Catalytic Z-selective cross-metathesis with secondary silyl- and benzyl-protected allylic ethers: Mechanistic aspects and applications to natural product synthesis

Article abstract of DOI:10.1002/anie.201302538

Get me a Z (olefin): Efficient catalytic cross-metathesis reactions that afford Z-disubstituted allylic silyl or benzyl ethers are reported (see scheme, MAP=monoalkoxide pyrrolide). The approach, in combination with catalytic cross-coupling, provides a general entry to otherwise difficult-to-access alkyne-containing Z olefins. Copyright

Full text of DOI:10.1002/anie.201302538

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Chemie
DOI: 10.1002/anie.201302538
Cross-Metathesis
Catalytic Z-Selective Cross-Metathesis with Secondary Silyl- and
Benzyl-Protected Allylic Ethers: Mechanistic Aspects and Applica-
tions to Natural Product Synthesis**
Tyler J. Mann, Alexander W. H. Speed, Richard R. Schrock, and Amir H. Hoveyda*
Allylic alcohols and derivatives are used regularly in stereo-
selective transformations, where the derived E and Z alkenes
typically deliver different diastereomers and one geometric
form reacts with higher stereoselectivity.[1] Some recently
developed Cu-catalyzed enantioselective allylic substitutions
require Z-allylic phosphates[2] or halides,[3] entities typically
prepared via the corresponding alcohols (Scheme 1). Another
because of steric factors, has not been disclosed. Also
unexplored are related transformations that generate
alkyne-bearing products (cf. 1 and 2, Scheme 1). The impor-
tance of the latter processes is twofold: 1) Catalytic CM of
acetylene-containing substrates is vulnerable to catalyst
deactivation. 2) Synthesis of alkyne-containing Z alkenes by
catalytic partial hydrogenation may be hampered by issues of
chemoselectivity and inseparable by-products.
Herein, we outline the first examples of efficient catalytic
CM processes that furnish Z-disubstituted allylic silyl or
benzyl ethers, many of which contain an alkyne group.[10]
Reactions are promoted at ambient temperature by 1.5–
6.0 mol% of a Mo-based MAP complex; Z alkenes are
obtained in eight hours in 39–87% yield and 78:22 to greater
than 98:2 Z:E ratio. The present studies reveal a number of
mechanistic insights regarding the influence of substrate
structure on CM efficiency and selectivity. Utility is demon-
strated through applications to stereoselective synthesis of
alkyne-containing natural products. It merits mention that the
more recently introduced Z-selective Ru-based catalysts are
yet to be employed effectively with alkenes that bear
a secondary allylic substituent.[11]
Scheme 1. Z-Allylic alcohols and their derivatives serve as substrates in
stereoselective transformations (left), and reside in biologically active
molecules (right). G=functional group, LG=leaving group.
example pertains to diastereoselective Ti-mediated cross-
coupling of allylic alcohols with imines or aldehydes.[4]
Biologically active molecules can contain Z-allylic alcohols
as well; anti-cancer and immunosuppressive agent falcarin-
diol[5] (1, Scheme 1) and related derivatives (e.g., 2)[6] contain
a Z alkene and neighboring alkyne units. Development of
efficient catalytic methods for Z-selective synthesis of allylic
ethers/alcohols is therefore a compelling objective.
We first probed the CM of sterically demanding silyl ether
3 and bromo alkene 4 in the presence of different catalysts at
228C and under a vacuum of 7.0 torr (930 Pascal) to minimize
post-CM isomerization and increase the reaction rate.[9a]
Contrary to Mo–bis(alkoxide)
6
and Ru–carbene
7
(5.0 mol%; Scheme 2), which generate 5 with a strong
preference for the E isomer[12] (5% Z isomer, 76–80%
yield; Table 1, entries 1 and 2, respectively), reaction with
MAP complex 8 (3.0 mol%) furnishes Z-5 in 95:5 Z:E
selectivity (69% yield; Table 1, entry 3). Although conversion
is lower with the MAP complex compared to 6 or 7 (79% vs.
95–98% conv.), the desired allylic ether is isolated in a similar
yield, indicating diminished by-product generation with the
stereogenic-at-Mo catalyst.[13] Catalytic CM with the more
sizeable arylimido-substituted complex 9 is less efficient
(64% conv. vs. 79% conv. for 8; Table 1, entry 4 vs. entry 3)
and 19% of the undesired E alkene is formed, likely because
of a smaller size difference between the arylimido and
aryloxide ligands (vs. in 8).[9a] The less active W–alkylidene
10[14] delivers 5 with the highest Z:E ratio (> 95:5), albeit in
20% yield (Table 1, entry 5).
Catalytic cross-metathesis (CM)[7] offers a broadly appli-
cable approach to olefin synthesis.[8] We have reported that
stereoselective CM of enol ethers or allylic amides with
terminal alkenes can be effected by Mo-based monoalkoxide
pyrrolide (MAP) complexes to afford the higher-energy
Z isomers.[9] Catalytic Z-selective CM with secondary allylic
ethers, starting materials that present a reactivity challenge
[*] T. J. Mann, Dr. A. W. H. Speed, Prof. A. H. Hoveyda
Department of Chemistry, Merkert Chemistry Center
Boston College
Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
Prof. R. R. Schrock
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Next, we probed the effect of cross partner concentration
(Table 2). Because reactions are carried out under vacuum,
excess amounts of a relatively volatile terminal alkene might
be needed; otherwise, 2.0–3.0 equivalents suffice (Table 2),
and the reaction proceeds efficiently with as little as 1.0–
[**] Financial support was provided by the NIH (GM-59426).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302538.
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Table 2: Effect of cross partner concentration on efficiency of Z-selective
CM.[a]
Entry
Equiv. of 4
Conv. [%][b,c]
Yield [%][d]
Z:E[c]
1
2
3
4
5
1.0
1.5
2.0
3.0
10
56
67
79
72
<2
45
65
69
65
NA
91:9
90:10
95:5
95:5
NA
[a] Reactions performed under N2 atmosphere with a vacuum of 7.0 torr
(930 Pascal). [b] Conversions refer to consumption of the substrate
(Æ2%). [c] Determined by 1H NMR analysis of unpurified mixtures.
[d] Yields of isolated and purified products. See the Supporting
Information for details. NA=not applicable.
that a large excess of the less hindered alkene partner can be
deleterious to CM efficiency (< 2% 5 with 10 equiv 4;
Table 2, entry 5); rapid homodimerization of 4 probably
leads to a burst of ethylene production and formation of
a significant amount of the methylidene complex, which is
exceptionally reactive and more prone to decomposition[15]
(vs. alkylidenes derived from 3 or 4).
Scheme 2. Complexes used in the initial screening shown in Table 1.
Mes=2,4,6-trimethylphenyl.
A range of tert-butyl(dimethyl)silyl allyl ethers can be
used (Table 3); the expected silyl ethers, or the corresponding
alcohols (after deprotection; Table 3, entries 1–3 and 5) are
isolated in 61–86% yield and 78:22–95:5 Z:E ratio. In one
Table 1: Initial evaluation of catalysts for stereoselective synthesis of Z-
5.[a]
Table 3: Synthesis of various allyl silyl ethers through Z-selective catalytic
CM.[a]
Entry
Complex; mol%[b]
Conv. [%][c,d] Yield [%][e]
Z:E (5)[d]
1
2
3
4
5
6; 5.0
7; 5.0
8; 3.0
9; 5.0
10; 5.0
95
98
79
64
25
80
76
69
62
20
5:95
5:95
95:5
81:19
>95:5
Entry
Z Alkene Product
Conv.
[%][b,c]
Yield
[%][d]
Z:E[c]
[a] Reactions performed under N2 atmosphere with a vacuum of 7.0 torr
(930 Pascal). [b] Complexes 6, 7, and 10 were prepared separately before
use, whereas 8 and 9 were synthesized from the corresponding
bis(pyrrolide) and the chiral aryl alcohol (5.0 mol% each) and used
in situ; 3.0 mol% of MAP complex 8 is available to catalyze the reaction
because the generation of 8 leads to around 30% bis(aryloxide), which is
significantly less active. [c] Conversions refer to consumption of the
substrate (Æ2%). [d] Determined by 1H NMR analysis of unpurified
mixtures. [e] Yields of isolated and purified products. See the Supporting
Information for details. TBS=t-butyl(dimethyl)silyl.
1
2
89
83
86
72
95:5
95:5
3
4
82
43
80[e]
37[e]
95:5
86:14
5
68
61[e]
78:22
1.5 equivalent of alkene 4. It is particularly noteworthy that
Z selectivity is diminished when less 4 is present (Table 2,
entries 1 and 2 vs. entries 3 and 4); this may be attributed to
the fact that, with lower amounts of the less hindered cross
partner being available, the catalytically active alkylidene
species react more frequently with the Z alkene product (5) to
engender olefin isomerization. Another important point is
[a] Reactions performed under N2 atmosphere with a vacuum of 7.0 torr
(930 Pascal) with 2.0–3.0 equiv. of the cross partner and 3.0 mol% of 8
(generated in situ). [b] Conversions refer to substrate consumption in
the CM step (Æ2%). [c] Determined by 1H NMR analysis of unpurified
mixtures. [d] Yields of purified products. [e] Overall yield (for CM and
desilylation). See the Supporting Information for details.
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Table 4: Synthesis of various allyl p-methoxybenzyl (PMB) ethers
through Z-selective catalytic CM.[a]
instance (Table 3, entry 4), CM does not proceed further than
43% conversion; this result might be due to unfavorable
steric interactions arising from the propinquity of the phenyl
moiety of the benzyl group, which happens to be positioned
most proximally to the adamantylimido unit in the syn-
substituted metallacyclobutane intermediate. In contrast,
a shorter phenyl or a longer and more flexible phen-ethyl
unit might engender a lower degree of steric repulsion with
the aforementioned catalyst moiety (see below for additional
data). Products bearing a relatively small n-alkyl substituent
are isolated with lower Z selectivity (Table 3, entries 4 and 5
vs. 1–3). Control experiments indicate that this is partly the
result of post-CM isomerization, a process expected to be
more facile with alkene products that carry smaller groups.
For example, after 4.0 h, 14 is isolated as an 85.15 Z:E mixture
(38% conv.), and after 36 h, the Z:E ratio drops to 69:31
(81% conv.); similarly, the selectivity with which the TBS
ether of 17 is generated is diminished significantly (from 82:18
in 4.0 h to 65:35 Z:E in 36 h).[16]
Entry
Z Alkene Product
Conv.
[%][b,c]
Yield
[%][d]
Z:E[c]
1
2
3
4
90
43
66
93
85
>98:2
39[e]
60[e]
87[f]
>98:2
>98:2
>98:2
We then turned to CM of less congested p-methoxybenzyl
ethers. Based on the aforementioned findings regarding the
susceptibility of the comparatively exposed Z alkene products
to isomerization (e.g., Table 2, entry 5), we were concerned
whether high stereoselectivity can be retained at high
conversion (vs. silyl ethers). Nevertheless, Z-disubstituted
allyl ethers, or alcohols after oxidative deprotection, are
obtained in 39–87% yield (over two steps; Table 4, entries 2–
4 and 6) and, to our surprise, in 90:10 to greater than 98:2 Z:E
ratios. Thus, high Z selectivity persists at late stages of CM,
and disubstituted alkenes are isolated with generally higher
stereoisomeric purity compared to silyl ethers (Table 3). The
lower efficiency with which 14 is generated versus 16 and 17
(Table 4, entries 1–3) is consistent with the observation
regarding the corresponding silyl ether (Table 3, entry 4).
Propargyl allyl silyl ethers were the third type of
substrates examined, partly as a preamble to the stereoselec-
tive synthesis of the class of natural products shown in
Scheme 1. The concern here was that, in spite of the presence
of a silyl ether, the relatively small alkynyl substituent might
expose the Z olefin product to post-metathesis isomerization.
Again, as with the benzyl ethers in Table 4, in most instances,
Mo-catalyzed CM proceeds readily and in 90:10 to greater
than 98:2 Z:E ratio (Table 5). Only in the case of alkyl-
substituted alkyne is none of the desired products formed
(Table 5, entry 5).
Several unexpected stereoselectivity variations have nota-
ble mechanistic implications. The first set of observations
relate to reactions of substrates that have smaller substituents
and deliver higher Z:E ratios (Tables 4 and 5 vs. Table 3). The
latter findings are in spite of the more hindered alkenes being
expected to furnish alkene products that are better protected
from post-CM isomerization and with higher kinetic Z selec-
tivities.[9] The observed differences are probably tied to the
relative abundance and reactivity of alkylidenes derived from
various cross partners. Unlike complexes originating from the
less hindered (non-allylic ether) monosubstituted olefins (cf.
A, Scheme 3), those represented by B–D are more sizeable
and less prone to causing post-CM isomerization.[17] With silyl
ethers in Tables 1, 2, and 3, generation of B is less facile (vs. C
5
82
70
92:8
6
7
89
91
87[e]
72
90:10
92:8
[a] Reactions performed under N2 atmosphere with a vacuum of 7.0 torr
(930 Pascal) with 2.0–3.0 equiv. of the olefin cross partner. [b] Con-
versions refer to consumption of the substrate in the CM step (Æ2%).
[c] Determined by 1H NMR analysis of unpurified mixtures. [d] Yields of
isolated and purified products. [e] Overall yields (for CM and debenzy-
lation steps). [f] Overall yield (for CM and desilylation steps). See the
Supporting Information for details. TES=triethylsilyl.
or D),[18] and the more reactive A is present at a higher
concentration. As a result, there is more extensive loss of
stereoselectivity through reaction with the Z alkene product.
Another set of observations relates to the effect of alkyne
substituents on catalytic CM (cf. Table 5). For instance, there
is 84% conversion to tert-butyl-substituted 25 with only
1.5 mol% 8 after 1.0 h (Table 5, entry 4) as opposed to 66–
72% conversion to 22–24 with twice the catalyst amount and
longer reaction times (8.0 h; Table 5, entries 1–3). What is
more, allylic ether 26 is not generated (Table 5, entry 5). To
establish if the above reactivity trends are a result of catalyst
deactivation or originate from lack of substrate reactivity, we
performed the experiment shown in Scheme 4. When silyl
ether 27, which undergoes catalytic CM to afford 22 (cf.
Table 5, entry 1), is subjected to the reaction conditions in the
presence of 28, disubstituted alkene 26 is, again, not formed
1
and nor is any 22 detected (according to H NMR analysis
< 2% conversion to any type of product). This finding
illustrates that an uncongested internal alkyne can result in
catalyst deactivation.[19] The proposed scenario explains the
lower catalyst loading and shorter reaction time required for
the larger tert-butyl-substituted alkyne substrate used in
Table 5, entry 4 (1.5 mol% 8 in 1.0 h vs. 3.0 mol% in 8.0 h
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Table 5: Synthesis of various alkynyl silyl ethers through Z-selective
catalytic CM.[a]
Entry Z Alkene Product
Mol%; Conv. [%][b,c] Yield
[%][d]
Z:E[c]
Scheme 4. An unhindered alkyne can lead to catalyst inhibition, as
shown by complete lack of reactivity when allylic silyl ethers 27 and 28
are subjected to the reaction conditions simultaneously.
1
2
3.0; 72
3.0; 73
68
64
>98:2
>98:2
for aryl-substituted variants in entries 1–3). The improved
Z selectivity with aryl-substituted products 22–24 may be
because there is, in spite of the higher loading, less active
catalyst available to prompt olefin isomerization. The lower
conversion in Table 5, entries 1–3 versus 4, are consistent with
the suggested scenario. It is especially noteworthy that CM of
alkyne-containing olefins cannot be efficiently promoted by
Ru-based complexes such as 7. For example, there is less than
2% conversion to any olefin metathesis products, including
no detectable homodimerization of 1-decene, when the
reaction involving a phenyl-substituted propargyl silyl ether
(cf. Table 5, entry 1) is attempted with 5.0 mol% 7 (228C,
16 h);[19] this observation is in contrast to the Ru-catalyzed
CM with non-acetylenic substrates (e.g., Table 1, entry 2).
Stereoselective syntheses of falcarindiol and derivatives 2
and 35 demonstrate the utility of the Z-selective cross-
metathesis (Scheme 5). CM of silyl ether 29 with 1-nonene
and deprotection furnishes propargyl alcohol 30 in 94%
overall yield and 92:8 Z:E ratio.[20] Subsequent Cu-catalyzed
cross-coupling with alkynyl bromide 31 affords falcarindiol.
Similarly, natural product 2 as well as its C16 epimer[21] can be
synthesized in 56% overall yield; the corresponding CM
proceeds in 92% yield and 92:8 Z:E selectivity. The
preparation of the related analogue 2 by altering the structure
of the cross partner, as well as synthesis of trocheliophor-
olide C (35)[22,23] further underscore the power of the catalytic
CM as a stereoselective coupling strategy. The routes in
Scheme 5 obviate the need for fragile Z enals and/or the
difficulties in site-selective partial hydrogenation of poly-
alkynyl substrates.
3
4
5
3.0; 66
1.5; 84
3.0; <2
60
>98:2
90:10
NA
76
NA
[a] Reactions performed under N2 atmosphere with a vacuum of 7.0 torr
(930 Pascal). [b] Conversions refer to consumption of the substrate in
the CM step (Æ2%). [c] Determined by 1H NMR analysis of unpurified
mixtures. [d] Yields of isolated and purified products. See the Supporting
Information for details.
Development of additional catalysts and methods for
stereoselective olefin metathesis are in progress.
Received: March 26, 2013
Revised: May 7, 2013
Published online: June 21, 2013
Keywords: allylic ethers · cross-metathesis · molybdenum ·
.
olefin metathesis · Z olefins
Scheme 3. Different Mo–alkylidenes present in solution: their ease of
formation and reactivity can influence the final Z:E ratios. Ad=ada-
mantyl.
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Scheme 5. Application of Z-selective CM of allylic ethers to the preparation of
falcarindiol (1) and derivatives 2 and 35 (proposed structure), which possess
anticancer, antifungal, and immunosuppressive activity. TIPS= triisopropylsilyl,
TMS=trimethylsilyl.
[10] For a comprehensive review on stereoselective synthesis
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[12] Control experiments indicate that reactions with 6 and 7 are
kinetically E-selective.
[13] Unlike reactions with Mo and W complexes 6 and 8–10, around
10% of an isomeric 1,2-disubstituted product are derived from
olefin-metathesis-based alkene isomerization/CM when Ru–
carbene 7 is used.
[14] For use of W complex 10 in Z-selective macrocyclic RCM
reactions, see: a) M. Yu, C. Wang, A. F. Kyle, P. Jakubec, D. J.
Dixon, R. R. Schrock, A. H. Hoveyda, Nature 2011, 479, 88 – 93;
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[16] The conversions indicated throughout this report correspond to
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[3] Y. Shido, M. Yoshida, M. Tanabe, H. Ohmiya, M. Sawamura, J.
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[17] In complexes represented by B – D, the electron density at the
alkylidene C is stabilized by the adjacent electron-withdrawing
À
C O bond, which lowers the catalytic activity. See: D. S. La, E. S.
Sattely, J. G. Ford, R. R. Schrock, A. H. Hoveyda, J. Am. Chem.
Soc. 2001, 123, 7767 – 7778.
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[18] Accordingly, treatment of MAP complex 8 with 1.0 equiv of the
three allylic ethers shown below affords the derived alkylidenes
with varying degrees of efficiency (2.0 h, 228C, C6D6; by
1H NMR analysis).
[20] An excess amount of the cross partner (10 equiv) is used in CM
leading to 30 due to the relative volatility 1-nonene.
[21] Because of the distal relationship between the stereogenic
centers in 2, the precise stereochemical identity of the natural
product is yet to be determined rigorously. Catalytic CM allows
access to either isomer through the use of the enantiomerically
pure alcohols. Control experiments indicate that there is no
influence on the efficiency or Z selectivity of CM if enantio-
merically pure catalyst/substrates are used in either isomeric
form.
ˇ
[22] T. Rezanka, V. M. Dembitsky, Tetrahedron 2001, 57, 8743 – 8749.
[23] The structure shown for 35 is that proposed for the isolated
natural product (see Ref. [22]). However, spectroscopic analysis
indicates that the suggested structure might require revision. For
similar issues regarding the other members of this family of
compounds, see: a) S. Hwang, J. H. Kim, H. S. Kim, S. Kim, Eur.
J. Org. Chem. 2011, 7414 – 7418; b) B. M. Trost, A. Quintard,
Org. Lett. 2012, 14, 4698 – 4700. Further details are provided in
the Supporting Information.
[19] Diminished catalyst activity might be due to deactivation of the
resulting alkylidene by the sterically accessible alkyne, gener-
ation of a stable metallacyclobutene and/or its subsequent
cleavage to afford a relatively unreactive disubstituted alkyli-
dene. Detailed studies are in progress.
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