Tetrahedron Letters
Reinvestigating the acyl cyclization to the precursor of diptoindonesin G
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Nan-Sheng Li , Geoffrey L. Greene
Ben May Department for Cancer Research, Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We reinvestigated the synthesis of the precursor of diptoindonesin G (2) by the intramolecular acyl
cyclization of compound 1 or compound 3 in the presence of trifluoroacetic anhydride (TFAA) [1,2].
Although the reaction of 3 with TFAA generated 2 smoothly as reported, the reaction of 1 with TFAA failed
to afford 2, and compound 1 was partially decomposed under the reaction conditions tested.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 5 January 2021
Revised 21 February 2021
Accepted 4 March 2021
Available online 11 March 2021
Keywords:
Diptoindonesin G
Precursor of diptoindonesin G
Acyl cyclization
Trifluoroacetic anhydride
TFAA
Breast cancer
Diptoindonesin G can be either naturally isolated from the stem
bark of tropical plants such as Hopea chinensis [3,4] or totally syn-
thesized [1,2,5,6,7]. It was reported that diptoindonesin G recipro-
silica gel chromatography was failed, the NMR and MS of the col-
lected samples confirmed mainly the recovery of 1. The reaction
of 1 with TFAA likely first formed anhydride derivative but it might
not be stable on TLC so we saw many pots along with the starting
material in a line. Side reaction may include the demethylation of
the methyl aryl ether of 1 if the reaction was carried out for the
long reaction time and high temperature. Other Lewis acids such
as AlCl3 and BBr3 were also examined. We observed compound 1
remained if AlCl3 was used and BBr3 caused the demethylation of
1 but still no acyl cyclization occurred. The conversion of 1 to 2
remains unsolved.
cally stabilizes ERb and destabilizes ER
Therefore, diptoindonesin G could be used to restore the balance
of ER and ERb for the treatment of human breast cancer [8].
a in breast cancer cells.
a
Recently diptoindonesin G was also found to trigger a switch from
basal- to luminal-like breast cancer subtype [9]. To continue our
research interest in the field of breast cancer studies, we reinvesti-
gated two synthetic methods for the synthesis of diptoindonesin G
reported in literature [1,5].
Kim et al reported several methods for the synthesis of diptoin-
donesin G [1,2,5]. After we followed Singh and Kim’s most recent
reported method [1] to prepare intermediate 1 in 7 steps with
40% overall yield (Scheme S1 in SI), we found the reaction of 1 with
TFAA (3 M equivalent) in anhydrous dichloromethane under the
reported reaction condition (either at room temperature, overnight
or at 0 °C – rt for 2 h) did not yield the cyclization product 2
(Scheme 1). The TLC and MS of the reaction mixture indicated com-
We then followed another method for the synthesis of diptoin-
donesin G reported by Kim et al and prepared an intermediate 3
starting from 12 in 8 steps with 36% overall yield [5]. The following
reaction of 3 with TFAA in anhydrous dichloromethane produced 2
smoothly (0 °C – rt, 2 h) [2,6]. Compound 2 was purified by silica
gel chromatography and could be converted into diptoindonesin
G as reported (Scheme 2) [2]. The TLC results for reaction of 3 with
TFAA are shown in Table S2.
pound
1 was partially remaining and partially decomposed
(Table S1 and MS in SI). We also tried to increase the reaction time
to 72 h and then increase the reaction temperature in refluxing
anhydrous dichloromethane (60 °C bath for 6 h) or 1,2-dichlor-
oethane (100 °C bath for 6 h) but still no compound 2 or only trace
amount of 2 was detected on TLC. Attempt to isolate new spots by
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Corresponding authors.
(G.L. Greene).
Scheme 1. Reaction of 1 with TFAA.
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Li, Nan-Sheng
