Synthesis of Linear (Z)-α,β-Unsaturated Esters by Catalytic Cross-Metathesis. The Influence of Acetonitrile

Article abstract of DOI:10.1002/anie.201608087

Kinetically controlled catalytic cross-metathesis reactions that generate (Z)-α,β-unsaturated esters selectively are disclosed. A key finding is that the presence of acetonitrile obviates the need for using excess amounts of a more valuable terminal alken

Full text of DOI:10.1002/anie.201608087

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International Edition: DOI: 10.1002/anie.201608087
German Edition: DOI: 10.1002/ange.201608087
Olefin Metathesis Very Important Paper
Synthesis of Linear (Z)-a,b-Unsaturated Esters by Catalytic Cross-
Metathesis. The Influence of Acetonitrile
Elsie C. Yu, Brett M. Johnson, Erik M. Townsend, Richard R. Schrock, and Amir H. Hoveyda*
Abstract: Kinetically controlled catalytic cross-
metathesis reactions that generate (Z)-a,b-unsa-
turated esters selectively are disclosed. A key
finding is that the presence of acetonitrile
obviates the need for using excess amounts of
a more valuable terminal alkene substrates. On
the basis of X-ray structure and spectroscopic
investigations a rationale for the positive impact
of acetonitrile is provided. Transformations
leading to various E,Z-dienoates are highly Z-
selective as well. Utility is highlighted by
application to stereoselective synthesis of the
C1–C12 fragment of biologically active natural
product (ꢀ)-laulimalide.
C
onspicuously absent from the list of avail-
able kinetically controlled stereoselective
olefin metathesis reactions[1,2] are cross-meta-
thesis (CM) processes that deliver linear (Z)-
a,b-unsaturated esters.[3–5] Such transforma-
tions would offer a valuable disconnection
that may be complementary to Wittig-type[6] or
alkyne partial hydrogenation reactions.[7]
A
case in point is a possible stereoselective route
to the C1–C12 segment of (ꢀ)-laulimalide,
a naturally occurring microtubule stabilizing
agent (Scheme 1a).[8] Z-Enoate i could accord-
ingly be synthesized through two Z-selective
CM steps (ii!i and v!iv). Small-ring lactones
are accessible through ring-closing metathesis
(RCM), but because of carbonyl coordination
to the metal center, these processes are at
times inefficient and demand elevated temper-
atures and relatively high catalyst loadings
(e.g., 20 mol%).[9] In such instances a Lewis
Scheme 1. The principal objectives of the study and the challenges involved.
acidic additive can enhance efficiency[10] but not always.[11]
Development of a Z-selective enoate CM requires that
the following problems are resolved (Scheme 1b): 1) The
carbonyl unit of a carboxylic ester-substituted alkylidene
might coordinate to the metal center to reduce reaction rates.
2) High efficiency might demand larger amounts of a structur-
ally complex alkenyl compound. For example, excess of the
more valuable a-alkenes ii or v might be required for high
efficiency (Scheme 1a). 3) Electronic factors do not favor
formation of productive metallacyclobutanes. Unlike macro-
cyclic RCM reactions,[12] where geometric constraints oppose
the mismatched electronic factors (see I, Scheme 1b), in CM
formation of electronically (and sterically) favored inter-
mediates II–III would lead to nonproductive metallacyclobu-
tanes (vs. IV–V, Scheme 1b). The active complex must
therefore be sufficiently long living for productive CM that
occurs subsequent to nonproductive cycles.
[*] E. C. Yu, B. M. Johnson, Prof. A. H. Hoveyda
Department of Chemistry, Merkert Chemistry Center, Boston College
Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
E. M. Townsend, Prof. R. R. Schrock
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
We began by probing the ability of a number of complexes
to promote CM between 1-decene (3.0 equiv) and acrylate 1a
(Table 1). With Ru-1[13] formation of Z-2a was fully Z-
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608087.
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Table 1: Examination of various complexes for CM of 1-decene and
acrylate 1a.[a]
Table 2: Influence of time and substrate ratios on the CM leading to Z-
2a.[a]
Entry
t [min]
Decene:1a
Conv. [%][b]
Yield [%][c]
Z:E[b]
79:21
53:47
>98:2
>98:2
1
2
3
4
5
30
5
3:1
3:1
1:1
1:3
79
82
30
20
62
56
ND
ND
5
[a] Performed under N2 atm. [b] Determined by analysis of 1H NMR
spectra of unpurified mixtures (ꢂ2%). [c] Yields of isolated and purified
products (ꢂ5%). See the Supporting Information for details. Abbrevia-
tion: ND, not determined.
possibility of Z-to-E conversion and because Mo-3 was
similarly efficient but delivered a more favorable Z:E ratio
than Mo-2a (cf. entries 4 and 6, Table 1) we reasoned that the
CM process with the former complex might be improved
under a different set of conditions. Accordingly, the studies
summarized in Table 2 were carried out. Under mild vacuum
(100 Torr) and with the same initial 1-decene:acrylate ratio as
before (3:1), there was 79% conversion to 2a after five
minutes and stereoselectivity improved to 79:21 Z:E (62%
yield; entry 1). However, the Z selectivity was diminished
within 30 minutes (53:47 Z:E; entry 2), further supporting the
post-metathesis isomerization scenario. Selectivity was con-
siderably higher (> 98%) with lesser amounts of 1-decene but
efficiency was poor (ꢁ 30% conv., entries 3 and 4) and
extended times did not improvement matters.
Entry
Complex
Conv. [%][b]
Yield [%][c]
Z:E[b]
1
2
3
4
5
6
Ru-1
Ru-2
Mo-1
Mo-2a
Mo-2b
Mo-3
27
<2
35
90
62
ND
NA
31
90
55
>98:2
NA
31:69
6:94
92:8
58:42
96
83
[a] Performed at ambient pressure (entries 1 and 2) or under 100 Torr
vacuum (entries 3–6). [b] Determined by analysis of 1H NMR spectra of
unpurified mixtures; conv. (ꢂ2%) with dmf as the internal standard.
[c] Yields of isolated and purified products (ꢂ5%). See the Supporting
Information for details. Abbreviations: Mes, 2,4,6-(Me)3C6H2; ND, not
determined; NA, not applicable.
To gain more information as to whether internal carbonyl
chelation hampers reactivity, spectroscopic analysis of the
reaction between Mo-2b with 1b was performed (Scheme 2).
An alkylidene proton resonance appeared in one hour at d
11.47 ppm, which probably belongs to the anti isomer Mo-4
selective but inefficient (Table 1, entry 1) and with
Ru-2[5e] none of the expected product was formed
(entry 2). Reaction with bis-alkoxide Mo-1 pro-
ceeded only to 35% conversion after 4 hours and
was mildly E-selective (31:69 Z:E). There was
90% conversion to the 1,2-disubstituted enoate
with monoaryloxide pyrrolide (MAP) complex
Mo-2a[14] but the E isomer was again formed
preferentially (6:94 Z:E, entry 4) probably due to
facile post-metathesis isomerization. The latter
scenario is consistent with the findings in entries 5
and 6: for CM with Mo-2b, which carries a more
sizeable aryloxide group, conversion was lower
(62% vs. 90% with Mo-2a) but 2a was obtained
with 92:8 Z:E selectivity. With the more active
pentafluorophenylimido Mo-3, there was 96%
conversion after four hours but a nearly equal
mixture of Z and E-2a was generated (58:42).
Our goal then became to find conditions that
would deliver high efficiency and Z selectivity
simultaneously. What made the task particularly
challenging was that enhanced efficiency would
have to be achieved without excess amounts of the
Scheme 2. Preparation and structural analysis of two ester-substituted Mo alkylidene
(non-enoate) terminal alkene. In light of the complexes.
2
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(JCH = 160 Hz).[15] We were also able to secure the X-ray
decreased substantially (14% conv., 60 min; Table 3, entry 4).
In a more concentrated solution (entry 5) 2a was formed in
ꢀ
structure of a closely related anti-alkylidene Mo-5; the Mo O
bond length (2.33 ꢀ) suggests Mo–carbonyl association. The
67% yield and 91% Z selectivity; there was no significant
change in efficiency or stereochemical purity with an equal
mixture of the two substrates (entry 6). With a 1:2 ratio of 1-
decene:1a (entry 7), Z-2a was isolated in 71% yield and 94:6
Z:E selectivity (228C, 1 h).
The method has appreciable range (Scheme 3). With a 1:2
ratio of the a-olefin:1a, Z-enoates 2b–h were isolated in up to
71% yield and > 98% Z selectivity. Reactions with aryl
olefins were hampered by stilbene formation, but those of
sterically hindered vinylcyclohexane afforded 2g in 64%
yield and 94:6 Z:E ratio. Transformations with 1,3-dienes
were less efficient but highly stereoselective (cf. Z,E-2h).[21]
Spectroscopic studies support acetonitrile-Mo coordina-
tion.[22] With more Me13CN the alkylidene proton singlet
moves downfield (Figure 1), consistent with previous obser-
vations.[23] The broader signal, and the absence of separate
resonances for the free and acetonitrile-containing species at
ꢀ
alkylidene C H resonance for Mo-5 appears at d 10.46 ppm
(JCH = 182 Hz), suggesting the major isomer in the initial
process to be anti.
We surmised that internal chelation might be weakened or
entirely inhibited if an external Lewis base, which would
likely be more readily displaced by an alkene substrate, were
to be coordinated to the Mo center. Turnover frequency could
be diminished, but turnover number could increase if olefin
binding and displacement of the external Lewis base were to
become more competitive. Further, the Lewis base-chelated
16-electron methylidene species would be less prone to
decomposition and less able to promote post-metathesis
isomerization.[16] Diminished reactivity could then translate to
superior chemoselectivity. As pointed out previously regard-
ing CM involving Mo-1,[17] an alkyl-substituted alkylidene
might react faster with an electron deficient acrylate and vice
versa. Nonetheless, the challenge here was to identify
a Lewis basic additive that would coordinate readily
with a Mo MAP complex and yet could be displaced by
an olefin.
Mindful of observations regarding increased enan-
tioselectivity of reactions with chiral Mo diolates in
tetrahydrofuran (vs. benzene),[18] we investigated the
CM of 1-decene and 1a in the same solvent. Efficiency
and Z selectivity was notably higher (2a in 70% yield
and 90:10 Z:E; entry 1, Table 3) and more so in a less
concentrated solution (93:7; entry 2). Still, after 30
minutes olefin isomerization became problematic
(69:31 Z:E; entry 3).
We then examined the impact of acetonitrile,[19]
envisioning that this mildly Lewis basic[20] but less
sterically demanding (vs. thf) additive might coordinate
to the Mo complex, disrupting internal chelation. This
would allow the acetonitrile-bound syn alkylidene, the
precursor to a productive metallacyclobutane (cf. IV,
Scheme 1b), to be formed (alkene substrate may dis-
place the MeCN). With acetonitrile as the solvent the model
CM remained highly Z-selective (> 98% Z) but efficiency
Scheme 3. (Z)-a,b-Unsaturated esters obtained through catalytic cross-meta-
thesis. Reactions performed at 100 Torr for 1 h (2b,c), at 100 Torr for 4 h
(2d–f) and at ambient pressure for 24 h (2g–h). See the Supporting
Information for details.
Table 3: Effect of coordinating solvents on the CM leading to Z-2a.[a]
Entry Solvent Mo-3 [m] t [min] Decene: Conv. Yield Z:E[b]
1a
[%][b] [%][c]
1
2
3
4
5
6
7
thf
thf
thf
0.1
0.025
0.025
5
5
3:1
3:1
3:1
3:1
2:1
1:1
1:2
79
71
90
14
88
79
75
70
53
64
ND
67
69
71
90:10
93:7
69:31
>98:2
91:9
91:9
94:6
30
60
60
60
60
MeCN 0.025
MeCN 0.1
MeCN 0.1
MeCN 0.1
[a] Performed under N2 atm. [b] Determined by analysis of 1H NMR
spectra of unpurified mixtures (ꢂ2%). [c] Yields of isolated and purified
products (ꢂ5%). See the Supporting Information for details. Abbrevia-
tion: ND, not determined.
Figure 1. Spectroscopic analysis indicating rapid and reversible forma-
tion of an acetonitrile complex derived from Mo-3 (600 MHz 1H NMR,
228C, C6D6; see the Supporting Information for details).
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different temperatures, implies
rapidly reversible complex for-
mation (Figure 1; in neat ace-
tonitrile; cf. Table 3). An addi-
tional resonance was detected
at
d
10.7 ppm when the
1H NMR spectrum of the
sample containing 0.5 equiva-
lents of Me13CN was recorded
at ꢀ60 to ꢀ808C; we attribute
this to the acetonitrile-free
complex, which was not simul-
taneously
present
when
5.0 equivalents of the additive
was present.[23]
E,Z-Dienoates may be pre-
pared through catalytic CM as
well (Scheme 4), allowing
access to either stereoisomer
of an a,b,g,d-unsaturated ester.
Either a t-butyl or a phenyl
ester may be accessed, as indi-
cated by synthesis of E,Z-4a
and E,Z-5a. Although prod-
ucts were obtained in similar
yield and Z selectivity in this
case, use of t-butyl dienoate
Scheme 4. (E,Z)-Dienoates obtained through catalytic Z-selective cross-metathesis. [a] Overall yield after
removal of the silyl group. [b] 1.5 equiv 1-decene used. [c] Reaction time=24 h. See the Supporting
Information for details.
often led to better outcomes.[21]
Here, adamantylimido Mo-6 is opti-
mal. For example, 5a was generated
with 87:13 Z:E selectivity with Mo-
3. There was < 2% conversion to
the desired product with Ru-1,2 and
Mo-1 (cf. Table 1). Two additional
points are noteworthy: 1) Because
the dienoate carbonyl group can no
longer associate intramolecularly
with the Mo center, addition of thf
or MeCN only led to lower reaction
rates. 2) Excess amounts of the ter-
minal alkene are needed as other-
wise formation of the less reactive[24]
Scheme 5. Application to stereoselective synthesis of the C1-C12 segment of laulimalide.
alkenyl-substituted Mo alkylidene species leads to lower
efficiency.
Acknowledgements
To complete the study, we examined the feasibility of the
aforementioned application regarding synthesis of laulima-
lide (Scheme 5). CM between alkene 6[9b] and 1a (2.0 equiv)
performed in a 10:1 MeCN:PhCN[25] mixture afforded 7 with
91:9 Z:E selectivity. Ester hydrolysis/silyl ether removal and
lactone formation occurred upon treatment with 10 mol% p-
toluenesulfonic acid, affording 8 in 74% overall yield.
Conversion to homoallyl ether 9[10b] was followed by
a second CM, delivering diene 10, formerly utilized in
a former synthesis of laulimalide,[9b] in 63% yield and 94:6
Z:E selectivity.
Financial support was provided by the NIH (GM-59426). We
are grateful to Dr. S. Torker, M. J. Koh, T. T. Nguyen, T. J.
Mann and Dr. E. T. Kiesewetter for helpful discussions.
Keywords: alkenes · catalysis · cross-metathesis · enoates ·
molybdenum
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4
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synthesis to preparation of laulimalide, discussing certain
difficult examples, see: a) J. Mulzer, E. ꢃhler, V. S. Enev, M.
Hanbauer, Adv. Synth. Catal. 2002, 344, 573 – 584; Also see:
Received: August 18, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Olefin Metathesis
Need a Lewis base: The first cases of Z-
selective catalytic cross-metathesis reac-
tions that afford a,b-unsaturated esters
are disclosed. The presence of an orga-
nonitrile is shown to be necessary for
high efficiency. Studies that elucidate the
influence of the added Lewis base, reac-
tions that afford E,Z-dienoates and ap-
plication to synthesis of C1–C12 segment
of laulimalide are described.
E. C. Yu, B. M. Johnson, E. M. Townsend,
R. R. Schrock,
A. H. Hoveyda*
&&&& — &&&&
Synthesis of Linear (Z)-a,b-Unsaturated
Esters by Catalytic Cross-Metathesis. The
Influence of Acetonitrile
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!