Enol ethers as substrates for efficient Z-and enantioselective ring-opening/cross-metathesis reactions promoted by stereogenic-at-Mo complexes: Utility in chemical synthesis and mechanistic attributes

Article abstract of DOI:10.1021/ja210946z

The first examples of catalytic enantioselective ring-opening/cross- metathesis (EROCM) reactions that involve enol ethers are reported. Specifically, we demonstrate that catalytic EROCM of several oxa-and azabicycles, cyclobutenes and a cyclopropene with an alkyl-or aryl-substituted enol ether proceed readily in the presence of a stereogenic-at-Mo monopyrrolide-monoaryloxide. In some instances, as little as 0.15 mol % of the catalytically active alkylidene is sufficient to promote complete conversion within 10 min. The desired products are formed in up to 90% yield and >99:1 enantiomeric ratio (er) with the disubstituted enol ether generated in >90% Z selectivity. The enol ether of the enantiomerically enriched products can be easily differentiated from the terminal alkene through a number of functionalization procedures that lead to the formation of useful intermediates for chemical synthesis (e.g., efficient acid hydrolysis to afford the enantiomerically enriched carboxaldehyde). In certain cases, enantioselectivity is strongly dependent on enol ether concentration: larger equivalents of the cross partner leads to the formation of products of high enantiomeric purity (versus near racemic products with one equivalent). The length of reaction time can be critical to product enantiomeric purity; high enantioselectivity in reactions that proceed to >98% conversion in as brief a reaction time as 30 s can be nearly entirely eroded within 30 min. Mechanistic rationale that accounts for the above characteristics of the catalytic process is provided.

Full text of DOI:10.1021/ja210946z

Article
pubs.acs.org/JACS
Enol Ethers as Substrates for Efficient Z- and Enantioselective Ring-
Opening/Cross-Metathesis Reactions Promoted by Stereogenic-at-
Mo Complexes: Utility in Chemical Synthesis and Mechanistic
Attributes
Miao Yu,§ Ismail Ibrahem,§ Masayuki Hasegawa,§ Richard R. Schrock,⊥ and Amir H. Hoveyda*,§
§Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
⊥Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: The first examples of catalytic enantioselective ring-
opening/cross-metathesis (EROCM) reactions that involve enol ethers
are reported. Specifically, we demonstrate that catalytic EROCM of
several oxa- and azabicycles, cyclobutenes and a cyclopropene with an
alkyl- or aryl-substituted enol ether proceed readily in the presence of a
stereogenic-at-Mo monopyrrolide-monoaryloxide. In some instances, as
little as 0.15 mol % of the catalytically active alkylidene is sufficient to
promote complete conversion within 10 min. The desired products are
formed in up to 90% yield and >99:1 enantiomeric ratio (er) with the
disubstituted enol ether generated in >90% Z selectivity. The enol ether
of the enantiomerically enriched products can be easily differentiated
from the terminal alkene through a number of functionalization procedures that lead to the formation of useful intermediates for
chemical synthesis (e.g., efficient acid hydrolysis to afford the enantiomerically enriched carboxaldehyde). In certain cases,
enantioselectivity is strongly dependent on enol ether concentration: larger equivalents of the cross partner leads to the
formation of products of high enantiomeric purity (versus near racemic products with one equivalent). The length of reaction
time can be critical to product enantiomeric purity; high enantioselectivity in reactions that proceed to >98% conversion in as
brief a reaction time as 30 s can be nearly entirely eroded within 30 min. Mechanistic rationale that accounts for the above
characteristics of the catalytic process is provided.
unaddressed. One deficiency concerns the limited range of
cross partners utilized: nearly all reactions have been with aryl-
substituted alkenes. Furthermore, several problems relating to
stereochemical control stand unresolved. High enantiomeric
ratios are observed in a number of EROCM reactions; in most
instances, however, either E-alkenes are formed predominantly
or exclusively,6a−d,7a−c,e or a mixture of olefin isomers is gene-
rated with little or no stereochemical control.7d,f Another problem
concerns the extensive reaction times (up to 120 h)7e,f that
might be required for achieving high conversion; a more facile
transformation is achievable but only at the expense of higher
catalyst loadings. The issue of catalyst efficiency is a growing
concern with transformations that are promoted by complexes
derived from ruthenium, which is a relatively rare and increas-
ingly precious metal.
1. INTRODUCTION
Advances in catalytic olefin metathesis during the last two
decades have transformed the way in which a great number of
organic molecules can be prepared.1 Cyclic structures of nearly
any size and/or variety as well as a considerable number of
unsaturated acyclic molecules are rendered easily accessible
through this remarkable class of transformations.2 Nonethe-
less, major advances remain to be achieved if catalytic olefin
metathesis is to reach its true potential.3 Discovery and deve-
lopment of catalysts that promote olefin metathesis efficiently
and can control stereoselectivitythat is, furnish high Z or E
selectivity and/or enantioselectivitystands as a critical and
challenging objective.
Since the first efficient cases of catalytic enantioselective
olefin metathesis were reported in 1998 (ring-closing),4,5 ring-
opening/cross-metathesis (ROCM) processes have received
significant attention.6,7 Chiral Mo alkylidenes and Ru-based
carbenes have been developed for desymmetrization of cyclic
alkenes, generating carbo- or heterocyclic dienes enantiose-
lectively. In 2007, we reported the first application of catalytic
enantioselective ring-opening/cross-metathesis (EROCM) to
the total synthesis of natural product baconipyrone C.8 In spite
of the above advances, a number of shortcomings remain
Enol ethers are easily accessible cross partners that might be
used in catalytic EROCM reactions9 to afford versatile enan-
tiomerically enriched products; there are, nonetheless, only a
small number of cases where such O-substituted alkenes have
been utilized as cross partners in intermolecular olefin metathesis
Received: November 30, 2011
Published: January 24, 2012
© 2012 American Chemical Society
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reactions; all reported processes have been catalyzed by an
achiral complex.10 A disclosure by Ozawa in 2000 outlines
a Ru-catalyzed transformation involving norbornene and
phenylvinyl ether; the desired product was obtained in only
17% yield and, notably, with 85% Z selectivity.11 Subsequent
studies by Rainier offer five additional examples of trans-
formations of ethylvinyl ether or enol acetate with 7-oxa- or 7-
azanorbornenes, promoted by achiral Ru-based carbenes; nearly
equal mixtures of Z- and E-alkenes were uniformly generated.12
Thus, to the best of our knowledge, catalytic ROCM or EROCM
reactions that involve an enol ether and which proceed with effec-
tive control of alkene stereoselectivity and/or enantioselectivity
have not been disclosed.
Table 1. ROCM Reactions Involving Enol Ethers Catalyzed
by Some Commonly Used Ru- and Mo-Based Complexes
a
We have developed stereogenic-at-Mo and W complexes that
display the unique ability to catalyze a range of olefin metathesis
reactions with unique levels of efficiency and stereoselectively.13
We have demonstrated that the Mo- or W-based monopyrrolide-
monoaryloxides promote ring-closing metathesis of dienes14 or
enynes15 in high yield and with exceptional enantioselectivity.
Subsequent investigations led us to establish that Z-selective
EROCM16 and homocoupling of terminal alkenes17 as well as
ethenolysis of Z-1,2-disubstituted olefins18 can be performed.
We have put forth the first examples of Z-selective cross-
metathesis processes with enol ethers serving as one set of
cross partners.19 Most recently we have shown that the corre-
sponding tungsten complexes can be used to promote Z-selective
macrocyclic ring-closing metathesis.20 In the case of catalytic
EROCM, highly enantio- and Z-selective, reactions proved to be
largely restricted to aryl olefins (i.e., styrenyl derivatives). Such a
drawback diminishes utility, since the resulting aryl-substituted
alkenes offer a limited range of possibilities for functionalization.21
Here, we report a protocol for efficient, enantio- and Z-selective
ROCM involving an alkyl- or aryl-substituted enol ether in com-
bination with oxa- or azabicyclic alkenes, cyclobutenes or a
cyclopropene. Transformations are promoted by 0.15−3.0 mol
% of a stereogenic-at-Mo monopyrrolide-monoaryloxide and
proceed to completion, typically at 22 °C, within 30 min. The
desired cyclic or acyclic dienes, containing an easily differentiable
terminal alkene and a vinyl ether in addition to one or more
tertiary or quaternary carbon stereogenic centers, are generated in
61−90% yield, 85:15−99:1 enantiomeric ratio (er) and 84:16 to
>98:2 Z:E selectivity. We show that, depending on the structure of
the cyclic alkene, the amount of the terminal olefin present and
the reaction time can have a significant influence on the enan-
tioselectivity and efficiency of the EROCM (but not enol ether
stereochemistry). As will be detailed below, such attributes are
mechanistically important, offering valuable insights regard-
ing the inner workings of this emerging class of olefin metathesis
catalysts.13−20
a
Reactions performed under N2 atmosphere; see the Supporting
b
Information for details. Conversion and alkene stereoselectivity were
determined by analysis of 400 MHz 1H NMR spectra of product
c
mixtures prior to purification. Yield of products after purification by
silica gel chromatography. nd = not determined.
enol ether moiety of the 2,4,6-trisubstituted pyran is generated as a
3:1 mixture of E and Z isomers. With the sterically more con-
gested enol ether 5b as the cross partner (entry 2, Table 1), 95%
of 4a disappears within 30 min, but oligomerization of the cyclic
alkene represents the predominant pathway. In a similar fashion,
with Mo-based diolate 2, the relatively strained alkene is consumed
rapidly, but the desired ROCM product is isolated in 10−14%
yield (entries 3−4, Table 1), and the product enol ether is
generated either nonselectively (1:1 Z:E; entry 3) or with
moderate preference for the Z isomer (80% Z, entry 4).
Finally, when chiral Mo diolate 3 is used, disappearance of
the starting materials is not detected even after 12 h.
2.2. Stereogenic-at-Mo Monopyrrolides as Catalysts
for EROCM Reactions with Enol Ethers and Utility in
Chemical Synthesis. 2.2.1. Initial Examination of Various
Mo-Based Monopyrrolides. Next, we investigated whether
stereogenic-at-Mo monopyrrolide-monoalkoxide or aryloxides
might not only promote EROCM reactions efficiently and with
high enantioselectivity, but deliver the resulting disubstituted
enol ether with a high degree of Z selectivity as well. We thus dis-
covered that reactions with Mo-based monopyrrolide monoalk-
oxide 7 and enol ethers 5a or 5b proceed with significantly
higher efficiency than observed with the complexes shown in
Table 1. As illustrated in entries 1−2 of Table 2, with 1.0 mol %
catalyst in the presence of 1.1 equiv of either cross partner, there
is complete consumption of oxabicycle 4a within 30 min at 22 °C
and 6a-b are obtained in 48% and 75% yield, respectively, and
with ∼80:20 Z:E selectivity (er is not applicable since 7 is
racemic). Based on the formerly proposed models to account
for Z selectivity observed in transformations promoted by
stereogenic-at-Mo complexes,16,19 we surmised that reactions
2. RESULTS AND DISCUSSION
2.1. Preliminary Studies with Commonly Used Ru-
and Mo-Based Complexes. We began by probing the ability
of widely used Ru- and Mo-based complexes to catalyze a
representative ROCM reaction with an enol ether. We selected
silyl-protected oxabicycle 4 as the substrate and examined
processes involving commercially and/or easily accessible
n-butylvinyl ether 5a or p-methoxyphenylvinyl ether 5b
(1.1 equiv vs 4). As the data in entry 1 of Table 1 illustrate, with
Ru carbene 1, 69% disappearance of the cyclic alkene is
observed after 30 min, but only 32% of the desired product (6a)
is isolated; the remainder of the substrate is likely consumed
through oligomerization. Furthermore, the resulting disubstituted
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It is when Mo complex 9a, bearing 3,3′-difluoroaryloxide and
a relatively small adamantylimido (vs 2,6-dialkylarylimido), is
used (entry 7, Table 2) that EROCM with n-butylvinyl ether 5a
proceeds with high efficiency (>98% conv, 87% yield), afford-
ing the desired pyran in high Z- and enantioselectivity (>98% Z
and 97:3 er). The corresponding reaction with p-methox-
yphenylenol ether (5b; entry 8, Table 2) proceeds to 60%
conversion, affording 6b in 41% yield, >98% Z selectivity but a
lower 88.5:11.5 er (vs 97:3 with 5a). The less efficient reaction
could be the result of the larger size of the aryl substituent in 5b
(vs n-Bu in 5a), exacerbated by the lower concentration of the
catalytically active complex (0.07 mol % monopyrrolide-
monoaryloxide generated in situ upon reaction of 1.0 mol %
bispyrrolide and aryl alcohol;22 45−50% of the relatively less
efficient bis-aryloxide14 formed as the major component of the
mixture). It follows that in the presence of the corresponding
dichloroaryloxide 9b (entries 9−10, Table 2), in situ formation
of which is more efficient (0.5 mol % of the desired alkylidene
generated), the EROCM products are isolated in higher yields
(6a in 87% and 6b in 80%), with enantioselectivity remaining
high (98:2 and 92:8 er, respectively) and Z selectivity complete
(>98%) in both instances. When the derived dibromide 9c is
employed (0.6 mol % generated from combination of 1.0 mol %
each of the bispyrrolide and aryl alcohol; entries 11−12), further
improvement in enantioselectivity is achieved and 6a-b are
generated in 99:1 and 98.5:1.5 er, respectively, without diminution
in efficiency (89% and 90% yield, respectively) or control of enol
ether stereochemistry (>98% Z). There is a nearly identical
outcome when diiodoaryloxide 9d is used (entries 13−14, Table 2).
Since preparation of the requisite diiodoaryl alcohol for 9d involves
a relatively lengthy procedure,23 we decided on dibromoaryloxide 9c
as the complex of choice for the follow-up investigations.
Table 2. Highly Efficient, Z- and Enantioselective ROCM
Reactions with Various Stereogenic-at-Mo Complexes
a
2.2.2. Mo-Catalyzed EROCM with Oxabicyclic Alkenes.
We then turned to examining transformations of oxabicyclic
alkenes of varying stereochemical identities that contain dif-
ferent protecting groups at their carbinol site. The results of
this phase of our investigations are summarized in Table 3.
When exo oxabicycle 10a is subjected to 1.1 equivalents of
n-butylvinyl ether 5a (entry 1, Table 3) or p-methoxyphe-
nylvinyl ether 5b (entry 3, Table 3), EROCM proceeds readily
to ≥97% conversion with >98% Z selectivity, but unexpectedly
and in stark contrast to the reactions with the corresponding
endo isomer 6a (cf. Table 2), enantioselectivity is minimal
(52:48 and 56.5:43.5 er for 11a and 11b, respectively). Sub-
sequent studies, further discussed below, allowed us to establish
that when larger amounts of enol ethers 5a-b are utilized, as the
data in entries 2 and 4 of Table 3 illustrate, the desired pyrans
are formed in high enantioselectivity as a single enol ether
isomer (>98% Z) and in 87−88% yield. The findings in entries
5−10 of Table 3, involving EROCM reactions of oxabicyclic
benzyl ethers indicate that the requirement for excess cross
partner for attaining high enantioselectivity is particular to exo
oxabicyclic substrates (compare to entries 9−14 of Table 2). It
should be noted that 12a-b (entries 5−6, Table 3) as well as
13a-b (entries 7−10) are generated with >98% Z selectivity
regardless of the conditions used.
a
Reactions performed under N2 atmosphere in C6H6; see the Supporting
b
Information for details. Except for alkylidene 7, all complexes were
prepared in situ from reaction of 1.0 mol % of the corresponding
bispyrrolide and enantiomerically pure arylalcohol (effective catalyst
loading shown). In the case of 9a−d the catalyst loading shown is
<1.0 mol %, since it represents the amount of monopyrrolide-monoaryloxide
generated in the solution, as judged by the analysis of 400 MHz 1H NMR
spectra (the remainder is either unreacted bispyrrolide or bisaryloxide, which
c
are substantially less active). Conversion and alkene stereoselectivity
were determined by analysis of 400 MHz 1H NMR spectra of product
d
mixtures prior to purification. Yield of products after purification by
silica gel chromatography (< 5%). Enantiomer ratios were
determined by HPLC analysis (< 2%); see the Supporting
Information for details. na = not applicable; nd = not determined.
e
catalyzed by a related alkylidene that carries a larger aryloxide
ligand might deliver improved stereoselectivity. Indeed, as the
findings in entries 3−4 of Table 2 indicate, when dimethylar-
ylimido aryloxide 8a is employed, 6a-b are generated exclusively
as Z enol ethers (>98%) with exceptional enantioselectivity (99:1
er, respectively); however, efficiency is less than desirable, as the
discrepancy between percent conversion and values of isolated
products (cf. entries 3−4, Table 2) indicates incomplete
transformation and significant oligomer formation. When the
sterically more demanding di(i-propyl)arylimido complex 8b is
used (entries 5−6, Table 2), none of the desired EROCM
products are generated within 30 min. After 12 h, under other-
wise identical conditions, reactions with 5a and 5b result in
48% and 31% conversion, 34% and 27% yield and 96.5:3.5 and
97.5:2.5 er, respectively (>98% Z in both cases).
2.2.3. Mo-Catalyzed EROCM with an Azabicyclic Alkene,
Two Cyclobutenes, and a Cyclopropene. Z-Selective Mo-
catalyzed EROCM with enol ethers is not limited to reactions
with oxabicyclic alkenes. As shown in entries 1−3 of Table 4,
reaction with endo azabicycle 14 delivers 2,6-disubstituted
piperidene. Although the process is significantly less efficient
when lower amounts of the enol ether cross partner are employed
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a
Table 3. Z- and Enantioselective ROCM Reactions Promoted by Stereogenic-at-Mo Complex 9c
a
Reactions performed under N2 atmosphere in C6H6 with 0.6 mol % 9c generated in situ from reaction of 1.0 mol % of the bispyrrolide and
b
enantiomerically pure aryl alcohol; reaction time = 30 min; see the Supporting Information for details. Conversion and alkene stereoselectivity were
determined by analysis of 400 MHz H NMR spectra of product mixtures prior to purification. Yield of products after purification by silica gel
chromatography (< 5%). Enantiomer ratios were determined by HPLC analysis (< 2%); see the Supporting Information for details. In addition,
∼20% of the product from cross-metathesis of 10a with another equivalent of 5a is generated (based on 400 MHz H NMR analysis).
c
1
d
e
1
(compare entries 1−2, Table 4), EROCM in the presence of 20
equivalents of 5b (entry 3) generates the desired product with 92%
Z selectivity, in 91:9 er and 90% yield. The relatively diminished
preference for the Z isomer compared to the transforma-
tions involving oxabicyclic alkenes (cf. Tables 2−3) might be
partly because to achieve high conversion with the less reac-
tive azabicycle, elevated temperatures are needed (60 °C vs 22
°C); the reactivity differential is likely the reason for the
necessity of a higher catalyst loading (3.0 vs 0.6 mol %) as well
as the need for excess cross partner (20 equiv 5b). Another
attribute of the reactions with azabicycle 14, one that is unlike the
EROCM of oxabicycles (cf. Table 3), relates to lower Z:E ratios
when fewer equivalents of 5a or 5b are employed. It is likely that
such a difference arises to a degree from alkene isomerization at
elevated temperatures: when the reaction in entry 1 of Table 4 is
analyzed after 30 min (2.0 equiv 5b, 60 °C), an 85:15 mixture
Z- and E-15 is observed (vs 75:25 after 3.0 h). Mechanistic factors
that account for dependence of stereo- and enantioselectivity on
enol ether concentration will be addressed below.
When bis-silylether cyclobutene 16 is used (entries 4−7,
Table 4), similar to endo oxabicycles (Table 3), lower amounts
of the catalyst (0.6 mol %) are sufficient for achieving >98%
conversion; however, the requirement for excess enol ether for
achieving higher enantioselectivity (cf. entries 4 vs 5 and 6 vs 7,
Table 4) is reminiscent of the exo oxabicyclic alkenes (Table 3;
see below for mechanistic rationale). With bis-benzyl ether
cyclobutene 18 as the cyclic alkene (entries 8 and 9, Table 4),
reactions are significantly more sluggish, in spite of the smaller
size of the alkoxy groups (vs OTBS in 16, entries 4−7 of Table 4).
Such a difference in efficiency might be the result of internal
chelation between the Mo center and the sterically accessible
and Lewis basic benzyloxy, leading to the lowering of reaction
rate.24 Accordingly, as shown in entries 8 and 9 of Table 4,
elevated temperatures (60 vs 22 °C in reaction of 16) are
required for achieving complete conversion to bis-benzyloxy
dienes 19a,b, which are formed in 85:15 er and isolated in 61
and 73% yield, respectively. It is noteworthy that the Z:E value
for synthesis of 19a is lower than all other examples; this might
partly arise from the elevated temperatures required for effi-
cient EROCM, which could cause Mo-catalyzed isomerization
of the kinetically preferred Z-enol ether. Isomerization of the
sterically more hindered 1,2-disubstituted alkene in 19b
likely occurs less readily (98% Z; entry 9, Table 4). Catalytic
EROCM of cyclopropene 20 (entries 10−11, Table 4) pro-
ceeds to >98% conversion in 30 min, affording 1,4-dienes
21a,b, bearing a quaternary carbon stereogenic center, with
complete Z selectivity, in 79 and 71% yield and 94.5:5.5 and
96.5:3.5 er, respectively. The lower enantioselectivities ob-
served with cyclobutenes 16 and 18 (entries 4−9, Table 4 vs
cyclopropene 20) is likely due to the lower degree of steric
differentiation between the two faces of the cyclic alkene
(i.e., the oxygen atom of the substituent reduces the effec-
tive size of the silyl and benzyl ether units).
2.2.4. Utility in Chemical Synthesis; Representative
Functionalization of the Enantiomerically Enriched Z-Enol
Ethers. A hallmark of the present class of catalytic reactions is
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monoaryloxide, leading to complete consumption of starting
materials within 10 min to afford the desired heterocyclic Z-
enol ethers in >70% yield and with exceptional stereoselectivity.
The enantiomerically enriched dienes available through
Mo-catalyzed EROCM can be functionalized in a variety of man-
ners; several preliminary examples are provided in Scheme 2.
Table 4. Z- and Enantioselective ROCM Reactions of Enol
Ethers with an Azabicycle, Cyclobutenes, and a
a
Cyclopropene Promoted by Stereogenic-at-Mo Complex 9c
Scheme 2. Representative Functionalization Procedures with
Enantiomerically Enriched Enol Ethers Obtained through
Mo-Catalyzed ROCM Reactions
a
Reactions performed under N2 atmosphere in C6H6; see the
b
Supporting Information for details. All complexes were prepared in
situ from reaction of 5.0 mol % (entries 1 and 8−9; effective catalyst
loading = 3.0 mol %) or 1.0 mol % of the corresponding bispyrrolide
and enantiomerically pure aryl alcohol (effective catalyst loading =
c
0.6 mol %). Conversion and alkene stereoselectivity were determined
by analysis of 400 MHz 1H NMR spectra of product mixtures prior to
d
purification. Yield of products after purification by silica gel
e
chromatography (< 5%). Enantiomer ratios were determined by
HPLC analysis (< 2%); see the Supporting Information for details.
PMP = p-methoxyphenyl.
the degree of efficiency with which these highly Z- and enantio-
selective processes proceed. As further demonstration of the
exceptional facility of the Mo-catalyzed transformations and as
the representative cases in Scheme 1 illustrate, we have been able
Scheme 1. Highly Efficient Mo-Catalyzed Z-Selective
a
EROCM Reactions
A noteworthy aspect of the present approach, in contrast to the
related previously reported protocols involving styrenyl cross
partners, is that the two alkenes of the products are elec-
tronically distinct and can be readily differentiated. Thus, as the
formation of 22 and 23 illustrates, the enol ether moiety can be
efficiently hydrolyzed to afford the desired aldehyde in 87% yield.
Aldehydes such as 22 and 23 are versatile intermediates, allow-
ing access to a range of additional enantiomerically enriched
molecules. γ−δ-Unsaturated aldehyde 23, bearing an all-carbon
quaternary stereogenic center26 at its β carbon constitutes the
product of a conjugate addition, which does not have a catalytic
enantioselective variant available.27
a
All reactions performed under the conditions shown for formation of
6a,b; for details on yields and er values, refer to Tables 2 and 3. See the
Supporting Information for details.
to establish that reactions can be performed in minimal solvent25
in the presence of only 0.15 mol % of the monopyrrolide-
The Z-enol ether of the EROCM products can participate in
stereoselective transformations; two examples are shown in
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Scheme 2. Preliminary studies indicate that diastereoselective
epoxidation/hydrolysis of 6a affords 24, which upon treatment
with diisobutylaluminum hydride is converted to diol 25 as a
3:1 mixture of diastereomers in 43% overall yield.28 Equally
noteworthy is the Cu-catalyzed diastereoselective cycloaddition29
that converts 10a to bispyran 27 in 5:1 diastereoselectivity and 68%
yield. Future development of more efficient strategies, reagents,
and catalysts for functionalization of enol ethers is expected to
enhance the utility of the enantiomerically enriched Z-enol
ethers accessed through catalytic EROCM.
2.3. Mechanistic Analysis. The Significance of Stereo-
genicity at the Mo Center. 2.3.1. Influence of Post-EROCM
Ring Closure on Product Enantiopurity; Rationale for the
Effect of Larger Equivalents of Enol Ether Cross Partner. As
described above, in the case of certain cyclic alkene substrates,
larger equivalents of the enol ether cross partner lead to higher
enantioselectivity (cf. Tables 3 and 4). Specifically, EROCM
reactions with oxabicyclic alkenes that contain an exo-siloxy or
-benzyloxy group (entries 1−4 and 7−10 in Table 3) otherwise
furnish 2,4,6-trisubstituted pyrans with relatively low enantio-
meric purity (52:48−82:18 er vs 92:8−96.5:3.5 er with excess
enol ether); this is in contrast to the corresponding endo deri-
vatives (cf. Table 2 and entries 5−6, Table 3). Another
set of transformations where enantioselectivity improves with
excess enol ether, albeit to a lesser degree, relates to reactions
with cyclobutenes 16 and 18 (cf. entries 4−9, Table 4).
A systematic investigation with different amounts of 5a or 5b,
summarized in Table 5, further underlines the strong depen-
dence of enantioselectivity in Mo-catalyzed EROCM of
the aforementioned selected cyclic alkenes. The level of
Z selectivity, however, is unaltered by enol ether concentration
in the above cases.
One likely reason for the dependence of enantioselectivity in
EROCM of exo- (but not endo-) oxabicyclic substrates is related
to the higher tendency of the corresponding products or the
derived alkylidenes to undergo ring closure; reformation of the
cyclic substrates leads to sequences of ring-opening/ring-
closing reactions that can result in diminution of kinetically
derived er values.30 As illustrated in Scheme 3, the pyran ring
within Mo alkylidene II is able to undergo ring-closing meta-
thesis (RCM) to regenerate 10a; although II can be converted
to the conformational isomer III, the energetic difference is not
such that the latter exists in solution exclusively. Such a chain of
events allows the overall transformation to occur under more
thermodynamically controlled (reversible) conditions, leading
to diminution of enantioselectivity. In contrast, the alkylidene
that is formed through reaction of the endo-oxabicycle (IV,
Scheme 3) is unlikely to participate in a similarly facile RCM to
regenerate the relatively more strained 4a (vs exo-isomer 10a),
since the relatively high-energy all-axial pyran likely isomerizes
rapidly to all-equatorial V, which cannot undergo RCM (Scheme
3). In the presence of excess amounts of enol ether, reaction with
intermediate complexes II or III takes place more readily, mini-
mizing the degree to which enantioselectivity-reducing equilibra-
tion takes place; therefore, higher er values are obtained with an
increase in enol ether concentration.
The validity of the above scenario is supported by the sub-
stantial variations in enantiomeric purity of EROCM products
as a function of reaction time; representative observations are
presented in Table 6. Whereas within 30 s, pyrans 11a and 11b
are obtained in 95:5 and 90:10 er (entries 1 and 2, Table 6),
after only 3 min, enantioselectivity is decreased (84.5:14.5 and
86:14, respectively; entries 3 and 7); particularly in the case of
11a, diminution of enantiomeric purity continues after 30 min
(entries 4 and 8, Table 6). Facile rates of RCM/ROM can
therefore lead to highly efficient erosion of er values.
Table 5. Influence of the Amount of Enol Ether Cross
Partner on the Efficiency and Enantioselectivity of EROCM
Reactions
a,b
To substantiate further the proposed mechanistic scenario,
we resubjected several enantiomerically enriched pyrans to the
reaction conditions to confirm that the aforementioned equili-
bration through RCM of pyran products is indeed detrimental.
As the findings summarized in Table 7 indicate, loss of enantio-
selectivity by post-EROCM isomerization afflicts the reactions
of exo bicyclic substrates (entries 3−4, Table 7) but, as predicted
by the model illustrated in Scheme 3, significantly less erosion
is observed with products derived from reactions of the endo
diastereomers (entries 1−2).
2.3.2. Mo Alkylidene Isomerization through Nonproduc-
tive Olefin Metathesis and Variations in Enantioselectivity;
Rationale for Enhanced Enantioselectivity Due to Increased
Enol Ether Concentration. Another key factor to be considered
is the identity of the alkylidene diastereomer (i.e., S or R at the
Mo center) that reacts with the cyclic alkene. As outlined in
Scheme 4, such principles can dictate which pyran-containing
alkylidene stereoisomer is involved (V vs X, Scheme 4) and
how critical is the facility with which the two oxygen-substi-
tuted alkylidene diastereomers isomerize (i.e., S-I vs R-I leading
to VII vs IX, respectively, in Scheme 4).
a
Reactions performed under N2 atmosphere in C6H6 at 22 °C; see the
b
Supporting Information for details. The requisite complexes were
prepared in situ from reaction of 1.0 mol % of the corresponding
bispyrrolide and enantiomerically pure aryl alcohol (effective loading
of 9c = 0.6 mol %); reaction time = 30 min in all cases. Conversion
c
and alkene stereoselectivity were determined by analysis of 400 MHz
d
1H NMR spectra of product mixtures prior to purification. Yield of
Previous investigations performed in these laboratories
involving examination of various kinetic parameters, and label-
ing studies as well as X-ray structures corresponding to the two
diastereomeric forms of the stereogenic-at-Mo complexes,31
products after purification by silica gel chromatography (< 5%).
e
Enantiomer ratios were determined by HPLC analysis (< 2%); see
the Supporting Information for details.
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Scheme 3. Relative RCM Rate of ROCM Products as a Function of Stereochemical Identity of the Intermediate Alkylidene
blocking of the approach of the incoming alkene, which likely
occurs anti to the pyrrolide, by the large aryloxide ligand. As
shown in Figure 1, the X-ray structure of the related R-
neophylidene isomer shows that the oxygen-based ligand is
held in a particularly unfavorable orientation for alkene sub-
strate approach, partly due to association of one of its halides
with the Lewis acidic metal center.
Table 6. Influence of Reaction Time on the Eficiency and
Enantioselectivity of ROCM Reactions
a,b
If one alkylidene diastereomer (e.g., S-I) reacts preferentially
with the cyclic alkene substrate, then two noteworthy issues
arise:
(1). How the rate with which the two diastereomeric oxygen-
substituted alkylidenes (S-I and R-I) isomerize influences the
overall reaction rate and enantioselectivity. At higher enol
ether concentration, alkylidene diastereomers interconvert
more readily as a result of an increasingly facile nonpro-
ductive (“degenerate”) olefin metathesis, as illustrated in
Scheme 5. When alkylidene isomerization proceeds rapidly, the
more reactive isomer remains more available, allowing EROCM
to proceed rapidly and enantioselectively through the inter-
mediacy of S-I. Both isomeric forms likely promote highly
Z-selective processes, since the size differential between the
adamantylimido and aryloxide ligands, the purported roots of
high alkene stereoselectivity, remains unaltered. The R alkyl-
idene (R-I) diastereomer can promote EROCM via VIII, IX,
and X (Scheme 4) to cause diminution of enantioselectivity,
unless it is quickly isomerized to the S isomer. Rapid conversion
a
Reactions performed under N2 atmosphere in the presence of 5.0
equiv of enol ether cross partner at 22 °C; see the Supporting
Information for details. The requisite were prepared in situ from
reaction of 1.0 mol % of the corresponding bispyrrolide and enantio-
b
merically pure aryl alcohol (effective loading of 9c = 0.6 mol %).
c
Conversion and alkene stereoselectivity were determined by analysis
of 400 MHz 1H NMR spectra of product mixtures prior to purification.
d
Yield of products after purification by silica gel chromatography
e
(< 5%). Enantiomer ratios were determined by HPLC analysis
(< 2%); see the Supporting Information for details.
point to one isomer as substantially more reactive (i.e., the S
isomer of complexes shown in Schemes 3 and 4 is more active).
The primary reason for such a difference appears to be the
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Table 7. Tendency of Diastereomeric ROCM Products to
Undergo Racemization
Scheme 4. Reaction through the S Mo Complex
Diastereomers is Likely More Facile. A Plausible
Mechanistic Model
a,b
a
Reactions performed under N2 atmosphere; see the Supporting
b
Information for details. Enantiomer ratios were determined by HPLC
analysis (< 2%); see the Supporting Information for details. Yield
d
of products after purification by silica gel chromatography (< 5%).
c
Enantiomer ratios were determined by HPLC analysis; see the Supporting
Information for details.
of R-I to S-I ensures a faster rate of formation and yield of the
desired EROCM product as well as higher enantioselectivity.
This proposal is in line with previous mechanistic investigations31
and is further supported by the deuterium scrambling observed
when a mixture of 5b and d3-5b are subjected to 1.2 mol % 9c
(C6D6, 22 °C; Scheme 5); facile scrambling of the atomic labels
takes place within 30 min, generating significant amounts of
d1-5b and d2-5b (detected through high resolution mass
spectrometry). Similarly, when an equal mixture of 5a and
d3-5b is treated with 1.2 mol % 9c, after 30 min all the volatiles
(including 5a and d2-5a) are removed and the remaining
1
residue is analyzed by 400 MHz H NMR spectroscopy, a
45:55 mixture of d1-5b and d2-5b is detected (Scheme 5).32
Such exchange of deuterium likely proceeds through a non-
productive olefin metathesis process via the symmetric metal-
lacyclobutane XI (Scheme 5). The significance of the rate of
isomerization of alkylidene diastereomers is especially relevant
to EROCM reactions with cyclobutene substrates, where sub-
stantially higher ring strain renders post-metathesis RCM un-
likely (in contrast to oxabicycles). The higher enantioselectivity
observed with increasing concentration of enol ether, as shown
in entries 11−14 of Table 5, is probably due to an increase in
the rate of nonproductive olefin metathesis of the enol ether cross
partner, leading to a steady concentration of the more active
and stereochemically discriminating S-I. Similar principles can
be used to explain why in reactions of exo-oxabicyclic alkenes
(e.g., entries 1 vs 2, Table 3), lower enol ether concentration
leads to formation of significant amounts of achiral bis-cross
products. Such a complication concerns EROCM with exo iso-
mers only because, as detailed above (Scheme 3), unlike endo
variants (cf. Table 2 and entries 5−6, Table 3) they can under-
go facile ring closure, allowing increasing amounts of initially
generated chiral pyran to be converted to the achiral bis-cross
product through the pathway shown below (via XIII in Scheme 6).
The above considerations suggest that the less reactive31 R-III
(Scheme 6), derived from S-I, reacts preferably through the
sterically less congested, symmetrically substituted metal-
lacyclobutane XII to produce the corresponding chiral pyran
in high enantioselectivity. In contrast, alkylidene X, a more
reactive and less discriminating S-Mo complex, can give rise to
the formation of the meso-bis-enol ether through metallacyclo-
butane XIII, while generation of the alternative product
enantiomer occurs through XV (Scheme 6). High yields and
enantioselectivities might thus depend on the fast rate of alkyli-
dene isomerization not only because the appropriate alkylidene
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such a way that leads to the chiral product (vs meso). The
improved enantioselectivity in reactions of azabicycle 14
(entries 1−3, Table 4) can be accounted for through similar
reasoning. Moreover, the effect of enol ether concentration on
Z−E selectivity is probably due to minimization of RCM of
the piperidene product to regenerate the starting azabicycle,
which undergoes ring closure faster than the more strained
oxabicycles.6c
(2). The predominant involvement of S-I as the initiating
alkylidene suggests the intermediacy of III (Scheme 3), which
possesses an R stereogenic Mo centeran isomeric form that,
as was described above, is relatively hesitant to react intermol-
ecularly with another alkene substrate. Accordingly, higher con-
centrations of enol ether could be required to enhance the rate
of intermolecular transformation with the cross partner,
minimizing the potentially more facile intramolecular RCM that
leads to loss of enantiomeric purity.
3. CONCLUSIONS
Examples of efficient and highly stereoselective olefin meta-
thesis reactions that involve enol ethers are uncommon; the
first cases of cross-metathesis reactions with this electronically
distinct class of alkenes were developed in these laboratories
only recently.19 In this disclosure, we put forward the first
instances of catalytic EROCM processes that proceed readily
and with exceptional Z selectivity, delivering the desired
products in high enantiomeric purity. The products obtained
from reactions of oxa- or azabicycles, cyclobutenes or cyclo-
propenes cannot be readily accessed by alternative protocols
and are amenable to site-selective functionalization of the enol
ether moiety and should thus prove to be of value in chem-
ical synthesis. As detailed above, enantioselectivity levels can
vary, dictated by various mechanistic aspects of the process.
Figure 1. X-ray structures of two diastereomers of a stereogenic-at-Mo
monopyrrolide monoaryloxide.
isomer can then efficiently participate in the ring-opening
process but also since the latter pathway delivers a diastereomer
(XII, Scheme 6) that reacts more readily with an enol ether in
a
Scheme 5. Interconversion of Diastereomeric Mo Complexes through Nonproductive Olefin Metathesis
a
See the Supporting Information for experimental details.
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Scheme 6. Reaction through Different Alkylidene Diastereomers Can Afford Entirely Different Products
Additionally, an aspect that is particular to the class of
stereogenic-at-metal catalysts used in these studies is the facility
with which the complex diastereomers interconvert, strongly
impacting the stereochemical outcome of the reaction. That is,
conditions that accelerate the rate of isomerization between the
diastereomeric forms of such complexes (e.g., excess cross
partner) by nonproductive olefin metathesis pathways can be
used to impact the reaction outcome.
ACKNOWLEDGMENTS
■
Financial support was provided the NIH (GM-59426).
Additional support was provided by the John LaMattina
Funds (graduate fellowship to M.Y.) and the Swedish Research
Council (postdoctoral fellowship to I.I.). We thank S. J. Meek,
S. J. Malcolmson, Robert V. O’Brien, and Rana M. Khan for
helpful discussions. X-ray crystallographic facilities at Boston
College are supported by the NSF (CHE-0923264).
The catalytic transformations described in this report bear
further testimony to the unique ability of monopyrrolide
stereogenic-at-metal complexes to promote highly efficient and
stereoselective olefin metathesis reactions. Design and
development of additional catalysts and methods for stereo-
and enantioselective olefin metathesis reactions involving enol
ethers, as well as application of catalytic EROCM processes
described herein to efficient preparation of biologically active
complex molecules19,20 are in progress.
REFERENCES
■
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data for substrates and
products; crystallographic information files. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
̈
amir.hoveyda@bc.edu
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formation and reversion of the minor isomer is higher) requires a
longer time to achieve equilibration, since with every reverse/forward
sequence, less of the minor enantiomer, which less readily participates
in the reverse reaction, is generated. The larger the amount of the
minor enantiomer generated with each cycle, the less time it takes to
accumulate 50% of that isomer (i.e., reach complete equilibration
between the two enantiomers).
(31) Meek, S. J.; Malcolmson, S. J.; Li, B.; Schrock, R. R.; Hoveyda,
A. H. J. Am. Chem. Soc. 2009, 131, 16407−16409.
(32) Enol ethers do not undergo homocoupling or cross-metathesis
reactions with other vinyl ethers. Thus, the observed deuterium scra-
mbling is not due to such processes followed by monomer re-
generation through ethynolysis.
2799
dx.doi.org/10.1021/ja210946z | J. Am. Chem.Soc. 2012, 134, 2788−2799