Enantioselective copper-catalyzed carboetherification of unactivated alkenes

Article abstract of DOI:10.1002/anie.201402462

Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein reported is a highly efficient copper-catalyzed cyclization of γ-unsaturated pentenols which terminates in C-C bond formation, a net alkene carboetherification. Both intra- and intermolecular C-C bond formations are demonstrated, thus yielding functionalized chiral tetrahydrofurans as well as fused-ring and bridged-ring oxabicyclic products. Transition-state calculations support a cis-oxycupration stereochemistry-determining step.

Full text of DOI:10.1002/anie.201402462

Angewandte
Chemie
DOI: 10.1002/anie.201402462
Asymmetric Catalysis
Enantioselective Copper-Catalyzed Carboetherification of Unactivated
Alkenes**
Michael T. Bovino, Timothy W. Liwosz, Nicole E. Kendel, Yan Miller, Nina Tyminska,
Eva Zurek,* and Sherry R. Chemler*
Abstract: Chiral saturated oxygen heterocycles are important
components of bioactive compounds. Cyclization of alcohols
onto pendant alkenes is a direct route to their synthesis, but few
catalytic enantioselective methods enabling cyclization onto
unactivated alkenes exist. Herein reported is a highly efficient
copper-catalyzed cyclization of g-unsaturated pentenols which
of 4-aryl-4-pentenoic acids, where carbon-radical-initiated
À
À
C C bond formation occurs prior to C O bond formation,
À
and copper-catalyzed C O bond-formation appears to be the
enantioselectivity determining step, has been demon-
strated.[18] In 2012 we reported a new copper-catalyzed
doubly intramolecular alkene carboetherification which pro-
duced bicyclic tetrahydrofurans with promising (up to 75%
ee) enantioselectivity using the (R,R)-Ph-box ligand
(Scheme 1).[19] At that time, we tentatively assigned the
absolute configuration of the product as shown (Scheme 1).
À
terminates in C C bond formation, a net alkene carboether-
À
ification. Both intra- and intermolecular C C bond formations
are demonstrated, thus yielding functionalized chiral tetrahy-
drofurans as well as fused-ring and bridged-ring oxabicyclic
products. Transition-state calculations support a cis-oxycupra-
tion stereochemistry-determining step.
O
xygen heterocycles, such as tetrahydrofurans, can be
found in numerous bioactive compounds.[1,2] Metal-catalyzed
carboetherification/cyclization of unsaturated alcohols is
a powerful complexity-building strategy for the synthesis of
functionalized saturated oxygen heterocycles from simple
unactivated alkenols. Significant effort in this field has
resulted in the synthesis of diverse oxygen heterocycle
products with predictable regio- and diastereoselectivity.[3–12]
While the related synthesis of enantiomerically enriched
nitrogen heterocycles by either palladium- or copper-cata-
lyzed enantioselective alkene carboamination methodologies
has been substantially developed in recent years,[13,14] advan-
ces in reaction technology for catalytic enantioselective
carboetherification/cyclization of unactivated alkenes have
largely remained elusive.[15] Notable exceptions include
palladium-catalyzed reactions of ortho-vinyl phenols, reac-
tions which proceed through quinone methide intermedi-
ates,[16] and palladium-catalyzed cyclizations of g- and d-
unsaturated phenols which terminate in carbonylation or
olefin insertion (whose substituted intermediates are unable
to undergo b-hydride elimination).[17] More recently, an
enantioselective copper-catalyzed oxytrifluoromethylation
Scheme 1. Enantioselective copper-catalyzed alkene carboetherification.
[a] The major enantiomer’s absolute stereochemistry was tentatively
(and incorrectly) assigned. [b] The major enantiomer’s absolute stereo-
chemistry rigorously assigned. Tf=trifluoromethansesulfonyl.
We report herein optimization of the enantioselective car-
boetherification reaction (up to > 95% ee) and a revision of
the absolute stereochemical assignment. Importantly, we
show herein the expansion of the method to involve
[*] M. T. Bovino, T. W. Liwosz, N. E. Kendel, Dr. Y. Miller,
Dr. N. Tyminska, Prof. E. Zurek, Prof. S. R. Chemler
Department of Chemistry, The State University of New York at
Buffalo, Buffalo, NY 14260 (USA)
À
intermolecular C C bond formation by alkyl Heck-type
couplings with vinyl arenes (Scheme 1).[13b,20] This method is
complementary in substrate scope to existing catalytic
enantioselective carboetherifications[15–18,21–23] as aliphatic
alcohols with unactivated terminal alkenes are excellent
substrates, and various vinylarenes can be used in the
coupling step.
E-mail: ezurek@buffalo.edu
schemler@buffalo.edu
[**] The National Institutes of Health (NIGMS RO1 078383), the donors
of the American Chemical Society Petroleum Research Fund (51672-
DNI6), and the Center for Computational Research at SUNY Buffalo
are acknowledged for support of this research. We thank William W.
Brennessel and the Crystallographic Facility at the University of
Rochester for obtaining the X-ray structure of 2b (CCDC 985356).
The promising level of enantioselectivity (75% ee)
obtained with 1,1-diphenyl-3,3-dibenzyl-4-pentenol (1a)
using the (R,R)-Ph-box ligand shown in Scheme 1 prompted
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402462.
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Table 1: Ligand screening.[a]
Figure 1. X-ray structure of 2b showing R,R absolute stereochemistry.
Thermal ellipsoids shown at 50% probability.[37]
Nr.
Substrate
Ligand
Yield [%][b]
ee [%][c]
1
2
3
4
5
1a
1a
1a
1a
1b
(R,R)-Ph-box
(S,S)-iPr-box
(S,S)-tBu-box
(S)-iPr-quinox
(S,S)-tBu-box
89
96
95
90
95
À75
93
>95
À20[d]
>95
Table 2: Effect of substrate structure on enantioselective intramolecular
carboetherification.[a]
Nr.
Substrate
Product
Yield [%][b]
ee [%][c]
[a] All reactions were run under anhydrous conditions at 0.1m under Ar
in sealed tubes with ca. 0.139 mmol 1 and 1 equiv K2CO3. [b] Yield of
product isolated after flash chromatography on silica gel. [c] Determined
by HPLC using a chiral stationary phase. [d] Enantiomers not baseline
resolved in this HPLC trace.
1[d]
3
4
71
70
2
us to screen additional ligands (Table 1). It should be noted
À
that these oxidative cyclizations are net C H functionaliza-
tions (arene functionalization) where the stoichiometric
oxidant, hypothesized to turnover [CuI] to [CuII] (see
Scheme 2), is the readily available and inexpensive activated
MnO2 (ca. 85%, < 5 mm). We were fortunate to quickly find
that the commercially available (S,S)-tBu-box ligand gave the
opposite enantiomer (determined by HPLC and optical
rotation) of the tetrahydrobenzofuran 2a with greater than
95% ee (Table 1, entry 3). Interestingly, the (S)-iPr-quinox
ligand, though not highly selective (20% ee), provides
a product enantiomeric to that obtained with (S,S)-tBu-Box
(compare Table 1 entries 3 and 4). Reaction of the chloro-
substituted pentenol 1b provided the corresponding tetrahy-
drobenzofuran adduct 2b in greater than 95% ee as well, and
we were able to obtain an X-ray crystal structure of 2b, thus
definitively assigning its absolute stereochemistry (using its
heavy atom) as R,R (Figure 1). This result indicated our
original, tentative assignment of the absolute stereochemistry
with the (R,R)-Ph-box ligand (Scheme 1) was incorrect.[19]
The scope of the copper-catalyzed enantioselective
doubly intramolecular alkene carboetherification was briefly
explored where both substrate backbone and alkene substi-
tution were varied using the optimized (Table 1, entry 3)
reaction conditions (Table 2). Reaction of the less substituted
pentenol 3 gave the tetrahydrobenzofuran 4 in 70% ee, which
was substantially better than previously observed (Scheme 1),
but not as high as that observed with the 1,1-diaryl substrates
1 (Table 1). The pentenols 5 and 7, containing 2,2-diaryl
substitution provided the oxabicyclo[3.2.1]octanes 6 and 8,
respectively, with good selectivity (Table 2, entries 2 and 3).
(E)-2,2-Diphenyl-4-hexenol (9) provided a 1:1 diastereomeric
5
6
77
82
3
4
7
9
8
99
96
84
10/11 (d.r.=1:1)
94/94
[a] Same reaction conditions as used for entry 3 of Table 1. [b] Yield of
isolated product. [c] Determined by HPLC using a chiral stationary
phase. [d] This substrate gives 37% ee using (S)-iPr-box and À37% ee
using (S)-iPr-quinox.
mixture of the oxabicyclo[3.2.1]octanes 10 and 11 with
surprisingly excellent enantioselectivity (Table 2, entry 4).
À
We next turned our attention to intermolecular C C
bond-forming reactions, whose development required con-
sideration of the carboetherification reaction mechanism. We
have provided evidence for a reaction mechanism involving
oxycupration across the alkene with concommittant gener-
ation of an unstable organocopper(II) intermediate which
undergoes homolysis to generate [CuI] and a carbon radical
intermediate (Scheme 2).[19] In that study, evidence for
a primary carbon radical intermediate was provided by
1) H-atom abstraction from 1,4-cyclohexadiene and 2) an
2
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Table 3: (Continued)
Entry Substrate
Alkene
Product
Yield ee
[%][b] [%][c]
4
5
13a
19, Ar=4-ClC6H4
80
80
5
6
20
22
13a
13a
21
84
90
>95
Scheme 2. Proposed intra- and intermolecular carboetherification
mechanism.
23/24 (d.r.=6:1)
86 (maj)
>95 (min)
isotopic labeling study which gave a 1:1 diastereomeric
product mixture from a Z-deuterated alkene.[19] In the case
of the doubly intramolecular carboetherification, the radical
adds to a pendant arene, and subsequent re-aromatization
under the oxidizing reaction conditions provides the observed
bicyclic products (Scheme 2). Intramolecularity in the arene
addition step seems important as we have not yet observed
intermolecular additions to arenes. We hypothesized that
7
8
17
17
13b
18b
88
70
>95
>95
Ar=4-
MeOC6H4
13c
Ar=4-
FC6H4
Ar=4-MeOC6H4
18c
Ar=4-FC6H4
À
intermolecular C C bond formation could occur if the carbon
radical intermediate were intercepted with superior radical
acceptors, namely, vinylarenes. Subsequent oxidation of the
resulting benzylic radicals would provide new vinyl arenes.
We were optimistic the vinyl arene additions would be
feasible as these radical acceptors worked in our related
copper-catalyzed enantioselective alkene carboamination/
alkyl-Heck-type reactions.[13b]
Table 3 summarizes the results of the enantioselective
copper-catalyzed coupling of variously substituted g-unsatu-
rated alcohols with various vinylarenes. 4-Pentenol (12)
underwent coupling with diphenylethylene to provide the
tetrahydrofuran 14 in excellent yield and good enantioselec-
tivity (Table 3, entry 1). The absolute stereochemistry of 14
was assigned as S by its conversion into a known tetrahy-
drofuran and optical rotation comparison (see the Supporting
Information for details). The absolute stereochemistry of all
other products was assigned by analogy to 2b and 14.
9
17
17
25
27
26
28
88
81
94
10
n.d.[e]
11
17
29a
X=OMe
30, E/Z>20:1
46
>95
Table 3: Intermolecular carboetherification/Heck-type couplings.[a]
Entry Substrate
Alkene
Product
Yield ee
[%][b] [%][c]
12
20
29b
X=tBu
31, E/Z>20:1
42
95
[a] Reactions were run under anhydrous conditions under Ar in a sealed
tube. 20 mol% of Cu(OTf)2 was complexed with 25 mol% (S,S)-tBu-box
(608C for 2 h in 1 mL PhCF3) then ca. 0.145 mmol alkenol substrate in
PhCF3 (0.1m total), 3 equiv vinylarene, 1 equiv K2CO3, 3 equiv MnO2, and
ca. 36 mg 4 ꢀ molecular sieves were added and the reaction stirred at
1008C for 16 h unless otherwise noted. [b] Yield of product isolated after
chromatography on silica gel. [c] Determined by HPLC using a chiral
stationary phase. [d] Reaction concentration of 0.08m used. [e] Not
determined. Enantiomers would not separate on several chiral HPLC
columns. Ts=4-toluenesulfonyl.
1[d]
12
13a
Ar=Ph
14
92
82
2
3
15
17
13a
13a
16
90
90
82
18a, Ar=Ph
>95
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As illustrated in entries 1–6 of Table 3, various alcohol
substitution patterns were tolerated, with the a,a-disubsti-
tuted alcohols 17 and 20 providing the highest level of
enantioselectivity (> 95% ee). The meso-dieneol 22 provides
a 6:1 ratio of diastereomers favoring the trans-substituted
tetrahydrofuran 23, even though the minor cis diastereomer
24 is formed with higher enantioselectivity (Table 3, entry 6).
Both electron-rich (p-MeO) and electron poor (p-F) 1,1-
diaryl ethylenes can be used in the coupling (Table 3, entries 7
and 8). It should be noted that conversion of the alkene of the
product into an aldehyde should be facile[13b] and would
extend their utility beyond diarylalkenes. Net benzofuran and
indole coupling adducts 26 and 28 were obtained by reaction
of the alkenols with heterocyclic vinylarenes 25 and 27,[24]
respectively (Table 3, entries 9 and 10). Additionally, both 4-
methoxy- and 4-tert-butyl styrene served as the vinylarene
component in this coupling reaction, thus giving homoallylic
ethers 30 and 31, respectively, in moderate yield and high
enantioselectivity (Table 3, entries 11 and 12).
The high enantioselectivity was used to further probe the
mechanism of this novel reaction. Involvement of the chiral
copper catalyst in the alkene addition step is evident from the
observed reaction enantioselectivity. This step is thought to
occur by enantioselective cis-oxycupration.[19] Cis-oxycupra-
tion presupposes that the alcohol moiety of the substrate first
coordinates to the copper(II) center in preference to the
alkene. This interaction is supported by reported coordination
preferences of copper(II) complexes.[25] An alternative trans-
oxycupration mechanism was thus considered less likely. To
further probe the enantiodetermining alkene addition step,
the pro-S (major) and pro-R (minor) cis-oxycupration tran-
sition states were modeled using density functional theory
calculations.
Unrestricted density functional theory calculations were
performed at the B3LYP/6-31 + G(d)[26–30] level of theory
using the Gaussian 09 software suite.[31] Single-point calcu-
lations using the polarizable continuum model[32] were carried
out to determine the solvation free energy, but CH2Cl2 (e =
8.93) was used instead of PhCF3 (e = 9.18) as the program
does not contain parameters for the latter. Calculations of the
pro-S (major) and pro-R (minor) cis-oxycupration transition
states at 1008C for 15 are illustrated in Figure 2. The major
transition state is 1.59 kcalmolÀ1 lower in Gibbs free energy,
thus translating to a calculated ee value of 79.1% (82% is
experimentally observed, Table 3, entry 2). While no steric
interactions of 2.2 ꢀ or less were observed in the major
transition state, two were observed in the minor transition
state, one between a substrate terminal alkene H and a ligand
backbone H, and another between a substrate a-carbon H
and a ligand backbone H (Figure 2). The Supporting Infor-
mation contains full details of the computational method-
ology employed, as well as in-depth analysis of the most
important computational results.
Figure 2. a) Calculated major transition state. b) Calculated minor
transition state. DDG° =1.59 kcalmolÀ1 (79.1% ee).
of the major transition state indicates that the unpaired
electron resides mainly on copper(II) (46%) but the emer-
À
gent terminal carbon atom (C1 Cu bond) also picks up spin
(26%) as does the oxygen adding to the alkene (21%).
Mulliken charge analysis indicates the internal alkene carbon
atom (C2) increases in positive charge from 0.16 in the
substrate to 0.95 at the major transiton state, and analysis of
the Wiberg bond indices[33–35] indicates the C1 Cu bond is
À
À
68% formed while the C2 O bond is 45% formed in the
major transition state. Taken together, these data support an
alkene addition with substantial polar character, though
radical contributions cannot be discounted. Tetrahedral
twist angle measurements indicate the major transition state
is a distorted tetrahedron (16.58 less than a perfect tetrahe-
dron) about the copper center, while the minor transition
state is almost perfectly tetrahedral. Natural Bond Order
(NBO) analysis of the two transition states indicate there are
more favorable bonding interactions in the major transition
state than in the minor.
In conclusion, we have rendered the copper-catalyzed
carboetherification of 4-alkenols highly enantioselective. We
have developed a new intra/intermolecular coupling reaction
of 4-alkenols with vinyl arenes and it results in net alkyl Heck-
type products where the alkyl component consists of an
enantiomerically enriched tetrahydrofuran. This reaction
extends the scope of what is possible by polar/radical reaction
cascades.[36] The enantioselectivity of the reaction can be
greater than 95% ee, and the absolute stereochemistry of the
major products was definitively assigned. DFT transition-
state calculations are consistent with a cis-oxycupration
stereodetermining transition state and there is good agree-
ment between experimental and calculated levels of enantio-
The electronic structure of the transition states was
further analyzed. Data were obtained in both vacuum and
dichloromethane; the latter is shown here. Inclusion of
solvent effects via single point calculations on gas phase
geometries did not have a notable effect on the results (see
the Supporting Information for a comparison). Spin analysis
4
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Received: February 15, 2014
Revised: March 25, 2014
Published online: && &&, &&&&
Keywords: alkenes · asymmetric catalysis · copper ·
.
enantioselectivity · heterocycles
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Communications
Asymmetric Catalysis
M. T. Bovino, T. W. Liwosz, N. E. Kendel,
Y. Miller, N. Tyminska, E. Zurek,*
S. R. Chemler*
&&&& — &&&&
Enantioselective Copper-Catalyzed
Carboetherification of Unactivated
Alkenes
A general scheme: A highly enantiose-
lective copper-catalyzed carboetherifica-
tion of 4-pentenols has been developed.
C bond formation can occur, thus form-
ing a range of chiral functionalized tetra-
hydrofurans. DFT transition-state calcu-
lations provide a rationale for the
À
Both intramolecular (formal C H func-
tionalization) and intermolecular (net
observed asymmetric induction.
À
alkyl Heck-type coupling; see scheme) C
6
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