Synthesis of the Proposed Structure of Afzeliindanone

Article abstract of DOI:10.1055/s-0040-1707470

A synthesis of the proposed structure of afzeliindanone was achieved by using an alkyne [2+2+2]-cyclotrimerization as a key step. The data for the synthetic material were found not to match those for the natural material, indicating a structural misassignment.

Full text of DOI:10.1055/s-0040-1707470

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–C
letter
A
en
Rita et al.
Letter
Synlett
Synthesis of the Proposed Structure of Afzeliindanone
Rita
OH
O
Mohamed Husaini bin Abdul Rahman
Sherilyn Shi Min Chong
Roderick W. Bates*
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0-0
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2-
8
1
1
5-4
9
7
0
MeO
HO
Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences,
Nanyang Technological University, 21 Nanyang Link,
637371, Singapore
MeO
Not the natural product!
PGO
roderick@ntu.edu.sg
Received: 10.03.2020
Accepted after revision: 19.03.2020
Published online: 07.04.2020
OH
O
DOI: 10.1055/s-0040-1707470; Art ID: st-2020-d0143-l
MeO
HO
MeO
PGO
Abstract A synthesis of the proposed structure of afzeliindanone was
achieved by using an alkyne [2+2+2]-cyclotrimerization as a key step.
The data for the synthetic material were found not to match those for
the natural material, indicating a structural misassignment.
1
2
Figure 1 Afzeliindanone (1) and a retrosynthesis. PG = protecting group.
Key words alkynes, cyclotrimerization, indanones, rhodium catalysis,
afzeliindanone
chloride to give diyne 2a. At this point, we attempted the
alkyne [2+2+2] cyclotrimerization of diyne 2a with acety-
lene gas in the presence of tris(triphenylphosphine)rhodi-
um(I) chloride3b–d as a catalyst (Table 1). The simple reac-
tion in ethanol gave only 11–33% of the desired biaryl prod-
uct 8, depending on how thoroughly the solution had been
purged with acetylene (Table 1, entries 1 and 2). In both
cases, the product was accompanied by alkyne 9, the prod-
uct of [2+2+2] dimerization of diyne 2a. To achieve pseudo
high dilution of diyne 2a to suppress this dimerization, a
solution of 2a was added over an extended period by sy-
ringe pump. Twelve hours proved too long, as catalyst de-
composition resulted in incomplete conversion, even if the
temperature was reduced to room temperature (entries 3
and 4). Addition over four hours gave a better result (entry
5), especially with a higher catalyst loading (entry 6), and a
75% yield of the desired indanol 8 was obtained.7
Deprotection of indanol 8 could be achieved by using
potassium hydroxide,5 but the resulting phenol 10 under-
went decomposition during a subsequent oxidation by IBX,
presumably due to the highly electron-rich ring. In contrast,
the mesyl-protected compound 8 could be easily oxidized
to the indanone 11 under Swern conditions. However, de-
composition occurred when deprotection was attempted
using potassium hydroxide. To complete the synthesis, we
resorted to a method that we previously employed in our
synthesis of -lycorane.8 Thus, treatment of indanone 11
Champy et al. reported the isolation of afzeliindanone
(1) from the West African shrub Uvaria afzelii in 2009.1 The
structure shown in Figure 1 was assigned on the basis of
NMR studies. Afzeliindanone was found to have some activ-
ity against Leishmania donovani and L. major, two of the
parasites associated with leishmaniasis. It was pointed out
that this structure is unusual for a natural product and that
it represents the first indanone isolated from a plant.2 Given
the arrangement of the indanone moiety and the second
aryl group as a 1,2,3-substitution pattern, we surmised that
this molecule might be amenable to synthesis by an alkyne
[2+2+2] cyclotrimerization3 from diyne 2.
To achieve this objective, guaiacol (3) was subjected to
iodination (Scheme 1).4 However, this reaction never went
to completion. Compounds 3 and the iodo derivative 4 are
separable by chromatography only with difficulty. Rather
than carry out a laborious separation of guaicol 3 and its
iodo derivative 4, we carried the mixture forward, and the
phenolic group was protected as a mesylate.5 (We originally
employed an acetate group, but this proved too labile in
subsequent steps.) Sonogashira coupling of mesylate 5 with
pent-4-yn-1-ol yielded the alkyne 6, which could be sepa-
rated from the guaiacol mesylate 4 arising from the incom-
plete iodination.6 Swern oxidation of the alcohol then gave
aldehyde 7, which was treated with ethynylmagnesium
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–C
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Rita et al.
Letter
Synlett
OH
(Ph3P)2PdCl2,
CuI, Et3N
OH
MeO
HO
MeO
RO
I
MeO
MsO
I2, NaOH, MeOH
51–64%
(from 3)
3
6
4 R = H
KOH, EtOH
5 R = Ms
OH
CHO
MgBr
THF
MeO
MsO
MeO
MsO
(COCl)2, DMSO,
Et3N
7
2a
77%
81%
OMs
OMe
OH
OH
(Ph3P)3RhCl,
MeO
MeO
EtOH
+
9
OH
see table
RO
MsO
(COCl)2,
DMSO,
Et3N
8
R = Ms
KOH, EtOH
50%
10 R = H
80%
O
MeO
RO
11 R = Ms
R = H
EtSH, NaOH,
DMSO
1
61%
Scheme 1 Synthesis of the proposed structure of afzeliindanone
Table 1 Optimization of the [2+2+2] Cyclotrimerizationa
(Figure 2), which confirmed the identity of the synthetic
material as 1.10 We, therefore, conclude that the structure of
the natural product had been misassigned, and is not that
shown in Figure 1. Errors in natural-product structure as-
signments have been discovered through total synthesis
previously.11 Furthermore, closer inspection of the NMR
data discussed in the original report1 merely deepens the
uncertainty; given the rather scant data reported, it is not
possible to assign a correct structure.12
Entry
Slow addition Temp (°C)
time (h)
Yield (%)
2a
8
9
1
2
3
4
5
6
noneb
nonec
12
60
60
60
25
60
60
0
0
11
33
35
13
49
75
71
48
0
22
32
trace
0
12
0
4
0
4d
0
a All reactions were carried out in EtOH using 4 mol% of Wilkinson’s cata-
lyst, except where otherwise stated.
b Acetylene was purged for 5–10 min before adding the reactants.
c Acetylene was purged for 20 min.
d 10 mol% of the catalyst was used.
with ethanethiol and sodium hydroxide in DMSO, to gener-
ate a reagent that was less basic but more nucleophilic, gave
the target molecule 1 in 61% yield.
To our dismay, however, we observed significant differ-
ences between the 1H NMR and 13C NMR spectra of our syn-
thetic material and those reported for the natural material.
Whereas the signals associated with the CH2CH2 moiety
and the methoxy group were in good agreement, correla-
tion of the signals of the aromatic rings was poor.9 To en-
sure that our synthetic material possessed the expected
structure, we performed an X-ray crystallographic study
Figure 2 X-ray crystallographic structure of the proposed structure of
afzeliindanone
In conclusion, we have completed a synthesis of the pro-
posed structure 1 of afzeliindanone and have shown that
this is not the structure of the natural product. Neverthe-
less, this work showed that the [2+2+2] cyclotrimerization
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–C

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Rita et al.
Letter
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of alkynes provides rapid access to biaryls of this type, es-
pecially when slow addition is employed.
(4) Fryatt, T.; Botting, N. P. J. Labelled Compd. Radiopharm. 2005, 48,
951.
(5) Bates, R. W.; Rama-Devi, T. Synlett 1995, 1151.
(6) In some runs, alkyne 6 was contaminated with the product of
Glaser coupling of the pentynol. This could be easily separated
after the subsequent Swern oxidation.
Funding Information
We thank Nanyang Technological University for supporting this work.
(7) 4-(1-Hydroxy-2,3-dihydro-1H-inden-4-yl)-2-methoxyphenyl
Methanesulfonate (8)
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A solution of diyne 2a (500 mg, 1.62 mmol) in EtOH (8 mL) was
purged with N2 gas for 10 min and then with acetylene gas for
30 min. A solution of RhCl(PPh3)3 (150 mg, 0.162 mmol, 10
mol%) in EtOH (12 mL) was similarly purged with N2 gas for 10
min and then with acetylene gas for 30 min. The solution of
diyne 2a was then slowly added to the solution of Wilkinson’s
catalyst at 60 °C over 4 h by using a syringe pump. The mixture
was stirred overnight then filtered through Celite and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy [silica gel, EtOAc–hexane (45:55)] to give a yellow solid;
yield: 407 mg (75%); mp 131–132 °C.
Acknowledgment
We thank Drs Wei Li and Yongxin Li for assistance in obtaining the X-
ray structure.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707470.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
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FTIR (nujol): 3439 cm–1. 1H NMR (400 MHz, CDCl3):  = 7.45 (d,
J = 6.8 Hz, 1 H), 7.37–7.28 (m, 3 H), 7.05–7.01 (m, 2 H), 5.31 (q,
J = 5.9 Hz, 1 H), 3.93 (s, 3 H), 3.22 (s, 3 H), 3.14–3.06 (m, 1 H),
2.90–2.83 (m, 1 H), 2.52–2.44 (m, 1 H), 1.99–1.90 (m, 1 H). 13C
NMR (100 MHz, CDCl3):  = 151.3, 146.2, 141.3, 141.1, 137.7,
137.6, 128.7, 127.7, 124.5, 123.9, 121.4, 113.5, 76.6, 56.2, 38.5,
36.3, 29.9. MS (ESI): m/z = 335.18 [M + H]+. HRMS (ESI): m/z [M
+ H]+ calcd for C17H19O5S: 335.0953; found: 335.1602, 335.2099.
(8) Doan, B. N. D.; Tan, X. Y.; Ang, C. M.; Bates, R. W. Synthesis 2017,
49, 4711.
(9) For a comparison of all of the NMR data, see the Supporting
Information.
(10) CCDC 1913019 contains the supplementary crystallographic
data for compound 1. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
References and Notes
(1) Okpekon, T.; Millot, M.; Champy, P.; Gleye, C.; Yolou, S.; Bories,
C.; Loiseau, P.; Laurens, A.; Hocquemiller, R. Nat. Prod. Res. 2009,
23, 909.
(2) For another example of an indanone natural product, see:
(a) Dai, J.; Krohn, K.; Flörke, U.; Draeger, S.; Schulz, B.; Kiss-
Szikszai, A.; Antus, S.; Kurtán, T.; van Ree, T. Eur. J. Org. Chem.
2006, 3498. For a review of indane and indene syntheses, see:
(b) Gabriele, B.; Mabcusco, R.; Veltri, L. Chem. Eur. J. 2016, 22,
5056.
(3) For a review, see: (a) Chopade, P. R.; Louie, J. Adv. Synth. Catal.
2006, 348, 2307. For examples of the use of Wilkinson’s catalyst,
see: (b) Grigg, R.; Scott, R.; Stevenson, P. Tetrahedron Lett. 1982,
23, 2691. (c) Neeson, S. J.; Stevenson, P. J. Tetrahedron 1989, 45,
6239. (d) McDonald, F. E.; Zhu, H. Y. H.; Holmquist, C. R. J. Am.
Chem. Soc. 1995, 117, 6605.
(11) Maier, M. E. Nat. Prod. Rep. 2009, 26, 1105.
(12) Attempts to contact the corresponding author of Ref. 1 met with
no reply.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–C