Efficient Synthesis of (?)-Corynoline by Enantioselective Palladium-Catalyzed α-Arylation with Sterically Hindered Substrates

Article abstract of DOI:10.1002/anie.201807302

Sterically hindered substrates can be employed in an enantioselective palladium-catalyzed α-arylation with the chiral monophosphorus ligand BI-DIME. This process enabled an efficient synthesis of the antidepressant (S)-nafenodone, a four-step enantioselective synthesis of the Sceletium alkaloid (+)-sceletium A-4, a concise five-step enantioselective synthesis of (?)-corynoline, as well as a three-step preparation of (?)-DeN-corynoline.

Full text of DOI:10.1002/anie.201807302

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Accepted Article
Title: Efficient Synthesis of (-)-Corynoline by Sterically Hindered
Enantioselective Palladium-Catalyzed α-Arylation
Authors: Wenjun Tang, Xiaofeng Rao, Naikai Li, Heng Bai, and Zheng
Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807302
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10.1002/anie.201807302
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Enantioselective Synthesis
Efficient Synthesis of (-)-Corynoline by Sterically Hindered
Enantioselective Palladium-Catalyzed α-Arylation
Xiaofeng Rao,§ Naikai Li,§ Heng Bai,§ Zheng Wang, and Wenjun Tang*
asymmetric synthesis of (S)-nafenodone (1), (+)-sceletium A-4 (2),
(-)-corynoline (4) and (-)-DeN-corynoline (5), by using an efficient
enantioselective α-arylation strategy.
Abstract: Sterically hindered enantioselective palladium-catalyzed
α-arylation powered by chiral monophosphorus ligand BI-DIME
has enabled the efficient synthesis of antidepressant (S)-nafenodone,
a 4-step enantioselective synthesis of sceletium alkaloid (+)-
sceletium A-4, a concise 5-step enantioselective synthesis of (-)-
corynoline as well as a 3-step preparation of (-)-DeN-corynoline.
Sterically hindered asymmetic cross-couplings[9] are among most
challenging and often required the development of novel metal
catalysts or ligands. For sterically hindered Suzuki-Miyaura cross-
coupling, we designed a bulky phosphorus ligand BI-DIME which
can tolerate a great deal of steric hindrance in cross-coupling.[10]
Consequently, the chiral BI-DIME type ligands have allowed the
enantioselective sterically hindered Suzuki-Miyaura cross-coupling
to occur under very mild conditions.[11] The enantioselective
palladium-catalyzed α-arylation[12] has provided one of the most
attractive methods for constructing chiral compounds bearing
benzylic all-carbon quaternary carbon centers. Despite its synthetic
relevance, limitation remains. Most known catalytic systems worked
well only for non-hindered aryl halides and few efficient examples
were reported for aryl halides containing ortho-substituents. For
example, high enantioselectivities were observed by Buchwald and
coworkers[12m] for a range of non-hindered aryl halides in palladium-
catalyzed arylation of ketone enolates by employing either BINAP
or a chiral dialkylphosphino-binaphthyl ligand. However, poor ees
and yields were obtained when 2-bromotoluene was used as the
reagent. Recently, an efficient enantioselective coupling between α-
fluoroketones and (hetero)aryl bromides was described by Zhou and
Hartwig,[12g] forming a series of α-aryl-α-fluoroketones in high
yields and excellent ee’s, with an exception of a moderate yield
(58%) and ee (67%) when 2-bromotoluene was employed. Partly
because of the poor tolerance of steric hindrance, few palladium-
catalyzed α-arylations have been successfully applied in total
synthesis of natural products.[13] Given the fact that BI-DIME was
efficient for various sterically hindered cross-coupling reactions, we
envisaged that its related ligands could be applicable to sterically
hindered α-arylation and its asymmetric version could be a powerful
method for the synthesis of chiral cyclic natural products and
therapeutic agents containing benzylic all-carbon quaternary centers.
We herein detailed our results.
Search for asymmetric catalytic methods for efficient construction
of all-carbon quaternary centers continues to be one of major
interests in organic synthesis. In particular, asymmetric catalytic
methods applicable to the synthesis of chiral natural products and
therapeutic agents containing all-carbon quaternary centers remain
in
high
demand.[1,2]
Chiral
2-alkyl-2-aryl-1,2,3,4-
tetrahydronaphthalene or quinoline structure exists in many
biologically important natural products and drugs such as
antidepressant (S)-nafenodone (1),[3] Sceletium alkaloids (+)-
sceletium A-4 (2)[4] and (+)-tortuosamine (3),[5] as well as
acetylcholinesterase inhibitors (+)-corynoline (ent-4),[6] (+)-DeN-
corynoline (ent-5),[7] and corynoloxine (6).[8] Although there have
been a great deal of synthetic efforts, efficient asymmetric syntheses
in particular via asymmetric catalytic methods are still lacking. For
example, Cushman completed an 8-step synthesis of (+)-corynoline
from piperonal taking advantage of a chiral auxiliary.[6d] Lautens
reported a formal synthesis of (+)-corynoline using an elegant
asymmetric carboiodination strategy. However, a lengthy 9-step
synthetic sequence was required after the key asymmetric
transformation to complete the synthesis.[6e] We herein report the
Figure 1. Cyclic natural products and therapeutic agents containing
chiral all-carbon quaternary centers
[]
Prof. Dr. W. Tang, Dr. X. Rao, Dr. N. Li, H. Bai, State Key
Laboratory of Bio-Organic and Natural Products Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese Academy
of Sciences, 345 Ling Ling Rd, Shanghai 200032, E-mail:
tangwenjun@sioc.ac.cn
Dr. Z. Wang, Informatics and Technology, Astra Zeneca China,
Shanghai
[§] X. Rao, N. Li and H. Bai contributed equally to this work.
[]
This work is dedicated to Professor Xiyan Lu on occasion of
his 90th birthday. We are grateful to the Strategic Priority
Research Program of the Chinese Academy of Sciences
XDB20000000,
CAS
(QYZDY-SSW-SLH029),
NSFC
(21725205, 21432007, 21572246), STCSM-18520712200, and
K.C. Wong Education Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Figure 2. Sterically hindered enantioselective α-arylation enabled by
chiral BI-DIME
1
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10.1002/anie.201807302
Angewandte Chemie International Edition
We looked into the reactions of 2-methyl-1-indanone (7a) with 2-
bromotoluene (8a) by employing a chiral metal catalyst. The
reactions were performed in toluene at 80 C for 24 h at 2.0 mol%
this transformation (entry 20). To demonstrate the practicality of this
transformation, 7a was subjected for α-arylation at 2 mol%
palladium loading on a gram scale and the resulting product 9a (1.41
g, 95% ee) was obtained in 87% isolated yield.
o
metal loading in the presence of a chiral phosphorus ligand (4.0
mol%). A series of chiral bis- or mono-phosphorus ligands were
employed. As shown in Table 1, the ligand structure significantly
impacts its reactivity and enantioselectivity. The arylation was
sluggish with Ni(COD)2 or Pd(OAc)2 as the catalyst precursor and
(S)-BINAP as the ligand (entries 1 and 2). To our delight, the
reactions proceeded smoothly when chiral monophosphorus ligands
L1~5 developed in our laboratory were employed. Excitingly,
excellent isolated yield and ee of 9a (93% yield, 95% ee) were
achieved when L1 was employed (entry 3). The enantioselectivities
decreased when L2 or L3 (entries 4 and 5) containing a methyl or
benzyl substituent at the 2-position of the oxophosphole ring was
applied. Ligand L4 bearing two phenoxy substituents on the low
aryl ring also provided a low ee (64%, entry 6). AntPhos (L5),
which was highly effective in dearomative cross-coupling
reaction,[2g-i] also gave only a moderate ee (entry 7). Among various
palladium precursors screened, Pd(OAc)2 was the best in terms of
yield (entries 3, 8-10). Further screening of solvent and base
demonstrated that toluene and NaOtBu were the good combination
for a high yield and good enantioselectivity (Table 1, entries 11-20).
The results showed that base exerted a significant effect on yield.
Excellent enantioselectivity was also obtained when KOtBu, LiOtBu
or Cs2CO3 was employed as the base, albeit with a decreased yield
(Table 1, entries 16~18). An organic base Et3N was ineffective for
Table 2. Scope of the sterically hindered α-arylation[a]
Table 1. Sterically hindered asymmetric α-arylation of 2-methyl-1-
indanone (7a)[a]
Base
Yield
(%)[b]
Ee
Entry
Metal precursor
Ligand
Solvent
(%)[c]
(S)-
BINAP
(S)-
1
2
Ni(COD)2
Pd(OAc)2
Toluene
Toluene
NaOtBu
NaOtBu
trace
10
--
-15
BINAP
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
L1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
THF
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
93
73
95
54
53
64
70
92
92
94
91
92
89
--
4
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
5
90
6
79
7
87
8
24
9
Pd2(dba)3
Pd[(cinnamyl]Cl]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
59
10
11
12
13
14
15
16
17
18
19
20
21[d]
91
[a] Unless otherwise specified, all reactions were performed at 80 C
for 24 h in toluene (1.0 mL) with 7 (0.2 mmol), 8 (0.4 mmol), Pd(OAc)2
(2.0 mol%), (R)-BI-DIME (4.0 mol%) and NaOtBu (0.4 mmol). The
absolute configuration of 9f was determined by X-ray crystallography,
the rests were assigned by analogy. Isolated yields and ee values
were determined by chiral HPLC.
36
79
DCE
45
DMF
trace
90
C6F6
90
90
93
95
--
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
45
We then looked into the substrate scope of sterically hindered α-
arylation. As shown in Table 2, various substituted 2-bromotoluenes
were applicable for the transformation. High yields and ee values
were achieved regardless of the substitution patterns and the
electronic properties of the aryl ring (9b~9f). Next, aryl bromides
with different ortho-alkyl substituents were studied. Besides ortho-
methyl group, ortho-ethyl, isopropyl, and benzyl substituents were
all compatible, providing excellent enantioselectivities (> 95% ee)
and good yields (9g~i). Aryl bromides 8j and 8k bearing an ortho-
vinyl and ortho-fluoro substituents were also good substrates to
form products 9j and 9k in excellent ee’s and slightly decreased
yields. Indanones with various substituents and electronic properties
LiOtBu
60
Cs2CO3
NaOMe
Et3N
76
N.R.
trace
87
--
NaOtBu
95
o
[a] Unless otherwise specified, all reactions were performed at 80 C
for 24 h in the selected solvent (1.0 mL) with 7a (0.2 mmol), 8a (0.4
mmol), metal precursor (2.0 mol%), ligand (4.0 mol%), and base (0.4
mmol). The absolute configuration of 9a was determined by analogy
according to the X-ray structure of 9f.[14] [b] Isolated yields. [c]
Determined by Chiral HPLC on chiracel AD-H column. [d] 7a (1.0 g).
2
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10.1002/anie.201807302
Angewandte Chemie International Edition
were also applicable. High yields and ee values were all observed on
substrates bearing methyl, methoxy and fluoro substituents on the
aryl rings (9l~o). Substrate 8p with an ethyl substituent at α position
was also suitable to form 9p in 87% yield and 92% ee. Benzyl,
substituted benzyl, 9-anthrylmethyl and 2-naphthylmethyl were all
tolerable at α position, providing products 9q-t in excellent ee’s. 1-
Bromonaphthalene was also applicable to the α-arylation (9u and
9v). To our delight, heteroaryl bromides were also suitable. 3-
Bromobenzo[b]thiophene was applied for α-arylation to form 9w in
81% ee. Reaction of α-methylindanone with substituted 3-
bromopyridine led to the resulting arylation products in good yields
and excellent ee’s (83% ee (9x) and 90% ee (9y), respectively).
Tetralone substrates were also applicable, providing products 9z and
9aa in excellent ee’s and yields.
bromide 15 in the presence of a Pd-(S)-BI-DIME catalyst provided
compound 16 in 70% yield and 92% ee. Next, the formation of a
piperidine ring was pursued. Radical dibromination at two benzylic
position with AIBN/NBS as reaction conditions formed dibromide
17, which was followed by treatment with methylamine provided
tertiary amine 18[14] in 37% yield over two steps. A subsequent
Büchner–Curtius–Schlotterbeck reaction[17] under conditions of
TMSCHN2/nBuLi converted successfully the sterically hindered
indanone 18 into (-)-corynolon 19 in 56% yield. LAH reduction
furnished the enantioselective synthesis of (-)-corynoline (4),[18]
whose spectra was in full agreement with commercially available
product and reported data. Thus, we have accomplished a 5-step
enantioselective synthesis of (-)-corynoline from known indanone
14, arguably the most efficient synthesis to date.
The absolute configuration of 9f was determined by its X-ray
structure,[14] in which the benzylic all-carbon quaternary center was
assigned as S configuration with (R)-BI-DIME as the ligand.
Arylation of 7a with a scalemic composition of L1 showed a good
linear relationship of ee’s between the ligand and product 9a,
indicating the reaction was catalyzed by a palladium catalyst with a
single BI-DIME ligand. To demonstrate the synthetic utility of this
methodology, the synthesis of a series of chiral natural products and
drugs were pursued. Thus, tetralone 10 reacted with PhBr with Pd-
(S)-BI-DIME as the catalyst to form 11 in 80% ee and 75% yield.
Ozonolysis followed by reductive amination by treatment with
HNMe2/Na(OAc)3BH formed antidepressant 1[3] in 70% yield.
Sceletium alkaloid (+)-sceletium A-4 (2) have received a number of
synthetic efforts.[4,5] However, most current synthetic routes were
lengthy and inefficient (>8 steps). We envisioned that the α-
arylation could be well suitable for an enantioselective synthesis of
2. Thus, quinolone 12 was prepared from 7,8-dihydroquinolin-
5(6H)-one in one step by allylation. α-Arylation of 12 with 3,4-
(MeO)2PhBr under catalysis of a Pd-(S)-BI-DIME catalyst led to the
coupling product 13 in 79% ee. Interstingly, the Pd-(S)-AntPhos
catalyt provided even better results in this case, forming 13 in 85%
ee and 70% yield. It should be noted that the arylation was well
compatible with the heterocyclic substrate, further demonstrating the
generality and practicality of the method. Ozonolysis followed by
reductive amination with H2NMe/Na(OAc)3BH as the reaction
conditions complete the asymmetric synthesis of (+)-sceletium A-4
(2) in only 4 steps and 37% overall yield from 7,8-dihydroquinolin-
5(6H)-one, which was significantly more efficient than reported
methods.[4,5] Further hydrogenolysis with Pd/C as the catalyst
according to a reported procedure[15] would also yield (+)-
tortuosamine (3).
Scheme 2. Enantioselective Synthesis of (-)-corynoline (4) and (-)-
DeN-corynoline (5)
DeN-corynoline[7] is
a
potent anti-inflammatory and/or
immunosuppressive agent, more active than corynoline in inhibition
for the adhesion of human polymorphonuclear leukocyte and
eosinophil to human umbilical vein cultured endothelial cells. The
reported synthesis of DeN-corynoline required 4 steps from
corynoline by degradation. Using the asymmetric α-arylation
technology, we successfully synthesized (-)-DeN-corynoline (5)
from indanone 14 in 40% overall yield through only three steps. It
was accomplished through an arylation to form 16, followed by a
Büchner–Curtius–Schlotterbeck reaction to yield 20, and a final
LAH reduction. This protocol can lead to a series of DeN-
corynoline analogs and should facilitate the discovery of new anti-
inflammatory or immunosuppressive agent.
In conclusion, an efficient sterically hindered palladium-catalyzed
α-arylation powered by chiral monophosphorus ligand BI-DIME is
developed for construction of chiral all-carbon quaternary centers.
This protocol is practical and efficient, featuring excellent
enantioselectivities and great functional group compatibility. The
method has enabled the efficient synthesis of a series of chiral
natural products and drugs bearing chiral all-carbon quaternary
centers including antidepressant (S)-nafenodone, an efficient 4-step
enantioselective synthesis of sceletium alkaloid (+)-sceletium A-4, a
concise 5-step enantioselective synthesis of (-)-corynoline as well as
a 3-step preparation of (-)-DeN-corynoline. This protocol is
expected to be widely applicable in drug discovery and process
chemistry.
Scheme 1. Enantioselective synthesis of (S)-nafenodone (1) and (+)-
sceletium A-4 (2)
Corynoline, isolated from corydalisincisa, is an
acetylcholinesterase inhibitor that exhibits diverse pharmacological
effects including inhibition of cell adhesion,[16a] fungi- and cyto-
toxicity.[16] Despite a number of synthetic efforts,[6] an efficient
enantioselective synthesis remains highly desirable. Considering the
synthetic challenge of the tetracyclic skeleton bearing three
contiguous chiral centers and one all-carbon quaternary center, we
designed a 5-step asymmetric synthesis of (-)-corynoline by
applying the sterically hindered enantioselective palladium-
catalyzed α-arylation. Thus, arylation of indanone 14 with aryl
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3
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10.1002/anie.201807302
Angewandte Chemie International Edition
Keywords: steric hindrance · α-arylation · corynoline · DeN-
corynoline · sceletium A-4 · enantioselectivity
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This article is protected by copyright. All rights reserved.

10.1002/anie.201807302
Angewandte Chemie International Edition
Enantioselective Synthesis
Xiaofeng Rao,§ Naikai Li,§ Heng Bai,§
Zheng Wang and Wenjun Tang*
__________ Page – Page
Efficient Synthesis of (-)-Corynoline by
Sterically Hindered Enantioselective
Palladium-Catalyzed α-Arylation
Sterically hindered enantioselective palladium-catalyzed α-arylation powered by
chiral monophosphorus ligand BI-DIME has enabled the efficient synthesis of
antidepressant (S)-nafenodone, a 4-step enantioselective synthesis of sceletium
alkaloid (+)-sceletium A-4, a concise 5-step enantioselective synthesis of (-)-
corynoline, as well as a 3-step preparation of (-)-DeN-corynoline.
5
This article is protected by copyright. All rights reserved.