Pd(II)-Catalyzed Enantioselective Desymmetrization of Polycyclic Cyclohexenediones: Conjugate Addition versus Oxidative Heck

Article abstract of DOI:10.1021/acs.orglett.9b03293

Pd(II)-catalyzed desymmetrization of polycyclic cyclohexenediones has been achieved with high enantio- and diastereoselectivities. Up to five contiguous stereocenters are desymmetrized, while simultaneously, an additional stereocenter is created by the enantioselective conjugate addition. Surprisingly, the conjugate addition products dominate even under typical oxidative Heck conditions, and these observations may provide some insight into the competition between the two related reactions.

Full text of DOI:10.1021/acs.orglett.9b03293

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd(II)-Catalyzed Enantioselective Desymmetrization of Polycyclic
Cyclohexenediones: Conjugate Addition versus Oxidative Heck
Claire J. C. Lamb, Filipe Vilela, and Ai-Lan Lee*
Institute of Chemical Sciences, Heriot-Watt University, Edinburgh EH14 4AS, Scotland, U.K.
S
* Supporting Information
ABSTRACT: Pd(II)-catalyzed desymmetrization of polycyclic
cyclohexenediones has been achieved with high enantio- and
diastereoselectivities. Up to five contiguous stereocenters are
desymmetrized, while simultaneously, an additional stereo-
center is created by the enantioselective conjugate addition.
Surprisingly, the conjugate addition products dominate even
under typical oxidative Heck conditions, and these observa-
tions may provide some insight into the competition between
the two related reactions.
d(II)-catalyzed oxidative Heck1 and conjugate addition2
recently developed the first Pd(II)-catalyzed oxidative Heck
3
Preactions are two mechanistically related
desymmetrization of cyclopentenediones 1 (Scheme 1), which
provides a novel and expedient way of enantioselectively
desymmetrizing all-carbon quaternary centers.9,10
chemical
transformations that have recently been exploited for various
elegant catalytic enantioselective reactions.4,5 The use of
Pd(II) rather than Pd(0) generally allows for lower temper-
atures, as well as compatibility with air-stable N,N-bidentate
ligands, such as pyridine-oxazoline (PyOx)6 (Scheme 1).1a
Exploiting Pd(II) catalysis for enantioselective desymmetriza-
tion7 reactions, however, has been much less explored but is a
potentially powerful method for installing multiple stereo-
centers or problematic all-carbon quaternary stereocenters8 in
an efficient one-step procedure. As a proof of concept, we
In an effort to challenge the Pd(II) desymmetrization
methodology even further, we sought to investigate polycyclic
cyclohexenediones 4 (Diels−Alder adducts of benzoquinones
and cyclopentadienes) as potential substrates. If this process is
successful, up to five contiguous stereocenters, including all-
carbon quaternary centers, can be desymmetrized in one
efficient step. Previous strategies for desymmetrizing 4 include
selective reduction of one of the ketones11 and organo-
catalyzed addition−elimination of nitroalkanes.12 The desym-
metrized scaffolds are important as they have been exploited as
chiral building blocks in natural product syntheses,13 so new
ways of desymmetrizing such scaffolds would be of interest.
Herein, we present the first Pd(II)-catalyzed intermolecular14
conjugate addition desymmetrization reaction, whereby meso
substrates 4 are desymmetrized to form up to six stereocenters
in one step (Scheme 1). Surprisingly, conjugate addition
products 5 dominate, even under conditions that would
typically yield oxidative Heck products, and these observations
may provide some insight into the competition between the
two related reactions.
Scheme 1. Pd(II)-Catalyzed Desymmetrizations
Selected optimization studies using substrate 4a are
presented in Table 1 (see the Supporting Information for
further optimization studies). Using previously established
oxidative Heck conditions15 (entry 1) surprisingly yielded only
conjugate addition product 5a in 74% yield and >20:1 dr.
Because this constitutes the first intermolecular Pd(II)-
catalyzed conjugate addition desymmetrization reaction and
successfully achieves our initial aim of desymmetrizing multiple
contiguous stereocenters (four in this case, with the added
Received: September 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03293
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. Selected Optimization Studies
Scheme 2. Substrate Scope of Polycyclic Cyclohexenediones
time
(h)
temp
(°C)
yield
a,b
d
entry
ligand
(%)
er
1
2
3
1,10-phenanthroline
24
24
24
24
24
72
72
72
rt
30
40
40
50
30
30
30
30
74
−
93:7
92:8
nd
85:15
92:8
nd
nd
nd
L-A
L-A
L-A
L-A
L-A
L-C
L-B
16
e
25
c
h
4
16
63
5
f
6
80
f
d
h
7
f
14
h
8
trace
fg
9 ,
d
h
L-A
72
35
a
b
c
d
Isolated yields. dr of >20:1. Carried out in air. er determined by
e
CSP-HPLC. Yield determined by 1H NMR analysis using 1,3,5-
trimethoxybenzene as the internal standard. For 72 h. DMA as the
solvent. Not determined.
f
g
h
bonus of creating a fifth stereocenter), we were pleased with
the result and progressed to investigate the enantioselective
reaction using chiral PyOx ligands (entries 2−9). Initial
attempts using tBuPyOx ligand L-A at 30 and 40 °C led to very
promising enantiomeric ratios (93:7 and 92:8, respectively)
but poor yields (16% and 25%, entries 2 and 3, respectively).
Replacing the O2 atmosphere with air is also detrimental to the
yield (entry 4).16 Although higher temperatures improve the
yield (50 °C, 63%), it is at the expense of the er (85:15, entry
5). Pleasingly, increasing the reaction time to 72 h at the lower
temperature of 30 °C successfully improves the yield to 80%
without affecting the er (entry 6). Switching from ligand L-A
to L-C or L-B resulted in very poor conversions (entry 7 or 8,
respectively), while substituting DMF for the less ligating
dimethylacetamide (DMA) also decreased the reactivity (entry
9).
With optimized conditions in hand, a substrate scope screen
of various polycyclic cyclohexenediones 4 was performed
(Scheme 2). First, however, a slightly higher temperature of 40
°C was found to be more appropriate for the general substrate
scope screen as it improved conversions without adversely
affecting the enantiomeric ratios. Substrate 4b, with dimethyl
substitution at the bridgehead positions and diphenyl
substitution at the alkene, proceeds smoothly with a good
yield and an excellent er (5b, 70%, 97:3 er). Methyl
substitution at the methylene bridge in 4c is also well-tolerated
(5c, 73%, 93:7 er), which means that five contiguous
stereocenters have been successfully desymmetrized, and
further creating a sixth (see also 5g). Acid sensitive acetal
functionality and chlorides are well-tolerated (5a, 80%, 92:8 er;
5a′, 65%, 90:10 er), but more importantly, unprotected ketone
functionality does not interfere with the reaction, with 4d and
4e furnishing the desired conjugate addition products 5d
(68%, 94:6 er) and 5e (72%, 92:8 er), respectively, in good
yields and enantiomeric ratios.
a
b
Isolated yield; dr of >20:1; er determined by CSP-HPLC. On a 0.1
c
d
mmol scale. At 30 °C. Pd(OAc)2 (10 mol %) and tBuPyOx L-A (11
mol %). 5-CF3 BuPyOx L-B (6 mol %), on a 0.05 mmol scale. 4-
e
f
t
g
t
CF3 BuPyOx L-C (6 mol %). 6h is the oxidative Heck product.
h
1,10-Phenanthroline as the ligand.
4f, however, performs sluggishly under these optimized
conditions, albeit with a very good er (5f, 43%, 97:3 er; see
the Supporting Information for optimization). At this point, we
decided to investigate more typical conjugate addition
conditions4b (conditions B). It was found that conditions B
worked well to furnish 5f and 5g in 68% and 64% yields,
respectively, with a good 95:5 er.
The behavior of the Diels−Alder adduct of benzoquinone
and anthracene 4h was very different from that of substrates
4a−g under optimized conditions A, yielding an inseparable
mixture of oxidative Heck (6h) and conjugate addition (5h)
products (91:9 6h:5h). Thus far, substrate 4h is the only one
to produce any oxidative Heck product 6 (vide infra).
However, under more typical conjugate addition conditions
B, conjugate addition product 5h is furnished exclusively (65%,
85:15 er). Unexpectedly, neither conditions A nor conditions
B could afford desired product 5i from the less substituted
substrate 4i (see the Supporting Information). We postulate
that the presence of the less substituted alkene (cf. 4a−h) at
So far, dichloro and diphenyl substitutions at the alkene have
been shown to be tolerated well under our original conditions
A, regardless of substitution at the bridgehead or methylene
bridge positions. Tetramethyl-substituted Diels−Alder adduct
B
DOI: 10.1021/acs.orglett.9b03293
Org. Lett. XXXX, XXX, XXX−XXX

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the far end of the molecule is interfering with the catalytic
cycle, potentially causing the substrate to act as a bidentate
diene ligand for Pd(II) (see the Supporting Information). The
Diels−Alder adduct of benzoquinone and phencyclone 4j also
fails to form any desired product 5j, although this could be
attributed to the very poor solubility of 4j.
Next, the arylboronic acid scope was investigated (Scheme
4). The results for 5b (para, 70%, 97:3 er), 5k (meta, 58%,
Scheme 4. Arylboronic Acid Substrate Scope
A 1 mmol scale reaction to produce 5e under the exact same
conditions demonstrates that the reaction is scalable, albeit
with a slight decrease in yield compared to that of the small
scale reaction (60% and 93:7 er vs 73% and 92:8 er).
Because 4h is the only substrate of those screened to show
any sign of oxidative Heck product 6h under what would
typically be considered oxidative Heck conditions (conditions
A, inseparable 9:91 5h:6h mixture), we were keen to
investigate whether the reaction could be pushed to yield
solely oxidative Heck product 6h. While higher temperatures
were found to favor oxidative Heck over conjugate addition, in
situ dehydrogenation17 of 6h to form benzoquinone 7 was also
favored at higher temperatures. Thus, benzoquinone 7 (which
is, unfortunately, achiral)18 is the sole observable product at
100 °C (Scheme 3). It should be noted that resubjecting
Scheme 3. Oxidative Heck to Benzoquinones 7 and 9 and
Control Reaction
a
Isolated yields; dr of >20:1; er determined by CSP-HPLC.
Pd(OAc)2 (10 mol %) and L-A (11 mol %). Increased catalyst
b
c
and ligand loading to promote full conversion to product due to co-
elution with the starting material during column chromatography.
d
e
Reacted for 92 h. Portionwise addition of catalyst and ligand at 5/6
f
mol % at the start and then a further 5/6 mol % after 24 h. Yield
determined by H NMR analysis using 1,3,5-trimethoxybenzene as
the internal standard. Reacted at 50 °C.
1
g
97:3 er), and 5l (ortho, 46%, 92:8 er) show a clear trend based
on sterics, with the ortho-substituted arylboronic acid reacting
most sluggishly (5l), although only a slight drop in er is
observed (92:8 vs 97:3). The unprotected hydroxyl group is
also compatible under these conditions (5m, 65%, 98:2 er).
Phenyl- and p-tolylboronic acids both furnished desired
products 5n and 5o in good yields and excellent enantiomeric
ratios (83% and 81%, respectively, 97:3 er). Electron-
withdrawing halogens are tolerated in the reaction, with m-
chloro-p-methoxy-phenylboronic acid and p-fluorophenylbor-
onic acid furnishing 5p (51%, 97:3 er) and 5q (67%, 96:4 er),
respectively. p-Amidophenylboronic acid reacted more slug-
gishly (5r, 42%), although the er of 98:2 is excellent. Increasing
the electron-withdrawing substituent from p-F to p-ethoxyester
caused a decrease in reactivity (5s, 13%) but still gave a good
er of 95:5. Although the reactivity shows some sensitivity to
the sterics and electronics of the arylboronic acids,
enantiomeric ratios remain very good throughout.
The absolute stereochemistry of the conjugate addition
products was determined through single-crystal X-ray
crystallography of compound 5a (see the Supporting
Information).24 The dr is excellent throughout (>20:1) for
4a−h, presumably because the aryl prefers to be delivered from
the less hindered exo face. According to literature reports, the
migratory insertion step is enantio-determining and the aryl
group transmetallates trans to the tert-butyl group of the chiral
oxazoline ligand to avoid steric hindrance.25 On the basis of
these assumptions, a model for asymmetric induction TS-A is
shown in Figure 1. Of the two possible trans approaches
conjugate addition product 5h to reaction conditions A results
in recovered 5h and no oxidative Heck product 6h or
benzoquinone 7 (Scheme 3). This control reaction indicates
that oxidative Heck product 6h observed in Scheme 2 is not
the result of dehydrogenation of 5h but a true oxidative Heck
reaction from 4h.
For comparison, a benzoquinone19,20 substrate 8 was also
found to form chiral benzoquinone product 9.21 In this case,
oxidative Heck coupling successfully occurs to form 9 in an
excellent 96% yield but with a poor 63:37 er.22 It is interesting
to note that the ease of reacting 8 compared to 4i indicates
that the alkene in 4i is indeed most likely responsible for its
nonreactivity (vide ante).23 Benzoquinone substrate 8 is more
planar and less puckered compared to related enediones 4a−g,
and the relative accessibility of the endo face in 8 may
potentially account for the disparity in enantiomeric ratios.
C
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isomerization of I to III be unfavorable, then the competing
protonolysis to form conjugate addition product 5 will
dominate. However, placing the Pd in the sterically hindered
endo face in III is presumably very unfavorable for tricyclic
systems 4a−g (compared to monocyclic systems such as 1),
which may explain why these substrates form only conjugate
addition product 5. Benzoquinone 8, however, has a much
more accessible endo face, so placement of Pd in its endo face
(III) is much more favorable, thereby allowing for oxidative
Heck couplings. By the same argument, substrate 4h, with its
unique tricyclic core structure (cf. 4a−g), is thought to exhibit
oxidative Heck reactivity due to the more favorable isomer-
ization to III.
In conclusion, we have developed the first Pd(II)-catalyzed
intermolecular conjugate addition desymmetrization reaction.
Desymmetrization of meso polycyclic cyclohexenediones 4 via
a conjugate addition reaction furnishes up to five contiguous
stereocenters while also creating an additional stereocenter in
one efficient step, in up to 98:2 er and >20:1 dr. Surprisingly,
only conjugate addition product 5 is observed for substrates
4a−g even under typical oxidative Heck reaction conditions,
while oxidative Heck is observed with substrates 4h and 8. The
observed trend is thought to be due to steric hindrance in the
endo face of 4a−g disfavoring the necessary Pd-enolate
isomerization step (I to III) required for the oxidative Heck
process.
Figure 1. Postulated model for asymmetric induction (substituents
omitted for the sake of clarity).
shown, only TS-A gives the correct enantiomer. TS-B is
presumably unfavorable due to steric hindrance between the
top of the bicyclic bridge and the tert-butyl group of the chiral
ligand. TS-A avoids this steric clash and results in the observed
R geometry.
The postulated mechanism for oxidative Heck versus
conjugate addition reaction is shown in Scheme 5,3 which
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 5. Plausible Mechanism for Pd(II)-Catalyzed
Conjugate Addition versus Oxidative Heck
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03293.
Optimization studies, all experimental details, character-
ization, and copies of NMR data (PDF)
Accession Codes
CCDC 1946937 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: A.Lee@hw.ac.uk.
ORCID
Filipe Vilela: 0000-0003-2701-9759
Ai-Lan Lee: 0000-0001-9067-8664
Notes
The authors declare no competing financial interest.
may provide insight into why only conjugate addition products
are observed for 4a−g, even under typical oxidative Heck
conditions, while 4h and 8 are the only substrates to show any
oxidative Heck products. Following transmetalation and
migratory insertion, Pd-enolate intermediate I has the β-H
anti to Pd (for cyclic substrates), so syn-β-H elimination
cannot immediately occur. To access oxidative Heck product
6, conditions that promote isomerization of the Pd-enolate I
→ II → III are presumably necessary, to place the β-H syn to
Pd, for the desired syn-β-H elimination to take place. Should
ACKNOWLEDGMENTS
■
The authors thank the Engineering and Physical Sciences
Research Council and CRITICAT Centre for Doctoral
Training for financial support (Ph.D. studentship to C.J.C.L.;
Grant EP/L016419/1). The authors thank Wiebke G. Daul
(Heriot-Watt University) for preliminary studies. Mass
spectrometry data were acquired at the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
D
DOI: 10.1021/acs.orglett.9b03293
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Letter
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(15) We have previously found that polar aprotic solvents tend to
promote the Pd(II)-catalyzed oxidative Heck reaction while
chlorinated solvents such as DCE are typically used to promote the
conjugate addition reaction. See refs 3 and 4 versus ref 5.
(16) While the conjugate addition reaction does not technically
require any oxidant, Pd(II)-catalyzed oxidative side reactions such as
homocoupling of 2 and phenol formation from 2 form Pd(0). While
these side reactions typically only occur in <10% combined yields,
running the reaction in O2 is thought to help by reoxidizing any Pd(0)
formed via these side reactions back to the active Pd(II) catalyst.
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Stahl, S. S. Palladium-Catalyzed Aerobic Dehydrogenation of Cyclic
Hydrocarbons for the Synthesis of Substituted Aromatics and Other
Unsaturated Products. ACS Catal. 2016, 6, 8201−8213. See also 9b.
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of symmetry 90° to the one that was broken in this molecule.
(19) For our previous work on Pd(II)-catalyzed oxidative Heck
couplings with benzoquinones, see: Walker, S. E.; Jordan-Hore, J. A.;
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Direct C-H Functionalization of Benzoquinone. Angew. Chem., Int. Ed.
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Functionalization of Quinones. Eur. J. Org. Chem. 2019, 2019, 2179−
2201.
(21) Benzoquinones can act as an oxidant to Pd(0) and thus be
reduced to the corresponding hydroquinones; DCBQ is therefore
added as an oxidant in this case.
(22) With ligand A, 9 is formed in 52% yield and 66:34 er. See the
Supporting Information for studies of the optimization of 8.
(23) Attempts were made to selectively reduce the more electron
rich alkene in 4i, but these were not successful.
(24) All other absolute stereochemistry assignments are by analogy.
(25) Holder, J. C.; Zou, L.; Marziale, A. N.; Liu, P.; Lan, Y.; Gatti,
M.; Kikushima, K.; Houk, K. N.; Stoltz, B. M. Mechanism an
Enatioselectivity in Pd-Catalysed Conjudate Addition of Arylboronic
Acids to B-substituted Cyclic Enones: Insights from Computational
and Experiment. J. Am. Chem. Soc. 2013, 135, 14996−15007.
F
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