Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin

Article abstract of DOI:10.1021/acs.joc.8b01551

We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E:Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.

Full text of DOI:10.1021/acs.joc.8b01551

Subscriber access provided by Kaohsiung Medical University
Article
Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via
Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin
Scott Savage, Andrew McClory, Haiming Zhang, Theresa Cravillion, Ngiap-Kie Lim, Colin
Masui, Sarah J. Robinson, Chong Han, Christoph Ochs, Pankaj D. Rege, and Francis Gosselin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01551 • Publication Date (Web): 10 Sep 2018
Downloaded from http://pubs.acs.org on September 11, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via
Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin
Scott Savage,† Andrew McClory,† Haiming Zhang,† Theresa Cravillion,† NgiapꢀKie Lim,† Colin Maꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
sui,‡ Sarah J. Robinson,‡ Chong Han,† Christoph Ochs,§ Pankaj D. Rege,§ and Francis Gosselin*,†
‡
†Department of Small Molecule Process Chemistry, Department of Small Molecule Analytical Chemistry, Genentech, Inc.,
§
1 DNA Way, South San Francisco, California 94080, United States; Department of Process Chemistry and Catalysis, F.
HoffmannꢀLa Roche AG, Grenzacherstrasse 124, CHꢀ4070 Basel, Switzerland
Supporting Information Placeholder
ABSTRACT: We report an efficient synthesis of GDCꢀ0810 based on a sequence involving a highly stereoselective lithium tertꢀ
butoxide mediated enolization–tosylation (≥95:5 E:Z) and a Pdꢀcatalyzed Suzuki‒Miyaura crossꢀcoupling as key steps. Global
deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control / isolation produced GDCꢀ
0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.
INTRODUCTION
this drug candidate, suitable for manufacturing kilogram
amounts of active pharmaceutical ingredient (API).
Scheme 1. Retrosynthetic Analysis of GDC-0810
Estrogen receptor positive (ER+) breast cancer accounts for
70‒80% of disease cases reported globally. Antihormonal
therapies based on selective estrogen receptor modulators
(SERMs) such as tamoxifen and aromatase inhibitors (AIs)
including anastrozole and letrozole have emerged as the standꢀ
ard of care for treating ER+ metastatic breast cancer.1 The
appearance of mutations in the ligandꢀbinding domain of ERꢀα
has led to the emergence of resistance mechanisms and stimuꢀ
lated interest in developing selective estrogen receptor degradꢀ
ers (SERDs). This novel class of ER ligands can potentially
overcome resistance mechanisms by utilizing a pathway that
involves ERꢀantagonism and removal from the signaling
pathway.2
Although efficient and suitable to prepare small amounts of
material for structure–activity relationship (SAR) purposes,
the discovery synthesis of GDCꢀ0810 was plagued with severꢀ
al drawbacks to establish the tetrasubstituted allꢀcarbon olefin
including poor regiochemistry, lack of isolation points and
,
inconsistent performance on kilogram scale.3 4 We sought to
Figure 1. Structure of SERD GDCꢀ0810 (1).
find a route that would provide improved stereoꢀ and regioꢀ
control towards accessing the most challenging structural feaꢀ
ture of GDCꢀ0810, its stereodefined tetrasubstituted acyclic
GDCꢀ0810 (1, Figure 1), is an orally bioavailable small moleꢀ
cule SERD under evaluation in clinical trials for the treatment
of metastatic ERꢀα positive breast cancer tumors. We describe
herein our efforts to develop a practical and highly stereoseꢀ
lective synthesis of this acyclic tetrasubstituted allꢀcarbon
olefin to support pharmaceutical and clinical development of
, ,
allꢀcarbon olefin.5 6 7 We also aimed to insert additional isolaꢀ
tion points in the process to provide better control over API
quality. As described in Scheme 1, a retrosynthetic analysis
guided us towards approaches that would rely on a Suzuki‒
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 7
Hꢀ6 to Hꢀ5 and dashed arrows indicate NOE responses from Hꢀ5
to Hꢀ8, Hꢀ9 and Hꢀ12.
Miyaura crossꢀcoupling of enol electrophiles 2 or 4. These
compounds were envisioned to be accessed via a stereoselecꢀ
tive enolization of complementary hindered aryl ketones 3
(route A) or 5 (route B).
1
2
3
4
5
6
7
8
Based on these results, we investigated the alternative route B
involving cinnamate ketone 9 (Scheme 2). Claisen condensaꢀ
tion of substituted phenylacetic acid 8 and methyl 4ꢀ
bromobenzoate initially used NaHMDS as the base, but we
found that switching to NaH eliminated the need for cryogenic
conditions and proved more economical.10 Aqueous quench of
the mixture led to extensive retroꢀClaisen reaction. Thus, addiꢀ
tion of anhydrous EtOH into the reaction mixture quenched
excess NaH and generated NaOEt in situ. Subsequent addition
of iodoethane afforded the ethyl ketone intermediate that was
telescoped into a palladiumꢀcatalyzed Heck crossꢀcoupling11
with tertꢀbutyl acrylate (120 mol %). The Heck reaction proꢀ
RESULTS AND DISCUSSION
As part of our investigation of Route A, we prepared the reqꢀ
uisite ketone 6 according to procedures described in our recent
,8
9
reports.7 Treatment of 6 with potassium tertꢀbutoxide (KOtꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bu) at 23 ºC and quenching with pꢀtoluenesulfonic anhydride
afforded the undesired enol tosylate isomer (E)-7 as the major
product in a variety of solvents with the highest E/Z ratio beꢀ
ing 90:10 in DMA (Table 1, entries 1
–
5). Evaluation of other
ceeded smoothly under catalysis of
1
mol
%
bases such as LiOtꢀBu and temperature effects (entries 6
–
7) or
PdCl2(dppf)•DCM / Et3N in DMA at 90 ºC. The crude ketone
product 9 was crystallized directly from the reaction mixture
by addition of aqueous EtOH. Recrystallization and charcoal
treatment provided ketone 9 in 61% yield over 3 steps with
>99 A % HPLC purity.
quenching with other electrophiles (methanesulfonic anhyꢀ
drideor diphenyl phosphoryl chloride failed to significantly
improve the Z/E ratios and additional efforts to reverse the
stereoselectivity were unfortunately met with little success.
The olefin E/Z configuration was examined by NMR spectrosꢀ
copy. Due to 1H NMR signal overlap in the aromatic region of
(E)-7, stepꢀNOESY was applied to access E/Zꢀindicative NOE
responses (Figure 2). First, the step function incorporated seꢀ
lective 1D TOCSY of Hꢀ6 to transfer magnetization to its scaꢀ
lar coupled partner, Hꢀ5. Second, selective 1D NOE irradiaꢀ
tion of Hꢀ5 resulted in enhancement of Hꢀ8, Hꢀ9, and Hꢀ12,
consistent with the (E)-7 isomer.9
Scheme 2. Synthesis of Cinnamate Ketone 9
Table 1. Indazole Ketone Enol Tosylate Formationa
entry
base
solvent
THF
convb (%)
Z/E ratiob
22:78
17:83
10:90
22:78
29:71
7:93
Table 2. Optimization of Stereocontrolled Enol Tosylate
Formationa
1
2
3
4
5
6
7
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
LiOtꢀBu
LiOtꢀBu
87
61
95
92
99
67
6
THFc
DMA
toluene
MTBE
THF
THFc
29:71
entry
base
electrophile
convb
(%)
E/Z ratiob
aConditions: (a) 6 (500 mg, 1.25 mmol) in solvent (2.5 mL)
was added base (1.75 mmol, 140 mol %) at 23 ºC, then Ts2O (570
mg, 1.75 mmol, 140 mol %) in THF (2.5 mL). Determined by
HPLC analysis of crude reaction mixture. Reaction performed at
b
1
2
NaOtꢀBu
KOtꢀBu
LiOtꢀBu
LiOtꢀBu
LiOtꢀBu
LiOtꢀBu
LiOtꢀBu
LiHMDS
NaHMDS
KHMDS
Ts2O
Ts2O
99
99
95
82
95
95
95
99
99
99
89:11
82:18
95:5
c
–20 ºC.
3
Ts2O
4
Ts2O
91:9c
89:11
90:10
83:17
64:36
52:48
83:17
5
Ms2O
(PhO)2POCl
Tf2O
6
7
8
Ts2O
9
Ts2O
Figure 2. NMR spectroscopic analysis of (E)ꢀ7: StepꢀNOESY
correlations. The solid arrow indicates a TOCSY response from
10
Ts2O
2
ACS Paragon Plus Environment

Page 3 of 7
The Journal of Organic Chemistry
aConditions: (a) 9 (500 mg, 1.24 mmol) in THF (2.5 mL) was
Figure 4. A subset of HTE screening results.
1
2
3
4
5
6
7
8
added base (1.74 mol, 140 mol %) at 23 ºC, then Ts2O (567 mg,
b
Using a microscale, highꢀthroughput experimentation apꢀ
proach, we evaluated a broad range of ligands and reaction
conditions using Pd(OAc)2 (10 mol %) as the precatalyst for
the key bondꢀforming Suzuki‒Miyaura crossꢀcoupling beꢀ
tween enol tosylate (E)-10 and NꢀTHPꢀindazoleboronic acid
pinacol ester 11a.14,15 A subset of the screening results is
shown in Figure 4.
1.74 mmol, 140 mol %) in THF (2.5 mL). Determined by HPLC
analysis of crude reaction mixture. cReaction performed at 0 ºC.
We evaluated a number of bases in preliminary experiments
studying the stereocontrolled enolization of ketone 9 (Table
2). NaOtꢀBu improved enolization stereoselectivity (entry 4)
relative to its HMDS counterpart (entry 9). We were gratified
to identify LiOtꢀBu (entry 3) as the base of choice to afford a
95:5 ratio of E/Z enol tosylates after quenching with pꢀ
toluenesulfonic anhydride, as ascertained by HPLC analysis of
the crude reaction mixture.12,13 Trapping the lithium enolate as
the corresponding methanesulfonate, diphenylphosphate and
Indazole 11a was prepared by palladiumꢀcatalyzed Miyaura
borylation15 of the corresponding NꢀTHPꢀ5ꢀbromoindazole in
toluene in 84% yield (eq 1).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
trifluoromethanesulfonate (entries 5–7) failed to improve the
E/Z quench selectivity, had poor physical properties or did not
provide improved performance in the downstream Suzuki‒
Miyaura crossꢀcoupling.14 In comparison, use of amide bases
such as Li, Na or KHMDS resulted in high levels of the undeꢀ
sired (Z)ꢀenol tosylate isomer (entries 8–10). Performing the
entire enolization / tosylation sequence at room temperature
allowed for >99% conversion and under the optimized condiꢀ
tions, we obtained (E)-10 contaminated with 5 A % HPLC of
undesired enol tosylate isomer (Z)-10 but simple crystallizaꢀ
tion from nꢀPrOH / H2O purged the minor (Z)-10 and resulted
in isolation of (E)-10 in 78% yield and ≥99.6 A % HPLC puriꢀ
ty. The structure of enol tosylate (E)-10 was unambiguously
confirmed through single crystal Xꢀray analysis (Figure 3).
Top conditions rapidly emerged with Xantphos as the ligand
of choice to provide tetrasubstituted allꢀcarbon olefin 12. Opꢀ
timization of the reaction conditions involved the use of
PdCl2(Xantphos) as the precatalyst, reduction of catalyst loadꢀ
ing to 1 mol % and increasing reaction concentration to 5.5
mL/g in toluene at 90 ºC and afforded olefin 12 in 97% assay
yield (eq 2). Although the crossꢀcoupling worked well in a
variety of solvents, we found that performing the reaction in
toluene allowed telescoping into the downstream global deproꢀ
tection step. Gratifyingly, and unlike previous observations
made on related systems in our laboratories, we did not obꢀ
serve olefin isomerization during the cross–coupling through
what we presume to be a zwitterionic palladium carbenoid
mechanistic manifold.6a
Figure 3. Xꢀray crystallographic analysis of (E)ꢀ10.
We next focused our attention on improving the global deproꢀ
tection and inserting an additional isolation point in the proꢀ
cess (Scheme 3). The original conditions relied on HCl in
MeOH / H2O to concomitantly remove the NꢀTHP and tertꢀ
butyl ester groups. These conditions resulted in transesterificaꢀ
tion of the cinnamate sideꢀchain and incomplete deprotection
of NꢀTHP aminal, presumably due to equilibrium between
reactive pyran byproducts and 1. These issues were circumꢀ
vented by the use of HCO2H / H2SO4 in toluene. Treatment of
the crude crossꢀcoupling reaction mixture with the acid mixꢀ
ture resulted in rapid THP cleavage and ester hydrolysis. Ulꢀ
timately, this afforded crude GDCꢀ0810 free acid as a crude
solution in toluene. After aqueous workup of the reaction,
addition of pyrrolidine directly to the toluene / CH3CN process
stream afforded crystalline GDCꢀ0810 pyrrolidine salt in a
92% isolated yield and a 98.9 A % HPLC purity. The purity of
GDCꢀ0810 was further upgraded with a salt break and final
crystallization from MTBE / CH3CN produced the correspondꢀ
ing API free acid in 97% yield and >99 A % HPLC purity.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Scheme 3. Final Deprotection and API Crystallization 1-(4-Bromophenyl)-2-(2-chloro-4-fluorophenyl)butan-1-
Page 4 of 7
1
one (8b). To a reactor under N2 was charged NaH (0.90 kg,
22.5 mol, 310 mol %, 60% dispersion in mineral oil) and THF
(1.25 kg), then heated to 66 ˚C. A solution of 2ꢀ(2ꢀchloroꢀ4ꢀ
fluoroꢀphenyl)acetic acid (8) (1.36 kg, 7.21 mol, 100 mol%),
methyl 4ꢀbromobenzoate (1.71 kg, 7.95 mol, 110 mol%), and
THF (1.70 kg) was then charged to the reactor over 3 h (cauꢀ
tion: gas evolution!). Once the addition was complete, the
reaction mixture was aged for 3.5 h, cooled to 40ꢀ50 ˚C and
EtOH (2.13 kg) was slowly charged to the reactor (caution:
gas evolution!). Iodoethane (2.6 kg, 16.7 mol, 230 mol %) was
then added over 1.5 h at 40–50 ˚C and aged for 12 h. Aqueous
NaOH (1.36 kg, 15% w/w solution) was charged to the reactor
and the reaction mixture was cooled to 15–25 ˚C and aged for
2 h. Aqueous HCl (4.28 kg, 12.3% w/w) was charged to obtain
pH 1–2. MTBE (3.52 kg) was added, the layers were cut and
the bottom aqueous layer was removed. Aqueous Na2CO3 (2 ×
7.48 kg, 17% w/w) was charged over 30 min and aged for an
additional 30 min. The layers were cut and the bottom aqueous
layer was removed. The organic layer was distilled to a miniꢀ
mum stir volume under vacuum at 40 ˚C. DMA (6.3 kg) was
charged, providing a crude DMA solution of 8b (82% yield,
93 A % HPLC purity), which was used directly in the next
2
3
4
5
6
7
8
9
CONCLUSIONS
In conclusion, we have developed an efficient and practical
kilogram scale synthesis of GDCꢀ0810 based on a sequence
involving a highly stereocontrolled enolization of ketone 9
mediated by LiOtꢀBu and crossꢀcoupling of resulting enol
tosylate (E)-10 with NꢀTHPꢀindazoleboronate 11a using
PdCl2(Xantphos) as the preꢀcatalyst. The endgame chemistry
relied on global deprotection using HCO2H / H2SO4, pyrroliꢀ
dine salt formation and salt break. The process provided crysꢀ
talline GDCꢀ0810 API in 40% overall yield from 2ꢀchloroꢀ4ꢀ
fluorophenylacetic acid (8) and >99 A % HPLC purity.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
1
General. All materials were purchased from commercial supꢀ
step: H NMR (500 MHz, DMSOꢀd6) δ 7.82 (d, J = 8.6 Hz,
pliers unless otherwise noted. H and 13C NMR spectra were
2H), 7.70 (d, J = 8.6 Hz, 2H), 7.47 (dd, J = 8.8, 2.7 Hz, 1H),
7.24 (dd, J = 8.8, 6.2 Hz, 1H), 7.17 (td, J = 8.5, 2.7 Hz, 1H),
4.97 (dd, J = 7.8, 6.4 Hz, 1H), 2.05 (sep, J = 14.1, 7.2 Hz, 1H),
1.74 (dt, J = 13.6, 7.4 Hz, 1H), 0.85 (t, J = 7.4 Hz, 3H); 13C
NMR (125 MHz, DMSOꢀd6) δ 198.5, 161.7, 159.8, 135.1,
133.7, 133.1, 133.1, 132.0, 130.6, 130.5, 130.1, 127.5, 117.1,
116.9, 115.2, 115.0, 49.7, 25.4, 11.6; HRMS (APCI) m/z:
calcd for C16H14BrClFO [M+H]+: 354.9901; found: 354.9888
(ꢁ 2.0 ppm).
1
obtained using a Bruker 500 MHz spectrometer, collected at
296K in the solvents indicated. HPLC analysis was performed
on an Agilent 1100 or 1200 series instruments. HRMS data
was acquired on a Thermo Scientific Discovery Orbitrap mass
spectrometer.
(E)ꢀ2ꢀ(2ꢀchloroꢀ4ꢀfluorophenyl)ꢀ1ꢀ(1ꢀ(tetrahydroꢀ2Hꢀpyranꢀ2ꢀ
yl)ꢀ1Hꢀindazolꢀ5ꢀyl)butꢀ1ꢀenꢀ1ꢀyl 4ꢀmethylbenzenesulfonate
((E)ꢀ7). A solution of ketone 6 (500 mg, 1.25 mmol) in THF
(2.5 mL) was added to KOtꢀBu (1.75 mmol, 140 mol%,
weighed in an inert glovebox) in THF (1.25 mL) and stirred
for 30 min at 23 ºC. Ts2O (570 mg, 1.75 mmol, 140 mol%) in
THF (2.5 mL) was added and the mixture was stirred for 30
min. The reaction was quenched with saturated aqueous
NaHCO3 (4 mL) and extracted with MTBE (2 × 4 mL). The
residue was chromatographed on SiO2 using iPrOAc:heptane
as eluent. The collected fractions were concentrated to afford
tert-Butyl
(E)-3-(4-(2-(2-chloro-4-
fluorophenyl)butanoyl)phenyl)acrylate (9). To an inerted
reactor was charged a solution of 8b (2.4 kg @ 25 wt % in
DMA, 0.60 kg, 1.69 mol, 100 mol %). The solution was heatꢀ
ed to 50–60 ˚C and tertꢀbutyl acrylate (0.259 kg, 2.02 mol,
120 mol%) and Pd(dppf)Cl2•DCM (13.5 g, 0.017 mol, 1.0
mol%) were charged. The reaction mixture was degassed with
3 vacuum / nitrogen purge cycles. Triethylamine (205 g, 2.02
mol, 120 mol %) was charged and the reaction mixture was
heated to 110–130 ˚C and aged for ≥2 h. The reaction mixture
was cooled to 40–50 ˚C and EtOH (6.15 kg) was added. Water
(15.0 kg) was charged slowly over 2 h and aged for an addiꢀ
tional 1 h after the addition was complete. The reaction mixꢀ
ture was seeded with 9 (6.0 g) and cooled to 20–30 ˚C over 1 h
and aged for an additional 1 h. The crude solids were filtered
and dried at 45 ˚C to afford crude 9 (0.48 kg (corrected), 87.9
A % HPLC purity). To an inerted 20 L reactor was charged
crude 9 (3.62 kg (corrected)) and heptane (34.4 kg). The batch
was heated to 50–60 ˚C and stirred until all solids were disꢀ
solved. The reaction mixture was treated with activated carbon
(0.37 kg) at 50–60 ˚C, and then filtered. The reaction mixture
was cooled to 25 ˚C over 2 h, then cooled further to 5 ˚C and
aged for an additional 2 h. The solids were filtered and washed
with preꢀcooled heptane (2.0 L, 0–5 ˚C). The solids were dried
under vacuum at 55 ˚C for at least 18 h to give 9 (3.39 kg,
1
(E)ꢀ7 as a white foam (440 mg, 64% yield): H NMR (500
MHz, CDCl3) δ 7.78 (1H, bs, H14), 7.46 (2H, dd, J = 8.3, 1.3
Hz, H26), 7.28 (1H, m, H12), 7.16 (1H, m, H23), 7.03 (1H, dt,
J = 8.5, 2.5 Hz, H2), 7.01ꢀ6.94 (5H, m, H5, H24 and H27),
6.79 (1H, td, J = 8.3, 2.6 Hz, H6), 5.58 (1H, dd, J = 9.7, 2.6
Hz, H17), 4.04 (1H, m, H21’), 3.71 (1H, m, H21”), 2.77 (1H,
dtd, J = 15.1, 7.5, 2.6 Hz, H8’), 2.52 (2H, m, H8” and H18’),
2.25 (3H, s, H29), 2.14 (1H, td, J = 5.7, 2.8 Hz, H19’), 2.02
(1H, m, H18”), 1.75 (2H, m, H19” and H20’), 1.65 (1H, m,
H20”), 0.93 (3H, t, J = 7.6 Hz, H9); 13C NMR (125 MHz,
CDCl3) δ 162.6 160.6 (s, C1), 144.5 (s, C10 and C28), 138.6
(s, C22), 134.5 134.4 (s, C3), 134.2 (d, C14), 134.0 133.9 (s,
C25), 133.2 (s, C4), 133.2 (s, C7), 132.6 (d, C5), 129.1 (d,
C27), 128.0 (d, C26), 127.6 (d, C24), 126.8 (s, C11), 123.8 (s,
C13), 122.4 (d, C12), 117.1 116.9 (d, C2), 114.1 113.9 (d,
C6), 109.2 (d, C23), 85.4 85.3 (d C17), 67.7 (t, C21), 29.5 (t,
C18), 25.1 (t, C8 and C20), 22.7 (t, C19), 21.4 (q, C29), 11.6
(q, C9). Peak assignments were confirmed through COSY,
HSQC and HMBC 2D NMR methods. HRMS (ESI) m/z:
calcd. for C29H29ClFN2O4S [M+H]+: 555.1515; found:
555.1510 (ꢁ 0.9 ppm).
1
64% overall yield and 99.0A% HPLC purity): H NMR (500
MHz, DMSOꢀd6) δ 7.90 (bd, J = 8.5 Hz, 2H), 7.76 (bd, J = 8.5
Hz, 2H), 7.53 (d, J = 16.0 Hz, 1H), 7.44 (dd, J = 8.8, 2.7 Hz,
1H), 7.24 (dd, J = 8.8, 6.2 Hz, 1H), 7.16 (td, J = 8.8, 2.7 Hz,
1H), 6.58 (d, J = 16.1 Hz, 1H), 4.98 (dd, J = 7.8, 6.5 Hz, 1H),
4
ACS Paragon Plus Environment

Page 5 of 7
The Journal of Organic Chemistry
1
2.05 (ddd, J = 13.7, 7.3, 6.5 Hz, 1H), 1.72 (dt, J = 13.7 ,7.8
Hz, 1H), 1.46 (s, 9H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (125
MHz, DMSOꢀd6) δ 197.2, 163.6, 160.1 158.1, 140.4, 137.0,
135.3, 132.1, 132.1, 131.6, 131.6, 128.9, 128.8, 127.0, 126.9,
121.0, 115.4, 115.2, 113.5, 113.4, 78.9, 48.2, 26.1, 23.9, 10.0;
HRMS (APCI) m/z: calcd for C23H25ClFO3 [M+H]+:
403.1471; found: 403.1461 (ꢁ 2.5 ppm).
afford boronate 11a as a white solid (9.77 g, 84% yield): H
NMR (500 MHz, DMSOꢀd6) δ 8.17 (bs, 1H), 8.16 (s, 1H),
7.72 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 8.4, 1.0 Hz, 1H), 5.85
(dd, J = 9.8, 2.6 Hz, 1H), 3.93ꢀ3.84 (m, 1H), 3.74 (ddd, J =
11.4, 8.0, 5.8 Hz, 1H), 2.46ꢀ2.36 (m, 1H), 2.06ꢀ2.00 (m, 1H),
1.96 (dq, J = 13.0, 3.5 Hz, 1H), 1.81ꢀ1.69 (m, 1H), 1.58 (tq, J
= 8.0, 3.9 Hz, 2H), 1.32 (s, 12H); 13C NMR (125 MHz,
DMSO) δ 141.2, 134.7, 131.9, 129.3, 124.5, 121.2, 110.3,
84.5, 84.0, 67.0, 29.4, 25.3, 25.2, 22.7; HRMS (ESI) m/z:
calcd. for C18H25BN2O3 [M+H]+: 329.2031; experimental:
329.2026 (ꢁ 1.5 ppm).
1
2
3
4
5
6
7
8
tert-Butyl
(E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-
(tosyloxy)but-1-en-1-yl)phenyl)acrylate [(E)-10]. To an
inerted 20 L jacketed glass reactor was charged 9 (1.20 kg,
2.98 mol, 100 mol %) and THF (3.20 kg). Lithium tertꢀ
butoxide (3.71 kg, 4.18 mol, 140 mol %, 1.0 M in THF) was
charged at 20–30 ˚C over 30 min. The reaction mixture was
stirred for 30 min and then a solution of pꢀtoluenesulfonic
anhydride (1.36 kg, 4.17 mol, 140 mol %) in THF (6.40 kg)
was added over 30 min while maintaining the internal temperꢀ
ature at 20–25 ˚C. The reaction mixture was aged for 30 min.
The batch was distilled under vacuum at 40–50 ˚C to obtain a
total volume of 6.67 L/kg. MTBE (2.67 kg) was charged and
the reaction mixture was cooled to 0–10 ˚C. Aqueous NaOH
(2.40 kg, 1 M solution) was charged while maintaining the
temperature < 20 ˚C. The reaction mixture was aged for 5 min,
then agitation was stopped and the bottom aqueous layer reꢀ
moved. The organic layer was washed with aqueous NaCl (2 ×
2.88 kg, 23% w/w). The bottom aqueous layer was removed
and then the organic layer was distilled under vacuum to a
minimum stir volume. 1ꢀPropanol (1.93 kg) was charged and
the mixture was again distilled under vacuum to a minimum
stir volume. 1ꢀPropanol (1.93 kg, 1.61 kg/kg) was charged and
the mixture was distilled under vacuum to a minimum stir
volume. 1ꢀPropanol (2.89 kg, 2.41 kg/kg) was charged and
check for removal of THF (< 0.6% w/w) by GC. The batch
was heated at 80–90 ˚C and H2O (1.80 kg, 1.50 kg/kg) was
added. The batch was cooled to 60 ˚C and seeded with (E)-10
(6.0 g) suspended in 1ꢀpropanol (25.0 g). The resulting slurry
was aged for ≥ 30 min, then cooled to 15–25 ˚C over 5 h. The
solids were filtered and the filter cake was washed with a mixꢀ
ture of 1ꢀpropanol (3.52 kg) and H2O (1.62 kg). The solids
were dried under vacuum at 55–65 ˚C to provide enol tosylate
(E)-10 as an offꢀwhite solid (1.30 kg, 78% yield and 99.6 A %
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tertꢀButyl
(E)ꢀ3ꢀ(4ꢀ((E)ꢀ2ꢀ(2ꢀchloroꢀ4ꢀfluorophenyl)ꢀ1ꢀ(1ꢀ
(tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)ꢀ1Hꢀindazolꢀ5ꢀyl)butꢀ1ꢀenꢀ1ꢀ
yl)phenyl)acrylate (12). To an inerted reactor was charged (E)ꢀ
10 (1.20 kg, 2.15 mol, 100 mol %), boronate 11a (0.794 kg,
3.21 mol, 150 mol %), PdCl2(Xantphos) (17.14 g, 0.02 mol,
1.0 mol%) and toluene (3.92 kg). The batch was degassed by
sparging with N2 for ≥ 20 min. To a separate container was
charged K3PO4•H2O (0.783 kg) and H2O (1.50 kg). This soluꢀ
tion was degassed by sparging with N2 for ≥ 20 min, then
transferred into the reactor. The combined reactor contents
were then further sparged with N2 for ≥ 20 min. The reactor
contents were heated to 80–100 ˚C. The reaction mixture was
aged for 4 h, cooled to 20–30 ˚C, and H2O (1.80 kg) was
charged. The layers were cut and the organic layer was
washed with aqueous NaCl (1.44 kg, 23% w/w), then washed
with H2O (1.20 kg). The organic layer was then treated with
Darco KBꢀWJ (0.120 kg) under agitation for ≥ 4 h. The slurry
was filtered and the filter cake was rinsed with toluene (0.836
kg). The combined filtrates were distilled under vacuum at 45–
55 ˚C to a total volume of 4.0 L/kg and stored as a toluene
solution of 12 for the next reaction: 1H NMR (500 MHz,
DMSOꢀd6) δ 8.14 (bs, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.69 (m,
1H), 7.41ꢀ7.33 (m, 5H), 7.28 (dd, J = 8.7, 3.5 Hz, 1H), 7.14
(td, J = 8.5, 2.7 Hz, 1H), 6.94 (m, 2H), 6.36 (d, J = 16.0 Hz,
1H), 5.86 (dd, J = 9.8, 2.5 Hz, 1H), 3.89 (m, 1H), 3.74 (ddd, J
= 11.4, 8.0, 5.9 Hz, 1H), 2.43 (m, 1H), 2.37 (q, J = 7.5 Hz,
2H), 2.05 (m, 1H), 1.98 (m, 1H), 1.75 (m, 1H), 1.59 (dd, J =
8.5, 4.3 Hz, 2H), 1.44 (s, 9H), 0.90 (t, J = 7.5 Hz, 3H); 13C
NMR (125 MHz, DMSOꢀd6) δ 166.0, 162.2, 160.2, 144.7,
143.4, 140.8, 139.0, 138.9, 136.8, 134.9, 134.2, 133.8, 133.7,
133.6, 133.5, 132.5, 130.0, 128.3, 128.0, 124.7, 121.2, 120.0,
117.0, 116.8, 114.7, 114.5, 110.9, 84.5, 80.3, 67.0, 29.4, 28.5,
28.3, 25.2, 22.7, 13.0; HRMS (ESI) m/z: calcd for
C35H37ClFN2O3 [M+H]+: 587.2471; found: 587.2470 (ꢁ 0.2
ppm).
1
HPLC purity): H NMR (500 MHz, DMSOꢀd6) δ 7.61 (m,
2H), 7.45ꢀ7.37 (m, 2H), 7.36 (m, 2H), 7.34 (d, J = 8.2 Hz,
2H), 7.14ꢀ7.08 (m, 2H), 6.90 (m, 2H), 6.42 (d, J = 16.0 Hz,
1H), 2.49 (dq, J = 15, 7.5, 1H), 2.36 (s, 3H), 2.25 (dq, J =
15.0, 7.6 Hz, 1H), 1.46 (s, 9H), 0.76 (t, J = 7.6 Hz, 3H); 13C
NMR (125 MHz, DMSOꢀd6) δ 165.8, 162.7, 160.8, 145.9,
143.5, 143.0, 135.5, 134.4, 134.0, 133.9, 133.45, 133.4, 132.9,
132.9, 130.4, 129.3, 128.4, 127.9, 121.1, 117.4, 117.2, 115.1,
115.0, 80.5, 28.3, 25.0, 21.5, 11.5; HRMS (ESI) m/z: calcd for
C30H30ClFNaO5S [M+Na]+: 579.1384; found: 579.1385 (ꢁ 0.1
ppm).
(E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-
yl)but-1-en-1-yl)phenyl)acrylic acid (GDC-0810, 1). To an
inerted reactor was charged the toluene solution of 12 (1.20
kg, 4.8 L). The temperature was maintained at 10–20 ˚C while
charging HCO2H (1.46 kg), followed by H2SO4 (0.44 kg, 98%
w/w) while maintaining the internal temperature at < 25 ˚C.
The reaction mixture was stirred at 15–25 ˚C for at least 4 h,
then sampled for HPLC analysis. Once complete, the reactor
contents were cooled to 0–10 ˚C and 50 wt % aqueous NaOH
(0.86 kg) was charged while maintaining the temperature at <
25 ˚C. Water (2.40 kg) was added and the mixture was stirred
for ≥ 5 min. Agitation was stopped and the bottom aqueous
layer was removed. The organics were distilled under vacuum
at 40 ˚C to a total volume of 3.42 L/kg. Toluene (2.09 kg) was
charged and the mixture was distilled under vacuum at 40 ˚C
to a total volume of 3.42 L/kg. Toluene (1.67 kg) was charged,
followed by addition of CH3CN (2.83 kg). The reactor conꢀ
1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-indazol-1-ium (11a). A roundꢀbottom
flask was charged with NꢀTHPꢀbromoindazole 11 (10.6 g,
35.6 mmol), bis(pinacolato)diboron (10.8 g, 42.7 mmol, 120
mol%), PdCl2(dppf) (260 mg, 0.36 mmol, 1 mol%), KOAc
(10.5 g, 106.7 mmol, 300 mol%) and toluene (50 mL). The
reaction was sparged with N2 bubbles and then heated at 100
ºC for 20 h. The mixture was cooled to rt, filtered on SiO2, and
the filter cake was washed with toluene (150 mL). The filtrate
was solventꢀswitched to heptane (150 mL) under vacuum and
cooled to 0 ºC for 1 h. The resulting solids were filtered and
washed with heptane (20 mL) and dried under vacuum to
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 7
Copies of NMR spectra and single crystal Xꢀray data for (E)-10.
The Supporting Information is available free of charge on the
ACS Publications website.
tents were heated to 55–65 ˚C and pyrrolidine (132 mL, 1.58
mol) was added. The reaction mixture was seeded (6.0 g) at
55–65 ˚C and aged for at least 10 min. Pyrrolidine (132 mL,
1.58 mol) was charged at 55–65 ˚C and the slurry was aged for
at least 1 h. The reactor contents were cooled to 15–25 ˚C and
aged for at least 1 h. The solids were filtered, washed with
CH3CN (2.83 kg) and dried under vacuum at 20–40 ˚C to give
GDCꢀ0810•pyrrolidine (1.01 kg, 91% yield over two steps,
1
2
3
4
5
6
7
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: gosselin.francis@gene.com
1
98.9 A % HPLC purity): H NMR (500 MHz, DMSOꢀd6) δ
ACKNOWLEDGMENT
8
9
8.10 (d, J = 1.0 Hz, 1H), 7.68 (t, J = 1.1 Hz, 1H), 7.56 (dd, J =
8.5, 1.0 Hz, 1H), 7.37–7.30 (m, 2H), 7.24 (d, J = 8.4 Hz, 2H),
7.19 (dd, J = 8.7, 1.7 Hz, 1H), 7.13 (dt, J = 2.5, 8.5 Hz, 1H),
7.09 (d, J = 15.7 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.29 (d, J =
15.7 Hz, 1H), 3.04–2.93 (m, 4H), 2.38 (q, J = 7.5 Hz, 2H),
1.81–1.70 (m, 4H), 0.90 (t, J = 7.5 Hz, 3H); 13C NMR (126
MHz, DMSOꢀd6) δ 170.6, 162.1, 160.1, 143.3, 141.4, 139.5,
138.3, 138.0, 137.1, 137.0, 134.3, 134.2, 134.1, 133.8, 133.7,
133.7, 133.6, 129.9, 128.0, 127.0, 126.9, 123.3, 120.7, 117.0,
116.8, 114.6, 114.5, 110.7, 44.7, 28.4, 24.7, 13.1; FTꢀIR (cm–
1) ν: 2975, 2930, 2871, 1637, 1540, 1507, 1486, 1374, 1347,
1256, 1197, 992, 939, 896, 851, 804, 725; HRMS (ESI) m/z
calcd for C26H21ClFN2O2 [M + H]+: 447.1270, found 447.1262
(ꢁ 1.8 ppm). To an inerted reactor was charged GDCꢀ
0810•pyrrolidine (1.01 kg, 1.95 mol, 100 mol %), MTBE
(1.48 kg), and 1N aqueous HCl (2.0 kg). The reaction mixture
was stirred at 30–50 ˚C until all solids were dissolved. The
layers were cut and the organic layer was washed with water
(1.18 kg) and then distilled at 60–80 ˚C to a total volume of
1.2 L/kg. The batch was cooled to 40–60 ˚C and charged with
CH3CN (2.29 kg). The reaction mixture was seeded with 1 (25
g) at 40–60 ˚C. The slurry was aged for 2 h and then cooled to
15–25 ˚C over 4 h. CH3CN (3.21 kg) was charged over 2 h and
then the reaction mixture was cooled to –15 to 5 ˚C over 3 h.
The resulting solids were filtered and the filter cake was
washed with CH3CN (0.70 kg) and dried under vacuum at
100–120 ˚C for 24 h to give GDC-0810 (1) as a white solid
(0.80 kg, 92% yield and 99 A % HPLC purity): 1H NMR (500
MHz, DMSOꢀd6) δ 8.11 (1H, d, J = 1.0 Hz, H15), 7.70 (1H, t,
J = 1.1 Hz, H14), 7.57 (1H, d, J = 8.5 Hz, H11), 7.46 – 7.32
(5H, m, H2, H5, H20, and H22), 7.20 (1H, dd, J = 8.5, 1.5 Hz,
H10), 7.14 (1H, td, J = 8.5, 2.7 Hz, H6), 6.96 (2H, d, J = 8.4
Hz, H19), 6.39 (1H, d, J = 16.0 Hz, H23), 2.39 (2H, q, J = 7.5
Hz, H25), 0.91 (3H, t, J = 7.5 Hz, H26); 13C NMR (125 MHz,
DMSOꢀd6) δ 168.0 (s, C24), 162.1 160.2 (s, C1), 144.9 (s,
C18), 143.8 (d, C22), 141.1 (s, C8), 139.5 (s, C12), 138.7 (s,
C7), 136.9 (s, C4), 134.2 (d, C15), 134.0 (s, C9) , 133.8 133.7
(d, C5), 133.6 133.5 (s, C3), 132.6 (s, C21), 130.1 (d, C19),
128.0 (d, C10), 127.9 (d, C20), 123.3 (s, C13), 120.8 (d, C14),
119.3 (d, C23), 117.0 116.8 (d, C2), 114.7 114.5 (d, C6),
110.7 (d, C11), 28.4 (t, C25), 13.1 (q, C26). 168.0 (s, C24),
162.1 160.2 (s, C1), 144.9 (s, C18), 143.8 (d, C22), 141.1 (s,
C8), 139.5 (s, C12), 138.7 (s, C7), 136.9 (s, C4), 134.2 (d,
C15), 134.0 (s, C9) , 133.8 133.7 (d, C5), 133.6 133.5 (s, C3),
132.6 (s, C21), 130.1 (d, C19), 128.0 (d, C10), 127.9 (d, C20),
123.3 (s, C13), 120.8 (d, C14), 119.3 (d, C23), 117.0 116.8 (d,
C2), 114.7 114.5 (d, C6), 110.7 (d, C11), 28.4 (t, C25), 13.1
(q, C26). Peak assignments were confirmed through COSY,
HSQC and HMBC 2D NMR methods. HRMS (ESI) m/z:
calcd for C26H21ClFN2O2 [M + H]+: 447.1270; found:
447.1263 (ꢁ 1.6 ppm).
We acknowledge Dr. Kelly Zhang and Ms. Lulu Dai for analytical
support and Dr. Antonio DiPasquale for Xꢀray crystallographic
analysis (Genentech).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) (a) Nillson, S. Gustafsson, J.ꢀÅ. Estrogen Receptors: Therapies
Targeted to Receptor Subtypes. Clin. Pharm. Ther. 2011, 89, 44–55.
(b) Martinkovich, S.; Shah, D.; Planey, S. L.; Arnott, J. A. Selective
Estrogen Receptor Modulators: Tissue Specificity and Clinical Utiliꢀ
ty. Clin. Inter. Aging 2014, 9, 1437–1452.
(2) (a) Chang, J.; Fan, W. Endocrine Therapy Resistance: Current
Status, Possible Mechanisms and Overcoming Strategies. AntiꢀCancer
Agents in Medicinal Chemistry 2013, 13, 464–475. (b) Khasraw, M.;
Harvey, S. L.; Bell, R. Hormonal Resistance in Breast Cancer: Evolvꢀ
ing Treatment Strategies. Curr. Breast Cancer Res. 2012, 4, 66–74.
(3) Lai, A.; Kahraman, M.; Govek, S.; Nagasawa, J.; Bonnefous,
C.; Julien, J.; Douglas, K.; Sensintaffar, J.; Lu, N.; Lee, K.ꢀj.; Apariꢀ
cio, A.; Kaufman, J.; Qian, J.; Shao, G.; Prudente, R.; Moon, M. J.;
Joseph, J. D.; Darimont, B.; Brigham, D.; Grillot, K.; Heyman, R.;
Rix, P. J.; Hager, J. H.; Smith, N. D. Identification of GDCꢀ0810
(ARNꢀ810), an Orally Bioavailable Selective Estrogen Receptor Deꢀ
grader (SERD) that Demonstrates Robust Activity in Tamoxifenꢀ
Resistant Breast Cancer Xenografts. J. Med. Chem. 2015, 58, 4888–
4904.
(4) (a) Ishiyama, T.; Matsuda, N.; Miyaura, N.; Suzuki, A. Platiꢀ
num(0)ꢀCatalyzed Diboration of of Alkynes. J. Am. Chem. Soc. 1993,
115, 11018–11019. (b) Ishiyama, T.; Matsuda, N.; Murata, M.; Ozaꢀ
wa, F.; Suzuki, A.; Miyaura, N. Platinum(0)ꢀCatalyzed Diboration of
Alkynes with Tetrakis(alkoxo)diborons:ꢂ An Efficient and Convenient
Approach to cisꢀBis(boryl)alkenes. Organometallics 1996, 15, 713–
720.
(5) The synthesis of tetrasubstituted olefins is reviewed in: Flynn,
A. B.; Ogilvie, W. W. Stereocontrolled Synthesis of Tetrasubstituted
Olefins. Chem. Rev. 2007, 107, 4698–4745.
(6) We recently reported on the method scope, structural, mechaꢀ
nistic and computational basis for the exceptionally high selectivity
observed in LiHMDS / Me2EtN mediated enolization of hindered
triaryl ketones: (a) Li, B.; Le, D.; Mack, K.; McClory, A.; Lim, N.ꢀK.;
Cravillion, T.; Savage, S.; Han, C.; Collum, D. B.; Zhang, H.;
Gosselin, F. Highly Stereoselective Synthesis of Tetrasubstituted
Acyclic AllꢀCarbon Olefins via Enol Tosylation and Suzuki–Miyaura
Coupling. J. Am. Chem. Soc. 2017, 139, 10777–10783. (b) Mack, K.;
McClory, A.; Zhang, H.; Gosselin, F.; Collum, D. B. Lithium Hexaꢀ
methyldisilazideꢀMediated Enolization of Highly Substituted Aryl
Ketones: Structural and Mechanistic Basis of the E/Z Selectivities. J.
Am. Chem. Soc. 2017, 139, 12182–12189.
(7) For an alternative route to GDCꢀ0810 involving stereospecific
elimination, see: (a) Lim, N.ꢀK.; Cravillion, T.; Savage, S.; McClory,
A.; Han, C.; Zhang, H.; DiPasquale, A.; Gosselin, F. Org. Lett. 2018,
20, 1114. For a general methodology involving stereospecific synꢀ
eliminations, see: (b) Lim, N.ꢀK.; Weiss, P.; Li, B.; McCulley, C.;
Hare, S.; Bensema, B.; Palazzo, T.; Tantillo, D. J.; Zhang, H.;
Gosselin, F. Synthesis of Highly Stereodefined Tetrasubstituted Acyꢀ
clic AllꢀCarbon Olefins via a SynꢀElimination Approach. Org. Lett.
2017, 19, 6212–6215.
(8) This sequence was based on modification from literature condiꢀ
tions: Ace, K. W.; Armitage, M. A.; Bellingham, R. K.; Blackler, P.
D.; Ennis, D. S.; Hussain, N.; Lathbury, D. C.; Morgan, D. O.;
ASSOCIATED CONTENT
Supporting Information
6
ACS Paragon Plus Environment

Page 7 of 7
The Journal of Organic Chemistry
O’Connor, N.; Oakes, G. H.; Passey, S. C.; Powling, L. C. Developꢀ
ment of an Efficient and Stereoselective Manufacturing Route to
Idoxifene. Org. Proc. Res. Dev. 2001, 5, 479–490.
(13) Both enol tosylate and mesylate were found to be crystalline
solids obtained in good yield and high selectivity for the desired (E)ꢀ
isomer (95:5 and 89:11 respectively). However, enol tosylate proved
vastly superior in terms of performance in the downstream Pd cataꢀ
lyzed crossꢀcoupling step.
(14) For reviews on Suzuki‒Miyaura coupling, see: (a) Miyaura,
N.; Suzuki, A. PalladiumꢀCatalyzed CrossꢀCoupling Reactions of
Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. (b)
Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Arꢀ
yl−Aryl Bond Formation One Century after the Discovery of the
Ullmann Reaction. Chem. Rev. 2002, 102, 1359–1470.
1
2
3
4
5
6
7
8
(9) Hu, H.; Bradley, S. A.; Krishnamurthy, K. Extending the Limꢀ
its of the Selective 1D NOESY Experiment with an Improved Selecꢀ
tive TOCSY Edited Preparation Function. J. Magn. Reson. 2004, 171,
201–206. The other ortho proton on the indazole phenyl ring is posiꢀ
tion Hꢀ24. Due to signal overlap of Hꢀ5 and Hꢀ24, NOE enhancement
of Hꢀ24 from Hꢀ5 was not discernible.
(10) NaH is safely handled through appropriate charge bags and is
approximately 6ꢀfold cheaper than NaHMDS on a mole basis. In
addition, NaH allowed higher volume efficiency for the reaction.
(11) For a review on the Heck reaction, see: Beletskaya, I. P.;
Cheprakov, A. V. The Heck Reaction as a Sharpening Stone of Pallaꢀ
dium Catalysis. Chem. Rev. 2000, 100, 3009–3066.
9
(15) Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)ꢀ
Catalyzed CrossꢀCoupling Reaction of Alkoxydiboron with
Haloarenes: A Direct Procedure for Arylboronic Esters. J. Org. Chem.
1995, 60, 7508–7510.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(12) The corresponding enol triflate was not stable upon storage
and, in our hands, the enol diphenylphosphate was obtained as an oil,
a drawback for purification.
7
ACS Paragon Plus Environment