Asymmetric Retro-Claisen Reaction by Synergistic Chiral Primary Amine/Palladium Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b02491

We described herein a chiral primary amine/palladium catalyzed asymmetric retro-Claisen reaction of β-diketones with salicylic carbonates. A series of chiral α-alkylated ketones and macrolides were obtained with good yields and excellent enantioselectivities upon a sequence of decarboxylative benzylation, retro-Claisen cleavage, and enamine protonation. This strategy features broad substrate scope, mild conditions, as well as high atom economy with salicylic carbonates as the o-quinone methide precursors.

Full text of DOI:10.1021/acs.orglett.9b02491

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Retro-Claisen Reaction by Synergistic Chiral Primary
Amine/Palladium Catalysis
Yanfang Han,†,‡ Long Zhang,§ and Sanzhong Luo*,§
†Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190,
China
‡School of Chemical Science, University of Chinese Academy of Sciences, Beijing 100490, China
§Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100084, China
S
* Supporting Information
ABSTRACT: We described herein a chiral primary amine/palladium catalyzed asymmetric retro-Claisen reaction of β-
diketones with salicylic carbonates. A series of chiral α-alkylated ketones and macrolides were obtained with good yields and
excellent enantioselectivities upon a sequence of decarboxylative benzylation, retro-Claisen cleavage, and enamine protonation.
This strategy features broad substrate scope, mild conditions, as well as high atom economy with salicylic carbonates as the o-
quinone methide precursors.
Scheme 1. Catalytic Asymmetric Retro-Claisen Reaction
s fundamental C−C bond formation and cleavage
Astrategies, Claisen reaction and its retro process have
been widely applied in organic synthesis for the construction of
new scaffolds such as long-chain keto-acids, macrocycles, and
complex natural products and fine chemicals.1 The resulting β-
dicarbonyl moiety also serves as a versatile precursor in late-
stage synthesis.2 In recent years, great progress has been made
in the catalytic retro-Claisen reaction by the catalysis with
Lewis acid,3 Brønsted acid,4 or Brønsted base.5 However,
catalytic asymmetric versions remained largely under-devel-
oped. Duthaler first reported an asymmetric retro-Claisen
reaction of prochiral bicyclic β-diketones with moderate
stereoselectivity using a stoichiometric amount of chiral
bases as nucleophiles.6 Later on, Grogan disclosed the first
enzyme-catalyzed asymmetric retro-Claisen reaction for the
desymmetrization of cyclic β-diketones.7 In this strategy, 6-
oxocamphor hydrolase plays a crucial role to provide a chiral
environment, activate nucleophilic water molecule, and
stabilize the enolate oxyanion ion intermediate.8 Afterward, a
phase-transfer catalyzed retro-Claisen reaction of a specific
racemic β-diketone was described by Tokunaga, and only a
single substrate was examined in this study.9 These three
examples all involved enol-protonation as the key stereogenic
step, and the scopes were rather limited.
excellent yields and enantioselectivities. However, the reaction
relied on a heterogeneous acid−base buffer system involving a
stoichiometric amount of KF and large loading of acid
additives, which is critical for the in situ generation of ortho-
quinone methide via fluoride anion mediated desilylation, thus
diminishing its applicability (Scheme 1, I). In seeking a
homogeneous reaction setting, we now reported the use of the
salicylic carbonate (benzo-1,3-dioxan-2-one)11 for enamine-
based retro-Claisen reaction. Though substituted benoxazi-
Recently, our group developed an enamine strategy for
asymmetric retro-Claisen reaction of β-diketones by merging
chiral primary amine catalysis and Lewis base activation
(Scheme 1, I).10 This reaction proceeded via a tandem
stereoselective C−C coupling/C−C cleavage/enamine proto-
nation to provide chiral α-tertiary ketones and macrolides with
Received: July 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02491
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Letter
nones have been widely applied in transition metal-promoted
decarboxylative transformations,12,13 the unsubstituted one,
i.e., salicylic carbonates, have surprisingly not been explored in
similar reactions. We found that a palladium catalyst could
facilitate the decarboxylative generation of ortho-quinone
methide from this salicylic carbonate (Scheme 1, II). Hence,
the synergistic catalysis with our chiral primary amine and
palladium complex allowed for effective decarboxylative
benzylation/retro-Claisen cascade in an atom-economic and
highly enantioselective manner under neutral and homoge-
neous conditions.
prolonging the reaction time to 48 h under the optimized
conditions (entry 11).
Having optimized the reaction conditions, we first examined
the functional-group tolerance of the reaction with the β-
diketones. Most β-diketones reacted well to give the desired
retro-Claisen cleavage products in good yields and excellent
enantioselectivities (Table 2, 3aa−3da), in the case of phenyl
a
Table 2. Substrate Scope
We initiated our investigation with the model reaction
shown in Table 1. 3-Methyl-2,4-pentanedione 1a was treated
Table 1. Screening and Optimization
a
b
c
entry
variation from standard conditions
none
no aminocatalyst
no adipic acid
no PdCp(allyl)
no PCy3
no PdCp(allyl), no PCy3
yield (%)
ee (%)
96
1
2
3
4
5
6
7
8
9
73
n.p.
25
34
21
32
53
35
92
97
97
97
97
95
97
83
n.d.
95
2.5 mol % PdCp(allyl), 2.5 mol % PCy3
0.5 mL THF
0.5 mL MeCN
40 °C
10
11
trace
91
48 h
a
Standard reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), chiral
amine (20 mol %), adipic acid (20 mol %), PdCp(allyl) (2 mol %),
b
PCy3 (4 mol %), 0.5 mL THF/MeCN(6/1), Ar, 60 °C, 24 h. NMR
yield measured by using 1,3,5-tirmethoxybenzene as the internal
c
standard. Determined by HPLC analysis.
with the salicylic carbonate 2a in the presence of chiral primary
amine catalyst, Pd catalyst, and acid additive. To our delight,
the desired C−C bond cleavage product 3aa was obtained in
73% yield and 96% ee under the optimized conditions (Table
1, entry 1). No desired product was observed in the absence of
aminocatalyst, suggesting the enamine catalysis process (Table
1, entry 2). The use of acidic additive improved the yield
greatly, without affecting the enantioselectivity (Table 1, entry
3). Optimization of the palladium complex led to the
identification of PdCp(allyl) (2 mol %) with PCy3 (4 mol
%) as the optimal catalyst. Control experiments revealed that
the reaction in the absence of palladium complex was rather
sluggish (Table 1, entries 4−6). Decreasing the ligand/
palladium ratio from 2:1 to 1:1 also led to a reduction in
yield (Table 1, entry 7), an indication of the critical role of
palladium complex in promoting the reaction likely by
facilitating the decarboxylation step. The reaction conditions
were further optimized (Table 1, entries 8−12). A mixture of
THF/MeCN (6:1) as solvent was found to give the best
results in terms of both yield and enantioselectivity. Slightly
heating at 60 °C was required for complete conversion (entry
10 vs entry 1). When free salicylic alcohol or salicylic acid was
used, no reaction was observed (not shown). Finally, an
optimal 91% yield and 95% ee could be obtained when
a
All reactions were performed with 1 (0.1 mmol), 2 (0.2 mmol),
chiral amine (20 mol %), adipic acid (20 mol %), PdCp(allyl) (2 mol
%), and PCy3 (4 mol %) in 0.5 mL of THF/MeCN(6/1) at 60 °C
under Ar. Yield of isolated product. Determined by HPLC analysis.
b
c
d
72 h. 95 h. 15 h.
ketone, the enantioselectivity was moderate (Table 2, 3ea). It
is noted that the C−C bond cleavage occurred exclusively on
the more bulky keto side in these reactions, suggesting that the
chiral primary amine catalyst was able to differentiate two
different keto groups to form an enamine intermediate with the
smaller keto moiety. A variety of symmetrical diketones with
different α-alkyl or α-heteroatom substituents could also be
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tolerated to give the expected products in 71−99% yields with
91−97% ee (Table 2, 3fa−3ka). A symmetrical ethyl
substituted diketone also worked, albeit with low reactivity
and moderate enantioselectivity (Table 2, 3la).
II). The low catalyst loading only slightly reduced the yield,
without affecting the enantioselectivity. We also performed a
gram-scale experiment on the 7 mmol scale with β-diketone 1a
and the cyclic carbonate 2b under standard conditions. The
desired product was obtained in comparable 70% yield and
89% ee (Scheme 2, III).
In summary, we have developed a highly atom-economic
symmetric retro-Claisen reaction of β-diketones with salicylic
carbonates by chiral primary amine/palladium synergistic
catalysis. The salicylic carbonate has been proved to be an
effective alternative to generate ortho-quinone methide
precursor via Pd-catalyzed decarboxylation. This synergistic
strategy enables the construction of chiral α-tertiary ketones
and chiral macrolides with good yields and excellent
enantioselectivities.
Cyclic β-diketones were next examined. 2-Acetylcyclopenta-
none, dominantly in its enol form, was not a workable
substrate in this reaction (not shown). In contrast, 2-
acetylcyclohexanone worked well to give 68% yield and 87%
ee (Table 2, 3ma). 4-Substituted 2-acetylcyclohexanone was
also applicable to deliver the desired products in 60% yield and
76% ee (Table 2, 3na). In the case of 2-acetylcycloheptanone,
the reaction furnished two C−C bond cleavage adducts,
corresponding to the major ring-enlarged macrolide in 32%
yield with 99% ee and the minor deactylation product in low
activity and poor enantioselectivity, respectively (Table 2, 3pa
and 3p′a). When 2-acetylcyclooctanone was employed in the
reaction, a sole macrolide product was obtained in 71% yield
and 97% ee (Table 2, 3oa). A large 2-acetylcyclododecanone
was also examined and could be converted into the desired
macrolide product in moderate yield and excellent enantiose-
lectivity (Table 2, 3qa). It should be noted it remains a
challenging subject to prepare large ring chiral macrolides in
asymmetric synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02491.
1
Experimental procedures, characterization data, and H
NMR and 13C NMR spectra and HPLC traces (PDF)
We then explored the scope of salicylic carbonates. Salicylic
carbonates bearing either electron-donating or electron-
withdrawing groups on the arene moiety participated in the
reaction smoothly to furnish the desired products in 33−90%
yields with 94−97% ee (Table 2, 3ab−3af). The highly active
dichloro-substituted salicylic carbonate could also be incorpo-
rated to the expected product in 67% yield and 89% ee in less
than 15 h (Table 2, 3ag). When the β-ketoester substrate 1r
was employed to react with the carbonate 2a under standard
conditions, no desired retro-Claisen cleavage product was
detected. Not unexpectedly, the reaction provided a single α-
benzylation adduct 3ra in 72% yield and >99% ee after acyl
protection of the free phenol moiety (Scheme 2, I).14
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: luosz@tsinghua.edu.cn
ORCID
Sanzhong Luo: 0000-0001-8714-4047
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (Grants
21390400, 21521002, 21572232, and 21672217) and the
Chinese Academy of Science (Grant QYZDJ-SSW-SLH023)
for financial support. S.L. is supported by the National
Program of Topnotch Young Professionals.
To evaluate the practicality of the current reaction, we
performed a 1 mmol scale with β-diketone 1a and 2f in the
presence of only 10 mol % of primary amine catalyst and 1 mol
% of Pd catalyst. The desired product was obtained in 75%
yield and 97% ee with a prolonged reaction time (Scheme 2,
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Org. Lett. XXXX, XXX, XXX−XXX