Enantioselective Palladium-Catalyzed Intramolecular α-Arylative Desymmetrization of 1,3-Diketones

Article abstract of DOI:10.1021/jacs.7b10365

An efficient enantioselective protocol has been reported to build highly oxygenated and densely substituted bicyclo[m.n.1] skeletons through intramolecular asymmetric α-arylative desymmetrization of 1,3-diketones. Employing Pd catalyst and FOXAP ligand, various bicyclo[m.n.1] skeleton with different size can be accessed with high enantio- and diastereoselectivities. Utilizing the present method as a key step, formal asymmetric total synthesis of the (-)-parvifoline has been demonstrated.

Full text of DOI:10.1021/jacs.7b10365

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Communication
Enantioselective Palladium-Catalyzed Intramolecular
#-Arylative Desymmetrization of 1,3-Diketones
Chendan Zhu, Dingyi Wang, Yue Zhao, Wei-Yin Sun, and Zhuangzhi Shi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b10365 • Publication Date (Web): 08 Nov 2017
Downloaded from http://pubs.acs.org on November 8, 2017
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Enantioselective PalladiumꢀCatalyzed Intramolecular αꢀArylative
Desymmetrization of 1,3ꢀDiketones
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Chendan Zhu, Dingyi Wang, Yue Zhao, WeiꢀYin Sun, and Zhuangzhi Shi*
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanꢀ
jing, 210093, China
ABSTRACT: An efficient enantioselective protocol has been
reported to build highly oxygenated and densely substituted
bicyclo[m.n.1] skeletons through intramolecular asymmetric αꢀ
arylative desymmetrization of 1,3ꢀdiketones. Employing Pd
catalyst and FOXAP ligand, various bicyclo[m.n.1] skeleton with
different size can be accessed with high enantioꢀ and diastereoꢀ
selectivities. Utilizing the present method as a key step, formal
asymmetric total synthesis of the (ꢀ)ꢀparvifoline has been
demonstrated.
Highly oxygenated and densely substituted bicyclo[m.n.1] frameꢀ
work is highly important building blocks in basic structural motifs
of many natural products and bioactive compounds.1 Most of
these compounds contain quaternary carbon centers adjacent to a
bridged ketone.2 Owing to the promising biological properties and
challenging structures of these molecules, considerable efforts
have been devoted to develop efficient methods to construct such
skeletons.3 Among them, Pdꢀcatalyzed intramolecular αꢀarylation
Figure 1. Inspiration for enantioselective desymmetrization of
symmetric 1,3ꢀdiketone to build bicyclo[m.n.1] skeleton.
of carbonyl compounds represents an attractive strategy, which
has been applied successfully in total synthesis of many nature
products including dysidavarone A4, welwitindolinones5 and so
center as the model substrate (Table 1). In presence of 10 mol%
on (Figure 1a).6 However, it’s necessary to carry out a high regioꢀ,
Pd(OAc)2, 11 mol % (R)ꢀBinap (L1), 1.0 equiv Cs2CO3, and 100
o
diastereoꢀ and enantioꢀcontrolled alkylation at α methylene group
for the subsequent αꢀarylation and cyclization to produce the deꢀ
sired enantiomeric pure products in the case of this strategy. Inꢀ
spired by the frequent occurrence of bicyclo[m.n.1] skeleton in
natural products, we offer a concise and scalable asymmetric cataꢀ
lytic strategy to access these chiral products directly.
mg 4 ÅM.S., at 80 C under an argon atmosphere in toluene, we
indeed observed the cyclization product 2a after 12 h in 93%
yield albeit with 18% ee (entry 1). To improve the result, we
evaluated various chiral bidentate ligands including JOSIPHOS,
PHOX, and FOXAP families (entries 2ꢀ6). (Sp, S)ꢀtBuꢀFOXAP
(L5) ligand was proved to be the best in terms of reactivity and
enantioselectivity (67% yield, 92% ee, entry 6). Extending the
reaction time to 48 h the product 2a yield was improved to 98%
yield without sacrificing the enantioselectivity (entry 7). Interestꢀ
ingly, the diastereoisomeric ligand (Rp, S)ꢀtBuꢀFOXAP (L6) also
gave 2a in 93% yield with 92% ee which indicated that the chiralꢀ
ity of the product is mainly determined by chiral oxazoline skeleꢀ
ton (entry 8).11 In addition, application of monodentate ligand L7
(entry 9) or chiral phosphine oxide ligand L8 (entry 10) resulted
inferior results and demonstrated that the tertiary phosphine group
in ligand L5 had a great influence on the reaction outcome. Deꢀ
creasing the catalyst loading or lowering of the reaction temperaꢀ
ture resulted in a much lower yield, but slightly higher ee values
were observed (entries 11ꢀ12). Moreover, other palladium source
like Pd2(dba)3 exhibited significantly worse reactivity (entry 13).
Finally, control experiments revealed that the absence of molecuꢀ
lar sieves dramatically reduced the yield (entry 14) and the reacꢀ
tion was unsuccessful without Cs2CO3 (entry 15).
Desymmetrization of symmetric 1,3ꢀdiketone7 is attractive for
reaction design due to the acidic α methylene group that can easiꢀ
ly be functionalized by deprotonation with various types substituꢀ
ents.8 Most of known processes so far have focused on the
desymmetrization of two carbonyl groups to deliver chiral bicyꢀ
clo[m.n.0] products.9 In view of the precedent work on asymmetꢀ
ric αꢀarylation of ketones with aryl (pseudo)halides,10 we wonꢀ
dered a related process to build bicyclo[m.n.1] skeleton involving
the combined αꢀarylation reaction and enantioselective desymmeꢀ
trization of 1,3ꢀdiketones with aryl halides in an intramolecular
fashion. Herein, we report the first enantioselective Pdꢀcatalyzed
desymmetrization of 1,3ꢀdiketones to afford a range of chiral biꢀ
cyclo[m.n.1] compounds (Figure 1b). The advantage of this methꢀ
od is that various bicyclo[m.n.1] skeleton bearing more than two
stereocenters can be readily prepared with excellent stereoselecꢀ
tivity using a modular operation. Compared to the intermolecular
asymmetric αꢀarylation only limited to construct αꢀcarbonyl quaꢀ
ternary stereogenic center, the generated tertiary center in our
method can be prevented to be racemized by this rigid structural
property under basic conditions.
With the set of optimized reaction conditions in hand, we first
examined the scope of this desymmetrization reaction (Table 2).
Substrates with a broad range of substitution at C4ꢀC6 on the
benzene ring were first examined. Electronꢀ neutral, donating and
withdrawing substituents were generally wellꢀtolerated, affording
To begin our studies, we have chosen 2ꢀ(2ꢀbromobenzyl)ꢀ2ꢀ
methylcyclohexaneꢀ1,3ꢀdione (1a) bearing a βꢀquaternary carbon
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Table 1. Screening of Representative Ligands and Different Conꢀ
ditions.a
Table 2. Substrate Scope.a
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[Pd]
(mol%)
L
T
time ee
yield
(%)c
entry
(mol%)
(oC) (h) (%)b
1
2
Pd(OAc)2 (10) (R)ꢀBinap (11) 80
12
12
12
12
12
12
48
48
48
48
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48
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48
18
54
ꢀ
93
69
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd2(dba)3 (5)
L1 (11)
L2 (11)
L3 (11)
L4 (11)
L5 (11)
L5 (11)
L6 (11)
L7 (11)
L8 (11)
L5 (5.5)
L5 (11)
L5 (11)
L5 (11)
L5 (11)
80
80
80
80
80
80
80
80
80
80
60
80
80
80
3
trace
52
4
74
83
92
5
55
6
67
7
92 98 (83)d
8
92
ꢀ15
0
93
14
9
10
11
12
13
14e
15f
trace
47
93
95
87
92
ꢀ
81
46
Pd(OAc)2 (10)
Pd(OAc)2 (10)
44
trace
aReaction conditions: 1a (0.10 mmol), 5ꢀ10 mol% [Pd], 5.5ꢀ11
mol% ligand, Cs2CO3 (0.10 mmol), 100 mg 4 Å M.S. in 1 mL
toluene for 12ꢀ48 hours under argon. bEnantiomeric excess values
were determined by chiral HPLC analysis. cYields were
determined by GC. dIsolated yield after chromatography. eWithout
f
molecular sieves. Without Cs2CO3.
the desired products 2bꢀ2i bearing methyl (2b), CF3 (2c), methꢀ
oxy (2d), F (2eꢀf), Cl (2g), ester (2h), and cyano (2i) functionaliꢀ
ties in good yields with excellent enantioselectivities. Moreover,
substrate 1j with multiple substituents at benzene ring also led to
excellent yield and enantioselectivity (87%, 90% ee). We found
that substrates with various R2 group at α methylene position also
gave chiral diketones 2kꢀp in 64ꢀ95% yields (87ꢀ94% ee). Particꢀ
ularly the substrate 1o with a substituent derived from (S)ꢀ(ꢀ)ꢀ
citronellal, the desired product 2o was observed in 83% yield with
an excellent diastereoselectivity (>14:1 dr). The scope of this
enantioselective desymmetrization could also be extended to preꢀ
pare products with different ring sizes (2qꢀ2u). Among them,
indole substrates 2t and 2u showed high reactivity generating
[5.3.1]ꢀ, and [6.3.1]ꢀbicyclic ring systems in good yields and high
levels of enantioinduction. Notably, this process is not only limꢀ
ited to cyclohexaneꢀ1,3ꢀdione as the electrophilic trap, cyclic 1,3ꢀ
diketones with different size are also effective to build [3.2.1]ꢀ,
[3.3.1]ꢀ, and [3.4.1]ꢀ bicyclic ring systems (2vꢀx). To determine
the absolute configuration of these products, we were fortunate to
get crystals of the products 2d, 2i and 2t and subjected to Xꢀray
crystallographic analysis.
aReaction conditions: 1 (0.10 mmol), 10 mol% Pd(OAc)2, 11
mol% L5, Cs2CO3 (0.10 mmol), 100 mg 4 Å M.S. in 1 mL
toluene, 80 oC, 48 hours, under argon; Isolated yields with ee
b
o
o
o
values determined by chiral HPLC. 96 h. c60 C. d90 C. e100 C.
g
f120 oC. 20 mol% Pd(OAc)2, 22 mol% L5.
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This utility can be exemplified by a short synthesis of (−)ꢀ
Scheme 1. Asymmetric Synthesis of Bicyclo[3.3.1] Skeleton
1
2
3
4
5
6
7
8
parvifoline,12 a sesquiterpene isolated from the species Coreopsis
with a special trimethyl benzocyclooctene structural unit.13 On the
basis of the above experimental results and the absolute configuꢀ
ration of (−)ꢀparvifoline, we used (Rp, R)ꢀtBuꢀFOXAP (L5') as the
ligand in catalytic desymmetrization, providing the key bicyꢀ
clo[3.3.1] skeleton 2j' on gramꢀscale in 94% yield and 92% ee
under the developed conditions. The absolute configuration of
this key intermediate was also confirmed by Xꢀray crystallogꢀ
raphy. Then oneꢀpot regioꢀ and stereoselective reduction of the
least hindered carbonyl group of 2j', mesylatation and followed
by a Grob fragmentation14 afforded the benzocyclooctene carboxꢀ
ylic acid 5 in 51% overall yield with 93% ee. It was then subjectꢀ
ed to esterification, reduction, and mesylation followed by a reꢀ
duction of the crude mesylate with LiEt3BH to provide chiral
product 6 in 69% overall yield. Finally, cleavage of the methyl
ether in 6 with EtSLi in dry DMF gave final product (ꢀ)ꢀ
parvifoline (7) in 90% yield with 92% ee, whose spectroscopic
properties were identical with the litearture.12b
Bearing Three Stereocenters.
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The observation of the stereoselectivities in L5ꢀL6 and a linear
relationship of enantiomeric purity between ligand and product
(see SI),15 coupled with our knowledge of the absolute palladium
stereochemistry,16 suggests the model for stereochemical inducꢀ
tion proposed in Figure 2. During oxidative addition, the bigger
aryl group coordinated to palladium center is trans to PPh2 group
in L5ꢀL6, and the smaller Br group on cis position. The diketone
skeleton like a tail of the aryl ring, occupies the opposite side of
We next investigated whether this strategy could be applied to
5ꢀsubstituted cyclohexaneꢀ1,3ꢀdiones that would provide products
containing three stereocenters. Interstingly, the catalytic desymꢀ
metrization and asymmetric cyclization of the diasteromeric mixꢀ
ture, 1y/1y' (trans/cis = 3.6:1) derived from commercially availaꢀ
ble material 3 and 4 provided the product 2y as single diastereꢀ
omer in 66% yield with 96% ee. To gain insight into this high
diastereoselectivity, we isolated the mixture of 1y and 1y' by colꢀ
umn chromatography. Both relative configurations of the products
were confirmed by Xꢀray crystallographic analysis. Catalytic
desymmetrization of the 1y provided the product 2y in 96% yield
with 96% ee. In contrast, only trace amount of product 2y' was
obtained probably due to steric hindrance between 5ꢀphenyl group
and two α methylene groups in this cisꢀconfiguration.
t
the sterically Bu group on the ligand. The same stereoselectivity
resulted from the diastereoisomers L5 and L6 is reasonable when
the favored site of α methylene groups attack palladium center
from the back side because of the bulk PPh2 group.
Scheme 2. Enantioselective Total Synthesis of (ꢀ)ꢀParvifoline.
Figure 2. Model Explaining the Observed Stereochemistry.
In summary, we have described a highly enantioselective Pdꢀ
catalyzed intramolecular αꢀarylative desymmetrization of 1,3ꢀ
diketones providing various functionalized bicyclo[m.n.1] archiꢀ
tectures with several stereocenters. As the key step, the utility of
this method has been highlighted by enantioselective total syntheꢀ
sis of (ꢀ)ꢀparvifoline. We expect broad utility of this simple protoꢀ
col for the synthesis of many other natural products.
ASSOCIATED CONTENT
Experimental procedures, characterization data and spectra of new
compounds, and Xꢀray crystal structures of 2d, 2i, 2t, 1y, 1y', 2y,
2j'. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
shiz@nju.edu.cn
Notes
The formed bicyclo[m.n.1] products can be used as precursors
for the preparation of chiral mediumꢀsized cyclic compounds.
The authors declare no competing financial interest.
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Int. Ed. 2015, 54, 4899.
(9) For some recent examples, see: (a) Wu, X.; Chen, Z.; Bai, Y.ꢀB.;
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ACKNOWLEDGMENTS
Dong, V. M. J. Am. Chem. Soc. 2016, 138, 12013. (b) Clarke, C.; Incertiꢀ
Pradillos, C. A.; Lam, H. W. J. Am. Chem. Soc. 2016, 138, 8068. (c)
Burns, A. R.; Solana González, J.; Lam, H. W. Angew. Chem., Int. Ed.
2012, 51, 10827.
We thank the “1000ꢀYouth Talents Plan”, the “Jiangsu Speciallyꢀ
Appointed Professor Plan”, and NSF of China (Grant
2167020084, 21401099) for financial support.
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ACS Paragon Plus Environment

Journal of the American Chemical Society
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152x127mm (300 x 300 DPI)
ACS Paragon Plus Environment

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Journal of the American Chemical Society
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154x107mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
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163x447mm (300 x 300 DPI)
ACS Paragon Plus Environment

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Journal of the American Chemical Society
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155x161mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
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136x145mm (300 x 300 DPI)
ACS Paragon Plus Environment

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Journal of the American Chemical Society
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425x254mm (300 x 300 DPI)
ACS Paragon Plus Environment

Journal of the American Chemical Society
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146x66mm (300 x 300 DPI)
ACS Paragon Plus Environment