Synthesis of Highly Stereodefined Tetrasubstituted Acyclic All-Carbon Olefins via a Syn-Elimination Approach

Article abstract of DOI:10.1021/acs.orglett.7b03141

An efficient synthesis of stereodefined tetrasubstituted acyclic all-carbon olefins has been developed via a bis(2,6-xylyl)phosphate formation of stereoenriched tertiary alcohols, followed by in situ syn-elimination of the corresponding phosphates under mild conditions. This chemistry tolerates a wide variety of electronically and sterically diverse substrates and generates the desired tetrasubstituted olefins in high yields and stereoselectivities (>95:5) in most cases. This stereocontrolled olefin synthesis has been applied to the synthesis of anticancer drug tamoxifen in three steps from commercially available 1,2-diphenylbutan-1-one in 97:3 stereoselectivity and 78% overall yield.

Full text of DOI:10.1021/acs.orglett.7b03141

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Synthesis of Highly Stereodefined Tetrasubstituted Acyclic
All‑Carbon Olefins via a Syn-Elimination Approach
Ngiap-Kie Lim,*,† Patrick Weiss,† Beryl X. Li,† Christina H. McCulley,‡ Stephanie R. Hare,‡
Bronwyn L. Bensema,‡ Teresa A. Palazzo,‡ Dean J. Tantillo,*,‡ Haiming Zhang,*,†
and Francis Gosselin†
†Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United
States
‡Department of Chemistry, University of California, Davis, 1 Shields Avenue, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: An efficient synthesis of stereodefined tetrasubstituted acyclic
all-carbon olefins has been developed via a bis(2,6-xylyl)phosphate
formation of stereoenriched tertiary alcohols, followed by in situ syn-
elimination of the corresponding phosphates under mild conditions. This
chemistry tolerates a wide variety of electronically and sterically diverse
substrates and generates the desired tetrasubstituted olefins in high yields
and stereoselectivities (>95:5) in most cases. This stereocontrolled olefin
synthesis has been applied to the synthesis of anticancer drug tamoxifen in three steps from commercially available 1,2-
diphenylbutan-1-one in 97:3 stereoselectivity and 78% overall yield.
tereodefined tetrasubstituted acyclic all-carbon olefins are a
1a−c
Sfundamental structural motif found in pharmaceuticals,
scaffolds for material science, molecular motors, and liquid
crystals.1d−f Tetrasubstituted olefins bearing a triphenylethylene
moiety constitute an important class of molecules critical to the
treatment of breast cancer1a−c and additional diseases such as
multiple sclerosis and infections of fungal, bacterial, and Ebola
virus (Figure 1).2 Several strategies for forming the key CC
double bond are well established,3 including McMurry coupling,4
Wittig and Horner−Wadsworth−Emmons reactions,5 dehydra-
tion of alcohols,6 conjugate addition to activated allenes,7
iterative Heck coupling of acrylates,8 functionalization of
enolates,9 and carbometalation of alkynes.10 However, concerns
olefins remains a stimulating challenge for the synthetic organic
community.3
of stereo- and regioselectivity have limited any specific strategy
During our process development of GDC-0810, a selective
estrogen receptor degrader in clinical studies for the treatment of
metastatic breast cancer,1c we sought to advance an efficient
route to stereodefined tetrasubstituted olefins. Herein we
describe a practical and mild protocol to access highly
stereodefined tetrasubstituted acyclic all-carbon olefins that can
be readily adapted to structural modifications on all four
quadrants (arbitrarily assigned clockwise as A, B, C and D) of
the olefin molecule (eq 1). The synthesis of stereoenriched
tertiary alcohols 2 was readily achieved via aryl Grignard addition
to ketones 1 in excellent yields and diastereoselectivity in most
cases (eq 2).6 In order to confirm the stereochemical
assignments of the tertiary alcohols, we obtained X-ray crystal
structures of most of the alcohol products (see the Supporting
from being fully adopted for general application. Hence, the
preparation of stereodefined tetrasubstituted acyclic all-carbon
Received: October 9, 2017
Figure 1. Tetrasubstituted olefins in various pharmacological targets.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03141
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,
b
a−c
Table 1. Optimization of Syn-Elimination Reaction
Scheme 1. Elimination Reaction Scope of Quadrants A−C
entry
R
temp (°C) conv (%) 3a (A%) Z/E ratio
1
2
3
4
5
6
C(O)t-Bu
150
150
150
150
45
<5
30
<5
22
68
72
88
92
35
<5
16
<5
17
59
72
84
91
37
93:7
CO2t-Bu
98:2
C(O)NMe2
SO2NMe2
P(O)(OPh)2
P(O)(O-2,6-xylyl)2
P(O)(O-2,6-xylyl)2
H
92:8
84:16
89:11
96:4
45
c
d
7
45
98:2
e
8
f
45
67:33
57:43
9
H
45
a
Reactions were performed with alcohol 2a, KHMDS (3.0 equiv),
PhEt (5.0 mL/mmol), and electrophile RCl (1.5 equiv) except for
b
entry 2 where Boc2O (1.5 equiv) was employed. Conversion, A%,
c
and Z/E ratio were determined by HPLC analysis. KH (3.0 equiv),
bis(2,6-xylyl)phosphoryl chloride (1.5 equiv) in dioxane (5.0 mL/
d
e
mmol). Isolated yield. Burgess reagent (1.5 equiv) was employed.
f
Martin sulfurane (1.5 equiv) was employed.
Information). We then investigated the syn-elimination of these
substrates via direct derivatization, first using alcohol 2a as a
model substrate (Table 1). Elimination of the pivalate of alcohol
2a did generate tetrasubstituted olefin 3a in a 93:7 Z/E ratio;
however, the reaction required very high temperature and the
conversion was low (Table 1, entry 1). Similarly, the
corresponding carbonate, carbamate, and sulfamate also required
harsh conditions to afford the elimination product (Table 1,
entries 2−4). To our pleasant surprise, alcohol 2a, upon
treatment with diphenylphosphoryl chloride and KHMDS,
formed predominantly the Z olefin isomer 3a in an 89:11 Z/E
ratio at a more practical 45 °C (Table 1, entry 5). Further
modifying the phosphate to bis(2,6-xylyl)phosphate and
employing potassium hydride as the base in dioxane led to the
formation of the tetrasubstituted olefin 3a in 98:2 Z/E ratio and
84% isolated yield (Table 1, entries 6 and 7). It is worth
mentioning that the direct dehydration using Burgess reagent11a
or Martin sulfurane11b without KHMDS produced unsatisfactory
conversion and Z/E ratio (Table 1, entries 8 and 9).
With optimized elimination conditions in place, we first
explored the scope and limitations of varying substituents in
quadrants A, B, and C (Scheme 1). In quadrant A, the
elimination reaction to produce olefins 3 occurred with markedly
high stereoselectivity (96:4−98:2) and yield (74−84%)
regardless of variation of electronic (3a vs 3b) and steric (3c
vs 3d) properties of groups or possession of heterocyclic
functionality (3d). Similarly, varying the electronic properties of
groups in quadrant B did not have a significant impact on the
stereoselectivity (3e vs 3f and 3h). However, when a larger
isopropyl group was installed in quadrant B, the stereoselectivity
suffered a slight loss to 91:9 (3g). Quadrant C is more sensitive to
both electronic and steric impacts. For example, the elimination
reaction was essentially nonselective when an electron-rich
substituent 4-MeOC6H4 was placed in quadrant C, resulting in a
45:55 mixture of E/Z isomers (3i), while electron-deficient
substituents in quadrant C (4-FC6H4 and 4-pyridyl) continued
to generate excellent stereoselectivity (97:3−98:2) in formation
of the olefin products (3j and 3l). When quadrant C was
a
All reactions were performed with KH (3.0 equiv) and bis(2,6-
xylyl)phosphoryl chloride (1.5 equiv) in dioxane (5.0 mL/mmol) at 45
°C, unless otherwise indicated in the SI. The number in parentheses is
b
the dr of the starting alcohol. Measured stereoisomer ratio by HPLC.
c
d
Isolated yield. Assigned stereochemistry confirmed by X-ray
crystallographic analysis.
substituted with a bulky 2-tolyl group, the stereoselectivity of the
elimination reaction again deteriorated, giving an 82:18 E/Z ratio
of the olefin products (3k).
We subsequently evaluated the substituent scope and
limitations of quadrant D (Scheme 2). Elimination of the
corresponding bis(2,6-xylyl)phosphates derived from alcohols
2m−u to olefins 3m−u is noticeably influenced by both steric
and electronic components of the substituents, as evident by
lower Z/E ratios observed for products 3n and 3s, which bear
electron-rich 4-MeOC6H4 and 3-thienyl moieties, and 3r which
contains a bulky 2-tolyl group. We were nevertheless encouraged
to discover that the remaining substrates bearing diverse
functionalities displayed high stereoselectivity (≥95:5). Hence,
selective elimination via phosphates12 can be readily extended to
a diverse scope of substrates. Furthermore, X-ray crystal
structures of several crystalline olefin products not only
confirmed our stereochemical assignments but also consistently
pointed to a predominant syn-elimination process (see the
Supporting Information).
B
DOI: 10.1021/acs.orglett.7b03141
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a−c
Scheme 2. Elimination Reaction Scope of Quadrant D
Figure 3. Structures along the reaction coordinate for syn-elimination of
bis(2,6-xylyl)phosphate 4. Geometries for TSS for P−O bond cleavage,
carbocation−phosphate complex, and TSS for deprotonation (selected
distances in Å) and relative free energies (kcal/mol) are shown; note
that the TSSs are only TSSs on the potential energy surface, not the free
energy surface.
a
All reactions were performed with KH (3.0 equiv) and bis(2,6-
xylyl)phosphoryl chloride (1.5 equiv) in dioxane (5.0 mL/mmol) at 45
°C, unless otherwise indicated. The number in parentheses is the dr of
b
c
the starting alcohol. Measured Z/E ratio by HPLC. Isolated yield.
d
Assigned stereochemistry confirmed by X-ray crystallographic
subjecting alcohol 2u with an electron-deficient 4-pyridyl
substituent in quadrant D to the elimination conditions. The
X-ray crystal structure of 4 (Figure 2) shows a syn relationship
between the phosphate and the benzylic proton, consistent with
a syn-elimination pathway occurring via discrete phosphate
intermediate. This phosphate species then could undergo a
further elimination reaction upon heating at 70 °C, producing
the tetrasubstituted olefins in 97:3 Z/E ratio and 77% yield (3u).
To demonstrate the synthetic utility of our chemistry, we
applied the phosphate elimination strategy to the synthesis of
tamoxifen (Scheme 3).13 Commercially available ketone 1,2-
diphenylbutan-1-one was treated with 4-iodophenylmagnesium
iodide, producing alcohol 2v with 98:2 dr in 95% yield. Alcohol
2v was then readily transformed to olefin 3v in high yield (85%)
and Z/E selectivity (97:3) using slightly modified phosphate
elimination conditions.14 Subsequent copper-catalyzed C−O
coupling with N,N-dimethyl-2-hydroxyethylamine furnished the
target tamoxifen in 96% yield and with no erosion of the Z/E
ratio.
e
f
analysis. Reaction performed at 80 °C. Reaction performed at 70 °C.
Figure 2. X-ray structure of bis(2,6-xylyl)phosphate 4.
Scheme 3. Highly Stereoselective Synthesis of Tamoxifen
We conducted DFT calculations on the elimination of 4
(Figure 2) to further elucidate the mechanism of the elimination
reaction. We were unable to locate transition-state structures
(TSSs) for concerted syn-elimination, likely a result of the very
crowded core of such putative TSSs and the tight grouping of
multiple aromatic rings leading to atypical reactivity.15 Instead,
two-step (E1) elimination was predicted to dominate, but the
intermediate complex in this process is predicted to reside on a
flat region of the potential energy and free energy surfaces
(Figure 3); effectively, the reaction is concerted but the
dissociation and deprotonation events occur very asynchro-
By performing the phosphorylation reaction at 23 °C, we were
able to isolate phosphate intermediate 4 in 61% yield by
C
DOI: 10.1021/acs.orglett.7b03141
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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than dissociation of the complex and stereochemistry is expected
not to be scrambled.
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In conclusion, we have developed a stereoselective synthesis of
tetrasubstituted acyclic all-carbon olefins by elimination of in situ
produced bis(2,6-xylyl)phosphates from stereoenriched tertiary
alcohols. The synthetic utility of this chemistry was further
demonstrated by a highly stereoselective three-step synthesis of
tamoxifen from 1,2-diphenylbutan-1-one in 97:3 Z/E selectivity
and 77% overall yield. Our computational studies indicate that
the elimination reaction involves a stepwise or concerted/
asynchronous syn-elimination that preserves stereochemical
information because the lifetime of the carbocation−phosphate
complex is exceedingly short. We believe that the highly
stereoselective synthesis of tetrasubstituted acyclic all-carbon
olefins under mild conditions disclosed here will provide a very
useful synthetic tool for organic chemists.
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03141.
(8) He, Z.; Kirchberg, S.; Frohlich, R.; Studer, A. Angew. Chem., Int. Ed.
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Experimental details and 1H and 13C NMR spectra (PDF)
Computational data (PDF)
X-ray crystallographic data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: lim.ngiapkie@gene.com.
*E-mail: djtantillo@ucdavis.edu.
*E-mail: zhang.haiming@gene.com.
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ORCID
Dean J. Tantillo: 0000-0002-2992-8844
Haiming Zhang: 0000-0002-2139-2598
Francis Gosselin: 0000-0001-9812-4180
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Drs. Xin Linghu, Filip Petronijevic, Andrew McClory,
and Chong Han (Genentech, Inc.) for helpful discussions, Lulu
Dai and Dr. Kenji Kurita (Genentech, Inc.) for supporting the
HPLC and HRMS collection, and Dr. Antonio DiPasquale
(Genentech, Inc.) for performing X-ray crystallographic analyses.
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