A concise synthesis of (+)-goniofufurone, (+)-7-epi-goniofufurone, (+)-crassalactones B and C

Article abstract of DOI:10.1016/j.tetlet.2019.06.001

The concise and efficient synthesis of (+)-goniofufurone, (+)-7-epi-goniofufurone, (+)-crassalactones B and C were achieved in 6 to 7 steps from the known D-glucono-δ-lactone derivative 9. An acid-mediated cascade cyclization was employed to construct the

Full text of DOI:10.1016/j.tetlet.2019.06.001

Accepted Manuscript
A concise synthesis of (+)-goniofufurone, (+)-7-epi-goniofufurone, (+)-crassa-
lactones B and C
Yanli Zhang, Xiaojing Liu, Feng Shui, Faling Zhou, Jing Cui, Xiaochuan Chen
PII:
S0040-4039(19)30531-3
https://doi.org/10.1016/j.tetlet.2019.06.001
TETL 50842
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 April 2019
30 May 2019
1 June 2019
Please cite this article as: Zhang, Y., Liu, X., Shui, F., Zhou, F., Cui, J., Chen, X., A concise synthesis of (+)-
goniofufurone, (+)-7-epi-goniofufurone, (+)-crassalactones B and C, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.06.001
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A concise synthesis of (+)-goniofufurone, (+)-
-epi-goniofufurone, (+)-crassalactones B
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7
and C
Yanli Zhang, Xiaojing Liu, Feng Shui, Faling Zhou, Jing Cui, Xiaochuan Chen
OH
OH
O
H
O
H
HO
O
HO
H
O
H
O
O
O
O
O
6 to 7 steps
(+)-goniofufurone
(+)-7-epi-goniofufurone
O
OH
O
OMe
H
O
O
OH
O
O
O
O
H
H
O
O
HO
O
H
O
(+)-crassalactone B
(+)-crassalactone C

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A concise synthesis of (+)-goniofufurone, (+)-7-epi-goniofufurone, (+)-crassalactones
B and C
a
a

Yanli Zhang , Xiaojing Liu , Feng Shui, Faling Zhou, Jing Cui, Xiaochuan Chen
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China.
—
——
ARTICLE INFO
ABSTRACT

Corresponding author.
E-mail address: chenxc@scu.edu.cn
Article history:
The concise and efficient synthesis of (+)-goniofufurone, (+)-7-epi-goniofufurone, (+)-
crassalactones B and C were achieved in 6 to 7 steps from the known D-glucono-δ-lactone
derivative 9. An acid-mediated cascade cyclization was employed to construct the furanofurone
bicyclic framework in one-pot.
Ra eceived
These authors contributed equally to this work.
Received in revised form
Accepted
Available online
2
019 Elsevier Ltd. All rights reserved.
Keywords:
Styryllactone
Goniofufurone
Crassalactone
Total Synthesis
Introduction
OH
7
OH
7
H
H
O
3
4
O
3
4
[1]
2
(
+)-Goniofufurone (1) (Fig. 1) and (+)-7-epi-goniofufurone
6
6
2
[2]
1
1
(
2), two bioactive furanofurone compounds isolated from the
HO 5
HO 5
O
O
O
H
O
H
trees of genus Goniothalamus, belong to naturally occurring
[3]
styryllactones, which have the characteristic skeleton structure
consisting of a functional styryl unit and a δ- or γ-lactone moiety.
Considerable styryllactones possessed significant to marginal
cytotoxic activity against human tumor cell lines, as well as
1
(+)-7-epi-goniofufurone (2)
(
+)-goniofufurone ( )
OH
H
O
O
O
pesticidal, anti-inflammatory, embryotoxic, immunosuppressant,
O
antibiotic and antimalarial activities.[
4,5]
As two representative
H
O
O
O
H
O
members, 1 and 2 showed significant antiproliferative activities
against some human malignant cell lines but were devoid of any
cytotoxicity against the normal fetal lung fibroblasts (MRC-
HO
(+)-crassalactone C (4)
O
O
H
(+)-crassalactone B ( )
3
[1,4,6]
5
).
Particularly, the K562 cells inhibitory activity of 2 with
an IC50 value of 0.028 μM was ca. 9-fold stronger than that of
clinical doxorubicin (IC50 = 0.25 μM). Moreover, a number of
Fig. 1. The structure of (+)-goniofufurone, (+)-7-epi-goniofufurone,
+)-crassalactones B and C.
[6]
(
their stereoisomers and analogues exhibited promising
[7]
antitumour properties. The combination of the remarkable
bioactivity and the interesting structures have aroused remarkable
interest of synthetic chemists. Various approaches to 1 and 2
have been developed starting from chiral materials or using the
by a chemical transformation of 1. Both 3 and 4 displayed a
[11]
potent cytotoxic against several cancer cell lines, as well as
[12]
antiproliferative activities against human tumour cell lines.
Remarkably, (+)-crassalactones B (3) and C (4) (IC50 4.4 and 2.6
μM, respectively) exhibited 8 and 14-times greater potency with
respect to control (+)-goniofufurone (1) in vitro antiproliferative
[8,9]
asymmetric synthetic methods.
(+)-Crassalactones B (3) and C (4), two 5-O- and 7-O-
[
12e]
activities against A549 cells.
Up to now, several synthesis of
cinnamoyl derivatives of (+)-goniofufurone (1), were isolated
from Polyalthia crassa rather than Goniothalamus species in
[
12a-d,13]
[14]
3
and 4 were achieved by Popsavin,
Prasad , respectively. However, D-glucono-δ-lactone (5), a
cheap chiral source, has not been employed in the synthesis of 1-
Mallesham
and
[15]
[10]
2
006. Their absolute configurations were determined indirectly
4
yet. In the past several years, we have been engaged in
enantioselective synthesis of natural products using commercial
[16]
carbohydrates as chiral pools.
As part of our continuing
interest in the synthesis of bioactive natural molecules and their
[17]
enantiomers from 5, we herein describe the synthesis of 1-4.

2
Tetrahedron
Results and discussion
aldehyde 14. Given the relative instability of 14, it was subjected
to the Wittig olefination procedure without purification. Wittig
reaction of 14 with (carbmethoxymethylene)triphenyl-
phosphorane proceeded with excellent stereoselectivity to afford
the desired Z-conjugated ester 15, which should readily undergo
the subsequent lactonization. Under weak acidic conditions (70%
AcOH), removal of the isopropylidene group in 15 and
concomitant lactonization occurred slowly, and lactone 16 was
obtained only in moderate yield after a long span (40 h), together
with recovered 15. To our delight, treatment of 15 with aqueous
TFA directly furnished the natural product 1 in 44% yield,
together with triol 17 (45%), which was easily converted to 1 via
a DBU-promoted intramolecular oxa-Michael addition. In this
one-pot transformation of 15 to 1, an efficient domino process
involving hydrolysis of acetonide, lactonization, removal of TBS
and Michael-type cyclization occurred with formation of the
furanofurone bicyclic structure. The spectroscopic and
Our synthetic strategy for the furanofurone-type styryllactones
-4 is illustrated in Scheme 1. 3 and 4 could be conveniently
1
obtained by esterification of 1 with cinnamoyl chloride at C-5 or
C-7 hydroxyl group. 1 and 2, as two C-7 epimers, would be
accessed through sequential lactonization/intramolecular oxa-
Michael addition of intermediates 6 and 7, respectively. It was
envisioned that 4 could also be generated exclusively from 6 via
C-7 hydroxyl esterification followed by the similar successive
cyclization. Both 6 and 7 could come from common ester 8 by
routine transformations including Wittig olefination and addition
of the Grignard reagent. The latter could be easily prepared from
the commercially available 5.
OH
4
O
O
3
and 4
D
spectrometric data ([α] , NMR, IR, and MS) for the synthetic 1
HO
OH
OH
O
[1,9c]
from 12 were in good accord with the reported values.
indicated the R configuration of C-7 in more polar isomer 12.
It
OH
Ph
Ph
7
5
1
OR
O
O
CO Et
2
OH
O
O
OH
O
O
a
b
Ph
OMe
Ph
TBSO
H
6
O
O
O
TBSO
O
O
O
OH
O
OMe
12
14
OR
O
2
7
OR
CO Et
OH
O
2
8
OH OH
Ph
TBSO
7
Ph
TBSO
O
CO Et
2
Scheme 1. The retrosynthetic analysis of natural products 1-4
O
O
1
6
The synthesis started with the known ester 9, which was
readily prepared via acetonation of 5 following literature
15
c
[18]
procedure. Treatment of ester 9 with TBSCl and imidazole in
DMF afforded silyl ether 10. Selective hydrolysis of the terminal
acetonide and oxidative cleavage of resulting diol occurred
OH
HO
OH OH
H
O
O
Ph
.
[17a,19]
Ph
simultaneously with H
5
IO
6
2H
2
O led to aldehyde 11.
+
Without further purification, aldonoester 11 was subjected to a
chemoselective addition with phenyl magnesium bromide to
afford equal amount of C-7 epimeric diols 12 and 13 (Scheme 2),
which could be separated by column chromatography.
OH
O
O
H
1
O
17
d
o
Scheme 3. Reagents and conditions: a) DIBAL, CH
2
Cl
2
, -78 C; b)
O (v:v =
o
Ph
3
P=CHCO
2
Et, MeOH, 0 C, 87% over 2 steps; c) TFA/H
2
O
O
O
O
O
O
1:1), rt, 44% for 1 and 45% for 17; (d) DBU, THF, rt, 82%.
a
O
b
O
OMe
OMe
Next, we set out to utilize less polar isomer 13 with 7S
configuration to synthesize 2 by the same procedures (Scheme 4).
Reduction of ester 13 to the corresponding aldehyde followed by
Wittig olefination gave Z-conjugated ester 18. Upon exposure to
TFA/H O, the similar sequential reaction of 18 also proceed to
2
afford natural product 2 and triol 19. The latter was also treated
OH
O
O
TBSO
O
9
10
O
O
OH
O
O
OH
O
O
c
+
with DBU to produce the former in good yield.
H
OMe
Ph
OMe
Ph
TBSO
OMe
TBSO
O
TBSO
O
OH
O
O
OH
O
O
a,b
Ph
TBSO
OMe
Ph
TBSO
c
1
1
12
13
O
O
CO2Et
Scheme 2. Reagents and conditions: a) TBSCl, imidazole, DMF, rt,
5%; b) H IO ·2H O, AcOEt, rt; c) PhMgBr, THF, -78 C, 42% for
5 6 2
o
9
1
13
18
2 and 40% for 13 over 2 steps.
OH OH
OH
HO
Although the absolute configuration of the new secondary
H
O
H
alcohol functionality in 12 and 13 was not assigned at this stage,
they both would be useful intermediates for epimeric natural
products 1 and 2 separately. Their stereostructures should be
deduced by their subsequent transformation into the
corresponding 1 and 2. Thus, more polar isomer 12 was
employed to carry out the subsequent reactions first (scheme 3).
Direct reduction of hydroxyl ester 12 with DIBAL afforded
Ph
Ph
+
OH
O
O
O
O
19
2
d
o
Scheme 4. Reagents and conditions: a) DIBAL, CH
2
Cl
Et, MeOH, 0 C, 74% over 2 steps; c) TFA/H
:1), rt, 37% for 2 and 48% for 19; (d) DBU, THF, rt, 87%.
2
, -78 C; b)
2
o
Ph
3
P=CHCO
2
O (v:v =
1

3
References and notes
[
[
[
1] X.P. Fang, J.E.Anderson, C.J. Chang, J.L. Mclaughlin, J. Chem. Soc.,
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Finally, we turned our attention to the synthesis of (+)-
crassalactones B (3) and C (4) from (+)-1 or 15 (Scheme 5).
Direct monoacylation of diol 1 with cinnamoyl chloride didn't
show obvious chemoselectivity to afford 3 and 4 in a similar
amount. On the other hand, secondary alcohol 15 was coupled
with cinnamoyl chloride to give the resulting ester 20. Under the
similar TFA conditions, the cleavage of O-TBS protecting group
in 20 was more difficult than 15 probably due to the acylation of
the vicinal hydroxyl, and unsaturated lactone 21 was obtained in
(1991) 1034–1043.
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Anal. 10 (1999) 161–170.
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C.E. Wiart, Based Complement. Altern. Med. 4 (2007) 299-311.
8
0% yield. When was stirred in MeOH in the presence of p-
TsOH, 4 was generated in 40% yield via a similar domino
deprotection and cyclization, together with 21 (43%). After
TBAF-mediated removal of the TBS protecting group in 21,
concomitant intramolecular oxa-Michael addition led to 4 with
[5] N. Suchaichit, K. Kanokmedhakul, N. Panthama, K. Poopasit, P.
Moosophon, S. Kanokmedhakul, Fitoterapia 103 (2015) 206–212.
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Kojić, G. Bogdanović, Org. Lett. 9 (2007) 4235–4238.
[7] (a) V. Popsavin, J. Francuz, S.B. Zelenović, G. Benedeković, M.
Popsavin, V. Kojic, G. Bogdanovic, Bioorg. Med. Chem. Lett. 23
7
7% yield.
(2013) 5507–5510; (b) G. Benedeković, J. Francuz, I. Kovačević, M.
O
OH
O
Popsavin, B. Sreco, V. Kojić, G. Bogdanović, V. Didjaković, V.
Popsavin, Eur. J. Med. Chem. 82 (2014) 449–458; (c) M. Svircev, G.
Benedeković, I. Kovacević, M. Popsavin, V. Kojić, D. Jakimov, T.
Srdic-Rajić, M.V. Rodić, V. Popsavin, Tetrahedron 74 (2018) 4761–
OH
O
O
H
Ph
O
Ph
H
O
a
O
H
Ph
+
Ph
H
O
O
4
768; (d) J. Francuz, I. Kovačević, M. Popsavin, G. Benedeković, B.
O
HO
O
HO
H
O
Srećo Zelenović, V. Kojić, D. Jakimov, L. Aleksić, G. Bogdanović, T.
Srdić-Rajić, E. Lončar, M.V. Rodić, V. Divjaković and V. Popsavin,
Eur. J. Med. Chem., 128 (2017) 13–24; (e) V. Popsavin, G.
Benedeković, B. Srećo, M. Popsavin, J. Francuz, V. Kojić, G.
Bogdanović, Bioorg. Med. Chem. Lett. 18 (2008) 5178–5181.
H
O
Ph
4
1
3
O
OH
O
Ph
O
O
c
[8] For the reviews on syntheses of styryl lactones, see: (a) M. Mondon, J.-
P. Gesson, Curr. Org. Synth. 3 (2006) 41–75; (b) G. Zhao, B. Wu, X.Y.
Wu, Y.Z. Zhang, Mini-Rev. Org. Chem. 2 (2005) 333–353; (c) Z.C.
Yang, W.S. Zhou, Heterocycles 45 (1997) 367–383.
[9] For recent synthesis of 1 and 2, see: (a) L. Hernández-García, L.
Quintero, H. Höpfl, M. Sosa, F. Sartillo-Piscil, Tetrahedron 65 (2009)
139–144; (b) K.R. Prasad, M.G. Dhaware, Synthesis 23 (2007) 3697–
b
Ph
TBSO
Ph
O
CO2Et
TBSO
O
CO2Et
15
20
O
O
O
3
705; (c) K.R. Prasad, S.L. Gholap, J. Org. Chem. 73 (2008) 2-11; (d) P.
Ph
Ph
O
OH
O
Ruiz, J. Murga, M. Carda, J.A. Marco, J. Org. Chem. 70 (2005) 713–
716; (e) V.K. Yadav, D. Agrawal, Chem. Commun. (2007) 5232–5234;
O
H
+
Ph
Ph
(f) M. Ralph, S. Ng, K.I. Booker-Milburn, Org. Lett. 18 (2016) 968–971;
TBSO
HO
(g) A.D. Wouters, A.B. Bessa, M. Sachini, L.A. Wessjohann, D.S.
Lüdtke, Synthesis 45 (2013) 2222–2233; (h) R.F. de la Pradilla, J.
Fernandez, A. Viso, J. Fernandez, A. Gomez, Heterocycles, 68 (2006)
H
O
O
O
21
4
d
1
579–1584; (i) P. Pal, A.K. Shaw, Tetrahedron 67 (2011) 4036–4047.
Scheme 5. Reagents and conditions: a) cinnamoyl chloride, Et
3
N,
[
10] P. Tuchinda, B. Munyoo, M. Pohmakotr, P. Thinapong, S. Sophasan, T.
o
DMAP, CH
chloride, Et
2
Cl
2
, 0 C to rt, 47% for 3 and 46% for 4; b) cinnamoyl
Santisuk, V. Reutrakul, J. Nat. Prod. 69 (2006) 1728–1733.
[11] G. Benedeković, M. Popsavin, J. Francuz, I. Kovačević, V. Kojić, G.
Bogdanović, V. Divjaković, V. Popsavin, Eur. J. Med. Chem. 87 (2014)
o
3
N, DMAP, CH
2
Cl
2
, 0 C to rt, 92%; c) p-TsOH, MeOH,
o
rt, 40% for 4 and 43% for 21; d) TBAF, THF, 0 C to rt, 77%.
2
37-247.
[
12] (a) V. Popsavin, G. Benedeković, B. Srećo, M. Popsavin, J. Francuz, V.
Kojić, G. Bogdanović, Org. Lett. 9 (2007) 4235-4238; (b) V. Popsavin,
G. Benedeković, B. srećo, J. Francuz, M. Popsavin, V. Kojić, G.
Bogdanović, V. Divjaković, Tetrahedron 65 (2009) 10596-10607; (c) V.
Popsavin, G. Benedeković, B. Srećo, M. Popsavin, J. Francuz, V. Kojić,
G. Bogdanović, Bioorg. Med. Chem. Lett. 18 (2008) 5178-5181; (d) G.
Benedeković, I. Kovacević, M. Popsavin, J. Francuz,V. Kojić, G.
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Popsavin, B. Srećo, G. Benedeković, J. Francuz, M. Popsavin, V. Kojić,
G. Bogdanović, Eur. J. Med. Chem. 45 (2010) 2876-2883.
Conclusion
In conclusion, we have developed a concise and economical
synthesis of four styryllactones 1-4, in which a cascade
cyclization of precursor 15 or 20 was employed to construct
furanofurone bicyclic framework in one-pot. By the approach, 1-
4
were synthesized in 6 to 7 steps from readily available D-
glucono-δ-lactone derivative 9. There is no expensive reagents
and materials used in the whole synthesis. This robust route
should enable easy access to structural styryllactones and their
analogues.
[13] V. Popsavin, G. Benedeković, M. Popsavin, V. Kojić, G. Bogdanović
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[14] G.V.M. Sharma, S. Mallesham, Tetrahedron: Asymmetry 21 (2010)
2
646-2658.
[15] K.R. Prasad, S.M. Kumar, Synthesis 45 (2013) 785-790.
[
16] (a) X. Liu, J. Jia, Y. Jia, H. Gu, J. Luo, X. Chen, Org. Lett. 20 (2018)
Acknowledgments
1
945–1948; (b) X. Li, L. Hu, J. Jia, H. Gu, Y. Jia, X. Chen, Org. Lett. 19
(
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This work was supported by grants from the National Natural
Science Foundation of China (21172153), the Sichuan
Sciencenand Technology Program (2019YJ0032) and “the
Fundamental Research Funds for the Central Universities”. We
thank the Comprehensive Training Platform of Specialized
Laboratory, College of Chemistry, Sichuan University, as well as
Prof. Xiaoming Feng group for spectral data measurement.
Nat. Prod. 80 (2017) 805–812; (d) X. Liu, L. Hu, X. Liu, J. Jia, L. Jiang,
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1
Chen, J. Org. Chem. 82 (2017) 3692–3701; (c) X. Liu, R. Chen, F.
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4
Tetrahedron
[
19]
J. Murga, E. Falomir, M. Cardaa, J. Alberto Marco, Tetrahedron:
A. Supplementary Material
Asymmetry 13 (2002) 2317–2327.
Supplementary
data
(experimental
procedures
and
1
characterization data for the compounds, and copies of H and
1
3
C NMR spectra for the compounds).

5
Highlights

The first employment of D-glucono--
lactone to synthesize the four
styryllactones


Concise and economical synthetic route
One-pot construction of the
furanofurone bicyclic framework