Palladium-Catalyzed α-Arylation of Cyclic Vinylogous Esters for the Synthesis of γ-Arylcyclohexenones and Total Synthesis of Aromatic Podocarpane Diterpenoids

Article abstract of DOI:10.1021/acs.orglett.7b00268

Described is a method for the formal γ-arylation of cyclohexenones allowing synthesis of a remote all-carbon quaternary center. The process involves the palladium-catalyzed α-arylation of a α-substituted cyclic vinylogous ester followed by the Stork-Danheiser transposition. The synthetic utility of this protocol is featured in the total syntheses of (±)-12-hydroxy-13-methylpodocarpa-8,11,13-trien-3-one, (±)-3β,12-dihydroxy-13-methylpodocarpane-8,11,13-triene, and (±)-O-methyl nimbinone.

Full text of DOI:10.1021/acs.orglett.7b00268

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed α‑Arylation of Cyclic Vinylogous Esters for the
Synthesis of γ‑Arylcyclohexenones and Total Synthesis of Aromatic
Podocarpane Diterpenoids
Wen-Yi Hou and Yen-Ku Wu*
Department of Applied Chemistry, National Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan
S
* Supporting Information
ABSTRACT: Described is a method for the formal γ-arylation
of cyclohexenones allowing synthesis of a remote all-carbon
quaternary center. The process involves the palladium-catalyzed
α-arylation of a α-substituted cyclic vinylogous ester followed
by the Stork−Danheiser transposition. The synthetic utility of
this protocol is featured in the total syntheses of ( )-12-
hydroxy-13-methylpodocarpa-8,11,13-trien-3-one, ( )-3β,12-
dihydroxy-13-methylpodocarpane-8,11,13-triene, and ( )-O-methyl nimbinone.
Scheme 1. Catalytic α-Arylation Approach for the Synthesis
of γ-Arylcyclohexenones
n all-carbon quaternary stereocenter bearing an aryl unit is
Aa prevailing structural motif in natural products and
molecules of pharmaceutical significance.1 A useful tactic for
rapid access to this substitution pattern is the direct α-arylation
of α-tertiary carbonyl compounds empowered by transition
metal catalysis.2 While the use of catalytic α-arylation of
carbonyl derivatives to form a quaternary carbon center
constitutes an extensively investigated field, analogous means
for installing an aromatic grouping at the γ-position of γ-
branched enone precursors have not yet reached the same level
of refinement.3 In particular, the construction of a γ-quaternary
aryl stereocenter through distal arylation of cyclic dienolate
species still represents a formidable challenge. Difficulties in
developing the γ-arylation protocol are posed by a few factors
including the liability of self-condensation through Michael
addition and issues of controlling regioselectivity. Despite these
obstacles, Hyde and Buchwald have demonstrated a few
examples of palladium-catalyzed direct γ-arylation of uncon-
jugated cyclohexenones to generate a remote all-carbon
quaternary center.4 Nevertheless, a general approach for the
synthesis of γ-aryl-γ-alkyl cycloalkenones from readily accessible
starting materials remains eminently desirable.5
In our quest for a united route to aromatic cyclic terpenoids,
we sought to develop a sequence for the formal γ-arylation of 2-
cyclohexenones that involves palladium-catalyzed α-arylation of
α-substituted cyclic vinylogous esters in tandem with the
Stork−Danheiser transposition6,7 (Scheme 1). Central to our
design plan is the exploitation of the regioselective enolate
formation of 3-alkoxy-2-cyclohexenones7 followed by parlaying
it into the catalytic arylation step. It is noteworthy that Zhang
and co-workers have reported a α-arylative, tertiary center-
forming reaction of 3-ethoxy-2-cyclohexenone under catalysis
of Pd(OAc)2 and BINAP; however, yields of the coupling
reaction fluctuated dramatically according to the electronic
properties of the aryl donors.8 At the outset of this project,
intermolecular arylative substitution of α-methine hydrogen of
generic structure 1 (R2 = alkyl) had not been delineated for
producing the strategic benzylic quaternary carbon.9 Until very
recently, such transformation was realized by Lautens and co-
workers,10 and it prompted us to disclose our effort in this field.
Herein, we present our studies in the Pd-catalyzed cross-
coupling reaction of 1 with various bromoarenes and synthetic
studies toward podocarpane-type diterpenoids.
Our investigations commenced employing dimethyl-substi-
tuted cyclic vinylogous ester 1a11 and bromoarene 4a as
coupling partners, wherein the use of 1a is pivotal to our
research endeavor toward the diterpenoid synthesis (vide
infra). Of numerous reaction parameters examined,12 the
conditions similar to those proven efficacious for the α-
arylation of α-branched esters by Hartwig and co-workers
afforded the cleanest reaction profile.13 In our case, the optimal
catalyst scheme called for the combination of Pd(dba)2 (1 mol
%) and P(t-Bu)3 (1 mol %) with lithium dicyclohexylamide
functioning as a base (Table 1, entry 4). On the other hand, the
reactions employing either LDA or LiTMP gave a significant
amount of intractable materials (entries 2 and 3). We showed
that the arylation of 1a by treating the air stable HBF4 salt of
14
P(t-Bu)3 worked reasonably well to produce 2a (entry 5).
The optimized conditions described above were utilized to
carry out the α-arylation of 1a with a range of aromatic
Received: January 25, 2017
© XXXX American Chemical Society
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Letter
a
Table 1. Effects of Base and Ligand on the α-Arylation of 1a
Table 2. Catalytic Cross-Coupling of 1a with Different
a
Aromatic Bromides
b
entry
base
ligand
P(t-Bu)3
yield (%)
1
2
3
4
5
LiHMDS
LDA
75
37
58
85
68
P(t-Bu)3
LiTMP
LiNCy2
LiNCy2
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3·HBF4
a
Reactions were conducted with 1 equiv of 4a (2.0 mmol) and 1.1
equiv of 1a. For detailed procedures, see the Supporting Information.
b
Yield of isolated product based on 4a. dba = trans,trans-
dibenzylideneacetone. LiHMDS: lithium hexamethyldisilazide. LDA:
lithium diisopropylamide. LiTMP: lithium 2,2,6,6-tetramethyl-
piperidide. LiNCy2: lithium dicyclohexylamide.
substrates 4b−k (Table 2). The reactions of electron-rich aryl
bromides produced desired aryl carbonyl products in good
yields (entries 1−4). Notably, the arylation is compatible with a
sterically demanding ortho-substituted substrate (4e), albeit at a
slower rate. Even electron-deficient bromoarenes 4f and 4g
were effectively cross-coupled with 1a (entries 5 and 6). The
scope of substituted bromobenzene appears broad in terms of
electronic and steric considerations, so we next examined the
compatibility of heterocyclic bromides in this transformation.
The reaction of thiophene 4h proceeded smoothly to install a
3-thienyl substituent at the α carbon of 1a (entry 7). This
method can accommodate N-silyl-indole 4i and N-Boc-
carbazole 4j to deliver the corresponding α-heteroarylated
compounds, but the reactions were relatively sluggish and
required either a longer reaction time (entry 8) or a higher
catalyst loading (entry 9). Although we found 4k failed to react
with 1a under the standard conditions,15 a modest yield of the
coupling product 2k could be obtained in the presence of
Pd(OAc)2 (entry 10). In this particular example, we observed a
noticeable competing pathway to give 2,6-dimethyl-3-ethox-
yphenol through oxidative aromatization of 1a.
In their comprehensive study,10 Lautens and colleagues
showed that the coupling of 1b with 4-bromoveratrole (4l)
catalyzed by commercially available palladacycle (Pd-P(t-Bu)3-
G2) was accompanied by alkene isomerization, thus generating
compound 5 in moderate yield (Scheme 2a). With our catalytic
system, the reaction of 1b and 4l furnished 2l as the sole
product, and a quaternary allyl aryl stereocenter was
conveniently synthesized (Scheme 2b). From a synthetic
standpoint, these examples are complementary tools for
assembling highly functionalized building blocks.
To further demonstrate the significance of our arylative
methodology, we embarked on total syntheses of ( )-12-
hydroxy-13-methylpodocarpa-8,11,13-trien-3-one (9),16
( )-3β,12-dihydroxy-13-methylpodocarpane-8,11,13-triene
(10),17 and ( )-O-methyl nimbinone (11).18 Compounds 9
and 10 belong to a family of podocarpane diterpenoids that
have been isolated from several terrestrial plant sources,19 and
compound 11 is known as a synthetic derivative of naturally
occurring nimbinone.20 These structurally unique bisnorditer-
penoids possess a γ-quaternary-γ-aryl cyclohexanone scaffold,
a
b
Scope was evaluated using 2.0 mmol of bromoarenes. Yield of
c
d
isolated product based on 4. Reaction time = 18 h. Reaction time =
4.5 h. With 7.5 mol % Pd(dba)2 and 8 mol % P(t-Bu)3·HBF4. With 5
mol % Pd(OAc)2 and 10 mol % P(t-Bu)3; Reaction time = 18 h.
e
f
and are therefore well suited for our methodology.21
Compound 9 exhibited notable biological profiles including
antifungal activity22 and in vitro cytotoxic activity against
selected human tumor cell lines with IC50 values ranging from
B
DOI: 10.1021/acs.orglett.7b00268
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Letter
took place uneventfully to give the desired arylated product 2m.
Conjugated dienone 6 was prepared via a Stork−Danheiser
transposition comprising 1,2-addition of vinylmagnesium
bromide followed by acidic hydrolysis. In this case, it was
necessary to apply cerium(III) chloride to facilitate the
organometallic addition to the sterically congested carbonyl
carbon.29 Intramolecular Friedel−Crafts reaction of 6 mediated
by a Lewis acid led to the formation of tricyclic compound 7.
Reductive alkylation of 7 under dissolving-metal conditions
gave 8 by establishment of the trans-decalin system and
introduction of the gem-dimethyl moiety.30 The facile removal
of the O-methyl group with boron tribromide delivered 9 in
74% yield. Accordingly, the total synthesis of racemic 12-
hydroxy-13-methylpodocarpa-8,11,13-trien-3-one (9) was
achieved in five steps and 18% overall yield from known
vinylogous ester 1a.11 When subjected to Luche conditions,31
ketone 9 was reduced in excellent diastereoselectivity, thus
accomplishing the first total synthesis of racemic 3β,12-
dihydroxy-13-methylpodocarpane-8,11,13-triene (10). Addi-
tionally, we showed that ( )-O-methyl nimbinone (11) could
be prepared through regioselective benzylic oxidation of a
common intermediate 8.32
In summary, we have developed a method for the Pd-
catalyzed α-arylation of cyclic vinylogous esters. This process
enables the synthesis of an all-carbon quaternary aryl
stereocenter and is effective with a range of aryl or heteroaryl
bromides. We have demonstrated the utility of the α-arylated
products in a Stork−Danheiser transposition that provides
ready access to densely substituted γ-arylcyclohexenones. The
combined arylation/Stork−Danheiser transposition sequence is
highlighted in a united route to aromatic podocarpane-type
diterpenoids. Further applications of this protocol in natural
product synthesis are underway and will be described in due
course.
Scheme 2. Reaction Courses of an Allyl Substrate
3.0 to 6.3 μM.23 Compound 10 displays anti-HCV activity24 as
well as inhibitory effects on lipopolysaccharide-induced NO
production.25 Despite promising biomedicinal potentials of
these targets, there has been only one total synthesis of 9,
described by Zhang and co-workers,26 and total synthesis of 10
is hitherto unknown.
Integrating our own protocol with a cyclialkylation-based
strategy developed by Majetich and co-workers allowed us to
streamline the synthesis of functionalized hydrophenanthrene
skeletons (Scheme 3).27 The coupling reaction of 1a with 4m28
Scheme 3. Total Synthesis of Aromatic Podocarpane
Diterpenoids
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00268.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yenkuwu@nctu.edu.tw.
ORCID
Yen-Ku Wu: 0000-0002-9269-7444
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology, Taiwan
(104-2113-M-009-022-MY2) for financial support of this work.
We also thank the Center of Interdisciplinary Science at
National Chiao Tung University for additional support. This
work is dedicated to Prof. Hsing-Jang Liu on the occasion of his
75th birthday.
C
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Letter
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Org. Chem. 2008, 12, 1050−1070. (c) Dhambri, S.; Mohammad, S.;
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