Formation of Chiral Allylic Ethers via an Enantioselective Palladium-Catalyzed Alkenylation of Acyclic Enol Ethers

Article abstract of DOI:10.1021/jacs.8b02751

This report details a palladium-catalyzed process to access highly functionalized, optically active allylic aryl ethers. A number of electron-deficient alkenyl triflates underwent enantioselective and site-selective coupling with acyclic aryl enol ethers

Full text of DOI:10.1021/jacs.8b02751

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Formation of Chiral Allylic Ethers via an Enantioselective
Palladium-Catalyzed Alkenylation of Acyclic Enol Ethers
Harshkumar H. Patel, Matthew B Prater, Scott O Squire, and Matthew S Sigman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02751 • Publication Date (Web): 17 Apr 2018
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Formation of Chiral Allylic Ethers via an Enantioselective Pal-
ladium-Catalyzed Alkenylation of Acyclic Enol Ethers
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Harshkumar H. Patel, Matthew B. Prater, Scott O. Squire Jr. and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States.
Supporting Information Placeholder
alkene and alcohol in the enol ether substrate. Successful impleꢀ
ABSTRACT: This report details a palladiumꢀcatalyzed process
mentation incorporates a heteroatom at the stereocenter formed in
the migratory insertion process to access enantioenriched aryl
allyl ether products (3).
to access highly functionalized optically active allylic aryl ethers.
A number of electronꢀdeficient alkenyl triflates underwent enanꢀ
tioꢀ and siteꢀselective coupling with acyclic aryl enol ethers in the
presence of a chiral palladium catalyst. This transform provides
chiral allylic ether products in high yields and excellent enantioꢀ
meric ratios furnishing a unique disconnection to incorporate
heteroatoms at a stereocenter. Finally, the applicability of the
products to target synthesis was demonstrated through the forꢀ
mation of a chiral allylic alcohol and the generation of a flavoneꢀ
inspired product.
Access to enantiomerically enriched aryl allyl ethers is of high
synthetic utility as they are represented in numerous ether containꢀ
ing natural products and pharmaceuticals.1 Substantial progress
has been reported for their synthesis using transitionꢀmetal catalyꢀ
sis.2 Most methods strategically rely on the reaction of symmetric
πꢀallyl intermediates of Pd,3 Rh,4 and Ir5 using phenoxides or
excess phenol as the trapping exogenous nucleophile. Alternativeꢀ
ly, branched allylic ethers can be accessed in high enantioselectivꢀ
ity using a distinct Pd(II)ꢀcatalyzed SN2' reaction of allylic trichloꢀ
roacetamidates.6 In spite of these advances, the alkenyl compoꢀ
nents installed using these methods are relatively simple inspiring
us to consider new reactions to obtain such products. Herein we
describe a palladiumꢀcatalyzed redoxꢀrelay enantioselective Heck
reaction of a new class of substrates, namely acyclic aryl enol
ethers. As illustrated below, this reaction provides facile access to
a range of diversely functionalized aryl allyl ethers, especially in
terms of the alkenyl component, in high enantioselectivity.
Figure 1. (a) Previously reported enantioselective redoxꢀrelay
Heck reaction. (b) Proposed enantioselective alkenylation of acyꢀ
clic enol ether. (c) Mechanistic hypothesis. (d) Anticipated issues.
In previous reports, the redoxꢀrelay Heck strategy has led to the
successful enantioselective coupling of acyclic disubstituted
alkenols with a range of aryl, alkenyl, and alkynyl groups (Figure
1a).7 The siteꢀselectivity observed in the migratory insertion step
is sensitive to the polarization of the alkene carbons in the transiꢀ
tion state, which is proposed to be stabilized by the C‒O dipole of
the alcohol moiety.8 Although the measured siteꢀselectivity for
allylic alcohols is generally high, it decreases substantially with
the increasing chainꢀlength between the alkene and the alcohol.9
To presumably further bias the migratory insertion improving site
selectivity of more remote functionalization reactions, we enviꢀ
sioned the coupling of alkenyl electrophiles with acyclic enol
ether substrates (Figure 1b). This is proposed to be due to inꢀ
creased nucleophilicity of carbon distal to the oxygen in the enol
ether substrate (2, Figure 1c).10 Furthermore, high siteꢀselectivity
was anticipated irrespective of the number of carbons between the
At the outset, we were concerned that the migratory insertion
event would be followed by βꢀalkoxy elimination instead of βꢀ
hydride elimination towards the alcohol (Figure 1d) as these proꢀ
cesses could be competitive on the basis of previous efforts of our
group.11 Additionally, the βꢀalkoxy aldehyde products 3 (n=0)
may not survive the relatively acidic conditions and undergo an
E1cB to form the α,βꢀunsaturated carbonyl product.12 Consistent
with this, early experiments of enol ethers 2a and 2b, easily preꢀ
pared through a twoꢀstep sequence from the propiolate ester,13
with the electron deficient vinylogous lactone triflate 1a in the
presence of a Pd(0) catalyst and a chiral pyridineꢀoxazoline ligand
L1 (Figure 2a), exclusively led to the undesired anticipated E1cB
product 4 in 70% yield. Considering the relatively Brønsted/Lewis
acidic conditions of this process, it was hypothesized that lowerꢀ
ing the basicity of the oxygen on the enol ether may slow the preꢀ
sumed E1cB process.
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cent to a stereocenter. Lastly, a dihydrobenzofuran derived
alkenyl triflate was also incorporated in 5k, albeit in low yield but
high enantioselectivity. It is noteworthy that diꢀ and triꢀsubstituted
alkenyl triflates performed poorly in this reaction with low conꢀ
version of 2c (see Supporting Information).17 Although, the preꢀ
cise cause for this difference in reactivity is unknown, it is asꢀ
sumed that the tetrasubstituted alkenyl triflates may slow βꢀ
hydride elimination to generate the diene.7b
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Table 1. Scope of alkenyl triflates in the redoxꢀrelay Heck reacꢀ
tion of acyclic aryl enol ether.
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Figure 2. (a) Palladiumꢀcatalyzed enantioselective alkenylation of
alkyl enol ether (b) Palladiumꢀcatalyzed enantioselective alkenylꢀ
ation of acyclic aryl enol ether.
To test this hypothesis, an enol ether substrate 2c containing an
aryl substituent, instead of an alkyl group, was prepared and reꢀ
acted with alkenyl triflate 1a under the standard redoxꢀrelay Heck
conditions (Figure 2b). The evaluation of the crude reaction mixꢀ
ture by 1H NMR indicated the formation of the desired βꢀ
alkenylated aldehyde product 3c in high yield (> 90% NMR
yield). However, an attempt to purify the βꢀphenoxy aldehyde
product 3c via silica gel chromatography resulted in partial deꢀ
composition of the product and formation of product 4, previously
observed. Thus, for characterization purposes and ease of hanꢀ
dling, the obtained aldehydes were transformed to the correspondꢀ
ing alcohols upon reduction of the crude mixture with sodium
borohydride. This allowed the resultant alcohol 5a to be isolated
in 90% yield and an excellent enantiomeric ratio (er) of 99:1 (Taꢀ
ble 1, 5a).
With the optimal conditions determined, we began the assessment
of a variety of electron poor alkenyl triflates (Table 1). The cyclic
five and sevenꢀmembered alkenyl triflates performed well in the
redoxꢀrelay Heck reaction to generate 5b and 5c in high yields
and high enantiomeric ratio of 98:2 and 94:6, respectively (see
Supporting Information for the determination of absolute configuꢀ
ration of compounds in Table 1, Table 2 and Table 3). The βꢀ
alkenylated product 5d containing a protected amine was also
formed in good yield and high enantioselectivity, although sodium
tris(1,1,1,3,3,3ꢀhexafluoroisopropoxy)borohydride14 was used
instead of sodium borohydride during the reduction step. The
relay Heck reaction also tolerated a hindered tetrasubstituted cyꢀ
clohexenone triflate. Unfortunately, in this case, a selective reducꢀ
tion of the aldehyde in the presence of the enone proved to be
challenging. Thus, over reduction afforded a diastereomeric mixꢀ
ture of diols (see Supporting Information), which was treated with
MnO2 to ultimately afford the chiral allylic ether 5e in good yield
and 93:7 er.15 Next, a variety of acyclic alkenyl triflates, convenꢀ
iently prepared from β–ketoesters in a stereodefined manner, were
subjected to the redoxꢀrelay Heck reaction.16 Both (E) and (Z)ꢀ
alkenyl triflates were added to enol ether 2c, forming 5f and 5g in
high yield and enantiomeric ratio of 93:7 and 92:8, respectively.
Additionally, acyclic alkenyl triflates having a benzyl substitution,
a remotely positioned phthalimide, and an alkyl silane were sucꢀ
cessfully integrated to yield 5h-5j in modest to good yields and
generally good enantioselectivity. Importantly, the olefins incorꢀ
porated in 5fꢀ5j did not undergo isomerization, thereby providing
a means to generate stereodefined tetrasubstituted alkenes adjaꢀ
Next, we evaluated a range of electronically diverse aryl enol
ethers. Electronꢀrich substituents on the phenol provided the deꢀ
sired allylic ether products 5lꢀ5o in good yields and high enantiꢀ
oselectivity (Table 2). The hindered orthoꢀsubstitution in 5m
showed no deleterious effects on either the yield or the enantioseꢀ
lectivity of the reaction. Interestingly, the use of an electronꢀpoor
group (for instance a pꢀBr substitution) on the phenyl ring of the
acyclic enol ether did not undergo reaction under these conditions.
Consequently, to tackle this issue, new conditions were identified
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empirically using THF as solvent, and ligand L2 (ꢀCF3 substitutꢀ
has the potential to deliver enantioenriched chiral allylic alcohols.
To this end, a one electron oxidative deprotection of the pꢀ
methoxyphenyl (PMP) ether was accomplished by treating comꢀ
pound 6 with CAN (Scheme 1a).18 The desired allylic alcohol 6a
was obꢀ
ed) instead of L1. Thereby, using the newly optimized reaction
conditions, a number of enol ethers having an electron poor subꢀ
stituent
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Table 2. Scope of allylic aryl enol ethers.
Table 3. Evaluation of aryl enol ether with varying chain lengths.
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tained in 80% isolated yield with no loss of the stereochemical
integrity (Scheme 1). In order to further demonstrate the synthetic
applicability of such chiral allylic ethers, we envisioned accessing
flavone derivatives containing an alkenyl group at the 2ꢀposition.
To accomplish this, the βꢀalkenylated aldehyde 3c generated after
the Heck reaction was subjected to a sequential Pinnick oxidaꢀ
tion/FriedelꢀCrafts cyclization19 affording the desired alkenylated
flavone product 7 in 78% overall yield and 94:6 enantiomeric
ratio, in single purification (Scheme 1b). A slight erosion of the
stereochemical integrity was observed and found to be associated
with the Pinnick oxidation step (see Supporting Information for
details). Such a strategy allows effective incorporation of highly
functionalized alkenyl groups into flavonoids, thereby expanding
the chemical space, as most reported flavonoids contain an aryl
group.20
on the phenyl ring, underwent the Heck reaction, and resulted in
the formation of alcohols 5rꢀ5t, upon reduction of the aldehydes,
in consistently high yield and enantioselectivity. The reason for
such disparity in the reactivity of electronically different arenes is
not currently understood.
As the redoxꢀrelay strategy is unique in establishing remote stereꢀ
ocenters, a range of aryl enol ether substrates having a different
number of methylenes between the alkene and the alcohol were
investigated (Table 3).13c Significantly, the use of a homoallylic
alcohol may allow the isolation of aldehyde products directly, as
the degradation via an E1cB process is not possible. Thus, the
reaction of the cyclic vinylogous lactone triflate 1a with a pꢀOMeꢀ
substituted aryl enol ether substrate 2u, using slightly higher cataꢀ
lyst loadings provided the γꢀalkenylated aldehyde product 3u in
87% yield and 97:3 enantiomeric ratio. Similarly, a sesamol or
phenol derived enol ether also provided the remotely alkenylated
aldehyde products 3v and 3w in consistently high yield and enanꢀ
tioselectivity. The alkenyl triflate was further installed at a more
remote position δ from the aldehyde to form allylic ethers 3x and
3y in good yield and high enantioselectivity.
Scheme 1. Derivatization of alkenylated products.
The use of a cleavable group in the acyclic enol ether substrate
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In summary, we have developed a unique method for the conꢀ
struction of highly functionalized chiral allylic ethers using a reꢀ
doxꢀrelay Heck strategy. The process utilizes conveniently synꢀ
thesized aryl enol ether substrates and readily accessible alkenyl
triflates to generate chiral allylic ether products in good yield and
enantioselectivity. The simple deprotection of the PMP ether proꢀ
vides direct access to chiral allylic alcohols in high enantiomeric
ratio. Future work is focused on expanding this approach to other
heteroatom containing alkenyl substrates.
ASSOCIATED CONTENT
Supporting Information
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Soc. 2013, 135, 6830.
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Experimental procedures and characterization data for new comꢀ
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sigman@chem.utah.edu
(11) Race, N. J.; Schwalm, C. S.; Nakamuro, T.; Sigman, M. S. J. Am.
Chem. Soc. 2016, 138, 15881.
Notes
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The authors declare no competing financial interests.
ACKNOWLEDGMENT
The work was supported by National Institute of Health (NIGMS
R01GM063540) and the National Science Foundation REU Proꢀ
gram for S.O.S. (CHEꢀ1358740).
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6
ACS Paragon Plus Environment