Enantioselective synthesis of 2,3-disubstituted indanones via Pd-catalyzed intramolecular asymmetric allylic alkylation of ketones

Article abstract of DOI:10.1021/ol402980v

A Pd-catalyzed intramolecular asymmetric allylic alkylation (AAA) reaction with "hard" carbanions has been developed for the first time, affording 2,3-disubstituted indanones with high diastereo- and enantioselectivities. The transformation of these produ

Full text of DOI:10.1021/ol402980v

ORGANIC
LETTERS
2013
Vol. 15, No. 23
6086–6089
Enantioselective Synthesis of
2,3-Disubstituted Indanones via
Pd-Catalyzed Intramolecular Asymmetric
Allylic Alkylation of Ketones
Xiao-Hui Li,† Bao-Hui Zheng,† Chang-Hua Ding,† and Xue-Long Hou*,†,‡
State Key Laboratory of Organometallic Chemistry and ShanghaiꢀHong Kong Joint
Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
xlhou@sioc.ac.cn
Received October 16, 2013
ABSTRACT
A Pd-catalyzed intramolecular asymmetric allylic alkylation (AAA) reaction with “hard” carbanions has been developed for the first time, affording
2,3-disubstituted indanones with high diastereo- and enantioselectivities. The transformation of these products into other core structures of
natural products has been demonstrated.
2,3-Disubstituted indanones with two chiral centers are
common subunits found in a variety of natural products
and biologically active compounds.1 Taiwaniaquinol B,2
nakiterpiosin,3 and (þ)-pauciflorol F4 are examples. Such
an indanone also served as the key precursor in the
synthesis of a tetracyclic framework of tetrapetalone A5
(Figure 1). Thus their synthesis has received a tremendous
amount of attention from the synthetic community and
many strategies have been developed to them.6 However,
the synthesis of 2,3-substituted indanones based on asym-
metric catalysis is rare.7 In the light of recent achievements
in Pd-catalyzed asymmetric allylic alkylation (AAA),8 we
envisioned that chiral 2,3-substituted indanones could
† State Key Laboratory of Organometallic Chemistry.
‡ ShanghaiꢀHong Kong Joint Laboratory in Chemical Synthesis.
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r
10.1021/ol402980v
Published on Web 11/08/2013
2013 American Chemical Society

potentially be generated via the Pd-catalyzed intramolec-
ular AAA of ketones. While the synthesis of carbo- and
heterocycles via an intramolecular Pd-catalyzed asym-
metric allylic substitution has been well documented,9 to
the best of our knowledge, there are no reports on the use
of “hard” carbanion nucleophiles in the intramolecular
Pd-catalyzed asymmetric allylic substitution reaction,
despite the fact that great progress has been made in the
use of hard carbanions as nucleophiles in the Pd-
catalyzed AAA reaction.10,11 We have worked in the
field of Pd-catalyzed AAA reactions for a couple of
years11,12 and have developed some hard carbanions as
nucleophiles.11 In this Letter, we disclose an enantio-
selective synthesis of 2,3-disubstituted indanones by an
intramolecular Pd-catalyzed AAA with a hard carbanion
as nucleophile. The usefulness of the products has also
been demonstrated.
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Figure 1. Some natural products containing 2,3-disubstituted
indanones substructure.
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An initial test was the reaction of substrate 1a in the
presence of 2.5 mol % of [Pd(η3-C3H5)Cl]2 and 5 mol % of
(Rphos,Ra)-SIOCPhox L1 in dimethoxyethane (DME),
with LiHMDS as base, which provided the cyclic ether
2a as the sole product in 82% yield. It was produced from
O-alkylation of the ketone enolate generated in situ, which
is an ambident nucleophile. It seems that O-alkylation is
a more favorable process to form a 5-membered ether
than5-memberedcyclicketone formation.13 Obviously the
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Org. Lett., Vol. 15, No. 23, 2013
6087

issue of chemoselectivity was the first critical issue to be
addressed in this Pd-catalyzed intramolecular AAA reac-
tion. By trial and error, we found that when tert-butanol
was the solvent with lithium hydroxide monohydrate as
the base, formation of the O-alkylation product 2a was
efficiently suppressed, and theC-alkylationproduct 3awas
promoted, although the yield was only 35%, because of
hydrolysis of the substrate 1a (Scheme 1). These results
encouraged us to study further the effect of the reaction
parameters, including bases, solvents, and reaction tem-
perature, on the reaction.
screened (entries 3ꢀ7). K3PO4 was identified as the best
among the bases screened in terms of both diastereo- and
enantioselectivities (entry 7). The solvent effect is impor-
tant on the enantioselectivity (entries 7ꢀ10). The reaction
in 2-methoxyethanol provided the product 3a in 80%
yield, 87/13 anti/syn ratio, and 75% ee (entry 10). The ee
value increased further to 82% by lowering the reaction
temperature from rt to 0 °C, but the dr was lower (entry 11).
Because the reaction in tert-butanol gave an excellent
diastereoselectivity, we wondered if the use of mixed
solvents of tert-butanol and 2-methoxyethanol could
make both dr and ee higher. Pleasingly, the dr increased
significantly from 84/16 to 93/7, whereas the enantios-
electivity changed from 82 to 84%, when the reaction was
run in 1:1 tert-butanol and 2-methoxyethanol (entry 12 vs
entry 11). An increase of ee value to 88% was observed
when the reaction was conducted at ꢀ20 °C (entry 13).
The substrate scope of the Pd-catalyzed intramolecular
AAA of ketones 1 was investigated under the optimized
reaction conditions (Figure 3). The reaction proceeded
well in all cases, affording indanones 3 bearing two vicinal
chiral centers in moderate-to-high yields with high diastereo-
and enantioselectivities, the dr being 90/10 to >95/<5
with the ee value being 67ꢀ89%. R-Substituents to the
carbonyl group exerted little influence on the diastereo-
and enantioselectivities of the reaction (3aꢀ3c). Ketone 1
with an ester group was a suitable substrate for providing
the product 3d with excellent dr and ee. The reaction was
compatible with a substrate 1 with a 1,2-disubstituted
allylic group, affording the corresponding indanone 3e in
95/5 dr and 89% ee albeit the yield being a little lower. The
effect of halide substituents on the aryl group of substrates
1 on the reaction was examined. The dr of both products 3f
and 3g was excellent, while the enantioselectivity was also
Scheme 1. Chemoselectivity of Pd-Catalyzed Intramolecular
Reactions of 1a
As shown in Table 1, the use of diethyl phosphate 1b, a
more stable substrate toward basic condition, and 10 mol
% of tetrabutylammonium fluoride (TBAF) significantly
increased the yield of product 3a to 83% (entry 1). The
reaction hardly proceeded in the presence of TBAF only
without addition of LiOH H2O (entry 2). The ee was
3
higher with (Sphos,Ra)-SIOCPhox L2 than with (Rphos,Ra)-
SIOCPhox L1 (Figure 2), although the yield was lower
(entry 3 vs entry 1). With (Sphos,Ra)-SIOCPhox L2 as
ligand, the influence of the bases on the reaction was
Table 1. Optimization of Reaction Conditions for Pd-Catalyzed Intramolecular AAA of Ketone 1ba
entry
base
solvent
yield (%)b
anti/sync
ee (%)d
1
LiOH H2O
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
iPrOH
MeOH
83
nr
56
80
58
70
81
87
88
80
84
72
70
88/12
ꢀ
40
ꢀ
3
2
ꢀ
3
LiOH H2O
87/13
89/11
69/31
94/6
47
44
16
18
44
47
76
75
82
84
88
3
4
tBuOLi
5
KOH
6
K2CO3
7
K3PO4
92/8
8
K3PO4
87/13
81/19
87/13
84/16
93/7
9
K3PO4
10
11
12
13
K3PO4
CH3OCH2CH2OH
K3PO4 at 0 °C
K3PO4 at 0 °C
K3PO4 at ꢀ20 °C
CH3OCH2CH2OH
tBuOH/CH3OCH2CH2OHe
tBuOH/CH3OCH2CH2OHe
91/9
a Conditions: molar ratio 1b/[Pd(η3-C3H5)Cl]2/L/base/TBAF = 100/2.5/5.0/200/10, 2.0 mL of solvent; entries 1 and 2: L1 used as ligand; entries
3ꢀ13: L2 used as ligand. b Isolated yield of 3a. c Determined by 1H NMR analysis. d Determined by chiral HPLC. e CH3OCH2CH2OH/tBuOH = 1/1.
6088
Org. Lett., Vol. 15, No. 23, 2013

Scheme 2. Transformations of Reaction Products
Scheme 3. Determination of Absolute Configuration of Product 4
Figure 3. Substrate scope of Pd-catalyzed intramolecular AAA
of ketones 1. Conditions: Molar ratio 1/[Pd(η3-C3H5)Cl]2/
(Sphos,Ra)-L2/K3PO4/TBAF = 100/2.5/5.0/200/10, 1.0 mL of
t
CH3OCH2CH2OH and 1.0 mL of BuOH; dr determined by
1H NMR; ee determined by chiral HPLC. Asterisk (*) indicates
CH3OCH2CH2OH/DME (1/1) used as solvent and tetrabutyl-
ammonium bromide (TBAB) used as additive.
time, obtaining 2,3-disubstituted indanones with high
diastereo- and enantioselectivities. The transformation of
these products into other core structures of natural pro-
ducts was demonstrated. Further investigations on the
intramolecular Pd-catalyzed AAA reaction with other
substrates, and applications of the protocol in organic
syntheses, are in progress.
high. The reaction also performed well for R-aryl ketones
1, providing the corresponding products in excellent drand
moderate enantioselectivity (3h and 3i). Indanones 3j and
3k with multiple functional groups were also prepared with
high yield and excellent diastereoselectivity.
Optically active 2,3-disubstituted indanones were sub-
jected to further modification. The reduction of product 3a
with NaBH4 followed by a protection of the hydroxyl
group afforded a 2,3-dihydro-1H-indene 4 with three
chiral centers, which possessed the core structure of tetra-
petalone A (Scheme 2). The absolute configuration of
product 4 was assigned as (1R,2S,3S) by X-ray analysis
of its single crystal (Scheme 3). Accordingly, the absolute
configuration of product 3a was (2S,3S). The reduction of
the carbonyl group of product 3d into the methylene group
was also feasible, as shown in Scheme 2. The resulting
product 5 is an important subunit of the natural product
veratramine.
Acknowledgment. This work was financially supported
by the Major Basic Research Development Program (2010-
CB833300), National Natural Science Foundation of China
(21272251, 21121062, 21032007), Chinese Academy of
Sciences, the Technology Commission of Shanghai Mu-
nicipality, and the Croucher Foundation of Hong Kong.
Supporting Information Available. Experimental pro-
cedure for synthesis of compounds 1, spectra of com-
pounds 1, 3aꢀ3k, 4, and 5, X-ray analysis data of 4 in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, we have achieved a Pd-catalyzed intra-
molecular AAA reaction with hard carbanions for the first
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 23, 2013
6089