Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and Suzuki-Miyaura Coupling

Article abstract of DOI:10.1021/jacs.7b05071

A highly stereocontrolled synthesis of tetrasubstituted acyclic all-carbon olefins has been developed via a stereoselective enolization and tosylate formation, followed by a palladium-catalyzed Suzuki-Miyaura cross-coupling of the tosylates and pinacol boronic esters in the presence of a Pd(OAc)₂/RuPhos catalytic system. Both the enol tosylation and Suzuki-Miyaura coupling reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the olefin products. Judicious choice of substrate and coupling partner provides access to either the E- or Z-olefin with excellent yield and stereochemical fidelity. Olefin isomerization was observed during the Suzuki-Miyaura coupling. However, under the optimized cross-coupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species.

Full text of DOI:10.1021/jacs.7b05071

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Article
Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-
carbon Olefins via Enol Tosylation and Suzuki#Miyaura Coupling
Beryl X. Li, Diane N. Le, Kyle A Mack, Andrew McClory, Ngiap-Kie Lim, Theresa Cravillion,
Scott Savage, Chong Han, David B. Collum, Haiming Zhang, and Francis Gosselin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b05071 • Publication Date (Web): 17 Jul 2017
Downloaded from http://pubs.acs.org on July 17, 2017
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Highly Stereoselective Synthesis of Tetrasubstituted Acyclic Allꢀ
carbon Olefins via Enol Tosylation and Suzuki‒Miyaura Coupling
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Beryl X. Li,† Diane N. Le,† Kyle A. Mack,‡ Andrew McClory,† NgiapꢀKie Lim,† Theresa Cravillion,†
Scott Savage,† Chong Han,† David B. Collum,‡ Haiming Zhang,†,* and Francis Gosselin,†,*
†Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
‡Baker Laboratory, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853‒1301,
United States
ABSTRACT: A highly stereocontrolled synthesis of tetrasubstituted acyclic allꢀcarbon olefins has been developed via a stereoseꢀ
lective enolization and tosylate formation, followed by a palladiumꢀcatalyzed Suzuki‒Miyaura crossꢀcoupling of the tosylates and
pinacol boronic esters in the presence of Pd(OAc)2/RuPhos catalytic system. Both the enol tosylation and Suzuki‒Miyaura coupling
reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the
olefin products. Judicious choice of substrate and coupling partner provides access to either Eꢀ or Zꢀolefin with excellent yield and
stereochemical fidelity. Olefin isomerization was observed during the Suzuki‒Miyaura coupling. However, under the optimized
crossꢀcoupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the
olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species.
INTRODUCTION
and McMurry15 reactions generally afford poor stereoselectiviꢀ
ties. Eliminations of highly functionalized tertiary alcohols
produce tetrasubstituted olefins;16 however, the synthesis of
the alcohol precursors is often challenging, and multiple elimꢀ
ination pathways frequently result in erosion of stereoconꢀ
trol.16 Carbometallation of internal alkynes is commonly emꢀ
ployed but suffers from chronic lack of regiocontrol and funcꢀ
tional group tolerance.17 Recent alternative approaches using
Lewisꢀacidꢀbased electrophiles to activate internal alkynes
followed by further functionalization are limited by combinaꢀ
tions of harsh reaction conditions, expensive reagents, and
poor regioselectivities.18 Therefore, the development of a genꢀ
eral, operationally simple, scalable, highly regioꢀ and stereoseꢀ
lective preparation of tetrasubstituted acyclic allꢀcarbon oleꢀ
fins, while a daunting challenge, will provide a useful new tool
for synthetic organic chemists.
Tetrasubstituted acyclic allꢀcarbon olefins have attracted treꢀ
mendous attention owing to their unique structural, physical,
and electronic properties.1 For example, they have been exꢀ
plored extensively for their potential use in molecular devices
and liquid crystals2 and are widely present in biologically acꢀ
tive compounds such as anticancer agents tamoxifen,3 idoxiꢀ
fene,4 and etacstil,5 as well as the selective estrogen receptor
degrader GDCꢀ0810 which binds to the estrogen receptor and
causes it to be degraded and thus downregulated (Figure 1).6
Moreover, stereodefined tetrasubstituted olefins are the founꢀ
dation for numerous asymmetric reactions such as dihydroxꢀ
ylation,7 epoxidation,8 and hydrogenation9 to stereospecifically
establish vicinal sp3ꢀhybridized carbon centers.
Scheme 1. Selected Strategies to Prepare Tetrasubstituted
Olefins
Figure 1. Biologically active compounds containing stereodefined
tetrasubstituted olefins
Consequently, a wide variety of synthetic strategies to conꢀ
struct tetrasubstituted acyclic allꢀcarbon olefins have been
developed.10,11 Classical synthetic methods including Wittig,12
Horner‒Wadsworth‒Emmons (HWE),12 Julia,13 Peterson,14
In support of our clinical and commercial development of
GDCꢀ0810, we were tasked to develop a highly efficient and
stereoselective synthesis of tetrasubstituted acyclic allꢀcarbon
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olefins. Herein we wish to report a highly viable method based
on stereoselective enol tosylate formation and subsequent Suꢀ
zuki‒Miyaura coupling (Scheme 2).
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Scheme 2. Stereoselective Olefin Synthesis via Enol Tosylꢀ
ate Formation and Suzuki‒Miyaura Coupling
equiv
of R3N
convb
(%)
yieldc
(%)
6
7
entry
R3N
2a/2a'b
8
9
1
2
3
4
5
6
7
8
9
Cy2NEt
iꢀPr2NEt
Et3N
5
5
5
5
5
3
2
1
0
97
87
90
33
99:1
96:4
98:2
44:56
99:1
99:1
99:1
98:2
97:3
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97
71
TMEDA
Me2NEt
Me2NEt
Me2NEt
Me2NEt
Me2NEt
97
74
100
100
100
99
96
RESULTS AND DISCUSSION
95
96(88)d
We initiated our studies by investigating the enolization and
tosylate formation of commercially available 1,2ꢀ
diphenylbutanꢀ1ꢀone (1a) by employing 2.0 equiv of MHMDS
or MOtꢀBu (M = Li, Na, K) in THF and quenching with 2.0
equiv of Ts2O in DCM. Unfortunately, the reactions generated
less than satisfactory conversions (<5‒97%) and E/Z selectiviꢀ
ties (23:77‒82:18). It has been reported previously that a highꢀ
ly Eꢀselective enol silylation of acyclic ketones mediated by
LiHMDS/R3N in toluene was readily achieved in which ≥2.0
equiv of LiHMDS were required for maximal E/Z selectivity
via an 8ꢀmembered transition state (eq 1).19
84
75
56
aStandard conditions: ketone 1a (1.0 mmol), LiHMDS in PhMe
(0.90 M, 2.0 equiv, 2.2 mL), R3N (0‒5 equiv), PhMe (1.0 mL),
23 °C; then Ts2O (2.0 equiv) in DCM (5.0 mL), 23 °C. Converꢀ
sion and E/Z ratio were determined by HPLC analysis of the reacꢀ
tion mixture. cAssay yield of desired 2a was determined by quanꢀ
titative HPLC analysis. The number in parentheses is the isolated
yield at both 1.0 mmol and 10.0 g (44.6 mmol) scale.
b
We next investigated the scope and limitations of the enolizaꢀ
tion and tosylation reactions using the optimized conditions
(Table 2). The aryl group directly connected to the carbonyl
moiety tolerated electronꢀdonating (4ꢀMe, 4ꢀMeO, 4ꢀCl) and
electronꢀwithdrawing (4ꢀF, 4ꢀCF3, 4ꢀCO2Et) substituents. All
reactions afforded >95:5 E/Z selectivities and 66%‒87% isoꢀ
lated yields of the Eꢀtosylate product (2b‒g). Substitution of a
3ꢀMeO group did not significantly impact the E/Z selectivity
and yield (2h, 98:2, 87%). However, a 2ꢀMe group substanꢀ
tially eroded the E/Z selectivity to 82:18, affording Eꢀisomer
2i and Zꢀisomer 2i' in 61% and 12% yield, respectively, after
chromatographic purification. The 2ꢀpyridyl substituted ketone
afforded 98:2 E/Z selectivity and 82% isolated yield of the
desired tosylate 2j.
We thus focused on the enolization and tosylate formation of
ketone 1a using 2.0 equiv of LiHMDS20 with a tertiary alkyl
amine (5.0 equiv) in toluene and quenching with 2.0 equiv of
Ts2O in DCM. As shown in Table 1, despite reasonable conꢀ
versions (87‒97%), reactions with bulkier amines tend to form
more side products, which lowers the yield (Table 1, entries
1‒3). Also, the chelating diamine base TMEDA only affords
44:56 ratio of the E/Z stereoisomers (Table 1, entry 4). With
Me2NEt being the most promising amine, the stoichiometry of
Me2NEt was then examined (Table 1, entries 5‒9). Two equiv
of Me2NEt were optimal, affording quantitative conversion
and 99:1 E/Z ratio. At <2.0 equiv of Me2NEt the E/Z selectiviꢀ
ty remained high, but the yield suffered (Table 1, entries 8‒9).
A preparative scale reaction using 10.0 g (44.6 mmol) of keꢀ
tone 1a under optimized conditions employing 2.0 equiv of
LiHMDS and 2.0 equiv of Me2NEt at 23 °C afforded pure Eꢀ
isomer in 88% yield (Table 1, entry 7). The structure of Eꢀ
isomer 2a was determined by standard analytical methods
including Xꢀray crystallography (Supporting Information).
The aryl group distal to the carbonyl also tolerated electroniꢀ
cally diverse substituents and afforded the tosylates 2k‒q in
95:5‒99:1 E/Z selectivity and 75‒95% isolated yields. Interestꢀ
ingly, the 2ꢀMe substituent had a less profound effect on the
E/Z selectivity (2r, 95:5) than in the case of 2i, albeit with a
lower isolated yield (50%). Surprisingly, the 2ꢀpyridyl substiꢀ
tuted ketone generated a 2:98 E/Z selectivity favoring the unꢀ
expected Zꢀisomer 2s' in 61% isolated yield. We attribute this
reversal in selectivity to lithium chelation by the 2ꢀpyridyl
nitrogen forcing Zꢀenolate formation (eq 2).
Table 1. Optimization of LiHMDSꢀmediated Enolization
and Tosylationa
2
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EtO2C
Me
The enol tosylation reaction is sensitive to steric changes on
the alkyl moiety proximal to the enolization site. Replacing the
1
2
3
4
5
6
7
8
MeO
Me
OTs
Me
OTs
Me
OTs
ethyl group with a smaller methyl group surprisingly afforded
lower conversion and E/Z selectivity (83:17). After purificaꢀ
tion, only 47% of the Eꢀtosylate 2t was isolated, along with
10% of the Zꢀtosylate 2t'. The hindered isopropyl moiety in 1u
afforded no product. Fortunately, the allyl, cyclopropylmethyl,
and nꢀbutyl substituted ketones readily afforded the desired
tosylates in high yields and selectivities (2v‒x). Xꢀray crystalꢀ
lographic analysis of tosylates 2 unambiguously established
the Eꢀolefin configuration (Supporting Information). A few
representative Xꢀray structures are shown in Figure 2.
2q
, 95:5, 78%
2p
, 99:1, 95%
2r, 95:5, 50%
Me
Me
Me
N
Me
OTs
OTs
OTs
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2s', 98:2, 61%
2t, 83:17,47%f
2u
, 0%
Table 2. Reaction Scope of Enol Tosylationa,b,c
Me
R2
R2
1. LiHMDS, Me2NEt
2. Ts2O
OTs
OTs
OTs
R3
R3
OTs
O
2v
2w
, 95:5, 82%
2x
, >99:1, 82%
R1
R1
, 95:5, 81%
1
2
aStandard conditions: ketone 1 (2.0 mmol), LiHMDS in PhMe
(0.90 M, 2.0 equiv, 4.4 mL), Me2NEt (0.43 mL, 2.0 equiv), PhMe
(2.0 mL), 23 °C; then Ts2O (2.0 equiv) in DCM (10.0 mL), 23 °C.
bE/Z ratio was determined by HPLC analysis of the reaction mixꢀ
ture. Isolated yield. The reaction was also performed employing
10.0 g (44.6 mmol) of ketone 1a. 12% of the Zꢀisomer 2i' was
Tosylate products
c
d
e
Me
Me
Me
OTs
isolated. f10% of the Zꢀisomer 2t' was isolated.
OTs
OTs
Me
MeO
2a, 99:1, 88%d
2b, 98:2, 82%
2c, 98:2, 66%
Me
Me
OTs
Me
OTs
OTs
F3C
Cl
F
2e
2d, 98:2, 74%
, >99:1, 78%
2f, 96:4, 80%
Me
OTs
Me
Me
MeO
OTs
OTs
Me
EtO2
C
Figure 2. Xꢀray structures of Eꢀtosylates 2a, 2e (top), 2m and 2v
2i, 82:18, 61%e
2g
2h
, 98:2, 87%
, 98:2, 87%
(bottom)
Next, we examined the Suzuki‒Miyaura coupling21 of Eꢀ
tosylate 2a and 4ꢀfluorophenyl pinacol boronic ester (3a) by
highꢀthroughput screening of phosphine ligands using
Pd(OAc)2 as the precatalyst and K3PO4•H2O as the base in
PhMe/H2O (3:1) at 70 °C. CMPhos,22 Xantphos,23 and
RuPhos24 generated the highest conversions and lowest E→Z
olefin isomerization (Figure 3).25 Further validation and optiꢀ
mization led to the optimal conditions using 1.0 equiv of Eꢀ
tosylate 2a, 1.1 equiv of boronic ester 3a, 1 mol % of
Pd(OAc)2, 2 mol % of RuPhos, and 1.5 equiv of K3PO4•H2O
in PhMe/H2O (0.5 M, 3:1) at 70 °C (eq 3). Under this set of
conditions, the reaction afforded complete conversion with
only 2% of isomeric Zꢀolefin observed in the crude product.
The Eꢀ and Zꢀisomers were inseparable by silica gel flash colꢀ
umn chromatography. Thus, the desired tetrasubstituted olefin
4a containing 2% of the Zꢀstereoisomer was isolated in 98%
yield on a 5.0 g (12.7 mmol) scale (Table 3, entry 1). 4ꢀ
Fluorophenylboronic acid and potassium 4ꢀfluorophenyl triꢀ
Me
MeO
Me
Me
Me
OTs
N
OTs
OTs
2k, 95:5, 84%
2j, 98:2, 82%
2l, 95:5, 75%
Cl
F
F3C
Me
Me
Me
OTs
OTs
OTs
2n
, 98:2, 76%
2m, 98:2, 80%
2o, 98:2, 88%
3
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fluoroboronate could be used in place of boronic ester 3a,
affording the same 98% yield and 98:2 E/Z ratio.
Table 3. Scope of Boronic Esters in the Suzuki‒Miyaura
Reactiona,b,c
1
2
3
4
5
3
1.1 equiv RBpin (
)
1 mol % Pd(OAc)2
2 mol % RuPhos
1.5 equiv K3PO4•H2O
Me
OTs
Me
R
PhMe/H2O (3:1), 70 °C
6
7
2a
4
8
9
Tetrasubstituted olefin products
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Me
Me
Me
F
Me
OMe
Figure 3. High–throughput screening of Suzuki‒Miyaura coupling
of Eꢀtosylate 2a and 4ꢀFC6H4Bpin (3a)
d
4a
4b
, 98:2 98%
4c
, 98:2, 98%
, 98:2, 96%
1.1 equiv 4ꢀFC6H4Bpin
1 mol % Pd(OAc)2
2 mol % RuPhos
Me
Me
Me
1.5 equiv K3PO4•H2O
Me
Me
(3)
PhMe/H2O (3:1), 70 °C
OTs
CF3
CO2Et
Cl
e,f
F
100% E
98%, E:Z = 98:2
4e
4d,
, >99:1, 97%
4f
, 99:1, 30%
98:2, 95%
Me
Me
EꢀTosylate 2a was coupled to a variety of electronically and
sterically diverse boronic esters (3) under the optimized reacꢀ
tion conditions (Table 3). Phenylboronic esters substituted at
the 4ꢀposition with either an electronꢀdonating group (Me,
MeO) or electronꢀwithdrawing group (CO2Et, CF3) generated
the crossꢀcoupling products (4b–e) in excellent yields and E/Z
selectivities. Reaction of 4ꢀchlorophenyl pinacol boronic ester
with Eꢀtosylate 2a afforded 4f in 99:1 E/Z ratio but in a disapꢀ
pointing 30% yield (46% conversion) of the isolated product.
We suspect that 4ꢀchlorophenyl pinacol boronic ester oliꢀ
gomerizes under our standard reaction conditions. The steriꢀ
cally demanding 2ꢀtolyl pinacol boronic ester required 2 mol
% of Pd(OAc)2 and 4 mol % of RuPhos to reach full converꢀ
sion but still afforded 86%yield and 98:2 E/Z ratio of product
4g. Highly hindered mesitylꢀderived pinacol boronic ester
provided essentially no product 4h. Similarly, 2ꢀpyridyl pinaꢀ
col boronic ester did not afford much of the coupling product
4i, presumably due to the propensity of protodeboronation of
the boronic ester under the reaction conditions.26 By contrast,
3ꢀthienyl and 5ꢀindazolyl pinacol boronic esters coupled to
give 4j‒k in moderate to good yields and excellent isomeric
ratios. Vinyl, alkynyl, cyclopropyl and alkyl boronic esters
were also examined. As expected, styryl pinacol boronic ester
produced 80% yield and 98:2 ratio of the coupling product 4l.
The reaction with phenylethynyl pinacol boronic ester, howꢀ
ever, required 2.1 equiv to reach completion, affording 61%
yield and 99:1 selectivity of 4m. Cyclopropyl pinacol boronic
ester failed to generate the desired olefin product possibly due
to decomposition during the reaction. Gratifyingly, when Eꢀ
tosylate 2a was treated with cyclopropylzinc bromide under
Negishi coupling27conditions, the reaction produced 95% yield
and 99:1 selectivity of olefin 4n. Although nꢀbutyl pinacol
boronic ester did not afford significant yield (<20%) of the
coupling product, nꢀbutylboronic acid underwent the Suzuki‒
Miyaura coupling smoothly, affording 98% yield and 99:1
selectivity of olefin 4o.
Me
Me
N
Me
Me
Me
4g, 98:2, 86%e
4h, <5%
4i
, <5%
Me
Me
Me
Ph
N
N
THP
S
4j, 97:3, 48%e
, 98:2, 80%
e
4l
4k, 98:2, 84%
Me
Me
Me
Me
Ph
f
g
h
4m
4n
, 99:1, 95%
4o
, 99:1, 61%
, 99:1, 98%
aStandard conditions: Eꢀtosylate 2a (1.0 mmol), boronic ester (1.1
equiv), Pd(OAc)2 (1 mol %), RuPhos (2 mol %), K3PO4•H2O (1.5
equiv), PhMe/H2O (1.5/0.5 mL), 70 °C. E/Z ratio were deterꢀ
b
mined by HPLC analysis of the isolated inseparable products.
cIsolated yield. dThe reaction was also performed employing 5.0 g
e
(12.7 mmol) of Eꢀtosylate 2a. Pd(OAc)2 (2 mol %) and RuPhos
f
(4 mol %) were employed. 2.1 equiv of boronic ester was emꢀ
ployed. gNegishi conditions: Eꢀtosylate 2a (1.0 mmol), cycloꢀ
propylzinc bromide (1.1 equiv, 0.50 M in THF, 2 mL), LiCl (0.50
M in THF, 2.2 mL), Pd(OAc)2 (1 mol %), RuPhos (2 mol %),
60 °C. h1.1 equiv of n-butylboronic acid was used.
We examined the reactivity of a variety of Eꢀtosylates (2) with
phenyl pinacol boronic ester as a coupling partner (Table 4).
The aryl group proximal to the tosylate can tolerate both elecꢀ
tronꢀdonating (Me, MeO, Cl) and electronꢀwithdrawing (F,
CO2Et, CF3) substituents at the 4ꢀposition as well as some
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steric congestion at the 2ꢀposition (5a–g), affording excellent
yields and stereochemical integrity of the desired olefin prodꢀ
1
2
3
4
5
6
7
8
Me
F
ucts. Eꢀtosylate with a 2ꢀpyridyl moiety afforded 5h in 65%
yield and 96:4 selectivity. Olefins 5a‒g are the complementary
stereoisomers to olefins 4a‒g in Table 3. It is noteworthy that
the modular nature of this methodology provides both isomers
with excellent stereocontrol. Similarly, couplings with 4ꢀ
fluorophenyl pinacol boronic ester showed that the aryl moiety
distal to the tosylate also tolerates electronꢀdonating and elecꢀ
tronꢀwithdrawing substituents at the 4ꢀposition (5i–m) as well
as steric congestion at the 2ꢀposition (5n). Replacing the ethyl
group with methyl, allyl, cyclopropylmethyl, or nꢀbutyl moieꢀ
ties (5o–r) caused no erosion in yields or selectivities.
F
F
5p
5q
5r
, 98:2, 99%
, 97:3, 97%
, 96:4, 94%
aStandard conditions: Eꢀtosylate 2a (1.0 mmol), boronic ester (1.1
equiv), Pd(OAc)2 (1 mol %), RuPhos (2 mol %), K3PO4•H2O (1.5
equiv), PhMe/H2O (1.5/0.5 mL), 70 °C. E/Z ratios were deterꢀ
mined by HPLC analysis of the isolated inseparable products.
b
9
cIsolated yield.
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The pyridylꢀcontaining Zꢀtosylate 2s' unexpectedly generated
in the enol tosylate reaction underwent the Suzuki‒Miyaura
reaction with 4ꢀfluorophenyl pinacol boronic ester, forming
the tetrasubstituted olefin 5s in a moderate 57% yield with
<1% olefin isomerization (eq 4).
Table 4. Scope of Eꢀtosylates in the Suzuki‒Miyaura Reacꢀ
tiona,b,c
1.1 equiv PhBpin
or 4ꢀFC6H4Bpin
1 mol % Pd(OAc)2
2 mol % RuPhos
1.5 equiv K3PO4•H2O
1.1 equiv 4ꢀFC6H4Bpin
1 mol % Pd(OAc)2
2 mol % RuPhos
R2
R1
R2
R1
R3
OTs
R3
1.5 equiv K3PO4•H2O
Me
N
Me
N
(4)
Ar
PhMe/H2O (3:1), 70 °C
PhMe/H2O (3:1), 70 °C
OTs
F
2
5
2s'
5s
57%, >99:1
Tetrasubstituted olefin products
Xꢀray crystal structures of several tetrasubstituted olefins unꢀ
ambiguously established the geometry of the double bonds.
Representative Xꢀray structures are shown in Figure 4.
Me
Me
Me
F
Me
MeO
5a, 98:2, 93%
5b, 96:4, 96%
5c, 93:7, 92%
Me
Me
Me
F3C
EtO2C
Cl
5d
5e
5f
, 98:2, 83%
, 96:4, 84%
, >99:1, 96%
Me
Me
Me
Me
Figure 4. Xꢀray structures of olefins 4a, 5d (top), 5j and 5o (botꢀ
tom)
N
Me
F
Olefin isomerizations have been previously noted in Suzuki‒
Miyaura couplings, but little is known about the cause of this
sideꢀreaction.25 We investigated the isomerization mechanism
by examining the crossꢀcoupling reaction of Eꢀtosylate 2a and
4ꢀfluorophenyl pinacol boronic ester (3a). Subjecting product
4a (E/Z = 98:2) to the standard coupling conditions caused no
change in the E/Z ratio after 20 h, which indicates that the
olefin product does not isomerize under the reaction condiꢀ
tions. Exclusion of light or addition of 2,6ꢀdiꢀtertꢀbutylꢀ4ꢀ
methylphenol (BHT, 5 mol %) to the coupling reaction had no
impact on the E/Z selectivity, arguing against a free radical
mechanism. Treating either Eꢀtosylate 2a or its Zꢀisomer 2a’
with Pd(OAc)2 omitting either RuPhos or the boronic ester or
both showed no isomerization. Thus, we deem that a Pd(II)ꢀ
catalyzed isomerization is an unlikely mechanism. Treating Eꢀ
tosylate 2a or its Zꢀisomer 2a' with low concentration (10
mol %) of boronic ester 3a using either Pd(0) generated from
5g
5h
5i
, 98:2, 99%
, 98:2, 93%
, 96:4, 65%
MeO
F
F3C
Me
Me
Me
F
F
F
5j
5k
5l
, >99:1, 93%
, 97:3, 98%
, 98:2, 93%
EtO2
C
Me
Me
Me
Me
F
F
F
5m, >99:1, 83%
5n, 97:3, 98%
5o, 97:3, 90%
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Pd(OAc)2 and RuPhos or RuPhosꢀPdꢀG3 showed that the
Notes
tosylates do not isomerize.29
1
The authors declare no competing financial interest.
2
3
4
5
6
7
8
9
Based on the above observations, we propose a plausible
mechanism for olefin isomerization shown in Scheme 3. Simiꢀ
lar to a mechanistic proposal published by Lipshutz,30 the Eꢀ
tosylate 2a undergoes a stereospecific Pd(0) insertion to give
Pd(II) intermediate Pdꢀ1, which transmetalates with the aryl
boronic ester to form intermediate Pdꢀ2. A subsequent tauꢀ
tomerization of Pdꢀ2 to zwitterionic palladium carbenoid speꢀ
cies31 Pdꢀ3 or Pdꢀ3' erodes the stereointegrity to generate inꢀ
termediate Pdꢀ4. Intermediates Pdꢀ2 and Pdꢀ4 reductively
eliminate to regenerate Pd(0) and produce the desired olefin 4
and its stereoisomer 4', respectively.
ACKNOWLEDGMENT
In memory of Dr. Andrew McClory who tragically passed away
on February 19, 2017. The authors would like to acknowledge
Colin Masui (Genentech, Inc.) for his support on highꢀthroughput
screening, Dr. Sarah Robinson (Genentech, Inc.) for her assisꢀ
tance in collecting HRMS data, Dr. Antonio DiPasquale (Genenꢀ
tech, Inc.) for obtaining Xꢀray structures, and Professor Scott
Denmark (University of Illinois at Urbana‒Champagne) and Proꢀ
fessor Stephen Buchwald (Massachusetts Institute of Technology)
for helpful discussions. DBC and KAM thank the National Instiꢀ
tutes of Health (GM077167 and GM039764) for financial support.
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ABBREVIATIONS
REFERENCES
Scheme 3. Proposed Mechanism of Olefin Isomerization
during Suzuki‒Miyaura Coupling
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CONCLUSION
We have developed a highly stereoselective synthesis of
tetrasubstituted acyclic allꢀcarbon olefins via a stereoselective
enolization and tosylate formation, followed by a palladiumꢀ
catalyzed Suzuki‒Miyaura crossꢀcoupling with pinacol boꢀ
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system. Both the enol tosylation and Suzuki‒Miyaura coupling
reactions tolerate an array of electronically and sterically diꢀ
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partner provides access to either Eꢀ or Zꢀolefin with excellent
yield and stereochemical fidelity. Mechanistic probes show
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through a zwitterionic palladium carbenoid species. Isomerizaꢀ
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coupling conditions.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
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1
Experiment details, spectral data, copies of H and 13C NMR
spectra, and Xꢀray crystallographic data (PDF)
AUTHOR INFORMATION
Corresponding Author
*zhang.haiming@gene.com
*gosselin.francis@gene.com
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