Synthesis of a selective estrogen receptor degrader via a stereospecific elimination approach

Article abstract of DOI:10.1021/acs.orglett.8b00035

An efficient synthesis of a selective estrogen receptor degrader, GDC-0810, bearing a challenging stereodefined (E)-tetrasubstituted all-carbon olefin core, is reported. The described synthetic route involves a highly diastereoselective addition of an ary

Full text of DOI:10.1021/acs.orglett.8b00035

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of a Selective Estrogen Receptor Degrader via a
Stereospecific Elimination Approach
Ngiap-Kie Lim, Theresa Cravillion,* Scott Savage, Andrew McClory, Chong Han,* Haiming Zhang,
Antonio DiPasquale, and Francis Gosselin
Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United
States
*
S Supporting Information
ABSTRACT: An efficient synthesis of a selective estrogen
receptor degrader, GDC-0810, bearing a challenging stereo-
defined (E)-tetrasubstituted all-carbon olefin core, is reported.
The described synthetic route involves a highly diastereose-
lective addition of an arylmagnesium reagent 3a to ketone 4,
yielding the key tertiary alcohol 2a in >99:1 dr. The
corresponding tert-butyl carbonate derivative was identified
among other leaving groups to provide the desired olefin geometry in a 98:2 E/Z ratio via a concerted elimination. A four-step
telescoped process was then developed starting from the tertiary alcohol 2a to produce GDC-0810 API as a pyrrolidine salt in
70% yield.
elective estrogen receptor modulators and degraders
Scheme 1. Retrosynthetic Analysis
S
(SERM/SERD) represent an important class of compounds
for the treatment of estrogen receptor positive (ER+) breast
1
2
cancer. Inspired by the first-in-class tamoxifen, an approved
therapeutic agent for the treatment and prevention of breast
3
cancer, there have been extensive discovery chemistry efforts
focusing on the development of the next generation SERM/
4
SERD therapy. A common structural feature of these
compounds is a tetrasubstituted all-carbon olefin core that
often poses a synthetic challenge with respect to control of regio-
5
and stereochemistry. GDC-0810 is a SERD currently in clinical
development for the treatment of ER+ breast cancer (Figure 1).
condensation of the 5-indazolyl methyl ester 5 and phenylacetic
acid 6.
The synthesis of the 5-indazolyl ketone 4 is depicted in
Scheme 2. Commercially available 5-bromoindazole 7 was
protected with 3,4-dihydro-2H-pyran to selectively form the
Figure 1. Structure of SERD GDC-0810 (1).
Scheme 2. Synthesis of 5-Indazolyl Ketone 4
The medicinal chemistry synthesis of GDC-0810 suffered from
6
several liabilities precluding its use on large scale. In this paper,
we demonstrate efficient access to the challenging tetrasub-
stituted olefin core through a highly stereocontrolled syn-
7
elimination approach.
Our retrosynthetic analysis is shown in Scheme 1. We
envisioned that the tetrasubstituted olefin found in GDC-0810
(
1) could be accessed via a concerted elimination of tertiary
alcohol derivative 2. The corresponding tertiary alcohol would be
generated via a diastereoselective addition of arylmagnesium
species 3a to ketone 4 consistent with the Felkin−Anh model. 5-
Indazolyl ketone 4 would be prepared from Claisen
8
Received: January 4, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00035
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
corresponding 1-THP-indazole 8 followed by Pd-catalyzed
carbonylation to give methyl ester 5 in 74% yield over two
steps. Following a literature procedure, formation of the sodium
Table 1. Optimization of Arylmagnesium Addition to Ketone
4
9
dianion of phenylacetic acid 6 using NaHMDS at −25 °C
followed by addition of methyl ester 5 in THF afforded ketone 9
in 66% isolated yield. Subsequent α-alkylation of ketone 9 with
iodoethane and potassium tert-butoxide in THF yielded key
intermediate 4 in 67% yield.
With ketone 4 in hand, we began to investigate the synthesis of
the tertiary alcohol 2a via reaction with functionalized
10
arylmagnesium reagent 3a. trans-Iodocinnamate 3b underwent
halogen−magnesium exchange with either i-PrMgCl or i-
PrMgCl·LiCl at −20 °C to give arylmagnesium 3a (Scheme 3).
Scheme 3. Synthesis of Arylmagnesium Reagent 3a
a
b
entry
additive (mol %)
temp (°C)
conv (%)
2a (%)
1
2
3
4
5
6
7
8
9
none
none
0
20
0
74
87
65
33
73
76
69
84
96
66
57
54
33
70
59
57
72
76
CeCl (140)
3
10a (140)
10b (140)
10b (140)
10c (140)
10d (140)
10d (140)
0
0
20
0
0
Careful examination of the impurity profile of this reaction
revealed two major impurities with the proposed structures
shown in Scheme 3 on the basis of HRMS analysis. Impurity 3c
20
a
Determined on the basis of consumption of ketone 4 by quantitative
HPLC analysis against a reference standard. Quantitative assay yield
based on HPLC analysis of the organic layer after aqueous workup.
b
(
ca. 10 A % HPLC) stemmed from a 1,4-addition of i-PrMgCl to
cinnamate 3b. Phenol 3d (5−10 A % HPLC) was presumed to be
a side product from oxidation of arylmagnesium reagent 3a.
11
yield of 2a (Table 1, entries 8 and 9). The reaction proceeded
with high stereoselectivity producing the product 2a with >99:1
diastereomeric ratio that was confirmed by HPLC analysis.
Given the formation of these impurities, trans-iodocinnamate
b and i-PrMgCl·LiCl were used in slight excess (140 mol % of
3
15
each) relative to ketone 4 to form the arylmagnesium reagent 3a
for the addition reaction. Under these conditions at 0 °C, only
Based on X-ray crystallographic analysis of 2a, we found the
relative configuration of the tertiary alcohol product to be
consistent with predictions based on the Felkin−Anh model for
74% conversion of ketone 4 could be achieved with a 66% assay
yield of desired product 2a as determined by quantitative HPLC
analysis (Table 1, entry 1). Increasing the reaction temperature
to 20 °C improved the conversion to 87%, but the yield of 2a
diminished to 57% (Table 1, entry 2). The incomplete
conversions under these conditions suggested a potential
stability issue with the arylmagnesium reagent 3a, which was
further evaluated at different temperatures. At 0 °C, 3a was found
to display poor stability with approximately 20% decomposition
within a few hours based on quantitative HPLC analysis. A
solvent screen was conducted to evaluate if any improvement to
stability and, hence, yield could be gained, however THF proved
to be the superior solvent. Further reducing the reaction
temperature to −20 °C also offered no advantage to the stability
of 3a and displayed unacceptably slow rate of reaction. Next, we
8
carbonyl additions (Figure 2).
12
evaluated a number of additives including CeCl , TMEDA
3
1
3
(
10a), DME (10b), diglyme (10c), and bis(2-dimethylami-
Figure 2. Molecular structure of tertiary alcohol 2a with 50% probability
ellipsoids.
14
noethyl) ether (10d) in an effort to improve the stability of 3a.
Additives such as CeCl and TMEDA led to incomplete
halogen−metal exchange and formation of multiple new
impurities (Table 1, entries 3 and 4). The runs using additives
3
We next investigated the derivatization and stereocontrolled
elimination of tertiary alcohol 2a with the objective to develop a
scalable process affording a high E/Z ratio of the tetrasubstituted
olefin 11, and ultimately GDC-0810, from a concerted syn-
elimination manifold. A number of derivatives of tertiary alcohol
1
0b and 10c did not show much improvement compared to the
ones without additives at either 0 or 20 °C (Table 1, entries 5−
). However, bis(2-dimethylaminoethyl)ether (10d) was found
to improve the stability of the resulting arylmagnesium reagent
a presumably by moderating the reactivity through the
7
16
7b
17
18
2a including imidates, esters, carbonates, carbamates, and
9
3
phosphates were readily prepared using NaHMDS or KHMDS
14
formation of a chelating magnesium complex. As a result, we
and evaluated for the key elimination step. Among those, esters,
carbonates, and carbamates were found to be promising and
were able to achieve 96% conversion at 20 °C with a 76% assay
B
DOI: 10.1021/acs.orglett.8b00035
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
selected for further examination. In contrast to our recent report
conducted at 130 °C or lower, while maintaining reasonable rate
of elimination, and obtain the tetrasubstituted olefin 11 in a >
96:4 E/Z ratio and a high yield. We next evaluated the other two
lead families of leaving groups: carbamates and carbonates. In
contrast to the ester case, the nonacidic byproducts from
elimination of carbonates and carbamates did not have any
negative impact on the E/Z ratio of the resulting tetrasubstituted
olefin (Table 2, entries 7 and 8), and therefore, base was not
needed in these cases. The carbamates also required high
temperature to maintain reasonable rate of elimination
exemplified by the case of dimethyl carbamate 2d (Table 2,
entry 6). Gratifyingly, carbonate derivatives showed promise
with respect to the minimum reaction temperature. The methyl
carbonate 2e underwent elimination at 110 °C, albeit with only a
of highly stereoselective syn-elimination via a phosphate
1
9
derivative, diphenyl phosphate 2i (see Scheme 1, compound
, where R = P(O)(OPh) ) was found to be unstable,
2
2
spontaneously eliminating even at −30 °C to generate the olefin
in poor stereoselectivity (E/Z = 2:1). In addition, preparation of
20
the trichloroacetimidate of 2a suffered from poor conversion
and low product yield, and thus attempts to synthesize this
compound were abandoned.
In agreement with the moderate E/Z ratio reported in the
9
literature for the concerted syn-elimination of the ester
derivative of a tertiary alcohol, we observed a 90:10 E/Z ratio
when pivalate 2b was subjected to the elimination conditions at
1
50 °C using HMDS as the base and xylene as the solvent (Table
2, entry 1). In the case of an acyl leaving group, addition of base
9
2:8 E/Z ratio (Table 2, entry 8). Examination of other leaving
groups including i-Bu (2f), i-Pr (2g), and t-Bu (2h) in the
carbonate family revealed a correlation between the increased
steric hindrance of the leaving groups and the higher elimination
temperature required, although fortunately all were optimized to
achieve good conversion at no higher than 130 °C (Table 2,
entries 8−11). The highest selectivity of the desired E-isomer
a
Table 2. Elimination of Tertiary Alcohol Derivatives
(
96:4) was achieved with the tert-butyl carbonate 2h, and this
could further be increased to 97:3 by switching the solvent from
anisole to ethylbenzene (Table 2, entry 12). By lowering the
reaction temperature further to 110 °C, we were able to obtain
the desired tetrasubstituted olefin 11 in 91 A % HPLC and a 98:2
E/Z ratio from 2h at the expense of a longer reaction time of 48 h
(
Table 2, entry 13).
In order to gain a preliminary understanding of the elimination
mechanism, we compared the rate of elimination of tert-butyl
carbonate 2h with the corresponding deuterium-labeled 2h in a
competition experiment and observed a secondary kinetic
15
isotope effect (KIE, k /kD = 1.3). Although the observed
H
KIE does not support a concerted syn-elimination pathway, it is
22
consistent with an asynchronous concerted E1 elimination
pathway that we proposed for the synthesis of all-carbon
tetrasubstituted olefins via elimination of phosphates supported
19
by DFT calculations. Basically, the dissociation step to form a
stabilized carbocation is followed by a very fast deprotonation
step with stereochemistry scrambling minimized.
With the optimal tert-butyl carbonate leaving group identified,
we further developed a four-step telescoped process from tertiary
alcohol 2a to the pyrrolidine salt of GDC-0810 (Scheme 4). The
derivatization of 2a was conducted in ethylbenzene using
a
Reaction conditions: 2b−h (0.150 mmol, 100 mol %), base (300 mol
b
(Boc) O and NaHMDS. Upon reaction completion, the
%
), solvent (30 mL/g). Based on HPLC analysis.
2
resulting mixture containing product 2h was heated to 130 °C
in the same pot to initiate the elimination without any workup.
The elimination was found to perform consistently using crude
vs purified 2h, providing the desired tetrasubstituted olefin 11 in
an E/Z ratio of 97:3. Subsequent global deprotection using
was required to neutralize the carboxylic acid byproduct and
prevent isomerization of the desired olefin product (Table 2,
entry 2). We further optimized the reaction conditions in a high-
throughput experimentation approach. From this screen, the
optimal conditions were identified as potassium carbonate and
anisole providing a significantly higher E/Z ratio of 97:3 (Table
21
H SO in conjunction with formic acid as a cation scavenger,
2
4
followed by pyrrolidine salt formation and final crystallization
yielded GDC-0810 pyrrolidine salt in 70% overall yield with a
2
, entry 3). Under these conditions, complete consumption of
9
8:2 E/Z ratio. The absolute stereochemistry of GDC-0810 was
the starting material pivalate was achieved at 150 °C after 24 h,
but only 56% conversion was observed after 40 h at 130 °C
unambiguously assigned by single-crystal X-ray diffraction
(Figure 3).
(
Table 2, entry 4). Similarly, the high temperature of 150 °C was
needed to eliminate other ester derivatives such as acetate 2c
Table 2, entry 5). Although we had obtained good selectivity,
In conclusion, we have identified an efficient route to GDC-
0810 API that features a highly diastereoselective Grignard
reaction of ketone 4 to provide the tertiary alcohol 2a followed by
a syn-elimination of tert-butyl carbonate derivative 2h to afford
the (E)-tetrasubstituted olefin core with excellent stereocontrol.
We also developed and demonstrated a telescoped process at
(
the required high temperature was at the edge of our desired
operating range for the reaction to maintain reproducible
performance during scale-up. Our optimization work then
focused on developing elimination conditions that could be
C
DOI: 10.1021/acs.orglett.8b00035
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthesis of 1·Pyrrolidine via a Telescoped
Sequence
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Kelly Zhang, Ms. Lulu Dai, and Ms. Midco Tsang
for analytical support, Dr. Sarah Robinson and Mr. Gilbert
Fernandez for their help with NMR and HRMS, and Dr. Joseph
Lubach and Ms. Rebecca Rowe for collection of mp data
(
Genentech, Inc.).
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(
ASSOCIATED CONTENT
Supporting Information
■
(
7
(
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00035.
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Experimental procedures, characterization data, and H
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AUTHOR INFORMATION
Corresponding Authors
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*
*
E-mail: cravillion.theresa@gene.com.
E-mail: han.chong@gene.com.
ORCID
2
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A. Concerted Organic and Bioorganic Mechanisms; CRC Press: Boca
Raton, 2000. (c) Dewar, M. J. S. J. Am. Chem. Soc. 1984, 106, 209.
Chong Han: 0000-0002-2863-3921
Haiming Zhang: 0000-0002-2139-2598
Francis Gosselin: 0000-0001-9812-4180
D
DOI: 10.1021/acs.orglett.8b00035
Org. Lett. XXXX, XXX, XXX−XXX