Molybdenum chloride catalysts for Z-selective olefin metathesis reactions

Article abstract of DOI:10.1038/nature21043

The development of catalyst-controlled stereoselective olefin metathesis processes has been a pivotal recent advance in chemistry. The incorporation of appropriate ligands within complexes based on molybdenum, tungsten and ruthenium has led to reactivity and selectivity levels that were previously inaccessible. Here we show that molybdenum monoaryloxide chloride complexes furnish higher-energy (Z) isomers of trifluoromethyl-substituted alkenes through cross-metathesis reactions with the commercially available, inexpensive and typically inert Z-1,1,1,4,4,4-hexafluoro-2-butene. Furthermore, otherwise inefficient and non-stereoselective transformations with Z-1,2-dichloroethene and 1,2-dibromoethene can be effected with substantially improved efficiency and Z selectivity. The use of such molybdenum monoaryloxide chloride complexes enables the synthesis of representative biologically active molecules and trifluoromethyl analogues of medicinally relevant compounds. The origins of the activity and selectivity levels observed, which contradict previously proposed principles, are elucidated with the aid of density functional theory calculations.

Full text of DOI:10.1038/nature21043

LETTER
doi:10.1038/nature21043
Molybdenum chloride catalysts for Z-selective
olefin metathesis reactions
Ming Joo Koh1, Thach T. Nguyen1, Jonathan K. Lam2, Sebastian Torker1, Jakub Hyvl2, Richard R. Schrock2 & Amir H. Hoveyda1
The development of catalyst-controlled stereoselective olefin Coordination of pyridine trans to chloride in Mo-4 suggests that an
metathesis processes1 has been a pivotal recent advance in chemistry. alkene substrate would probably bind similarly, reminiscent of the
The incorporation of appropriate ligands within complexes based formerly examined MAP systems (olefin trans to pyrrolide)21.
on molybdenum2, tungsten3 and ruthenium4 has led to reactivity
To evaluate the chemistry of MAC complexes, we first examined
and selectivity levels that were previously inaccessible. Here we their effectiveness in promoting the ring-opening/cross-metathesis
show that molybdenum monoaryloxide chloride complexes between 1,2-dichloroethene and cyclooctene (Fig. 1b). Whereas after
furnish higher-energy (Z) isomers of trifluoromethyl-substituted 10min there was 65% conversion to 1 with Mo-1a (>98% conversion
alkenes through cross-metathesis reactions with the commercially after 1h), with Mo-5a the reaction proceeded to 94% conversion and
available, inexpensive and typically inert Z-1,1,1,4,4,4-hexafluoro-2- stereocontrol was considerably higher (>98:2 versus 76:24 Z,Z:Z,E);
butene. Furthermore, otherwise inefficient and non-stereoselective ring-opening/cross-metathesis with the bulkier Mo-5b was similarly
transformations with Z-1,2-dichloroethene and 1,2-dibromoethene efficient and stereoselective. There was less than 5% conversion to
can be effected with substantially improved efficiency and 1 after 1 h with the pyridine-bound Mo-2, which implies that the
Z selectivity. The use of such molybdenum monoaryloxide chloride derived four-coordinate entity is catalytically active.
complexes enables the synthesis of representative biologically active
Cross-metathesis of terminal alkenes with MAC complexes was
molecules and trifluoromethyl analogues of medicinally relevant inefficient (<10% conversion); the reasons for which remain to be
compounds. The origins of the activity and selectivity levels determined. We therefore turned to evaluating cross-metathesis with
observed, which contradict previously proposed principles5, are (Z)-1,2-disubstituted olefins, which can be purchased or accessed in
elucidated with the aid of density functional theory calculations.
one step through catalytic cross-coupling22 between commercially
Substitution of an oxygen-based ligand with a pyrrolide moiety available Z-1-bromo-1-propene and an aryl- or alkenylboronic acid
converts a molybdenum (Mo) or tungsten (W) alkylidene (for or pinacol ester (see Supplementary Information for details). In the
example, Mo-1a; Fig. 1a) to a uniquely efficient and stereoselective1 event, whereas with Mo-1a there was 34% and 73% conversion to
olefin metathesis catalyst. In Z-selective processes, an alkene binds 2 and 3, respectively (Fig. 1b), with Mo-5b these compounds were
trans to the pyrrolide5, generating a metallacyclobutane with sterically isolated in ≥80% yield. Moreover, although cross-metathesis with
differentiated imido (smaller) and aryloxide (larger) ligands6. Mo-1a was either non-selective (2, 52:48 Z:E) or E-selective (3, 28:72
Kinetically E-selective cross-metathesis reactions were recently intro- Z:E, probably owing to post-metathesis isomerization), with Mo-5b
duced as well7. Nevertheless, critical shortcomings persist. For instance, only the Z product was detected. The same applies to Z,E-diene 4, for
with Mo monoaryloxide pyrrolide (MAP) catalysts, cross-metathesis of which there was 53% conversion to β-chlorostyrene with Mo-1a (from
Z-1,2-dihaloalkenes with aryl olefins or 1,3-dienes is often inefficient cross-metathesis with the styrenyl olefin) and stereoselectivity was
and non-stereoselective8. In addition, cross-metathesis reactions that not determined because of a complicated product mixture. Similarly,
generate Z-alkenes that carry a trifluoromethyl group are unknown; cross-metathesis of 1,2-dibromoethene with methyl oleate was more
these moieties can impart increased bioavailability, metabolic stability, efficient and Z-selective with Mo-5b (Fig. 1b); use of Mo-5a—a less
lipophilicity or binding selectivity9,10 to biologically active molecules11 hindered complex that may generate shorter living alkylidenes—led
and are needed for future advances in agrochemicals12 and materials13 to diminished efficiency (32% conversion to 5 and 6). The higher
research. Yet, the state-of-the-art for synthesis of trifluoromethyl- Z selectivities in MAC-catalysed reactions were surprising because
substituted olefins is at a primitive stage. The available protocols are Z-to-E isomerization is often an issue with more active complexes.
either minimally stereoselective14,15 or afford E isomers predominantly16 Consistent with the commonly used stereochemical model1,5,6, we
(for example, cross-metathesis with gaseous 3,3,3-trifluoropropene17), expected the size difference between the imido and aryloxide moieties to
and the small number of methods for preparing Z-trifluoromethyl determine stereoselectivity, not the identity of the anionic ligand trans to
olefins are expensive and/or impractical18,19. Partial hydrogenation the metallacyclobutane.
of alkynyl substrates is possible, but over-reduction can be an issue20.
The main question then was whether a MAC complex can catalyse
As part of an initiative to synthesize halo-substituted Mo alkylidenes— cross-metathesis reactions with Z-1,1,1,4,4,4-hexafluoro-2-butene
intermediates in stereoselective cross-metathesis reactions that (7; >98% Z)—a hydrofluoroolefin that can be bought in small
afford alkenyl halides7,8—we discovered that treatment of Mo-1b amounts (USD 295 per 5 g from Synquest) or bulk quantities as a
with 1,2-dibromoethene and pyridine gives monoaryloxide bromide foam-blowing agent and that has ozone depleting potential (ODP)
complex Mo-2 (Fig. 1a). Subjection of Mo-2 to tris(pentafluorophenyl) and global warming potential (GWP) values of zero and low,
borane afforded the four-coordinate species Mo-3, which is not respectively23. Furthermore, 7 is a non-flammable liquid at ambient
sufficiently stable to be isolated. Procedures for the preparation of temperature and convenient to use (boiling point of +33°C versus
multi-gram quantities of monoaryloxide chloride (MAC) derivatives –22°C for 3,3,3-trifluoropropene). However, compound 7, which is
(for example, Mo-4) from readily accessible and inexpensive materials used in industrial applications, is generally inert, probably because
were subsequently developed (details in Supplementary Information). of its hindered and severely electron-deficient alkene. To the best
1Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA. 2Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, USA.
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RESEARCH LETTER
Figure 1 | Initial findings and
synthesis of Z-alkenyl halides.
a, Formation of a monoaryloxide
bromide complex (Mo-2). Lewis
acid treatment afforded the four-
coordinate species Mo-3. The
corresponding chloride complexes,
such as Mo-4, can be prepared
from readily available and
a
Alkylidene H,
12.44 p.p.m.
Alkylidene H,
11.04 p.p.m.
Br
Br
N
N
N
N
CMe2Ph
Mo
CMe2Ph
Mo
64:36 Z:E (0.65 equiv.)
H
Br
O
H
O
Pyridine, 80 °C, 60 h
(25% yield)
inexpensive materials.
Mo-1b
Mo-2
X-ray of Mo-2
b, Synthesis of Z-alkenyl halides.
Monoaryloxide chloride (MAC)
complexes Mo-5a and Mo-5b
are most effective in promoting
Z-selective ring-opening/
Alkylidene H,
12.42 p.p.m.
Detected
by 1H NMR
(alkylidene H,
11.34 p.p.m.)
1.0 equiv. B(C6F5)
Toluene, –30 °C, 0.5 h
Br
N
N
t-Bu
N
cross-metathesis (versus the
Br
Mo
CMe2Ph
Mo
corresponding pyrrolide or MAP
systems). Cross-metathesis of
Z-1,2-dichloroethene and various
types of olefins are exceptionally
efficient and stereoselective with
the MAC complex Mo-5b, which
can also promote Z-selective
cross-metathesis with a 64:36 Z:E
mixture of 1,2-dibromoethene.
1H NMR spectra were recorded in
C6D6; stereoselectivities measured
by 1H NMR analysis ( 2%); yields
are for isolated/purified products
H
Cl
i-Pr
i-Pr
O
i-Pr
i-Pr
H
O
i-Pr
i-Pr
Mo-4
X-ray of Mo-4
Mo-3
b
F
F
F
Cl
Cl
F
F
+
>98:2 Z:E
(1.25 equiv.)
N
N
N
N
CMe2Ph
CMe2Ph
N
N
Mo
Mo
Mo
CMe2Ph
5.0 mol%
Mo complex
C6H6, 22 °C
i-Pr
i-Pr
i-Pr
Cl
Cl
O
O
( 5%). All experiments were
i-Pr
Et
Et
O
Et
Et
performed in triplicate (at least).
See Supplementary Information
for details. Boc, tert-
i-Pr
i-Pr
Et
Et
Cl
Mo-5b
Mo-1a
Mo-5a
butoxycarbonyl; G, functional
groups; ND, not determined.
94% conversion to 1, 10 min 98% conversion to 1, 10 min
Cl
65% conversion to 1, 10 min
76:24 Z,Z:Z,E
1
>98:2 Z,Z:Z,E
>98:2 Z,Z:Z,E
G
Cl
Cl
Mo complex
G
Me
Me
Cl
Cl
+
+
C6H6, 22 °C, 4 h
>98:2 Z:E (10 equiv.)
(Volatile)
Boc
N
MeO
Ph
Cl
Cl
Cl
2
3
4
With 5.0 mol% Mo-1a:
With 5.0 mol% Mo-1a:
With 5.0 mol% Mo-1a:
>98% conversion, 34% to 2, 52:48 Z:E
With 5.0 mol% Mo-5b:
>98% conversion, 73% to 3, 28:72 Z:E
With 5.0 mol% Mo-5b:
>98% conversion, 31% to 4, Z:E ND
With 5.0 mol% Mo-5b:
>98% conversion, 80% yield, >98:2 Z:E
>98% conversion, 83% yield, >98:2 Z:E
>98% conversion, 83% yield, >98:2 Z:E
With 5.0 mol% Mo-1a:
60% conversion, 45% to 5 and 6, 89:11 Z:E
With 3.0 mol% Mo-5b:
MeO
Br
Br
MeO
15C7
Mo complex
O
O
+
Br
H
C6H6, 22 °C, 4 h
5
95% conversion, 90% yield (
5)
64:36 Z:E
(8.0 equiv.)
+
85% yield ( ), >98:2 Z:E
6
Methyl oleate
H15C7
Br
6
of our knowledge, this organofluoride has not been used in organic
Many (Z)-1,2-disubstituted alkenes, commercially available or
chemistry; our efforts to access Z-trifluoromethyl-substituted alkenes accessible in one step from naturally occurring Z-olefins (for example,
(for example, cross-metathesis of methyl oleate with 7) with known Mo Z-3-hexen-1-ol) or through cross-coupling, can be used (Fig. 2b).
complexes or ruthenium (Ru) carbenes were unsuccessful (no desired Products containing an ether (8c), an α-alkoxy ester capable of chelating
products were detected).
to the Mo centre (8d), or a carbamate (8e) were easily accessed. Cross-
In contrast, with Mo-5a and Mo-6a, cross-metathesis of methyl metathesis with alkenes containing a tosylate (8f), an alkyne (8g),
oleate and 7 afforded appreciable amounts of 8a and 8b (Fig. 2a). In a tertiary amine (8h), or a sulfide (8i) was efficient and Z-selective.
considering ways that Z selectivity might be improved, we reasoned A 1,4-diene (8j), a crotyl–pinacolatoboron (8k), or a crotylsilane (8l)
that, other than post-metathesis isomerization, formation of the unde- were suitable substrates. Transformations with hindered α-branched
sired E isomer might originate from initial isomerization of the olefin 1,2-disubstituted alkenes (8m, n) and β-substituted styrenes (8o–q)
substrate6. Accordingly, with Mo-6b—a more congested and longer proceeded smoothly. Cross-metathesis with aryl olefins needed
living MAC complex—cross-metathesis was complete in 4h, furnishing (Z)-β-isopropylstyrenyl substrates so that homocoupling would be less
8a and 8b in 98:2 Z:E selectivity and 90% and 65% yield, respectively. competitive. Paraffin tablets containing a MAC species6 may be used
Further study indicated that with 2.0 mol% Mo-6b and 5 equiv. of 7 (no glove box); for instance, with a pellet containing Mo-6b (about
the transformation was complete in only 15min with nearly the same 3.0 mol%, toluene, 35 °C, 2 h), 8e was obtained in 74% yield and
yields and Z selectivities (slightly lower yields with Mo-5b).
>98:2 Z:E ratio.
2
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LETTER RESEARCH
F3C
CF3
a
MeO
15C7
MeO
5.0 mol% complex
C6H6, 22 ºC, 4 h
H15C7
CF3
<5% conversion with all other
Mo, W or Ru complexes
+
O
7
+
O
H
F3C
>98:2 Z:E,
(20 equiv.)
Used as received
Methyl oleate
8a
8b
(Volatile)
N
N
N
N
N
N
CMe2Ph
t-Bu
t-Bu
Mo
Mo
Mo
With 5.0 equiv. 7, 2.0 mol% Mo-6b,
22 °C, 15 min:
Cl
Cl
Cl
i-Pr
i-Pr
O
O
O
i-Pr
i-Pr
Further
optimized:
>98% conversion, 95% yield (8a),
>98:2 Z:E
i-Pr
i-Pr
>98% conversion, 67% yield (8b),
>98:2 Z:E
Mo-5a:
Mo-6a:
Mo-6b:
69% conversion, 66% yield (8a), 91:9 Z:E
69% conversion, 36% yield (8b), 91:9 Z:E
79% conversion, 64% yield (8a), 81:19 Z:E
79% conversion, 36% yield (8b), 81:19 Z:E
>98% conversion, 90% yield (8a), 98:2 Z:E
>98% conversion, 65% yield (8b), 98:2 Z:E
F3C
CF3
b
G
R
2.0–5.0 mol% Mo-6b
G
CF3
F3C
R
7
>98:2 Z:E,
(5.0–10 equiv.)
Used as received
G = various moieties
R = Me, Et or i-Pr
C6H6, 22 °C, 2–12 h
8
(Volatile)
O
CF3
CF3
O
CF3
O
O
O
BocN
CF3
PMBO
CF3
BnO
Me
TsO
(i-Pr)3Si
8g:
8c:
8d:
8e:
R = Et, 3.0 mol%, 2 h:
8f:
R = Et, 5.0 mol%, 4 h:
87% conversion, 77% yield,
>98:2 Z:E
R = Et, 2.0 mol%, 2 h:
73% conversion, 70% yield,
97:3 Z:E
R = Et, 2.0 mol%, 2 h:
82% conversion, 77% yield,
>98:2 Z:E
R = Et, 5.0 mol%, 2 h:
>98% conversion, 80% yield,
>98% conversion, 82% yield,
>98:2 Z:E
>98:2 Z:E
CF3
CF3
(pin)B
CF3
Et3Si
CF3
CF3
Bn2N
Ph
PhS
8h:
8i:
8j:
8k:
8l:
R = Et, 3.0 mol%, 2 h:
>98% conversion, 92% yield,
>98:2 Z:E
R = Et, 3.0 mol%, 2 h:
>98% conversion, 69% yield,
95:5 Z:E
R = Me, 3.0 mol%, 2 h:
92% conversion, 62% yield,
97:3 Z:E
R = Me, 5.0 mol%, 2 h:
>98% conversion, 70% yield,
97:3 Z:E
R = Me, 3.0 mol%, 2 h:
92% conversion, 62% yield,
94:6 Z:E
Boc
N
MeO
S
BocN
Me
CF3
CF3
Ph2(t-Bu)SiO
CF3
CF3
CF3
8m:
8n:
8o:
8p:
8q:
R = Me, 5.0 mol%, 4 h:
>98% conversion, 85% yield,
>98:2 Z:E
R = Me, 5.0 mol%, 4 h:
>98% conversion, 88% yield,
>98:2 Z:E
R = i-Pr, 5.0 mol%, 12 h:
89% conversion, 59% yield,
>98:2 Z:E
R = i-Pr, 5.0 mol%, 12 h:
92% conversion, 64% yield,
>98:2 Z:E
R = i-Pr, 5.0 mol%, 12 h:
90% conversion, 61% yield,
>98:2 Z:E
Figure 2 | Mo MAC complexes engage a typically inert trifluoromethyl-
substituted alkene. a, Mo MAC complexes, of which Mo-6b is optimal,
can catalyse cross-metathesis of Z-1,2-disubstituted alkenes and reagent 7
with exceptional Z selectivity. b, Various alkyl and aryl olefins, including
those that contain Lewis basic esters, carbamates and amines or
α-branched moieties, may be used in efficient and exceptionally
Z-selective cross-metathesis reactions. The requisite Z-1,2-disubstituted
alkene starting materials may either be purchased or prepared in one step
from commercially available compounds. PMB, para-methoxybenzyl;
Bn, benzyl; Boc, tert-butoxycarbonyl; pin, pinacolato; Ts, tosyl group.
Stereoselectivities measured by 1H NMR analysis ( 2%); yields are for
isolated and purified products ( 5%). All experiments were performed in
triplicate (at least). See Supplementary Information for details.
Product 8r has been transformed to glycosidase inhibitor 1024 syntheses of 8w (from epalrestat29, an aldolase reductase inhibitor)
(Fig. 3a). Conversion of the commercially available aldehyde 11 to and 8x (from artesunate30, an anti-malarial agent), emphasize the
Z-alkene 12 followed by cross-metathesis with 7 afforded 8s—an inter- compatibility of Mo MAC complexes with some key polar functional
mediate en route to hvRI receptor inhibitor 1325. Previously, 8s was groups.
prepared by Wittig reaction with aldehyde 11 and 2,2,2-trifluoroethyl
Two central points merit further discussion. (1) Cross-metathesis
diphenylphosphine oxide (not commercially available), affording a reactions with terminal alkenes would be more desirable, but, as
mixture of E/Z isomers (exact ratio and yield not reported22). Several mentioned earlier, the (Z)-1,2-disubstituted alkenes used here are
examples show that synthesis of trifluoromethyl analogues of medici- readily accessed. Considering the high value of the Z-trifluoromethyl-
nally relevant agents can be facilitated (Fig. 3b). Z-alkene 15, previously substituted alkenes, the ease of their preparation and the paucity of
accessed in five steps and 27% overall yield from commercially available alternative methods, the present approach offers a compelling solution
enantiomerically pure 14, was transformed to 8t in 84% yield and to a longstanding problem. For instance, the Z-allyl–pinacolatoboron
>98% Z selectivity, enabling synthesis of a trifluoromethyl analogue 8k (see Fig. 2b), a product that may be used to access an assortment
of hormaomycin26. Cross-metathesis of 16, derived from analgesic of desirable trifluoromethyl-containing products through future
zucapsaicin27, delivered 8u (86% yield, >98% Z). The transformation developments in diastereo- and/or enantioselective additions to
of 17 (obtained from sulbactam28, a β-lactamase inhibitor) to 8v, and electrophiles, was obtained by reaction of commercially available
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RESEARCH LETTER
HO
HO
CF3
a
Me
CF3
N
O
O
N
N
Ref. 24
3.0 mol% Mo-6b
O
O
O
HO
N
H
5.0 equiv. 7,
C6H6, 22 °C, 2 h
Et
9
8r
10
>98% conversion, 80% yield,
(Glycosidase inhibitor)
>98:2 Z:E
O
MeO
MeO
i-Pr
MeO
MeO2C
F3C
MeO
NH
F3C
O
10 mol% Mo-6b
Ref. 25
Wittig reaction
MeO2C
CHO
MeO2C
O
10 equiv. 7,
C6H6, 22 °C, 12 h
11
13
12
8s
(commercially
available)
hvRI receptor inhibitor
75% yield,
>98:2 Z:E
82% conversion, 53% yield,
>98:2 Z:E
O2N
Me O
NH HN
b
H
O
Boc
N
Boc
N
Boc
N
O
5.0 mol% Mo-6b
Ref. 26
Me
Et
NH
HN
Me
O
OH
OTBS
OTBS
Me
F3C
Me
O
10 equiv. 7,
C6H6, 22 °C, 4 h
HO
O
NO2
O
14
8t
HN
15
(5 steps;
27% overall yield;
O
N
(commercially
available)
>98% conversion, 84% yield,
HN
O
>98:2 Z:E
F3C
>98:2 Z:E)
N
Cl
HO
Triꢀuoromethyl-hormaomycin
(parent compound:
antibiotic, anti-bacterial)
O
CF3
O
i-Pr
O
i-Pr
1. TBSOTf, Et3N,
CH2Cl2, 0 → 22 °C, 0.5 h
N
Boc
N
N
Boc
5.0 mol% Mo-6b
H
TBSO
HO
TBSO
10 equiv. 7,
C6H6, 22 °C, 4 h
2. Boc2O, DMAP,
MeCN, 22 °C, 1 h
OMe
OMe
OMe
8u
Zucapsaicin
16
>98% conversion, 86% yield,
(topical analgesic)
75% overall yield
>98:2 Z:E
c
Me
O
Me
O
H
O
S
O
O
O
H
O
O
H
H
S
S
Me
Me
Ph
O
N
S
CF3
O
Me
O
5.0 mol% Mo-6b
N
N
Me
S
Me
O
Me
O
O
O
O
O
O
5.0 equiv. 7,
C6H6, 22 °C, 2 h
O
O
CF3
8w
8x
Et
CF3
(derived from epalrestat,
an aldolase reductase inhibitor)
>98% conversion, 92% yield,
>98:2 Z:E
(derived from artesunate,
an anti-malarial agent)
>98% conversion, 81% yield,
17
8v
(derived from sulbactam,
a β-lactamase inhibitor)
>98% conversion, 83% yield,
>98:2 Z:E
>98:2 Z:E
Figure 3 | Utility and functional group compatibility. a, Mo MAC-
catalysed cross-metathesis provides direct access to biologically active
molecules. This includes the preparation of 8r, precursor to glycosidase
inhibitor 10 (ref. 24). Styrenyl compound 8s, which has been converted to
hvR1 receptor inhibitor 13 (ref. 25), is notable because it involves reaction
between severely hindered alkenes. b, MAC complexes can be used to
prepare and probe the activity of Z-trifluoromethyl derivatives of new
drug candidates, benefitting from the advantages of a trifluoromethyl unit.
One example is conversion of previously reported 15 (ref. 26) to 8t en
route to a trifluoromethyl-substituted derivative of hormaomycin;
alternatively, 8u may be applied to synthesis of the trifluoromethyl
analogue of zucapsaicin. c, Despite their high Lewis acidity, Mo MAC
complex tolerate Lewis basic functional groups that regularly appear in
therapeutic agents (for example, 8v–8x). TBS, tert-butyldimethylsilyl;
Boc, tert-butoxycarbonyl; Tf, trifluoromethylsulfonyl; DMAP,
4-dimethylaminopyridine. Stereoselectivities measured by
1H NMR analysis ( 2%); yields are for isolated/purified products
(
5%). All experiments were performed in triplicate (at least).
See Supplementary Information for details.
Z-crotyl–pinacolatoboron. (2) The development of compounds that characteristic that is more evident in Fig. 4Ab, in which Td,dist is the
contain a Z-trifluoromethyl-substituted olefin and/or a related reference point. There is strong correlation between the barrier to ts1
derivative with desirable biological activity has probably been and the extent of C–C double bond activation in the Mo π complex (pc,
hampered by the absence of direct and practical methods to obtain Fig. 4Ac). Whereas the methyl–Mo complex emerges as the least activated
such species, despite their considerable potential9,10
.
(C=C, 1.350Å), the more Lewis acidic chloro species has the longest
Density functional theory calculations shed light on why MAC (most tightly) chelated C=C bond (1.368Å), a trend consistent with the
complexes are singularly effective. We first probed the influence lowest unoccupied molecular orbital (LUMO) energies for the distorted
of several anionic ligands on the reaction of Z-2-butene with Mo-7 ground-state complexes (Td,dist; see the Supplementary Information for
(Fig. 4Aa). Although the energy for distortion of the chloro detailed study of electronic effects). The overall energy requirement
complex is relatively high (8.9kcal mol−1), the ensuing metallacy- appears to be derived from a combination of the cost of structural
clobutane (mcb) formation (Td,dist/pc → ts1, where Td,dist is the distortion (Td → Td,dist) and mcb formation (Td,dist/pc → ts1); the
distorted tetrahedral complex, pc is the π complex and ts1 is the model MAC system has the smallest barrier (12.5kcal mol−1) and
transition state for metallacylobutane formation) is the most facile, a the largest is for the methyl and methoxy derivatives (Fig. 4Aa). These
4
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LETTER RESEARCH
A
X = Me
X = OMe
X = PyrMe2
X = Pyr
X = CN
a
c
18.9
18.3
Electronic
effects
12
10
8
20
20
Me
(1.350)
13.5
10.4
X = Cl
15
CN
(1.360)
12.2
8.9
10.1
10.0
14.1
14.0
13.2
12.5
10
10
Pyr
(1.362)
6
7.7
6.7
9.2
6.5
OMe
(1.361)
8.7
8.2
8.9
8.8
8.7
8.4
4
5
5
Cl
2.5
1.8
1.2
(1.368)
0.0
PyrMe
(1.363)
2
2
3.4
2.4
0
20
0
–1.3
15.5
10.8
0
1.345 1.350 1.355 1.360 1.365 1.370 1.375
15
-5
C=C bond length in pc (Å)
b
Change in
reference point
10
10
6.7
6.4
6.1
5.9
5.8
4.1
0.2
0.0
0.0
5
5
d
Steric effects
3.3
in ts1
0.0
5.3
3.6
–2.4
–3.4
0
0
1.7
1.3
1.0
0.3
–3.7
–4.5
–6.4
–6.9
–7.0
–2.2
–5
-5
–8.2
–8.7
2.17 Å
-10
–8.9
–10
2.39 Å
Me
–12.2
Me
N
Me
Me
N
Me
-15
Me
2.10 Å
N
X
Me
Me
Me
Me
Me
Me
N
N
2.21 Å
Me
N
Me
Me
N
X
Mo
X
Me
Me
X
Me
X
X
Mo
Mo
Mo
Mo
Mo
OMe
I
II
Mo-7
Td
OMe
OMe
OMe
CMe
MeO
OMe
ac
Td,dist
pc
ts1
mcb
R
N
R
N
B
Me
Cl
Me
Cl
Cl
F
a
b
c
R
N
Cl
R
X
X
Mo
F
F
Mo
F
Me
Me
Me
Me
N
30
Me
Me
OAr
OAr
X
Mo
X
Mo
23.0
14.5
F
20.4
N
N
OAr
Me
N
OAr
17.3
12.3
17.3
12.3
N
20
10
0
Mo
15.8
11.2
Mo
Me
12.6
9.3
14.1
Cl
O
O
0.2
3.1
0.0
0.0
0.0
Me
Cl
Me
Me
Mo-8
Mo-9
LnMo
LnMo
MoLn
MoLn
Td,1 ts1 mcb ts2 Td,2
Td,1 ts1 mcb ts2 Td,2
Figure 4 | Computational and mechanistic studies. A, Electronic effect
of the anionic ligand on degenerate olefin metathesis of Z-2-butene with
model complexes Mo-7 (a–c) and the influence of steric factors with
larger aryloxide moieties (d). B, Comparison of the reactivity and
selectivity of Mo-8,9 (depicted in a) with Z-2-butene (b) and Z-1,2-
dichloroethene (c). In A and B, the energy values correspond to the
free energy (ΔG, in kcal mol−1) determined with density functional
theory at the MN12SX/Def2TZVPP//ω−B97XD/Def2SVP level in
benzene as solvent (SMD, Solvation Model based on Density). PyrMe2,
2,5-dimethylpyrrolide; Pyr, pyrrolide; ac, acetonitrile complex; Td,
tetrahedral complex; Td,dist, distorted tetrahedral complex; pc,
π complex; ts1, transition state for metallacylobutane formation; mcb,
metallacyclobutane; ts2, transition state for metallacyclobutane cleavage;
R, aryl or alkyl group; Ar, aryl group. See Supplementary Information for
details, including studies with other density functionals.
principles are distinct from those of a previous study, which were 20.4 kcal mol−1 for the chloro and dimethylpyrrolide complexes,
performed on less-substituted mcb intermediates, where methyl- respectively) compared to the more diminutive methoxy complexes
molybdenum complexes were assigned higher reactivity (versus (barrier to ts1 of 12.5kcal mol−1 and 14.0kcal mol−1 for the chloro and
methoxy-molybdenum) on the basis of the principle that a stronger dimethylpyrrolide systems, respectively; Fig. 4Aa).
σ-donating ligand helps to make a trans ligation site available5. This
The improved efficiency and Z selectivity in generating alkenyl
work shows that neither a methyl- nor a methoxy-substituted species is halides with MAC complexes arise from differences in chemoselectivity.
capable of delivering the activity level of a chloro-molybdenum species. These differences are indicated by a larger gap in the energy that is
We then investigated the transformation between Z-2-butene and required to overcome the ts1 activation barrier in reactions of Mo-8
Mo-8 and Mo-9 (see Fig. 4B), with the methoxy ligand replaced by a (MAP) with Z-2-butene (17.3 kcal mol−1; Fig. 4Bb) and Z-1,2-
much larger 2,6-dimesityl-phenoxy moiety. We find that in transition dichloroethene (23.0 kcal mol−1; Fig. 4Bc) compared to those for
state I (Fig. 4Ad), the aryloxide moiety tilts towards the Cl ligand with the transformation with MAC complex Mo-9 (12.3 kcal mol−1 for
longer C–H····H–C distances (2.21Å and 2.39Å). In MAP complex II, Z-2-butene and 14.5 kcal mol−1 for Z-1,2-dichloroethene). Alkyl-
the aryloxy group and the reacting alkene are forced into closer con- substituted MAP alkylidenes bearing a pentafluorophenyl amido ligand
tact (2.10Å and 2.17Å). The increased steric pressure has a stronger are more prone to react with an aliphatic alkene (compared to the less
effect on the activation barriers (barrier to ts1 of 12.1kcal mol−1 and Lewis basic 1,2-dichloroalkene) to afford homocoupling products and
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RESEARCH LETTER
so Z-to-E isomerization/cross-metathesis becomes an issue (that is, 11. Liu, X., Shimizu, M. & Hiyama, T. A facile stereocontrolled approach to
CF3-substituted triarylethenes: synthesis of panomifene. Angew. Chem. Int. Ed.
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12. Fujita, M., Hiyama, T. & Kondo, K. Practical and stereocontrolled synthesis of
there is repulsion between F atoms of the arylimido ligand and the
Cl atoms of the dichloroalkene; see the Supplementary Information
for details). With excess dihaloalkene, cross-metathesis becomes
more favourable and homocoupling is less competitive. With a MAC
species, which is capable of reacting with either alkene at comparable
rates, adventitious homocoupling and E isomer generation is minimal,
especially with excess dihaloalkene; control experiments indicate that
Z-to-E interconversion of these reagents is slow.
both (1R*,3S*)- and (1R*,3R*)-3-(2-chloro-3,3,3,-trifluoro-1-propenyl)-2,2-
dimethylcyclopropanecarboxylates. Tetrahedr. Lett. 27, 2139–2142 (1986).
13. Shimizu, M., Takeda, Y., Higashi, M. & Hiyama, T. Synthesis and photophysical
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14. Hafner, A., Fischer, T. S. & Bräse, S. Synthesis of CF3-substituted olefins by
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thiazole as trifluoromethylation agent. Eur. J. Org. Chem. 2013, 7996–8003
(2013).
15. Choi, S. et al. Hydrotrifluoromethylation and iodotrifluoromethylation of
alkenes and alkynes using an inorganic electride as a radical generator.
Nat. Commun. 5, 4881 (2014).
16. Choi, W. J. et al. Mechanisms and applications of cyclometalated Pt(ii)
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fluorinated olefins. Chem. Commun. 2001, 1692–1693 (2001).
18. Ramachandran, P. V. & Mitsubishi, W. (Z)- or (E)-selective hydrogenation of
potassium (3,3,3-trifluoroprop-1-yn-1-yl)trifluoroborate: route to either isomer
of β-trifluoromethylstyrenes. Org. Lett. 17, 1252–1255 (2015).
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21. Marinescu, S. C., Schrock, R. R., Li, B. & Hoveyda, A. H. Inversion of
configuration at the metal in diastereomeric imido alkylidene monoaryloxide
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Similar arguments may be extended to reactions that deliver
Z-alkenyl bromides (Fig. 1b). Despite a more active MAC complex,
which is capable of causing post-metathesis isomerization, and
the presence of 36% E-1,2-dibromoethene, cross-metathesis is
exceptionally Z-selective. This might be attributed to lower reactivity of
the E isomer, which is supported by the diminished Z:E ratio (41:59) of
recovered reagent after cross-metathesis of methyl oleate with 2.3 equiv.
of 1,2-dibromoethene (about 1.5 equiv. of Z isomer) with 5.0 mol%
of Mo-5b (4h). Mo MAC complexes do not promote efficient cross-
metathesis with E-1,2-dichloroethene or E-1,1,1,4,4,4-hexafluoro-2-
butene (<10% conversion); we attribute this to rapid decomposition
of the derived metallacyclobutanes. Subjection of Z-methyl oleate to a
3:2 mixture of Z- and E-1,2-dichloroethene and 3.0 mol% Mo-6a led
to only 20% conversion to the cross-metathesis products (C6H6, 22°C,
4h versus >98% conversion and 97% yield with the pure Z isomer).
This is unlike the case with the bulkier 1,2-dibromoethene, for which
the E isomer reacts at a sufficiently slower rate so that cross-metathesis
can proceed to completion.
These Mo MAC complexes are able to catalyse—with unprecedented
efficiency and selectivity—the formation of three types of products
that are important in the preparation and identification of potential
medicines and functional small molecules. The ability to promote trans-
formations with Z-1,1,1,4,4,4-hexafluoro-2-butene (7), a compound
not previously used in a chemical transformation, is particularly
noteworthy. Computational studies teach us that, contrary to
expectations5, the chloride complexes exhibit higher activity compared
to MAP species owing to enhanced Lewis acidity and diminution in
steric repulsion within a trigonal bipyramidal intermediate.
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Online Content Methods, along with any additional Extended Data display items and
Source Data, are available in the online version of the paper; references unique to
these sections appear only in the online paper.
Received 31 October; accepted 30 November 2016.
Published online 23 January 2017.
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Supplementary Information is available in the online version of the paper.
Acknowledgements This research was supported by the United States National
Institutes of Health, Institute of General Medical Sciences (GM-59426). M.J.K.
acknowledges support through LaMattina and Bristol-Myers Squibb Graduate
Fellowships. We thank P. Müller for helping to obtain various X-ray structures
and X. Shen for advice and experimental assistance. We are grateful to XiMo,
AG for gifts of paraffin tablets.
6. Meek, S. J., O’Brien, R. V., Llaveria, J., Schrock, R. R. & Hoveyda, A. H. Catalytic
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Author Contributions M.J.K. and T.T.N. were involved in the discovery, design
and development of the new Z-selective cross-metathesis strategies and
their applications. J.K.L., J.H. and R.R.S. were involved in the synthesis and
characterization of Mo MAC complexes. S.T. designed and performed the
computational investigations, developed the models for the observed levels and
patterns in reactivity and stereoselectivity. A.H.H. directed the investigation and
wrote the manuscript with suggestions from M.J.K., T.T.N., J.K.L., S.T. and R.R.S.
9. Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J. & Meanwell, N. A.
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Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare competing financial interests:
details are available in the online version of the paper. Readers are welcome to
comment on the online version of the paper. Correspondence and requests for
materials should be addressed to A.H.H. (amir.hoveyda@bc.edu).
6
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LETTER RESEARCH
METHODS
1-t-butyl 2-hex-3-enyl pyrrolidine-1,2-dicarboxylate (22.0mg, 0.0740mmol). The
General procedure for cross-metathesis with a MAC complex. In a N2-filled vial was sealed with a septum, then evacuated and back-filled with N2 three times
glove box, an oven-dried 8-ml vial equipped with a magnetic stir bar was charged to remove oxygen. Z-1,1,1,4,4,4-hexafluoro-2-butene (7; 43μl, 0.370mmol) and
with alkene substrate and the corresponding organohalogen reagent (Z-1,1,1,4,4, toluene (74μl) were added by syringe and the resulting mixture was allowed to
4-hexafluoro-2-butene, Z-1,2-dichloroethene or 1,2-dibromoethene). A solution stir at 35°C for 2h under N2 atmosphere. The reaction was quenched by addition
of an appropriate MAC complex in benzene was then added. The resulting mixture of MeCN (1.5ml) and the mixture was allowed to stir at 22°C for 10min. The
was allowed to stir for 15min–12h at 22°C, after which the reaction was quenched slurry was filtered through a short plug of silica gel and eluted with MeCN (2ml).
by the addition of wet (undistilled) CDCl3 (per cent conversion was determined The filtrate was concentrated and analysis of the unpurified mixture revealed 98%
by 1H NMR analysis of the unpurified mixture). Purification was performed consumption of (S,Z)-1-tert-butyl 2-hex-3-enyl pyrrolidine-1,2-dicarboxylate. The
through silica gel chromatography, preparative thin-layer chromatography resulting green oil was purified by silica gel chromatography (4% Et2O/pentane
and/or Kugelrohr distillation.
to 20% Et2O/pentane) to afford 8e (18.5mg, 0.0548mmol, 74% yield) in >98:2
General procedure for cross-metathesis with a paraffin tablet containing a Z:E ratio as colourless oil.
MAC complex. An oven-dried 8-ml vial equipped with a magnetic stir bar was Data availability. The data generated during and/or analysed during the current
charged with a paraffin tablet (9 wt% in Mo-6b, 20.0mg, 2.2μmol) and (S,Z)- study are available from the corresponding author on reasonable request.
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