3-(Methoxycarbonyl)Cyclobutenone as a Reactive Dienophile in Enantioselective Diels–Alder Reactions Catalyzed by Chiral Oxazaborolidinium Ions

Article abstract of DOI:10.1002/anie.202014308

Cyclobutenone has been used as a highly reactive dienophile in Diels–Alder reactions, however, no enantioselective example has been reported. We disclose herein a chiral oxazaborolidine-aluminum bromide catalyzed enantioselective Diels–Alder reaction of 3-alkoxycarbonyl cyclobutenone with a variety of dienes. Furthermore, a total synthesis of (?)-kingianin F was completed for the first time via enantioenriched cycloadduct bicyclo[4.2.0]octane derivative.

Full text of DOI:10.1002/anie.202014308

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Accepted Article
Title: 3-(Methoxycarbonyl)cyclobutenone as a Reactive Dienophile
in Enantioselective Diels-Alder Reactions Catalyzed by Chiral
Oxazaborolidinium Ions
Authors: Peng Yan, Changxu Zhong, Jie Zhang, Yu Liu, Huayi Fang,
and Ping Lu
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3-(Methoxycarbonyl)cyclobutenone as a Reactive Dienophile in
Enantioselective Diels−Alder Reactions Catalyzed by Chiral
Oxazaborolidinium Ions
Peng Yan, Changxu Zhong, Jie Zhang, Yu Liu, Huayi Fang, and Ping Lu*
Abstract: Cyclobutenone has been used as a highly reactive
dienophile in Diels-Alder reactions, however, no enantioselective
example has been reported. We disclose herein
a chiral
oxazaborolidine-aluminum bromide catalyzed enantioselective
Diels−Alder reaction of 3-alkoxycarbonyl cyclobutenone with a variety
of dienes. Furthermore, a total synthesis of (−)-kingianin F was
completed for the first time via enantioenriched cycloadduct
bicyclo[4.2.0]octane derivative.
Cyclobutenones have shown unique reactivity due to their
inherent ring strain, thus they have been recognized as important
building blocks in organic synthesis for decades.[1] Strain−release
driven ring opening of cyclobutenones enable rapid assembly of
Figure 1. Selected natural products with a bicyclo[4.2.0]octane scaffold.
intermolecular Diels−Alder reaction of cyclobutenone has not
been explored yet.
complex
molecules.[2]
However,
functionalization
of
cyclobutenones to access enantiomerically pure four−membered
ring moiety is less studied.[3]
Diels−Alder reaction has proved to be
a fundamental
transformation to generate complex molecules efficiently both in
academic and industry areas.[8] In 2010, Danishefsky disclosed
that Diels−Alder reaction of the parent cyclobutenone 1 and an
array of dienes gave diverse bicyclo[4.2.0]octene derivatives in
good yields under mild conditions (Scheme 1a).[9] Later, the
preparation of a more reactive dienophile 2-bromocyclobutenone
was further explored.[10,11] Of note, cyclobutenone 1 and 2-
bromocyclobutenone had to be stored in solution to inhibit
Bicyclo[4.2.0]octane motifs exist in many natural products,
some representative examples are depicted in Figure 1. About 80
protoilludanes and related sesquiterpenes have been isolated
and these molecules feature
framework.[4] SNF4435
and D, featuring
bicyclo[4.2.0]octadiene motif, possess immunosuppressive and
anticancer Kingianins A-N, family of
activity.[5]
a
common tricyclic 5/6/4-
C
a
core
a
bicyclo[4.2.0]octadiene dimers, showed significant binding affinity
for the protein Bcl-xL.[6]
polymerization. We envisioned that
a
highly reactive
cyclobutenone with better stability would provide a practical
approach to access enantioenriched bicyclo[4.2.0]octane
derivatives. Herein we report our work on unique reactivity of 3-
Several
strategies
to
synthesize
enantioenriched
bicyclo[4.2.0]octane moiety have been developed,[7] however, the
methoxycarbonylcyclobutenone
2
as
dienophile
in
enantioselective Diels−Alder reaction under the catalysis of chiral
[*]
P. Yan, C. Zhong, Prof. Dr. P. Lu
oxazaborolidinium ion[12,13] (Scheme 1b).
Department of Research Center for Molecular Recognition and
Synthesis, Department of Chemistry, Fudan University
220 Handan Lu, Shanghai 200433, P. R. China
E-mail: plu@fudan.edu.cn
Homepage: http://rcmrs.fudan.edu.cn/Data/View/173
J. Zhang, Prof. Dr. Y. Liu
College of Chemistry and Life, Advanced Institute of Materials
Science, Changchun University of Technology, Changchun 130012,
P. R. China
Prof. Dr. H. Fang
School of Materials Science and Engineering, Tianjin Key Lab for
Rare Earth Materials and Applications, Nankai University, Tianjin,
300350, P. R. China
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. The Diels−Alder reaction of cyclobutenone.
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The cyclobutenone 2 was easily prepared from commercially
available 3-oxocyclobutane-1-carboxylic acid on a multigram
scale (Scheme 2). In contrast to parent cyclobutenone 1, the
product 2 was purified by column chromatography and could be
stored in a neat state for months in a freezer without any
decomposition.
presence of cat-1. The exo products 6c and 6d were obtained
when furan and benzofuran were employed. The absolute
configuration of adduct 6c was determined by X-ray
crystallographic analysis,[19] and the stereochemical outcome of
the reaction could be preliminarily explained by the depicted
model for complex cat-1-cyclobutenone 3 in Figure 2. Low
catalyst loading (5 mol%) was sufficient in the 2 mmol-scale
reaction of 2,3-dimethyl-1,3-butadiene, and the corresponding
product 6e was achieved in 90% yield and 92% ee. The
cycloaddition reaction of 1,3-butadiene (in CH2Cl2 or hexane)
provided product 6f in 98% yield and 93% ee in the presence of
10 mol% cat-3. In addition, exocyclic conjugate dienes were
applicable to the reaction of cyclobutenone 2, giving the
corresponding adducts 6g-6l in 74-97% yield and 90-95% ee.
Oxidation of 6h with DDQ led to tetrahydronaphthalene 6h’ (see
SI), which could be viewed as the cycloadduct from o-
quinodimethane and cyclobutenone 2. Heterocyclic dienes were
also tolerated under above conditions, and the products 6m-6o
were furnished in 80-92% yield and 92-96% ee.
Scheme 2. The preparation of cyclobutenone 2.
We commenced our studies with the reaction of dienophile 2
and Dane’s diene 3 (Table 1). Treatment of 2 and 3 in CH2Cl2 at
room temperature afforded the adduct 4 smoothly in 79% yield
with a 2:1 diastereoselectivity. Several chiral Lewis acid and
Brnsted acid catalytic systems were then examined, including
chiral phosphoric acid,[14] Feng’s N,N-dioxide-metal complex[15]
and chiral titanium complex,[16] only low conversion was obtained
in these cases. Gladly, when Corey’s chiral oxazaborolidinium ion
(COBI) catalytic system was employed,[17,18] the reaction gave the
desired adduct 4 in good yield and high diastereoselectivity. After
optimization, we found cat-2 furnished adduct 4 in 93% ee and
Table 2. Substrate scope of symmetric 1,3-dienea
10:1 dr.[19]
Table 1. Optimization of enantioselective Diels−Alder reactiona
a2 (0.2 mmol), 3 (0.3 mmol), LA (20 mol%), CH2Cl2, −78 oC. The ee values were
determined by HPLC analysis on a chiral stationary phase. All results are
corrected to (S)-catalyst. See Supporting Information (SI) for more details. Tf =
trifluoromethanesulfonyl; 2-Nap = 2-naphthyl.
a2 (0.2 mmol), 5 (0.3-2 mmol), cat (20 mol%), CH2Cl2. All results are corrected
to (S)-catalyst. The ee values were determined by HPLC analysis. bcat-1 was
used. c 5 mol% cat-1 was used. dcat-3 was used. e10 mol% cat-3 was used. Ts
= p-toluenesulfonyl.
We next examined the Diels-Alder reaction of cyclobutenone 2
with an array of symmetric 1,3-diene 5 under the catalysis of COBI
(Table 2). The reaction of 1,3-cyclopentadiene and 1,3-
cyclohexadiene with cyclobutenone 2 afforded the corresponding
endo adducts 6a and 6b in high yield and enantioselectivity in the
An array of 2-substituted 1,3-dienes 7 was also explored (Table
3). The reaction of 2-bromofuran and cyclobutenone 3 provided
the exo product 8a in 84% yield and 98% ee in the presence of
cat-1. The absolute configuration of 8a was determined by X-ray
crystallographic analysis.[19] The reaction of 2-benzyloxycarbonyl
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cyclobutenone 2’ with isoprene or myrcene gave the
corresponding adducts 8b and 8c in good regioselectivity and
importance of -CH-O interaction between cyclobutenone and
COBI catalyst (Figure 2). We assumed that the steric hindrance
posed by 3-substitution group would inhibit decomposition or
polymerization of cyclobutenone under strong Lewis acid.[21] In
addition, the electron deficient methoxycarbonyl group in 2 would
enhance the reactivity of C=C double bond, leading to the
successful COBI-catalyzed cycloaddition.
Figure 2. Proposed model for the reactive complex of cat-1 and cyclobutenone
2.
Table 3. Substrate Scope of Unsymmetric 1,3-Dienea
Scheme 3. Comparison of Reactivity and Natural Charge Analysis of
Cycobutanones.
a2 (0.2 mmol), 7 (0.3-2 mmol), cat (20 mol%), CH2Cl2. See SI for details. All
results are corrected to (S)-catalyst. The ee values were determined by HPLC
analysis. bcat-1 was used. ccat-3 was used. dcat-4 was used. ecat-2 was used.
f−90 oC. TBS = t-butyldimethylsilyl; TBDPS = t-butyldiphenylsilyl.
Scheme 4. Further transformations of cycloadducts 6e and ent-6f. MSH = O-
(mesitylsulfonyl)hydroxylamine; NHPI = N-hydroxyphthalimide; PTSA = p-
toluenesulfonamide; Ms = methanesulfonyl.
enantioselectivity. 2-Alkyl and aryl substituted 1,3-butadienes 7d-
7f afforded the corresponding products 8d-8f in good yield and
selectivity. In addition, cycloadduct 8g could be obtained in 70%
yield and 90% ee in the presence of cat-2 at −90 oC. Besides, the
exo adduct 8h, bearing a tricyclic 5/6/4-framework, could be
furnished in 80% yield and 82% ee. The structure of 8h was
determined by X-ray crystallographic analysis of its desilylation
derivative (8h’, see SI).[19]
We next turned to compare the different reactivity of
cyclobutenones (Scheme 3). Surprisingly, the reaction of
cyclobutenones 1 and 9 gave no conversion under standard
conditions at −78 oC, while these two cyclobutenones led to
decomposition after elevating reaction temperature. Gladly, the
[4+2]-reaction of cyclobutenone 10 and furan provided desired
adduct 11 in 75% yield and 99% ee. Of note, the gem-
dimethylcyclobutane moiety was found in a variety of classes of
natural products.[20] Cyclobutanone 12, with methyl group at the
2-position, afforded adduct 13 in 37% ee, indicating the
As shown by Danishefsky, bicyclo [4.2.0]octane motifs could be
transformed to ring expansion products, viewed as otherwise
directly inaccessible Diels-Alder products.[9] Thus adduct 6e,
bearing a quaternary methoxycarbonyl group, was examined
under ring expansion conditions (Scheme 4a). Lactone 14 and
lactam 15 were obtained in good yield and regioselectivity
uneventfully. Cyclopentanone 16 could also be achieved via a
two-step sequence (Me3S•BF4; LiI).[22] In addition, photo induced
decarboxylation of 6e afforded product 17 in 46% yield over three
steps.[23] Furthermore, the methoxycarbonyl group of ent-6f could
be transformed to methyl group smoothly (Scheme 4b).
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completed in a further three-step sequence as reported by
Sherburn.[24a]
In conclusion, we reported here a chiral oxazaborolidinium ion
catalyzed highly enantioselective and regioselective Diels-Alder
reaction of 3-alkoxycarbonyl cyclobutenone with a series of
dienes. 3-Alkoxycarbonyl group played a critical role in reactivity
and stability of dienophile cyclobutenone. Enantioenriched
cycloadduct bicyclo[4.2.0]octene derivatives could be used as
versatile intermediates in the total synthesis of related natural
products, leading to the first completion of (−)-kingianin F.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (22071028, 21772024, 21921003), the
1000-Youth Talents Program.
Conflict of interest
The authors declare no conflict of interest.
Keywords: cyclobutenone • chiral oxazaborolidinium ion • Diels-
Alder reaction • strain-released driven• bicyclo[4.2.0]octane
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Scheme 5. Synthesis of (−)-kingianin F. HMPA = hexamethylphosphoramide;
DCC = N,N’-dicyclohexylcarbodiimide; DAMP = 4-(dimethylamino)pyridine;
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; NMO = N-methylmorpholine N-
oxide;
hydroxybenzotriazole; EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride; Hantzsch ester diethyl 1,4-dihydro-2,6-dimethyl-3,5-
TPAP
=
tetrapropylammonium
perruthenate;
HOBT
=
=
pyridinedicarboxylate; (S)-DTBM-Segphos = (S)-(+)-5,5’-bis[di(3,5-di-tert-butyl-
4-methoxyphenyl)phosphino]-4,4’-bi-1,3-benzodioxole.
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10.1002/anie.202014308
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Peng Yan, Changxu Zhong, Jie Zhang,
Yu Liu, Huayi Fang, and Ping Lu*
Page No. – Page No.
3-Alkoxycarbonyl Cyclobutenone as a
Reactive Dienophile in Chiral
Oxazaborolidinium Ion Catalyzed
Enantioselective Diels−Alder
Reaction
The first enantioselective Diels-Alder reaction of cyclobutenone has been
developed, and 3-methoxycarbonyl group shows remarkable effect on stability and
reactivity. Based on enantioenriched adduct, the total synthesis of (−)-kingianin F
was completed.
This article is protected by copyright. All rights reserved.