wanted to sim-
plify the analysis and hence oxidized the mixture of alcohols to
ketone 12 in 88% yield. 1H, C NMR and HRMS data confirmed
the formation of ketone 12.
13
1
2
of 37% and 36%, respectively. On the basis of these results,
Please cite this article in press as: Jadhav, A. R.; et al. Tetrahedron Lett. (2015±, http://dx.doi.org/10.1016/j.tetlet.2015.07.057

A. R. Jadhav et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
R
R
O
O
R
O
LDA, 10, THF
8 °C, 1h
PCC, DCM
7
OH
reflux, 20 min
O
6
7
. R = H
. R =
13. R = H, , 67%
14. R =
1
5. R = H, , 89%
, 71%
16. R =
,
85%
2
CuI, Me S, MeMgBr,
THF, 0 °C
R
O
O
1
. R = H, 91%
. R =
2
,
88%
Scheme 5. Synthesis of 1 and 2.
Acknowledgments
V.H.J. thanks DST, New Delhi for the INSPIRE Faculty Award (IFA
2, CH-44± and Fast Track Grant (CS-041/2013±. V.H.J. also thanks
1
the Director, NCL for providing all the infra-structural facilities.
Supplementary data
Supplementary data (detailed experimental procedure, charac-
terization of the products and copies of spectra are provided± asso-
ciated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.07.057.
References and notes
Figure 2. MTT assay results for (a± compound 1 and (b± compound 2.
1. Singh, I. P.; Bharate, S. B. Nat. Prod. Rep. 2006, 23, 558–591.
2
3
.
.
Li, Y. J.; Ge, Z. X.; Liu, H. Hecheng Huaxue. 2004, 12, 555–558.
Singh, I. P.; Sidana, J.; Bharate, S. B.; Foley, W. J. Nat. Prod. Rep. 2010, 27, 393–
4
16.
catalytic asymmetric synthesis of norsampsones using Koga alkyla-
tion and studies of its biological activities are currently ongoing.
Since norsampsones C, showed anticancer activity (IC50
4
.
Njardarson, J. T. Tetrahedron 2011, 67, 7631–7666.
1
3
5. Marianna, D.; Emmanuel, A. T. Biomimetic. Org. Synth. 2011, 433–467; Haslam,
E. Shikimic Acid Metabolism and Metabolites; John Wiley & Sons: New York,
1
993.
Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106, 3963–3968.
7. Weng, J. R.; Tsao, L. T.; Wang, J. P.; Wu, R. R.; Lin, C. N. J. Nat. Prod. 2004, 67,
796–1799.
>20
lM± we thought to screen the synthesized compounds 1 and
6.
2
for their anticancer activity using MTT assay against HeLa cell
1
lines. Compounds 1 and 2 exhibited moderate antiproliferative
efficacy for cancer cells. As illustrated in Figure 2, IC50 values for
8.
Chiu, N. Y.; Chang, K. H. In The Illustrated Medicinal Plants of Taiwan; SMC
Publishing: Taipei, 1986; vol. II, 138.
the compounds 1 and 2 were 19 and 7
lM, respectively, that prove
9. Tian, W.; Yu, Y.; Yao, X.; Chen, H.; Zhang, Y. D. X.; Yao, X. Org. Lett. 2014, 16,
the anti cancer potential of compounds 1 and 2 and open a way for
future therapeutic applications of these compounds in cancer
treatment.
3448–3451.
1
0. (a± Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 14200–14201; (b± Spessard, S. J.; Stoltz, B. M. Org. Lett.
2
002, 4, 943–1946.
In summary a simple, flexible, and highly efficient synthetic
approach for the synthesis of (± ± debenzoyl analogs of norsamp-
sones 1 and 2 has been developed. The overall yields of 1 and 2
was found to be 37% and 36%, respectively, over six steps.
Compounds 1 and 2 exhibited promising anticancer activity
against HeLa cell lines.
11. Ahmad, N. M.; Rodeschini, V.; Simpkins, N. S.; Ward, S. E.; Blake, A. J. J. Org.
Chem. 2007, 72, 4803–4815.
1
2. Various attempts for synthesis of (± ± norasampsones were tried by reacting 15
and 16 with CuI, MeMgBr and further adding PhCHO to trap the enolate in situ,
but unfortunately our continuous attempts failed to obtain norsampsones A–D.
3. Imai, M.; Hagihara, A.; Kawasaki, H.; Manabe, K.; Koga, K. J. Am. Chem. Soc.
1
1994, 116, 8829–8830.
Please cite this article in press as: Jadhav, A. R.; et al. Tetrahedron Lett. (2015±, http://dx.doi.org/10.1016/j.tetlet.2015.07.057