Total Synthesis of Termicalcicolanone A via Organocatalysis and Regioselective Claisen Rearrangement

Article abstract of DOI:10.1021/acs.orglett.9b00731

A total synthesis of an anticancer xanthone natural product termicalcicolanone A utilizing multiple nucleophilic aromatic substitutions and pericyclic reactions has been developed. The pyrano[3,2-b]xanthen-6-one scaffold was constructed via NHC-catalyzed

Full text of DOI:10.1021/acs.orglett.9b00731

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Termicalcicolanone A via Organocatalysis and
Regioselective Claisen Rearrangement
Saki Ito,† Taiki Kitamura,‡ Sundaram Arulmozhiraja,*,§,∥ Kei Manabe,‡ Hiroaki Tokiwa,§,∥
and Yumiko Suzuki*,†
†Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo
102-8554, Japan
‡School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
§Department of Chemistry, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
∥Research Center for Smart Molecules, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan
S
* Supporting Information
ABSTRACT: A total synthesis of an anticancer xanthone natural
product termicalcicolanone A utilizing multiple nucleophilic
aromatic substitutions and pericyclic reactions has been developed.
The pyrano[3,2-b]xanthen-6-one scaffold was constructed via
NHC-catalyzed aroylation to produce the benzophenone inter-
mediate, Claisen cyclization to form the pyran ring, and intra-
molecular 1,4-addition to construct the xanthone framework. The
prenyl group was introduced in the final stages of the synthesis
through regioselective Claisen rearrangement. The synthesis has
been achieved in 19 steps.
ermicalcicolanone A (1) (Figure 1) is a natural product
isolated from the Madagascan plant Terminalia calcicola
xanthones from diphenyl ether intermediates5 or to prepare
benzophenones as starting materials for cyclization to
xanthones by reactions such as Ullmann-type reaction and
nucleophilic aromatic substitution (SNAr).6 One of the
recently introduced methods is the one-step synthesis of
xanthones from easily accessible benzaldehydes and benzenes.7
However, none of these methods is universal for the synthesis
of highly functionalized xanthones that were found in naturally
occurring compounds8 due to problems such as accessibility to
the starting materials and orientation effects of the
substituents. Thus, synthetic chemists search for efficient
ways to construct xanthones with functionalities at specific
positions. In this study, we demonstrated an alternative
synthetic route to produce multioxygenated xanthone natural
products that consists of N-heterocyclic carbene (NHC)-
catalyzed aroylation (to prepare the benzophenone inter-
mediate),9 nucleophilic aromatic substitutions, and an intra-
molecular 1,4-addition to the quinone moiety.
As outlined in Scheme 1, our retrosynthetic strategy involves
the introduction of a prenyl group to the core by Claisen
rearrangement in the final step, and the pyran ring could be
formed through Claisen cyclization. The xanthone framework
could be constructed via successive SNAr reactions with O-
nucleophiles from the fluorinated benzophenone 3,10 which
were prepared from 3,4,5-trifluoronitrobenzene 4 and 2-
fluorobenzaldehyde derivative 5 through NHC-catalyzed
T
Figure 1. Structure of termicalcicolanone A (1).
H. Perrier through an activity-guided fractionation of the
ethanol extract.1 This natural product is classified as a
xanthonoid because of its xanthone core bearing phenolic
hydroxy groups. Xanthonoids have various biological activities,
e.g., antitumor,2 antibacterial,3 and antivirus.4 In fact,
xanthonoide 1 exhibits antiproliferative activity against the
A2780 human ovarian cancer cell line with an IC50 value of
40.6 μM.1 Despite the importance of this class of natural
products, the total synthesis of 1 has not been reported.
Herein, we report the first total synthesis of this important
natural product 1 and present the synthetic scheme for this
class of natural products.
It is often not straightforward to construct highly substituted
xanthones with functionalities at specific positions. Common
methods to access xanthone frameworks are based on the
Friedel−Crafts reaction, which is used either to construct
Received: February 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Retrosynthesis of 1
Scheme 3. Intermediates in Claisen Rearrangements of 7
and 10
nucleophilic aroylation reaction and other transformations.
Unlike the scheme normally employed in traditional natural
product synthesis, this synthetic strategy is similar to the one
used in medicinal chemistry, i.e., employing SNAr reactions
multiple times using the fluorine groups and the nitro group as
leaving groups.
Our main concern, before initiating the synthesis, was the
regioselective introduction of the prenyl group at position 8 of
1. Therefore, we first conducted model reactions to confirm
our synthetic strategy. The Claisen rearrangement of the
model compoundxanthone 6proceeded in refluxing
toluene regioselectively to afford 8-prenylated product 7 in
62% yield (Scheme 2). The regioisomer 8 was not detected. In
contrast, the rearrangement of benzophenone 9 afforded 2-
prenylated 10 in 63% yield and 4-prenylated product 11 in
30% yield.
xanthone 6, 8-prenylxanthone 7 was obtained via intermediate
A. The rearrangement to the 6-position would afford 8 via
intermediate B. The intermediate A has a 10π aromatic system
involving a 4-pyrone ring (in blue) as shown in the resonance
structure A′. In contrast, the pyrone ring of B is not
incorporated in the aromatic system, and therefore, the
reaction involving the formation of B is unfavorable compared
with that of A. On the other hand, both benzophenone
products 10 and 11 were, respectively, generated through
intermediates C and D having the conjugated diketone
structures (in blue).
The regioselectivity in the reaction of the model compounds
can be explained through the stability of the reaction
intermediates A−D (Scheme 3).11,12 In the reaction of
To understand the regioselectivity further, a putative step of
the Claisen rearrangement of the model compounds involving
the reactants (6 and 9), transition states (TSA, TSB, TSC, and
TSD), and intermediates (A−D) was theoretically studied
using density functional theory (DFT), and the relative
energies are depicted in Figure 2. Two conformers each (6,
6′ and 9, 9′) for the reactants were considered. As the
experiments were conducted in refluxing toluene, all of the
calculations were performed at 383.15 K incorporating solvent
(toluene) effects. The calculations clearly show (Figure 2) that
formation of products 7 (from the reactant 6 via intermediate
A) and 10 (from 9 via C) should be energetically favored as
they are connected to the energetically more stable conformers
of the reactants (6 and 9) via transition states (TSA and TSC)
with smaller activation barriers (23.2 and 25.3 kcal/mol)
through the energetically favored intermediates A (3.78 kcal/
mol) and C (6.67 kcal/mol). Therefore, aromatic Claisen
rearrangements via the intermediates A and C are both
thermodynamically and kinetically favored. As expected, the
intermediate A is more stable than B by 8.81 kcal/mol, and C
is energetically more favored than D by 0.95 kcal/mol. These
findings support our experimental results on Claisen rearrange-
ments. It should also be mentioned that there is a good
correlation between the calculated results and the exper-
imentally observed regioselectivity: the difference in activation
energy in favor of A over B (7.37 kcal/mol) is larger than that
Scheme 2. Claisen Rearrangement of Model Compounds
B
DOI: 10.1021/acs.orglett.9b00731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Construction of the Pyrano[3,2-b]xanthen-6-one
a
Scaffold
Figure 2. B3LYP/6-311+G(2d,p) relative energies (in kcal/mol) of
Claisen rearrangements involving the model reactants 6 and 9.
a
Reagents and conditions: (a) 1,3-dimethylimidazolium iodide, NaH,
DMF, 0 °C to rt, 2 h; 76%; (b) HBr aq, AcOH, reflux, 20 h; quant;
(c) DHP, CSA, CH2Cl2, rt, 30 min.; 93%; (d) K2CO3, BnOH, rt, 48
h; 82%; (e) benzaldoxime, NaH, DMSO, 0 °C to rt, 4 h; 87%; (f) 3-
chloro-3-methyl-1-butyne, DBU, CuCl2, CH2Cl2, 0 °C to rt, 2.5 h;
84%; (g) toluene, reflux, 24 h; quant; (h) BnOH, NaH, DMF, 0 °C to
rt, 21 h; 90%; (i) p-TsOH, CH2Cl2, MeOH, rt, 30 min.; quant; (j)
TsCl, K2CO3, acetone, reflux, 7 h; 92%; (k) HBr aq, AcOH, reflux, 4
h; 78%; (l) MnO2, CH2Cl2, rt, 24 h; (m) TBI, toluene, reflux, 3 h;
quant (two steps).
in favor of C over D (3.68 kcal/mol), and similarly, as
mentioned above, the energy difference between A and B is
larger than that between C and D; in parallel, product 11 with
a yield of 30% was observed, whereas 8 was not observed. The
foregoing facts suggest introducing the prenyl group after the
construction of the xanthone framework in the total synthesis
is necessary. In addition, the results of the model reactions
indicate that the Claisen rearrangement in the actual total
synthesis would proceed with complete regioselectivity.
The synthesis commenced with NHC-catalyzed aroylation
in which the 4-fluoro group of trifluoronitrobenzene 4 was
selectively substituted with the aroyl group originating from
aldehyde 5 to produce benzophenone 12 (Scheme 4).10 After
conversion of the methyl ether 12 to the tetrahydropyran
(THP) ether, the fluoro group at position 4 (numbering in
termicalcicolanone A) was substituted with the benzyloxy
group. Then the nitro group was converted to the hydroxy
group via SNAr reaction using benzaldoxime anion10,13
affording hydroxybenzophenone 13, which was then propargy-
lated. Since the resulting propargyl ether is unstable, it was
subjected to Claisen cyclization directly after the isolation by
column chromatography without any further purification. The
substitution of the remaining fluoro groups with the benzyloxy
groups produced tribenzyloxylated 14. After conversion of the
THP ether of 14 to the acid-tolerant tosylate, the
debenzylation in acidic condition was performed to yield
trihydroxylated 15, which was then subjected to oxidation with
manganese dioxide. In this reaction, the quinone intermediate
16 was supposedly generated in situ and then subsequently
underwent intramolecular 1,4-addition to produce tetracyclic
triketone 17 with a slight amount of its tautomer 18. The
mixture of 17 and 18 was treated with tetrabutylammonium
iodide in refluxing toluene10 to obtain 18 quantitatively from
15 in two steps. Thus, the construction of the core framework,
pyrano[3,2-b]xanthen-6-one scaffold, was accomplished.
For the regioselective Claisen rearrangement to introduce
the prenyl group at position 8 of the core, the oxygen atom
attached at position 7 needed to be propenylated. Therefore,
after protecting group manipulation, 1,1-dimethypropenyl
ether 21 was prepared from 19 (Scheme 5) in the reaction
with ester 20 catalyzed by palladium(0). The Claisen
rearrangement of this doubly MOM-protected intermediate
21 suffered from the instability of prenylated product 23:
Either of the MOM ethers was gradually cleaved as time
proceeded. The attempted Claisen rearrangement from 21 led
to a complicated mixture containing 23, which gradually
decomposed and could not be separated from undesired
products. Hence, one of the MOM ethers was cleaved using
zinc chloride to produce 22. Only one product was observed;
however, the exact structure was not determined, and the
product was then subjected to Claisen rearrangement followed
by removal of the remaining MOM group. Thus, the total
synthesis of 1 was accomplished.
In conclusion, the total synthesis of anticancer natural
product termicalcicolanone A (1) was achieved for the first
time in 19 steps in a 4.2% overall yield. The feature of our
synthesis is the regioselective Claisen rearrangement and the
multiple use of SNAr reaction including organocatalysis−NHC-
catalyzed aroylation. We have demonstrated that the NHC-
catalyzed preparation of a highly functionalized benzophenone
C
DOI: 10.1021/acs.orglett.9b00731
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Organic Letters
Letter
MEXT, Japan. We thank Prof. David G. I. Kingston (Virginia
Tech), who reported the isolation and the cytotoxicity of
termicalcicolanone A, for personal communications. We also
thank Mr. Kotaro Nishiyama, Mr. Yuki Fujimaki, and Ms. Yuki
Ejima (Univ. Sophia) for their support of this work.
Scheme 5. Synthesis of 1 from 19: Introduction of the
Prenyl Group
a
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00731.
Detailed experimental procedures, computational details,
optimized structures, characterization data (PDF)
1H and 13C NMR spectra of all purified compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: raja@rikkyo.ac.jp.
*E-mail: yumiko_suzuki@sophia.ac.jp.
ORCID
Kei Manabe: 0000-0002-9759-1526
Hiroaki Tokiwa: 0000-0002-3790-1799
Yumiko Suzuki: 0000-0002-8226-5867
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Shiseido Female Scientist Grant
and a Grant-in-Aid for Scientific Research on Innovative Areas
“Advanced Molecular Transformations by Organocatalysts”
from the Japan Society for the Promotion of Science and
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