A concise synthesis of paucifloral f and related indanone analogues via palladium-catalyzed α-arylation

Article abstract of DOI:10.1021/jo102298p

A concise approach to synthesize paucifloral F was developed via a stereoselective palladium-catalyzed R-arylation reaction. The approach has also been applied in the synthesis of indanone analogues of Paucifloral F.

Full text of DOI:10.1021/jo102298p

NOTE
pubs.acs.org/joc
A Concise Synthesis of Paucifloral F and Related Indanone Analogues
via Palladium-Catalyzed r-Arylation
Yang Yang,* Dean Philips, and Shifeng Pan
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, United States
S Supporting Information
b
ABSTRACT: A concise approach to synthesize paucifloral F
was developed via a stereoselective palladium-catalyzed
R-arylation reaction. The approach has also been applied in
the synthesis of indanone analogues of Paucifloral F.
ndanone and indane are privileged structures1 in drug dis-
covery research, commonly seen in many pharmaceutical
I
compounds exhibiting a variety of interesting biologic activities.
For example, indanones and indanes are incorporated in some
marketed drugs such as Donepezil and Indinavir. Donepezil (1)
was discovered as a potent AchE (acetylcholinesterase) inhibitor
applied in the treatment of mild to moderate Alzheimer’s
disease,2 while Indinavir3 was identified as an HIV protease
inhibitor applied in the treatment of AIDS disease. On the other
hand, indanone and indane structures are also commonly found
in numerous bioactive natural products.4 For example, indane
compound Caraphenol B (2) was isolated from Caragna sinica,
which was used in Chinese folk medicine for treating asthenia
syndrome and vascular hypertension.5 Interestingly, potent
cytotoxic similar natural indanone products 3 and Pterosin B
were isolated from marine cyanobacterium6 and pteris ensiformis
burm7 independently (Figure 1). Our ongoing medicinal chem-
istry research project recently led us to pursue screening and
synthesis of some multifunctionalized indanone compounds. In
this context, we became interested in paucifloral F (5).
Figure 1
Paucifloral F is a polyphenolic natural product belonging to a
larger family of compounds believed to arise from the dimeriza-
tion of resveratrol8 (Figure 2). Resveratrol (4) is the simplest and
the most widely distributed polyphenolic products exhibiting a
variety of biologic activities.9 Some of those activities potentially
provide health benefits such as antiaging/life extension10 and
cancer prevention.11 Despite its promising array of bioactivities,
the clinical potential of resveratrol has been barely proved.12 This
is in part due to the poor drug-like properties of resveratrol itself.13
Therefore, there is increasing interest in its more complex oligo-
mers including paucifloral F and other unnatural analogues. Inspired
by the biosynthetic pathway, the Snyder group published their
total synthesis of Paucifloral F along with other complicate resveratrol-
based natural products via an elegant biomimetic strategy in 2009.14
Sarpong et al. also reported a total synthesis of paucifloral F using
a Larock annulation strategy.15 However, when we approached
the architecture of this natural product, we preferred keeping the
indanone moiety as a core structure for the possible structural
derivatization in the synthesis. Therefore we were interested in
Figure 2
developing a novel and concise synthetic approach toward
paucifloral F, which is more amenable for conducting analogue
Received: November 18, 2010
Published: February 03, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 1
Scheme 2
Table 1. Palladium-Catalyzed R Arylation of Indanone 9
Scheme 3
cat./
ligandc
temp yielda
entry
base/solvent
(oC)
(%) 11/12b
1
2
3
4
5
6
7
A/Dppf
NaOtBu (3 equiv) /dioxane
100
110
100
70
0
0
B/X-Phos Cs2CO3 (5 equiv) toluene
C/P(tBu)3 NaHMDS (3 equiv) toluene
C/BINAP NaOtBu (3 equiv) dioxane
C/DtBPF NaOtBu (3 equiv) dioxane
C/DtBPF KHMDS (3 equiv) dioxane
C/DtBPF KHMDS (2.2 equiv) dioxane
>5
80
78
81
77
1.5/1
1/2
100
100
75
observed. (Scheme 2). The bulky 3,5-dimethoxyphenyl group at
the β-position of the indanone ring may account for the stereo-
chemical result in R-arylation. We believe excess base in the
reaction system led to the second enolation of the indanone
coupling product. Quenching the reaction at higher temperature
yields predominately the low-energy favored trans product (11),
as the result of thermodynamic control.22 Subsequent treatment
of compound 11 with BBr3 in DCM led to global phenol
demethylation to give synthetic paucifloral F in moderate yield
(49%). The analytical data of our synthetic paucifloral F sample are
identical with the corresponding data reported in the literature.23
Beyond the total synthesis of paucifloral F, we have also demon-
strated the amenability of our route to the synthesis of analogues of
paucifloral F. Starting from intermediate 9, structural diversification at
the R position of indanone scaffold can be conveniently realized
through the similar arylation reactions. Under similar reaction con-
ditions, some close analogue compounds of paucifloral F were
synthesized in good yields (Scheme 3), the results of which are
summarized in Table 2. We expect that the close analogues of
paucifloral F (16a-e, 17a-e)24 are potentially valuable in the
biological activity study toward resveratrol-based natural products.
In conclusion, a concise approach to synthesize paucifloral F
was developed via a stereoselective palladium-catalyzed R-aryla-
tion strategy. Our total synthesis of paucifloral F is highly
convergent and practical (four steps in good overall yield from
simple commercial available materials). This approach has also
been demonstrated to be amenable to synthesis of analogues to
conduct structural diversification at the indanone core of the
naturalproduct. Weexpect that this approach can be applied to the
synthesis of other indanone-based natural products in the future.
2/1
5/1
a Conversion yields were determined by HPLC. b Ratios between 11 and
12 were determined by HPLC. c Cat: Pd(dppf)Cl2 (A); Pd(OAc)2 (B);
Pd2(dba)3 (C).
synthesis. Herein, we account our effort on the synthesis of
paucifloral F and its analogue compounds via a stereoselective
palladium-catalyzed carbonyl R-arylation strategy.
We envisioned that the construction of paucifloral F could be
realized via R-arylation of the corresponding indanone compound
(9) with 4-bromo anisole (10). Such a strategy allows for the
convenient introduction of structural diversity at the R position
of the indanone core. Thus the key intermediate 9 was assembled
via a two-step synthesis. The chalcone intermediate 13 was
prepared by an aldol reaction of corresponding 3,5-dimethoxy-
acetophenone (11) with 3,5-dimethoxybenzaldehyde (12).16
The subsequent cyclization of 13 was carried out cleanly in
TFA to give indanone 9 in good yield17 (Scheme 1).
The palladium-catalyzed R-arylation of indanone 9with 4-bromo-
anisole 10 was explored extensively under various conditions.18
The screened coupling conditions and their results are summar-
ized in Table 1. The results show that using catalyst Pd2(dba)3
with DtBPF as ligand was superior among others providing good
yields19 (entries 5, 6, and 7). However, in most cases, a dehydro-
genated byproduct (12) was observed. We found that by reduc-
ing the amount of base employed and the temperature of the
reaction, the production of 12 could be minimized.20 (entry 7).
On the other hand, we also found that under most reaction con-
ditions employed, the arylation reactions proceed with excellent
stereoselectivity. Only the trans isomer was observed and isolated
from the reaction. The stereochemistry of the product (11) was
confirmed via 2-D NMR.21 In the ROESY experiment of 11,
there is an ROE signal between the proton at carbon number 8
and the proton at carbon 26. Another ROE signal between the
protons at carbon number 7 and the proton at carbon 17 was also
’ EXPERIMENTAL SECTION
Representative Procedure for Palladium-Catalyzed r-
Arylation Reaction
trans-3-(3,5-Dimethoxyphenyl)-4,6-dimethoxy-2-(4-metho-
xyphenyl)-2,3-dihydro-1H-inden-1-one (11). To the flask contain-
ing DtBPF (0.025 mmol 0.05 equiv) and Pd2(dba)3 (0.05 mmol,
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The Journal of Organic Chemistry
NOTE
Table 2. The Synthesis of Analogues of Paucifloral F
25 °C) δ 3.36 (d, J = 2.4 Hz, 1H), 4.18 (d, J = 2.4 Hz, 1H), 5.85 (d, J = 2.0
Hz, 2H), 5.99 (t, J = 2.4 Hz, 1H), 6.52 (d, J = 2.0 Hz, 1H), 6.57 (d, J = 2.0
Hz, 1H), 6.62 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, MeOD, 25 °C) δ 53.2, 66.3, 100.5, 101.7, 106.4, 110.9,
116.5, 129.9, 132.0, 136.1, 140.0, 147.5, 157.3, 157.6, 159.6, 160.8, 209.3;
LC-MS 100% (purity), m/e 365 (M þ 1); HRMS calcd for C21H17O6
(M þ 1) 365.1025, found 365.1025.
’ ASSOCIATED CONTENT
S
Supporting Information. Characterization of the synthe-
b
sized compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: yyang@gnf.org.
’ ACKNOWLEDGMENT
Dedicate to Prof. T. H. Chan. We are grateful to Ms. Tiffany
Chuan for the assistance in 2D NMR and Dr. Eric Peters for high
resolution MS. We also thank Drs. Xuebin Liao, Yahua Liu, and
Porino Va for discussion and proof reading.
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0.1 equiv) in dioxane (1 mL) was added KHMDS (1.1 mmol, 2.2 equiv).
The reaction was then purged with nitrogen and stirred at room
temperature for 10 min. Indanone (9) (0.5 mmol, 1 equiv) was then
added to the reaction followed by 1-bromo-4-methoxybenzene (10)
(1.5 mmol, 3 equiv). The reaction temperature was raised to 80 °C and
the mixture was stirred at the same temperature for 5 h. The reaction was
quenched with ice-cold 1 N HCl solution (10 mL) and extracted with
EtOAc (3 ꢀ 20 mL). The combined organic layer was washed with brine
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was purified by flash chromatograph to give product as a colorless oil
(148 mg, isolation yield: 69%). 1H NMR (400 MHz, CDCl3 25 °C) δ
3.56 (d, J = 2.8 Hz, 1H), 3.59 (s, 3H), 3.61 (s, 6H), 3.68 (s, 3H), 3.78 (s,
3H), 4.35 (d, J = 2.8 Hz, 1H), 6.07 (d, J = 2.4 Hz, 2H), 6.23 (t, J = 2.4 Hz,
1H), 6.61 (d, J = 2.4 Hz, 1H), 6.75 (m, 2H), 6.81 (d, J = 2.0 Hz, 1H), 6.92
(d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3, 25 °C) δ 55.9, 55.2,
55.2, 55.6, 55.8, 64.1, 96.4, 98.1, 105.1, 106.5, 114.3, 128.8, 131.5, 137.6,
138.7, 145.9, 157.8, 158.7, 160.8, 162.0, 205.9; LC-MS 100% (purity),
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435.1807, found 435.1811.
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was added BBr3 (10 equiv 1 M in DCM, 2 mL) at 0 °C. The reaction was
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(5 mL) and extracted with the mixed solvent of chloroform and
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with brine (10 mL) and dried over sodium sulfate. After concentration,
the crude product was purified by flash chromatography. Synthetic
paucifloral F (34 mg, 49%) was obtained. 1H NMR (400 MHz, MeOD,
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NOTE
(13) Oral bioavailability of resveratrol is low. It is rapidly metabo-
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(21) For 2-D NMR of 11 see the Supporting Information
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(24) Unfortunately, the attempted synthesis of 17b failed. Only a
trace of 17b was detected after the demethylation reaction, which was
conducted at room temperature in the presence of BBr3. We suspect that
the nitrile group could not be well tolerated under such conditions.
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