Palladium-catalyzed asymmetric direct intermolecular allylation of α-aryl cyclic vinylogous esters: Divergent synthesis of (+)-oxomaritidine and (?)-mesembrine

Article abstract of DOI:10.1021/acs.orglett.0c04125

We demonstrate that α-aryl cyclic vinylogous esters are competent substrates in the direct intermolecular Pd-catalyzed asymmetric allylic alkylation, enabling a straightforward enantioselective synthesis of 6-allyl-6-aryl-3-ethoxycyclohex-2-en-1-ones, common motifs embedded in numerous structurally diverse natural products. As an initial demonstration of the utility of this protocol, the first catalytic enantioselective total synthesis of (+)-oxomaritidine and an improved five-step catalytic enantioselective synthesis of (?)-mesembrine have been completed divergently.

Full text of DOI:10.1021/acs.orglett.0c04125

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Letter
Palladium-Catalyzed Asymmetric Direct Intermolecular Allylation of
α‑Aryl Cyclic Vinylogous Esters: Divergent Synthesis of
(+)-Oxomaritidine and (−)-Mesembrine
Wei Wang,† Jun Dai,† Qiqiong Yang, Yu-Hua Deng,* Fangzhi Peng,* and Zhihui Shao*
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ABSTRACT: We demonstrate that α-aryl cyclic vinylogous esters are
competent substrates in the direct intermolecular Pd-catalyzed asymmetric
allylic alkylation, enabling a straightforward enantioselective synthesis of 6-allyl-
6-aryl-3-ethoxycyclohex-2-en-1-ones, common motifs embedded in numerous
structurally diverse natural products. As an initial demonstration of the utility of
this protocol, the first catalytic enantioselective total synthesis of (+)-oxomar-
itidine and an improved five-step catalytic enantioselective synthesis of
(−)-mesembrine have been completed divergently.
Pd-catalyzed asymmetric allylic alkylation (Pd-AAA)3 of α-
atalytic asymmetric construction of all-carbon quaternary
Cstereocenters is of great interest yet challenging in modern aryl-monosubstituted cyclic vinylogous esters would be a direct
and flexible method for the enantioselective construction of this
important structural class. However, unlike α-monosubstituted
cycloalkanones, α-monosubstituted cyclic vinylogous esters
have proved to be a class of very challenging substrates in the
direct intermolecular Pd-AAA.4 In 2006, Trost and co-workers
studied the direct intermolecular Pd-AAA of α-alkyl mono-
substituted cyclic vinylogous esters 2 with their previously
reported method of α-monosubstituted cyclohexenones3d by
alkylating the kinetically generated enolates of 2.5 However,
poor enantioselectivity (<30% ee) was obtained (Scheme 1a),
despite numerous optimization attempts, highlighting the
significant difference between cycloalkanones and cyclic vinyl-
ogous esters. Finally, they relied on a decarboxylative approach
that delivered 6,6-dialkyl-3-alkoxycyclohex-2-en-1-ones with
good enantioselectivity.5,6 Since then, there have been no
successful reports of the direct intermolecular Pd-AAA with α-
monosubstituted cyclic vinylogous esters.
chemical synthesis. In particular, catalytic enantioselective
approaches which are applicable to the total synthesis of natural
products containing chiral all-carbon quaternary stereocenters
remain more demanding.1 Enantioenriched 6-alkyl-6-aryl-3-
ethoxycyclohex-2-en-1-ones (1) represent a very attractive
structural motif integrated into numerous structurally diverse
natural products (Figure 1). Despite the importance of this
structural motif, a general and straightforward method for its
enantioselective synthesis has not yet been reported.2
Given the importance and versatility of enantioenriched 1 and
the lack of a general and direct method for its enantioselective
synthesis, and promoted by our recent work in the Pd-catalyzed
enantioselective allylation of vinylogous amides,7 we revisited
Received: December 14, 2020
Published: January 27, 2021
Figure 1. Chiral 6-alkyl-6-aryl-3-ethoxycyclohex-2-en-1-ones 1 and
selected natural products.
https://dx.doi.org/10.1021/acs.orglett.0c04125
© 2021 American Chemical Society
Org. Lett. 2021, 23, 920−924
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Scheme 1. Direct Intermolecular Pd-AAA of α-
Monosubstituted Cyclic Vinylogous Esters (LG = Leaving
Group)
Table 1. Selected Optimization Studies in the Pd-AAA of
a
Vinylogous Ester 4a
the longstanding unsolved direct intermolecular Pd-AAA of α-
monosubstituted cyclic vinylogous ester substrates. We
envisaged whether the difference between α-aryl- and α-alkyl-
substitutents of cyclic vinylogous esters could result in the
strikingly different facial discriminations, and if so, a direct
enantioselective synthesis of 1 would be achieved. Furthermore,
a Stork−Danheiser type transposition would convert 1 in one
step to enantioenriched γ-allyl-γ-aryl-substituted cyclohexe-
nones, a motif that also still poses a significant challenge in
organic synthesis.8 Herein, we report the realization of this
strategy, and preliminary studies on the utility of enantioen-
riched 1 in divergent catalytic enantioselective total synthesis of
(+)-oxomaritidine and (−)-mesembrine.9
To test our hypothesis, we initiated our study with Pd-AAA of
cyclic vinylogous ester 4a to form enantioenriched 5a (Table 1).
When the reaction was performed in the presence of Trost
ligand L1 and NaHMDS as the base in THF, the desired product
5a was obtained in 65% yield with 80.5:19.5 er (entry 1). To
improve the enantioselectivity, various solvents were examined
and no better results were obtained. Next, chiral ligands were
screened. Among them, Trost ligand L2 provided 91.5:8.5 er,
albeit in a moderate yield of 57% (entry 2). Subsequent base
screening indicated that the use of KHMDS can improve the
chemical yield to 76% with the retention of enantioselectivity
(entry 7). Decreasing the reaction temperature can further
improve the enantioselectivity, and we ultimately determined
that the designed reaction could afford 5a in 71% yield with 94:6
er in the presence of L2 as the chiral ligand and KHMDS as the
base at −20 °C (entry 13; for details, see the Supporting
Information).
a
Reaction conditions: 4a (0.2 mmol, 1.0 equiv), allyl acetate (2.0
equiv), [(η3-C3H5)PdCl]2 (2.5 mol %), L (5 mol %) in THF (2.0
mL) at −78 to 0 °C. Yield of isolated product 5a. Determined by
chiral HPLC analysis. −78 °C to −20 °C. −78 °C to −30 °C.
b
c
d
e
yields and enantioselectivity (Scheme 2). The C2-methyl
vinylogous ester 4g was also tolerated well in this reaction,
giving the desired product 5g in 67% yield with 95:5 er.
Moreover, the seven-membered vinylogous ester 4h was also a
suitable substrate for the direct intermolecular Pd-AAA,11 which
gave the corresponding allylated product 5h in 64% yield with
90.5:9.5 er. The direct intermolecular Pd-AAA reaction of 4a
was performed on a 1 mmol scale, giving 5a with comparative
results (67% yield, 93.5:6.5 er). We tentatively made the
following explanation about why this allylation having the aryl
group displayed high er whereas the alkylated substrate reacted
with low er: (1) the electronic property between the aryl group
and the alkyl group is different; (2) the π−π stacking interaction
With the optimized procedure in hand, we investigated the
substrate scope of the direct intermolecular Pd-AAA of α-aryl
cyclic vinylogous esters.10 Pleasingly, various vinylogous esters 4
bearing electron-neutral, electron-rich, and electron-deficient
aryl groups could be applied in the transformation to provide the
desired 6-allyl-6-aryl-3-ethoxycyclohex-2-en-1-ones in good
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Scheme 2. Pd-Catalyzed AAA of α-Aryl Cyclic Vinylogous
Esters
Scheme 3. Concise, Divergent, and Enantioselective Total
Syntheses of (+)-Oxomaritidine and (−)-Mesembrine
a
a
Reaction conditions: 4 (0.2 mmol, 1.0 equiv), allyl acetate (2.0
equiv), [(η3-C3H5)PdCl]2 (2.5 mol %), L2 (5 mol %) in THF (2.0
mL) at −78 °C to −20 °C. Yield of isolated product 5. Er determined
by chiral HPLC analysis. DME (1,2-dimethoxyethane) as the
b
c
solvent. DME as solvent, at −78 °C to −40 °C.
intermediate 7, a reductive amination/cyclization cascade
afforded (−)-mesembrine20,21 in one step. This catalytic
enantioselective total synthesis of mesembrine takes only five
steps from commercially available starting materials.
between the aryl group and the chiral ligand might also be
responsible for the high er in the allylation having the aryl group.
Having achieved the direct intermolecular Pd-AAA of α-aryl-
substituted cyclic vinylogous esters, we preliminarily explored its
utility in the enantioselective divergent natural product
synthesis. One crinine-type Amaryllidaceae alkaloid (+)-oxo-
maritidine12 and one Sceletium alkaloid (−)-mesembrine13 were
selected as our present synthetic targets. Crinine-type alkaloids,
a large subclass (over 80 members) of the Amaryllidaceae
alkaloid family, have attracted much attention from synthetic
chemists due to their interesting bioactivities and diverse
structures.14 However, catalytic enantioselective synthesis
remained rather limited,15 and the catalytic enantioselective
total synthesis of oxomaritidine, to the best of our knowledge, has yet
to be developed.16 One route for the enantioselective synthesis of
(+)-oxomaritidine was developed as in Scheme 3. (S)-5d,
obtained above, was treated with DIBAL-H to afford γ-allyl-γ-
aryl-substituted cyclohexenone 6 on aqueous acidic workup in
70% yield.17 Oxidative cleavage of the allyl group afforded the
aldehyde 7. 7 underwent intermolecular reductive amination to
afford the cis-aryl hydroindole 9 on N-Boc-protection. 9 was
transformed into the corresponding enone 10 via Saegusa
oxidation.18 The removal of the N-Boc group of 10 with
trifluoroacetic acid followed by the Pictet−Spengler-type
cyclization delivered (+)-oxomaritidine in 83% overall yield.
Since oxomaritidine has been previously transformed into
maritidine,19 this also constitutes an enantioselective formal
synthesis of (+)-maritidine. Divergently, from the common
In conclusion, a direct enantioselective synthesis of 6-allyl-6-
aryl-3-ethooxycyclohex-2-en-1-ones, an important structural
motif common in natural products chemistry, has been achieved
through the development of the first direct intermolecular Pd-
AAA of α-aryl-substituted cyclic vinylogous ester substrate class.
Unlike α-alkyl-substituted cyclic vinylogous esters, α-aryl-
substituted cyclic vinylogous esters underwent the direct
intermolecular Pd-AAA with good enantioselectivity. Based on
the preliminary exploration of this method, the first catalytic
enantioselective total synthesis of Amaryllidaceae alkaloid
(+)-oxomaritidine and a short, five-step catalytic enantioselec-
tive total synthesis of Sceletium alkaloid (−)-mesembrine were
achieved divergently. The synthetic utility conferred by the α-
aryl cyclic vinylogous ester substrate class is expected to find
further applications in the enantioselective synthesis of other
structurally diverse alkaloid natural products.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04125.
Experimental procedures, analytical data, copies of NMR
spectra for all new compounds and HPLC spectra for all
chiral compounds (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
Yu-Hua Deng − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education, Yunnan Provincial
Center for Research & Development of Natural Products, and
School of Chemical Science and Technology, Yunnan
University, Kunming 650091, China; orcid.org/0000-
0002-1983-8490; Email: dengyuhua@ynu.edu.cn
Fangzhi Peng − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education, Yunnan Provincial
Center for Research & Development of Natural Products, and
School of Chemical Science and Technology, Yunnan
University, Kunming 650091, China; Email: pengfangzhi@
ynu.edu.cn
Zhihui Shao − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education, Yunnan Provincial
Center for Research & Development of Natural Products, and
School of Chemical Science and Technology, Yunnan
University, Kunming 650091, China; orcid.org/0000-
0003-4531-3417; Email: zhihui_shao@hotmail.com
Authors
Wei Wang − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education, Yunnan Provincial
Center for Research & Development of Natural Products, and
School of Chemical Science and Technology, Yunnan
University, Kunming 650091, China
Jun Dai − Key Laboratory of Medicinal Chemistry for Natural
Resource, Ministry of Education, Yunnan Provincial Center for
Research & Development of Natural Products, and School of
Chemical Science and Technology, Yunnan University,
Kunming 650091, China
Qiqiong Yang − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education, Yunnan Provincial
Center for Research & Development of Natural Products, and
School of Chemical Science and Technology, Yunnan
University, Kunming 650091, China
(2) For selected racemic syntheses, see: (a) Zhao, Y.; Zhou, Y.; Liang,
L.; Yang, X.; Du, F.; Li, L.; Zhang, H. Palladium-Catalyzed Sequential
Arylation and Allylic Alkylation of Highly Functionalized Ketones: A
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04125
Author Contributions
†W.W. and J.D. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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Vranken, D. L. Asymmetric Transition Metal-Catalyzed Allylic
Alkylations. Chem. Rev. 1996, 96, 395. (b) Trost, B. M.; Crawley, M.
L. Asymmetric Transition-Metal-Catalyzed Allylic Alkylations: Appli-
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ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21672184, 21861042, 21801221), the
Program for Changjiang Scholars and Innovative Research
Team in University (IRT17R94), the Program for Innovative
Research Team (in Science and Technology) in University of
Yunnan Province, Yunling Scholar of Yunnan Province, and
Yunnan Province Government [2018FY001(016), YNQR-
QNRC-2018-005, 2019FD126]. Dedicated to Prof. Albert S.
C. Chan on his 70th birthday.
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Org. Lett. 2021, 23, 920−924