Enantioselective Synthesis of γ-Functionalized Cyclopentenones and δ-Functionalized Cycloheptenones Utilizing a Redox-Relay Heck Strategy

Article abstract of DOI:10.1002/adsc.201901239

In this report, the desymmetrization of cyclic enones under relay Heck conditions with an array of aryl boronic acids, alkenyl triflates and indole derivatives is described. This method grants facile access to diverse γ-functionalized cyclopentenones and δ-functionalized cycloheptenones. Using this approach, a formal synthesis of (S)-baclofen was completed in high yield and excellent enantioselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201901239

Title: Enantioselective Synthesis of γ-Functionalized Cyclopentenones
and δ-Functionalized Cycloheptenones Utilizing a Redox-Relay
Heck Strategy
Authors: Qianjia Yuan, Matthew Prater, and Matthew Sigman
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901239
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10.1002/adsc.201901239
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Synthesis of γ-Functionalized Cyclopentenones
and δ-Functionalized Cycloheptenones Utilizing a Redox-Relay
Heck Strategy
Qianjia Yuan,a,b Matthew B. Prater,a,b and Matthew S. Sigmana*
a
Department of Chemistry, University of Utah, 315 S 1400 E, Salt Lake City, Utah 84112, USA; fax: (801)-581-8433,
E-mail: matt.sigman@utah.edu
These authors contributed equally
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. In this report, the desymmetrization of cyclic
enones under relay Heck conditions with an array of aryl
boronic acids, alkenyl triflates and indole derivatives is
described. This method grants facile access to diverse γ-
functionalized cyclopentenones and δ-functionalized
cycloheptenones. Using this approach, a formal synthesis of
(S)-baclofen was completed in high yield and excellent
enantioselectivity.
Keywords: Asymmetric Catalysis; C–C Coupling; Heck
Reaction; Palladium
Optically active, γ-substituted cyclopentenones are
important building blocks with applications in the
pharmaceutical industry.[1] To traditionally access
these compounds, multiple synthetic steps are often
required with a prevalence of ring-closing procedures.
These include Ru–catalyzed ring-closing metathesis,[1]
enantioselective Nazarov cyclizations,[2] Pauson-
Khand
reactions,[3]
and
We
Au–catalyzed
envisioned
cycloisomerizations.[4]
a
complementary strategy to yield the desired
functionalized cyclopentenone core directly from 3-
cyclopentone
through
enantioselective
Scheme 1. A. Previous reports of redox-relay Heck reaction
with acyclic alkenes, representative examples. B. Previous
use of endocyclic alkenes. C. Desymmetrization reported by
Correia. D. Proposed method to synthesize γ-functionalized
cyclopentenones.
desymmetrization using a redox-relay Heck reaction.
If successful, products of type 3 are formed that would
simplify the synthesis of enantiomerically enriched γ-
substituted cyclopentenones.
Similar redox-relay Heck reactions have been
extensively studied in our laboratory. These reactions
differ from the traditional Heck reaction in that the
unsaturation of the olefin is carried along a carbon
chain via successive β-hydride eliminations and
migratory insertions toward a redox acceptor, such as
an alcohol, therefore resulting in the remote
functionalization of an aldehyde or ketone (Scheme
1A).[5] Our previous reports[5] were heavily focused on
the use of acyclic alkenyl substrates to access remotely
functionalized carbonyl products (Scheme 1A). More
recently, we have extended our efforts to the use of
cyclic substrates, namely ene-lactams, to access
conjugated lactam products (Scheme 1B).[6] Inspired
by this result, and the disclosures of Correia[7] and
others[8] in the desymmetrization of cyclopentenes
such as A, (Scheme 1C) we envisioned that the use of
symmetric cyclic enones, such as cyclopentenone 1a,
would extend the synthetic utility of the redox-relay
Heck reaction. A benefit of cyclic systems is that after
migratory insertion has occurred to generate
intermediate B, intermediate C is formed due to the
syn nature of β-hydride elimination.[9] Herein we
1
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10.1002/adsc.201901239
Advanced Synthesis & Catalysis
disclose the successful Pd-catalyzed enantioselective
desymmetrization of symmetric cyclic enones with
arylboronic acids, alkenyl triflates, and indole
derivatives to generate optically active γ-substituted
cyclopentenones (3).
Inclusion of additional electron withdrawing groups
(3h) reduced the yield to 63%, likely due to a
decreased rate of migratory insertion.[10] Lastly, a
benzodioxole (3j), napthyl (3k), and indole (3l) were
successfully
incorporated
delivering
the
corresponding products in excellent yields and
enantioselectivities. It should be noted that the scope
in terms of aryl boronic acid is similar to our original
reports using acyclic alkenols.[5b, 5e]
We began our studies by investigating previously
reported arylation conditions used to functionalize di-
and trisubstituted acyclic alkenols,[5b, 5e] albeit without
a copper additive.[5f] When these optimized conditions
were applied to cyclopentenone 1a and phenyl boronic
acid 2a, we were fortunate to discover the arylated
product 3a was formed in 92% yield and 95:5
enantiomeric ratio (er), with only a detectable amount
of diarylated product 4a (Table 1, entry 1). Utilizing
THF as solvent provided a similar yield, albeit in
reduced enantioselectivity (entry 2). Longer reaction
times (entry 3) and increasing the equivalents of
boronic acid (entry 4) led to the amplified formation of
4a. Switching to a more electron rich ligand (L2)
produced the undesired diarylation compound 4a as
the major product (entry 5), and performing the
reaction at 0 °C had little effect on the outcome of the
reaction (entry 6).
Table 2. Arylboronic Acid Scope
Table 1. Optimization of Conditions
Reaction conducted with 1a (0.2 mmol) and 2a (0.4 mmol).
a)The ratio of 3a:4a was determined by 1H NMR of the crude
mixture. b)THF was used as solvent. c)Reaction performed at
0 °C.
Following these observations, we examined the scope
of this transformation for a variety of arylboronic acids
(Table 2). Electron withdrawing groups (4-chloro and
4-trifluoromethyl) were well tolerated producing
products 3b (79%) and 3c (71%), both with excellent
enantioselectivities. Electron donating groups such as
4-methoxy (3d), 4-methyl (3e), and 3-methoxy (3f)
also provided the desired products in excellent yields
and enantiomeric ratios. A methyl group at the ortho
position was also tolerated delivering the
corresponding product in 74% yield and 93:7 er (3g),
indicating that the more sterically hindered arene had
only a minor impact on the reaction outcome.
Reaction conducted with 1a (0.2 mmol and 2 (0.4 mmol in
DMF (2 mL) at 0 °C. The ratio of 3:4 was determined by 1H
NMR of the crude mixture. Absolute stereochemistry
determined to be (R) for 3a by comparing optical rotation
with literature value (See supplementary information), all
others assigned by analogy. a)0.3 mmol of 2 was used.
This Heck arylation was readily applied to the formal
synthesis of biologically active compound baclofen, a
muscle relaxer used in the treatment of multiple
sclerosis (Scheme 2).[11] This process is scalable to 1.0
mmol.
2
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10.1002/adsc.201901239
Advanced Synthesis & Catalysis
Based on our success with cyclopentenone 1a, we then
examined whether the reaction would tolerate a larger
ring. Cycloheptenone 1b was a successful substrate for
both arylation and alkenylation (Table 4). The use of
phenyl boronic acid with cycloheptenone 1b led to
nearly complete consumption of 1b to give 7a in only
four hours. As previously observed (Table 1, entry 3),
longer reaction times led to the formation of the
diarylation product analogous to 4a. An electron poor
boronic acid also performed well, generating 7b in
91% yield and excellent er. The use of a vinylogous
lactone triflate as the coupling partner produced the
desired product 7c in 71% yield in modest
enantioselectivity while an acyclic alkenyl triflate
yielded product 7d in 56% and high enantioselectivity.
Unfortunately, the use of unsymmetric cyclic
alkenones (i.e., 3-cyclohexenone) results in poor site
selectivity as a result of poor electronic bias between
the alkene carbons in the migratory insertion event
(not pictured).
Scheme 2. Formal synthesis of (S)-baclofen. Reaction
conducted with 1a (1.0 mmol), 2b (2.0 mmol), and
Pd(MeCN)2(OTs)2 in 10 mL DMF.
Next, we examined the scope of alkenyl triflates with
cyclopentenone 1a (Table 3) using similar reaction
conditions in the absence of the terminal oxidant, O2.
A Pd0 precatalyst was required to initiate the oxidative
addition of the alkenyl triflate.[5g] We explored various
alkenyl triflates that have historically been successful
in the acyclic systems.[5j, 5g] This includes the use of 6-
membered endocyclic alkenyl triflates to cleanly
generate products 6a (86%) and 6b (67%). Excellent
enantioselectivity is observed with these coupling
partners. A 5-membered endocyclic alkenyl triflate led
to the formation of 6c (97%) with a modest reduction
of enantioselectivity. The use of a vinylogous lactone
triflate provided product 6d in 98% yield and a 92:8 er.
Acyclic alkenyl triflates are also compatible with this
transformation and gave products 6e and 6f in good
yield and er.
Table 4. 7-Membered Enone Substrate Scope
Table 3. Scope of Alkenyl Triflates
Absolute stereochemistry determined to be (R) for 3a by
comparing optical rotation to literature value (see
a)
supporting information), all others assigned by analogy.
Arylation reaction conducted with 1b (0.2 mmol), 2 (0.3
mmol), Pd(MeCN)2(OTs)2 (10 mol %), Cu(OTf)2 (3 mol %),
L1 (20 mol %), 3Å MS, O2 (balloon) and DMF. b)Reaction
time was 4h. c)Alkenylation reaction conduced with 1b (0.2
mmol), 5 (0.2 mmol), Pd(dba)2 (10 mol %), L3 (12 mol %),
3Å MS, and DMF.
Next, we postulated that other nucleophiles
successfully used in related redox-relay Heck
reactions may be compatible as these substrates were
found to be relatively reactive. Pleasingly, alkenyl
triflate 8a provided 9a in 87% yield with 90:10 er
(Scheme 3). Additionally, a dehydrogenative Heck
reaction using indole 8b resulted in alkylation at the
C3 position to yield 9c (28% yield) in low er.[6e] Using
our recently reported aza-Wacker type conditions
resulted in the desired product, albeit it was isolated as
a racemate (see supporting information for details).[12]
Reaction conduced with 1a (0.4 mmol) and 5 (0.2 mmol) in
DMF (2 mL). Absolute stereochemistry determined to be
(R) for 3a by comparing optical rotation to literature value
(see supporting information), all others assigned by analogy.
a)20 mol % Pd(dba)2 used.
3
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10.1002/adsc.201901239
Advanced Synthesis & Catalysis
fraction was collected and the aqueous layer was extracted
with EtOAc(2 × 30 mL). The combined organic layers were
then washed with brine (3 × 10 mL), dried over Na2SO4,
decanted, and concentrated under reduced pressure to give
the crude product. The crude product was purified by
chromatography on silica gel and afforded the desired
product.
Acknowledgements
This work was supported by National Institute of
Health(NIGMSR01 GM063540)
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In summary, we have developed a method for the
direct preparation of γ-functionalized cyclopentenones
and
δ-functionalized
cycloheptenones
from
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General Arylation Procedure:
To a 10 mL Schlenk flask was added Pd(CH3CN)2(OTf)2
(10.6 mg, 0.1 equiv), ligand L1 (6.5 mg, 0.12 equiv), 3 Å
MS (60 mg), and DMF (2.0 mL). A three-way adapter fitted
with a balloon of O2 was then added to the Schlenk flask and
evacuated via house vacuum and refilled with O2 three times
while stirring. The resulting mixture was stirred under an O2
atmosphere for 15 min. The substrate 1 (0.20 mmol, 1.0
equiv) and arylboronic acid 2 (0.40 mmol, 2.0 equiv) was
then added. The resulting mixture was stirred for another 24
h at 0 oC. The reaction progress was monitored by TLC, and
upon complete consumption of 1, the mixture was then
transferred to a separatory funnel with EtOAc (30 mL) and
partitioned with saturated brine (5 mL). The organic fraction
was collected and the aqueous layer was extracted with
EtOAc(2 × 30 mL). The combined organic layers were then
washed with brine (3 × 10 mL), dried over Na2SO4, decanted,
and concentrated under reduced pressure to give the crude
product. The crude product was purified by chromatography
on silica gel and afforded the desired product.
General Alkenylation Procedure:
Under nitrogen atmosphere, to a 2 mL vial equipped with a
stir bar was added Pd(dba)2 (11.5 mg, 0.02 mmol, 0.1
equiv.), ligand (6.0 mg, 0.024 mmol, 0.12 equiv.), 3Å
molecular sieve (60 mg), and anhydrous DMF (2.0 mL).
The resulting mixture was stirred for 10 min. Triflate 5 (1.0
equiv.) and substrate 1 (0.4 mmol, 2.0 equiv.) were then
added. The resulting mixture was stirred for another 48 h at
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0 C. The reaction progress was monitored by TLC, and
upon complete consumption of triflate 5, the mixture was
then transferred to a separatory funnel with EtOAc (30 mL)
and partitioned with saturated brine (5 mL). The organic
4
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10.1002/adsc.201901239
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201901239
Advanced Synthesis & Catalysis
COMMUNICATION
Enantioselective Synthesis of
γ-Functionalized
Cyclopentenones Utilizing a
Heck Redox-Relay Strategy
Adv. Synth. Catal. Year, Volume, Page – Page
Qianjia Yuan, Matthew B. Prater, Matthew S.
Sigman*
6
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