Palladium Catalyzed Stereoselective Arylation of Biocatalytically Derived Cyclic 1,3-Dienes: Chirality Transfer via a Heck-Type Mechanism

Article abstract of DOI:10.1021/acs.orglett.0c00708

Microbial arene oxidation of benzoic acid with Ralstonia eutropha B9 provides a chiral highly functionalized cyclohexadiene, suitable for further structural diversification. Subjecting this scaffold to a Pd-catalyzed Heck reaction effects a regio-and ster

Full text of DOI:10.1021/acs.orglett.0c00708

pubs.acs.org/OrgLett
Letter
Palladium Catalyzed Stereoselective Arylation of Biocatalytically
Derived Cyclic 1,3-Dienes: Chirality Transfer via a Heck-Type
Mechanism
‡
‡
̈
Andrew J. Paterson, Petter Dunås, Martin Rahm,* Per-Ola Norrby, Gabriele Kociok-Kohn,
Simon E. Lewis,* and Nina Kann*
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ABSTRACT: Microbial arene oxidation of benzoic acid with
Ralstonia eutropha B9 provides a chiral highly functionalized
cyclohexadiene, suitable for further structural diversification.
Subjecting this scaffold to a Pd-catalyzed Heck reaction effects a
regio- and stereoselective arylation of the cyclohexadiene ring, with
1,3-chirality transfer of stereogenic information installed in the
microbial arene oxidation. Quantum chemical calculations explain
the selectivity both by a kinetic preference for the observed arylation position and by reversible carbopalladation in competing
positions. Further product transformation allowed the formation of a tricyclic ketone possessing four stereogenic centers. This
demonstrates the capability of the method to introduce stereochemical complexity from planar nonchiral benzoic acid in just a few
steps.
Scheme 1. Arylation of Microbial Arene Oxidation Products
he biocatalytic transformation of arenes into dearomat-
Tized cis-dihydroxylated species can be achieved using
arene dioxygenase enzymes via microbial arene oxidation
(MAO).1 While complete oxidation affords a catechol, the use
of mutant strains2 or recombinant organisms3 allows isolation
of the intermediate chiral diol, enabling conversion of a flat
arene into a chiral functionalized scaffold, suitable for further
transformations. Many dioxygenase enzymes are known and
generally lead to ortho/meta dihydroxylation with respect to
pre-existing functionality.4 However, benzoate dioxygenase
(BZDO), expressed by R. eutropha B9,5 transforms benzoic
acid with complementary selectivity, affording ipso/ortho
dihydroxylated product 1 as a single enantiomer (Scheme
1a). Compound 1 has been subjected to various trans-
formations such as oxidations and acetalization6 and been used
for preparing natural products7 and pharmaceuticals.8 One
diversification approach could involve metal-catalyzed cross-
coupling of the diene sp2-carbons.9 The Mizoroki−Heck
reaction10 allows arylation of an alkene under Pd-catalysis and
can potentially lead to chirality transfer from one ring carbon
to another. Such chirality transfer has been demonstrated in
the synthesis of C-glycosides,11 where the coupling effects a
double bond migration and 1,3-chirality transfer (Scheme 1b).
However, achieving selectivity with a diene such as 1 could be
challenging. Studies of Pd-catalyzed reactions involving
substrates obtained via MAO are limited,6c,12 and to the best
of our knowledge, Heck arylation of 1 and its derivatives has
not been described. Furthermore, this type of chirality transfer
in intermolecular Heck reactions has not been investigated to
any great extent outside of glycal arylations. We herein report
Received: February 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00708
© XXXX American Chemical Society
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our findings concerning the conversion of esters and amides 2,
obtained from 1, into chiral arylated 1,4-dienes such as 3
(Scheme 1c). A quantum chemical study was also conducted
to elucidate the origin of the high selectivity.
Scheme 2. Scope and Limitations of Aryl Halides in the
Reaction with 2a
a
Results and Discussion. Ester 2a (Table 1), with an acetal
protected cis-diol, was chosen as a suitable substrate and was
Table 1. Optimization of the Pd-Catalyzed Arylation of 2a
a
with Iodobenzene
b
entry
base
base (equiv)
additive
3aa (%)
1
2
3
4
5
6
7
8
9
AgOAc
NaOAc
DIPEA
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
2
2
2
2
1.4
1.4
1.4
1.4
1.4
1.4
−
−
−
−
60
24
34
18
61
70
70
64
78
80
−
PPh3
dppe
P(OEt)3
P((4-CF3)C6H4)3
P((4-CF3)C6H4)3
c
de
,
10
a
Performed under reflux conditions in a Carousel 12 Plus Reaction
b
c
Station from Radleys, using a metal heating block. NMR yield. 10
mol % dppe. 5 mol % Pd(OAc)2. 10 mol % P((4-CF3)C6H4)3.
d
e
subjected to Pd-catalyzed arylation with iodobenzene. With a
diene such as 2a, several products can potentially be formed
under these conditions. However, we were gratified to see that
using iodobenzene, Pd(OAc)2, and AgOAc in acetonitrile
resulted in the completely regio- and diasteroselective arylation
of 2a to form diene 3aa in 60% yield (Table 1, entry 1).
Through this reaction, stereochemical information initially
present in the diol moiety is transferred to a more distal
position.
Other bases and silver sources are less effective (entries 2−
4), but the amount of silver salt could be reduced to 1.4 equiv,
maintaining the same reactivity (entry 5). However, a
palladium loading of 10% and 4 equiv of the aryl iodide
were necessary for full conversion and a high degree of product
formation. A range of phosphine ligands were subsequently
screened (entries 6−9), and P((4-CF3)C6H4)3 (entry 9) was
identified as most effective. After reassessing the reaction
conditions, the use of P((4-CF3)C6H4)3 allows the palladium
and ligand loading to be reduced to 5% and 10%, respectively,
while maintaining comparable reactivity (entry 10; see
Supporting Information (SI) for full optimization).
a
Performed in a Carousel 12 Plus Reaction Station from Radleys,
using a metal heating block. NMR yields (isolated yields in
parentheses). Products formed with complete diastereoselectivity.
With the optimized conditions in hand, we investigated the
scope of arylation reagents using ester 2a (Scheme 2). Aryl
iodides with electron-rich or -neutral substituents at the para
position perform comparably well, providing the arylated
products in good yields (compounds 3aa−3ad). Electron-
deficient arenes afford products in somewhat lower yields
(3ae−3af). Notably, 1-bromo-4-iodobenzene reacts selectively
at the Ar−I bond, producing 66% of 3ae. Different substitution
patterns on the aryl ring are also tolerated with 2- or 3-
substituted aryl iodides (3af−3am). In terms of limitations,
certain functional groups are not tolerated on the aryl iodide,
including aldehyde, phenol, and amine. Whereas indole can be
coupled to the 7-position (3am), other heterocyclic aryl
iodides are unsuccessful. Likewise, other aryl halides or
pseudohalides do not react under these conditions. A crystal
structure of compound 3ah (Figure 1) verifies this structure
unequivocally.
We next investigated the scope of the starting diene. In
addition to ester 2a, amides and secondary esters perform well,
affording 3ba−3db in good yields (Scheme 3). Furthermore, a
Weinreb amide, as in 3eb, could be applied and is potentially
useful for postfunctionalization. Substrates 1 and 4−6 were
also tested but did not afford arylated products.
B
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Scheme 4. Further Transformations of 3ba, 3bf, and 3bi
Figure 1. Solid state structure of compound 3ah. Ellipsoids are
represented at 50% probability. H atoms are shown as spheres of
arbitrary radius. CCDC 1961899.
a
Scheme 3. Substrate Scope and Limitations
intramolecular Claisen condensation, and this feature was
investigated. Treating 7bf with NaOMe in methanol led to the
formation of aromatized fluorenone 8 in 71% yield, following
elimination of H2O. While this demonstrates the applicability
of these products as enolates, valuable stereochemical
information is lost here. To explore other possibilities, we
subjected 3bi, with two acetal functionalities, to acidic
conditions, envisaging that both groups could be deprotected
in one step (Scheme 4, route B). A subsequent acid catalyzed
aldol reaction could then result in a cyclized product. We were
delighted to see that the use of p-TsOH in wet acetonitrile led
to the formation of tricyclic compound 9. Remarkably, this
product, which contains four stereogenic centers, forms with
complete diastereoselectivity. This reaction demonstrates that
our method can be utilized to build up significant molecular
complexity from a flat achiral starting material, benzoic acid.
In order to explain the high regioselectivity and facial
selectivity of the transformation, we have performed a
quantum chemical study, relying on Density Functional
Theory (DFT) calculations. Our calculations, which were
done with Gaussian16,13 were mostly performed at the B3LYP-
D3/def2-TZVP//def2-SVPD level of theory. The Solvent
Model Density (SMD) method was used to include implicit
consideration of acetonitrile solvation effects.14 More details of
the calculations are given in the Supporting Information. The
B3LYP-D3 functional has a reported mean average deviation
from CCSD(T)/CSB results of 1.6 and 2.3 kcal/mol for
barrier heights and reaction energies, respectively, in a
selection of Pd-catalyzed reactions.15 The method has also
previously been used to model Heck reactions.16
The formation of 3aa, without phosphine ligands, was
chosen as a model system for our calculations (Table 1, entry
5). Because the experimental reaction was performed with a
silver additive in a polar solvent, a fast halide abstraction from
palladium was assumed. In other words, all structures were
modeled using acetate and acetonitrile ligands.
An extensive screening of migratory insertion transition
states and their conformational space was conducted (see SI).
Transition state structures (TS1−TS8) for the eight possible
arylations are shown in Figure 2. For each possibility, the
complexes are depicted in their lowest energy ligand
conformations. The lowest energy pathway, TS1 (see SI,
Figure S86), leads to C−C bond formation in the C-4 position,
a
Performed in a Carousel 12 Plus Reaction Station from Radleys,
using a metal heating block. NMR yields (isolated yields in
parentheses). Products formed with complete diastereoselectivity,
with the exception of 3db, formed as a 1:1 mixture of diastereomers.
We subsequently explored further synthetic transformations
of products 3. Cleavage of the acetal in 3ba and 3bf, using
CF3COOH, afforded ketones 7ba and 7bf in high yields
(Scheme 4, route A). Compound 7bf, containing a ketone and
a proximal ester group, could potentially undergo an
C
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Figure 2. Top: Gibbs energy profile (1M, 298 K, in kcal/mol) for four of the migratory insertion transition states. Single point energies are
calculated at the B3LYP-D3/def2-TZVP and M06/def2-TZVP (within parentheses) levels of theory. Bottom: Structures for higher energy
migratory insertion transition states. Energies are shown relative to TS1.
on the face anti to the acetonide moiety. It corresponds well to
previously reported Heck-type migratory insertion transition
states, with an almost fully formed Pd−C bond along with a
developing C−C bond.17 Our calculations predict that TS1 is
favored by 1.8 kcal/mol over the second lowest, TS2 (Figure
2). The predominance of TS1 in determining the reaction
outcome agrees well with our experimental results, in which
3aa is the only observed Heck product. In addition to TS2,
other transition states near in energy to TS1 might contribute
under our experimental conditions. These are TS3, predicted
to lie 2.1 kcal/mol higher than TS1, as well as TS4 and TS5,
higher by 2.3 and 2.4 kcal/mol, respectively.
The insertion products following TS1, TS2, and TS3 all
correspond to structures with palladium bound to an sp3-
carbon. These structures, IN1, IN2, and IN3, are all relatively
close in energy, with IN2 somewhat less stable, possibly due to
steric effects from installing the palladium syn to the acetonide.
Insertion product IN5 is different and is significantly more
stable compared to IN1-3. The difference can be explained as a
result of the formation of a palladium π-allyl system. The
insertion products IN2 and IN3 do not have any available β-
hydrogens, and therefore both lack obvious forward reaction
paths toward a Heck-type product (the same holds true for the
insertion product following TS4).
One possibility in the absence of β-hydrogens is a reverse
carbopalladation. In a Heck-type reaction, the migratory
insertion is generally viewed as irreversible;17b,c,18 there are
however known examples of β-carbon elimination when no β-
hydrogens are available.19 We have estimated the backward
reaction barriers for migratory insertion products IN2 and IN3
to ∼21 kcal/mol and ∼26 kcal/mol, respectively. These
barriers imply that such processes are accessible under the
experimental conditions. Therefore, if formed, the formation of
IN2 and IN3 should be reversible, and these should be able to
proceed to Heck-product 3aa. With a backward reaction
barrier of ∼33 kcal/mol, the formation of IN5 is irreversible.
In contrast to IN2 and IN3, intermediate IN1 possesses a
hydrogen in a syn orientation with respect to the palladium. As
expected, a β-hydride elimination is predicted to follow. The β-
hydride elimination forming product 3aa was computed to
have a barrier of 16 kcal/mol (TS9). In accordance with the
increased stability of the π-allyl system, the barrier for β-
hydride elimination in IN5 (TS10) was calculated to be 26
kcal/mol, which should be attainable under the experimental
conditions. If formed, IN5 should proceed to form Heck-
product 10 (Figure 2).
Conclusions. We here present a methodology for Pd-
catalyzed diastereoselective arylation of dienes derived from
D
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Author Contributions
‡A.J.P. and P.D. contributed equally.
enzymatic cis-dihydroxylation of benzoic acid. This approach
allows for a chirality transfer from the diol moieties of these
microbial arene oxidation products to a more distal position,
increasing the chiral pool of molecules available by enzymatic
dearomatization. The reaction effects coupling of a range of
aryl iodides in moderate to excellent yields and selectivity and
provides the opportunity to form tricyclic scaffolds via further
transformations. A quantum chemical investigation indicates
that there is a kinetic preference for arylation in the observed
position. Interestingly, it was also found that reversibility in the
other accessible carbopalladations might be kinetically relevant
for the high selectivity toward the formed Heck product.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Swedish Research Council (N.K., Grant 2015-05360), the
Swedish Research Council Formas (N.K., Grant 2015-1106),
the Engineering and Physical Sciences Research Council
(S.E.L., Grant EP/L016354/1), and the Carl Trygger
Foundation (A.P., Grant CTS 16:235) are gratefully acknowl-
edged for funding. Computational resources were provided by
the Swedish National Infrastructure for Computing (SNIC) at
C3SE. We thank Dr. Carl Johan Wallentin, Dept. of Chemistry
and Molecular Biology, University of Gothenburg, and Prof.
Christer Larsson, Dept. of Biology and Biological Engineering,
Chalmers University of Technology, for discussions.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00708.
Experimental procedures and spectroscopic data, and X-
ray data for compound 3ah (PDF)
Computational chemistry details (Geometries of all
calculated structures are available on ioChem-BD; see
http://dx.doi.org/10.19061/iochem-bd-6-23) (PDF)
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Accession Codes
CCDC 1961899 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 Authors
■
Nina Kann − Department of Chemistry and Chemical
Engineering, Chalmers University of Technology, SE-41296
Gothenburg, Sweden; orcid.org/0000-0002-4457-5282;
Email: kann@chalmers.se
Simon E. Lewis − Centre for Sustainable Chemical Technologies
and Department of Chemistry, Convocation Avenue, University
of Bath, Bath BA2 7AY, U.K.; orcid.org/0000-0003-4555-
4907; Email: S.E.Lewis@bath.ac.uk
Martin Rahm − Department of Chemistry and Chemical
Engineering, Chalmers University of Technology, SE-41296
Gothenburg, Sweden; orcid.org/0000-0001-7645-5923;
Email: martin.rahm@chalmers.se
Authors
Andrew J. Paterson − Department of Chemistry and Chemical
Engineering, Chalmers University of Technology, SE-41296
Gothenburg, Sweden; orcid.org/0000-0001-7169-2524
Petter Dunås − Department of Chemistry and Chemical
Engineering, Chalmers University of Technology, SE-41296
Gothenburg, Sweden; orcid.org/0000-0002-3779-3265
Per-Ola Norrby − Data Science and Modelling, Pharmaceutical
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