Copper-Catalyzed Enantioselective Hydroalkoxylation of Alkenols for the Synthesis of Cyclic Ethers

Article abstract of DOI:10.1021/acs.orglett.0c01691

The copper-catalyzed enantioselective intramolecular hydroalkoxylation of unactivated alkenes for the synthesis of tetrahydrofurans, phthalans, isochromans, and morpholines from 4- and 5-alkenols is reported. The substrate scope is complementary to existing enantioselective alkene hydroalkoxylations and is broad with respect to substrate backbone and alkene substitution. The asymmetric induction and isotopic labeling studies support a polar/radical mechanism involving enantioselective oxycupration followed by C-[Cu] homolysis and hydrogen atom transfer. Synthesis of the antifungal insecticide furametpyr was accomplished.

Full text of DOI:10.1021/acs.orglett.0c01691

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Letter
Copper-Catalyzed Enantioselective Hydroalkoxylation of Alkenols
for the Synthesis of Cyclic Ethers
Dake Chen, Ilyas A. Berhane, and Sherry R. Chemler*
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ABSTRACT: The copper-catalyzed enantioselective intramolecular hydroalkoxylation of unactivated alkenes for the synthesis of
tetrahydrofurans, phthalans, isochromans, and morpholines from 4- and 5-alkenols is reported. The substrate scope is
complementary to existing enantioselective alkene hydroalkoxylations and is broad with respect to substrate backbone and alkene
substitution. The asymmetric induction and isotopic labeling studies support a polar/radical mechanism involving enantioselective
oxycupration followed by C−[Cu] homolysis and hydrogen atom transfer. Synthesis of the antifungal insecticide furametpyr was
accomplished.
Scheme 1. Catalytic Enantioselective Hydroalkoxylations of
Unactivated Alkenes
he hydroalkoxylation (or hydroetherification) of alkenes,
a
1−3
and intramolecular,4−12 has
Tboth intermolecular
engaged the efforts of numerous research groups over the
past several decades.13,14 Acyclic and cyclic ethers and esters,
compounds that can be made by this transformation, have
demonstrated broad utility from fuel additives2 to moieties of
bioactive small molecules.15−21 The synthesis of enantioen-
riched ethers is particularly relevant to the latter application.
The catalytic enantioselective alkene hydroalkoxylation has
presented a contemporary challenge, and notable solutions
have emerged. In this regard, a number of enantioselective
cyclizations of alcohols onto electron-deficient alkenes (oxa-
Michael reactions), catalyzed by chiral Brønsted acids, have
been reported.14,22−27 An enantioselective protonation/cycli-
zation onto electron-rich enol ethers28 has also been achieved.
Reports of transition metal catalyzed enantioselective hydro-
alkoxylations of allenes have also appeared.29−35 Conversely,
few effective solutions for the catalytic enantioselective
hydroalkoxylation of electronically neutral alkenes have been
identified (Scheme 1). Reports of transition metal catalyzed
enantioselective intramolecular hydroetherifications include
the titanium-catalyzed cyclization of 2-allylphenols (Scheme
1a),36 the copper(I)-catalyzed cyclization of 2,2-diphenyl-4-
pentenol (single substrate, 71% ee),37 a cobalt-catalyzed
cyclization of 2,2-disubstituted-4-pentenols (Scheme 1b),8
and an intermolecular iridium-catalyzed coupling of alkenes
with phenols (single substrate, 36% ee).38 An enantioselective
mercury-promoted hydroalkoxylation that employs stoichio-
metric amounts of a chiral mercury catalyst has also been
reported.39 Thus, far, the scope of the intramolecular
a
L*, R* = chiral ligand.
enantioselective transition metal catalyzed methods has been
limited to terminal alkene substrates for the formation of chiral
five-membered rings (Scheme 1a and 1c). A highly
enantioselective intramolecular hydroalkoxylation catalyzed
Received: May 18, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01691
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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by a chiral imidophosphate Brønsted acid has recently been
reported for the cyclization of 1,1-disubstituted alkenols
(Scheme 1c).40 Other enantioselective metal-free strategies,
such as enzyme-catalyzed alkene protonation41 and photo-
catalytic chiral ion paired C−O bond formation,42 have been
reported for specific substrates with varying degrees of
enantioselectivity. Herein we report the enantioselective
intramolecular hydroalkoxylation of a range of 4- and 5-
alkenols catalyzed by chiral copper(II) bis(oxazoline) com-
plexes (Scheme 2b).
Table 1. Effect of Reaction Conditions on the
Enantioselective Hydroalkoxylation
a
Scheme 2. Copper-Catalyzed Carboetherification and
Projected Hydroalkoxylation
b
c
entry
1
L*
[O]
[H]
solvent
2a (%)
ee (%)
L1
L2
L3
L4
L5
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
Ag2CO3
air
C6H8
C6H8
C6H8
C6H8
C6H8
C6H8
C6H8
C6H8
C6H8
C6H8
C6H8
C6H8
C6H8
C6H8
C10H16
C14H12
i-PrOH
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
DCE
PhCH3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
52
85
71
46
80
97
79
52
57
77
82
5
12
86
61
95
<5
−
de
,
2
3
4
5
6
7
8
9
−76
83
99
−71
99
97
97
98
99
99
nd
98
98
nd
98
nd
e
f
e
g
h
10
11
12
13
14
15
16
17
h
i
air
MnO2
MnO2
MnO2
MnO2
j
We have disclosed the copper(II)-catalyzed enantioselective
carboetherification of alkenols involving net C−O and C−C
bond formation across the alkene (Scheme 2a).43−46 These
carboetherificatons were demonstrated primarily for the
synthesis of tetrahydrofurans, spirocyclic tetrahydrofurans,
and phthalans. The C−O bond formation is thought to
occur by alkene oxycupration44 while the C−C bond
formation, either intramolecular or intermolecular, is proposed
to occur by addition of a carbon radical intermediate to an
unsaturated moiety. The existence of a carbon radical (e.g., II,
Scheme 2) was supported, in part, by observation of C−H
bond formation upon addition of 1,4-cyclohexadiene, a well-
known hydrogen atom transfer (HAT) reagent.43,47,48 1,4-
Cyclohexadiene (C6H8) is an attractive hydrogen-atom donor
due to its low molecular weight, and its favorable hydrogen-
atom donor kinetics (BDE = 76 kcal/mol, aromaticity driving
force).47,48 Herein is reported development of this protocol to
target enantioselective alkene hydroalkoxylation.
Parameters impacting the enantioselective copper-catalyzed
hydroalkoxylation of tertiary alkenol 1a are illustrated in Table
1. A screen of ligands and temperature (Table 1, entries 2−6)
identified (S,S)-t-Bu-Box (L4) and 120 °C as optimal,
providing 2a in 97% isolated yield and 99% ee (Table 1,
entry 6). Application of (S,S)-i-Pr-Box (L3) gave 2a with 83%
ee, the next highest selectivity (Table 1, entry 3). Lowering the
catalyst loading from 20 mol % to 15 mol % diminished the
yield (79% isolated) without diminishing the selectivity (97%
ee) (Table 1, entry 7). 1,2-Dichloroethane (DCE) and toluene
were acceptable reaction solvents, but gave lower levels of
conversion (Table 1, entries 8 and 9). When the reaction was
performed in the absence of K2CO3 (1 equiv), 2a was still
a
Unless otherwise noted, all reactions were run in sealed tubes with
dry solvent at 0.1 M w/r to alkenol 1a, 20 mol % Cu(OTf)2, 25 mol %
ligand, 3 equiv hydrogen atom donor source, 1 equiv K2CO3, 4 Å mol.
sieves and with either MnO2 (260 mol %, <5 μ, 85% MnO2 by
b
weight), Ag2CO3 (100 mol %), or air (1 atm) at 120 °C. Isolated
yields of 2a following flash chromatography on silica gel are reported.
c
% ee was determined by chiral gas chromatography (CP-Chirasil-Dex
d
e
f
CB column). Taken from ref 43. Reaction run at 100 °C. 15 mol %
[Cu] and 18 mol % L4 was used. Reaction run at 110 °C. No
K2CO3 was used. 1 mmol (1a) scale. 60% conversion to the
respective carboetherification product was observed. nd = not
determined.
g
h
i
j
formed but in 77% isolated yield (99% ee) (Table 1, entry 10).
Oxidants other than MnO2 were briefly explored (Table 1,
entries 11−13). Use of Ag2CO3 (1 equiv) as a stoichiometric
oxidant resulted in an 82% isolated yield of 2a in 99% ee. Use
of air (1 atm) resulted in 5% of 2a formed. Application of air as
an oxidant in the absence of K2CO3 resulted in higher
conversion (12% of 2a), but a considerable amount of starting
1a still remained. Under the optimal conditions (Table 1, entry
6), the reaction could be run on 1 mmol scale without
significant loss of efficiency or selectivity (Table 1, entry 14).
Other hydrogen atom donors were briefly explored. Use of γ-
terpinene led to diminished conversion to product (Table 1,
entry 15). Conversely, 9,10-dihydroanthracene proved to be an
excellent hydrogen atom donor and 2a was obtained in high
yield and enantioselectivity (Table 1, entry 16).49 Isopropanol,
which has previously been used as a hydrogen atom donor,50
was ineffective in this reaction but did not substantially inhibit
B
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formation of the carboetherification adduct 2 (Table 1, entry
17).
The scope of the enantioselective hydroalkoxylation of a
range of 4-alkenols was examined (Scheme 3). The optimal
good to moderate, with a decrease observed for the electron-
poor p-CF3 styrene product 2i. The lower enantiomeric excess
of 2i might indicate a competing racemic pathway, perhaps an
electronically driven decrease in HAT rate that enables ring
opening to an alkoxy radical and racemic reclosure.43 1,1-
Disubstituted alkenes converted to 1,1,3,3-tetrasubstituted
phthalans 2j and 2k in excellent yields and moderate (64%)
to excellent (92%) enantioselectivity, respectively. Phenols
were unreactive in this transformation (not shown).
a
Scheme 3. Alkenol Hydroetherification Scope
A range of primary alcohols also underwent copper-catalyzed
hydroalkoxylation in good yields (Scheme 3). The primary
alcohols suffered from competitive oxidation to their respective
aldehyde under the standard conditions using MnO2 as a
stoichiometric oxidant (see e.g., 2p, Scheme 3), however, so
the milder oxidant, Ag2CO3, was applied instead. The
enantioselective hydroalkoxylation/cyclization of 2,2-diphen-
yl-4-pentenol to 2-methyl-4,4-diphenyltetrahydrofuran 2l was
challenged by a competing intramolecular carboetherification
process (as in Scheme 2a) under the otherwise optimal
hydroalkoxylation conditions. Fortunately, an 82% yield of the
desired 2l was obtained when the 1,4-cyclohexadiene loading
was increased to 5 equiv. The 1,2-disubstituted alkenol, (E)-
2,2-diphenyl-5-phenyl-4-pentenol, cyclized efficiently under
standard conditions to give tetrahydrofuran 2m. Both reactions
occurred with moderate enantioselectivity. 2-Indanyl-4-pente-
nol cyclized to give tetrahydrofuran 2n efficiently (93% yield)
but in a 65% ee. The related, predominantly (E) (E:Z =
78:22), 2-indanyl-5-methyl-4-pentenol cyclized to give 2-
ethyltetrahydrofuran 2o in 93% ee. A 64:36 E/Z 2-indanyl-5-
methyl-4-pentenol sample gave 2o in 84% ee, indicating the E
alkene is more selective than the Z. (E)-5-Aryl-4-pentenols
underwent the hydroetherification to produce 2-benzyl
tetrahydrofurans 2p and 2q in moderate levels (ca. 50% ee)
of enantioselectivity while the reaction of (Z)-5-phenyl-4-
pentenol resulted in racemic 2p. Tetrahydrofuran 2r and
phthalan 2s were produced in good yields but low
enantioselectivity from their respective alkenol substrates.
The enantioselective hydroalkoxylation was also extended to
the synthesis of 3-methylisochromans 4 (Scheme 4a). A steric
matching between ligand and substrate quickly became
apparent. Primary benzyl alcohols 3a and 3e gave 4a and 4e
with 82% and 68% ee, respectively when (S,S)-t-Bu-Box was
applied as the chiral ligand, and in lower enantioselectivity
when (S,S)-i-Pr-Box was used. Chroman 4e was formed in
higher enantioselectivity and conversion when DCE was
applied as solvent instead of PhCF3. Tertiary benzyl alcohols
4b−d efficiently cyclized to give 1,1-dialkyl-3-methylisochro-
mans 4b−4d with high enantioselectivity. These sterically
demanding alcohols paired best with the less sterically
demanding ligand; e.g., 4d was formed in much higher
enantioselectivity when (S,S)-i-Pr-Box was applied as a chiral
ligand (96% ee) instead of (S,S)-t-Bu-Box (72% ee). A
carboxylic acid substrate, 6-allyl-2-methoxybenzoic acid, gave
O-methylmellein,52 4f, in moderate yield and low enantiose-
lectivity under these conditions. The enantioselective synthesis
of morpholines 6 from N-allyl amino alcohols 5 was also
feasible (Scheme 4b). Terminal alkenes 5a and 5b gave 2-
methylmorpholines 6a and 6b in excellent enantioselectivity
using (S,S)-t-Bu-Box. The (S,S)-i-Pr-Box ligand performed
better in the synthesis of morpholines 6c−e from 1,1-
disubstituted alkene 5c and (E)-1,2-disubstituted alkenes 5d
and 5e, although the enantioselectivity ranged from poor (6c)
to moderate and good (6d and 6e). When the (S,S)-t-Bu-Box
a
Reaction conditions from Table 1, entry 6 for tertiary alcohol
substrates and entry 11 for primary alcohol substrates were applied.
b
9,10-Dihydroanthracene was used instead of 1,4-cyclohexadiene.
c
9,10-Dihydroanthracene-9,9,10,10-d4 was used instead of 1,4-cyclo-
hexadiene. 10% of the corresponding carboetherification adduct was
d
also obtained. 5 equiv of 1,4-cyclohexadiene was used due to
competitive intramolecular carboetherification (giving a known43
e
[3.2.1]-bicyclic ether, as in Scheme 2a). MnO2 instead of Ag2CO3
was used, 38% of the corresponding aldehyde of 1 was obtained. The
transferred H atom is illustrated on 2b and 2j for clarity.
reaction conditions (Table 1, entry 6) give 2,2,5-trisubstituted
tetrahydrofuran 2a-H from alkenol 1a in 98% yield and 99%
ee. Alkenol 1a provided tetrahydrofuran 2a-D in similar yield
and enantioselectivity (85% yield, 96% ee) when 9,10-
dihydroanthracene-9,9,10,10-d4 (>95%) was applied as an
atom transfer reagent51 under otherwise identical conditions.
This conversion serves as an isotopic labeling experiment to
support the proposed carbon radical H/D atom transfer
mechanism (Scheme 2 and vide infra). 2,2,5,5-Tetrasubstituted
tetrahydrofuran 2b, which originated from enantioselective
hydroetherification of a 1,1-disubstituted alkene, was formed
with high efficiency and selectivity (81% yield, 97% ee). A
range of highly enantioenriched phthalans 2c−2f originating
from differently substituted tertiary 2-vinylbenzyl alcohols were
formed in excellent yields. (E)-1,2-Diaryl alkene variants
(stilbenes) of these benzyl alcohols also reacted to form 2g−
2j in good yields, while the enantioselectivity ranged from very
C
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a
with higher enantioselectivity than primary alkenols. Homol-
ysis of the C−Cu(II) bond of IV then gives alkyl radical V and
[Cu(I)]. Hydrogen atom abstraction from 1,4-cyclohexadiene
by radical V gives 2, and oxidation of both the cyclohexadienyl
radical to benzene and [Cu(I)] back to [Cu(II)] by the
stoichiometric oxidant (Ag2CO3 or MnO2) completes the
catalytic cycle (Scheme 5).
Scheme 4. Synthesis of Isochromans and Morpholines
The synthetic utility of this method is illustrated for the
enantioselective synthesis of (R)-furametpyr (Limber), and its
(+)-enantiomer could be correlated to the (R)-configuration
for the first time (Scheme 6).15 Furametpyr, a tetrahydroiso-
Scheme 6. Enantioselective Synthesis of (R)-
(+)-Furametpyr
a
Reaction conditions from Table 1, entry 11 were applied but with
b
the (S,S)-i-Pr-Box (L3). Reaction was run with (S,S)-t-Bu-Box (L4).
c
d
Reaction was run at 105 °C with MnO2 (2.6 equiv). Reaction was
benzofuran carboxamide, has been used as a fungicide to
control sheath blight in rice crops in Japan.53,54 Although the
enantiomers have been separated by chiral chromatogra-
phy15,16 and individually studied,15 the absolute configuration
of each enantiomer, as correlated with its respective optical
rotation sign, has not previously been assigned. A previous six-
step racemic synthesis of furametpyr started from 4-
acetaminophthalide.16 Our synthesis of (R)-(+)-furametpyr
was also accomplished in six steps and is enantioselective
(Scheme 6). Conversion of methyl 3-bromo-2-methyl-
benzoate 7 to phosphonium bromide 8 followed by Wittig
olefination and Grignard addition provided alkenol 1t. Copper-
catalyzed enantioselective hydroalkoxylation provided bro-
mophthalan 2t in 97% yield and 97% ee. Buchwald−Hartwig
coupling55 of 2t with amide 9 provided (R)-(+)-furametpyr
(10) in 60% yield.
run in DCE, 105 °C.
ligand was applied for the synthesis of 6e, the selectivity
remained excellent (90% ee) but the isolated yield was
significantly diminished (29%).
The proposed catalytic cycle for the conversion of 1 to 2 is
illustrated in Scheme 5. Coordination of alcohol 1 to the
[Cu(II)] catalyst gives intermediate III. Cis-oxycupration via
TS-A gives organocopper(II) species IV. TS-A leads to the
major enantiomer of 2; it minimizes steric interactions
between the ligand and C(1) of the alkenol. These sterics
are more pronounced for tertiary alkenols, which can
rationalize the selectivity trend that tertiary alkenols react
Scheme 5. Proposed Hydroalkoxylation Catalytic Cycle
In conclusion, we have developed a copper-catalyzed
enantioselective hydroalkoxylation for a range of aliphatic 4-
and 5-alkenols. On the whole, this method and the prior art
(summarized in Scheme 1) support enantioselective hydro-
alkoxylation as a competitive approach for enantioenriched
cyclic ether synthesis.56 Efforts to elucidate a more nuanced
mechanistic analysis that can better rationalize electronic and
steric effects on reactivity and selectivity are underway and will
be reported in due course.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01691.
Experimental procedures and HPLC traces; NMR
spectra of new compounds; X-ray structures of 6a and
10 (PDF)
D
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Accession Codes
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Letter
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CCDC 1978103 and 1992008 contain the supplementary
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emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
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Takano, H. Fungicidal substituted carboxylic acid derivatives. US
4877441, United States Patent, Oct. 31, 1989.
■
Sherry R. Chemler − Chemistry Department, State University of
New York at Buffalo, Buffalo, New York 14260, United States;
orcid.org/0000-0001-6702-5032; Email: schemler@
buffalo.edu
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Authors
Dake Chen − Chemistry Department, State University of New
York at Buffalo, Buffalo, New York 14260, United States
Ilyas A. Berhane − Chemistry Department, State University of
New York at Buffalo, Buffalo, New York 14260, United States
(19) Humber, L. G.; Ferdinandi, E.; Demerson, C. A.; Ahmed, S.;
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Complete contact information is available at:
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(21) Li, W.; Wiesenfeldt, M. P.; Glorius, F. J. Am. Chem. Soc. 2017,
139, 2585−2588.
Notes
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The authors declare no competing financial interest.
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We thank Mr. Shea D. Myers (SUNY at Buffalo) and Prof.
Jason B. Benedict (SUNY at Buffalo) for obtaining the X-ray
structures of 6a (CCDC 1978103) and 10 (CCDC 1992008).
We thank Ms. Lauren Rosch (SUNY at Buffalo) for checking/
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