Stereoselective access to Z and e macrocycles by ruthenium-catalyzed Z-selective ring-closing metathesis and ethenolysis

Article abstract of DOI:10.1021/ja311241q

The first report of Z-selective macrocyclizations using a ruthenium-based metathesis catalyst is described. The selectivity for Z macrocycles is consistently high for a diverse set of substrates with a variety of functional groups and ring sizes. The same catalyst was also employed for the Z-selective ethenolysis of a mixture of E and Z macrocycles, providing the pure E isomer. Notably, an ethylene pressure of only 1 atm was required. These methodologies were successfully applied to the construction of several olfactory macrocycles as well as the formal total synthesis of the cytotoxic alkaloid motuporamine C.

Full text of DOI:10.1021/ja311241q

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Communication
Stereoselective Access to Z- and E-Macrocycles by Ruthenium-
Catalyzed Z-Selective Ring-Closing Metathesis and Ethenolysis
Vanessa M. Marx, Myles B. Herbert, Benjamin Keith Keitz, and Robert Howard Grubbs
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja311241q • Publication Date (Web): 17 Dec 2012
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Stereoselective Access to Z- and E-Macrocycles by Ruthenium-
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Vanessa M. Marx, Myles B. Herbert, Benjamin K. Keitz, and Robert H. Grubbs*
Arnold and Mabel Beckman Laboratories of Chemical Synthesis, Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, California, 91125
Supporting Information Placeholder
ABSTRACT: The first report of Z-selective macrocyclizations
using a ruthenium-based metathesis catalyst is described.
Selectivity for Z-macrocycles is consistently high for a diverse
set of substrates with a variety of functional groups and ring
sizes. The same catalyst was also employed for the Z-selective
ethenolysis of a mixture of E and Z macrocycles, providing the
pure E-isomer. Notably, only an atmospheric pressure of eth-
Scheme 1. Macrocyclic RCM of diene 1a to E-1 and Z-1.
ylene was required. These methodologies were successfully
applied to the construction of several olfactory macrocycles,
as well as the formal total synthesis of the cytotoxic alkaloid
motuporamine C.
The macrocyclic motif is widely prevalent in an abundance
of natural products and pharmaceuticals, and also provides
the backbone for a unique class of olfactory compounds,
termed macrocyclic musks. Originally derived from natural
sources, macrocyclic musks have been rapidly gaining popu-
Figure 1. Prominent Z-selective metathesis catalysts.
ruthenium-based metathesis catalysts bearing N-heterocyclic
carbene ligands, the E-isomer is often favored, as in the mac-
rocyclic RCM of diene 1a, which produces 14-membered lac-
tones E-1 and Z-1 in a ca. 12:1 ratio (Scheme 1).4 However, it
can be difficult to predict the thermodynamic product a priori,
larity in the perfume industry as alternatives to synthetic ni-
troarene and polycyclic musks, which exhibit bioaccumulation
and toxicity hazards.1,2 In general, many biologically and in-
and the reaction will frequently proceed with minimal or in-
dustrially relevant macrocyclic compounds feature an internal
verse selectivity to that which was anticipated.5 This issue has
olefin. The alkene geometry is instrumental in the resulting
been circumvented indirectly through the implementation of
biological activity or olfactory properties of the compound of
ring-closing alkyne metathesis (RCAM), followed by Lindlar-
or Birch-type reductions to generate stereopure Z- or E-
interest, which can be adversely affected by even minute
amounts of stereoisomeric impurities. In addition, stereo-
macrocycles respectively.3,6 Fürstner and co-workers have
chemically pure macrocyclic olefins are often utilized as plat-
also developed a complementary method for the synthesis of
E-macrocycles from cycloalkynes, employing a hydrosilyla-
tion/desilylation sequence.7 More recently, a report has ap-
forms to stereospecifically install other functional groups.
Although in some cases it might be possible to separate a mix-
ture of E- and Z-isomers chromatographically or by crystalli-
peared detailing the use of vinylsiloxanes to promote stere-
zation, these methods are by no means general and often re-
oselective
ring-closing
metathesis,
generating
E-
quire extensive optimization for each individual compound.
Furthermore, with respect to macrocyclic musks in particular,
certain perfumes often contain a specific mixture of E- and Z-
olfactory macrocycles.2 Hence, selective methods for the prep-
aration of both E- and Z-olefin containing macrocycles are of
paramount importance.
Ring-closing metathesis (RCM) has become a ubiquitous
tool for the synthesis of carbo- and heterocylic ring systems,
and is particularly well-suited for the efficient synthesis of
macrocycles.3 Unfortunately, most metathesis catalysts exhibit
minimal kinetic selectivity, and thus for medium- to large-
sized ring systems in which both E- and Z-isomers are acces-
sible, the product distribution at high conversion reflects the
thermodynamic energetic difference between the two. For
alkenylsiloxanes, which upon desilylation yield Z-
macrocycles.8
Accordingly, a considerable effort has been expended in
the search for metathesis catalysts exhibiting kinetic selectivi-
ty. This has resulted in numerous current reports detailing the
successful realization of Z-selective homo-coupling, cross-
metathesis, and ring-opening/cross-metathesis reactions em-
ploying tungsten and molybdenum-based catalyst systems.9 In
addition, a single report has emerged detailing the Z-selective
ethenolysis of straight-chain olefins, resulting in pure E-
olefins from an E/Z mixture with a molybdenum catalyst.10
Recently, in an elegant publication, the Schrock and Hoveyda
groups disclosed the first example of catalyst systems capable
of performing a highly Z-selective macrocyclic RCM reaction,
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Table 1. Z-Selective macrocyclizations employing ruthe-
of these respective rate constants (kRCM/koligomer), as well as the
nium catalyst 2.a
rate of catalyst decomposition.15 Macrocyclic ring closure in
general is entropically disfavored. In the case of macrocyclic
RCM reactions mediated by 2, the transformation might also
suffer from a significant negative enthalpic contribution as a
result of steric interactions with the NHC moiety in transition
states leading to productive turnovers.16 Thus, in order to
favor ring closure with respect to oligomerization, dilute con-
ditions (3 mM) and elevated temperatures (60 °C) were re-
quired. The application of a static vacuum (20 mtorr) was also
necessary, as refluxing conditions under either an inert at-
mosphere or while sparging with argon resulted in an in-
creased formation of oligomerization products.14 An increase
in temperature (80 °C) decreased the yield of Z-1, likely as a
result of catalyst decomposition, and a further increase in
dilution (1 mM) resulted in prohibitively slow reaction times.
An increase in the catalyst loading (10 mol%) or reaction time
(48 h) did not increase conversion to Z-1.17
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A variety of substrates readily underwent macrocyclic
RCM with ruthenium catalyst 2, utilizing the single set of
standard reaction conditions optimized for lactone Z-1 (Table
1).18 In almost all cases, consumption of the diene precursor
was high, resulting in ca. 80% conversion to macrocyclic
products; unprotected amide 13a was the sole exception,
which reached only ca. 50% conversion to Z-13. Protection of
12a as its tert-butylcarbamate derivative 13a restored activi-
ty, and resulted in higher yields of Z-14.19 The larger, 16-, 17-,
and 20-membered ring lactones (Z-5, Z-7, and Z-6) gave the
highest yields (72%, 71%, and 75% respectively),20 whereas
the reaction was less efficient for the smaller 13-membered
ring lactone Z-4 (40% yield). In general, the Z-selectivity was
high for all macrocyclizations (75-94% Z), although it was
necessary to mask ketone (Z-8) and alcohol (Z-10) functional-
ity in order to maintain high Z-selectivity.21 The origin of the
considerable bias exhibited by 2 for the production of Z-
olefins has been attributed to a strong preference for the for-
mation of side-bound metallocyclobutanes in these systems,
in which transition states leading to E-olefins are strongly
disfavored, as a result of unfavorable steric interactions with
the mesityl ring of the N-heterocyclic carbene ligand.16
It is noteworthy that macrolides Z-4, Z-7, and Z-8 are cur-
rently in demand by the perfume industry (marketed as yuzu
lactone, ambrettolide and civetone respectfully).2 Fürstner
and co-workers had previously accessed these compounds by
RCAM/Lindlar hydrogenation,22 as ring-closing metathesis
strategies had failed to proceed with adequate Z-selectivities
for these types of ring systems.23 Macrocyclic lactam Z-13 is
also an intermediate en route to Goldring and Weiler’s total
synthesis of the cytotoxic alkaloid motuporamine C.24.25 In this
case, Z-13 had been obtained following RCM and purification
from a mixture with its E-isomer (only 44% Z), using radial
chromatography. Fürstner and co-workers had also previous-
ly employed a RCAM/Lindlar hydrogenation sequence to ac-
cess motuporamine C stereospecifically.26
utilizing the monoaryloxide-pyrrolide (MAP) catalysts 3a and
3b (Figure 1), to generate a 16-membered lactone.12 They
further showcased the utility of these types of complexes in
the synthesis of the 16-membered core of epothilone C (85%
yield, 96% Z), and the 15-membered core of nakadomarin A
(90% yield, 97% Z), using tungsten catalyst 3c.
Recently, we have developed a family of chelated rutheni-
um-based catalysts that promote highly Z-selective homo-
coupling, cross-metathesis, and ring-opening metathesis
polymerization reactions.13 Herein, we disclose the first re-
port of Z-selective macrocyclic RCM using a ruthenium-based
catalyst system (2), applicable to a broad range of ring sizes
and functional groups. Additionally, we report the first in-
stance of Z-selective ethenolysis of macrocycles, resulting in
pure E-macrocycles from an E/Z-mixture, using the same cata-
lyst system (2). We have successfully applied these strategies
to the stereoselective synthesis of a selection of olfactory mac-
rocycles, and the formal total synthesis of the cytotoxic alka-
loid motuporamine C.
We initiated our studies by optimizing reaction conditions
for the macrocyclic RCM of diene 1a, producing lactone Z-1 in
58% yield and 85% Z (Table 1). Although all reagents were
initially combined in a glovebox, using rigorously degassed
anhydrous dichloroethane, the reaction could also be conven-
iently set-up on the benchtop, with commercial anhydrous
dichloroethane used directly as received, generating Z-1 in
49% yield and 86% Z. The main competing process in the
macrocyclic RCM to Z-1 was oligomerization of diene 1a,14
and the amount of Z-1 produced is dependent upon the ratio
In a complementary approach to the synthesis of the Z-
macrocycles shown above in Table 1, we were also able to
further exploit catalyst 2 for the isolation of pure E-macrocy
cles, through the selective degradation of the Z-isomer in the
corresponding E-dominant mixtures (Scheme 2).27 Ring-
opening via ethenolysis is simply the reverse of the macrocy-
clic RCM reaction. Thus, as high Z-selectivity was evidenced in
the forward reaction (cf. Table 1), it was expected that the
reverse reaction would also display high selectivity for Z-
olefins.28 Indeed, exposure of an E/Z mixture of lactone 6
(69% E) to ethylene (1 atm) in the presence of catalyst 2 (2
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utilize an atmospheric pressure of ethylene for Z-selective
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ethenolysis should enable the widespread use of this applica-
tion in particular, for both bench-top and industrial scales, as
an effective method for the isolation of pure E-macrocycles
without advanced chromatography or alternative purification
techniques. Therefore, as improved Z-selective catalysts based
on ruthenium are discovered, the utility of these complemen-
tary methodologies will only increase. As in the past, organic
chemists will find these ruthenium-based systems to have
broad applicability.
Scheme 2. Z-Selective ethenolysis of E/Z-6.29
Table 2. Z-Selective ethenolysis of a mixture of E-
dominant macrocycles.
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ASSOCIATED CONTENT
Supporting Information
Experimental details and characterization data for all com-
pounds. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
rhg@caltech.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Dr. David VanderVelde is thanked for assistance with NMR
experimentation and analysis. This work was financially sup-
ported by NIH (R01-GM031332), the NSF (CHE-1212767), and
the NSERC of Canada (fellowship to V.M.M.). Instrumentation
on which this work was carried out was supported by the NIH
(NMR spectrometer, RR027690). Materia, Inc. is thanked for
its donation of metathesis catalyst 2.
mol%) led to the complete degradation of Z-6 after only 2
hours at 35 °C (Scheme 2). Notably only an atmospheric pres-
sure of ethylene was necessary.30 It is also significant to men-
tion that the corresponding ring-opened diene was also re-
covered, and thus could subsequently be recyclized in subse-
quent macrocyclic RCM reactions if desired.
We were able to apply similar reaction conditions to mac-
rocycles containing ketone (8), alcohol (10), and amide (13)
functionality (Table 2). In general, complete consumption of
the Z-macrocycle occurs within two hours, affording the pure
E-macrocycle in good yield. The lower yield of ketone-
containing product E-8 is likely a result of the elevated tem-
perature required to form the E-isomer exclusively, which
might also be expected to accelerate undesired degradation of
the E-macrocycle. Additionally, an increase in oligomerization
was also observed in this case, thus reducing the yield of the
recovered diene 8a.
In summary, we have demonstrated the first example of a
ruthenium metathesis catalyst that is capable of promoting Z-
selective macrocyclic RCM. This represents the first systemat-
ic study of the scope of Z-selective macrocyclic RCM with re-
spect to a broad range of ring sizes. The transformation is
amenable to a variety of functional groups, and proved appli-
cable in the synthesis of a number of olfactory macrocycles as
well as the formal total synthesis of motuporamine C. In addi-
tion, it has been shown that the same catalyst system can
promote Z-selective ethenolysis of macrocyclic compounds
that are present in an E/Z mixture, providing pure E-
macrocycles. It is anticipated that both methods will realize
extensive use in the synthesis of natural products and phar-
maceuticals, as well as in the perfume industry. The ability to
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(27) See supporting information for details regarding the
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(29) Yields are isolated, and were calculated based on theo-
retical amount of pure E-isomer.
(30) This is in comparison to the molybdenum-based sys-
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