Asymmetric synthesis of chiral cycloalkenone derivatives via palladium catalysis

Article abstract of DOI:10.1039/c3sc53250j

The palladium-catalyzed oxidative desymmetrization of meso-dibenzoates yields γ-benzoyloxy cycloalkenones in good yields and with excellent levels of enantioselectivity. These compounds serve as precursors to a broad range of substituted cycloalkenones, including well-established synthetic building blocks and elaborated cycloalkanone derivatives. The ability to prepare both enantiomers of the oxidative desymmetrization products enables a unified strategy toward stereochemically diverse epoxyquinoid natural products.

Full text of DOI:10.1039/c3sc53250j

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Asymmetric synthesis of chiral cycloalkenone
derivatives via palladium catalysis†
Cite this: DOI: 10.1039/c3sc53250j
*
Barry M. Trost, James T. Masters, Jean-Philip Lumb and Dahlia Fateen
The palladium-catalyzed oxidative desymmetrization of meso-dibenzoates yields g-benzoyloxy cycloalkenones
in good yields and with excellent levels of enantioselectivity. These compounds serve as precursors to a broad
range of substituted cycloalkenones, including well-established synthetic building blocks and elaborated
cycloalkanone derivatives. The ability to prepare both enantiomers of the oxidative desymmetrization
products enables a unified strategy toward stereochemically diverse epoxyquinoid natural products.
Received 27th November 2013
Accepted 13th January 2014
DOI: 10.1039/c3sc53250j
www.rsc.org/chemicalscience
product enantiomers without requiring lengthier or otherwise less
practical synthetic sequences. This consideration is of particular
Introduction
importance given that both enantiomers of certain building
blocks (e.g., 1 and ent-1) have been employed in synthesis.4
Asymmetric catalysis may present an opportunity to prepare
both enantiomers of a target with equal facility through catalyst
control. These preparations may also benet from high atom and
step economy.5,6 Several innovative, catalytic asymmetric syntheses
of g-substituted cycloalkenones have been described.7 These
methods oen target or perform best for a specic cycloalkenone
ring size or type of g-substituent. A general method for the
synthesis of chiral cycloalkenones of various ring sizes and with
different g-substituents would complement these approaches.
Herein we report such a strategy using asymmetric palla-
dium catalysis. This process affords enantioenriched cyclo-
pentenones, cyclohexenones, and cycloheptenones bearing
various heteroatom substituents at the g-position. This protocol
also enables the efficient, asymmetric synthesis of more densely
functionalized cyclohexenone-derived natural products.
Our group has demonstrated that palladium-catalyzed allylic
alkylation presents a unique method for the oxidation of allylic
esters (Fig. 2).8 In this process, ionization of allylic ester 7
generates p-allylpalladium intermediate 8, which undergoes
selective O-alkylation with nitronate 9 to yield 10. Fragmenta-
tion then provides a,b-unsaturated product 11 and oxime 12,
which can be recycled to 9.9
Chiral cycloalkenones are prominent structural motifs in
organic synthesis.1 Chiral g-substituted cycloalkenones in
particular are important building blocks in both natural
product and pharmaceutical synthesis. Heteroatom-substituted
cycloalkenones such as 1–5 (Fig. 1) have been used extensively
in these endeavors.2 Chemoselective elaboration of these
building blocks may also provide densely substituted products
in which every carbon is differentially functionalized. This is
exemplied by cyclohexenone derivative 6, a general structure
that encompasses a number of natural products.
A number of syntheses of such chiral cycloalkenones have
been reported, many of which involve enzymatic processes or
multi-step derivations of chiral pool materials.3 These well-
established approaches can provide products with very high levels
of enantioenrichment, but they may not permit access to both
Meso-1,4-allylic dibenzoates are excellent substrates for
this process. When compounds 13–15 (Fig. 3) are subjected to
the reaction conditions in the presence of our chiral ligand
L1, an oxidative desymmetrization proceeds. This delivers
Fig. 1 Diverse chiral cycloalkenones.
Department of Chemistry, Stanford University, Stanford, CA 94305-4401, USA. E-mail:
bmtrost@stanford.edu
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and copies of NMR spectra and HPLC chromatograms. See DOI:
10.1039/c3sc53250j
Fig. 2 Pd-catalyzed allylic oxidation.
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yields on such a scale were highly variable and generally lower
than yields on smaller scale. This was the case even when the
consumption of 14 was high (TLC). Contemporaneously, other
operations involving 17 revealed its sensitivity toward aqueous
or alcoholic base. Suspecting that such a base (e.g., KOH, from
the KH used to generate nitronate 9) may have been the cause of
the lowered yields on larger scale, we instituted several opera-
tional modications to improve the robustness of the oxidative
desymmetrization reaction. Specically, in the preparation of 9,
the commercial KH dispersion in mineral oil was washed with
THF, rather than the more typical hexanes, to remove not only
the oil but also any KOH present in the material. In addition,
the reactions were limited in duration while monitoring for the
consumption of the meso-dibenzoate (TLC). Once the diben-
zoate was fully or largely consumed, the reaction mixture was
thoroughly quenched with pH 7 buffer prior to extractive
workup.
Validation of these modications came in the form of
increased and more consistent reaction yields. For example, the
oxidation of 14 / 17 proceeded in a reproducible ca. 67% yield
on multi-gram scale (9 mmol, a 35-fold increase in scale from
our original report) while maintaining excellent enantiose-
lectivity (Fig. 5). Applying this modied protocol to 13 and 15
was similarly successful.10
Fig. 3 Oxidative desymmetrization of meso electrophiles. (a) Yield at
68% conversion (b.r.s.m.).
g-benzoyloxy cycloalkenones 16–18 in good yields and with
excellent enantioselectivity. Importantly, either enantiomer of
the desired product can be obtained from the same meso
precursor simply by selecting either (R,R)- or (S,S)-L1.
With the aforementioned building blocks and natural
product motifs serving as motivation, we sought to expand
upon this entry into chiral g-substituted cycloalkenones. We
envisioned pairing this oxidative desymmetrization with the
palladium-catalyzed allylic alkylation of heteroatom nucleo-
philes. This would enable access to a diverse set of g-substituted
cycloalkenones (Fig. 4). Complementing this, ester hydrolysis
would provide g-hydroxy cycloalkenones.
Fig. 5 Multi-gram scale synthesis of 17.
The palladium-catalyzed allylic alkylation (Pd-AA) of cyclo-
alkenones 16–18 with heteroatom nucleophiles proved highly
effective.11 Chiral g-substituted cyclopentenone, cyclohexenone,
and cycloheptenone products were obtained in good yields and
with very good to excellent levels of enantioselectivity (Table 1).
Alkylation with carboxylic, phenolic, and alcoholic nucleophiles
successfully delivered oxygenated building blocks ent-2 and 4 as
well as products 19–21. This synthesis of ent-2 is particularly
signicant, as alkyl alcohols are typically poor nucleophiles in
palladium-catalyzed allylic alkylation.11a The preparation of
acetoxyenone 19 is also noteworthy, as our attempts to engage
the diacetate analogue of 14 in the oxidative desymmetrization
were unsuccessful. Thus, this strategy of Pd-catalyzed oxidative
desymmetrization and Pd-catalyzed transesterication repre-
sents a new and useful solution to this limitation. Alkylation
with nitrogen nucleophiles was also successful, with potassium
phthalimide as well as alkyl amines reacting smoothly to
provide products 22–25.
Fig. 4 Strategy for the synthesis of diverse cycloalkenone derivatives.
We also anticipated that the g-substituents of the cyclo-
alkenones so produced would direct the diastereoselectivity of
subsequent intra- and intermolecular reactions involving the
enone moiety. This would enable the rapid assembly of
molecular complexity with excellent stereocontrol. Further
manipulations would install additional functionality at the
remaining positions, leading to fully elaborated structures of
the type 6.
Notably, the products of conjugate addition were not
observed in any of these cases. Moreover, despite the sensitivity
Results and discussion
In pursuit of these goals, it was necessary to perform the of 17 toward hydroxide or alkoxide base, the basic nature of the
reactions did not hinder us from obtaining good yields of the
desired products.
synthesis of cyclohexenone 17 from meso-diester 14 on larger
(multi-gram) scale. It was soon discovered that the isolated
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Table 1 Scope of Pd-catalyzed allylic alkylation (Pd-AA) of 16–18a
Table 1 (Contd.)
eeb [%]
93
Nucleophile
Electrophile
Product
Yield [%]
eeb [%]
Nucleophile
NaOAc
Electrophile
Product
Yield [%]
64c
16
18
63e
94
NaOAc
17
17
75
62
96
91
a
Reactions performed with 0.1 or 0.2 mmol 16–18 (99% ee), 2.5 mol%
(h3-C3H5)2Pd2Cl2, and 15 mol% PPh3 at 0.2 M and 23 ꢀC for 0.5–20 h. For
b
complete details, see the ESI.†
Determined by chiral HPLC.
c
Performed at 0 ꢀC with 2.5 mol% Pd2dba3$CHCl3 and 7.5 mol%
d
e
(S,S)-L1. 10% of 16 (79% ee) was recovered. Cs2CO3 added. 7.5 mol
% dppf used in place of PPh3. PMB ¼ para-methoxybenzyl, TBS ¼ tert-
butyldimethylsilyl.
The transformations proceeded with high levels of chirality
transfer. This occurred despite the potential for racemization
via p–s–p interconversion involving an O-bound palladium
enolate, a means by which the enantiotopic faces of the p-
allylpalladium species might be equilibrated as in the case of
butenolide electrophiles.12 The substitution appears to proceed
primarily through overall double inversion, with the absolute
stereochemistry of the starting material being conserved in the
product.13
17
80d
98
Further elaboration of these Pd-AA products to more
complex cycloalkanone derivatives could be achieved through
reactions that engaged the enone moiety with the g-substituent.
For example, exposure of ethanolamine derivative 24 to buff-
ered TBAF effected desilylation and oxa-Michael addition,
providing bicyclic morpholine derivative 26 (Fig. 6). The rapid,
stereocontrolled synthesis of this compound further highlights
the utility of this tandem oxidative desymmetrization/allylic
substitution process: the former reaction sets high stereo-
chemical purity at the g-position that is relayed in the diaster-
eoselective conjugate addition, and the latter enables the
introduction of a useful bis-nucleophile unit for a convergent
synthesis of 26.
17
17
66d
92
99
69
Compounds 16–18 were also converted to the corresponding
enantioenriched g-hydroxycycloalkenones 1, 5, and 27 (Fig. 7).
In evaluating methods to hydrolyze these base-sensitive
HN(nPr2)
17
17
69
85
99
87
Fig. 6 Elaboration of 24 to bicyclic ketone 26. Reagents and condi-
tions: TBAF$3H2O, AcOH, THF, 0 / 23 ꢀC, 2 h, 77%.
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g-substituted cyclohexenone to direct the diastereoselectivity of
an intermolecular nucleophilic epoxidation. For instance,
g-hydroxycyclohexenone 1 is known to undergo hydroxyl-
directed syn epoxidation.17 Thus, the preparation of 1 from 17
establishes access to cis product 36, the core structure of 34 and
35. In contrast, 17 could be expected to undergo anti-selective
epoxidation. Hydrolysis would then deliver trans product 37,
featuring the absolute and relative stereochemistry of 28. Per-
forming the latter procedure with ent-17 would provide ent-37, a
precursor to 29–33. Through this strategy, the core structures of
all of the stereochemically diverse products 28–35 could be
accessed from a common precursor, meso-diester 14.
Focusing on the synthesis of (ꢁ)-tricholomenyn A (28), we
investigated the epoxidation of 17 (Fig. 10). Pleasingly, upon
exposure to H2O2 and catalytic benzyltrimethylammonium
hydroxide (Triton B),18 17 cleanly underwent epoxidation to give
38 as a single diastereomer (1H NMR) and in 99% ee (chiral
HPLC). Thus, the oxygenation and the absolute and relative
stereochemistry of the trans epoxyquinoids were set, with
excellent enantio- and diastereoselectivity, in three steps from
commercial 1,3-cyclohexadiene.19 The fact that the oxidative
desymmetrization delivered 17 with a g-benzoyloxy substituent
proved to be a signicant synthetic advantage, as the epoxida-
tion of the g-acetoxy analogue led to poorer diastereoselectivity
Fig. 7 Synthesis of g-hydroxycycloalkenones. Reagents and condi-
tions: 0.2 mmol 16–18 (99% ee), Me3SnOH, 1,2-dichloroethane, 80 ꢀC,
14 h. Yields at (a) 65%, (b) 73%, and (c) 66%, conversion (b.r.s.m.).
compounds, Me3SnOH—which is most typically used for the
hydrolysis of methyl esters to their acids14—emerged as the
optimal reagent for this transformation. To the best of our
knowledge, this represents its rst use for the saponication of
an acyloxy group at a secondary stereocenter, to yield a chiral
alcohol. In these events, the g-hydroxy products were obtained
with excellent levels of enantioenrichment, and the sense of
absolute stereochemistry was retained in the products.15
Emboldened by the chemo-, enantio-, and diastereoselective
preparation of the products illustrated in Table 1, Fig. 6 and 7, we
next examined the synthesis of more densely functionalized
cyclohexenone-derived natural products. We targeted several
members of the epoxyquinoid class of natural products,
compounds 28–35 (Fig. 8).16 These biologically active natural
products bear an intriguing stereochemical feature: although
structurally similar to each other, certain members exhibit the
opposite sense of absolute stereochemistry (e.g., 28 vs. 29–33),
while others display different relative stereochemistry between
the epoxide and the alcohol (e.g., 31 and 32 vs. 34 and 35).
Moreover, forat least one member ofthis family(harveynone, 29),
both enantiomers are naturally occurring yet are derived from
dissimilar sources and exhibit different biological activities.16a
and to the formation of byproducts. These results are consistent
20
´
with the observations of Bayon, Figueredo, and co-workers.
Hydrolysis and acetylation proceeded smoothly, affording
39. Completion of the synthesis then required oxidation of the
ketone to an enone, a-iodination, and side chain installation. A
number of oxidation conditions were investigated on both 38
and 39 (e.g., selenylation/elimination, Saegusa-Ito oxidation,
bromination/elimination, IBX oxidation of a silyl enol ether,21
and Pd(TFA)2-catalyzed aerobic oxidation22), all of which led to
no or trace product and/or decomposition.23 Procedures
involving the use of a lithium enolate at temperatures above
ꢁ78 ꢀC proved especially problematic, leading to extensive
decomposition. As oxidations of this sort have been performed
on g-silyloxy, a,b-epoxyketones,18 we suspected that the
Fig. 8 Stereochemically diverse epoxyquinoid natural products.
We proposed a unied strategy toward the structural cores of
28–35 from chiral cyclohexenones 17 and ent-17 (Fig. 9). This
approach would exploit the ability of an appropriately
Fig. 10 Total synthesis of (ꢁ)-tricholomenyn A (28). Reagents and
conditions: (a) H2O2 (30% aq.), 10 mol% Triton B (40% aq.), THF, 0 ꢀC,
45 min, 79%; (b) LiOH, MeOH, 0 ꢀC, 1 h, 83%; (c) Ac2O, DMAP, MeCN,
0 / 23 ꢀC, 10 min, 88%; (d) LiHMDS, THF, ꢁ78 ꢀC, 30 min, then 40,
ꢁ78 ꢀC, 30 min, 58%; (e) I2, PhI(OCOCF3)2, pyridine, BHT, CH2Cl2,
23 ꢀC, 24 h, 49–66%; (f) 10 mol% Pd(OAc)2, 10 mol% CuI, 20 mol%
AsPh3, 43, THF, 0 ꢀC, 1 h 30 min, 55–60%. Triton B ¼ benzyl-
trimethylammonium hydroxide, DMAP ¼ 4-dimethylaminopyridine,
HMDS ¼ hexamethyldisilazane, BHT ¼ butylated hydroxytoluene.
Fig. 9 Stereodivergent access to epoxyquinoid precursors.
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incompatibility was due to the ester moiety, the electrophilic Mukaiyama protocol, we considered performing this reaction
nature of which promoted side reactions. However, rather than on 44 to deliver 45 directly in one step. Indeed, this protocol
lengthening the synthesis with
a protection/deprotection proved very effective, providing the enone in good yield. From
sequence involving alcohol 37, we investigated procedures in 45, syntheses of 29 and 30 are known.29
which the ketone enolate of 39 could be both formed and
reacted at low temperature. We turned to the method of
Mukaiyama,24 which involved sulfenylation of the lithium eno-
Conclusions
late of 39 with 40 and subseꢀquent elimination, both of which We report a strategy for the synthesis of a diverse set of chiral
proceeded efficiently at ꢁ78 C to deliver 41.
cycloalkenone derivatives via asymmetric palladium catalysis.
The conversion of 41 to iodoenone 42 initially proved chal- Using a newly optimized reaction procedure, the oxidative
lenging, as typical conditions (I2 in CH2Cl2/pyridine25) led to desymmetrization of meso-dibenzoates 13–15 affords cyclo-
decomposition. This may have been the result of interactions alkenones 16–18 in good yields and with excellent enantiose-
between the acetoxy group of 41 and these co-solvent amounts lectivity. These products serve as platforms from which a variety
of pyridine. Success was realized by applying the conditions of of substituted cycloalkenones can be prepared through palla-
Benhida26a (as applied by Hayashi26b), which employ only stoi- dium-catalyzed allylic alkylation, including established
chiometric pyridine and a more activated iodinating reagent.
building blocks such as ent-2 and 4. The products are obtained
From 42, cross coupling with known stannane 4316e afforded in good yields and with high levels of enantioenrichment. This
(ꢁ)-tricholomenyn A (28), the analytical data for which matched Pd-AA approach also enables the convergent introduction of
literature data. The observed optical rotation ([a]2D3 ¼ ꢁ 234.6ꢀ useful functionality, allowing for the synthesis of more elabo-
(c ¼ 0.96, CH2Cl2)) was in line with that reported for material rate cycloalkanone derivatives. The hydrolysis of 16–18 to
obtained using enzymatic resolution as the source of chirality enantioenriched g-hydroxycycloalkenone building blocks is
([a]2D9 ¼ ꢁ 235.7ꢀ (c ¼ 1.47, CH2Cl2)).27
also demonstrated.
Synthetic access to natural products 29–33 was then estab-
Cyclohexenones 17 and ent-17 provide entry points to epox-
lished through the synthesis of ent-37 from ent-17 (prepared yquinoid natural products 28–35 through stereoselective
from 14 in 98% ee using (S,S)-L1). Silylation afforded 44, from transformations and through reactions that elaborate the entire
which syntheses of 31–33 are known (Fig. 11). The analytical data cyclohexenone structure. This approach to these stereochemi-
for 44, including optical rotation, was in line with data reported cally diverse products proceeds with excellent levels of enantio-
for material prepared through an enzymatic approach.18
and diastereoselectivity, and it establishes a concise, unied
strategy starting from a single meso precursor (14).
Acknowledgements
We thank the National Institutes of Health (GM33049) and the
National Science Foundation (CHE-0948222) for their generous
support of our programs. J.T.M. gratefully acknowledges
support from an Abbott Laboratories Stanford Graduate
Fellowship. J.-P.L. is the recipient of an NIH postdoctoral
fellowship (GM083428). We also thank Johnson-Matthey for
their generous gi of palladium salts.
Fig. 11 Syntheses of epoxyquinoids 29–33. Reagents and conditions:
(a) TBSCl, imidazole, CH2Cl2, 23 ꢀC, 16 h, 88%; (b) LiHMDS, THF,
ꢁ78 ꢀC, 30 min, then 40, ꢁ78 ꢀC, 1 h, 66%.
Notes and references
1 See: (a) T.-L. Ho, Enantioselective Synthesis: Natural Products
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The asymmetric synthesis of 44 has itself been the subject of
past studies, for both natural product synthesis and pharma-
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reduction,18 enzymatic resolution,28a chiral pool material,28b or
asymmetric deprotonation,28c strategies that either required
eight or more steps or, in the latter case, delivered more modest
(77–85%) ee. The ve-step procedure presented herein, which
provides 98–99% ee, complements these approaches.
The oxidation of ketone 44 to enone 45 has previously been
performed via silyl enol ether formation followed by either
selenylation/elimination18 or stoichiometric Saegusa-Ito oxida-
tion.28a Given our successful oxidation of ketone 39 via the
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P. Bayon and M. Figueredo, Eur. J. Org. Chem., 2011,
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1534.
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a
compared to a smaller scale reaction, an incompletely 22 T. Diao and S. Stahl, J. Am. Chem. Soc., 2011, 133, 14566.
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base. The results listed in Fig. 3 were obtained using this
modied reaction procedure (>1 mmol scale). For
complete experimental details, see the ESI.†
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yields. For further discussion, see the ESI;† see also
K. C. Nicolaou, T. Montagnon, P. S. Baran and Y.-L. Zhong,
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