Catalyst- And Silane-Controlled Enantioselective Hydrofunctionalization of Alkenes by Cobalt-Catalyzed Hydrogen Atom Transfer and Radical-Polar Crossover

Article abstract of DOI:10.1021/jacs.0c05017

The catalytic enantioselective synthesis of tetrahydrofurans, which are found in the structures of many biologically active natural products, via a transition-metal-catalyzed hydrogen atom transfer (TM-HAT) and radical-polar crossover (RPC) mechanism is described herein. Hydroalkoxylation of nonconjugated alkenes proceeded efficiently with excellent enantioselectivity (up to 94% ee) using a suitable chiral cobalt catalyst, N-fluoro-2,4,6-collidinium tetrafluoroborate, and diethylsilane. Surprisingly, the absolute configuration of the product was highly dependent on the steric hindrance of the silane. Slow addition of the silane, the dioxygen effect on the solvent, thermal dependence, and DFT calculation results supported the unprecedented scenario of two competing selective mechanisms. For the less-hindered diethylsilane, a high concentration of diffused carbon-centered radicals invoked diastereoenrichment of an alkylcobalt(III) intermediate by a radical chain reaction, which eventually determined the absolute configuration of the product. On the other hand, a more hindered silane resulted in less opportunity for a radical chain reaction, instead facilitating enantioselective kinetic resolution during the late-stage nucleophilic displacement of the alkylcobalt(IV) intermediate.

Full text of DOI:10.1021/jacs.0c05017

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Article
Catalyst- and Silane-Controlled Enantioselective
Hydrofunctionalization of Alkenes by Cobalt-Catalyzed
Hydrogen Atom Transfer and Radical-Polar Crossover
Kousuke Ebisawa, Kana Izumi, Yuka Ooka, Hiroaki Kato, Sayori
Kanazawa, Sayura Komatsu, Eriko Nishi, and Hiroki Shigehisa
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Jul 2020
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Journal of the American Chemical Society
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Catalyst- and Silane-Controlled Enantioselective Hydrofunctionaliza-
tion of Alkenes by Cobalt-Catalyzed Hydrogen Atom Transfer and
Radical-Polar Crossover
Kousuke Ebisawa, Kana Izumi, Yuka Ooka, Hiroaki Kato, Sayori Kanazawa, Sayura Komatsu, Eriko
Nishi, Hiroki Shigehisa*
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Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi Nishitokyo-shi, Tokyo 202-8585, Japan
ABSTRACT: Catalytic enantioselective synthesis of tetrahydrofurans, which are found in the structures of many biologically
active natural products, via a transition-metal catalyzed-hydrogen atom transfer (TM-HAT) and radical-polar crossover
(RPC) mechanism is described herein. Hydroalkoxylation of non-conjugated alkenes proceeded efficiently with excellent
enantioselectivity (up to 94% ee) using a suitable chiral cobalt catalyst, N-fluoro-2,4,6-collidinium tetrafluoroborate, and
diethylsilane. Surprisingly, absolute configuration of the product was highly dependent on the steric hindrance of the silane.
Slow addition of the silane, the dioxygen effect in the solvent, thermal dependency, and DFT calculation results supported
the unprecedented scenario of two competing selective mechanisms. For the less-hindered diethylsilane, a high concentra-
tion of diffused carbon-centered radicals invoked diastereoenrichment of an alkylcobalt(III) intermediate by a radical chain
reaction, which eventually determined the absolute configuration of the product. On the other hand, a more hindered silane
resulted in less opportunity for radical chain reaction, instead facilitating enantioselective kinetic resolution during the late-
stage
nucleophilic
displacement
of
the
alkylcobalt(IV)
intermediate.
Introduction
zation of alkenes based on a TM-HAT reaction mechanism
1
2
had not been reported until recently (Figure 1b). Such
difficulty is unsurprising given the inherently challenging
construction of a chiral carbon from a reactive prochiral
radical center. However, Pronin and coworkers eventually
reported the highly enantioselective formation of epoxides
The transition-metal-catalyzed-hydrogen atom transfer
TM-HAT) of alkenes has recently attracted significant at-
(
1
tention in synthetic organic chemistry. Originally, Halpern
proposed the transfer of a hydrogen atom from a cobalt
2
hydride species for the hydrogenation of anthracene. A
3
4
few years later, Halpern (Mn) and Marko (Co) reported
the hydrogenation of styrenes and established the TM-HAT
mechanism using kinetic and spectroscopic experiments.
Independently, Drago and Mukaiyama reported the cata-
lytic hydration of alkenes under aerobic conditions. These
alkene-chemoselective reactions and their modifications
have been recently used in the synthesis of complex mole-
5
6
1
b,7
cules, such as natural products. The catalytic hydrations
have now been advanced to applications in diverse hydro-
functionalization and other useful transformations (Figure
8 9
1
a, left) . The mechanism of these relevant reactions is
9
n,9r,10
also becoming clearer.
Our group has previously reported diverse hydrofunction-
alizations using cobalt Schiff base catalyst, N-
fluorocollidinium salt, and a silane reagent (Figure 1a,
a
1
1
right). A remarkable and unique mechanistic feature of
this reaction is that the radical species generated by TM-
HAT was transformed via single-electron oxidation into a
cationic species that can receive various nucleophiles. This
radical-polar crossover (RPC) mechanism enabled the pro-
tonation of alkenes without a proton source, realizing ex-
cellent chemoselectivity and functional group tolerance.
Despite numerous reports and our previous preliminary
results, high enantioselectivity for the hydrofunctionali-
1
1c
Figure 1. Previous examples and this work
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Table 1. Screening of cobalt catalysts and silanesa
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Best conditions: 1a (0.1 mmol), C7 (10 mol%), 3 (2 equiv.), diethylsilane (S1, 2 equiv.), CH
2
Cl
2
(4.0 mL), CF
3
CH OH (0.2 mL),
2
a
−
10 °C, 30 min (the same result was obtained after 24 h), 77% Reaction times for experiments under conditions other than
b
the optimum ones were 24−36 h (see SI). Isolated yields are shown. The yield in parentheses is an NMR yield using 1,4-bis-
trifluoromethylbenzene as the internal standard. 4 equiv. of silane.
c
from a tertiary allylic alcohol by a TM-HAT and RPC ap-
tionally examined the mechanism of this catalysis and the
unique silane effect.
1
3
proach using a finely tuned cobalt complex. Importantly,
they proposed the presence of an alkylcobalt(IV) interme-
diate with the contribution of a cation–π interaction in the
asymmetric induction. More recently, Lu reported enanti-
Results and Discussion
We started to explore the enantioselective hydroalkoxyla-
tion of alkenyl alcohol 1a (>200 runs, >30 cobalt catalysts,
and >20 silanes) and identified the optimal reaction condi-
tions as the use of the cobalt catalyst C3 (10 mol%), N-
fluoro-2,4,6-collidinium tetrafluoroborate,
14
oselective hydrazone formation initiated by TM-HAT.
Since we obtained our preliminary result of enantioselec-
16
11c
tivity, we have been extensively exploring alternative
17
and dieth-
reaction conditions to improve the reaction. Eventually, we
found the high enantioselectivity of our catalytic hydroal-
koxylation of unactivated alkenes afforded chiral tetrahy-
drofurans, which are found in the structures of many bio-
logically active natural products, via a TM-HAT and RPC
approach (Figure 1c). Herein, we describe the process
leading to the optimal reaction conditions of a chiral cobalt
catalyst, N-fluoro-2,4,6-collidinium tetrafluoroborate, and
diethylsilane. To our surprise, the absolute configuration
of the product was highly dependent on the steric hin-
drance of the silane reagent, which is typically viewed as a
hydrogen source for the cobalt hydride species. This
silane-controlled product selectivity is unique in TM-HAT
chemistry. Therefore, we experimentally and computa-
18
ylsilane in dichloromethane/trifluoroethanol (20:1) at -
1
0 °C to afford cyclic ether (S)-2a in excellent yield and
19
enantioselectivity (Table 1). Screening of various chiral
cobalt complexes revealed that the bulky ligands (C3−C8)
reported by Katsuki are preferable to the simpler salen
1
5
20
21
ligand (C1) or β-ketoiminate ligand (C2). Notably, the
axial chirality of the binaphthyl unit had a significant im-
pact on the enantioselectivity; even C3, lacking chirality on
the diamine, provided higher enantioselectivity than C1 or
C2. The introduction of two methyl groups on the diamine
(C4) did not sufficiently improve the enantioselectivity;
however, enantioselectivities were enhanced for diphenyl
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Table 2. Substrate scope of enantioselective hydroalkoxylation of alkenyl alcohol
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Conditions: 1b-t (0.1 mmol), C3 (10 mol %), 3 (2 equiv.), S1 (2 equiv.), CH
2
Cl
Isolated yields are shown. S8 was used instead (36 h). temperature = −20 °C.
C5) or cyclohexyl (C7) diamines, probably by further lock-
2
(4.0 mL), CF
3
CH OH (0.2 mL), −10 °C, 16 h.
2
a
b
(
After establishing the optimal reaction conditions, we ex-
plored the scope of the enantioselective hydroalkoxylation
with various alkenyl alcohols (Table 2). We commenced
with the examination of the steric effects by introducing a
methyl group on the phenyl rings, and found no significant
difference in the results obtained with 4-methyl (2b), 3-
methyl (2c), 2-methyl (2d), 3,5-xylyl (2e), 1-naphthyl (2f),
and 2-naphthyl (2g) substitutions. We next investigated
the electronic effect of the aromatic ring. While the intro-
duction of a methoxy group did not change the yield or
enantioselectivity (2h), introduction of a halogen substitu-
ent slightly decreased the enantioselectivity (2i-2k). Ex-
amination of the functional group tolerance of this reaction
revealed that the product could be obtained from alkenyl
alcohols bearing an acid-sensitive acetal (2l), fluoro-anion-
sensitive silyl ether (2m), or base-sensitive acetate (2n).
Replacing the phenyl ring with heterocycles such as thio-
phene (2o) or N-tosyl indole (2p) resulted in comparable
yields and enantioselectivities. Unfortunately, introducing
a methylthio group (2q) or other subunits such as indane
(2r), N-Ts-piperidine (2s), or bisphenethyl (2t) in place of
the diaryl groups reduced the enantioselectivity. We brief-
ly examined the substrate scope the reaction using S8 and
ing the conformation of the ligand. The conformation of the
ligand is crucial for reactivity and enantioselectivity, as
also reflected by the significantly worse results obtained
upon using the diastereomers C6 and C8. Extensive
screening showed that silane reagents had significant im-
22
pact on the enantioselectivity. A secondary silane was
essential for obtaining the excellent enantioselectivity of
(S)-2a. Among secondary silanes, the sterically least hin-
dered diethylsilane (S1) was found to be optimal. To our
surprise, the use of the sterically more hindered diiso-
propylsilane (S6) afforded (R)-2a as the major enantiomer.
This result is remarkable because in the typical TM-HAT
mechanism, the silane reagent acts as a hydrogen source
for the cobalt hydride species, and is not directly involved
in the asymmetric induction. The more hindered di-tert-
butylsilane (S7) resulted in no reaction of 1a. The stereo-
chemistry of the major enantiomer formed using a tertiary
silane (S8 and S9) was also (R)-2a, which is the same as
that when using S6. A primary silane afforded a near
23
racemate. Therefore, steric hindrance of the silane de-
termined the absolute configuration of the product.
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obtained the (R)-enantiomers of 2b, 2f, 2j, and 2r with this radical chain reaction gives rise to an equilibrium be-
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moderate enantioselectivities. Reactions forming a 6-
membered ring (2u, low conversion), using a disubstituted
alkene (2v, low conversion), or using a MOM-protected
alkenyl alcohol (2b, 16%, 1% ee) were found to be ineffec-
tive under our conditions.
tween two diastereomeric alkylcobalt(III) complexes, and
converges on the specific stable complex. Originally, Kochi
reported the alkyl rearrangement of an alkylcobalt com-
2
9
plex by a radical chain reaction. Wayland also experimen-
tally and computationally examined a cobalt-catalyzed
living radical polymerization, including a radical chain
The proposed reaction pathways depicted in Figure 2 are
30
mechanism.
consistent with those found in the literature. As postulated
2
4
for the cobalt(III) hydride-HAT to alkenes, a caged radi-
(D) A last possibility is an enantiodetermining nucleophilic
displacement of the alkylcobalt(IV) complex to afford a
cyclic ether product. There can be some degree of energet-
ic difference between the two transition states derived
from each diastereomeric alkylcobalt(IV) complex. Pronin
proposed such an enantioselective kinetic resolution of
alkylcobalt(IV) complex with the prior epimerization via
9
n,9r,25
cal-catalyst pair 4 initially forms.
Subsequently, bi-
furcation of the reaction would be possible as follows: (1)
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the formation of cage-collapsed alkylcobalt(III) complex 5,
2
6
followed by single-electron oxidation to generate scalem-
1
0a,11f,13,27
ic alkylcobalt(IV) intermediate 6;
or (2) the pair
collapse is bypassed and the escaped diffused radical 4′ is
captured by a cationic cobalt(III) complex, whereupon the
1
3
radical chain mechanism.
pathways converge to the key alkylcobalt(IV) intermediate
Given the enantiodiversity of the resultant cyclic ether, it is
assumed that our enantioselective catalysis might contain
no fewer than two enantiodetermining steps among these
four scenarios. In the following sections, we discuss the
refinement of these hypotheses (Figure 3) experimentally
and computationally, elucidating the silane effect.
28
6
.
The C−O bond would be formed by nucleophilic dis-
placement with stereoinversion to afford 7 instead of the
tentative formation of a planar carbocation.
11d,13,27c,27d,27g
Finally, deprotonation of 7 by 2,4,6-collidine would afford
product 2.
Figure 2. Proposed mechanism
With a reasonable reaction mechanism in hand, the possi-
ble enantiodetermining steps are discussed individually
(Figure 3) as follows.
(
A) A first possibility is the enantiodetermining formation
Figure 3. Hypothetical enantiodetermining steps
of an alkylcobalt(III) complex from a cobalt(II) complex
and carbon-centered radical, creating a stereocenter on the
corresponding carbon atom. This process can occur within
the solvent cage or after cage escape.
Silane screening (Table 1) indicated that the steric hin-
drance of the silane reagent was dramatically crucial for
the absolute configuration of the product and its degree of
enantioselectivity. To examine the role of the silane rea-
gent in more detail, we controlled the concentration of
silane reagent in the solution by its slow addition (Table
3). The enantioselectivities using secondary silanes such as
S1 and S4, providing (S)-2a as the major enantiomer, were
reduced from 93% and 78% ee to 80% and 61% ee, re-
spectively, when slow addition was used (entries 2, 4).
Furthermore, the addition of S4 over 80 h changed the
(B) Formation of an alkylcobalt(IV) complex from a cation-
ic cobalt(III) complex and a diffused carbon-centered radi-
cal also generates a stereocenter on the corresponding
carbon atom. Pronin suggested this enantiodetermining
step as one possibility in their reaction.1
3
(
C) Even once the alkylcobalt(III) complex is formed, a
diffused carbon-centered radical can react with the al-
kylcobalt(III) complex by homolytic displacement (S 2);
H
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centered radical, as the enantiodetermining step leading to
major enantiomer from (S)-2a to (R)-2a (entry 5). On the
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other hand, the enantioselectivity using hindered silane S8,
providing (R)-2a as the major enantiomer, increased from
58% to 69% ee by slow addition over 2 h (entry 7).
(R)-2a.
We next investigated the thermal dependency of the enan-
tioselectivity by comparing S1 and S8 (Figure 4). It is tra-
ditionally considered that a lower temperature improves
enantioselectivity. However, we found that the situation
for S1 is not simple; the ee variation was not monotonic
with the temperature. The slightly convex Eyring plot is
characterized by two lines with an inversion point (Tinv
−10 °C). On the other hand, using S8 resulted in a typical
rising linear Eyring plot.
These results clearly indicate that no fewer than two of
enantiodetermining steps (A)−(D) in Figure 3 were com-
peting in the cobalt catalysis. The relative contribution of
the steps appears to depend on the concentration of the
silane reagent. Apparently, the smallest silane, S1, which
has the shortest reaction time among all the silane rea-
gents, has the highest reactivity and generates the highest
concentration of the downstream intermediates (e.g. a
cobalt(III) hydride, carbon-centered radical). For example,
a hypothetical radical chain reaction (C) fits the experi-
mental results; the rate of the radical chain disproportion-
ation to the more stable scalemic alkylcobalt(III) interme-
diate should depend on the concentration of a diffused
carbon-centered radical and alkylcobalt(III) intermediate.
Conversely, the reaction with hindered silane S8 would
include minimal influence of a radical chain. The slightly
higher enantioselectivity from the slow addition would
result from attenuation of the radical chain contribution;
the concentration of intermediates might not affect the
enantiodetermining step leading to (R)-2a. This would be
understandable in view of intramolecular displacement
3
1
=
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The nonlinearity for S1 is generally interpreted as evi-
dence for a reaction pathway with at least two enantiode-
termining steps weighted differentially according to the
32
temperature. If radical chain reaction (C) occurs, we
should consider the possibilities of 1) the ratio of the dia-
stereomeric alkylcobalt(III) intermediate (equilibrium
constant) changing at lower temperature, and 2) a nega-
tive effect toward the radical chain by interruption of the
cage escape in the higher viscosity of the solvent at lower
33
temperature. A balance of these factors would result in
the unusual Eyring plot. For S8, the derived activation pa-
rameters indicated that the differential enthalpy is a major
contributor to the enantiodetermining step. It is to be not-
ed that the Eyring plot for S8 and the derived activation
parameters might entail the influence of a radical chain
reaction, as indicated from the silane-slow addition exper-
iment. If so, in view of the slightly dropping regression line
of the Eyring plot of S1, the actual differential enthalpy of
the related enantiodetermining step could be slightly high-
er. Pronin ruled out enantioselective radical capture (A)
because of its considerably larger differential enthalpy
compared with the known activation enthalpy of a diffu-
(
D), independent of the concentration of carbon centered
radical. However, the contributions of hypotheses (A) and
B) to the enantioselectivity should not be completely
(
ruled out.
Table 3. Mechanistic experiments
13
sion-controlled process (2 kcal/mol). Even though our
differential enthalpy is close to the value of 2 kcal/mol, it
remains uncertain whether hypothesis (A) can be ruled
out because of the partial influence of the radical chain
reaction.
a
Yields based on GC using 1,3,5-tri-tert-butylbenzene as an
b
internal standard. Each reaction time was measured from
the start of the addition.
During the optimization of reaction conditions using S1,
we found that deoxygenation of the solvent is crucial for
high enantioselectivity. Indeed, the run without deoxygen-
ation of trifluoroethanol decreased the enantioselectivity
from 93% to 72% ee (Table 3, entry 8). This result is un-
derstandable because dioxygen can quench the carbon-
centered radical. The inhibition of a radical chain reaction
in a cobalt-catalyzed reaction was previously reported by
Figure 4. Eyring plots. Activation parameters calculated
‡
from these Eyring plots were ΔΔH = −2.13 kcal/mol and
‡
‡
ΔΔS = −5.53 kcal/mol·K for S1, and ΔΔH = 1.81 kcal/mol
‡
and ΔΔS = 12.7 kcal/mol·K for S8.
To gain additional insight into the mechanism and enanti-
oselectivity, we next performed density functional theory
(DFT) studies, commencing with the Co−C bond formation
affording alkylcobalt(III) complex 5. The transition state
2
9
Kochi. On the other hand, the enantioselectivity using S8
was not affected by dioxygen (entry 9). This result sup-
ports step (D), where there is no involvement of carbon-
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Figure 5. (A) Lowest-energy diastereomeric alkylcobalt(III) complex (B) Lowest-energy TSs of nucleophilic displacement.
All energies are in kcal mol .
-
1
was searched by elongating the Co−C bond of the alkylco-
balt complex. For complex 5, only a regular increase in
energy was observed until the complete dissociation. Way-
land reported, in the same process for their cobalt catalysis,
that there is no transition state (barrierless) on the elec-
tronic energy surface and this process requires mostly an
entropic contribution to bring together the radical and
cobalt complex. Given the Eyring study using S8, our cal-
culated result is inconsistent with a rising linear plot,
which indicates an enthalpically controlled process.
plex 6 leading to (S)-2a; however, the energetic difference
is too small to explain quantitatively.
To further validate the radical chain reaction leading to
(S)-2a using S1, we computed the energetic difference of
diastereomeric alkylcobalt(III) intermediate 5 (Figure 5a).
The energy of (R)-5a, leading to (S)-2a, was 1.76 kcal/mol
lower than that of (S)-5a. This difference in energy agrees
with the enantioselectivity observed for (S)-2a. Apparently,
there are favorable CH/π interactions between the aro-
matic rings (naphthyl and phenyl) of the ligand and the
34
35
On the other hand, we found the transition state of the
Co−C bond formation affording alkylcobalt(IV) complex 6
by the same approach as that used for 5. Transition state
(R)-TS1a, leading to (S)-2a, is 0.91 kcal/mol more stable
than (S)-TS1a (Figure SI9). This result might indicate en-
antiodetermining bond formation of alkylcobalt(IV) com-
two phenyl groups of the substrate. Indeed, the differ-
ence in energy is smaller for the diastereomers 5r (0.79
kcal/mol) than for the diastereomers 5f (1.93 kcal/mol).
They are also in nearly quantitative agreement with the
experimentally observed enantioselectivities of 2r (62%
ee) and 2f (93% ee).
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Journal of the American Chemical Society
opment is warranted to take full advantage of this selectiv-
We next computed the energies of the diastereomeric
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
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5
5
5
5
5
5
5
5
5
5
6
transition states of the nucleophilic displacement at the
same level of theory. The detailed geometry optimization
revealed that the Co−C bond needed to be rotated from the
geometry of the alkylcobalt(III) complex to obtain the
transition state. The transition state (R)-TS2a, leading to
ity. Expansion of the substrate scope of the enantioselec-
tive hydrofunctionalization by the RPC mechanism and
detailed mechanistic studies are currently ongoing.
Associated Content
(S)-2a, is 0.54 kcal/mol less stable than (S)-TS2a. This
Supporting Information. Experimental procedures and analyti-
result clearly reflects the preference of affording (R)-2a
using S8. In addition, the relative Gibbs free energy be-
tween the diastereomeric transition states correlated with
the bond length of the Co−C bond. The difference in energy
is larger for TS2f (0.76 kcal/mol) and smaller for the dia-
stereomeric transition state TS2r (0.16 kcal/mol). The
difference between these values, less than 1 kcal/mol, is
not high enough for quantitative discussion. However, this
result is qualitatively consistent with the enantioselectivi-
ties of 2f and 2r using S8 (72% ee and 32% ee, respective-
ly, Table 2). In the structures of (S)-TS2a and (S)-TS2f, we
found the same CH/π interactions between the aromatic
rings of the ligand and substrate as was observed in (R)-5a.
Together, these CH/π interactions would be the origin of
the enantioselectivity for not only the diastereomeric al-
kylcobalt(III) complex, but also the transition state of the
nucleophilic displacement. In our DFT study, Grimme’s
dispersion correction, known to be efficient in CH/π inter-
1
13
cal data ( H and C NMR) for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
*cgehisa@musashino-u.ac.jp.
Funding Sources
This work was supported by JSPS KAKENHI Grant number
17K15426, the Uehara memorial foundation, Takeda Sci-
ence Foundation, Takeda Award in Synthetic Organic
Chemistry, japan, the research foundation for pharmaceu-
tical sciences.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
3
6
acting system, is essential for explaining the observed
enantioselectivity (Table SI1).
We thank the reviewers for their careful reading of the
manuscript and their helpful comments. We thank Dr. Kou
Hiroya (Musashino university) for our liberal research envi-
ronment. We thank Dr. Masahiro Anada (Musashino universi-
ty) for chiral columns. We thank Dr Sumie Tajima (HULINKS
Ink) for the introductory Gaussian guide. We thank Dr. Hi-
royuki Morimoto (Kyushu University) for their helpful advice
of ITO. The computation was carried out using the computer
facilities at Research Institute for Information Technology,
Kyushu University. Dedicated to the memory of Professor Dr.
Tsutomu Katsuki, Dr. Jack Halpern, Dr. Teruaki Mukaiyama,
and Tadaharu Shigehisa.
Conclusion
We developed a catalytic enantioselective synthesis of tet-
rahydrofurans via a cobalt-catalyzed HAT/RPC approach.
Intramolecular hydroalkoxylation of an alkenyl alcohol
proceeded efficiently with excellent enantioselectivity us-
ing chiral cobalt catalyst C7, N-fluoro-2,4,6-collidinium
tetrafluoroborate, and diethylsilane. A series of chiral tet-
rahydrofurans were synthesized by this method. The abso-
lute configuration of the product was found to depend on
the bulkiness of the silane used.
According to silane-slow addition and deoxygenation ex-
periments, the concentration of intermediates such as a
carbon-centered radical influences the absolute configura-
tion of the product. The DFT calculations provided a plau-
sible explanation for the catalyst- and silane-controlled
enantioselectivity. After HAT, the unselective pair collapse
would form an alkylcobalt(III) intermediate 5 as a resting
state. Use of a small secondary silane, represented by S1,
invoked an extensive radical chain reaction between the
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30. Li, S.; de Bruin, B.; Peng, C. H.; Fryd, M.; Wayland, B. B.,
Exchange of organic radicals with organo-cobalt complexes
formed in the living radical polymerization of vinyl acetate. J. Am.
Chem. Soc. 2008, 130, 13373-13381.
31. Mayr, H.; Ofial, A. R., The Reactivity–Selectivity Principle:
An Imperishable Myth in Organic Chemistry. Angew. Chem. Int.
Ed. 2006, 45, 1844-1854.
32. Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P., The
Isoinversion Principle—a General Model of Chemical Selectivity.
Angew. Chem. Int. Ed. 1991, 30, 477-515.
1
7. Umemoto, T.; Harasawa, K.; Tomizawa, G.; Kawada, K.;
Tomita, K., Syntheses and Properties of N-Fluoropyridinium Salts.
Bull. Chem. Soc. Jpn. 1991, 64, 1081-1092.
1
8. (a) Trifluoroethanol also accelerates the dissolution of 3 in
the reaction mixture, even at -40°C; (b) The use of carefully
degassed mixed solvent was essential for high yields and
enantioselectivity (Figure SI3).
1
9. (a) Although Sawamura synthesized 2a in 39% yield and 71%
ee by a different method, they did not mention the absolute
configuration. We determined the absolute configuration of this
compound by chemical transformation from a known compound;
see Supporting information. For Sawamura's report, See:
Murayama, H.; Nagao, K.; Ohmiya, H.; Sawamura, M.,
Copper(I)-catalyzed
intramolecular
hydroalkoxylation
of
unactivated alkenes. Org. Lett. 2015, 17, 2039-41; (b) 2a was
intact for 24 h under the reaction conditions. Thus, the
enantioselective decomposition of the product can be ruled out.
2
0. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N.,
Highly selective hydrolytic kinetic resolution of terminal epoxides
catalyzed by chiral (salen)Co(III) complexes. Practical synthesis
of enantioenriched terminal epoxides and 1,2-diols. J. Am. Chem.
Soc. 2002, 124, 1307-1315.
2
1. Nagata, T.; Yorozu, K.; Yamada, T.; Mukaiyama, T.,
Enantioselective Reduction of Ketones with Sodium Borohydride,
Catalyzed by Optically Active(β-Oxoaldiminato)cobalt(II)
Complexes. Angew. Chem. Int. Ed. 1995, 34, 2145-2147.
22. The runs resulting in less than moderate yields tended to have
a considerable amount of recovered starting material together with
a small amount of byproduct (Figure SI4).
33. Andrade, E. N. D. C., The Viscosity of Liquids. Nature 1930,
125, 309-310.
34. de Bruin, B.; Dzik, W. I.; Li, S.; Wayland, B. B., Hydrogen-
Atom Transfer in Reactions of Organic Radicals with [CoII(por)].
(por=Porphyrinato) and in Subsequent Addition of [Co(H)(por)]
to Olefins. Chem. Eur. J. 2009, 15, 4312-4320.
35. Wheeler, S. E.; Seguin, T. J.; Guan, Y.; Doney, A. C.,
Noncovalent Interactions in Organocatalysis and the Prospect of
Computational Catalyst Design. Acc. Chem. Res. 2016, 49, 1061-
1069.
36. Dey, R. C.; Seal, P.; Chakrabarti, S., CH/π Interaction in
Benzene and Substituted Derivatives with Halomethane: A
Combined Density Functional and Dispersion-Corrected Density
Functional Study. J. Phys. Chem. A 2009, 113, 10113-10118.
37. Although Co−C homolysis of the alkylcobalt(IV) intermediate
(retro-reaction of radical capture) is known, our DFT study
indicated the preference of nucleophilic displacement for (R)-6a
(Figure SI10).
38. In contrast to the landmark example of Pronin case (3-exo
cylization, Ref. 13), this work, including the more favored 5-exo
cylization, would minimize the epimerization of alkylcobalt(IV)
intermediate 6, which is essential for dynamic kinetic resolution.
Thus, the activation energy of (S)-TS2 is even lower than that of
(R)-TS2; after the extremely diastereoenriched alkylcobalt(IV)
intermediate (R)-6 is formed, the fast and spereospecific
2
3. Use of phenylsilane could invoke the silylation of the
hydroxyl group, a much weaker nucleophile, before the cylization.
This would lead to the Co(IV)-C bond cleavage to form a Co(II)
speices and an unstable planar secondary carbocation, followed by
unselective capture by a silyl ether. see: (a) Yasuhiko, G.;
Yoshihiro, Y.; Taketo, I.; Tohru, Y., Convenient and Selective
Preparation of Mono-alkoxyphenylsilanes from Phenylsilane and
Alcohols. Chem. Lett. 2006, 35, 714-715.; (b) Fujita, S.; Abe, M.;
Shibuya, M.; Yamamoto, Y., Intramolecular Hydroalkoxylation of
Unactivated Alkenes Using Silane-Iodine Catalytic System. Org.
Lett. 2015, 17, 3822-3825.
24. The reversibility of the HAT step was proved by a deuterium
experiment (Figure SI5).
2
5. Eisenberg, D. C.; Norton, J. R., Hydrogen-Atom Transfer
Reactions of Transition-Metal Hydrides. Isr. J. Chem. 1991, 31,
5
2
5-66.
6. The actual oxidant of 5 has remained unclear, though it is
assumed to be 3 or a cationic cobalt(III) complex (Figure SI6). .
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nucleophilic displacement that follows would produce (S)-2 as the
major product.
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