High Trans Kinetic Selectivity in Ruthenium-Based Olefin Cross-Metathesis through Stereoretention

Article abstract of DOI:10.1021/acs.orglett.6b00031

The first kinetically controlled, highly trans-selective (>98%) olefin cross-metathesis reaction is demonstrated using Ru-based catalysts. Reactions with either trans or cis olefins afford products with highly trans or cis stereochemistry, respectively. This E-selective olefin cross-metathesis is shown to occur between two trans olefins and between a trans olefin and a terminal olefin. Additionally, new stereoretentive catalysts have been synthesized for improved reactivity. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.6b00031

Letter
pubs.acs.org/OrgLett
High Trans Kinetic Selectivity in Ruthenium-Based Olefin Cross-
Metathesis through Stereoretention
†
‡
†
,‡
Adam M. Johns, Tonia S. Ahmed, Bradford W. Jackson, Robert H. Grubbs,*
,†
and Richard L. Pederson*
‡The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering. California
Institute of Technology, Pasadena, California 91125, United States
†Materia, Inc., Pasadena, California 91107, United States
*
S Supporting Information
ABSTRACT: The first kinetically controlled, highly trans-
selective (>98%) olefin cross-metathesis reaction is demon-
strated using Ru-based catalysts. Reactions with either trans or
cis olefins afford products with highly trans or cis stereo-
chemistry, respectively. This E-selective olefin cross-metathesis
is shown to occur between two trans olefins and between a
trans olefin and a terminal olefin. Additionally, new stereo-
retentive catalysts have been synthesized for improved
reactivity.
ransition-metal-catalyzed olefin metathesis is widely
T
accepted as a powerful synthetic methodology for the
1
construction of carbon−carbon double bonds. Broad functional
group tolerance and straightforward implementation have
allowed for the application of this technology to a variety of
1
a
Figure 2. Stereoselective ethenolysis affording E-olefins.
fields. In recent years, syntheses of well-defined catalysts and
detailed mechanistic studies have resulted in Ru-, W-, and Mo-
based complexes capable of Z-selective olefin metathesis.
2
3
7
Birch-type reductions and Wittig olefinations with stabilized
ylides ), but most suffer from limited substrate compatibility, the
8
Mechanistically similar, each complex is posited to afford cis-
olefins by sterically controlling the geometry of substituent4s
decorating the key metallacyclobutane intermediate (Figure 1).
need for specialized substrates, or the generation of stoichio-
metric amounts of waste. An important advance was the
discovery of an efficient two-step transformation composed of
catalytic trans-hydrosilylation of an alkyne followed by mild
9
protodesilylation. Subsequent improvements have afforded the
direct semihydrogenation of alkynes to E-alkenes catalyzed by a
1
0
11
frustrated Lewis pair, an acridine-based PNP iron complex, or
12
an in situ mixture of Cp*Ru(COD)Cl/AgOTf. Though each of
these systems require an appropriate alkyne, Cp*Ru(COD)Cl/
AgOTf has been demonstrated to tolerate a variety of reducible
functionalities.
Figure 1. Key steric interactions in theorized metallocyclobutane
intermediates resulting in Z-selectivity.
During the course of internal investigations with dithiolate-
ligated ruthenium complexes (Figure 3), we observed that they
were competent for transformations with E-olefins in contrast to
other Z-selective catalysts. In fact, reactions of E-olefins afforded
E-products in high stereopurity. Herein we report the first
kinetically controlled, highly trans-selective olefin cross-meta-
thesis.
Catalyst 1 was reacted with cis and trans isomers of 5-
tetradecene (5C14) independently (Table 1). Unexpectedly,
after 2 h at 40 °C, reactions of each starting material (>98%
Though trans-olefins are usually thermodynamically preferred
to cis-olefins, kinetically E-selective olefin metathesis remains
challenging. Allowing metathesis reactions to achieve equili-
5
brium affords trans-enriched olefins that can subsequently be
“
purified” by Z-selective ethenolysis/alkenolysis to afford trans-
6
olefins in high stereopurity (Figure 2). While products are
accessible in high purity, utilizing an equilibrium mixture of olefin
as starting material limits the overall yield of the transformation.
Furthermore, alkenolysis/ethenolysis introduces an additional
purification step.
2g
Alternate methods for the stereoselective preparation of trans-
olefins include well-established organic transformations (e.g.,
Received: January 5, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00031
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
subsequently examined (Table 2). Catalyst 2 was remarkably
efficient at catalyzing the self-metathesis of cis-methyl 9-
octadecenoate as a 0.01 mol % (100 ppm) loading afforded an
equilibrium distribution of product within 2 h with excellent
stereoretention (>99% Z) (entry 1). Under these same
conditions, no reaction was observed with trans-methyl 9-
octadecenoate (entry 2). Catalyst 1 (0.5 mol %) only afforded
2
0% conversion of cis-methyl 9-octadecenoate and failed to
afford any reaction with trans-methyl 9-octadecenoate after 2 h
entries 3 and 4). Fortunately, increasing the catalyst loading
restored reactivity with trans-methyl 9-octadecenoate (entries
(
5
−7), and after 20 h, 1 (7.5 mol %) afforded a near-equilibrium
13
distribution of products with good stereoretention (96% E).
The small amount of erosion in E-selectivity after prolonged
reaction times may be attributed to catalyst decomposition.
The disparity in the reactivity between the cis and trans isomers
was also observed during investigations into the cross-metathesis
of matched stereoisomers of 4-octene and 1,4-diacetoxy-2-
butene (Table 3). Contacting a mixture of cis-1,4-diacetoxy-2-
butene and cis-4-octene (4:1) with 1 (3.0 mol %) afforded cis-2-
hexenyl acetate in 91% yield (>99% Z) (entry 1). Reactions
between trans-1,4-diacetoxy-2-butene and trans-4-octene were
considerably slower (entries 2 and 3), but after 72 h, a mixture of
trans-1,4-diacetoxy-2-butene and trans-4-octene (4:1) with 1
Figure 3. Ruthenium-based metathesis catalysts in this study.
a
Table 1. Self-Metathesis of 5-Tetradecene
5C14
% 5C14 (Z/E)
%5C10 (Z/E)
%9C18
>
>
98% cis
50 (97/3)
54 (4/96)
25 (97/3)
23 (5/95)
25
23
(
7.5 mol %) afforded trans-2-hexenyl acetate in 47% yield (>99%
E).
Though transformations possessed high levels of stereo-
98% trans
a
General conditions: 5-tetradecene (0.150 mL, 0.588 mmol), 1 (4.5
mg, 0.0059 mmol), 1 mL of THF, 40 °C, 2 h. Yields and
stereoselectivities were determined by gas chromatography.
retention, the prolonged reaction times and elevated catalyst
loadings required for substrates with trans stereochemistry
warranted an improved catalyst. Inspired by the lack of reactivity
14
stereoisomerically pure) catalyzed by 1 mol % of 1 reached a
near-equilibrium distribution of products while retaining the
stereochemistry of the starting material in high fidelity.
Interested in expanding the substrate scope and improving
catalyst activity, the self-metathesis of methyl 9-octadecenoate
between 2 and trans substrates, and in accord with the
proposed model (vide infra), we sought to examine the effect of
reducing the steric bulk of the NHC ligand. Catalysts 3 and 4
were prepared, providing examples where o-methyl groups on
the mesityl ring of the NHC ligand in 1 have been replaced with
smaller fluorine atoms.
(MO) catalyzed by 1 and 2 (the sIPr analogue of 1) was
a
Table 2. Self-Metathesis of Methyl Oleate
c
c
d
e
entry
1
Ru (mol %)
MO
time (h)
0.5
% MO (Z/E)
% DE (Z/E)
% 9C18 (Z/E)
2 (0.01)
>99% Z
>97% E
>99% Z
64 (>99/1)
53 (>99/1)
18 (>99/1)
23 (>99/1)
18 (>99/1)
24 (>99/1)
1
.5
2
b
b
b
51 (>99/1)
24 (>99/1)
24 (>99/1)
f
f
2
3
2 (0.01)
1 (0.5)
0.5
100 (<1/99)
100 (<1/99)
100 (<1/99)
90 (>99/1)
84 (>99/1)
80 (>99/1)
100 (<1/99)
98 (<1/99)
92 (<1/99)
93 (<1/99)
72 (1/99)
ND
ND
f
f
1
.5
2
ND
ND
f
f
ND
ND
0.5
5 (>99/1)
8 (>99/1)
10 (>99/1)
5 (>99/1)
8 (>99/1)
10 (>99/1)
1
.5
2
f
f
4
5
1 (0.5)
1 (2.5)
>97% E
>97% E
2
ND
ND
4
1 (<1/99)
4 (<1/99)
3 (<1/99)
14 (3/97)
10 (<1/99)
1 (<1/99)
4 (<1/99)
3 (<1/99)
14 (3/97)
10 (<1/99)
2
0
4
0
4
0
6
7
1 (5.0)
1 (7.5)
>97% E
>97% E
2
80 (<1/99)
b
b
b
2
51 (4/96)
24 (4/96)
24 (4/96)
a
General conditions: methyl-9-octadecenoate (0.150 mL, 0.442 mmol), 1 mL of TMF, rt. Yields and stereoselectivities were determined by GC.
b
c
d
e
Isolated yield (stereoselectivity determined by GC). MO = methyl-9-octadecenoate. DE = “diester” = dimethyl 9-octadecenedioate. 9C18 = 9-
f
octadecene. Not detected.
B
DOI: 10.1021/acs.orglett.6b00031
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Cross-Metathesis of 4-Octene and 1,4-Diacetoxy-2-
butene
in tetrahydrofuran (2.0 mL) (Table 5). After 1 h, 2 afforded a
75% yield of cis-4-tridecene with >98% Z (entry 1). Prolonged
a
a
Table 5. Cross-Metathesis of 1-Decene and 4-Octene
b
1
4C8 /1,4-
time
(h)
%
conv
c
entry (mol %)
DAB
% yield
Z/E
b
1
3.0
cis/cis
0.25
54
94
95
95
9
49
>99/1
>99/1
>99/1
>99/1
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
entry
1
Ru
4C8
time (h)
% conv
% yield
Z/E
1
2
5
1
2
4
5
2
1
2
4
5
2
.5
91
2
cis
1
2
4
1
2
4
1
2
4
1
2
4
1
2
4
1
2
4
1
2
4
1
2
4
90
90
89
90
91
92
84
85
84
36
36
36
82
87
88
50
54
53
66
74
79
43
51
53
75
75
74
3
98/2
97/3
.5
91
91 (83)
6
96/4
2
5.0
trans/trans
2
3
4
5
6
7
8
trans
cis
12/88
12/88
13/88
>99/1
>99/1
>99/1
<1/99
<1/99
<1/99
>99/1
97/3
15
19
22
33
15
21
30
33
50
11
4
17
4
20
1
3
4
55
55
58
7
7
7
31
3
7.5
trans/trans
11
19
trans
cis
27
7
31 (25)
47
7
58
59
57
21
26
29
42
49
54
19
25
31
a
General conditions: 4-octene (0.100 mL. 0.32 mmol), 1,4-diacetoxy-
-butene (0.406 mL. 2.55 mmol), 0.5 mL of THF, rt. Yields and
stereoselectivities were determined by gas chromatography (isolated
yields in parentheses). 4C8 = 4-octene. 1,4-DAB = 1,4-diacetoxy-2-
butene.
2
97/3
trans
cis
<1/99
<1/99
<1/99
>99/1
>99/1
>99/1
<1/99
<1/99
<1/99
b
c
To evaluate these new catalysts, a mixture of trans-1,4-
diacetoxy-2-butene and trans-4-octene (4:1) was combined with
ruthenium catalyst (3.0 mol %) to yield trans-2-hexenyl acetate
Table 4). After 72 h, 1 afforded 13% yield of trans-2-hexenyl
acetate (entry 1), whereas 3 and 4 afforded improved yields of 24
and 28%, respectively (entries 2−4).
trans
(
a
General conditions: 1-decene (0.050 mL, 0.26 mmol), 4-octene
0.125 mL. 0.79 mmol), Ru (0.0078 mmol), 2 mL of THF, rt. Yields
and stereoselectivities were determined by GC. 4C8 = 4-octene.
(
b
Table 4. Cross Metathesis of trans-4-Octene and trans-1,4-
Diacetoxy-2-butene
a
exposure to reaction conditions eroded the observed selectivity.
Catalysts 1, 3, and 4 were less active but afforded 54−58% yield
of cis-4-tridecene with exceptional stereoretention (>99% Z)
entry
1
Ru
time (h)
% conv
% yield
Z/E
b
1
1
2
4
0
2
0
2
ND
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
<1/99
(
entries 3, 5, and 7). Self-metathesis of cis-4-tridecene to afford 9-
octadecene and 4-octene was the major contributor to the fact
that conversions were on average 25−30% higher than observed
yields. As previously observed, reactions with trans-4-octene
were less productive. Unlike reactions of cis-4-octene, the
disparity between conversion and yield is largely attributed to
isomerization of 1-decene. After 4 h, catalyst 2 afforded 4% yield
but managed to convert 92% of the starting 1-decene (entry 2).
Stereoretention is likely poor due to the significant amount of
isomerization observed. Catalyst 1 afforded a marginally better
5
4
72
1
2
4
72
1
2
4
72
15
2
13
2
2
3
3
4
5
5
12
25
4
11
24
4
7
7
15
29
14
28
7
% yield with significantly less isomerization though stereo-
retention was excellent (>99% E) (entry 4). Yields were
noticeably better in reactions conducted with catalysts 3 and 4,
affording 29 and 31% yield of cis-4-tridecene, respectively, with
excellent stereoretention (>99% E) (entries 6 and 8).
Maintaining the side-bound geometry of the metallocyclobu-
tane requisite for these catalysts to facilitate Z-selective
transformations, the observed E-selectivity is proposed to arise
from the ability of the substituent at the β position of the
metallacycle to point “up” into the “open” space located in front
of the plane containing the N−C−N bonds of the NHC and
between the two N-aryl groups (Figure 4). Due to steric
repulsion, substituents at the α positions are forced down, away
a
General conditions: trans-4-octene (0.050 mL. 0.32 mmol), trans-1,4-
diacetoxy-2-butene (0.203 mL, 1.27 mmol), Ru (0.0096 mmol, 3 mol
), 1 mL of THF, rt. Yields and stereoselectivities were determined by
%
b
gas chromatography. Not determined.
Additionally, this family of catalysts was evaluated for the more
demanding cross-metathesis of 1-decene and 4-octene. Mitigat-
ing catalyst decomposition in the presence of terminal olefin in
addition to outpacing the self-metathesis of the desired product
was challenging. Reactions were conducted by combining a
mixture of 1-decene and cis-4-octene (1:3) with 1−4 (3.0 mol %)
C
DOI: 10.1021/acs.orglett.6b00031
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Mol, J. C. Olefin Metathesis and Metathesis Polymerization; Academic
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rnroos, K. W.; Jensen, V. R. J. Am. Chem. Soc. 2013,
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metathesis.
2
(
015, 517, 181.
̈
3) (a) Flook, M. M.; Jiang, A. J.; Schrock, R. R.; Muller, P.; Hoveyda,
from the NHC. Provided the disubstituted olefin used for cross-
metathesis initially has trans stereochemistry, the kinetic product
should also have trans stereochemistry. Comparison of the
reactivities of catalysts 1−4 supports this model. As the size of the
ortho substituents of the N-aryl groups decreases (F < Me < iPr),
conversions tend to increase, presumably due an increase in
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In summary, we have demonstrated the first kinetically
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high stereopurity. Reactions of E-olefinic hydrocarbons
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high E-stereoselectivity. These findings support the proposed
model whereby trans-olefinic substrates are increasingly
compatible with catalysts as steric encumbrance is reduced.
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5
(
848.
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(
ASSOCIATED CONTENT
Supporting Information
̈
■
(
(
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00031.
Chem., Int. Ed. 2013, 52, 14131.
12) Radkowski, K.; Sundararaju, B.; Fu
013, 52, 355.
13) Results similar to those in Table 2, entry 7, were attainable by
conducting the reaction with 1 mol % of 1 at 45 °C for 5 h.
14) The self-metathesis of trans-methyl-9-octadecenoate conducted
(
̈
rstner, A. Angew. Chem., Int. Ed.
2
(
Experimental procedures, preparations for complexes 2−4
and compound characterizations (PDF)
(
AUTHOR INFORMATION
Corresponding Authors
■
in the presence of 7.5 mol % 2 did not afford any desired product.
*
E-mail: rhg@caltech.edu.
*E-mail: rpederson@materia-inc.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Office of Naval Research (N00014-
4-1-0650) and the NSF (CHE-1502616) is acknowledged.
■
1
T.S.A. acknowledges support from the National Science
Foundation for a Graduate Research Fellowship. Any opinion,
findings, and conclusions or recommendations expressed in this
material are those of the authors and do not necessarily reflect the
views of the National Science Foundation.
REFERENCES
■
(
1) (a) Grubbs, R. H.; Wenzel, A. G.; O’Leary, D. J.; Khosravi, E., Eds.
Handbook of Metathesis; Wiley−VCH: Weinheim, 2015. (b) Ivan, K. J.;
D
DOI: 10.1021/acs.orglett.6b00031
Org. Lett. XXXX, XXX, XXX−XXX