Enantioselective palladium catalyzed conjugate additions of ortho-substituted arylboronic acids to β,β-disubstituted cyclic enones: Total synthesis of herbertenediol, enokipodin A and enokipodin B

Article abstract of DOI:10.1039/c4ob01085j

The palladium-catalyzed conjugate addition (Michael addition) of ortho-substituted arylboronic acids to β,β-disubstituted cyclic enones, in particular 3-methyl cyclopent-2-enone and 3-methyl cyclohex-2-enone, is reported. With an achiral bipyridine-based palladium catalyst, good yields are obtained with a variety of ortho-substituted arylboronic acids. In the asymmetric version, good to very high enantiomeric excesses (up to 99% ee) are obtained, though the yields are moderate. The decreased yields are attributed to significant protodeboronation of the arylboronic acid. The developed methodology allows the efficient enantioselective synthesis of the very crowded, biologically active, sesquiterpenes herbertenediol, enokipodin A, and enokipodin B. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob01085j

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Enantioselective palladium catalyzed conjugate
additions of ortho-substituted arylboronic acids to
β,β-disubstituted cyclic enones: total synthesis of
herbertenediol, enokipodin A and enokipodin B†
Cite this: Org. Biomol. Chem., 2014,
12, 5883
Jeffrey Buter, Renée Moezelaar and Adriaan J. Minnaard*
The palladium-catalyzed conjugate addition (Michael addition) of ortho-substituted arylboronic acids to
β,β-disubstituted cyclic enones, in particular 3-methyl cyclopent-2-enone and 3-methyl cyclohex-
2-enone, is reported. With an achiral bipyridine-based palladium catalyst, good yields are obtained with a
variety of ortho-substituted arylboronic acids. In the asymmetric version, good to very high enantiomeric
excesses (up to 99% ee) are obtained, though the yields are moderate. The decreased yields are attributed
to significant protodeboronation of the arylboronic acid. The developed methodology allows the efficient
enantioselective synthesis of the very crowded, biologically active, sesquiterpenes herbertenediol, eno-
kipodin A, and enokipodin B.
Received 26th May 2014,
Accepted 20th June 2014
DOI: 10.1039/c4ob01085j
www.rsc.org/obc
workers, has been employed, but also in these systems the use
Introduction
of ortho-substituted arylboronic acids is very limited.4,5
The catalytic asymmetric construction of quaternary stereo-
In 2011, the Stoltz laboratory reported the first asymmetric
centers is widely regarded as one of the major challenges in palladium-catalyzed conjugate addition of arylboronic acids to
synthetic organic chemistry.1 One efficient strategy to achieve cyclic β-disubstituted enones using tBuPyOx as the ligand.6
this goal is the conjugate addition of carbon nucleophiles to Shortly thereafter we reported the asymmetric Michael
β,β-disubstituted unsaturated carbonyl compounds.2
addition of arylboronic acids to cyclic β-disubstituted enones
Employing asymmetric copper catalysis, the groups of Alex- and lactones, catalyzed by PdCl2-(R,R-PhBOX) (Scheme 1).7
akis, Fillion and Hoveyda successfully added trialkylalumi-
num, dialkylzinc and alkyl Grignard reagents to a variety of
β,β-disubstituted unsaturated electrophiles.3 Though addition
of the corresponding arylaluminum and arylzinc reagents was
feasible, the general use of aryl Grignard reagents is still pro-
blematic due to their high reactivity. Moreover, the use of
ortho-substituted aryl groups (either in the β,β-disubstituted
unsaturated electrophile or in the organometallic reagent) is
precarious, generally leading either to failure of the reaction,
or low to moderate ee.3p,q,s,t A notable exception has been
reported by Hoveyda and co-workers who obtained excellent
enantioselectivities (>95%) with anisole and o-tolyl aluminum
reagents.3r Alternatively, rhodium-catalyzed conjugate addition
of organoboron reagents, developed by Hayashi and co-
Statingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG
Groningen, The Netherlands. E-mail: a.j.minnaard@rug.nl; Tel: (+31) 503634258
†Electronic supplementary information (ESI) available: 1H-NMR, 13C-NMR, APT,
optical rotations, high-resolution mass and chiral HPLC analyses are provided
for the complete substrate scope and compounds 1–13. See DOI: 10.1039/
Scheme 1 The current state of the art in Pd-catalyzed asymmetric
c4ob01085j
Michael additions to create benzylic quaternary stereocenters.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 5883–5890 | 5883

View Article Online
Paper
Organic & Biomolecular Chemistry
tuted arylboronic acids was fruitless, leading only to trace
amounts of product. It was reasoned, however, that increasing
the catalyst loading from 1 mol% to 5 mol%, extending the
reaction time and changing the stoichiometry of the reaction
(7 equivalents of enone instead of 2 equivalents of boronic
acid)11 could change this situation. This indeed proved to be
the case, and a wide range of ortho-substituted arylboronic
acids could be employed in the conjugate addition (Table 1).
As evident from Table 1, the Michael additions to 3-methyl
cyclopent-2-enone generally gave satisfying results. As
expected, an increase in the steric bulk of the ortho-substituent
led to diminished yields, but in the case of the relatively small
ortho-fluoro and ortho-chloro arylboronic acid low yields were
obtained as well (20% and 12% respectively, entries 5 and 7).
These low yields might be attributed to electronic effects, thus
Scheme 2 Selected natural products bearing ortho-substituted
benzylic quaternary stereocenters.
Both systems showed high enantioselectivities, high yields,
broad functional group tolerance, mild reaction conditions
and a considerable scope in both the cyclic Michael acceptor
and the arylboronic acid. In addition, in both systems the reac-
tions can be carried out in air. However, to date, the successful
application of a broad range of ortho-substituted arylboronic
acids has not been reported,8 although the Stoltz laboratory
managed the asymmetric conjugate addition of o-fluoro aryl-
boronic acid to 3-methyl cyclohex-2-enone in an enantiomeric
excess of 77%. A quaternary center vicinal to an ortho-sub-
stituted phenyl ring is a very congested situation indeed.
Very recently Sigman and co-workers reported the asym-
metric Pd-catalyzed remote benzylic quaternary stereocenter
formation using arylboronic acids.9 A broad substrate scope,
consisting exclusively of linear substrates, was reported with
very good to excellent enantioselectivities (86–98% ee), and
yields generally ranging from 50 to 80%. However, when using
the ortho-substituted o-tolylboronic acid and dibenzofuran-
4-boronic acid the yields dropped significantly to 35% and
25% respectively, showing the problems associated with ortho-
substitution.
Table 1 Pd-catalyzed conjugate addition of ortho-substituted aryl-
boronic acids to β-methyl cyclic enones
Entry
Boronic acid (R =)
Enone (n =)
Isolated yield (%)
1
2
3
4
5
6
7
8
Me
Me
OMe
OMe
F
F
Cl
0
1
0
1
0
1
0
1
82
41
69
55
20 (51)a
7 (10)a
12 (31)a
8%
Cl
9
10
0
1
69
14 (20)a
Asymmetric synthesis of benzylic quaternary centers with
ortho-substitution is desired, since many natural products bear
such a moiety, several of which are presented in Scheme 2. We
also envision this transformation beneficial in the sense that
direct installation of the ortho-substituted benzylic stereocen-
ter can significantly shorten synthetic endeavors of such
natural products.
Here, we present the palladium-catalyzed conjugate
addition of ortho-substituted arylboronic acids to β-methyl sub-
stituted cyclic enones, both in an asymmetric and a non-asym-
metric fashion. The developed methodology is applied in the
total synthesis of the sterically congested, biologically active,
sesquiterpenes herbertenediol and enokipodin A and B.
11
12
0
1
73
20 (34)a
13
14
0
1
67
44
15
16
0
1
65
17 (28)a
17
18
0
1
78
63
19
20
0
1
87
73
21
22
0
1
83
76
Results and discussion
In a recent report,10 we showed efficient conjugate addition to
cyclic β-substituted enones employing 1 mol% of a Pd(TFA)2/
2,2-bipyridine catalyst, two equivalents of boronic acid, at
a The yield between brackets refers to reactions performed with 10 mol%
60 °C for 18 h. Under these conditions the use of ortho-substi- of Pd(TFA)2 and 15 mol% of 2,2-bipyridine.
5884 | Org. Biomol. Chem., 2014, 12, 5883–5890
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
in order to achieve acceptable yields for these substrates the
catalyst loading was doubled to 10 mol% leading to 51% and
31% isolated yield for ortho-fluoro and ortho-chloro phenyl-
boronic acid, respectively.
Table 2 Optimization of the reaction conditions in the conjugate
addition of ortho-tolylboronic acid to β-methyl cyclopentenone
With these results in hand, we expanded the reaction scope
in the Michael acceptor to 3-methyl cyclohex-2-enone. In all
cases the isolated yields significantly dropped, though ortho-
methyl, ortho-methoxy, and 2-methoxy-5-methyl phenylboronic
acid (entries 2, 4 and 18) gave acceptable yields (41%, 55% and
63% respectively). In contrast with 3-methyl cyclopent-2-enone,
doubling of the catalyst loading did not always result in signifi-
cantly better yields. In the case of ortho-chloro phenylboronic
acid (entry 8) only 8% of the desired product was isolated after
two days of reaction, which clearly indicates the limits of this
approach.
The conjugate addition of ortho-substituted arylboronic
acids to 3-methyl cyclohept-2-enone was shortly investigated
but did not lead to yields over 10% using 8 mol% of catalyst.
This result is surprising to us since in our previously reported
system, 3-methyl cyclohept-2-enone was tolerated as a sub-
strate (using phenylboronic acid).10 Since no electronic
reasons can be given to describe the failure of the reaction, we
attribute this to steric hindrance.
Catalyst
loading
A : B
Strategy
Silver salt
Additive(s)
None
ratioa
Previous reported
conditions7
Lewis acid
15 mol%
15 mol%
AgSbF6
(40 mol%)
AgSbF6
1 : 5
1 : 4
i.e. Sc(OTf)3,
Yb(OTf)3,
In(OTf)3,
Ce(OTf)3
(40 mol%)
7 eq. of
enone
NH4PF6
(40 mol%)
Water (8 eq.)
NH4PF6
(20 mol%)
NH4PF6
activation
(40 mol%)
Change of
15 mol%
15 mol%
AgSbF6
2.5 : 1
20 : 1
stoichiometry
Dichloroethane
as solvent
(40 mol%)
AgCF3CO2
(40 mol%)
Lowering the
8 mol%
4 mol%
4 mol%
AgCF3CO2
(20 mol%)
AgCF3CO2
(10 mol%)
AgPF6
18 : 1
12 : 1
3.5 : 1
catalyst loadingb
(10 mol%)
None
(10 mol%)
a The ratio was determined by GC/MS analysis. b Water (8 eq.) was
added as an additive.
With the Michael addition of ortho-substituted arylboronic
acids to cyclic β,β-disubstituted enones accomplished, we ambi-
tioned the asymmetric variant of this transformation using our
previously developed catalyst. This reaction is expected to be
significantly more challenging since steric interactions are
more pronounced in enantioselective catalysis. Initial studies
using o-tolylboronic acid, employing 15 mol% of catalyst
PdCl2-(R,R-PhBOX), and 40 mol% AgSbF6 at 60 °C, clearly
showed this was the case since the impurity profile of the reac-
tion was dominated by homo-coupling of the arylboronic acid.
Therefore we set out to optimize the reaction to reduce this
unwanted side-product (Table 2).
Lewis acid activation of the enone increases its reactivity as
a Michael acceptor. The use of 40 mol% of either Mg, Zn, Fe
or Cu triflate gave negligible results and therefore the stronger
coordinating rare-earth metal triflates Sc(OTf)3, Yb(OTf)3,
In(OTf)3, and Ce(OTf)3 were applied. A slight enhancement of
the product versus homocoupling ratio was observed but still
the reaction was greatly in favor of the latter. Homo-coupling
of arylboronic acids is generally observed using Pd-catalysis,12
and can be counter-balanced by changing the stoichiometry of
the reaction, applying the reaction partner in excess.13 As
β-methyl cyclopentenone and β-methyl cyclohexenone are less
expensive than most arylboronic acids, this is an attractive
approach. Using three equivalents of enone, the product ratio
changed to 1.5 : 1 in favor of the Michael adduct. A further
enhancement to 2 : 1 was observed using five equivalents of
enone and ultimately a 2.5 : 1 ratio was found using seven
equivalents.
enlarged by adding NH4PF6 (30 mol%) and water (5 eq.) to
their system. We adopted these conditions by changing the
solvent from MeOH–H2O to dichloroethane, and the silver salt
from AgSbF6 to AgCF3CO2 to obtain a similar system, still
using 7 eq. of the enone.15 This proved to be highly beneficial
for the formation of the Michael adduct since the product
ratio dramatically increased to 20 : 1. With this result in hand,
the catalyst loading was lowered to 8 mol% leading to a slight
decrease of the product ratio (18 : 1). Further reduction to
4 mol% of catalyst resulted in a respectable 12 : 1 ratio in favor
of the Michael adduct, however at the cost of longer reaction
times. Finally we also attempted to reduce the number of addi-
tives (AgCF3CO2 and NH4PF6) by combining them in the form
of AgPF6. Surprisingly, this led to an unaccountable lowering
of the product ratio to 3.5 : 1.
With the reaction conditions optimized, the scope of the
reaction was studied (Table 3). An immediate observation was
that very good to excellent enantioselectivities were obtained,
albeit that the isolated yields were moderate, and in some
cases low. For some reactions (entries 4, 6, 7, 11, 17, 19), due
to the initially low isolated yield, the catalyst loading was
doubled. This led, as expected, to an approximate doubling of
the yield. Interestingly, in some cases (entries 11 vs. 12, 15 vs.
16, 17 vs. 18 and 21 vs. 22) addition to 3-methyl cyclohex-2-
enone gave higher yields than addition to 3-methyl cyclopent-
2-enone. These results are in contrast to the conjugate
addition reactions with the bipyridine system (Table 2). It is
also notable that the conjugate additions to 3-methyl cyclohex-
2-enone give equal or higher enantiomeric excesses (up to 22%
During this optimization process, Stoltz and Houk reported
a mechanistic investigation of the Pd-catalyzed asymmetric
Michael addition of arylboronic acids to enones.14 It was
shown that the chemical yields previously obtained, could be
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 5883–5890 | 5885

View Article Online
Paper
Organic & Biomolecular Chemistry
jugate addition, protodeboronation16a,12b might be associated
with: (1) Pd-catalyzed protodeboronation,16c (2) Ag-catalyzed
protodeboronation,16d–h (3) heat-induced protodeborona-
tion,16i,j (4) fluoride-mediated protodeboronation (with PF6− as
a potential F− source),16k,l (5) acid-catalyzed protodeborona-
tion16m–o and finally (6) water-induced protodeboronation.16p
It is likely that more than one of these factors plays an impor-
tant role here but we were not able to suppress this unwanted
side-reaction.17
Table 3 Asymmetric Pd-catalyzed conjugate addition of arylboronic
acids to β-methyl cyclic enones
Entry Boronic acid (R =) Enone (n =) Isolated yield (%) eea (%)
That the moderate yields obtained here do not stand out, is
apparent from a recent report by the Sigman group, as dis-
cussed earlier.9 For their asymmetric Pd-catalyzed remote
benzylic quaternary stereocenter formation using arylboronic
acids, the yields are typically 50–80%, however when using
o-tolylboronic acid and dibenzofuran-4-boronic acid the yields
dropped significantly to 35% and 25% respectively.
Despite significant protodeboronation, the substrate scope
is respectable, although some ortho-substituted arylboronic
acids and functionalized enones failed to react (Fig. 1). It is
not surprising that larger ortho-substituents such as CHO,
NO2, CF3, iPr and CO2Me impeded the reaction. In addition,
di-ortho substitution was not tolerated. Variation of the five-
membered enone in terms of substitution at the α- or γ-posi-
tion also led to failure of reaction, as did substituting the α′-
position of 3-methyl cyclohex-2-enone with a geminal dimethyl
moiety.
Being able to construct the sterically very congested motif
of an ortho-substituted arene connected to a quaternary stereo-
center created the opportunity for the asymmetric total syn-
thesis of the biologically active natural products
herbertenediol (1), enokipodin A (2), and B (3). Herbertenediol
(1) is a sesquiterpene isolated from the liverworts Herberta
adunca18 and Radula perrottetii,19 and has been subjected to
biological studies, which showed potent anti-lipid peroxidation
activity in rat brain homogenates (100% inhibition at 1 µg
mL−1).20
To date, seven asymmetric syntheses of herbertenediol have
been reported,21 with the shortest route reported by Abad and
co-workers21d comprising ten linear steps. Here the quaternary
stereocenter was introduced by means of substrate control, as
in the approach of Lin21e and Kita et al.21f,g The Bringmann
laboratory employed a kinetic resolution,21b as did the Monti
group,21h to furnish enantiopure material. Meyers21a and
1
2
3
4
5
6
7
8
Me
Me
OMe
OMe
F
F
Cl
0
1
0
1
0
1
0
1
23
16
90
98
80
96
95
95
45
20 (42)b
20
13 (23)b
8 (12)b
n.d.c
94
Cl
n.d.c
9
10
0
1
51
36
93
93
11
12
0
1
20 (38)b
26
85
95
13
14
0
1
36 (55)b
19
92
94
15
16
0
1
25
44
94
99
17
18
0
1
19 (32)b
28
80
91
19
20
0
1
12 (21)b
n.d.c
74
84
21
22
0
1
n.d.c
17
68
90
a Enantiomeric excess was determined using chiral HPLC analysis.
b The yield between brackets refers to reactions performed with double
catalyst loading (8 mol%). c n.d. = not determined, the yield of these
reaction is <10%. For the absolute configuration see ref. 30.
ee higher, entry 21 vs. 22) than the additions to 3-methyl cyclo-
pent-2-enone.
The general observation that the yields are higher, and ee’s
are lower, for conjugate additions to cyclopentenone compared
to cyclohexenone might be the consequence of steric hin-
drance. The chiral environment of the catalyst allows “easy”
access of the cyclopentenone (resulting in a faster reaction,
higher yield) but with a decreased facial bias (lower ee). On the
other hand, cyclohexenone does not enter the chiral environ-
ment of the catalyst that easily but when it does, it does so
with an increased facial bias.
The moderate yields were found to result from significant
protodeboronation of the boronic acids. According to litera-
ture, this side reaction can be attributed to multiple factors,
especially when taken into account the low reaction rate of the
asymmetric Michael addition. Given the conditions of the con-
Fig. 1 Unreactive substrates and boronic acids in the Pd-catalyzed
asymmetric Michael addition.
5886 | Org. Biomol. Chem., 2014, 12, 5883–5890
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Fukuyama21c relied on the use of a chiral auxiliary. We mation, leading to an inseparable mixture of mainly oligo-
reasoned that direct introduction of the quaternary stereocen- meric products, and only minor amounts of desired product.
ter by means of an asymmetric conjugate addition of a suitable This observation is in line with a very recent report by Yoshida
substituted phenylboronic acid allowed to shorten the syn- and co-workers, who also encountered reproducibility issues.29
thesis of herbertenediol considerably.
Alternatively, Meyers and co-workers described a reduction
The synthesis of herbertenediol started with the asym- protocol in which 7 was converted into the corresponding thio-
metric conjugate addition of 2,3-dimethoxy-5-methyl phenyl- ketone and was subsequently reduced with RANEY® nickel
boronic acid to 3-methyl cyclopentenone employing 8 mol% of (Ra/Ni), leading to 8 in 58% yield over the two steps.21a This
PdCl2-(R,R-PhBOX), and afforded the desired Michael adduct 5 strategy proved to be reproducible in our hands, providing us
in 55% yield and high enantioselectivity (92% ee, Scheme 3). with 8 in 65% yield. An important, previously not reported,
In order to selectively install the geminal dimethyl moiety observation was that freshly prepared Ra/Ni had to be used for
without generating (hard to separate) regioisomers, 5 was sub- reproducible results; with commercial Ra/Ni, the reaction did
jected to an oxidative dehydrogenation. Initially, several stoi- not provide the desired product. This is likely due to the high
chiometric oxidation procedures (DDQ,22 IBX,23 and iodic activity of freshly prepared Ra/Ni (in which H2 is adsorbed on
acid24) were applied, which led to low isolated yields (<30%) the catalyst) compared to commercial Ra/Ni (no absorbed H2
and over-oxidized products.25 A suitable alternative was found for safe shipment). Demethylation using BBr3 then furnished
in the Pd(TFA)2/4,5-diazafluorenone catalyzed oxidation, herbertenediol in 82% yield, in a total of six steps, the shortest
recently developed by Stahl and co-workers.26 Stahl reported asymmetric synthesis to date.30
cyclopentenone oxidation with oxygen (7.2 bar, 9% in N2)
In 2000, the sesquiterpenes enokipodin A and B were iso-
using 5 mol% of catalyst, whereas catalyst decomposition was lated from the culture broth of the edible mushroom “enoki-
observed at atmospheric pressure. Also in the current case, oxi- dake” (Flammulina velutipes).31 It was found that these
dation of 5 at atmospheric pressure led to catalyst decompo- oxidized α-cuparenone-type compounds pose antimicrobial
sition and only 15% conversion (GC/MS) was observed after 12 activity against Cladosporium herbarum and Bacillus subtilis.32
and 24 h. For practical reasons we decided to increase the cata- However, it is mainly their sterically congested structure that
lyst loading to 40 mol%, at atmospheric oxygen pressure, has attracted the synthetic community to embark on asym-
which yielded 79% of enone 6.
metric syntheses of these molecules.33 Two of the three endea-
With 6 in hand, a one-pot geminal dimethylation as vors produced enokipodin B in a longest linear sequence of
described by Srikrishna was employed yielding 77% of 7.27 In eleven steps, and one additional step for the enokipodin A syn-
order to acquire fully reduced product 8, several procedures thesis. Kuwahara’s approach was based on the use of a chiral
were considered. Deoxygenation by means of a classic Wolff– auxiliary33c,d whereas Yoshida installed the quaternary stereo-
Kishner reduction was reported to be problematic in related center by substrate control.33b In the most recent, ten step
systems and was therefore rejected.28 Deoxygenation employ- formal, enokipodin B synthesis, Hoveyda directly installed the
ing a Mozingo reduction (thioketalization/RANEY® nickel benzylic quaternary center using an elegant multicomponent
desulfurization with the saturated analogue of 7) also has been Ni-, Zr-, and Cu-catalyzed strategy.33a
reported to be problematic,21a although it was successfully
applied recently in a very similar system.27 To clarify these con-
tradicting literature reports we performed the reaction under
similar conditions as reported.27 In our hands the reaction
proved to be extremely slow and prone to side-product for-
Scheme 4 Asymmetric total synthesis of enokipodin A and enokipodin
Scheme 3 Asymmetric total synthesis of herbertenediol.
B.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 5883–5890 | 5887

View Article Online
Paper
Organic & Biomolecular Chemistry
Our synthesis of enokipodin A and B started with the asym-
metric Michael addition of boronic acid 9 to 3-methyl cyclo-
pent-2-enone, yielding 10 in 21% yield and good
2 C. Hawner and A. Alexakis, Chem. Commun., 2010, 46, 7295.
See also: A. Alexakis, N. Krausse and S. Woodward, in Copper-
catalyzed Asymmetric Synthesis, ed. A. Alexakis, N. Krausse
and S. Woodward, Wiley-VHC, Weinheim, 2014, ch. 2.
3 For Selected examples: (a) K. P. McGrath and
A. H. Hoveyda, Angew. Chem., Int. Ed., 2014, 53, 1910;
(b) D. Willcox, S. Woodward and A. Alexakis, Chem.
Commun., 2014, 50, 1655; (c) D. Müller and A. Alexakis,
Chem. – Eur. J., 2013, 19, 15226; (d) D. Müller and
A. Alexakis, Org. Lett., 2013, 15, 1594; (e) C. Bleschke,
M. Tissot, D. Müller and A. Alexakis, Org. Lett., 2013, 15,
2152; (f) J. A. Dabrowski, M. T. Villaume and
A. H. Hoveyda, Angew. Chem., Int. Ed., 2013, 52, 8156;
(g) J. A. Dabrowski, F. Haeffner and A. H. Hoveyda, Angew.
Chem., Int. Ed., 2013, 52, 7694; (h) D. Müller and
A. Alexakis, Chem. Commun., 2012, 48, 12037; (i) D. Müller,
M. Tissot and A. Alexakis, Org. Lett., 2011, 13, 3040;
( j) M. Tissot, A. Pérez Hernández, D. Müller, M. Mauduit
and A. Alexakis, Org. Lett., 2011, 13, 1524; (k) T. L. May,
J. A. Dabrowski and A. H. Hoveyda, J. Am. Chem. Soc., 2011,
133, 736; (l) C. Hawner, D. Müller, L. Gremaud, A. Felouat,
S. Woodward and A. Alexakis, Angew. Chem., Int. Ed., 2010,
49, 7769; (m) A. Wilsily and E. Fillion, J. Org. Chem., 2009,
74, 8583; (n) A. Wilsily and E. Fillion, Org. Lett., 2008, 10,
2801; (o) E. Fillion and A. Wilsily, J. Am. Chem. Soc., 2006,
128, 2774; (p) A. Wilsily and E. Fillion, J. Org. Chem., 2009,
74, 8583; (q) C. Hawner, K. Li, V. Cirriez and A. Alexakis,
Angew. Chem., Int. Ed., 2008, 47, 8211; (r) T. L. May,
M. K. Brown and A. H. Hoveyda, Angew. Chem., Int. Ed.,
2008, 47, 7358; (s) M. Vuagnoux-d’Augustin and A. Alexakis,
Chem. – Eur. J., 2007, 13, 9647; (t) E. Fillion and A. Wilsily,
J. Am. Chem. Soc., 2006, 128, 2774.
a
enantioselectivity of 74% ee (Scheme 4). Introduction of the
α,β-unsaturation was subsequently achieved using the pre-
viously described Pd(TFA)2/4,5-diazafluorenone catalyzed oxi-
dation, in 54% yield. Dimethylation followed by hydrogenation
of enone 12 gave ketone 13 (60% yield over two steps), a
common synthetic intermediate to access the desired natural
products. Indeed, enokipodin A and B were both readily
obtained in just one step, from 13 by either a cerium
ammonium nitrate oxidation, leading to enokipodin B in 84%
yield, or a BBr3 mediated demethylation, providing enokipodin
A in 57% yield. Though not the synthesis with the highest
enantiomeric excess, we did manage to reduce the longest
linear sequence from ten (enokipodin B) and eleven (enokipo-
din A) to only five steps.
Conclusion
In summary, we successfully incorporated ortho-substituted
arylboronic acids in both the non-stereoselective as well as the
asymmetric Pd-catalyzed Michael addition to β-disubstituted
cyclic enones. In the non-stereoselective reaction, good yields
are obtained with 3-methyl cyclopent-2-enone as the substrate
and moderate yields with 3-methyl cyclohex-2-enone. In the
asymmetric reaction, very good to excellent enantioselectivities
are obtained, although yields stay moderate. Nevertheless,
based on this method, the asymmetric total synthesis of the
biologically active sesquiterpenes herbertenediol, enokipodin
A and enokipodin B was achieved with routes that are con-
siderably shorter than previously reported.
4 (a) R. Shintani, W.-L. Duan and T. Hayashi, J. Am. Chem.
Soc., 2006, 128, 5628; (b) R. Shintani, Y. Tsutsumi,
M. Nagaosa, T. Nishimura and T. Hayashi, J. Am. Chem.
Soc., 2009, 131, 13588; (c) R. Shintani, M. Takeda,
T. Nishimura and T. Hayashi, Angew. Chem., Int. Ed., 2010,
49, 3969; (d) R. Shintani and T. Hayashi, Org. Lett., 2011,
13, 350.
5 For reports on quaternary stereocenter formation using
arylboronic acids see: (a) P. Mauleón and J. C. Carretero,
Chem. Commun., 2005, 4961; (b) B. T. Hahn, F. Tewes,
R. Fröhlich and F. Glorius, Angew. Chem., Int. Ed., 2010, 49,
1143.
Acknowledgements
The Dutch Science Organization NWO is acknowledged for
funding. Mrs Tiemersma-Wegman is kindly acknowledged for
HRMS analysis.
Notes and references
1 Quaternary Stereocenters: Challenges and Solutions for
Organic Synthesis, ed. J. Christoffers and A. Baro, Wiley-
VCH, Weinheim, 2005. For selected reviews on the syn-
thesis of quaternary stereocenters, see: (a) I. Denissova and
L. Barriault, Tetrahedron, 2003, 59, 10105; (b) C. J. Douglas
and L. E. Overman, Proc. Natl. Acad. Sci. U. S. A., 2004, 101,
5363; (c) J. Christoffers and A. Baro, Adv. Synth. Catal.,
2005, 347, 1473; (d) B. M. Trost and C. Jiang, Synthesis,
2006, 369; (e) J. T. Mohr and B. M. Stoltz, Chem. – Asian J.,
2007, 2, 1476; (f) P. G. Cozzi, R. Hilgraf and
N. Zimmermann, Eur. J. Org. Chem., 2007, 5969;
(g) J. P. Das and I. Marek, Chem. Commun., 2011, 47, 4593.
6 K. Kikushima, J. C. Holder, M. Gatti and B. M. Stoltz, J. Am.
Chem. Soc., 2011, 133, 6902.
7 A. L. Gottumukkala, K. Matcha, M. Lutz, J. G. de Vries and
A. J. Minnaard, Chem. – Eur. J., 2012, 18, 6907.
8 As stated by the authors from ref. 6 “Substituents at the
2-position of the arylboronic acid were detrimental to the
yields and stereoselectivity of the reaction with enone
(3-methyl hex-2-enone), although 2-fluorophenylboronic
acid underwent the desired reaction to provide a product in
32% yield and 77% ee”. Later work (see ref. 14) showed
that the yield could be enhanced to 77% for the same
transformation.
5888 | Org. Biomol. Chem., 2014, 12, 5883–5890
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
9 T.-S. Mei, H. H. Pater and M. S. Sigman, Nature, 2014, 508,
340.
10 (a) A. L. Gottumukkala, J. Suljagic, K. Matcha, J. G. de Vries
and A. J. Minnaard, ChemSusChem, 2013, 6, 1636; (b) For a
similar transformation see: S. Lin and X. Lu, Org. Lett.,
2010, 12, 2536.
11 The use of 7 eq. of Michael acceptor resulted from the
optimization of the conditions for the enantioselective
transformation (vide infra). Though not ideal, the enone is
significantly cheaper than the boronic acids and could be
easily retrieved in pure form by flash chromatography.
12 Undesired Pd-catalyzed homo-coupling as a side-product is
excess of boronic acid see: (a) Y. Takaya, M. Ogasawara and
T. Hayashi, J. Am. Chem. Soc., 1998, 120, 5579. For protode-
boronation suppression by temperature lowering see:
(b) T. Hayashi, M. Takahashi, Y. Takaya and M. Ogasawara,
J. Am. Chem. Soc., 2002, 124, 5052; In our catalytic system
an excess of arylboronic acid leads to significant biaryl for-
mation. This product, in some cases, proved to be very
difficult to separate from the desired Michael adduct. Low-
ering the reaction temperature led to significant retar-
dation of the catalytic process.
18 A. Matsuo, S. Yuki and M. Nakayama, J. Chem. Soc., Perkin
Trans., 1986, 701.
mentioned in: (a) G. A. Molander and B. Biolatto, J. Org. 19 M. Toyota, T. Kinugawa and Y. Asakawa, Phytochemistry,
Chem., 2003, 68, 4302; (b) A. J. J. Lennox and G. C. Lloyd- 1994, 37, 859.
Jones, Isr. J. Chem., 2010, 50, 664; (c) A. J. J. Lennox and 20 Y. Fukuyama, Y. Kiriyama and M. Kodama, Tetrahedron
G. C. Lloyd-Jones, Chem. Soc. Rev., 2014, 43, 412. Lett., 1996, 37, 1261.
13 Homo-coupling suppression by using an excess of boronic 21 Asymmetric total
syntheses
of
herbertenediol:
acid is mentioned in: M. S. Wong and X. L. Zhang, Tetra-
hedron Lett., 2001, 42, 4087.
14 J. C. Holder, L. Zou, A. N. Marziale, P. Liu, Y. Lan, M. Gatti,
K. Kikushima, K. N. Houk and B. M. Stoltz, J. Am. Chem.
Soc., 2013, 135, 14996.
(a) A. P. Degnan and A. I. Meyers, J. Am. Chem. Soc., 1999,
121, 2762; (b) G. Bringmann, T. Pabst, P. Henschel,
J. Kraus, K. Peters, E.-M. Peters, D. S. Rycroft and
J. D. Connolly, J. Am. Chem. Soc., 2000, 122, 9127;
(c) Y. Fukuyama, K. Matsumoto, Y. Tonoi, R. Yokoyama,
H. Takahashi, H. Minami, H. Okazaki and Y. Mitsumoto,
Tetrahedron, 2001, 57, 7127; (d) A. Abad, C. Agulló,
A. C. Cuñat, D. Jiménez and R. H. Perni, Tetrahedron, 2001,
57, 9727; (e) A.-M. Zhang and G.-Q. Lin, Chin. J. Chem.,
2001, 19, 1245; (f) Y. Kita, J. Futamura, Y. Ohba,
Y. Sawama, J. K. Ganesh and H. Fujioka, J. Org. Chem.,
2003, 68, 5917; (g) Y. Kita, J. Futamura, Y. Ohba,
Y. Sawama, J. K. Ganesh and H. Fujioka, Tetrahedron Lett.,
2003, 44, 411; (h) S. Acherar, G. Audran, F. Fotiadu and
H. Monti, Eur. J. Org. Chem., 2004, 5092. For racemic synth-
eses see: (i) Y. Fukuyama, Y. Kiriyama and M. Kodama,
Tetrahedron Lett., 1996, 37, 1261; ( j) P. D. Gupta, A. Pal,
A. Roy and D. Mukherjee, Tetrahedron Lett., 2000, 41, 7563;
(k) Y. Fukuyama, K. Matsumoto, Y. Tonoi, R. Yokoyama,
H. Takahashi, H. Minami, H. Okazaki and Y. Mitsumoto,
Tetrahedron, 2001, 57, 7127; (l) A. Srikrishna and M. S. Rao,
Tetrahedron Lett., 2001, 42, 5781; (m) A. Srikrishna and
M. S. Rao, Synlett, 2002, 340; (n) A. Srikrishna and
G. Satyanarayana, Tetrahedron, 2006, 62, 2892.
15 The silver salt was changed to get the same counter-ion as
reported by Stoltz et al. (see ref. 6 and 14).
16 For general remarks on protodeboronation (a) D. G. Hall,
in Boronic Acids: Preparation and Applications in Organic Syn-
thesis, Medicine and Materials – Second Completely Revised
Edition, ed. D. G. Hall, Wiley-VCH, Weinheim, 2011, ch. 1;
(b) See ref. 12b. For specific types of protodeboronation
reactions
see:
(1)
Pd-catalyzed
protodeboronation:
(c) H. G. Kuivila, J. F. Reuwer Jr. and J. A. Mangravite, J. Am.
Chem. Soc., 1964, 86, 2666 (2) Ag-catalyzed protodeborona-
tion: (d) A. Michaelis and P. Becker, Chem. Ber., 1882, 15,
180; (e) W. Seaman and J. R. Johnson, J. Am. Chem. Soc.,
1931, 53, 711; (f) J. R. Johnson, M. G. van Campen Jr. and
O. Grummitt, J. Am. Chem. Soc., 1938, 60, 111;
(g) H. G. Kuivila, J. F. Reuwer Jr. and J. A. Mangravite,
J. Am. Chem. Soc., 1964, 86, 2666; (h) C. Pourbaix,
F. Carreaux, B. Carboni and H. Deleuze, Chem. Commun.,
2000, 1275; (3) Heat induced protodeboronation:
(i) M. A. Beckett, R. J. Gilmore and K. Idrees, J. Organomet.
Chem., 1993, 455, 47; ( j) C.-Y. Lee, S.-J. Ahn and 22 H. E. Zimmerman and R. D. Little, J. Am. Chem. Soc., 1974,
C.-H. Cheon, J. Org. Chem., 2013, 78, 12154; (4) Fluoride 96, 4623.
mediated protodeboronation: (k) S. Nave, R. P. Sonawane, 23 K. C. Nicolaou, T. Montagnon, P. S. Baran and Y.-L. Zhong,
T. G. Elford and V. K. Aggarwal, J. Am. Chem. Soc., 2010, J. Am. Chem. Soc., 2002, 124, 2245.
132, 17096; (l) M. J. Hesse, C. P. Butts, C. L. Willis and 24 K. C. Nicolaou, T. Montagnon and P. S. Baran, Angew.
V. K. Aggarwal, Angew. Chem., Int. Ed., 2012, 51, 12444; (5) Chem., Int. Ed., 2002, 41, 1386.
Acid-catalyzed protodeboronation: (m) H. G. Kuivila and 25 Over-oxidation was observed mainly in the form of benzylic
K. V. Nahabedian, J. Am. Chem. Soc., 1961, 83, 2159; oxidation.
(n) H. G. Kuivila and K. V. Nahabedian, J. Am. Chem. Soc., 26 T. Diao, T. J. Wadzinski and S. S. Stahl, Chem. Sci., 2012, 3,
1961, 83, 2164; (o) K. V. Nahabedian and H. G. Kuivila, 887.
J. Am. Chem. Soc., 1961, 83, 2167; (6) Protodeboronation by 27 A. Srikrishna and P. C. Ravikumar, Tetrahedron, 2006, 62,
hydrolysis: (p) A. D. Ainley and F. Challenger, J. Chem. Soc.,
1930, 2171.
17 For general strategies to mitigate protodeboronation, see
ref. 12b; For protodeboronation suppression by addition of
9393.
28 (a) D. H. R. Barton, D. A. J. Ives and B. R. Thomas, J. Chem.
Soc., 1955, 2056; (b) D. H. R. Barton, D. A. J. Ives and
B. R. Thomas, J. Chem. Soc., 1954, 903.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 5883–5890 | 5889

View Article Online
Paper
Organic & Biomolecular Chemistry
29 M. Yoshida, T. Kasai, T. Mizuguchi and K. Namba, Synlett, 33 For asymmetric enokipodin
A and B syntheses see:
2014, 25, 1160.
(a) K. P. McGrath and A. H. Hoveyda, Angew. Chem.,
Int. Ed., 2014, 53, 1910; (b) M. Yoshida, Y. Shoji and
K. Shishido, Org. Lett., 2009, 11, 1441; (c) M. Saito and
S. Kuwahara, Biosci., Biotechnol., Biochem., 2005, 69, 374;
(d) S. Kuwahara and M. Saito, Tetrahedron Lett., 2004,
45, 5047. For racemic syntheses see: (e) A. Srikrishna
and M. S. Rao, Synlett, 2004, 374; (f) F. Secci,
A. Frongia, J. Ollivier and P. P. Piras, Synthesis, 2007,
999; (g) J. A. Luján-Montelongo and J. G. Avila-Zarraga,
Tetrahedron Lett., 2010, 51, 2232; (h) D. Lebœuf,
C. M. Wright and A. J. Frontier, Chem. – Eur. J., 2013,
19, 4835.
30 Comparison of the optical rotation of the synthetic
material with that of the natural source revealed that the
absolute stereochemistry matched that of the natural
product. Therefore we conclude that the conjugate addition
of the boronic acid 4 to 3-methyl cyclopent-2-enone, using
PdCl2-(R,R-PhBOX), furnishes the Michael adducts with the
(S)-configuration.
31 N. K. Ishikawa, K. Yamaji, S. Tahara, Y. Fukushi and
K. Takahashi, Phytochemistry, 2000, 54, 777.
32 N. K. Ishikawa, Y. Fukushi, K. Yamaji, S. Tahara and
K. Takahashi, J. Nat. Prod., 2001, 64, 932.
5890 | Org. Biomol. Chem., 2014, 12, 5883–5890
This journal is © The Royal Society of Chemistry 2014