Catalytic Asymmetric Radical-Polar Crossover Hydroalkoxylation

Article abstract of DOI:10.1021/jacs.9b10645

Asymmetric intramolecular hydrofunctionalization of tertiary allylic alcohols is described. This metal hydride-mediated catalytic radical-polar crossover reaction delivers corresponding epoxides in good to high enantioselectivity and constitutes the first example of asymmetric hydrogen atom transfer-initiated process. A series of modified cobalt salen complexes has proven optimal for achieving good efficiency and asymmetric induction. Experimental data suggest that cationic cobalt complexes may be involved in the enantiodetermining step, where cation-πinteractions in the catalyst contribute to the asymmetric induction.

Full text of DOI:10.1021/jacs.9b10645

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Communication
Catalytic asymmetric radical-polar crossover hydroalkoxylation
Christopher A. Discolo, Eric E. Touney, and Sergey V. Pronin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10645 • Publication Date (Web): 23 Oct 2019
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Catalytic asymmetric radical-polar crossover hydroalkoxylation
Christopher A. Discolo‡, Eric E. Touney‡, and Sergey V. Pronin*
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Department of Chemistry, University of California, Irvine, California 92697-2025, United States
Supporting Information Placeholder
tertiary allylic alcohols to the corresponding
enantioenriched epoxides. We present data suggesting
that cationic cobalt complexes may be involved in the
enantio-determining step,
ABSTRACT:
Asymmetric
intramolecular
hydrofunctionalization of tertiary allylic alcohols is
described. This metal hydride-mediated catalytic radical-
polar crossover reaction delivers corresponding epoxides
in good to high enantioselectivity and constitutes the
first example of asymmetric hydrogen atom transfer-
initiated process. A series of modified cobalt salen
complexes has proven optimal for achieving good
efficiency and asymmetric induction. Experimental data
suggest that cationic cobalt complexes may be involved
in the enantio-determining step, where cation–π
interactions in the catalyst contribute to the asymmetric
induction.
scalemic Co(II),
intramolecular
displacement
Me
[Co]
OH
R
Me
silane, oxidant
OH
R
O
R
via
- [H
]
Me
R
R
R
R
OH
R
scalemic
alkylcobalt(IV)
13 examples
80–95% ee
prochiral
alkene
Figure 1. Catalysis by alkylcobalt(IV) complexes allows
for efficient asymmetric induction in HAT-initiated
hydrofunctionalizations.
where cation– interactions in the catalyst contribute to
the asymmetric induction. We also demonstrate the
application of this chemistry in a formal Markovnikov
hydrofunctionalization of tertiary allylic alcohols for
Metal hydride-initiated radical reactions serve as a
highly chemoselective means for Markovnikov
hydrofunctionalization of alkenes under mild
conditions.1,2 The intermediate carbon-centered radicals
generated upon hydrogen atom transfer (HAT)3 to a
carbon-carbon double bond can react with atom and
group transfer reagents,4 undergo addition to multiple
bonds,5 and participate in cross-coupling reactions6 to
introduce new functional groups and structural motifs.
However, corresponding stereoselective processes are
represented almost exclusively by the instances of
stereochemical relay, including examples of auxiliary-
controlled hydration and hydrohydrazination of ,-
unsaturated amides.2,7 These limitations are not
surprising due to the inherent challenge associated with
enantiodifferentiation in prochiral alkyl radical
intermediates.8 In this context, early reports of a highly
selective cis addition of putative cobalt(III) hydride
intermediates9 to 1,2-disubstituted alkenes involving
rapid collapse of a radical pair in a solvent cage
constitute the only relevant instances of efficient
stereocontrol.10,11 Here we show the first example of a
enantioselective
installation
of
trisubstituted
stereocenters including those bearing amine, sulfide, and
nitrile functionalities.
Building on the earlier work in the field,12 we recently
reported HAT-initiated radical-polar crossover reactions
of tertiary allylic alcohols that afforded corresponding
epoxides and semipinacol rearrangement products.13 In
that setting, the outcome of the hydrofunctionalization
event was under strong catalyst control, which suggested
participation of alkylcobalt complexes as electrophilic
intermediates.14 We reasoned that a proper choice of a
scalemic chiral catalyst would allow for efficient
enantioinduction provided that generation of the product
could be limited to the putative alkylcobalt-based
pathway. Initial experiments with tetrahydropyran
derivative 1 and enantioenriched complex 4, which had
previously proven competent in the HAT-initiated
synthesis of epoxides,13 delivered product 2 with low but
measurable enantiomeric excess (Table 1). Extensive
experimentation
with
modifications
in
the
ethylenediamine-derived fragment led to identification
of a series of o-biaryl-substituted complexes that
delivered the desired product with improved levels of
asymmetric induction. Thus, application of complex 5
highly
enantioselective
HAT-initiated
hydrofunctionalization (Figure 1). This radical-polar
crossover process is catalyzed by a series of modified
cobalt salen complexes and allows for conversion of
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delivered epoxide 2 with moderate enantioenrichment.
demonstrated optimal performance among the evaluated
catalysts.15 The process could also be conducted at low
catalyst loadings without detrimental effects on the
enantioselectivity, but required extended reaction times
to achieve appreciable conversion of alcohol 1.
1
2
3
4
5
6
7
8
Introduction of extended aromatic motifs in the o-biaryl
substituent (e.g., complexes 6 and 7) allowed for
significant enhancement of enantioselectivity and a
complementary increase in the efficiency. Ultimately,
dibenzofuran-containing complex 8
Brief exploration of the substrate scope identified a
Table 1. Effect of the Catalyst Structure on the
Enantioenrichment and Yield of Epoxide 2a,b
Table 2. Preliminary Substrate Scope of the HAT-Initiated
Enantioselective Hydrofunctionalizationa
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a0.05 M of allylic alcohol; see SI for details. bReaction
c
time was 18 h. Yields were based on internal standard
1
d
and determined by H NMR. Yield of isolated material
for characterization purposes was 48%. eAbsolute
configuration was determined by X-ray crystallographic
analysis. fReaction time was 48 h. gAt –60 °C. hYield of
isolated material for characterization purposes was 38%.
iEpoxide was not observed.
aReaction time was 18 h, catalysts 4–8 were ≥95% ee;
see SI for details. bYields were based on internal
series of cyclic dialkyl(vinyl)carbinols that successfully
participated in our enantioselective HAT-initiated
1
standard and determined by H NMR, see SI for details.
cReaction with 0.5 mol% of catalyst 8 afforded 51%
yield (65% conversion of alcohol 1) after 48 h.
hydro-functionalization.
Thus, derivatives of
tetrahydropyran and piperidine (products 2, Table 1, and
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9–11, Table 2) and their bicyclic counterparts (products
therefore proposed that cationic cobalt complexes may
experience cation– interactions between the radical
cation of the salen motif and the biaryl substituents of
the ethylenediamine-based fragment (Figure 2).20 In this
setting, extension of the participating arenes would lead
to more stabilizing interactions and their energetic
benefits would be manifested enthalpically.21 We found
that enantioselectivity correlated strongly with both the
polarizability and the quadrupole moment of the
aromatic hydrocarbons correspon-
1
2
3
4
5
6
7
8
12 and 13) underwent conversion to the corresponding
epoxides with good to high levels of asymmetric
induction. Single-crystal X-ray analysis of product 11
established the absolute configuration of the newly
formed stereocenter to be R, which is likely shared with
other enantioenriched epoxides obtained in this study.
Similarly good performance was observed with various
functionalized cyclohexanes (products 14–20). Simple
cyclohexanes including those containing only alkyl
substituents (products 21–23) produced low to moderate
degrees of enantioinduction. Application of acyclic
substrates was unsuccessful (e.g., product 24).
Attempted reactions of cycloalkanols containing five-
and seven-membered rings led to the corresponding
semipinacol rearrangement products (e.g., 25 and 26),16
which were produced with low levels of stereocontrol.
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OH
Me
O
t-Bu
O
+
N
+
N
Co
+
O
+
O
+
t-Bu
O
L
t-Bu
t-Bu
Analysis of the differential activation parameters in
the hydrofunctionalization of allylic alcohol 1 in the
presence of catalysts 5–8 revealed that enantioselectivity
was enthalpically controlled and the magnitude of
differential enthalpy correlated positively with the
expanse of the aromatic moieties (Table 3).17 This
enthalpic gain
Figure 2. Representation of a radical cation of the putative
alkylcobalt(IV) intermediate derived from catalyst 8 and
substrate 1 (L is likely to be solvent). Red dotted lines
indicate the proposed cation– interactions between the
radical cation of the salen motif and the biaryl substituents.
ding to the varied substituents in complexes 5–7.22 Since
the strength of cation– interactions should primarily be
a function of electrostatic and dispersion forces,23,24 the
observed correlations between the underlying physical
properties and the degree of asymmetric induction
suggest that cation– interactions contribute to the
improved stereochemical outcomes. Should the effect of
the substituents be largely steric in nature, such
significant correlations would not be expected.17,25 This
proposal is also consistent with the observation that
introduction of electron-rich arenes results in additional
enhancement of enantioselectivity (e.g., compare
complexes 7 and 8).26 We note that continued expansion
of the aromatic moieties (e.g., introduction of pyrenyl
and triphenylenyl groups) becomes detrimental to the
performance of the catalyst. We attribute this effect to
increasing steric interactions between the biaryl
fragments and the bulky tert-butyl substitutents of the
hydroxynaphthaldehyde-derived motif, which could lead
to disruption of the cation– interactions.
Analysis of structural features found in the well-
performing allylic alcohols (see Table 2) revealed
additional correlations. The presence of properly
positioned heteroatom-containing substituents appears to
result in superior enantioselectivity during the epoxide
formation. For example, functionalized epoxides 18–20
were produced with good enantioselectivities.27 In
contrast, epoxides 21–23 were obtained with
significantly lower asymmetric induction under identical
conditions, suggesting that steric factors are not the sole
determinant in enantioselectivity. The superior outcomes
observed with products 18–20 may stem from additional
stabilizing interactions between the functionalized
Table 3. Eyring Analysis of Enantioselectivity in the
Hydrofunctionalization of Allylic Alcohol 1a
aBased on six data points per catalyst, T = 233–292 K,
see SI for details.
was attenuated by the corresponding increase in the
differential entropy terms observed across the series of
catalysts 5–8. These data are in principle consistent with
a simple steric explanation that increasing the size of the
arene fragment leads to destabilization of the minor
transition state assembly in the enantio-determining step.
However, current understanding of the electronic
structure of relevant cobalt complexes also suggests an
intriguing possibility for the role of stabilizing non-
covalent interactions in the observed effects. Previous
spectroscopic
and
computational
studies
of
alkylcobalt(IV) glyoximates, porphyrins, and corrins as
well as cobalt(III) salen derivatives indicate that radical
cations resulting from ligand-to-metal charge transfer
can contribute to the electronic structure.18,19 We
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cyclohexane fragment and the radical cation of the
cobalt salen motif in the enantio-determining step.
Similar considerations should be applicable in the cases
of products 2, 9–17.28
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Taken all together, these observations suggest
involvement of cationic cobalt complexes in the
enantiodetermining step. For example, diastereomeric
alkylcobalt(IV) intermediates may undergo kinetic
resolution29 during the intramolecular nucleophilic
displacement (see equation 1). In this scenario, an
increase in the cation– interactions in the catalyst
would stabilize the electrophiles, leading to a later
transition state and enhanced
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application in medicinal chemistry efforts.37 Similar
displacements with a thiolate, an allyl Grignard
reagent,and Nagata’s reagent delivered corresponding
sulfide 28, alkene 29, and nitrile 30, respectively, with
good efficiency. In all cases, excellent levels of
stereoinversion were observed, demonstrating potential
of this approach in the enantioselective synthesis of
polyfunctional building blocks.
Me
[Co]
OH
R
Me
Me
[Co]
OH
R
[Co]
OH
R
[Co-H]
OH
R
R
HAT
R
R
R
– e
– e
enantio-determining
displacement
Me
R
[Co]
OH
R
Me
R
[Co]
OH
R
Me
(1)
O
R
R
In summary, we show the first example of a highly
enantioselective HAT-initiated hydrofunctionalization
catalyzed by a series of new cobalt salen complexes. Our
observations are consistent with the proposed
participation of alkylcobalt(IV) complexes, which
accounts for strong catalyst control and allows for direct
enantioselectivity. Additional interactions between the
heteroatom-containing substituents of the well-
performing substrates and the radical cation of the salen
motif would have a similar effect on the displacement.
Diastereomeric alkylcobalt(IV) intermediates may
interconvert upon epimerization of the stereocenter
bearing the homolytically-labile carbon-cobalt bond.30
Relevant rearrangements of alkyl substituents in
organocobalt complexes were previously demonstrated
to proceed via a radical chain mechanism.31 Formation
of alkylcobalt(IV) intermediates may involve oxidation
of the corresponding alkylcobalt(III) complexes,14 which
can be generated via HAT from the putative cobalt(III)
hydride intermediates to alkenes followed by radical pair
collapse.32,33 An alternative scenario may involve
enantio-determining diffusion of alkyl radicals into the
solvent cage during the capture by cationic cobalt(III)
complexes en route to the corresponding alkylcobalt(IV)
intermediates.34–36 Both scenarios are also consistent
with the superior performance of polar solvents:
cyclization of allylic alcohol 1 in the presence of catalyst
8 produces epoxide 2 only in 26% ee when acetone is
replaced with dichloromethane.
conversion
of
dialkyl(vinyl)carbinols
to
the
corresponding scalemic epoxides. The experimental data
suggest that cationic cobalt complexes may be involved
in enantio-determining step, where cation– interactions
in the catalyst contribute to the superior asymmetric
induction obtained with the new cobalt salen derivatives.
The radical-polar crossover reactivity described herein is
expected to serve as a starting point for overcoming the
challenges of absolute stereocontrol in the development
of asymmetric HAT-initiated processes and for future
studies of the mechanistic underpinnings associated with
this fascinating class of chemical transformations.38
ASSOCIATED CONTENT
Experimental procedures, characterization data for new
compounds, and CIF file for compound 11. This material is
available free of charge via the Internet at
http://pubs.acs.org.
Combination of our HAT-initiated cyclization of
dialkyl(vinyl)carbinols with the well-established
reactivity of trisubstituted epoxides in SN2 reactions
provides an entry into a formal enantioselective
hydrofunctionalization of tertiary allylic alcohols with
Markovnikov selectivity. Thus, reaction of epoxide 11
with Boc-protected piperazine produced aminoalcohol
27 in high yield (Scheme 1). Related structural motifs
previously found
AUTHOR INFORMATION
Corresponding Author
spronin@uci.edu
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
Scheme 1. Derivatization of Epoxide 11
ACKNOWLEDGMENT
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unactivated alkenes with Morita-Baylis-Hillman adducts. Org. Lett.
Financial support for this work was provided by the NSF
(CAREER CHE-1848076). Acknowledgment is made to
the Donors of the American Chemical Society Petroleum
Research Fund for partial support of this research (PRF
58063-DNI1). Funding from the School of Physical
Sciences at the University of California Irvine and the Chao
Family Comprehensive Cancer Center is also gratefully
acknowledged. We thank Professors Larry Overman, Chris
Vanderwal, and Scott Rychnovsky for providing routine
access to their instrumentation and helpful discussions. We
also thank Professors Elizabeth Jarvo and Vy Dong for
providing access to their SFC systems and Dr. Joseph Ziller
and Daniel Huh for X-ray crystallographic analysis.
2018, 20, 1355. (o) Yang, L.; Ji, W.-W.; Lin, E; Li, J.-L; Fan, W.-X.;
Li, Q.; Wang, H. Synthesis of alkylated monofluoroalkenes via Fe-
catalyzed defluorinative cross-coupling of donor alkenes with gem-
difluoroalkenes. Org. Lett. 2018, 20, 1924. (p) Zhang, Y.; Huang, C.;
Lin, X.; Hu, Q.; Hu, B.; Zhou, Y.; Zhu, G. Modular synthesis of
1
2
3
4
5
6
7
8
alkylarylazo
compounds
via
iron(III)-catalyzed
olefin
hydroamination. Org. Lett. 2019, 21, 2261. (q) Zhou, X.-L.; Yang, F.;
Sun, H.-L.; Yin, Y.-N.; Ye, W.-T.; Zhu, R. Cobalt-catalyzed
intermolecular hydrofunctionalization of alkenes: evidence for a
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Y.; Lynch, V.; Schultz, A. J.; Wang, X.; Krische, M. J.
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Co(dpm)2-silane (dpm
= 2,2,6,6-tetramethylheptane-3,5-dionate):ꢀ
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pathways. J. Am. Chem. Soc. 2002, 124, 9448. (b) Waser, J.; Carreira,
E. M. Convenient synthesis of alkylhydrazides by the cobalt-
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(22) See Supporting Information for details.
(23) For a discussion of the role of dispersion forces in cation–
interactions see: Tsuzuki, S.; Mikami, M.; Yamada, S. Origin of
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(26) Additional support for the role of stabilizing interactions is
offered by the observation that atropisomers of complex 7, which are
expected to be sterically dissimilar, exhibit equivalent performance in
the hydrofunctionalization of alcohol 1. See SI for details.
(27) Epoxides 17 and 19 were obtained in 80% ee at –40 °C.
(28) For discussion of alkyl fluoride–cation interactions relevant to
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(15) Corresponding hydrogenation products constituted the
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processes.
(16) These observations are consistent with our previous studies.
See ref. 13 for details.
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the first examples of intermolecular fluoride ion abstractions. J. Am.
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neutral cobalt(II) intermediates en route to alkylcobalt(III) complexes
is unlikely because the magnitude of the differential activation
enthalpy obtained for catalyst 8 in the reaction of alcohol 1 (see Table
3) is considerably larger than the activation enthalpy associated with
this diffusion-controlled process (ca. 2 kcal/mol, see: Tsou, T.-T.;
Loots, M.; Halpern, J. Kinetic determination of transition-metal–alkyl
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radical alkene cross-coupling: a computational and mechanistic study.
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(30) For discussion of homolysis of relevant alkylcobalt(IV)
complexes see ref. 18b,c.
(31) (a) Samsel, E. G.; Kochi, J. K. Radical chain mechanism for
alkyl rearrangement in organocobalt complexes. J. Am. Chem. Soc.
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(32) (a) Radical pair formation via the HAT: Sweany, R. L.;
Halpern,
J.
Hydrogenation
of
α
-methylstyrene
by
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a
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(34) Lande, S. S.; Kochi, J. K. Formation and oxidation of alkyl
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O
O
N
O
N
O
t-Bu
t-Bu
Co
t-Bu
t-Bu
Me
R
cat.
OH
R
O
R
silane & oxidant
R
asymmetric HAT-initiated
hydrofunctionalization
13 examples
80–95% ee
prochiral
alkene
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