Sulfoxide-Based Enantioselective Nazarov Cyclization: Divergent Syntheses of (+)-Isopaucifloral F, (+)-Quadrangularin A, and (+)-Pallidol

Article abstract of DOI:10.1002/chem.201603664

The synthesis of enantiomerically pure 3-aryl substituted indanones is developed using an enantioselective sulfoxide-based Knoevenagel condensation/Nazarov cyclization procedure. After the reductive desulfonation of the methyl para-tolyl sulfoxide-containing chiral auxiliary under mild conditions, selected enantiomerically pure indanone is used for the divergent total syntheses of three resveratrol natural products (+)-isopaucifloral F, (+)-quadrangularin A, and (+)-pallidol.

Full text of DOI:10.1002/chem.201603664

A Journal of
Accepted Article
Title: Sulfoxide-based Enantioselective Nazarov Cyclization: Divergent Syntheses of
(+)-Isopaucifloral F, (+)-Quadrangularin A and (+)-Pallidol
Authors: Xun Sun; Mei-Lin Tang; Peng Peng; Zheng-Yu Liu; Jian Zhang; Jian-Min
Yu
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To be cited as: Chem. Eur. J. 10.1002/chem.201603664
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Sulfoxide-based Enantioselective Nazarov Cyclization: Divergent
Syntheses of (+)-Isopaucifloral F, (+)-Quadrangularin A and (+)-Pallidol
Mei-Lin Tang, Peng Peng, Zheng-Yu Liu, Jian Zhang, Jian-Ming Yu and Xun Sun*
Abstract: A highly enantioselective synthesis of enantiomerically
pure 3-aryl substituted indanones is developed through a sulfoxide-
based Nazarov cyclization. After reductive desulfonation under mild
conditions, selected enantiomerically pure indanone is merged into
the divergent total syntheses of three resveratrol natural products,
(+)-isopaucifloral F, (+)-quadrangularin A and (+)-pallidol.
bakers’ yeast reduction of 3-arylindanones[7], rhodium-catalyzed
asymmetric transformations[8], and palladium-catalyzed reductive
Heck reaction[9]. Another elegant approach is the Nazarov
cyclizatin[10-12]. Flynn and co-workers, in particular, implemented
Evans’ oxazolidinones to control Nazarov cyclization, which
resulted in an enantioselective synthesis of 1 with notable
success;[12b] however, the multiple steps towards the enone
substrates and removal of auxiliary may deteriorate the overall
Indanone frameworks are ubiquitous substructures in natural
products and biologically active compounds.[1] Among them, in
particular, 3-arylindanones 1 bearing the C3 substitution are
privileged structure components of many pharmaceutical agents
as well as utilized as numerous functionalized intermediates in
syntheses of bioactive compounds.[2] Typical examples include
efficiency. We envisioned
a more practical and efficient
alternative involving the C2-substituted enantiomerically pure
methyl para-tolyl sulfoxide auxiliary within α,β-unsaturated
carbonyl compounds as substrates 10a (Figure 2). The
efficiency, regioselectivity, and stereoselectivity of this approach
could be attribute to that: (1) enantiomerically pure methyl para-
tolyl sulfoxide auxiliary bearing an electron-withdrawing sulfoxide
group facilitates the Knoevenagel reaction[13] accomplished by
straightforward condensation of aldehyde and enantiomerically
pure β-arylketosulfoxide; (2) enantiomerically pure methyl para-
tolyl sulfoxide[14] is readily available, extensively used, and
undoubtedly one of the most efficient auxiliaries in asymmetric
synthesis, employed for the stereoselectively control of the new
stereogenic center at C3 in the Nazarov cyclization process; (3)
methyl para-tolyl sulfoxide auxiliary is easily reductive cleavage
under mild conditions with high efficiency[15]. Herein, we presnet
a enantiomerically pure methyl para-tolyl sulfoxide controlled
Nazarov cyclization to establish the 3-arylindenones in high yield
with excellent enantioselectivities, which was further elaborated
into requisite functionality for rapid divergent total syntheses of
three resveratrol-based oligomers (+)-isopaucifloral 5, (+)-
quadrangularin A 6, and (+)-pallidol 7.
treating
cocaine
abuse
agent
(+)-indatraline
2[3],
a
antihypertensive agent (+)-iranadalone 3[4], as well as
micromolar telomerase inhibitor (+)-brazilin 4[5] (Figure 1).
Moreover, the enantiomerically pure 3-arylindanone unit is also
embedded in resveratrol-based oligomers, such as (+)-
isopaucifloral F 5, (+)-quadrangularin A 6 and (+)-pallidol 7,
which were found to exhibit anti-osteoporosis, neuroprotective
and estrogen-like activity, respectively.[6] As a result, novel
strategies and tactics for the enantioselective synthesis of 3-
arylindanones with high levels of efficiency from readily available
starting materials are of great interest from the synthesis
community.
Figure 1. Selected pharmaceuticals and natural products bearing 3-
arylindanones
Figure 2. Strategy to access enantiomerically pure 3-arylindanones.
In the past decades, a limited number of methods for
enantioselective formation of 1 have been pursued, such as
[*]
M.-L. Tang, P. Peng, Z.-Y. Liu, J. Zhang, J.-M. Yu, and Prof. Dr. X.
Sun
Department of Natural Products Chemistry, School of Pharmacy,
Fudan University, 826 Zhangheng Road, Shanghai 201203 (China)
E-mail: sunxunf@shmu.edu.cn
Prof. Dr. X. Sun
Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai
201203 (China)
Supporting information for this article is available on the WWW
Scheme 1: Regents and conditions: (a) LDA, THF, -78 0C, 1 h; then
methyl 3,5-dimethoxybenzoate, 12 h, 96%; (b) piperidine (0.2 equiv),

Chemistry - A European Journal
10.1002/chem.201603664
COMMUNICATION
acetic acid (0.4 equiv), toluene, 100 0C, 8 h, 95%. LDA = lithium
diisopropylamide, THF = tetrahydrofuran.
conversion (entry 5). The cyclization product 11a was gained in
excellent yield (95%) at elevated temperature (35 C) (entry 6).
0
Further optimization of reaction conditions including temperature
and loading of promoter would deteriorate the reaction outcome
(entries 7-9).
Initially, enone 10a bearing a enantiomerically pure sulfoxide
was chosen as a model substrate since it could be readily
prepared via a two-step protocol from enantiomerically pure
sulfoxide methy-p-tolysulfoxide (8) (Scheme 1).[14] The Claisen-
Table 2: The scope of formation 3-arylindanones using enantiomerically
pure sulfoxide controlled Nazarov cyclizations.
type condensation of sulfoxide
8
with methyl 3,5-
dimethoxybenzoate proceeded smoothly to deliver β-keto
sulfoxide 9a in excellent yield. Subsequent Knoevenagel
condensation of 9a with 3,5-dimethoxybenzaldehyde was
conducted in the presence of catalytic piperidine and acetic acid
to give the desired enone 10a (E/Z = 1:0.7) in good overall yield.
Table 1: Optimization of the Nazarov reaction condition.[a]
Entry
Promoter
(equiv)
Temp
(0C)
25
solvent
Yield[b]
[%]11a
45
d.r.[c]
11a
ee[d]
[%]12a
86
1
2
3
4
5
6
7
8
9
AlCl3(1.1)
AlCl3(1.1)
AlCl3(1.1)
AlCl3(1.1)
AlCl3(1.1)
AlCl3(1.1)
AlCl3(1.1)
AlCl3(0.55)
AlCl3(0.2)
CH2Cl2
EtNO2
PhNO2
DCE
99:1
25
N. R.
N. R.
N. R.
75
25
25
25
toluene
toluene
toluene
toluene
toluene
99:1
99:1
99:1
99:1
99:1
98
98
90
98
98
35
95
50
90
35
83
35
57
[a] Reaction conditions: 9 (0.15 mmol), promoter (0.16 mmol), solvent
(1.2 mL) under N2 atmosphere for 12 h at 25 0C unless other noted. [b]
Isolated yield of 11a. N.R. = no reaction. [c] Diastereoselectivity (trans/cis)
was determined by 1H NMR (400 MHz, CDCl3). [d] Enantioselectivity was
determined by chiral HPLC analysis, see the Supporting Information for
details. DCE = 1,2-dichloroethane.
With the sufficient amount of 10a in hand, we started to
investigate the Nazarov cyclization conditions. Firstly, a series of
Brønsted acids[17], such as H2SO4, H3PO4, CF3COOH, and
CH3SO3H, were screened for the reaction (see the Supporting
Information, Table S1). However, no desired product was
observed. To our delight, evaluation of various Lewis acids
revealed that AlCl3 afforded the desired cyclization product 11a
in 45% yield with high diastereoselectivity (99:1) (entry 1, Table
1). To verify the efficiency of chirality control by enantiomerically
pure sulfoxide, reductive cleavage of the auxiliary using zinc
powder produced 3-arylindanone 12a quantitatively with good
enantioselectivity (86%). It means two pairs of diastereomers
derived from Nazarov cyclization reached a ratio of 93/7.
Encouraged by the initial success, optimization of solvent
Having identified the optimal conditions, we turned our attention
to investigate the scope of enantiomerically pure sulfoxide-
controlled Nazarov cyclization. A series of enones with different
R1 groups was surveyed under the optimal conditions (Table 2).
When para- or meta- substituted C3-aryl group were used, the
Nazarov cyclizations and reductive desulfonation proceeded
screening
identified toluene
to result
in excellent
diastereoselectivity (11a, dr 99:1) and enantioselectivity of 12a
(98% e.e.) albeit in moderate yield (75%) due to the incomplete

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COMMUNICATION
smoothly with high enantioselectivities and good to excellent
overall yields (78%-94% yields, 97%-99% e.e.,12a-12n). In
contrast, ortho-substituted aryl substrate led to moderate yield
and good e.e. of desired products (82% yield, 98 e.e.,12o).
Interestingly, substrates with 6-methoxynaphthalyl group also
afforded the desired products in 78% yield (12p). In addition,
heteroaryls as R1 group, such as 2-furanyl, 2-thienyl, 3-thienyl,
3-benzothienyl, were also tolerated to give the corresponding
cyclization products in good yields (66-77%, 12q-12u). To further
verify the efficiency of the current approach, substituent effects
at aryl ring as R2 groups were executed. We were pleased to
find that 3-methoxyl and 3,4-dimethoxyl substituted substrates
were compatible for the reaction and the corresponding products
were isolated in good isolated yields (12v-12z). However, when
the R2 group at aryl ring was attached with 4-methoxyl or no
substituent, the Nazarov cyclizations reaction could not proceed
under the standard conditions (11aa-11ab). Notably, reductive
cleavage of the auxiliary ((S)-methyl-p-tolylsulfoxide) of 11a-11z
using zinc powder furnished 3-arylindanones 12a-12z with high
enantioselectivities and excellent (almost quantitatively, see the
Supporting Information table S2, S3 and S4).
Scheme 3: Total syntheses of (-)-quadrangularin A 6. a) LiHMDS (2.5
equiv), PhNTf2 (1.8 equiv), THF, −25 °C, 2 h; b) 13, (1.5 equiv),
Fe(acac)3 (0.05 equiv), THF/NMP (20:1), 0 °C, 65% for 14 with two
steps; c) Pd(OAc)2 (0.05 equiv), 15 (4 equiv), TEMPO (4 equiv), KF (4
equiv), propionic acid, RT, 12h, 89% for 16; d) BBr3 (12 equiv), CH2Cl2,
0 °C-RT, 12h, 55%. KHMDS = potassium hexamethyldisilazane, THF =
tetrahydrofuran, NMP = N-methyl-2-pyrrolidinone, TEMPO = 2,2,6,6-
tetramethyl-1-piperidinyloxy.
Scheme 2: The plausible mechanism of the C2 substituted
enantiomerically pure sulfoxide-controlled Nazarov cyclization.
The assignment of absolute configuration of diastereomers
11a-11z was based on the X-ray crystal structure analysis of
11a (see the Supporting Information).[18] Moreover, the absolute
configuration of 12a-12z could be confirmed to be S by
comparison with the known data[7,12b] and X-ray crystallographic
analysis of 12a (see the Supporting Information). A possible
reaction mechanism was described as follows using 10a as an
example (Scheme 2). Initially, the promoter AlCl3 with substrate
10a via two point binding to form the intermediate A, which was
followed by isomerization to afford the oxyallyl cation B.
Intermediate B subsequently underwent Friedel-Crafts type
cyclization to furnish intermediate C (or C’). This was followed by
deprotonation to give intermediate D (or D’). Finally, the
promoter AlCl3 was left to obtain the product 11a (or 11a’). In
this process, the key stage was that transition-state structure B
underwent Friedel-Crafts type cyclization to furnish intermediate
Scheme 4: Total syntheses of (+)-isopaucifloral F 5 and (+)-pallidol 7. a)
K2OSO2(OH)2 (0.1 equiv), 2,6-lutidine (1.0 equiv), NaIO4 (3.0 equiv),
acetone/water (3:1), RT, 8h, 73% for 17; b) BH3·THF (10 equiv), THF, RT,
18h, then NaOH (0.25 M)/H2O2 (30%) (3:1), 1h, Na2SO3, 0 °C, 81% for
18; c) AlCl3 (5 equiv), CH2Cl2, RT, 2h, 70% for 19; d) BBr3 (10 equiv),
CH2Cl2, 0 °C-RT, 12h, 54% for (+)-isopauciflorol F 5; BBr3 (12 equiv),
CH2Cl2, 0 °C-RT, 12h, 81% for (+)-pallidol 7.

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COMMUNICATION
C (or C’), sterically favoring transition-state C over transition-
state C’. Thus the major product 11a was obtained.
Keywords: Nazarov cyclization • 3-arylindanones • total
synthesis
To further illustrate the application, divergent total synthesis
resveratrol-based oligomers, such as (+)-isopaucifloral F 5,
(+)-quadrangularin A 6 and (+)-pallidol 7 were undertaken[19,20]
using indanone 12b. Treatment of substrate 10b (scale up to 10
mmol) under the optimal reaction conditions and the subsequent
reductive cleavage of the auxiliary allowed the isolation of (S)-
12b in 92% ee (81% yield and >99.5% e.e. after one
recrystallization from Et2O/hexane). Further elaborations of
optical pure 12b led to functionalized intermediate compound 16
(methylated precursors of quadrangularin A) with three steps as
shown in Scheme 3. Triflation of 12b followed by cross-coupling
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condensation, AlCl3-promoted Nazarov cyclization, and
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Acknowledgements
Financial support was provided by the National Natural Science
Foundation of China (No: 81373276), the Shanghai Municipal
Committee of Science and Technology (No. 14XD1400300 and
13431900101) and Specialized Research Fund for the Doctoral
Program of Higher Education (No. 20130071110070). We also
thank Prof. Bang-Guo Wei (Fudan University) and Prof. Ran
Hong (Shanghai Institute of Organic Chemistry) for helpful
discussions.

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Chemistry - A European Journal
10.1002/chem.201603664
COMMUNICATION
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Asymmetric Synthesis
COMMUNICATION
Mei-Lin Tang, Peng Peng, Zheng-Yu Liu,
Jian Zhang, Jian-Min Yu and Xun Sun*
Page No. – Page No.
Sulfoxide-based Enantioselective
Nazarov Cyclizations: Divergent Total
Syntheses of (+)-Isopaucifloral F, (+)-
Sulfoxide-mediates! Enantioenriched 3-arylindanones are readily prepared in high
yields through an enantiomerically pure methyl para-tolyl sulfoxide-based
Knoevenagel condensation/Nazarov cyclization/Reductive cleavage process. The
synthetic application of this methodology was illustrated in the divergent total
syntheses of three resveratrol-derived natural products (+)-isopaucifloral F, (+)-
quadrangularin A and (+)-pallidol.
Quadrangularin A and (+)-Pallidol