Carbonylative, Catalytic Deoxygenation of 2,3-Disubstituted Epoxides with Inversion of Stereochemistry: An Alternative Alkene Isomerization Method

Article abstract of DOI:10.1021/jacs.0c02653

Reactions facilitating inversion of alkene stereochemistry are rare, sought-after transformations in the field of modern organic synthesis. Although a number of isomerization reactions exist, most methods require specific, highly activated substrates to achieve appreciable conversion without side product formation. Motivated by stereoinvertive epoxide carbonylation reactions, we developed a two-step epoxidation/deoxygenation process that results in overall inversion of alkene stereochemistry. Unlike most deoxygenation systems, carbon monoxide was used as the terminal reductant, preventing difficult postreaction separations, given the gaseous nature of the resulting carbon dioxide byproduct. Various alkyl-substituted cis- A nd trans-epoxides can be reduced to trans- A nd cis-alkenes, respectively, in >99:1 stereospecificity and up to 95% yield, providing an alternative to traditional, direct isomerization approaches.

Full text of DOI:10.1021/jacs.0c02653

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Carbonylative, Catalytic Deoxygenation of 2,3-Disubstituted
Epoxides with Inversion of Stereochemistry: An Alternative Alkene
Isomerization Method
Jessica R. Lamb,† Aran K. Hubbell,† Samantha N. MacMillan, and Geoffrey W. Coates*
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ABSTRACT: Reactions facilitating inversion of alkene stereochemistry are
rare, sought-after transformations in the field of modern organic synthesis.
Although a number of isomerization reactions exist, most methods require
specific, highly activated substrates to achieve appreciable conversion
without side product formation. Motivated by stereoinvertive epoxide
carbonylation reactions, we developed a two-step epoxidation/deoxygena-
tion process that results in overall inversion of alkene stereochemistry.
Unlike most deoxygenation systems, carbon monoxide was used as the terminal reductant, preventing difficult postreaction
separations, given the gaseous nature of the resulting carbon dioxide byproduct. Various alkyl-substituted cis- and trans-epoxides can
be reduced to trans- and cis-alkenes, respectively, in >99:1 stereospecificity and up to 95% yield, providing an alternative to
traditional, direct isomerization approaches.
Scheme 1. Direct Alkene Isomerization Strategies (A, B)
and Alternative Epoxide Deoxygenation Methods (C, D)
INTRODUCTION
■
Alkenes are abundant, readily accessible, and easily function-
alized building blocks in synthetic organic chemistry.1
However, accessing cis-alkenes from their corresponding trans
stereoisomers (and vice versa) remains an important, yet
challenging, objective in the field of organic chemistry and
natural product synthesis.2 For decades, transition-metal
catalysts have been reported to isomerize cis-alkenes to more
thermodynamically favorable trans stereoisomers (Scheme
1A);2a,3 however, highly activated stilbene- or maleate-derived
starting materials are required to avoid competing olefin
migration pathways.2d,3f,4 Additionally, uphill energetics
prevent isomerization of trans-alkenes to cis-olefins. In contrast,
photoisomerizations can facilitate the complementary trans to
cis isomerizations2,5 (Scheme 1B) but only for chromophoric
starting materials, resulting in a limited substrate scope.
Therefore, a general method for the formation of alkyl-
substituted (E)- and (Z)-alkenes from (Z)- and (E)-alkenes,
respectively, is highly desirable.
Stereoretentive epoxidations followed by stereoinvertive
deoxygenation offer an attractive alternative to isomerization
approaches. While deoxygenations are quite prevalent in both
biological6 and organic chemistry,7 most methods generate
alkenes with retention of stereochemistry (Scheme 1C). Since
early work by Sharpless and co-workers in 1972,8 many
synthetic routes have employed these stereoretentive epox-
idation/deoxygenation strategies as protection/deprotection
sequences to prevent undesired reactivity at a particular
alkene.9 However, this well-established method requires
superstoichiometric amounts of tungsten hexachloride and n-
butyllithium and often results in mixtures of alkene stereo-
Received: March 6, 2020
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A

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isomers.8 Although a number of other catalytic methods have
been developed in the last five decades,9c,10 most systems still
require expensive stoichiometric reductants that demand
postreaction separations. Additionally, highly activated, aryl-
substituted, or alicyclic epoxides are often necessary to
promote reactivity.10a−c,11 The few complementary systems
capable of alkyl epoxide deoxygenation9,10e−h,12 often need
very high temperatures, limiting the practicality of these
stereoretentive approaches.
Chart 1. [Lewis Acid]+[Mn(CO)5]− Catalysts Screened for
the Deoxygenation of cis-Epoxides (S = THF)
A limited number of deoxygenations proceed with stereo-
inversion,9b,10g,h,13 demonstrating the promise of epoxide
deoxygenation reactions beyond protecting group chemistry.
The phosphorus betaine method, developed by Vedejs and
Fuchs in 1971, is one of the most commonly employed
stereoinvertive deoxygenation processes to date,13a,b but
stoichiometric amounts of lithium diphenylphosphide and
methyl iodide are required. Although other noteworthy
approaches are both catalytic and stereoinvertive,10g,h,13g
most still rely on harsh conditions and specific substrates to
achieve reactivity. There lacks a mild, clean, and stereoinvertive
catalytic epoxide deoxygenation method to act as an alternative
to both trans- to cis- and cis- to trans-alkene isomerization.
Groundbreaking work by Kunz and co-workers10g,h outlines
an iridium-catalyzed epoxide deoxygenation system, which, to
the best of our knowledge, is the first report to use carbon
monoxide (CO) as a terminal reductant with a Lewis acidic
and nucleophilic catalyst. Although this approach requires the
use of stoichiometric carbon monoxide (CO),9a,10d,g,h,13c,14
gaseous carbon dioxide (CO2) is the only byproduct,
minimizing challenging postreaction separations. However,
aside from two stereoinvertive cases, this seminal report uses
mostly terminal epoxides or 2,3-disubstituted epoxides which
exhibit stereoretention.
To develop a stereoinvertive deoxygenation system, we drew
upon our knowledge of stereoinvertive epoxide carbonylation
reactions (Scheme 1D).15 We hypothesized that our previously
developed carbonylation complexes ([Lewis acid]+[M-
(CO)x]−) would facilitate stereoinversion due to SN2 attack
by the metal carbonyl on the epoxide.15c,16 Additionally, our
existing systems readily carbonylate alkyl-substituted epoxides,
suggesting that this deoxygenation method will also tolerate
these unactivated alkyl substrates, offering a highly stereo-
specific process with a wide substrate scope.
Table 1. Activity of Catalysts 1−3 for the Deoxygenation of
cis-2,3-Disubstituted Epoxides
a
conversion (%)
b
entry
catalyst
5a
6a
1
2
3
4
5
6
7
1
2
62
56
63
62
55
87
92
2
2
3a
3b
3c
3d
3e
<1
<1
<1
<1
<1
a
Determined by 1H NMR analysis of the crude reaction mixture.
>99:1 E:Z in all cases.
b
trans-alkene 5a in 62% conversion with 2% of the undesired
ketones 6a, from a simple alkyl-substituted epoxide, 4a (Table
1, entry 1). To minimize this side product formation,
additional ligands were screened. Catalyst 2, which features a
salen ligand with a phenylenediamine backbone, exhibited
lower activity, and formation of 6a persisted (Table 1, entry 2).
In contrast, the catalyst [(salcy)Al(THF)2]+[Mn(CO)5]− (3a;
salcy = N,N′-bis(3,5-di-tert-butylsalicylidene)-rac-1,2-cyclohex-
anediamine) demonstrated a modest increase in conversion
(63%) with no observable side product (Table 1, entry 3).
Therefore, electronic alterations were made to this ligand
framework to increase overall activity. Although introducing p-
CPh3 (3b) and p-Br (3c) moieties offered no improvement in
conversion (62 and 55%, respectively; Table 1, entries 4 and
5), both p-Cl and p-OMe substitution (3d,e) greatly improved
the activity (Table 1, entries 6 and 7). Catalyst 3e provided the
highest overall conversion (92%) and was chosen for substrate
scope development. Single crystals of 3d were studied by X-ray
diffraction and revealed the anticipated planar salen ligand
geometry, two coordinated tetrahydrofuran molecules, and
RESULTS AND DISCUSSION
■
Deoxygenation of cis-2,3-Disubstituted Epoxides. We
began by selecting a Lewis acid catalyst and nucleophilic
cocatalyst to facilitate such deoxygenation reactions (Chart 1).
Our previously reported carbonylation processes featured a
cobalt tetracarbonyl nucleophile, which inserted CO and acted
as a leaving group to facilitate β-lactone ring closure.15
However, deoxygenation reactions do not require such a
leaving group, since the reaction proceeds via a five-membered
intermediate or β-oxygen elimination (vide infra).17 Therefore,
−
manganese pentacarbonyl (Mn(CO)5 ) was selected as the
ideal nucleophile for further catalyst optimization (Chart 1);
although it is known to have superior nucleophilicity in
comparison to cobalt tetracarbonyl, it is an inferior leaving
group, precluding β-lactone ring closure and therefore
carbonylation.18
Next, we screened the Lewis acid component of these
complexes for the deoxygenation of cis-epoxides to trans-
alkenes (Table 1). The porphyrin-based catalyst 1 produced
−
Mn(CO)5 counterion (Figure 1).
Finally, after screening reaction conditions such as solvent
and CO pressure (see the Supporting Information for
additional details), we successfully deoxygenated various cis-
2,3-disubstituted epoxides to trans-alkenes without side
product formation (Table 2; unless otherwise stated, yields
were obtained by 1H NMR spectroscopy due to product
B
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internal alkyne 5k, which have additional methylene spacers,
were produced in 67 and 77% yields, respectively (Table 2,
entries 10 and 11).
Deoxygenation of trans-2,3-Disubstituted Epoxides.
The deoxygenation of trans-2,3-disubstituted epoxides to
generate (Z)-alkenes is of particular interest, since trans- to
cis-alkene isomerization still remains a difficult challenge in the
field. Therefore, we screened conditions for this type of
transformation. Although previously less active for the
deoxygenation of cis-epoxides, catalyst 3b exhibited the highest
activity for the deoxygenation of trans-epoxide 7a (15%, Table
3, entry 1). Because this observed conversion was quite
Figure 1. X-ray crystal structure of one independent molecule of
catalyst 3d. Ellipsoids are drawn at the 50% probability level. All
hydrogen atoms and atoms of the minor disordered component are
omitted for clarity.
Table 3. Effect of Solvent on trans-2,3-Disubstituted
Epoxide Deoxygenation
Table 2. Deoxygenation of cis-2,3-Disubstituted Epoxides to
trans-Alkenes
a
entry
solvent
THF
2-MeTHF
EtOAc
1,4-dioxane
benzene
toluene
conversion (%)
1
2
3
4
5
6
15
48
55
65
77
95
a
1
Determined by H NMR analysis of crude reaction mixture. >99:1
Z:E in all cases.
modest, additional solvents were screened to further improve
reaction efficiency. With 2-methyltetrahydrofuran (2-MeTHF),
a sterically bulky analogue of tetrahydrofuran (THF), the
conversion increased to 48% (Table 3, entry 2). Reaction rates
continued to increase as the solvent donicity decreased from
ethyl acetate (EtOAc) to 1,4-dioxane and benzene (Table 3,
entries 3−5). However, toluene proved to be the optimal
solvent, generating cis-alkene 8a in 95% conversion (Table 3,
entry 6).
With optimized conditions in hand, various trans-2,3-
disubstituted epoxides were successfully deoxygenated to
produce cis-alkenes (Table 4; unless otherwise stated, yields
were obtained by 1H NMR spectroscopy due to product
volatility). Substrates containing both a methyl group and alkyl
chain produced the corresponding cis-alkenes in up to 95%
yield (Table 4, entries 1−3). Introducing alkyl chains on either
side of the epoxide slowed the deoxygenation reaction (Table
a
1
Determined by H NMR spectroscopy using hexamethyldisiloxane
as an internal standard due to product volatility unless otherwise
stated. >99:1 E:Z in all cases. Percent conversion from 4b after using
b
c
d
4.0 mol % of 3e for 4 h. 4.0 mol % of 3e for 5 h. 10.0 mol % of 3e.
e
Table 4. Deoxygenation of trans-2,3-Disubstituted Epoxides
to cis-Alkenes
4.0 mol % of 3e for 14 h at 65 °C.
volatility). Substrates with a methyl group and an alkyl chain
were successfully reduced in excellent yields (Table 2, entries
1−4). To explore whether this transformation can tolerate
larger substituents in both the 2- and 3-positions, we screened
a substrate with two n-propyl groups. After the catalyst loading
was increased, product 5e was produced in 48% yield,
indicating that methyl substitution is not necessary, and
bulkier groups can occupy both sides of the substrate with only
a moderate decrease in reaction rate (Table 2, entry 5).
Unfortunately, adding additional steric bulk, such as a
cyclohexyl group, aryl group, or silyl-protected alcohol close
to the epoxide resulted in attenuated reaction rates and lower
yields (4f−i, Table 2, entries 6−9). However, carbonate 5j and
a
entry
trans-epoxide (7)
R1
R2
Et
nPent
nHex
nPr
yield 8 (%)
1
2
3
4
5
7b
7a
7c
7d
7e
Me
Me
Me
nPr
Me
61
95
86
b
59
Ph
83
a
1
Determined by H NMR spectroscopy using hexamethyldisiloxane
as an internal standard due to product volatility unless otherwise
stated. >99:1 Z:E in all cases. 91% yield by H NMR spectroscopy
with 10 mol % of 3e.
b
1
C
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4, entry 4), which is consistent with the reduced activity
observed using cis-epoxides (Table 2, entry 5). Aryl
substituents were also tolerated (Table 4, entry 5), indicating
that this system can deoxygenate epoxides used in previously
reported systems as well as traditionally challenging alkyl
substrates.7−13
Scheme 3. Proposed Mechanism for the Deoxygenation of
cis-2,3-Disubstituted Epoxides
Mechanistic Studies. With a well-established scope of cis-
and trans-epoxides in hand, we investigated the reaction
mechanism to better understand this deoxygenation system.
To demonstrate that these reactions proceed with inversion of
stereochemistry, we compared the 1H NMR spectra of alkenes
synthesized from cis- and trans-2-octene oxide to the 1H NMR
spectra of commercial cis- and trans-2-octene (Scheme 2).
Scheme 2. Spectroscopic Evidence of Stereochemical
Inversion
white CaCO3 precipitate resulted, confirming the production
of CO2 during the reaction (see the Supporting Information
for additional details).
Diagnostic peak shapes and chemical shifts (alkenyl protons at
∼5.4 ppm and methyl protons at ∼1.6 ppm) facilitated
confirmation that this process is stereoinvertive. Similar
comparisons were performed for other alkene products (see
the Supporting Information for additional details).
To narrow down possible reaction mechanisms, we drew
upon our knowledge of Lewis acid-mediated, lactone
decarboxylation reactions (Scheme 3, pathway 1), which we
previously observed during the carbonylation of 2,2-disub-
stituted epoxides.21 This stereoretentive pathway occurred via
the formation of a stable zwitterionic intermediate
Given the observed inversion of stereochemistry, we propose
that the beginning of the catalytic cycle is similar to that of our
previously studied carbonylation reactions (Scheme 3). After
loss of a solvent molecule and epoxide binding to the Lewis
acid, Mn(CO)5− performs an SN2 attack on an oxirane carbon,
ring-opening the epoxide to produce an alkyl manganese
species with inverted stereochemistry (intermediate A). On the
basis of previous carbonylation results using similar Lewis acid
complexes, we conceived three pathways by which the reaction
may continue from A: CO insertion occurs,19 producing
intermediate B, followed by ring closure, generating a β-
lactone intermediate that is subsequently decarboxylated via a
stereoretentive, Lewis acid-mediated process (pathway 1), a
molecule of CO is inserted by manganese carbonyl, forming
acyl manganese intermediate B, from which an alkene is
generated (pathway 2),19 or the manganese alkyl (A) forms a
β-agostic interaction with the aluminum alkoxide before
undergoing β-oxygen elimination (pathway 3). After either
proposed pathway 2 or 3, the resulting μ-oxo complex (C)
undergoes CO insertion and decarboxylation to regenerate the
active catalyst.
+
(−O2CCH2CR2 ) featuring a carboxylate anion and a tertiary
carbocation.22 However, 2,3-disubstituted epoxides would
result in the formation of a secondary carbocation, which
would produce a less stable zwitterion. To determine whether
pathway 1 was feasible, β-butyrolactone, which would also
afford a secondary carbocation, was subjected to deoxygena-
tion conditions. The starting material was completely
recovered, and propylene was not observed, suggesting that
pathway 1 does not occur.
To determine the feasibility of pathways 2 and 3, we turned
to a report by Komiya and co-workers exhibiting a thiirane
desulfurization reaction using platinum−manganese com-
plexes.17 A five-membered ring intermediate (similar to
intermediate B) was isolated, and its structure was determined
by X-ray crystallography. On the basis of these results, we
propose that after formation of intermediate A (Scheme 3)
reversible CO insertion19 forms a similar five-membered
intermediate with manganese coordinated to the aluminum
alkoxide (Scheme 3, intermediate B). From this intermediate
an alkene with overall inversion of stereochemistry is generated
in addition to the Al−O−Mn complex (C), which is similar to
the Pt−S−Mn intermediate proposed by Komiya and co-
workers (Scheme 3, pathway 2).17 However, this report
suggests that, because CO insertion is reversible, β-oxygen
elimination may occur after generation of intermediate A,
To determine whether CO2 was being generated as a
byproduct of the reaction and affirm the plausibility of the
proposed mechanisms, we performed a qualitative limewater
experiment.20 While the reactor was vented, the gas was
bubbled through a saturated solution of Ca(OH)2 in water. A
D
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producing the same products (Scheme 3, pathway 3). Given
this literature precedent, we believe that one of these pathways
is occurring (Scheme 3, pathways 2 and/or 3). Notably, while
the report by Komiya and co-workers appears to be
stoichiometric in the platinum−manganese complex,17 our
active catalyst may be regenerated via CO insertion and
subsequent decarboxylation. Additionally, it is worth noting
that we cannot rule out a mechanism proposed by Kunz and
co-workers, which demonstrates attack of a CO ligand by
alkoxide A to form a metallacycle that undergoes Lewis acid-
mediated decarboxylation.10g,h
Although we cannot distinguish between these pathways, we
believe that understanding all possible mechanisms provides an
explanation for the lower reaction rates observed during the
deoxygenation of trans-epoxides. After epoxide binding and
ring opening, rotation is necessary to achieve a syn-periplanar
geometry for β-oxygen elimination or the formation of
intermediate B. However, with trans-epoxides specifically,
eclipsing alkyl substituents hinder rotation and therefore
formation of intermediate A (Scheme 4), slowing the overall
reaction rate.
reactions that traditionally result in a mixture of alkene
stereoisomers.23
CONCLUSION
■
We have developed a highly efficient method for the
deoxygenation of both cis- and trans-2,3-disubstituted epoxides
with inversion of stereochemistry. Our carbonylative approach
is complementary to many traditional deoxygenation
methods,7−9,10a−h,11−13 which are commonly stereoretentive.
Additionally, this system uses CO as the terminal reductant
and produces only CO2 as a byproduct, avoiding cumbersome
postreaction purifications often required by other processes.
Various alkyl-substituted epoxides were readily reduced,
affording a complementary approach to existing isomerization
methods2,3,5 which, like many deoxygenation systems, suffer
from substrate scope limitations and undesired side product
formation. Mechanistic studies suggested that eclipsing
interactions reduced the rate of trans-epoxide deoxygenation
specifically. Taking advantage of the observed difference in
epoxide reactivity, a mixture of alkene stereoisomers was
separated, demonstrating a promising application for epoxide
deoxygenation. Because the stereochemical inversion of
alkenes remains an important, yet challenging, transformation
in the field of organic chemistry, our stereoinvertive
deoxygenation method offers an additional, useful synthetic
methodology with potential applications in natural product
synthesis.
Scheme 4. Proposed Mechanistic Rationale for the Lower
Reactivity of trans-2,3-Disubstituted Epoxides
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c02653.
■
sı
Synthetic procedures, characterization data of all new
compounds, control reactions, and additional data
(PDF)
Separation of Alkene Stereoisomers. We envisioned
that the observed differential in reaction rates between trans-
and cis-epoxide deoxygenations could be exploited to separate
stereochemical mixtures of alkenes (Scheme 5). After
Crystallographic data for 3d (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Geoffrey W. Coates − Department of Chemistry and Chemical
Biology, Baker Laboratory, Cornell University, Ithaca, New
York 14853-1301, United States; orcid.org/0000-0002-
3400-2552; Email: coates@cornell.edu
Scheme 5. Separating Alkene Stereoisomers with
Stereoinvertive Epoxide Deoxygenation
Authors
Jessica R. Lamb − Department of Chemistry and Chemical
Biology, Baker Laboratory, Cornell University, Ithaca, New
York 14853-1301, United States; orcid.org/0000-0001-
9391-9515
Aran K. Hubbell − Department of Chemistry and Chemical
Biology, Baker Laboratory, Cornell University, Ithaca, New
York 14853-1301, United States; orcid.org/0000-0001-
9087-5553
Samantha N. MacMillan − Department of Chemistry and
Chemical Biology, Baker Laboratory, Cornell University,
Ithaca, New York 14853-1301, United States; orcid.org/
0000-0001-6516-1823
epoxidation of an alkene mixture, the cis-epoxide could be
reduced selectively by a catalyst that was observed to be
particularly slow for trans-epoxide deoxygenation. At that
point, the leftover trans-epoxide could be separated and
deoxygenated to isolate the opposite alkene stereoisomer. To
address this challenge, a mixture of 4a and 7a was subjected to
deoxygenation conditions using catalyst 3e. Gratifyingly, 4a
was reduced selectively, with only minimal consumption of 7a.
Thus, the observed selectivity demonstrates that this system
can be used as a facile separation strategy, which is particularly
important due to the prevalence of noteworthy olefin-forming
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c02653
Author Contributions
†J.R.L. and A.K.H. contributed equally.
E
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(5) For select examples of trans to cis photoisomerization systems,
see: (a) Singh, K.; Staig, S. J.; Weaver, J. D. Facile Synthesis of Z-
Alkenes via Uphill Catalysis. J. Am. Chem. Soc. 2014, 136, 5275−5278.
(b) Pearson, C. M.; Snaddon, T. M. Alkene Photo-isomerization
Inspired by Vision. ACS Cent. Sci. 2017, 3, 922−924.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the U.S. Department of
Energy, Office of Science, Office of Basic Energy Sciences,
under Award DE-FG02-05ER15687. J.R.L. acknowledges a
graduate fellowship from the National Science Foundation
(DGE-1144153). A.K.H. acknowledges a training grant
fellowship from the National Institute of General Medical
Sciences (NIGMS T32-GM008500). This content is solely the
responsibility of the authors and does not necessarily represent
the official views of the National Institute of General Medical
Sciences or the National Institutes of Health. This work made
use of the NMR Facility at Cornell University which is
supported, in part, by the NSF under Award CHE-1531632.
We thank Dr. Michael Mulzer for synthesizing various epoxide
starting materials.
(6) For select examples of epoxide deoxygenations in biology, see:
(a) Whitlon, D. S.; Sadowski, J. A.; Suttie, J. W. Mechanism of
Coumarin Action: Significance of Vitamin K Epoxide Reductase
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Model Studies for a Molecular Mechanism of Action of Oral
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P. C.; Suttie, J. W. A Chemical Model for the Mechanism of Vitamin
K Epoxide Reductase. J. Org. Chem. 1983, 48, 3301−3305.
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(7) (a) Wittig, G.; Haag, W. Uber Triphenyl-phosphinmethylene als
Olefinbildende Reagenzien. Chem. Ber. 1955, 88, 1654−1666.
(b) Clive, D. L. J.; Denyer, C. V. New Method for Converting
Epoxides into Olefins: Use of Triphenylphosphine Selenide and
Trifluoroacetic Acid. J. Chem. Soc., Chem. Commun. 1973, 253a.
(8) Umbreit, M. A.; Nieh, M. T.; Flood, T. C.; Sharpless, K. B.
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6538−6540.
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