Synthesis of (+)-altholactone, (+)-7-epi-altholactone, (?)-etharvensin, and (+)-alumheptolide-A using Pd-catalyzed carbonylation

Article abstract of DOI:10.1016/j.tetlet.2018.09.062

Syntheses of (+)-altholactone isolated from Goniothalamus giganteus and its C-7 epimer (+)-7-epi-altholactone, (?)-etharvensin and (+)-alumheptolide-A were achieved. The lactone ring of these compounds was constructed using Pd-catalyzed carbonylation.

Full text of DOI:10.1016/j.tetlet.2018.09.062

Accepted Manuscript
Synthesis of (+)-altholactone, (+)-7-epi-altholactone, (-)-etharvensin, and (+)-
alumheptolide-A using Pd-catalyzed carbonylation
Yuki Miyazawa, Yasunao Hattori, Hidefumi Makabe
PII:
S0040-4039(18)31163-8
https://doi.org/10.1016/j.tetlet.2018.09.062
TETL 50301
DOI:
Reference:
Tetrahedron Letters
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16 August 2018
19 September 2018
25 September 2018
Please cite this article as: Miyazawa, Y., Hattori, Y., Makabe, H., Synthesis of (+)-altholactone, (+)-7-epi-
altholactone, (-)-etharvensin, and (+)-alumheptolide-A using Pd-catalyzed carbonylation, Tetrahedron Letters
(2018), doi: https://doi.org/10.1016/j.tetlet.2018.09.062
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Synthesis of (+)-altholactone, (+)-7-epi-
altholactone, ()-etharvensin, and ()-
alumheptolide-A using Pd-catalyzed
carbonylation
Leave this area blank for abstract info.
Yuki Miyazawa, Yasunao Hattori, Hidefumi Makabe*

1
Tetrahedron Letters
Synthesis of (+)-altholactone, (+)-7-epi-altholactone, ()-etharvensin, and ()-
alumheptolide-A using Pd-catalyzed carbonylation
Yuki Miyazawa,a Yasunao Hattori,b Hidefumi Makabe*a
aGraduate School of Science and Technology, Department of Agriculture, Division of Food Science and Biotechnology, Shinshu University, 8304 Minami-
minowa, Kami-ina, Nagano, 399-4598, Japan
bCenter for Instrumental Analysis, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan
* Corresponding author. Tel. +81 265 77 1630; fax +81 265 77 1700; e-mail: makabeh@shinshu-u.ac.jp
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Syntheses of (+)-altholactone isolated from Goniothalamus giganteus and its C-7 epimer (+)-7-
epi-altholactone, ()-etharvensin and ()-alumheptolide-A were achieved. The lactone ring of
these compounds was constructed using Pd-catalyzed carbonylation.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
natural product
polyketides
styryl lactone
carbonylation
The trees of Goniothalamus genus, a group of Annonaceae
family, have been in relation to the traditional medicines in Asian
countries. McLaughlin and co-workers isolated a numbers of
styryl lactones from Goniothalamus giganteus.1 These styryl
lactones showed cytotoxicity against human cancer cell lines.2
Due to the unique structure and significant biological activities,
much attentions were paid to the synthesis of these compounds.3-
aldehyde 6. Aldehyde 6 would be prepared from known diol 7
(Scheme 1).5,6
15
Here, we wish to report the synthesis of (+)-altholactone (1),
which is one of the styryl lactones described above, its C-7
epimer (+)-7-epi-altholactone (2),6 ()-etharvensin (3),12,16 and
()-alumheptolide-A (4)17 isolated from Goniothalamus arvensis
using palladium-catalyzed carbonylation and cyclization as the
key step (Figure 1).18-22
Scheme 1. Synthetic strategy of (+)-altholactone (1), (+)-7-epi-
altholactone (2), ()-etharvensin (3), and ()-alumheptolide-A (4).
Figure 1. Structures of (+)-altholactone (1), (+)-7-epialtholactone
(2), ()-etharvensin (3), and ()-alumheptolide-A (4).
Scheme 2 shows the synthesis of (+)-7-epi-altholactone (2).
Aldehyde 6 was prepared in 4 steps according to the reported
procedure.6 To synthesize Z-vinyl iodide 8, we tried to introduce
terminal alkyne. However, Corey-Fuchs reaction of 6 using CBr4
and PPh3 followed by treatment with n-BuLi and iodine gave 8 in
low yield with complex mixture.23 Using Ohira-Bestmann
reagent24,25 and diethylphosporyl chloride in the presence of LDA
to introduce terminal alkyne26 did not work well, either. After
searching reaction conditions, we reached to use the Wittig
The synthetic strategy was shown in Scheme 1. ()-
Etharvensin (3) and alumheptolide-A (4) would be synthesized
from (+)-altholactone (1). (+)-Altholactone (1) would be
synthesized from (+)-7-epi-altholactone (2). The ,-unsaturated
-lactone ring of 2 would be constructed using palladium-
catalyzed carbonylation and cyclization of Z-vinyl iodide 5. The
Z-vinyl iodide 5 would be synthesized via Wittig reaction of

2
Tetrahedron
reaction.27 Wittig reaction of 6 with CH2IP+Ph3I in the
presence of HMPA gave Z-iodide 16 (Z/E = 20:1). The
presence of KHMDS gave Z-vinyl iodide 8 (Z/E = 20:1) in good
yield. Deprotection of the acetonide group of 8 using 2M HCl
afforded cyclization precursor 5. With the cyclization precursor
was in hand, we examined palladium-catalyzed carbonylation
and cyclization to obtain 2.18-22 Treatment of 5 with 3 mol % of
Cl2Pd(PPh3)2 under 1 atom of CO in the presence of Et3N gave
1
(+)-7-epi-altholactone (2) in an excellent yield. The H and 13C
NMR data of the synthetic (+)-7-epi-altholactone (2) were
consistent with those of the reported values (Scheme 2).6
deprotection of the two benzyl ethers were problematic. Using
TiCl4, BCl3, TMSI, BBr3, and Sn(OTf)2 did not afford 11. Diol
11 was obtained in 31% yield only when 16 was treated with 10
equiv. of SnCl4.
Scheme 2. Synthesis of (+)-7-epi-altholactone (2).
Next, we tried to invert the configuration of hydroxyl group
at C-7 position of (+)-7-epi-altholactone (2) to synthesize (+)-
altholactone (1) using reported procedure.6 However,
transformation from compound 10 to (+)-altholactone (1) using
basic condition afforded decomposed product (Scheme 3).
Scheme 5. Synthesis of cyclization precursor.
In seeking a high-yielding synthetic route, we chose a
combination of PMB and Bz groups as a protecting group instead
of benzyl group according to the procedures shown in Scheme 6.
Protection of the 1,2-diol of D-glucose with acetone in the
presence of H2SO4 gave alcohol 17. Protection of the secondary
hydroxy group of 17 using PMBCl and NaH in the presence of
TBAI afforded 18.28 Selective deprotection of the acetonide
group with 80% AcOH gave diol 19. Cleavage of the 1,2-diol of
19 with NaIO4 afforded aldehyde 20. Grignard reaction of 20
with phenylmagnesium bromide afforded 21 and its diastereomer
with a ratio of 5:1. Undesired diastereomer was separated using
silica gel column chromatography. The absolute configuration of
the newly formed carbinol center was determined to be S using
advanced Mosher method (the data is shown in Figure S1 in the
supporting information).29 Treatment of 21 with p-TsCl in
pyridine afforded 22. Tosylate 22 was treated with ethylene
glycol in the presence of p-TsOH gave 23. Protection of the diol
of 23 with BzCl in pyridine furnished 24. Deprotection of the
acetal with TFA gave aldehyde 25. Wittig reaction of 25 with
CH2IP+Ph3I in the presence of KHMDS gave vinyl iodide 26
(Z/E = 12:1). Deprotection of the benzoate group of 26 using 1M
NaOH afforded cyclization precursor 11. At this stage, E-isomer
was removed using silica gel column chromatography.
Palladium-catalyzed carbonylation and cyclization of 11 afforded
(+)-altholactone (1) in 91% yield. Treatment of 1 with conc.
H2SO4 in EtOH under reflux for 1.5 h furnished ()-etharvensin
(3) in 36% and ()-alumheptolide-A (4) in 62% yield. Cortes and
co-workers reported that treatment of 1 with conc. H2SO4 in
EtOH under reflux for 1.5 h furnished ()-etharvensin (3)
exclusively in 90% yield.17 Prolonged reaction time frm 1.5 to 3
h afforded 3 and 4 in 28% and 40% yield. Further prolonged
reaction time to 5 h furnished 3 exclusively in 62% yield.
However, in our experiment, treatment of 1 with conc. H2SO4 in
EtOH under reflux for 1.5 h gave the mixture of ()-etharvensin
(3) and ()-alumheptolide-A (4) in 36 and 62% yield. The
physicochemical data, 1H and 13C NMR data of the synthetic (+)-
altholactone (1), ()-etharvensin (3), and ()-alumheptolide-A (4)
were consistent with those of the reported values.11,12,16,17
H
H
H
H
O
O
O
O
1) aq. NaOH
2) TFA
Ph
Ph
Ph
Ph
Tf2O
EtCO2Cs
O
DMF
O
O
O
O
O
O
pyridine
O
H
H
H
H
EtCO2
HO
HO
TfO
44% (2 steps)
(+)-7-epi-altholactone (2)
9
10
(+)-altholactone (1)
Scheme 3. Attempted synthesis (+)-altholactone (1) using
reported procedure.
Since we could not synthesize (+)-altholactone (1) from (+)-
7-epi-altholactone (2), we changed the synthetic plan. Alternative
synthetic strategy shows in Scheme 4. The ,-unsaturated -
lactone ring would be constructed using palladium-catalyzed
carbonylation and cyclization of Z-vinyl iodide 11. The Z-vinyl
iodide 11 would be synthesized via Wittig reaction of aldehyde
12. Aldehyde 12 would be prepared from diol 13. Compound 13
would be synthesized from D-glucose using known procedure
(Scheme 4).4
Scheme 4. Changed synthetic strategy of (+)-altholactone (1),
()-etharvensin (3), and ()-alumheptolide-A (4).
Scheme 5 shows the synthesis of cyclization precursor 11 of
(+)-altholactone (1). Compound 14 was prepared according to the
reported procedure.4 Protection of the secondary hydroxy group
of 14 using BnBr and NaH in the presence of NaI afforded 15.
Removal of the acetal under the acidic condition gave aldehyde
12. Wittig reaction of 12 with CH2IP+Ph3I and KHMDS in the

3
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Scheme 6. Synthesis of (+)-altholactone (1), ()-etharvensin (3),
and ()-alumheptolide-A (4).
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In conclusion, syntheses of (+)-altholactone (1), (+)-7-epi-
altholactone (2), ()-etharvensin (3), and ()-alumheptolide-A (4)
were achieved using palladium-catalyzed carbonylation and
cyclization. The syntheses of other styryl lactones are now
underway using this strategy.
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Lett. 1999; 40: 8641-8645.
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Acknowledgements
This work was supported by JSPS KAKENHI Grant Number
15K07408 to H. M.
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Supplementary Material
References and notes
Supplementary data associated with this article can be found,
in the online version at doi:
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Cassady JM, Chang C –J, McLaughlin JL. Tetrahedron Lett. 1985; 26:
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Cassady JM, Chang C–J, McLaughlin J L. Tetrahedron 1989; 45: 2627-
2640.

4
Tetrahedron
・Syntheses of (+)-altholactone and (+)-7-epi-
altholactone were achieved.
・The lactone ring was constructed using Pd-
catalyzed carbonylation in good yield.
・()-Etharvensin and ()-alumheptolide-A were
synthesized from (+)-altholactone.