Vanadium-Catalyzed Synthesis of Geometrically Defined Acyclic Tri- and Tetrasubstituted Olefins from Propargyl Alcohols

Article abstract of DOI:10.1021/acscatal.8b04567

A highly selective formation of geometrically defined acyclic tri- and tetrasubstituted alkenes from inexpensive and readily available propargyl alcohols is described. Through vanadium oxo catalysis, tri- and tetrasubstituted α-chloro-, bromo-, and iodo-e

Full text of DOI:10.1021/acscatal.8b04567

Research Article
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2019, 9, 1584−1594
Vanadium-Catalyzed Synthesis of Geometrically Defined Acyclic Tri-
and Tetrasubstituted Olefins from Propargyl Alcohols
Barry M. Trost* and Jacob S. Tracy
Department of Chemistry, Stanford University, 333 Campus Drive, Stanford, California 94305, United States
S
* Supporting Information
ABSTRACT: A highly selective formation of geometrically defined
acyclic tri- and tetrasubstituted alkenes from inexpensive and
readily available propargyl alcohols is described. Through vanadium
oxo catalysis, tri- and tetrasubstituted α-chloro-, bromo-, and iodo-
enone olefins can be synthesized with the kinetic E-geometry.
Complementary tetrasubstituted β-chloro-, bromo-, and iodo-
enone olefins with Z-geometry can be accessed through a metal-
free 1,2-aryl shift. The utility of these geometrically defined vinyl
halides is demonstrated through cross-coupling reactions to form
all-carbon tetrasubstituted olefins with near complete retention of
starting olefin geometry as well as through the total synthesis of
( )-myodesmone.
KEYWORDS: vanadium, tetrasubstituted olefins, alkenes, halogenation, vinyl halides, propargyl alcohols,
Meyer−Schuster rearrangement
defined tetrasubstituted acyclic olefin motif is found in natural
products12 and commercialized pharmaceuticals,13 and is of
interest in materials science.14 Within this class of compounds,
tetrasubstituted vinyl halides are of particular interest due to
their versatility as substrates for metal-catalyzed cross-coupling
reactions, allowing for the rapid formation of libraries of
tetrasubstituted all-carbon olefins. Our approach to synthesiz-
ing such valuable substrates involved the trapping of
catalytically generated vanadium enolates, formed from tertiary
propargyl alcohols, by an electrophilic halide (Figure 1, top).
Control of this electrophilic trapping would provide ready
access to geometrically defined tetrasubstituted olefins
containing a valuable halide functional group handle. At the
onset, we predicted the geometric selectivity to arise from a
steric differentiation of the two vanadium enolate faces.
Approach of the electrophile from the same face as the small
R group (RS) would be favored over approach from the face of
the more sterically demanding large R group (RL) (Figure 1,
bottom). A result of this facial selectivity is the production of
tetrasubstituted olefins with the difficult to obtain kinetic E-
geometry, where the bulkier ketone and RL group sit on the
same side of the olefin. While there are a few scattered reports
of such a process in the literature, they all suffer from poor
geometric selectivity (generally less than 2:1) and require
either the use of expensive gold catalysts or harsh acidic
conditions that limit functional group tolerance (Scheme 1).15
Successful use of our earth-abundant vanadium catalyst system
INTRODUCTION
■
Enolate chemistry is perhaps the most fundamental and well-
studied method for the generation of carbon bonds.1 Despite
the intensive research efforts in this area, the generation of
enolates is still commonly plagued by the use of stoichiometric
amounts of strong base, cryogenic temperatures, and/or
stoichiometric additives that generate waste and lower atom
economy.2 Our group has devised a method for the mild,
catalytic, and chemoselective generation of metal enolates
starting from cheap and readily available propargyl alcohols. In
this method, an inexpensive vanadium oxo complex catalyzes a
1,3-transposition of the propargyl alcohol to form a vanadium
allenolate that can undergo trapping by a series of carbon-
based electrophiles,3 even in the presence of a competing
simple protonation pathway that would lead to the Meyer−
Schuster product. Such a general strategy, which can be termed
“sigmatropic functionalization”,4 offers a very promising
pathway for the rapid and economic generation of chemical
complexity.
One chemical motif that remains a significant synthetic
challenge in modern organic chemistry is the geometrically
defined tetrasubstituted acyclic olefin.5 While recent advances
in this area have been made based upon the elimination of
alcohols,6 the functionalization of enolates,7 conjugate addition
to allenyl aldehydes,8 carbometalaton of internal alkynes,9 and
the use of strongly electrophilic reagents to activate internal
alkynes,10 these methods generally suffer from issues related to
regioselectivity, functional group tolerance, and/or the use of
difficult to access starting materials.
Received: November 15, 2018
Revised: January 7, 2019
Published: January 10, 2019
In addition to serving as a valuable building block for a wide
variety of asymmetric transformations,11 the geometrically
© 2019 American Chemical Society
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Table 1. Optimization of the Formation of E-Chloro-
Trisubstituted Olefins
a
1
E:Z ratio determined via H NMR of the crude reaction mixture.
b
c
OV(OSiPh3)3 used as catalyst. 1.0 M, 2.5 mol % OV(OSi(p-
ClC6H4)3)3.
of the mass balance was accounted for by the Meyer−Schuster
product that results from simple protonation of the vanadium
enolate. Switching to the more electron withdrawing catalyst
OV(OSi(p-ClC6H4)3)3 resulted in an improvement of the E:Z
selectivity to 4:1 (entry 2). This improvement in selectivity is
thought to be attributed to the more electron deficient 4-
chlorophenyl silanol vanadium complex forming a more
stabilized enolate. As a result, a later transition state that
incorporates more carbon-chloride bond character better
accentuates the steric difference between the two faces of the
enolate (see Figure 1). Dropping the reaction temperature
from 80 to 65 °C led to a further improvement in selectivity
and a large improvement in yield to 87% (entry 3).
Figure 1. Proposed catalytic cycle (top) and source of selectivity
(bottom).
Scheme 1. Synthesis of Geometrically Defined
Tetrasubstituted Enone Olefins
A major improvement in selectivity was observed by
decreasing the equivalents of electrophile from 2 to 1.05.
Under these conditions, the desired product was isolated in
85% yield and with a 20:1 E:Z ratio (entry 4). Such a drastic
improvement in selectivity, coupled with the observation of
high E:Z selectivity at low conversion with 2 equiv of NCS (see
the Supporting Information, Table S1), strongly suggests that
the excess halide, perhaps through a radical intermediate, is
acting to isomerize the kinetically formed E product into the
thermodynamic Z product. Lowering the catalyst loading to
2.5 mol % while increasing the reaction concentration to 1.0 M
resulted in a reduction of both the E:Z ratio and conversion
(entry 5). While PhMe gave similar results to those of
acetonitrile (entries 6 and 7), use of THF resulted in low
conversion and provided the Z-olefin isomer as the major
product (entry 8).
would provide an economical and functional group tolerant
approach to overcome the significant issue of geometric
selectivity.
With a set of optimized conditions for the formation of E-
chloro-olefins in hand (Table 1, entry 4), the scope of
chlorination was explored (Table 2, part A). Both electron-rich
and electron-poor aromatic groups on RL performed well,
giving high yields and selectivities (Table 2, 2−5). In some
cases, use of PhMe as solvent was beneficial to the E:Z ratio,
but there was no general trend observed. Ortho substituted
aromatic RL groups required a slightly elevated reaction
temperature of 75 °C, but did not impact yield or selectivity
(5). Heteroaromatic groups were also well-tolerated at RL
under the reaction conditions (6 and 7), as was branching on
RESULTS AND DISCUSSION
■
We began our studies with the use of secondary alcohol 1.
Initial screening was performed with a secondary alcohol due
to the larger steric differentiation in the nucleophilic trapping
step between hydrogen and an aryl group as compared to that
of an alkyl and aryl group. Treatment of 1 with 5 mol %
OV(OSiPh3)3, 2 equiv of N-chlorosuccinimide (NCS), and 2
equiv of MgO as a general base in acetonitrile at 80 °C resulted
in 61% of the desired trisubstituted olefin 2 in a 2:1 E:Z ratio
of olefin geometric isomers (Table 1, entry 1). The remainder
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of the alcohol was required to prevent ethereal dimerization of
the propargyl alcohol starting material (3, 9, and 11).
Table 2. Scope of the E-Selective Vanadium Chlorination
Reaction
a
We next investigated the use of tertiary propargyl alcohols
that would result in the formation of tetrasubstituted olefins
(Table 2, part B). For dimethyl substitution at the propargylic
position (RS = RL = Me), a higher reaction temperature was
required (14). Even though product 14 contains readily
enolizable protons alpha to the ketone, further acidified by
their benzylic nature, no chlorine incorporation at that position
was observed, highlighting the mild nature of the reaction
conditions. Excellent selectivity for the kinetic E-product was
obtained when RL was aryl, and RS was methyl (10:1 to 15:1,
15−17). For this class of substrates, both electron-rich and
electron-poor aryl groups were tolerated at RL, as were aryl and
branched alkyl groups on the alkyne at R. When RL and R are
both large aromatic groups, as in the case of 18, the E:Z
selectivity begins to drop. This decrease in selectivity is a result
of an increase in steric crowding between RL and R during the
allenolate sp carbon rehybridization in the enolate trapping
transition state that begins to compete with the steric
differentiation between the electrophile and RS/RL (Figure 1,
vide supra). Finally, switching RS from methyl to a larger ethyl
group resulted in a modest reduction in E:Z selectivity to 4:1
(19).
Having observed the ability of excess NCS to isomerize the
kinetically formed E-olefin to the thermodynamic Z-olefin, we
sought to develop one-pot conditions to both form the initial
E-product and then isomerize it via an addition−elimination
mechanism to the Z-product. To do so, a series of additives
were added to the reaction mixture after complete con-
sumption of the starting propargyl alcohol was observed. Use
of phosphines, added neat or in solution, led to only small
amounts of isomerization and complete conversion of the
phosphine to the phosphine oxide (Table 3, entries 1−3).
Table 3. Optimization for the One-Pot Synthesis of
Thermodynamic Z-Chloro-olefins
a
Reactions performed at 0.2 mmol scale. E:Z ratio determined via 1H
b
NMR of the crude reaction mixture. Slow addition of the alcohol to
the reaction. PhMe used as solvent. 75 °C. 40 °C. 110 °C. 80 °C.
c
d
e
f
g
the alkyne at R (6). In the case of indole substitution, a slow
addition of the alcohol was required to obtain a higher yield
and E:Z selectivity. The lower selectivity of this substrate (4:1)
was due to the proclivity of the product to undergo
isomerization: a pure sample of the E-product was observed
to isomerize to a 1:1 mixture of E:Z isomers simply by standing
in CDCl3 overnight. Functional group tolerance of this process
was found to be very high. Silyl-protected alcohols, enolizable
esters, and even olefins, terminal alkynes, and silyl-protected
alkynes were all well-tolerated by the reaction conditions (8−
12). All of these functional groups, known to be sensitive to
electrophilic halide sources, were not observed to undergo any
halide incorporation. Switching RL from an aryl group to an
alkyl group required a significantly elevated reaction temper-
ature (110 °C) due to less stabilization of the developing
partial positive charge at the carbinol carbon during the
transition state of the 1,3-transposition.16 While a good yield
was obtained, the higher reaction temperature resulted in
significant product isomerization, with the isolated product
having a 1:5 E:Z ratio favoring the thermodynamic Z product
(13). For several of the secondary alcohol substrates
containing electron-rich aromatic groups at RL, a slow addition
a
1
E:Z ratio determined via H NMR of the crude reaction mixture.
While addition of 20 mol % 1,4-diazabicyclo[2.2.2.]octane
(DABCO) in MeCN resulted in minimal isomerization,
addition of 20 mol % 4-(dimethylamino)pyridine (DMAP)
in MeCN resulted in the isolation of the desired product in a
promising 2:1 Z:E ratio and with an 84% yield (Table 3,
entries 4 and 5). Using the same 20 mol % DMAP but
switching the addition solvent from MeCN to the more polar
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DMF resulted in near complete isomerization of the product to
the thermodynamic Z-olefin (>20:1 Z:E) in 79% isolated yield.
With a set of conditions for the one-pot synthesis of Z-
chloro-olefins (Table 3, entry 6), a very brief scope was
explored. In each case, the desired product was obtained in
good yield and in >20:1 Z:E selectivity (Table 4, 20−22). In
in acetonitrile at 65 °C resulted in isolation of 80% of the
tetrasubstituted olefin 26 in a 6:1 E:Z ratio (Table 5, entry 1).
Table 5. Optimization of the Formation of E-Bromo-
Tetrasubstituted Olefins
Table 4. Brief Scope of the One-Pot Synthesis of Z-Chloro-
a
olefins
a
b
Reactions performed at 0.2 mmol scale. Slow addition of the
alcohol to the reaction.
these substrates, no halogenation of a terminal allyl double
bond or loss of a silyl alcohol protecting group was observed.
With access to both E- and Z-trisubstituted olefins, NOE
analysis was able to definitively assign the olefin geometry for
both sets of products (Figure 2).
a
1
E:Z ratio determined via H NMR of the crude reaction mixture.
b
Reaction performed without any catalyst.
Lowering the temperature to 50 °C had little impact on
reactivity or selectivity (entry 2). Switching electrophilic
bromine sources from 25 to N-bromophthalimide (NBP)
resulted in a slight improvement in E:Z ratio at 65 and 40 °C
(entries 3 and 4). Switching to less polar solvents, such as 1,2-
dichloroethane (DCE) and PhMe, led to significant improve-
ments in selectivity, with PhMe resulting in an isolated yield of
82% and an E:Z ratio of 20:1 (entries 5 and 6). Finally, a
control experiment run without use of the vanadium catalyst
led to recovery of the starting alcohol (entry 7).
The developed conditions worked well for a wide range of
tertiary propargyl alcohols, yielding geometrically defined E-
tetrasubstituted bromo-olefins (Table 6). Both electron-rich
and electron-poor substituents on the aromatic RL give rise to
good reactivity and high olefin selectivity (27−33). Ortho
substitution on RL gave rise to a slight reduction in selectivity
(29), while branching on the alkyne R group is well-tolerated
with no impact on the reaction outcome (31 and 32).
Functional group tolerance was found to be remarkably high
for a process that involves the trapping of a metal enolate with
an electrophilic bromine reagent. A propargyl alcohol bearing a
methyl aryl ketone was found to undergo the desired
transformation, with the methyl ketone acting as neither an
electrophile to the catalytically generated enolates nor as a
nucleophile to the NBP, successfully yielding diketone 33 in
good yield and olefin selectivity. Protected amines and
alcohols, free alcohols, and alkyl halides were all well-tolerated
(34−37). Conjugated alkenes at R posed no issues and
generated divinyl ketones (32 and 38). Remarkably, no
Michael-addition of either the vanadium enolate or starting
propargyl alcohol was observed with unsubstituted vinyl
ketone product 38. Distal alkenes were also tolerated by the
reaction, showing no bromine incorporation (39).
Figure 2. Confirmation of olefin geometry through 1H NOE analysis.
While DMAP in DMF was successful at the isomerization of
trisubstituted olefins, it was unable to isomerize the kinetic E-
tetrasubstituted olefins to their thermodynamic Z-configura-
tion. After screening a number of addition−elimination and
radical-based isomerization conditions, we eventually found
that irradiation of E-tetrasubstituted-choloro-olefin 17 with
350 nm wavelength light resulted in a 1:1 photoequilibrium of
E and Z products, separable via silica chromatography
(Scheme 2). With access to both E and Z products, use of
ROESY 1H NMR data allowed for confirmation of the assigned
olefin geometry.
Scheme 2. Photoequilibrium of Tetrasubstituted Enone 17
Having established the ability of our vanadium system to
provide selective access to geometrically defined E- and Z-
trisubstituted as well as E-tetrasubstituted chloro-olefins, we
turned our attention to the corresponding bromination
process. Treatment of tertiary propargyl alcohol 24 with 5
mol % OV(OSi(p-ClC6H4)3)3, 1.05 equiv of dibromo-
Meldrum’s acid (25), and 2 equiv of MgO as a general base
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Table 6. Scope of the E-Selective Vanadium Bromination
Reaction
Scheme 3. Gram-Scale Synthesis
a
Scheme 4. Mild Conditions of the Vanadium Bromination
Reaction
crude reaction mixtures showed no evidence for the presence
of any elimination products. However, silica gel purification of
Troc-protected alcohol product 49 resulted in complete
elimination of the protected alcohol to give diene 38, while
silica gel purification of alkyl bromide product 37 resulted in
an inseparable 1:1 mixture of 37 and elimination product 50.
Clean alkyl bromide 51 could be isolated from the crude
reaction mixture following a reductive quench with diisobuty-
laluminum hydride (DIBAl-H) prior to chromatography. The
proclivity of these sensitive products to readily undergo
elimination during mild silica gel chromatography while
remaining intact during the Lewis acidic (OV(OSi(p-
ClC6H4)3)3) and Brønsted basic (vanadium enolate and
MgO) reaction conditions is notable.
a
Reactions performed at 0.2 mmol scale. E:Z ratio determined via 1H
b
c
NMR of the crude reaction mixture. 55 °C. Yield based on
d
recovered starting material (brsm). 10 mol % OV(OSi(p-C6H4)3)3.
e
1.05 equiv of 25 used as Br+ source, 65 °C. Product reduced at
f
completion of the reaction and characterized as the alcohol. NIS
(1.05 equiv) used.
In the case of bromination, changing RS from methyl to
longer chain alkyl groups had little impact on selectivity (12:1
to 16:1, 39−41). Even adding branching to the alkyl group at
RS resulted in an impressive 3:1 E:Z ratio (42). Exocyclic
geometrically defined tetrasubstituted olefins could also be
formed starting from cyclic propargyl alcohols, albeit with a
slightly diminished E:Z ratio of 7:1 (43). Geometrically
defined E-trisubstituted bromo-olefins could also be selectively
generated starting from secondary propargylic alcohols (44).
The analogous iodination process proceeded cleanly by simply
switching the electrophile from NBP to N-iodosuccinimide
(NIS) (45). Finally, these reactions proved to be scalable and
could be run at gram-scale with no impact on yield or
selectivity (Scheme 3).
To definitively characterize both the bond connectivity and
the geometric selectivity of the products, a single crystal
suitable for X-ray diffraction was grown of biphenyl alcohol 35.
Indeed, the X-ray structure confirmed both our assignment of
bond connectivity as well as E-olefin geometry (Figure 3).
The remarkably mild nature of this transformation is
highlighted by the reactivity of propargyl alcohols 47 and 48
(Scheme 4). Both of these ketone products (49 and 37) have
the ability to undergo an E1cb elimination. In each case, the
Figure 3. X-ray crystal structure of 35.
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During the course of our work, a very similar reportedly
gold-catalyzed process to obtain tetrasubstituted α-chloro-,
bromo-, and iodo-enone olefins with E-geometry was
published.17 However, when we compared the reported
products with those obtained from our process, the
spectroscopic data did not match. Theorizing that their
products might be arising from a halide induced pinnacol/
Meerwein 1,2-aryl migration, we subjected propargyl alcohol
52 to the reported reaction conditions but omitted the gold
catalyst (Scheme 5). Under these conditions, we obtained β-
Table 7. Optimization of the Metal-Free Synthesis of Z-
Tetrasubstituted Halo Olefins
Scheme 5. Gold-Free Formation of β-Haloenones
a
Reactions performed at 0.2 mmol scale. Z:E ratio determined via 1H
b
c
NMR of the crude reaction mixture. Complex reaction mixture. 2
d
equiv of K2CO3, 40 °C. Conversion measured via 1H NMR of crude
e
reaction mixture. 1.1 equiv of NBS.
stabilize partial positive charges developing in the transition
state. Finally, the loading of NBS could be decreased to 1.1
equiv, and the reaction concentration could be increased to 0.5
M with no impact on yield or selectivity (entries 8 and 9).
Both electron-rich and electron-neutral aromatic groups
were capable of undergoing the halogen-initiated 1,2-aryl shift
(Table 8, 53−57). While 4-bromophenyl was shown to
undergo clean migration, most electron withdrawing aromatic
groups led to rapid decomposition. Silyl-protected alcohols
bromo-enone 53 in 79% yield and with an improved 14:1 Z:E
ratio compared to the 5:1 ratio reported with gold present.
Importantly, the structure of 53 was confirmed via 2-D NMR
(HMBC, HSQC, ROESY, see the Supporting Information),
and its characterization data matched that erroneously assigned
in the original report to α-bromo-enone 28. While such a
metal-free rearrangement is known for the ring expansion of
cyclic propargyl alcohols,18 as well as for specialized propargyl
alcohols bearing haloalkynes,19 there is little in the literature
about simple acyclic propargyl alcohols participating. Just one
publication containing only two examples of iodination with I2
in periodic acid is reported.20 Seeing the utility of developing a
general process that would result in enones with geometrically
defined tetrasubstituted olefins bearing a range of halides at the
β-carbon, complementary to the vanadium process that places
the halide at the α-position, we decided to further optimize the
reaction.
Table 8. Scope of the Metal-Free Synthesis of Z-
Tetrasubstituted Halo Olefins
Lengthening the reaction time from 14 to 23 h resulted in a
complex mixture of products (Table 7, entries 1 and 2).
Adding 2 equiv of K2CO3 to the reaction resulted in complete
recovery of starting material, even at 40 °C, highlighting the
importance of a mildly acidic reaction environment (entry 3).
Doubling the reaction concentration resulted in an improved
Z:E ratio of 20:1 and a yield of 95% (entry 4). Water was
found to be important for reactivity, as running the reaction
under anhydrous conditions led to a mere 6% conversion after
20 h (entry 5). While switching the organic solvent from
MeCN to DMF resulted in both lower yield and selectivity
(entry 6), use of hexafluoroisopropanol (HFIP) as the organic
solvent resulted in a large improvement in rate with the
reaction reaching completion within 2 h (entry 7). This large
rate enhancement likely results from the increased hydrogen-
bond donation of HFIP and its corresponding ability to better
a
Reactions performed at 0.2 mmol scale. Z:E ratio determined via 1H
b
c
NMR of the crude reaction mixture. 65 °C. NIS used (1.1 equiv).
d
TCICA (1.5 equiv), 5:1 MeCN/H2O (0.17 M), room temperature
(rt).
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remained intact during the course of the reaction (58), as did
protected amines (59). Branching (60) or aromatic sub-
stitution (61) on the alkyne at R3 was well-tolerated, although
a slight decrease in Z:E selectivity was observed in the case of
R3 = aryl. The corresponding iodination process could be
performed simply by switching the electrophilic halide source
from NBS to NIS (62), while chlorination could be achieved
utilizing trichloroisocyanuric acid (TCICA) in an acetonitrile/
water mixed solvent system (63).
Scheme 7. Suzuki Coupling for the (A) Formation of Triaryl
Olefins and (B) Formation of Tetrasubstituted Chiral
Allylic Alcohol
To illustrate the synthetic utility of both halogenation
methods, we sought to utilize the geometrically defined vinyl
halides for cross-coupling. Treatment of both β-bromo-enone
53 and α-bromo-enone 30 under more “standard” Suzuki
cross-coupling conditions (Scheme 6, condition A) led to a
Scheme 6. Suzuki Cross-Coupling Conditions
geometrically defined tetrasubstituted olefin (67) could also be
generated in high er (enantiomeric ratio) through the CBS
reduction of the corresponding ketone.25 Subsequent Suzuki
coupling allows access to chiral allylic alcohols bearing an all-
carbon, geometrically defined tetrasubstituted acyclic olefin
(Scheme 7B). In all of the Suzuki couplings performed, 3,5-
dimethoxyphenylboronic acid was utilized as the nucleophilic
donor to ensure sufficient resolution of the newly installed aryl
1
proton peaks in the H NMR spectrum to allow for the
definitive assignment of E/Z stereochemistry in the final
products.
significant scrambling of olefin geometry. However, we were
delighted to find that conditions initially reported by Lipschutz
(condition B),21 utilizing Pd(PPh3)2Cl2 with K2CO3 in a
THF/water solvent system at room temperature, gave rise to
the desired all-carbon tetrasubstituted products in high yields
and with near complete conservation of starting olefin
geometry (64 and 65). Both of these cross-coupling products
containing geometrically defined 1,2-diaryl substituted olefins
share a similar carbon backbone with diethylstilbestrol, a
former drug used for the treatment of prostate22 and breast
cancer.23
These cross-coupling conditions could also be utilized on
vinyl bromide 61, giving triaryl tetrasubstituted olefin 66 in
good yield and with excellent conservation of original olefin
geometry. The geometrically defined acyclic triaryl olefin motif
is an important scaffold in medicinal chemistry and shared by a
number of FDA approved and clinical phase drugs for the
treatment of breast cancer,13a,b dyspareunia,13c and cyclical
mastalgia24 (Scheme 7A). Chiral allylic alcohols containing a
The utility of the halo-olefin products was further high-
lighted in the total synthesis of ( )-myodesmone (69), a
furanoid sesquiterpene ketone isolated from Myoporum deserti
and Myoporum acuminatum.26 Starting from 3-acetylfuran, α-
allylation under conditions developed by Negishi resulted in
ketone 70 in 78% yield (Scheme 8).27 Nucleophilic addition of
lithium acetylide 71 gave rapid access to propargyl alcohol 72
in 73% yield. Treatment of this electron-rich propargyl alcohol
under the standard bromination conditions (Table 5, entry 6
vide supra) resulted in the isolation of less than 15% of the
desired vinyl bromide 68. It was found that a rapid
electrophilic bromine-initiated background decomposition
pathway associated with the furan was funneling the starting
material away from the vanadium-catalyzed process. By
switching the electrophilic bromine source to dibromo-
Meldrum’s acid 25 and utilizing the lithium alkoxide in place
of the free alcohol, the vanadium-catalyzed sigmatropic
functionalization process could become more competitive
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Scheme 8. Total Synthesis of ( )-Myodesmone
Scheme 10. Unusual Rearrangement to Cyclopentadiene
Products
with the background decomposition pathway, giving vinyl
bromide 73 in an improved 35% yield. Subsequent intra-
molecular Heck coupling followed by chemoselective Crabtree
hydrogenation resulted in ( )-myodesmine in 67% yield over
two steps.
In the course of our model studies toward the synthesis of
myodesmone, we came across a couple of noteworthy
observations. When the radical cyclization of 39 was explored,
the 6-endo-trig cyclization product 75 was preferred 4:1 to the
expected 5-exo-trig product (Scheme 9). While not the desired
transformation, this type of cyclohexene scaffold maps onto the
structure of a subclass of tetrahydrocannabinol natural
products.
cheap and readily available propargyl alcohols. The economic
and earth-abundant vanadium-catalyzed process results in the
kinetically controlled formation of E-α-halo-enones and shows
remarkable functional group tolerance, while a metal-free
process results in complementary Z-β-halo-enones. These halo
olefins have been shown to undergo cross-coupling reactions
with retention of olefin configuration to construct biologically
relevant, geometrically defined di- and triaryl acyclic olefin
scaffolds. Additionally, the utility of these products has been
demonstrated through the total synthesis of the sesquiterpene
myodesmone. The importance of these tetrasubstituted
products and the need for further exploration of these olefin
structures are highlighted by the unexpected palladium-
catalyzed formation of a rearranged cyclopentadiene ring.
Scheme 9. Intramolecular Cyclization of 39
ASSOCIATED CONTENT
* Supporting Information
a
■
81% isolated yield of a 4:1 mixture of 6-endo-trig and 5-exo-trig
S
cyclization products.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.8b04567.
Additionally, in the course of our unsuccessful exploration of
reductive-Heck conditions for the cyclization of 39, we
observed an unexpected carbon-bond rearrangement. By
utilizing a slight modification of the Heck conditions reported
above (PPh3 instead of dppf and HCO2Na instead of NaOAc),
cyclopentadiene product 76 was isolated in preference to
either the Heck or the reductive-Heck products. Formation of
this product is thought to proceed through simple Heck
product 77 that, upon internal migration of the exocyclic
double bond, undergoes a series of 1,5-hydride and 1,5-acyl
shifts to arrive at the thermodynamic carbon skeleton (Scheme
10). This unexpected behavior highlights the unique and
underexplored reactivity that these geometrically defined
tetrasubstituted olefins possess.
Additional experimental details, characterization data,
spectra, and X-ray analysis (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: bmtrost@stanford.edu.
■
ORCID
Barry M. Trost: 0000-0001-7369-9121
Jacob S. Tracy: 0000-0001-9261-7865
Notes
The authors declare no competing financial interest.
CONCLUSION
■
ACKNOWLEDGMENTS
In summary, we have developed a highly efficient method for
the formation of both tri- and tetrasubstituted geometrically
defined chloro, bromo, and iodo acylic olefins starting from
■
J.S.T. acknowledges support from the Franklin Veatch
Memorial Award.
1591
DOI: 10.1021/acscatal.8b04567
ACS Catal. 2019, 9, 1584−1594

ACS Catalysis
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ACS Catal. 2019, 9, 1584−1594