Efficient and selective formation of macrocyclic disubstituted Z alkenes by ring-closing metathesis (RCM) reactions catalyzed by Mo- or W-based monoaryloxide pyrrolide (MAP) complexes: Applications to total syntheses of epilachnene, yuzu lactone, ambrettolide, epothilone C, and nakadomarin A

Article abstract of DOI:10.1002/chem.201204045

The first broadly applicable set of protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Cyclizations are performed with 1.2-7.5 mol % of a Mo- or W-based monoaryloxide pyrrolide (MAP) complex at 22 °C and proceed to complete conversion typically within two hours. Utility is demonstrated by synthesis of representative macrocyclic alkenes, such as natural products yuzu lactone (13-membered ring: 73 % Z) epilachnene (15-membered ring: 91 % Z), ambrettolide (17-membered ring: 91 % Z), an advanced precursor to epothilones C and A (16-membered ring: up to 97 % Z), and nakadomarin A (15-membered ring: up to 97 % Z). We show that catalytic Z-selective cyclizations can be performed efficiently on gram-scale with complex molecule starting materials and catalysts that can be handled in air. We elucidate several critical principles of the catalytic protocol: 1) The complementary nature of the Mo catalysts, which deliver high activity but can be more prone towards engendering post-RCM stereoisomerization, versus W variants, which furnish lower activity but are less inclined to cause loss of kinetic Z selectivity. 2) Reaction time is critical to retaining kinetic Z selectivity not only with MAP species but with the widely used Mo bis(hexafluoro-tert-butoxide) complex as well. 3) Polycyclic structures can be accessed without significant isomerization at the existing Z alkenes within the molecule.

Full text of DOI:10.1002/chem.201204045

DOI: 10.1002/chem.201204045
Efficient and Selective Formation of Macrocyclic Disubstituted Z Alkenes by
Ring-Closing Metathesis (RCM) Reactions Catalyzed by Mo- or W-Based
Monoaryloxide Pyrrolide (MAP) Complexes: Applications to Total
Syntheses of Epilachnene, Yuzu Lactone, Ambrettolide, Epothilone C, and
Nakadomarin A
[
a]
[a]
[b]
[b]
[b]
Chenbo Wang, Miao Yu, Andrew F. Kyle, Pavol Jakubec, Darren J. Dixon,
[
c]
[a]
Richard R. Schrock, and Amir H. Hoveyda*
Abstract: The first broadly applicable
set of protocols for efficient Z-selective
formation of macrocyclic disubstituted
alkenes through catalytic ring-closing
metathesis (RCM) is described. Cycli-
zations are performed with 1.2–
tolide (17-membered ring: 91% Z), an
advanced precursor to epothilones C
and A (16-membered ring: up to 97%
Z), and nakadomarin A (15-membered
ring: up to 97% Z). We show that cata-
lytic Z-selective cyclizations can be
performed efficiently on gram-scale
with complex molecule starting materi-
als and catalysts that can be handled in
air. We elucidate several critical princi-
ples of the catalytic protocol: 1) The
complementary nature of the Mo cata-
lysts, which deliver high activity but
can be more prone towards engender-
ing post-RCM stereoisomerization,
versus W variants, which furnish lower
activity but are less inclined to cause
loss of kinetic Z selectivity. 2) Reaction
time is critical to retaining kinetic Z se-
lectivity not only with MAP species
but with the widely used Mo bis(hexa-
fluoro-tert-butoxide) complex as well.
3) Polycyclic structures can be accessed
without significant isomerization at the
existing Z alkenes within the molecule.
7
.5 mol% of a Mo- or W-based mono-
aryloxide pyrrolide (MAP) complex at
28C and proceed to complete conver-
2
sion typically within two hours. Utility
is demonstrated by synthesis of repre-
sentative macrocyclic alkenes, such as
natural products yuzu lactone (13-
membered ring: 73% Z) epilachnene
Keywords: catalysis · macrocyclic Z
alkenes
· molybdenum · olefin
metathesis · synthesis · tungsten
(
15-membered ring: 91% Z), ambret-
Introduction
are several reasons for such a strong predilection. Alkenes
are relatively robust and yet can be readily modified in a va-
riety of ways once the cyclization products are in hand; C–C
double bonds do not typically require protection and un-
masking in the course of a synthesis route; by comparison,
and as an example, the alcohol and carboxylic acid (or
equivalents thereof) required to bring about a lactonization
must often be differentiated from other polar functional
groups at the time of the ring closure. Reliability is another
factor—an attribute that receives increasing credence with
every new total synthesis that utilizes this set of processes.
Catalytic RCM has played a prominent role in connection
with the synthesis of macrocyclic alkenes, a structural motif
Few transformations have had as palpable an impact on or-
ganic chemistry as catalytic alkene ring-closing metathesis
RCM). During the last two decades, the routes to count-
less molecules, natural products or otherwise, with one or
more cyclic moieties have contained an RCM reaction that
generates a small-, medium-, or large-ring olefin. There
[
1]
(
[2]
[
a] Dr. C. Wang, M. Yu, Prof. A. H. Hoveyda
Department of Chemistry
Boston College
[3]
Chestnut Hill, MA 02467 (USA)
Fax : (+1) 617-552-1442
found in an array of biologically active molecules. Since
[4]
[5]
the disclosures by Villemin and Tsuji in 1980, concerning
non-stereoselective macrocyclic RCM reactions promoted
by (ill-defined) W-based complexes, making evident the po-
tential value of catalytic RCM, a glaring deficiency in cata-
lytic alkene metathesis has persisted: the absence of cata-
lysts that reliably deliver kinetic control of stereoselectivity
in the formation of large-ring olefins. Dependence on sub-
strate control—attaining stereoselectivity that would origi-
nate from the thermodynamic preference for one alkene ge-
ometry—does not typically lead to the selective formation
of the targeted isomer; E and Z olefins are frequently gen-
E-mail: amir.hoveyda@bc.edu
[
b] A. F. Kyle, Dr. P. Jakubec, Prof. D. J. Dixon
Department of Chemistry
Chemistry Research Laboratory
University of Oxford
Oxford OX1 3TA (UK)
[
c] Prof. R. R. Schrock
Department of Chemistry
Massachussetts Institute of Technology
Cambridge, MA 02139 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204045.
2726
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Chem. Eur. J. 2013, 19, 2726 – 2740

FULL PAPER
erated in near equal ratios or, even less favorably, it is the
undesired product that is obtained predominantly. A catalyst
class that furnishes dependable control of the stereochemi-
cal outcome in a macrocyclization would enhance the utility
of this important collection of catalytic processes. In spite of
such a shortcoming, it is catalytic RCM that is perhaps com-
monly viewed as the most suitable approach to macrocyclic
ring formation; such is true even in the precarious situations
where the cyclization must be implemented after a multistep
sequence is expended to obtain the requisite precursor—
when a non-selective RCM can reduce the yield of the de-
sired alkene isomer and the entire synthesis route by 50%
or more (see below for examples).
Cyclizations of starting materials ranging from sparsely to
amply functionalized dienes outline the relationship be-
tween optimal catalyst activity and the nuances of substrate
structure. Our investigations indicate that the more confor-
mationally mobile substrates might require Mo-based com-
plexes; in contrast, with the relatively preorganized unsatu-
rated chains, use of the less active W catalysts can be pref-
erable. We elucidate the basis of the high chemoselectivity
furnished by W-based catalysts; such complexes catalyze
RCM but exhibit minimal tendency to react with the result-
ing and relatively strained macrocyclic Z olefin and cause
isomerization to the E isomer. The latter attribute is high-
lighted through a total synthesis of nakadomarin A, where
the RCM process used to install the cyclooctene moiety pro-
ceeds without significant erosion of Z:E ratio at the sensi-
tive fifteen-membered ring alkene site. We demonstrate that
with the relatively robust W-based alkylidenes, which can be
handled without rigorous exclusion of air and moisture,
gram-scale RCM reaction of a structurally complex diene
can be carried out efficiently and with effective kinetic con-
trol of stereoselectivity.
Development of complexes that preferentially provide the
Z alkenes constitutes a hard challenge. One principal com-
plication arises from the reversible nature of catalytic olefin
metathesis, which threatens the survival of the often ener-
getically less favored Z isomer. There are, therefore, two
distinct but equally significant requirements for successful
design of efficient Z-selective catalysts that promote macro-
cyclic RCM: not only must such species facilitate the forma-
tion of the higher energy alkene isomer with exceptional se-
lectivity, they must then refrain from reacting with it to
cause adventitious Z-to-E isomerization. The latter compli-
cation regarding chemoselectivity grows increasingly daunt-
ing as substrate conversion escalates and the concentration
of the product surpasses that of the starting terminal olefins.
Herein, we detail the outcome of our investigations re-
garding the development of the first class of catalytic olefin
metathesis reactions that provide high efficiency and Z se-
lectivity in the synthesis of macrocyclic disubstituted al-
Results and Discussion
Mechanistic models for Z selectivity in macrocyclic RCM
promoted by MAP complexes: We begin by an analysis of
the origin of Z selectivity in the projected macrocyclic RCM
reactions and some of the structural features that lead to ef-
fective catalysis by Mo- and W-based MAP complexes. Such
an examination helps elucidate the nature of some of the
difficulties faced in the course of development of the pres-
ent class of transformations.
[6]
kenes; we show that an assortment of large-ring structures
can be accessed stereoselectively through transformations
promoted by Mo- or W-based monoaryloxide pyrrolide
[
10]
Based on the Z-selective ring-opening/cross-metathesis
as well as cross-metathesis reactions studied before,
[7]
[11]
(
MAP) complexes. Syntheses of yuzu lactone, epilachnene,
we
ambrettolide, as well as anticancer and antibacterial agents
projected that control of olefin stereochemistry originates
from sufficient size differential between the imido (Figure 2)
and aryloxide ligands of the catalyst. Thus, as shown in
Figure 2, the bulky and freely rotating aryloxide can force
the alkene, tethered to the metal–alkylidene, to coordinate
with the metal center so that the resulting metallacyclobu-
tane substituents are oriented towards the smaller imido
unit (cf. III, Figure 2). Productive decomposition of III
would furnish alkene complex IV and subsequent release of
macrocyclic Z olefin produces methylidene complex V,
which can react with another diene molecule to re-generate
I/II.
[8]
[9]
epothilones A and C and nakadomarin A (Figure 1)
have been accomplished through catalytic Z-selective RCM.
In all cases, reactions with previously available catalysts
either afford a near equal mixture of alkene isomers
(
ꢀ 65:35) or furnish the undesired E alkene predominantly.
[12]
Olefin metathesis is inherently reversible; as depicted
by the general pathway in Figure 3 (box), the kinetically
generated Z alkene can be catalytically isomerized to the
(
often) lower energy E isomer. Consequently, the same fac-
tors that lead to high Z selectivity make available a pathway
for catalytic post-RCM isomerization. The steric repulsion
between the alkylidene substituent and the sizeable arylox-
ide, shown in complex VI (Figure 3), culminates in a strong
preference for modes of reaction represented by I/II
(Figure 2). It follows that re-association of an E macrocyclic
Figure 1. Natural products with a Z macrocyclic alkene examined in this
study.
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2727

A. H. Hoveyda et al.
Figure 3. A general scheme for catalytic post-RCM isomerization; struc-
tural attributes that result in high Z selectivity can also lead to facile
post-RCM isomerization.
alyst optimal for a more conformationally mobile substrate,
versus one that is more rigid, might be distinct; such studies,
together with subsequent investigations involving the more
highly functionalized dienes (i.e., precursors to epothilone C
and nakadomarin A), would help delineate factors regarding
the suitability of different catalyst classes and various sub-
strate types.
Figure 2. Key structural features of MAP alkylidenes responsible for high
Z selectivity in macrocyclic RCM reactions.
Stereoselective synthesis of epilachnene: We chose the fif-
teen-membered ring macrolactone epilachnene (cf.
[
13]
alkene with the complex, as featured in VII (Figure 3),
would be similarly unfavorable compared to the correspond-
ing system containing the Z isomer (cf. IV, Figure 2). That
is, the Z olefin products are more susceptible towards under-
going ring-opening reactions that lead to Z-to-E isomeriza-
tion (cf. Figure 3), whereas any E alkene formed is less
prone to re-enter the catalytic cycle. The above considera-
tions further emphasize the central challenge in designing
olefin metathesis catalysts that efficiently and selectively de-
liver the less energetically favored stereoisomers: the metal
complex must be sufficiently active and discriminating to
generate the Z alkene with a strong preference but not too
potent so that the fragile kinetic selectivity can be pre-
served.
Scheme 1), secreted by the Mexican bean beetle as part
[14]
of its pupae defense mechanism,
to serve as the initial
platform for our investigations. The basis for this selection
was partly because the aza-macrolide natural product has
been synthesized through catalytic diene RCM as well as
alkyne RCM/catalytic hydrogenation strategies; any limita-
tion in the state-of-the-art in connection with either synthe-
sis route could be evaluated and addressed. A catalytic ster-
eoselective RCM furnishing epilachnene would represent a
more efficient approach than those formerly outlined, and
would likely be applicable to the synthesis of an assortment
of other sparingly substituted macrocycles.
[15]
Previous syntheses of epilachnene: The results of extant in-
vestigations regarding synthesis of epilachene are summar-
ized in Scheme 1. In the presence of Mo-based bis-alkoxide
1, Ru-based bis-phosphines 2a and 2b or those that
bear an N-heterocyclic carbene (2c,d),
monly used in olefin metathesis, diene 3 is preferentially
converted to the undesired E isomer (67–75%). To address
this problem, as shown in Scheme 1, an alternative stereose-
lective route, involving W- or Mo-catalyzed alkyne metathe-
Z-Selective macrocyclic RCM of less substituted dienes: We
began by examining reactions of several relatively unfunc-
tionalized diene precursors as the means to investigate sev-
eral fundamental aspects of the cyclization process. The in-
fluence of ring size and different types of linking units (e.g.,
carboxylic esters or amides) on the efficiency and stereose-
lectivity of macrocyclization reactions would hence be
probed. We surmised that the requirements rendering a cat-
[16]
[17]
[18]
[19,20]
complexes com-
[21]
[22]
sis, was introduced. Catalytic RCM with the diyne sub-
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Z-Selective Ring-Closing Metathesis
FULL PAPER
diyne precursor to 4 (before amine protection) was accom-
plished in eleven steps (longest linear sequence of eight
[22]
steps); in contrast, diene 3 is prepared in five steps from
inexpensive materials; such discrepancy is due to several
factors, among which is the larger number of inexpensive
commercially available olefinic compounds.
4
) Catalytic alkyne RCM may need elevated temperatures
(
Scheme 1). However, more recent advances have led to the
development of catalysts that do not call for the use of
chlorinated solvents and/or an additive and operate at ambi-
[24]
ent temperature.
Z-Selective diene RCM with MAP complexes: Treatment of
[25]
unsaturated amine 3 with 1.2 mol% Mo-based adamanty-
limido alkylidene 6 or 5.0 mol% W-based metallacyclobu-
tane arylimido complex 7 (Scheme 2) delivers epilachnene
in 70% and 82% yield and 91% Z selectivity. The suitabili-
ty of the aforementioned complexes was established through
an initial screening of a simpler model system, details of
which were disclosed in the preliminary account of this in-
[6]
vestigation. Several additional aspects of the above find-
ings are noteworthy:
[26]
1
) Metallacyclobutane 7 is sufficiently robust that it can
be weighed in air and various manipulations can be per-
formed in a fume hood with standard glassware. The W-cat-
alyzed cyclization, performed at 0.1 gram-scale, entailed
handling of the W-based complex in air at nearly 80% hu-
midity level.
2
) Metallacyclobutane 7 is prepared by subjection of a sol-
ution of the corresponding neophylidene complex to an at-
mosphere of ethylene; this complex can be viewed as a
more attractive option for catalyzing olefin metathesis reac-
tions, compared to its more sterically congested alkylidene
precursor, perhaps due to a faster rate of initiation [i.e., re-
lease of ethylene in solution affords the active methylidene
(cf. V, Figure 2)].
Scheme 1. Previous approaches to epilachnene involving catalytic ring-
closing alkene and alkyne metathesis reactions; unless otherwise noted,
findings are from this study. Fmoc=9-fluorenylmethoxycarbonyl.
3
) The Z-selective synthesis of epilachnene by catalytic
diene RCM does not demand protection and deprotection
of the amine unit, underscoring the stability of the Mo- and
W-based alkylidenes towards this commonly occurring class
of functional groups (in contrast to the corresponding alkyli-
dynes; cf. Scheme 1).
strate delivers the macrocyclic alkyne in approximately 70%
yield; subsequent partial hydrogenation, promoted by Lin-
dlarꢁs catalyst (i.e., deposited Pd-containing Pb salts) leads
to the formation of the Z olefin. The latter route delivers
exceptional Z selectivity (<2% E); however, several issues
are worthy of note:
Stereoselective synthesis of yuzu lactone, ambrettolide and
other relatively unfunctionalized Z-macrocyclic olefins:
Macrocyclic esters or amides of different ring sizes can be
synthesized by the use of Mo or W alkylidenes 6 and 7 with
unprecedented Z selectivity and with efficiency levels that
should render the method of notable utility; relevant results
are summarized in Table 1. The disparity between the per-
cent conversion and yield is largely due to adventitious oli-
1) The basic amine must be masked in order to achieve
high catalyst activity, leading to the addition of two steps to
the synthesis route (protection and removal of the Fmoc
group); the deprotection step was reported to proceed in
[22]
62% yield (Scheme 1).
2) Preparation of methyl-substituted internal alkyne, typi-
1
cally involving deprotonation of the corresponding acetylene
and alkylation with iodomethane, is needed (vs. terminal
C–C triple bonds); otherwise, oligomerization processes
gomerization (as judged by H NMR analysis).
Two of the macrocycles are natural products: the thirteen-
membered camphor- and minty-smelling yuzu lactone (en-
tries 1–4, Table 1), and seventeen-membered musk-odored
ambrettolide (entries 17–20). For comparison, and to under-
line the uniqueness of the MAP complexes, the data regard-
[23]
dominate.
) In general, preparation of alkyne-containing substrates
tends to be less concise than that of dienes. Synthesis of
3
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2729

A. H. Hoveyda et al.
9
6
3:7 E:Z ratio in entries 5 and
in Table 1. Yet, catalytic
RCM reactions with 6 or 7 pro-
vide 80–82% of the Z macrocy-
clic alkene, pointing to a sub-
stantial degree of catalyst con-
trol with the MAP complexes
(
entries 7 and 8, Table 1).
Z-Selective macrocyclic RCM
en route to epothilone C: The
next phase of our studies re-
lates to examining the catalytic
RCM reaction that have served
as precursors to epothilones C
[29]
and A. In such instances, lack
of stereoselectivity in the RCM
reactions is costly since cycliza-
tion takes place at the end of a
multistep route to the requisite
[30]
diene;
further complicating
the matter, as reported pre-
[29c]
viously
and in our experi-
ence, the desired macrolactone
is virtually inseparable from the
E
isomer. Moreover, it has
been demonstrated that olefin
stereochemistry impacts the
level of biological activity. Fi-
nally, access to the appropriate
[31]
Scheme 2. Practical and Z-selective synthesis of epilachnene.
macrocyclic alkene precursors
ing the RCM promoted by Mo alkylidene 1 and Ru-based
carbene 2c are presented in Table 1; with the latter two
complexes, in all cases, substantial amounts of the E alkenes
are formed and at times with a significant preference (93%
E in entries 5 and 6, Table 1). With Mo- and W-based alkyli-
denes 6 and 7, there is 69–73% Z selectivity in the forma-
tion of thirteen-membered yuzu lactone, whereas a higher
are required if the subsequent functionalizations are to pro-
ceed with the desired sense of stereochemical control (e.g.,
epoxidation or cyclopropanation ).
[29]
[32]
One goal of this segment of our studies was to showcase
the practical utility of the catalytic RCM approach. A highly
Z-selective RCM leading to epothilone A—particularly if
performed on gram-scale and in a practical manner—would
bear notable implications regarding the efficiency with
which macrocyclic natural products and their corresponding
analogues, including those that are not accessible through
fermentation procedures, can be accessed in meaningful
quantities. Additionally, the substrate is significantly more
functionalized and thus its conformational mobility more re-
stricted than those probed earlier. Accordingly, we set out
to establish whether the requirements for optimal Z-selec-
tive macrocyclic RCM are distinct from those that effect
cyclizations furnishing the less substituted macrocycles.
93:7 Z:E ratio can be obtained with sixteen-membered ring
1
0 (entry 15, Table 1), the identity of which was further con-
[27]
firmed through X-ray crystallography.
The above-men-
tioned Z selectivity variations as a function of ring size sug-
gest that a comparatively strained ring (e.g., yuzu lactone)
undergoes ring-opening more readily (cf. Figure 2 and 3)
and alkene isomerization proceeds at a faster rate. In this
vein, when the RCM with complex 6 leading to yuzu lactone
is analyzed after 10 min (20% conv.), 82% of the Z alkene
is found in the mixture (vs. 69:31 Z:E after one hour). It can
be concluded that, at least in certain cases involving rela-
tively strained products, post-RCM isomerization is more
competitive, giving rise to relatively high E:Z selectivity
when the highly active bis-alkoxide 1 is used (e.g., 83% E,
Effect of catalyst structure on Z selectivity: The RCM-
based approach towards the sixteen-membered ring moiety
of epothilone C has been investigated by several research
[
28]
[29]
entry 1 vs. 44% E, entry 13, Table 1).
Calculations indi-
groups;
the desired Z olefin was formed as the minor
ꢁ
1
cate that the E-8 isomer is 1.9 kcalmol lower in energy
isomer in most cases and in equal amounts to the undesired
[27]
[30]
than its corresponding Z isomer, thus predicting approxi-
mately 96% E selectivity in a cyclization that is under ther-
modynamic control; such findings compare favorably with
E alkene in others; the examples in entries 1–3 of Table 2
are representative (see below for a more detailed analysis of
these earlier findings). As with epilachnene (cf. Scheme 1),
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Z-Selective Ring-Closing Metathesis
FULL PAPER
[
a]
Table 1. Synthesis of macrocyclic esters and amides through catalytic Z-selective RCM.
[b]
[e]
Entry
Macrocyclic Z alkene
Complex
Loading
[mol%]
Conditions
Conv.
[%]
Yield
[%]
Z:E
[
c]
[d]
A
H
U
G
R
N
U
G
1
2
3
4
1
2c
6
5.0
5.0
3.0
5.0
ambient
ambient
7.0 torr
7.0 torr
92
93
63
74
30
46
49
46
17:83
15:85
69:31
73:27
7
5
6
7
8
1
2c
6
5.0
5.0
3.0
5.0
ambient
ambient
7.0 torr
7.0 torr
97
98
74
82
67
74
50
54
7:93
7:93
80:20
82:18
7
9
1
2c
6
5.0
5.0
3.0
5.0
ambient
ambient
7.0 torr
7.0 torr
96
98
72
56
68
50
nd
21:79
15:85
95:5
nd
1
1
1
0
1
2
7
<20
13
14
15
16
1
2c
6
5.0
5.0
3.0
5.0
ambient
ambient
7.0 torr
7.0 torr
93
98
81
<20
53
60
69
nd
56:44
66:34
93:7
nd
7
17
18
19
20
1
2c
6
5.0
5.0
3.0
5.0
ambient
ambient
7.0 torr
7.0 torr
95
95
85
90
65
61
77
78
23:77
24:76
91:9
7
88:12
[
2
a] Reactions were carried out in purified toluene (5.0 mm) at 228C for one h under an atmosphere of N or under vacuum, as noted; see the Supporting
Information for details. [b] Complexes 1, 2c and 7 were prepared prior to use, whereas alkylidene 6 was synthesized in situ from the corresponding bis-
pyrrolide and aryl alcohol, proceeding in approximately 60% yield (3.0 mol% effective catalyst loading). See the Supporting Information for details.
1
[
c] Conversion and Z:E ratios measured by analysis of 400 MHz H NMR spectra of unpurified mixtures; Z:E ratios for 10 and ambrettolide was estab-
1
3
lished by analysis of C NMR spectra; the variance of values are estimated to be ꢂ2%. [d] Yield of isolated products (isomeric mixtures) after purifica-
tion; the variance of values are estimated to be ꢂ5%. nd=not determined.
the indirect route of utilizing catalytic alkyne RCM/partial
hydrogenation strategy has been applied to this problem;
similar analysis regarding the two strategies applies here as
well.
Use of Mo-based adamantylimido alkylidene 6 and W-
mization of the concentration of the exceptionally reactive
and relatively unstable methylidene complexes (cf. V,
Figure 2), which can be generated by reaction of an alkyli-
dene intermediate with the volatile ethylene (formed as by-
product). When the W-catalyzed RCM is performed with
3.0 mol% 13 at 0.05m concentration, 12a is formed in 63%
yield and 97% Z selectivity (entry 9, Table 2).
[33]
based di ACHTUNGTRENNUNG( iPr)imido complex 7 (entries 4 and 5 of Table 2)
gives rise to a significant reversal of selectivity in favor of
the desired Z-12a, delivering 85:15 and 79:21 Z:E selectivi-
ty, respectively. We attribute the improved stereochemical
control with the Mo complex (6 vs. 7) to the larger size dif-
ference between an adamantylimido and the aryloxide li-
In a similar fashion, diene 11b, a diastereoisomer of 11a,
can be converted to macrocyclic olefin 12b in 84% yield
and with 91% Z selectivity [Eq. (1)]. The relatively lower
degree of stereochemical control, versus RCM of 11a (96:4
Z:E), might be because there is a stronger inherent prefer-
ence for the formation of the undesired E alkene in the case
of 11b (i.e., substrate- vs. catalyst-control are in stronger op-
position); this is reflected in the slightly higher percentage
of E isomer generated when the reaction is carried out with
Mo bis-alkoxide 1 (28% Z vs. 33% Z with 11a). The finding
in Equation (1) bodes well for the utility of MAP complexes
in the preparation of analogues of this class of naturally oc-
gands (vs. a 2,6-(iPr) phenylimido in 7; cf. Figure 2). Support
2
for the above proposal is found in the exceptional Z selec-
tivity observed with W-based alkylidene 13 (structure shown
in Scheme 3) even at a relatively high concentration for a
[34]
macrocyclization (0.05m),
when reaction of the active
complex with the Z macrocycle is more likely to occur;
under the latter conditions, macrolactone 12a is isolated in
up to 86% yield and with only 4% contamination with the
undesired E isomer (entry 8, Table 2). The positive influence
[36]
curring molecules.
[35]
of reduced pressure (entries 6 and 7, Table 2), as detailed
The above findings, collectively, reaffirm the notion that it
is the capacity to generate high kinetic Z selectivity together
[11]
previously, is tied to enhancing catalyst longevity by mini-
Chem. Eur. J. 2013, 19, 2726 – 2740
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2731

A. H. Hoveyda et al.
stereoisomeric
purity
with
which a macrocyclic product is
isolated, we chose to examine
the extent of the influence of
such processes, vis-ꢂ-vis the for-
mation of macrolactone 12a in
greater detail.
Studies with Mo-based bis-alk-
oxide 1: We first probed the
ring closure performed in the
with possessing the appropriate balance of sufficient (but
not too high) reactivity levels that render W complex 13 the
most attractive choice for macrocyclic RCM of the heavily
functionalized dienes such as 11a (another relevant case will
be presented below). The validity of such reactivity/Z selec-
tivity relationships finds additional support in the variations
in the conversion and Z selectivity values obtained for RCM
of dienes leading to sparsely functionalized macrocyclic lac-
tones 8, 14, and ambrettolide, respectively (Scheme 3). Com-
pared to the transformations with complexes 6 and 7, W-
based alkylidene 13 provides generally lower conversion as
a result of its subordinate activity (vs. Mo- based MAP com-
plexes). On the other hand, higher Z:E values are observed
in reactions with the corresponding conformationally more
flexible dienes when 13 is employed (e.g., vs. 11a): the less
effective complex does not promote post-RCM isomeriza-
tion or no more than to a minimal degree.
presence of Mo complex 1, a transformation originally dis-
[29b]
closed in 1997 (entry 1, Table 2).
The highly reactive
complex (1) generates 67:33 Z:E ratio; based on our investi-
gations described above, we suspected that post-RCM iso-
merization might be partly responsible for such preference.
To probe this possibility, we investigated the degree of ster-
eochemical control in the RCM of 11a promoted with bis-
alkoxide 1 as a function of time. These studies led us to de-
termine that, remarkably, as illustrated in Scheme 4, within
only ten minutes, there is 92% conversion to 12a, which is
isolated in 89% yield (inseparable isomeric mixture) and
72:28 Z:E selectivity. When the RCM reaction is performed
at 7.0 torr, Z selectivity is not improved, indicating that the
selectivity largely represents the degree of kinetic control.
The latter finding is significantly superior to 33% Z report-
ed previously for the same reaction being performed with
[29b]
20 mol% 1 for the duration of one hour (86% yield).
The same considerations likely apply to the RCM process
shown in Equation (1) (with diastereomer 11b). These find-
ings point to the importance of the need for careful determi-
nation of the optimal catalyst loading and/or reaction time
Study of olefin metathesis-based post-RCM isomerization
in reactions with 12a: Considering the significant role that
stereoisomeric interconversion can play in determining the
[
a]
Table 2. Catalytic RCM for stereoselective total syntheses of epothilones C and A.
[
b]
[c]
Entry
Complex
Loading
[mol%]
Conditions
t [h]
Temp. [8C]
Conv.
[%]
Yield
[%]
Z:E
[
c]
[d]
A
T
N
T
E
N
N
[
[
e]
e]
1
2
3
4
5
6
7
8
9
1
20
10
5.0
10
10
10
10
5.0
3.0
ambient; 1.0 mm (C
ambient; 1.5 mm (CH Cl )
2 2
6
H
6
)
1.0
20
16
1.5
2.5
2.5
2.5
2.0
3.0
22
25
40
22
22
22
22
22
22
>98
>98
96
87
72
77
98
98
97
86
85
nd
nd
nd
nd
86
86
63
33:67
54:46
34:66
85:15
79:21
96:4
96:4
96:4
97:3
2b
2d
6
ambient; 1.0 mm (C
ambient; 1.0 mm (C
ambient; 1.0 mm (C
ambient; 1.0 mm (C
1.0 torr; 1.0 mm (toluene)
1.0 torr; 0.01 m (toluene)
1.0 torr; 0.05 m (toluene)
7
H
6
H
6
H
6
H
8
6
6
6
)
)
)
)
7
13
13
13
13
[
2
a] Reactions were carried out under an atmosphere of N or vacuum; see the Supporting Information for details. [b] Complex 2d, 7 and 13 were pre-
pared prior to use, whereas alkylidene 6 was synthesized in situ from the corresponding bis-pyrrolide and aryl alcohol, proceeding in approximately 60%
yield of the MAP complex (ca. 3.0 mol% effective catalyst loading). See the Supporting Information for details. [c] Conversion and Z:E ratios measured
1
by analysis of 500 MHz H NMR spectra of unpurified mixtures; the variance of values are estimated to be ꢂ2%. [d] Yield of isolated products after pu-
rification (isomeric mixture); the variance of values are estimated to be ꢂ5%. nd=not determined. [e] See Ref. [29b]. [f] See Ref. [29a].
2732
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Chem. Eur. J. 2013, 19, 2726 – 2740

Z-Selective Ring-Closing Metathesis
FULL PAPER
conspire to furnish relatively
moderate
pared to that delivered with W-
based alkylidene 13 (cf.
Z selectivity com-
Table 2). Further, the higher ac-
tivity of the Mo bis-alkoxide,
versus a MAP complex such as
1
3, manifested by a more effi-
cient post-RCM isomerization,
leads to a more facile erosion
of kinetic selectivity.
2
) Although there is no de-
tectable difference in selectivity
during the first ten minutes of
the Mo-catalyzed transforma-
tion (Scheme 4), substantial Z-
to-E
isomerization
occurs
within 30 min (72:28!33:67
Z:E). In stark contrast, in the
cyclization with Ru-based car-
bene 2d, the E isomer is fa-
vored early on (Scheme 4), sug-
gesting that the cyclization
process might be kinetically E-
selective. The relatively low ac-
tivity of the Ru complex makes
it unlikely that olefin isomeriza-
tion is occurring.
Scheme 3. Reactivity versus Z selectivity furnished by W-based complex 13.
Studies with MAP complexes:
We then turned to a more de-
tailed analysis of the possible
impact of post-RCM isomeriza-
tion in reactions with Mo- and
W-based complexes 6 and 13.
Due to the relatively high Z se-
lectivities observed with the
latter two alkylidenes (ꢃ85:15),
we chose to investigate the
extent of loss of stereoselectivi-
ty which could occur upon re-
subjection of a sample of 92:8
mixture Z- and E-12a to a solu-
tion containing the activated
forms of alkylidenes 6 and 13,
respectively. Thus, as depicted
Scheme 4. Z Selectivity as a function of time in RCM promoted by complex 1.
in Scheme 5, a sample of Mo
complex 6 was pre-treated with
when carrying out catalytic RCMs that generate disubstitut-
ed macrocyclic alkenes; vigilant analysis of changes in the
olefin stereochemistry as the cyclization progresses, regard-
less of which class of catalysts is being employed, might be
necessary for achieving the best results.
diallylether to generate methylidene 15, the species released
upon RCM and responsible for initiation of a new catalytic
cycle (cf. V, Figure 2). Subsequent in vacuo removal of resid-
ual diallylether and the ethylene generated was followed by
the addition of ten equivalents of 12a (corresponding to
10 mol% catalyst loading). After 90 min, the macrolactone
was recovered as an 81:19 mixture of Z and E isomers (vs.
the initial 92:8 ratio). In contrast, when an identical proce-
dure is performed with W alkylidene 13, there is no detecta-
Two additional points regarding this aspect of our studies
are worthy of note:
1) The reduced size differential between the arylimido
and hexa-fluoro-tert-butoxide ligands within Mo complex 1
Chem. Eur. J. 2013, 19, 2726 – 2740
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2733

A. H. Hoveyda et al.
formed on gram-scale with MAP alkylidene 13 in an effi-
cient and stereoselective fashion. We surmised that the relia-
bility of the catalytic protocol would be more convincingly
illustrated if the Z-selective RCM were to be carried out
with a starting material prepared by a relatively protracted
[30,29a]
sequence (i.e., 16 steps for 11a).
To accomplish this
task, however, first, a significant revision of the originally re-
ported route to 11a had to be implemented; otherwise,
access to sufficient quantities of the diene proved to be too
costly and labor intensive. A modified synthesis Scheme was
[37]
accordingly developed,
allowing us to secure nearly 12
grams of 11a. Some of the notable attributes of the revised
route for preparation of enantiomerically pure 11a include a
highly diastereoselective aldol addition (96:4 vs. 60:40 d.r.
reported previously), the need for fewer equivalents of
enantiomerically pure intermediates and smaller number of
[27]
purifications through silica gel chromatography.
We subsequently determined that in the presence of
6
.5 mol% W complex 13, RCM can be effected with gram
quantities of 11a to afford macrocycle 12a, precursor to
epothilones C and A, in 83% yield and with 95% Z selec-
tivity (Scheme 6). The transformation reaches 95% conver-
sion within four hours at 228C and proceeds readily when
performed in a typical laboratory fume hood with humidity
levels reaching approximately the 80% level.
Scheme 5. Olefin metathesis-based post-RCM isomerization of macrocy-
clic epothilone C precursor 12a with a Mo- and a W-based complex.
TBS=tert-butyldimethylsilyl.
ble loss of stereoselectivity (Scheme 5). The above experi-
ments demonstrate that, whereas some loss of Z selectivity
can take place in the course of RCM when Mo complex 6 is
used, the methylidene derived W-based alkylidene 13 reacts
with exceptional chemoselectivity with the terminal alkenes
of 11a in preference to the cyclic disubstituted olefin in 12a.
The small amount of E-12a, formed in the reactions with 13,
is probably due to a lack of perfection in kinetic selectivity
(
i.e., reaction via complex related to VI, Figure 3).
Practical aspects of W-catalyzed macrocyclic RCM: Di-
chlorophenylimido MAP alkylidine 13 is sufficiently stable
such that it can be handled and weighed in open air; the
requisite apparatus can be set up and reactions performed
in a typical fume hood without the need for strict exclusion
Scheme 6. A practical catalytic method for Z-selective macrocyclic RCM.
Z-Selective RCM reactions en route to nakadomarin A:
The final stage of our investigations corresponds to the for-
mation of two ring structures, one macrocyclic and the other
a cyclooctenyl moiety, en route to stereoselective total syn-
thesis of nakadomarin A. The earlier approaches utilized
olefin metathesis to prepare the larger ring structure of na-
kadomarin A, albeit with relatively low efficiency (15–
30 mol% Ru complex) and minimal or stereoselectivity in
[27]
of air and moisture.
When complex 13, which must be
stored under inert atmosphere (e.g., N ) for long-term stor-
2
age, is exposed to air, there is ꢀ10% decomposition within
ten minutes (as judged by spectroscopic analysis), more than
sufficient time to set up a reaction.
To challenge further the practical aspects of the W-cata-
lyzed protocol, we chose to establish whether the W-cata-
lyzed RCM of the relatively complex diene 11a can be per-
[38]
favor of the undesired isomer (~2:1–1:2 E:Z). Due to the
2734
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Chem. Eur. J. 2013, 19, 2726 – 2740

Z-Selective Ring-Closing Metathesis
FULL PAPER
ineffective stereochemical control in the macrocyclic ring
formation, as with epilachnene and epothilone C, strategies
involving alkyne RCM/partial hydrogenation sequence have
strained tetracyclic diyne-diamide was thus required
(100 mol% Mo(CO) , 500 mol% 2-fluorophenol, 0.26 mm,
6
[39c]
C H Cl, reflux, 2.5 h; 39% yield).
The relative facility of
6
5
[22,39]
been introduced.
We demonstrated in our initial disclo-
catalytic RCM with diene 18 (Scheme 7) and the strong re-
sistance of the aforementioned diyne in regards to cycliza-
tion point to the sensitivity of the alkyne metathesis cata-
lysts towards basic amines as well as the comparative ease
with which a less strained macrocyclic alkene can be synthe-
sized (vs. a large ring alkyne).
Study of olefin metathesis-based strategies en route to to-
wards nakadomarin A offers a distinct framework for outlin-
ing some of the advantages offered by high-oxidation metal
complexes (Mo- and W-based) versus Ru carbenes. The role
of adventitious olefin-metathesis-based isomerization on the
observed stereoselectivity can be further probed in the con-
text of another relatively complex but structurally distinct
polycyclic molecule (vs. epothi-
[
6]
sure that in the presence of W alkylidene 13, macrocyclic
RCM reactions with tetracyclic substrate 16 as well as the
more strained pentacyclic 18 proceed efficiently and with
exceptional Z selectivity (90% yield and 97:3 Z:E and 63%
yield and 94:6 Z:E, respectively); these advances are sum-
marized in Scheme 7.
Attempts to effect alkyne RCM of the Me-substituted
diyne corresponding to 18 and bearing the two Lewis basic
tertiary amines, with either Mo- or W-based alkylidynes, in-
[24]
cluding the more recently developed variations, has been
reported to lead to <5% conversion even with 30–50 mol%
of a metal complex and at 808C (up to 18 h). Use of a less
lone C precursor 11a). What is
more, the polycyclic constitu-
tion of nakadomarin A pro-
vides the opportunity for inves-
tigation of whether the alkene
within the eight-membered ring
can be formed through Mo- or
W-catalyzed RCM after the rel-
atively sensitive macrocyclic
olefin has been generated and
without significant diminution
in the stereochemical purity of
the latter. Such studies would il-
lustrate whether the RCM cata-
lysts can be used for stereose-
lective preparation of polycyclic
structures where the stereo-
chemical integrity of one or
more Z alkene units must be
preserved while additional rings
are being generated.
Comparison of macrocyclic
RCM reactions with Ru- versus
W-based complexes: In contrast
to the findings in Scheme 7, the
most selective formerly report-
ed procedure for conversion of
1
8 to nakadomarin A involved
the use of 20 mol% Ru carbene
b; three equivalents of
2
a
strong Brønsted acid was also
required so that 63% Z selec-
[38d]
tivity could be achieved.
The
difficult nature of the latter
RCM process originates largely
from the relatively high ring
strain associated with the Z
alkene-containing macrocycle.
Hence, it is the less active first-
Scheme 7. W-Catalyzed Z-selective RCM en route to nakadomarin A. BOC=tert-butyloxycarbonyl.
Chem. Eur. J. 2013, 19, 2726 – 2740
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2735

A. H. Hoveyda et al.
generation Ru carbene (vs. 2c and 2d), which must be
added at a slow rate to the reaction mixture, that preserves
the small kinetic preference for the Z alkene isomer.
Study of olefin metathesis-based post-RCM isomerization
in catalytic RCM of diene 16: We subjected samples of fif-
teen-membered ring structure 17, consisting of 97% of the
Z alkene to solutions of Mo-based methylidene 15 and that
derived from W-based complex 13 (Scheme 8). As in the
case of 12a, substantial loss of Z selectivity is detected
within one hour in the case of Mo complex 6 (from 3% to
18% E). In contrast to the macrocycle precursor to epothi-
lone C where alkene isomerization is undetected (cf.
Scheme 5), however, the presence of the less reactive meth-
ylidene derived from 13 leads to recovery of a sample of 17
that is of slightly lower Z:E ratio (93:7 vs. 97:3; Scheme 8).
It is likely that, as a result of diminished steric hindrance
and a higher degree of angle strain within the macrocyclic
unit of 17, in contrast to 12a, there is a stronger sensitivity
towards ring-opening/ring-closing sequence (cf. Figure 3),
culminating in lowering of stereochemical purity at the ole-
finic site. Considering that the reaction time for the conver-
sion of 16 to 17 is two hours (cf. Scheme 7; vs. 1.0 h in
Scheme 8), it is probably that at least part of the 3% E-17
obtained is the result of some post-RCM isomerization,
rather than any imperfection in kinetic selectivity delivered
by W complex 13. The above findings emphasize the diffi-
culty posed by an efficient and highly Z-selective macrocy-
clic RCM route to the polycyclic natural product.
Scheme 8. Examination of catalyst-induced post-RCM isomerization of
nakadomarin A precursor 17 with a Mo- and a W-based complex.
active Ru carbene 2b (entry 2, Table 3), 100 mol% loading,
heating to 408C and 24 h of reaction time are required for
achieving >98% conversion, but formation of the cyclooc-
tene ring proves costly: there is substantial reduction in the
Synthesis of the cyclooctene ring through catalytic RCM;
impact on macrocyclic alkene stereochemistry: Studies with
diamide 19: As mentioned earlier, an intricate RCM reac-
tion leading to nakadomarin A involves conversion of pen-
tacyclic diamide 19 to hexacyclic 20 (Table 3), which can be
synthesized from 17 in four
[40]
macrocyclic Z:E ratio (72% vs. 95% Z). There is no de-
tectable conversion to 20 with W-based alkylidene 13, even
when 30 mol% of the starting complex is utilized (entry 3,
Table 3). When 10 mol% of Mo-based MAP alkylidene 21
steps and 66% overall yield.
Table 3. Synthesis of nakadomarin A cyclooctene ring through catalytic RCM of a diamide precursor. Effi-
ciency and competitive Z-to-E isomerization of the macrocyclic alkene.
The resulting hexacyclic prod-
uct would subsequently be con-
verted to the target molecule
through reduction of the amide
functional groups (e.g., dibal–
H). Can the strained hexacyclic
natural product be synthesized
without significant isomeriza-
[
a]
tion of the macrocyclic
alkene?
Z
Conversion of bis-amide
diene 19 to eight-membered
ring lactam 20 proceeds to 60%
conversion in the presence of
[b]
[c]
Entry
Complex
Loading
[mol%]
Solvent
toluene
CH Cl
2 2
toluene
toluene
t [h];
Temp.
[8C]
Conv.
[%]
Yield
[%]
Z:E (macrocycle)
[c]
[d]
A
H
U
G
R
N
U
G
1
2
3
4
1
30
100
30
6.0
24
24
24
22
40
22
80
60
>98
<5
39
90
na
32
90:10
72:28
na
2b
13
21
30 mol% Mo complex 1 after
10
72
95:5
six hours at 228C (entry 1,
Table 3); the desired product is
obtained with minor loss of
macrocyclic alkene stereoiso-
[
a] Reactions were carried out in purified toluene (5.0 mm) at 228C an atmosphere of N
see the Supporting Information for details. [b] Complex 1, 2b, and 13 were prepared prior to use, whereas al-
kylidene 21 was synthesized in situ from the corresponding bis-pyrrolide and aryl alcohol. See the Supporting
2
or under vacuum;
1
Information for details. [c] Conversion and Z:E ratios measured by analysis of 400 MHz H NMR spectra of
meric purity. With the less unpurified mixtures. [d] Yield of isolated and purified product. na=not applicable.
2736
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Z-Selective Ring-Closing Metathesis
FULL PAPER
is employed (entry 4), ring closure occurs without loss of
stereochemistry in spite of the elevated temperature and ex-
tended reaction time (808C, 24 h); nevertheless, a large por-
tion of 19 remains unreacted (28%) and there is significant
amount of hompocoupling product under the somewhat
severe conditions (hence, 32% yield of 20 in entry 4,
(entries 2 and 3, Table 4: 95:5!85:15 and 82:18 Z:E, respec-
tively); it is noteworthy that W complex 7 delivers similar
degrees of Z-to-E olefin isomerization as is observed with
Mo species 6 (see Scheme 2 for another example). There is
minimal RCM when Mo-based MAP complex 21 is used
(entry 4, Table 4). The higher activity obtained with alkyli-
dene 6 as opposed to 21 can be attributed to the smaller size
of the adamantylimido ligand (vs. the 2,6-dialkylphenylimi-
do). In all instances, where complete disappearance of
triene 22 is observed (entries 1–3, Table 4), a relatively wide
gap exists between the conversion and isolated yield values
(>98% conv vs. 32–43% yield). The origin of the latter dis-
crepancy is the formation of a considerable amount of un-
identifiable byproducts that likely arise from oligomeriza-
tion reactions involving the two terminal olefins in 22 or
those generated through ring-opening of the macrocyclic
moiety (determined by spectroscopic analysis). It is similarly
feasible that the terminal alkenes that serve as precursors to
either the large or medium rings, some generated through a
ring-opening process, can participate in RCM reactions with
one another, leading to the formation of the alternative pol-
ycyclic products. Parallel issues regarding byproduct forma-
tion were observed in Mo-catalyzed reactions with diamide
19 (Table 3, entries 1 and 4).
[41]
Table 3).
There are several possible reasons for the comparative
lack of efficiency in catalytic RCM reactions for converting
19 to 20. The angle strain associated with the formation of
the desired hexacyclic diene is compounded by the presence
of the two rigidifying amide groups; a related rationale has
been put forth vis-ꢂ-vis cyclooctene formation through
[39b]
RCM with a macrocyclic diyne substrate.
The sterically
hindered vinyl group bearing a substitution at its allylic site
can discourage facile ring closure. Finally, there is the possi-
bility that the alkylidenes and carbenes derived from initial
reaction at the either of the terminal alkenes might be parti-
ally deactivated due to intramolecular chelation with a
[42]
neighboring Lewis basic amide carbonyl.
Studies with diamine 22: Based on the above-mentioned im-
pediments we synthesized diamine 22 (dibal–H, 75% yield)
and examined the possibility of converting it to nakadomar-
in through catalytic RCM. As shown in entry 1 of Table 4,
the presence of 10 mol% bis-alkoxide 1 gives rise to com-
plete erosion of Z selectivity within one hour (95:5!55:45
Z:E). With the sterically more demanding Mo alkylidene 6
or tungstacyclobutane 7, substrate 22 is consumed at the
same rate, but formation of the eight-membered ring amine
is accompanied by significantly less diminution in Z:E ratio
Considering the outcome of the experiments summarized
in Scheme 5 and 8 in connection with post-RCM isomeriza-
tion, it follows that with W-based MAP complex 13 forma-
tion of the cyclooctene ring occurs with the least degree of
loss in the stereoselectivity at the macrocyclic alkene site.
Specifically, as shown in Scheme 9, with 5.0 mol% of W
Table 4. Synthesis of nakadomarin A cyclooctene through catalytic RCM
of a diamine precursor. Efficiency and competitive Z-to-E isomerization
[
a]
of the macrocyclic alkene.
[
b]
[c]
Scheme 9. Synthesis of nakadomarin A through cyclooctene formation by
W-catalyzed RCM. Minimal isomerization at macrocyclic alkene site.
Entry
Complex
Conv.
Yield
[%]
Z:E (macrocycle)
[
c]
[d]
[%]
1
2
3
4
1
6
7
21
>98
>98
>98
17
32
38
43
nd
55:45
85:15
82:18
nd
complex 13, hexacyclic diamine 22 can be transformed to
nakadomarin A in 56% yield (64% based on recovered sub-
strate) with 91:9 Z:E ratio for the larger ring olefin. With
10 mol% 13, under otherwise identical conditions, the natu-
ral product is obtained in 48% yield and 88:12 Z:E ratio
(>98% conversion); thus, with lower catalyst loading, a
better balance between efficiency and preservation of kinet-
ic selectivity can be achieved, resulting in 12% of recovered
[
1
[
a] Reactions were carried out in purified toluene at 228C for 6.0 h under
.0 torr of under vacuum; see the Supporting Information for details.
b] Complexes 1, 6, and 7 were prepared prior to use; alkylidene 21 was
synthesized in situ from the corresponding bis-pyrrolide and aryl alcohol.
See the Supporting Information for details. [c] Conversion and Z:E ratios
measured by analysis of 400 MHz H NMR spectra of unpurified mix-
tures. [d] Yield of isolated products after purification; the variance of
1
values are estimated to be < ꢂ5%. nd=not determined.
Chem. Eur. J. 2013, 19, 2726 – 2740
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2737

A. H. Hoveyda et al.
22 and less product decomposition and post-RCM isomeri-
zation.
Comparison with the previous approaches: Conversion of
pentacyclic diamine 22 to nakadomarin
A demands
40 mol% of Ru carbene 2b and eight hours of reaction
time, as shown in Scheme 9. Moreover, significantly more
dilute conditions (0.3 vs. 5.0 mm) and 300 mol% of camphor-
sulfonic acid are needed (60–70% conv., 27% yield and
60% E, otherwise). It is worthy of note that, in spite of the
fact that formation of the cyclooctene moiety in the majority
of the formerly reported total syntheses of nakadomarin A
was implemented in the absence of the rigidifying macrocy-
[38,39c]
clic alkene,
proved necessary for achieving a reasonably efficient cycli-
zation.
20–100 mol% of a Ru-based carbene
[38a–c,e]
Figure 4. Efficient and Z-selective and complementary Mo- and W-cata-
lyzed macrocyclic RCM.)
Conclusion
The ability of Mo- and W-based MAP species to promote
Z-selective macrocyclic ring formation substantially enhan-
ces the effectiveness of one of the most critical and com-
monly employed transformations in chemistry. Successful
applications to total syntheses of epilachene, epothilone C,
and nakadomarin A leads to a near doubling of the overall
efficiency with which these notable biologically active natu-
ral products can be accessed through an RCM-containing
route. Our findings confirm that in planning a multistep
pathway for the preparation of a complex molecule, the Mo
as well as the W complexes can be relied upon to deliver
the desired outcome at the late stages of an extended syn-
thesis scheme. As the result of the appropriate reactivity ex-
hibited by the Mo or W catalysts, which are tolerant of basic
amines, RCM reactions can be carried out often with mini-
mal or no alkene isomerization.
An outcome of the present studies is the complementarity
of the Mo- and W-based catalysts. In situations where the
substrate dienes do not enjoy a higher degree of preorgani-
zation, the high activity of Mo-based alkylidenes might be
needed; in cases where the relatively rigid starting materials
are involved, and in particular where post-RCM isomeriza-
tion can be detrimental, the relatively less active W alkyli-
denes might emerge as the catalysts of choice (Figure 4).
The elucidation of the finely balanced activity profile fur-
nished by the Mo and W monopyrrolide complexes and the
significance of reaction time to the preservation of kinetic
selectivity in catalytic olefin metathesis reactions are two of
the noteworthy lessons learned in the course of these inqui-
ries. Equally noteworthy is the possibility of accessing poly-
cyclic ring structure through W-catalyzed RCM reactions
that are efficient and do not cause significant Z-to-E isomer-
ization of an alkene site within the same molecule.
lysts and strategies detailed above. The advances put forth
in this report are expected to exert a wide-ranging and im-
mediate impact on the synthesis of an assortment of organic
molecules.
Experimental Section
Procedure for gram-scale Z-selective macrocyclic ring-closing metathesis:
ꢃ
A 500 mL Schlenk flask was fitted with an Airfree connecting adapter.
The connecting adapter was fitted with a rubber septum; the flask was
then connected to an N -filled manifold. The apparatus was flame-dried
2
and charged with diene 11a (1.05 g, 1.43 mmol, used without azeotropic
removal of water through distillation with benzene). W-based complex
1
3·toluene (99.0 mg, 0.0926 mmol) was weighed on a balance (in air) and
added to the reaction vessel. (The remaining W complex was transferred
back to an N -filled dry box.) The resulting mixture was subjected to
vacuum, back-filled with N three times and charged with mesitylene
285 mL, freshly distilled); the valve on the connecting adapter was
2
2
(
closed to isolate the septum from the vessel. The resulting solution was
exposed to vacuum (0.60 torr) and allowed to stir for four hours at 228C,
after which the reaction was quenched through the addition of diethyl
ether (ca. 1 mL; undistilled). Purification by silica gel chromatography
(hexanes/Et
Z/E) as a white foam along with recovered starting material (55.5 mg,
.0756 mmol, 5.3%).
Compound 12a: IR (neat): n˜ =2955 (m), 2924 (s), 2854 (m), 1743 (m),
2
O, 20:1) afforded 12a (0.833 g, 1.18 mmol, 83% yield, 95:5
0
1
1
697 (w), 1462 (m), 1378 (w), 1254 (m), 1182 (w), 1158 (w), 1097 (w),
ꢁ1
1
066 (w), 1019 (w) cm
3
; H NMR (600 MHz, CDCl ): d=6.96 (1H, s),
6.57 (1H, s), 5.53 (1H, dt, J=11.2, 4.2 Hz), 5.42–5.23 (1H, m), 5.02 (1H,
d, J=10.2 Hz), 4.03 (1H, dd, J=10.2, 1.2 Hz), 3.89 (1H, d, J=8.4 Hz),
3
2
.05–2.96 (1H, m), 2.82 (1H, dd, J=16.2, 1.2 Hz), 2.79–2.70 (2H, m),
.70 (3H, s), 2.67 (1H, dd, J=16.2, 10.2 Hz), 2.40–2.33 (1H, m), 2.11
(
3H, d, J=1.2 Hz), 2.10–2.06 (1H, m), 1.90–1.82 (1H, m), 1.62–1.46 (3H,
m), 1.30–1.00 (1H, m), 1.19 (3H, s), 1.14 (3H, s), 1.09 (3H, d, J=6.6 Hz),
0.95 (3H, d, J=6.6 Hz), 0.94 (9H, s), 0.84 (9H, s), 0.12 (3H, s), 0.10 (3H,
1
3
s), 0.07 (3H, s), ꢁ0.10 ppm (3H, s); C NMR (100 MHz, CDCl
3
): d=
The impact of catalytic Z-selective macrocyclic RCM is
not limited to the target molecules examined here; routes
leading to a number of other complex and biologically
2
5
1
15.2, 171.5, 164.8, 152.7, 138.8, 135.3, 123.0, 119.7, 116.3, 79.8, 79.5, 76.6,
3.6, 48.2, 39.1, 38.0, 32.0, 31.6, 29.4, 28.6, 26.6, 26.4, 25.2, 24.4, 19.4, 19.3,
+
8.9, 18.8, 17.9, 15.5, ꢁ3.0, ꢁ3.1, ꢁ3.5, ꢁ5.5 ppm. HRMS (ESI ) [M+
[43]
+
active molecules can be made more efficient by the cata-
H] calcd for C38
H
67NO
5
SSi
2
: 706.4357, found: 706.4348.
2738
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 2726 – 2740

Z-Selective Ring-Closing Metathesis
FULL PAPER
Acknowledgements
[10] a) I. Ibrahem, M. Yu, R. R. Schrock, A. H. Hoveyda, J. Am. Chem.
Soc. 2009, 131, 3844–3845; b) M. Yu, I. Ibrahem, M. Hasegawa,
R. R. Schrock, A. H. Hoveyda, J. Am. Chem. Soc. 2012, 134, 2788–
2799.
[11] S. J. Meek, R. V. OꢁBrien, J. Llaveria, R. R. Schrock, A. H. Hovey-
da, Nature 2011, 471, 461–466.
[12] For an early report on the significance reversible nature of catalytic
olefin metathesis in the context of natural product synthesis, see:
a) Z. Xu, C. W. Johannes, A. F. Houri, D. S. La, C. A. Cogan, G. E.
Hofilena, A. H. Hoveyda, J. Am. Chem. Soc. 1997, 119, 10302–
10316; for a notable application, see: b) A. B. Smith III, C. M.
Adam, S. A. Kozmin, D. V. Paone, J. Am. Chem. Soc. 2001, 123,
5925–5937.
This research was funded by the NIH (GM-59426). C. W. and M. Y. con-
tributed equally to this research. M. Y. was a John LaMattina and Astra-
Zeneca Graduate Fellow; A. F. K. was the recipient of an EPSRC-Glax-
oSmithKline Synthesis Studentship, and P. J. of an EPSRC Postdoctoral
Fellowship. D. J. D. acknowledges support through an EPSRC Leader-
ship Fellowship. We thank B. Li for assistance in securing X-ray struc-
tures, and S. J. Meek, S. J. Malcolmson, D. L. Silverio, R. V. OꢁBrien, T. J.
Mann, E. T. Kiesewetter, and S. Torker for valuable discussions. We are
grateful to D. L. Silverio for assistance in computational analysis and K.
Wu for experimental assistance, and to Boston College for providing
access to computational facilities.
[
13] A. B. Attygalle, K. D. McCormick, C. L. Blankespoor, T. Eisner, J.
Meinwald, Proc. Natl. Acad. Sci. USA 1993, 90, 5204–5208.
14] C. Rossini, A. Gonzꢆlez, J. Farmer, J. Meinwald, T. Eisner, J. Chem.
Ecol. 2000, 26, 391–397.
[
[
1] For relatively recent reviews on various aspects of catalytic olefin
metathesis, see: a) R. R. Schrock, A. H. Hoveyda, Angew. Chem.
[
[
15] A. Fꢄrstner, K. Langemann, Synthesis 1997, 792–803.
16] a) R. R. Schrock, J. S. Murdzek, G. C. Bazan, J. Robbins, M.
DiMare, M. OꢁRegan, J. Am. Chem. Soc. 1990, 112, 3875–3886;
b) G. Bazan, J. H. Oskam, H.-N. Cho, L. Y. Park, R. R. Schrock, J.
Am. Chem. Soc. 1991, 113, 6899–6907; c) G. Bazan, R. R. Schrock,
H.-N. Cho, V. C. Gibson, Macromolecules 1991, 24, 4495–4502.
17] a) G. C. Fu, R. H. Grubbs, J. Am. Chem. Soc. 1992, 114, 7324–7325;
b) W. J. Zuercher, M. Hashimoto, R. H. Grubbs, J. Am. Chem. Soc.
2
003, 115, 4740–4782; Angew. Chem. Int. Ed. 2003, 42, 4592–4633;
b) Handbook of Metathesis (Ed.: R. H. Grubbs), Wiley-VCH, Wein-
heim, Germany, 2003; c) S. T. Diver, A. J. Giessert, Chem. Rev.
2
004, 104, 1317–1382; d) A. H. Hoveyda, D. G. Gillingham, J. J. Van
Veldhuizen, O. Kataoka, S. B. Garber, J. S. Kingsbury, J. P. A. Harri-
ty, Org. Biomol. Chem. 2004, 2, 8–23; e) A. H. Hoveyda, A. R. Zhu-
gralin, Nature 2007, 450, 243–251; f) T. J. Donohoe, L. P. Fishlock,
P. A. Procopiou, Chem. Eur. J. 2008, 14, 5716–5726; g) C. Samojlo-
wicz, M. Bieniek, K. Grela, Chem. Rev. 2009, 109, 3708–3742;
h) G. C. Vougioukalakis, R. H. Grubbs, Chem. Rev. 2010, 110, 1746–
[
[
1
996, 118, 6634–6640.
18] a) P. Schwab, M. B. France, J. W. Ziller, R. H. Grubbs, Angew.
Chem. 1995, 107, 2179–2181; Angew. Chem. Int. Ed. Engl. 1995, 34,
2
039–2041; b) P. Schwab, R. H. Grubbs, J. W. Ziller, J. Am. Chem.
1
787; i) A. M. Lozano-Vila, S. Monsaert, A. Bajek, F. Verpoort,
Soc. 1996, 118, 100–110.
Chem. Rev. 2010, 110, 4865–4909; j) A. H. Hoveyda, S. J. Malcolm-
son, S. J. Meek, A. R. Zhugralin, Angew. Chem. 2010, 122, 38–49;
Angew. Chem. Int. Ed. 2010, 49, 34–44.
[
19] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953–
9
56.
[
20] a) J. S. Kingsbury, J. P. A. Harrity, P. J. Bonitatebus, A. H. Hoveyda,
J. Am. Chem. Soc. 1999, 121, 791–799; b) S. B. Garber, J. S. Kings-
bury, B. L. Gray, A. H. Hoveyda, J. Am. Chem. Soc. 2000, 122,
[
2] For reviews regarding applications of catalytic olefin metathesis in
natural product synthesis, see: a) J. A. Love in Handbook of Meta-
thesis Vol. 2 (Ed.: R. H. Grubbs), Wiley-VCH, Weinheim, Germany,
8
168–8179; c) see reference [1d].
2
003, pp. 296–322; b) K. C. Nicolaou, P. G. Bulger, D. Sarlah,
Angew. Chem. 2005, 117, 4564–4601; Angew. Chem. Int. Ed. 2005,
4, 4490–4527; c) Metathesis in Natural Product Synthesis (Eds.: J.
Cossy, S. Arsenyadis, C. Meyer) Wiley-VCH, Weinheim, Germany,
010; d) A. Fꢄrstner, Chem. Commun. 2011, 47, 6505–6511.
[
21] For reviews on catalytic alkyne metathesis reactions, see: a) A.
Fꢄrstner, P. W. Davis, Chem. Commun. 2005, 2307–2320; b) W.
Zhang, J. S. Moore, Adv. Synth. Catal. 2007, 349, 93–120.
4
[
[
[
[
22] A. Fꢄrstner, O. Guth, A. Rumbo, G. Seidel, J. Am. Chem. Soc. 1999,
2
1
21, 11108–11113.
[
3] <For general overviews regarding macrocyclic ring-closing metathe-
sis reactions, see: a) A. Gradillas, J. Perez-Castells, Angew. Chem.
23] O. Coutelier, A. Mortreux, Adv. Synth. Catal. 2006, 348, 2038–2042,
and references therein.
24] J. Heppekausen, R. Stade, R. Goddard, A. Fꢄrstner, J. Am. Chem.
Soc. 2010, 132, 11045–11057.
25] Mo-based MAP complexes are routinely prepared in situ through
reaction of the corresponding bis-pyrrolide and the requisite alco-
hol. In the case of alkylidene 6, the formation of the complex pro-
ceeds in approximately 60% yield; thus, use of 2.0 mol% of the pre-
cursors leads to 1.2 mol% catalyst loading.
2
006, 118, 6232–6247; Angew. Chem. Int. Ed. 2006, 45, 6086–6101;
b) A. Gradillas, J. Pꢅrez-Castells in Metathesis in Natural Product
Synthesis (Eds.: J. Cossy, S. Arsenyadis, C. Meyer), Wiley-VCH,
Weinheim, Germany, 2010, pp. 149–182.
[
[
[
4] D. Villemin, Tetrahedron Lett. 1980, 21, 1715–1718.
5] J. Tsuji, S. Hashiguchi, Tetrahedron Lett. 1980, 21, 2955–2958.
6] For the preliminary account of this work, see: M. Yu, C. Wang, A. F.
Kyle, P. Jakubec, D. J. Dixon, R. R. Schrock, A. H. Hoveyda, Nature
2
011, 479, 88–93.
[26] A. J. Jiang, J. H. Simpson, P. Mꢄller, R. R. Schrock, J. Am. Chem.
Soc. 2009, 131, 7770–7780.
[27] See the Supporting Information for details.
[
7] a) R. Singh, R. R. Schrock, P. Mꢄller, A. H. Hoveyda, J. Am. Chem.
Soc. 2007, 129, 12654–12655; b) S. J. Malcolmson, S. J. Meek, E. S.
Sattely, R. R. Schrock, A. H. Hoveyda, Nature 2008, 456, 933–937;
c) E. S. Sattely, S. J. Meek, S. J. Malcolmson, R. R. Schrock, A. H.
Hoveyda, J. Am. Chem. Soc. 2009, 131, 943–953; for an overview re-
garding the potential utility of this catalyst class in chemical synthe-
sis, see: reference [1j].
8] a) G. Hçfle, N. Bedorf, H. Steinmetz, D. Schomburg, K. Gerth, H.
Reichenbach, Angew. Chem. 1996, 108, 1671–1673; Angew. Chem.
Int. Ed. Engl. 1996, 35, 1567–1569; b) R. J. Kowalski, P. Giannaka-
kou, E. Hamel, J. Biol. Chem. 1997, 272, 2534–2541; c) D. M.
Bollag, P. A. McQueney, J. Zhu, O. Hensens, L. Koupal, J. Liesch,
M. Goetz, E. Lazarides, C. M. Woods, Cancer Res. 1995, 55, 2325–
[28] For example, when the RCM reaction, catalyzed by Mo-based bis-
alkoxide 1 in entries 1 and 5 are examined after one minute, the
product mixture consists of 28:72 Z:E (vs. 17:83 after one h) and
25:75 Z:E (vs. 7:93 after one h)ratio of isomers, respectively (23%
and 35% conv.). For a study of post-RCM isomerization with reac-
tions that are catalyzed by Ru-based carbenes and afford macrocy-
clic alkenes, see: C. W. Lee, R. H. Grubbs, Org. Lett. 2000, 2, 2145–
2147.
[29] a) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vallberg, F. Roschan-
gar, F. Sarabia, S. Ninkovic, Z. Yang, J. I. Trujillo, J. Am. Chem. Soc.
1997, 119, 7960–7973; b) D. Meng, P. Bertinato, A. Balog, D.-S. Su,
T. Kamenecka, E. J. Sorensen, S. J. Danishefsky, J. Am. Chem. Soc.
1997, 119, 10073–10092; c) D. Schinzer, A. Bauer, O. Bçhm, M. A.
Limberg, M. Cordes, Chem. Eur. J. 1999, 5, 2483–2491; d) S. C.
Sinha, J. Sun, G. P. Miller, M. Wartmann, R. A. Lerner, Chem. Eur.
J. 2001, 7, 1691–1702.
[
2
333; for an overview on biological chemistry of epothilones, see:
d) K. C. Nicolaou, F. Roschangar, D. Vourloumis, Angew. Chem.
998, 110, 2120–2153; Angew. Chem. Int. Ed. 1998, 37, 2014–2045.
9] J. Kobayashi, D. Watanabe, N. Kawasaki, M. Tsuda, J. Org. Chem.
997, 62, 9236–9239.
1
[
1
Chem. Eur. J. 2013, 19, 2726 – 2740
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2739

A. H. Hoveyda et al.
[
30] For reviews and overviews regarding the use of catalytic RCM ap-
proaches to total synthesis of epothilones, including some biological
activity studies, see: a) C. R. Harris, S. J. Danishefsky, J. Org. Chem.
2023; c) I. S. Young, M. A. Kerr, J. Am. Chem. Soc. 2007, 129, 1465–
1469; d) P. Jakubec, D. M. Cockfield, D. J. Dixon, J. Am. Chem. Soc.
2009, 131, 16632–16633; e) B. Cheng, F. Wu, X. Yang, Y. Zhou, X.
Wan, H. Zhai, Chem. Eur. J. 2011, 17, 12569–12572.
1999, 64, 8434–8456; b) J. Mulzer, J. Monat. Chem. 2000, 131, 205–
238; c) K. C. Nicolaou, A. Ritzen, K. Namoto, Chem. Commun.
2001, 1523–1535; d) A. Rivkin, Y. S. Cho, A. E. Gabarda, F. Yoshi-
[39] a) M. G. Nilson, R. L. Funk, Org. Lett. 2010, 12, 4912–4915; b) A. F.
Kyle, P. Jakubec, D. M. Cockfield, E. Cleator, J. Skidmore, D. J.
Dixon, Chem. Commun. 2011, 47, 10037–10039; c) P. Jakubec, A. F.
Kyle, J. Calleja, D. J. Dixon, Tetrahedron Lett. 2011, 52, 6094–6097.
[40] A similar RCM reaction involving a bis-amide derivative has been
reported under identical conditions as shown in entry 2 of Table 3
(see reference [39a]); however, there is no mention of any changes
in the stereosiomeric purity of the macrocyclic alkene.
mura, S. J. Danishefsky, J. Nat. Prod. 2004, 67, 139–143; e) A.
Rivkin, T.-C. Chou, S. J. Danishefsky, Angew. Chem. 2005, 117,
2
898–2910; Angew. Chem. Int. Ed. 2005, 44, 2838–2850; f) K.-H.
Altmann, B. Pfeiffer, S. Arseniyadis, B. A. Pratt, K. C. Nicolaou,
ChemMedChem. 2007, 2, 396–423; g) J. Mulzer, K.-H. Altmann, G.
Hçfle, R. Mꢄller, K. Prantz, Chimie 2008, 11, 1336–1368.
[
[
31] K. H. Altmann, G. Bold, G. Caravatti, D. Denni, A. Flçrsheimer, A.
Schmidt, G. Rihs, M. Wartmann, Helv. Chim. Acta 2002, 85, 4086–
[41] When Mo-based MAP complex is used at 228C to effect the conver-
sion of 19 to 20, only approximately 30% conversion is observed
(24 h, toluene); Z:E was not determined due to formation of by-
products. Since adamantylimido complex 6 tends to be less robust
than the corresponding arylimido variants (e.g., 21 in entry 4,
Table 3), RCM at elevated temperatures was not examined.
[42] For an example and spectroscopic examination of catalyst deactiva-
tion by a resident Lewis basic functional group in an metathesis re-
action involving a Mo-based alkylidene, see: E. S. Sattely, G. A.
Cortez, D. C. Moebius, R. R. Schrock, A. H. Hoveyda, J. Am. Chem.
Soc. 2005, 127, 8526–8533.
[43] For representative examples where a Z-selective catalyst for macro-
cyclic RCM would significantly improve the overall efficiency of the
total synthesis, see: a) J. M. Humphrey, Y. Liao, A. Ali, T. Rein, Y.-
L. Wong, H.-J. Chen, H-A. K. Courtney, S. F. Martin, J. Am. Chem.
Soc. 2002, 124, 8584–8592; b) A. Fꢄrstner, F. Stelzer, A. Rumbo, H.
Krause, Chem. Eur. J. 2002, 8, 1856–1871; c) J. She, J. W. Lampe,
A. B. Polianski, P. S. Watson, Tetrahedron Lett. 2009, 50, 298–301;
d) B. J. Smith, G. A. Sulikowski, Angew. Chem. 2010, 122, 1643–
1646; Angew. Chem. Int. Ed. 2010, 49, 1599–1602.
4
110.
32] J. Johnson, S.-H. Kim, M. Bifano, J. DiMarco, C. Fairchild, J. Gou-
goutas, F. Lee, B. Long, J. Tokarski, G. Vite, Org. Lett. 2000, 2,
1
537–1540.
33] A. Fꢄrstner, C. Mathes, C. W. Lehmann, Chem. Eur. J. 2001, 7,
299–5317.
[
[
[
5
34] The lower yield of 12 at higher concentration is (at least partly) due
to larger amounts of adventitious homocoupling products.
35] When RCM of 11a is performed under the same conditions as in
entry 6 of Table 2 but at 1.0 torr of vacuum, 97% conversion to 12a
is observed (85% yield, 96:4 Z:E).
36] For representative studies in connection with epothilone analogues,
see: a) reference [8d]; b) K. C. Nicolaou, Y. He, F. Roschangar, N. P.
King, D. Vourloumis, T. Li, Angew. Chem. 1998, 110, 89–92; Angew.
Chem. Int. Ed. 1998, 37, 84–87.
[
[
[
37] For details of the revised synthesis schemes and what particular
shortcomings were addressed and in what manner, see the Support-
ing Information.
38] a) T. Nagata, M. Nakagawa, A. Nishida, J. Am. Chem. Soc. 2003,
1
25, 7484–7485; b) K. Ono, M. Nakagawa, A. Nishida, Angew.
Received: November 12, 2012
Chem. 2004, 116, 2054–2057; Angew. Chem. Int. Ed. 2004, 43, 2020–
Published online: January 23, 2013
2740
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 2726 – 2740