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Justia Patents US Patent Application for HIGHLY EFFICIENT SYNTHESIS OF Z-MACROCYCLES USING STEREORETENTIVE, RUTHENIUM-BASED METATHESIS CATALYSTS Patent Application (Application #20210355099)
HIGHLY EFFICIENT SYNTHESIS OF Z-MACROCYCLES USING STEREORETENTIVE, RUTHENIUM-BASED METATHESIS CATALYSTS
Jun 2, 2021 - CALIFORNIA INSTITUTE OF TECHNOLOGY
A highly efficient, Z-selective ring-closing metathesis system for the formation of macrocycles using a stereoretentive, ruthenium-based catalyst supported by a dithiolate ligand is reported. This catalyst is demonstrated to be remarkably active as observed in initiation experiments showing complete catalyst initiation at −20° C. within 10 min. Using easily accessible diene starting materials bearing a Z-olefin moiety, macrocyclization reactions generated products with significantly higher Z-selectivity in appreciably shorter reaction times, in higher yield, and with much lower catalyst loadings than in previously reported systems. Macrocyclic lactones ranging in size from twelve-membered to seventeen-membered rings are synthesized in moderate to high yields (68-79% yield) with excellent Z-selectivity (95%-99% Z).
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METHODS AND SYSTEMS FOR ATOMIC LAYER ETCHING AND ATOMIC LAYER DEPOSITION
This application is a Continuation of application Ser. No. 16/611,329, filed Nov. 6, 2019; which is a national stage of PCT International Application No. PCT/US2018/029106, filed Apr. 24, 2018; which claims the benefit of U.S. Provisional Patent Application No. 62/503,155 filed May 8, 2017 and the benefit of U.S. Provisional Patent Application No. 62/521,647 filed Jun. 19, 2017, the contents of which are incorporated herein by reference in their entirety.
STATEMENT OF FEDERAL SUPPORT
This invention was made with government support under grant number GM031332 awarded by the National Institutes of Health, grant number CHE1502616 awarded by the National Science Foundation and grant number N00014-14-1-0650 awarded by the Office of Naval Research. The government has certain rights in the invention.
This invention relates generally to the use of Ruthenium based metathesis catalysts in the synthesis of metathesis of olefins and olefin compounds, more particularly, in the use of such catalysts in the synthesis of Z-macrocycles. The invention has utility in the fields of organic synthesis, pharmaceutical industry as well as in flavors and fragrances.
Transition-metal catalyzed ring-closing metathesis (RCM) has become a powerful method for generating cyclic molecules (Grubbs, R. H., Wenzel, A. G., O'Leary, D. J., Khosravi, E., Eds. Handbook of Metathesis; Wiley-VCH: Weinheim, 2015).
It is used widely in the synthesis of several pharmaceuticals as well as in the production of pheromones and musks, as replacements for toxic synthetic polycyclic and nitroarene musks [(a) Michrowska, A.; Wawrzyniak, P.; Grela, K. Eur. J. Org. Chem. 2004, 2053. (b) Rimkus, G. G. The Handbook of Environmental Chemistry; Springer: Berlin, 2004; Vol. 3X. (c) Rowe, D. J. Chemistry and Technology of Flavors and Fragrances; Blackwell: Oxford, U. K., 2005. (d) Gradillas, A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086. (e) Ohloff, G.; Pickenhagen, W.; Kraft, P. Scent and Chemistry: The Molecular World of Odors; Verlag Helvetica Acta: Zuirich, 2011. (f) Marx, V. M.; Herbert, M. B.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 94. (g) Higman, C. S.; Lummiss, J. A. M.; Fogg, D. E. Angew. Chem., Int. Ed. 2016, 55, 3552].
The stereochemistry of the alkene, E- or Z-, in these cyclic structures is often crucial to the biological activity of a molecule or its olfactory characteristics, and small amounts of impurity of the other stereoisomer in chemical mixtures, can drastically decrease their potency. It is often particularly difficult to separate E- and Z-isomers as techniques for their separation are not general. As such, methods for producing stereochemically pure cyclic compounds are of paramount importance.
Controlling olefin stereochemistry in RCM reactions can be difficult. When using common non-selective metathesis catalysts, selectivity is controlled by the thermodynamic stability of the olefin products and can vary depending on ring size and double bond position [(a) Fürstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942. (b) Fürstner, A.; Langemann, K. Synthesis 1997, 792. (c) Goldberg, W. P. D.; Hobber, A. S.; Weiler, L. Tetrahedron Lett. 1998, 39, 4955. (d) Lee, C. W.; Grubbs, R. H. Org. Lett., 2000, 2 (14), 2145. (e) Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H. Nature 2011, 479, 88].
Furthermore, high catalyst loadings are often needed for macrocyclization reactions using RCM. In these instances, removal of residual metals, the presence of which can be undesirable in the end product or could potentially isomerize products, can be difficult. For some applications, this requires further purification with lead tetra acetate or phosphine additives or with multiple chromatographic columns followed by treatment with charcoal [(a) Paquette, L. A.; Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.; Mendez-Andino, J.; Yang, J. Org. Lett. 2000, 2, 1259. (b) Maynard, H.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 4137]. Reducing catalyst loadings required for these reactions is thus an important goal.
One established method for stereoselectively generating Z-macrocycles is ring-closing alkyne metathesis followed by Lindlar hydrogenation [(a) Fürstner, A.; Mathes, C.; Lehmann, C. W. Chem. Eur. J. 2001, 7, 5299. (b) Nilson, M. G. & Funk, R. L. Org. Lett. 2010, 12, 4912]. Z-macrocycles have also been synthesized by reaction of terminal olefins with internal vinyl silanes followed by protodesilylation (Wang, Y.; Jimenez, M.; Hansen, A. S.; Raiber, E.-A.; Schreiber, S. L.; Young, D. W. J. Am. Chem. Soc. 2011, 133, 9196). However, these approaches require multiple steps to synthesize the desired product, and thus more direct methods using olefin metathesis are desirable. In 2011, the first report of Z-selective RCM was disclosed. Mo- and W-based catalysts 1-3 of FIG. 1, were used to synthesize a sixteen-membered macrocyclic lactone (91-95% Z), nakadomarin A (90-97% Z), and epothilone C (69-97% Z) (Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H. Nature 2011, 479, 88). While these catalysts afforded exceptional selectivity, they required catalyst loadings of catalyst 5 to 6 mol %. One year later, Z-selective cyclometallated ruthenium-based catalyst 4 of FIG. 1 (7.5 mol %) was reported to generate macrocyclic lactones, lactams and ketones (75-94% Z) with the purpose of synthesizing pheromones and fragrances (Marx, V. M.; Herbert, M. B.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 94; Herbert, M. B.; Marx, V. M.; Pederson R. L.; Grubbs, R. H. A.C.I.E. 2013, 52, 310). This method was limited by long reaction times, required the use of high boiling solvents and elevated temperatures, and delivered most products with generally ca. 85% Z-selectivity.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1. Catalysts used previously to selectively generate highly Z-macrocycles.
FIG. 2. Model for Z-selectivity using stereoretentive metathesis catalysts in cross-metathesis.
FIGS. 3A-3B. FIG. 3A shows proposed disfavored and favored metallacyclobutane intermediates in macrocyclization reactions implementing stereoretentive catalyst 5. FIG. 3B shows synthesis of diene substrates from acyl chlorides and Z-hydroxy olefins.
FIGS. 4A-4B. FIG. 4A shows the reaction of catalyst 5 with butyl vinyl ether. FIG. 4B shows the plot of ln([Ru]/[Ru]0) versus time for initiation experiments conducted with catalysts 4 and 5 at 0° C. and −20° C. monitored by disappearance of the benzylidene signal by 1H NMR. Plots remain approximately linear for three half-lives of the reaction.
FIG. 5. Proposed favored metallacyclobutane intermediate in macrocylization reaction of Z-olefin with a terminal olefin leading to Z-macrocycles with 95-99% Z-selectivity.
In 2016, the first demonstration of high stereoretention in transition metal-catalyzed olefin metathesis was reported (Johns, A. M.; Ahmed, T. S.; Jackson, B. W.; Grubbs, R. H.; Pederson, R. L. Org. Lett. 2016, 18 (4), 772). Using Ru catalysts supported by dithiolate ligands, cross metathesis between two Z-olefins or between a Z-olefin and a terminal olefin generated products with high Z-selectivity (>96% Z) (Koh, M. J.; Khan, R. K. M.; Torker, S.; Yu, M.; Mikus, M. S.; Hoveyda, A. H. Nature 2015, 517, 181). Conversely, cross metathesis between two E-olefins or between an E-olefin and a terminal olefin, generated products with kinetic E-selectivity (>98% E). The proposed model for Z-selectivity is based on a proposed side-bound metallacyclobutane intermediate in which stereoselectivity arises from the α-substituents of the metallacyclobutane favorably pointing down, away from the two large N-aryl groups of the N-heterocyclic carbene ligand (FIG. 2). Given that the reacting olefin has Z-stereochemistry, the β-substituent points down in the favored proposed intermediate. Subsequent cycloreversion of this metallocyclobutane intermediate leads to the formation of the Z-product.
Based on this model for selectivity, it was expected that highly Z-selective RCM to generate Z-macrocycles could be possible from diene substrates containing a Z-olefin and a terminal olefin using these catalysts (FIG. 3A). These substrates are easily synthesized in high yield by reaction of commercially available Z-hydroxy olefins with alkenoyl chlorides (FIG. 3B). Substrates were designed such that RCM of these substrates would give the desired product as well as a gaseous byproduct, propylene or 1-butene, which could be readily removed from the reaction mixture.
For these reactions, catalyst 5, bearing an NHC with N-2,6-di-iso-propylphenyl groups, was chosen due to its remarkable activity in cross-metathesis reactions of Z-olefins. To compare the initiation rates of catalyst 4 and catalyst 5, the reactions of butyl vinyl ether with each catalyst were monitored using 1H NMR experiments (FIGS. 4A and 4B). Under standard conditions at 30° C., catalyst 5 had already fully initiated within the 15 s required to acquire the first spectrum, and thus a rate constant could not be determined (Keitz, B.; Endo, K.; Patel, P. R. Herbert, M. B.; Grubbs, R. H. J. Am. Chem. Soc., 2012, 134 (1), 693). The reaction was then monitored at 0° C. and was completed within 2 min with catalyst 5 while catalyst 4 required 1.5 h. Values of kinit for catalyst 4 and catalyst 5 at this temperature were determined to be 1.00×10−3 s−1 and 2.42×10−2 s−1, respectively. Thus, there is a magnitude of difference in the initiation rates of these catalysts, krel=kinit5/kinit4=24.2. Furthermore, full initiation of catalyst 5 was remarkably complete at −20° C. within 10 min with kinit=6.14×10−3 s−1. Negligible Fischer carbene formation could be observed using catalyst 4 at −20° C. This stark difference in initiation rate is a direct reflection of the significantly greater activity of 5 compared to catalyst 4.
RCM was then attempted using catalyst 5 and was shown to be possible using a variety of substrates, (6)-(12) (Table 1). Using a standard catalyst loading of 6 mol % often used in macrocyclization reactions, reactions were completed within 1 h in dichloromethane under static vacuum (30 mTorr) at 40° C. Twelve-membered to seventeen-membered rings were all synthesized with high Z-selectivity (95-99% Z) in moderate to high yields (68-79% isolated yield). Yuzu lactone, (Z-7), is in high demand by the perfume industry and can be synthesized more rapidly and selectively using catalyst 5 than in previous reports. Larger macrocyclic lactones, fifteen-membered to seventeen-membered rings, were synthesized in slightly higher yields than with smaller twelve-membered to fourteen-membered rings.
Synthesis of macrocycles using Catalyst 5.
Entry Substrate Product Yield a Z/E b
1 70% >99/1 2 68% 95/5 3 67% 95/5 4 72% 98/2 5 74% 99/1 6 79% 95/5 7 75% 95/5 a Isolated yields. b Selectivity determined by gas chromatography. Selectivities of Z-7 and Z-8 were determined by 1H NMR.
Given the exceptional activity exhibited by catalyst 5 in initiation experiments and its high activity in macrocyclic RCM (TON of 11-13 were achieved using 6 mol % catalyst loading), the limit for the catalyst loading required for reaction was examined. Using 0.5 mol % 5, TON of 100 were attained in the macrocyclization of (8) within 1 h as determined by observation of aliquots of the reaction by 1H NMR. With 1 mol % catalyst 5, complete conversion of the starting material to the macrocyclic product and a small amount of unidentified byproduct, possibly an oligomer of the starting material, was observed. This is significantly lower than reported catalyst loadings, used for achieving high conversion in previously reported Z-selective macrocyclizations.
In summary, highly active, stereoretentive Ru-based catalyst 5 was used for generating highly Z-macrocycles (95-99% Z) from easily available diene substrates with a Z-olefin moiety. The exceptional activity exhibited by this catalyst was determined through initiation studies and showed that full catalyst initiation could be achieved at −20° C. within minutes. Twelve-membered to seventeen-membered macrocycles including yuzu lactone were synthesized using this method in moderate to high yields (67-79% yield). These reactions were completed in significantly shorter times and using lower catalyst loadings than in previously reported Z-selective systems was shown to be possible with TON of up to 100. Further studies using stereoretention for E-selective macrocyclization are underway.
In another embodiment the invention provides a method for generating Z-macrocycles via macrocyclic ring-closing metathesis of diene substrate bearing a Z-olefin moiety in the presence of a stereoretentive Ru-based catalyst of Formula (I):
R and R0 are independently nil, H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl;
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently H, methyl, ethyl, propyl, iso-propyl, iso-propoxy, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano;
R15, R16, R17, and R18 are independently H or methyl;
X1, X2, X3, and X4 are independently H, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; and
Y is oxygen, sulfur, nitrogen, or iodo.
In another embodiment the invention provides a method for generating Z-macrocycles via macrocyclic ring-closing metathesis of diene substrate bearing a Z-olefin moiety in the presence of a stereoretentive Ru-based catalyst of Formula (II):
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano;
Z1 and Z2 are independently cyano or nitro; and
DETAILED DESCRIPTION Terminology and Definitions
Unless otherwise indicated, the invention is not limited to specific reactants, reaction conditions, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments and is not to be interpreted as being limiting.
As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an olefin" includes a single olefin as well as a combination or mixture of two or more olefins, reference to "a substituent" encompasses a single substituent as well as two or more substituents, and the like.
As used in the specification and the appended claims, the terms "for example," "for instance," "such as," or "including" are meant to introduce examples that further clarify more general subject matter. Unless otherwise specified, these examples are provided only as an aid for understanding the invention and are not meant to be limiting in any fashion.
In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings.
The term "diene bearing a Z-olefin moiety" or "diene with a Z-olefin moiety" as used herein means an unsaturated hydrocarbon containing two double bonds wherein one of them is an internal double bond in the Z-configuration.
The term "product internal olefin" as used herein means an internal olefin present in a ring-closing metathesis product formed by a ring-closing metathesis reaction, wherein each of the olefinic carbons (i.e., the carbons of the carbon-carbon double bond) of the internal olefin may have an E-configuration or a Z-configuration.
The term "nil," as used herein, means absent or nonexistent.
The term "methyl," as used herein, represents a group of formula "—CH3."
The term "ethyl," as used herein, represents a group of formula "—CH2CH3."
The term "propyl," as used herein, represents a group of formula "—CH2CH2CH3."
The term "iso-propyl," as used herein, represents a group of formula "—CH(CH3)2."
The term "iso-propoxy," as used herein, represents a group of formula "—OCH(CH3)2."
The term "butyl," as used herein, represents a group of formula "—CH2CH2CH2CH3."
The term "sec-butyl," as used herein, represents a group of formula "—CH(CH3)(CH2CH3)."
The term "tert-butyl," as used herein, represents a group of formula "—CH(CH3)2."
The term "phenyl," as used herein, represents a group of formula "—C6H5."
The term "fluoro," as used herein, represents a group of formula "—F."
The term "chloro," as used herein, represents a group of formula "—Cl."
The term "bromo," as used herein, represents a group of formula "—Br."
The term "iodo," as used herein, represents a group of formula "—I."
The term "nitro," as used herein, represents a group of formula "—NO2."
The term "dimethylaminosulfonate," as used herein, represents a group of formula "—NHSO2Me2."
The term "diethylaminosulfonate," as used herein, represents a group of formula "—NHSO2Et2."
The term "cyano," as used herein, represents a group of formula "—C—N."
The formula "O," as used herein, represents an oxygen atom.
The formula "N," as used herein, represents a nitrogen atom.
The formula "S," as used herein, represents a sulfur atom.
The formula "H," as used herein, represents a hydrogen atom.
Stereoretentive Ru-Based Catalysts
The invention provides a method for generating Z-macrocycles via macrocyclic ring-closing metathesis of diene substrate bearing a Z-olefin moiety in the presence of a stereoretentive Ru-based catalyst of Formula (I):
In another embodiment the invention provides a method for generating Z-macrocycles via macrocyclic ring-closing metathesis of diene substrate with a Z-olefin moiety in the presence of a stereoretentive Ru-based catalyst of Formula (I), wherein:
R is nil, iso-propyl, or butyl;
R0 is nil;
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently H, methyl, iso-propyl, or fluoro;
R11, R12, R13, and R14 are independently H, phenyl, iso-propoxy, nitro, diethylaminosulfonate, or dimethylaminosulfonate;
X1, X2, X3, and X4 are independently H, fluoro, or chloro; and
Y is oxygen, sulfur, or iodo.
In another embodiment the invention provides a method for generating Z-macrocycles via macrocyclic ring-closing metathesis of diene substrate bearing a Z-olefin moiety in the presence of a stereoretentive Ru-based catalyst of Formula (I), wherein:
R is nil, iso-propyl, or tert-butyl;
R1 is methyl, iso-propyl, or fluoro;
R2 is H or methyl;
R5, is H, methyl, iso-propyl, or fluoro;
R10 is H, methyl, iso-propyl, or fluoro;
R11 is H;
R13 is H, nitro, iso-propoxy, diethylaminosulfonate, or dimethylaminosulfonate;
R14 is H or phenyl;
R15 is H or methyl;
X1 is H, fluoro, or chloro;
X2 is H or fluoro;
X4 is H, fluoro, or chloro; and
In another embodiment the invention provides a method for generating Z-macrocycles via macrocyclic ring-closing metathesis of a diene substrate bearing a Z-olefin moiety in the presence of a stereoretentive Ru-based catalyst of Formula (I), wherein the stereoretentive Ru-based catalyst is selected from:
In another embodiment the invention provides a method for generating Z-macrocycles via macrocyclic ring-closing metathesis of diene substrate bearing a Z-olefin moiety in the presence of a stereoretentive Ru-based catalyst of Formula (II), wherein:
R is iso-propyl;
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently H or methyl;
R11, R12, R13, and R14 are independently H;
Z1 and Z2 are independently cyano; and
Y is oxygen or sulfur.
R1 is methyl;
R2 is H;
R10 is methyl;
R11, R12, R13, and R14 are H;
Z1 and Z2 are cyano; and
In another embodiment the invention provides a method for generating Z-macrocycles via macrocyclic ring-closing metathesis of diene substrate bearing a Z-olefin moiety in the presence of a stereoretentive Ru-based catalyst selected from:
Diene Substrates Bearing a Z-Olefin Moiety
An example of a diene substrate bearing a Z-olefin moiety for use in the present invention may be represented by Formula (III):
R′ is methyl, ethyl, or propyl; n is 1, 2, 3, or 4; and m is 4, 5, 6, or 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety is represented by Formula (III), wherein R′ is methyl or ethyl; n is 1, 2, 3, or 4; and m is 4, 6, or 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety is represented by Formula (III), wherein R′ is methyl; n is 2; and m is 4 or 6.
In one embodiment, the diene substrate bearing a Z-olefin moiety is represented by Formula (III), wherein R′ is methyl; n is 3; and m is 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (III), wherein R′ is ethyl; n is 1, 2, 3, or 4; and m is 6 or 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (III), wherein R′ is ethyl; n is 1 or 2; and m is 6.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (III), wherein R′ is ethyl; n is 1, 2, 3, or 4; and m is 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (III), wherein R′ is ethyl; n is 1; and m is 6.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (IV):
R″ is methyl, ethyl, or propyl; q is 1, 2, 3, or 4; and p is 4, 5, 6, or 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety is represented by Formula (IV), wherein R″ is methyl or ethyl; q is 1, 2, 3, or 4; and p is 4, 6, or 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (IV), wherein R″ is methyl; q is 2; and p is 4 or 6.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (IV), wherein R″ is ethyl; q is 1, 2, 3, or 4; and p is 6 or 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (IV), wherein R″ is ethyl; q is 1 or 2; and p is 6.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (IV), wherein R″ is ethyl; q is 1, 2, 3, or 4; and p is 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (IV), wherein R″ is ethyl; q is 1; and p is 6.
Another example of a diene substrate bearing a Z-olefin moiety for use in the present invention may be represented by Formula (V):
R″′ is methyl, ethyl, or propyl; s is 1, 2, 3, or 4; and t is 4, 5, 6, or 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety is represented by Formula (V), wherein R″′ is methyl or ethyl; s is 1, 2, 3, or 4; and t is 4, 6, or 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety is represented by Formula (V), wherein R″′ is methyl; s is 2; and t is 4 or 6.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (V), wherein R″′ is ethyl; s is 1, 2, 3, or 4; and t is 6 or 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (V), wherein R″′ is ethyl; s is 1 or 2; and t is 6.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (V), wherein R″′ is ethyl; s is 1, 2, 3, or 4; and t is 7.
In one embodiment, the diene substrate bearing a Z-olefin moiety can be represented by Formula (V), wherein R″′ is ethyl; s is 1; and t is 6.
Z-Macrocyclic Products
The Z-macrocyclic product of the invention, comprises an internal olefin, wherein the internal olefin is in a Z-selectivity of 90%, or of 95%, or of 99%.
In some embodiments, the invention provides a method that produces a compound (i.e., a product, olefin product; e.g., ring-close metathesis product, a Z-macrocyclic product) having a carbon-carbon double bond (e.g., a product internal olefin) in a Z/E selectivity ratio of 95/5, or 96/4, or 97/3, or 98/2, or in some cases, of 99/1. In some cases, 100% of the carbon-carbon double bond produced in the metathesis reaction may have a Z-configuration. The Z- or cis selectivity may also be expressed as a percentage of product formed (e.g., ring-close metathesis product, Z-macrocyclic product).
In one embodiment, the Z-macrocyclic product has a carbon-carbon double bond in a Z-configuration and is represented by the structure of Formula (VI):
n is 1, 2, 3, or 4; and m is 4, 5, 6, or 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VI), wherein n is 1, 2, 3, or 4; and m is 4, 6, or 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VI), wherein n is 2; and m is 4 or 6.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VI), wherein n is 3; and m is 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VI), wherein n is 1, 2, 3, or 4; and m is 6 or 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VI), wherein, n is 1 or 2; and m is 6.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VI), wherein n is 1, 2, 3, or 4; and m is 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VI), wherein, n is 1; and m is 6.
In one embodiment, the at least one Z-macrocyclic product has a carbon-carbon double bond in a Z-configuration and is represented by the structure of Formula (VII):
q is 1, 2, 3, or 4; and p is 4, 5, 6, or 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VII), wherein q is 1, 2, 3, or 4; and p is 4, 6, or 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VII), wherein q is 2; and p is 4 or 6.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VII), wherein q is 1, 2, 3, or 4; and p is 6 or 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VII), wherein, q is 1 or 2; and p is 6.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VII), wherein q is 1, 2, 3, or 4; and p is 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VII), wherein, q is 1; and p is 6.
In o embodiment, the Z-macrocyclic product has a carbon-carbon double bond in a Z-configuration and is represented by the structure of Formula (VIII):
s is 1, 2, 3, or 4; and t is 4, 5, 6, or 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VIII), wherein s is 1, 2, 3, or 4; and t is 4, 6, or 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VIII), wherein s is 2; and t is 4 or 6.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VIII), wherein s is 1, 2, 3, or 4; and t is 6 or 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VIII), wherein, s is 1 or 2; and t is 6.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VIII), wherein s is 1, 2, 3, or 4; and t is 7.
In another embodiment, the at least one Z-macrocyclic product is represented by the structure of Formula (VIII), wherein, s is 1; and t is 6.
EMBODIMENTS
In one embodiment, the invention provides a method for producing at least one Z-macrocyclic product represented by Formula (VI):
n is 1, 2, 3, or 4; m is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VI) is a twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95, or 98, or 99; comprising:
subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (III):
R′ is methyl, ethyl, or propyl; n is 1, 2, 3, or 4; m is 4, 5, 6, or 7;
to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (I):
to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (II):
In one embodiment, the invention provides a method for producing at least one Z-macrocyclic product represented by Formula (VII):
q is 1, 2, 3, or 4; p is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VII) is a twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95, or 98, or 99; comprising:
subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (IV):
R″ is methyl, ethyl, or propyl; q is 1, 2, 3, or 4; p is 4, 5, 6, or 7;
In one embodiment, the invention provides a method for producing at least one Z-macrocyclic product represented by Formula (VI), wherein: n is 1, 2, 3, or 4; m is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VI) is an eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95, or 98, or 99; comprising: subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (III), wherein: R′ is methyl, ethyl, or propyl; n is 1, 2, 3, or 4; m is 4, 5, 6, or 7; to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (I), wherein: R and R0 are independently nil, H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently H, methyl, ethyl, propyl, iso-propyl, iso-propoxy, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano; R15, R16, R17, and R18 are independently H or methyl; X1, X2, X3, and X4 are independently H, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; and Y is oxygen, sulfur, nitrogen, or iodo.
In one embodiment, the invention provides a method for producing at least one Z-macrocyclic product represented by Formula (VI), wherein: n is 1, 2, 3, or 4; m is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VI) is an eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95, or 98, or 99; comprising: subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (III) wherein: R′ is methyl, ethyl, or propyl; n is 1, 2, 3, or 4; m is 4, 5, 6, or 7; to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (II), wherein, R and R0 are independently nil, H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano; R15, R16, R17, and R18 are independently H or methyl; Z1 and Z2 are independently cyano or nitro; and Y is oxygen, sulfur, nitrogen, or iodo.
In one embodiment, the invention provides a method for producing at least one Z-macrocyclic product represented by Formula (VII), wherein: q is 1, 2, 3, or 4; p is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VII) is an eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95, or 98, or 99; comprising: subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (IV) wherein: R″ is methyl, ethyl, or propyl; q is 1, 2, 3, or 4; p is 4, 5, 6, or 7; to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (I), wherein: R and R0 are independently nil, H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently H, methyl, ethyl, propyl, iso-propyl, iso-propoxy, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano; R15, R16, R17, and R18 are independently H or methyl; X1, X2, X3, and X4 are independently H, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; and Y is oxygen, sulfur, nitrogen, or iodo.
In one embodiment, the invention provides a method for producing at least one Z-macrocyclic product represented by Formula (VII), wherein: q is 1, 2, 3, or 4; p is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VII) is an eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95, or 98, or 99; comprising: subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (IV) wherein: R″ is methyl, ethyl, or propyl; q is 1, 2, 3, or 4; p is 4, 5, 6, or 7; to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (II), wherein, R and R0 are independently nil, H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano; R15, R16, R17, and R18 are independently H or methyl; Z1 and Z2 are independently cyano or nitro; and Y is oxygen, sulfur, nitrogen, or iodo.
s is 1, 2, 3, or 4; t is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VIII) is an eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95, or 98, or 99; comprising:
subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (V):
R″′ is methyl, ethyl, or propyl; s is 1, 2, 3, or 4; t is 4, 5, 6, or 7;
In one embodiment, the invention provides a method for producing at least one Z-macrocyclic product represented by Formula (VIII):
In one embodiment, the invention provides a method for producing at least one Z-macrocyclic product as described above, comprising: subjecting a diene substrate bearing a Z-olefin moiety as described above, to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst selected from:
General Information—Materials and Methods
Unless otherwise specified, all manipulations were carried out under air-free conditions in dry glassware in a Vacuum Atmospheres Glovebox filled with N2. General solvents were purified by passing through solvent purification columns. Commercially available substrates were used as received. All solvents and substrates were sparged with Argon before bringing into the glovebox and filtered over neutral alumina (Brockmann I) prior to use. Catalyst 5, CAS [1865771-19-2], was synthesized according to literature procedure described in Johns, A. M.; Ahmed, T. S.; Jackson, B. W.; Grubbs, R. H.; Pedersen, R. L. Org. Lett. 2016, 18 (4), 772. Catalyst 4, CAS [1352916-84-7], was synthesized according to literature procedure described in U.S. Pat. No. 9,597,674 B2.
Kinetic NMR experiments were performed on a Varian 600 MHz spectrometer with an AutoX probe. Spectra were analyzed using MestReNova Ver. 8.1.2. 1H and 13C NMR characterization data were obtained on a Bruker 400 with Prodigy broadband cryoprobe and referenced to residual protio-solvent.
The following abbreviations are used in the examples:
mL milliliter L liter ° C. degrees Celsius CD2Cl2 deuterated dichloromethane CDCl3 deuterated chloroform DCM dichloromethane HCl hydrochloric acid NaHCO3 sodium dicarboxylate Et2O diethyl ether MgSO4 magnesium sulfate C823 Dichloro(benzylidene)bis(tricyclohexyl phosphine) ruthenium (II) [CAS 172222-30-9] aq. aqueous sat. saturated
EXAMPLES Synthesis of Diene Substrates Bearing a Z-olefin Moiety Example 1 Synthesis of (Z)-hex-4-en-1-yl oct-7-enoate (6)
To a 100 mL round-bottom flask charged with a stir bar were added dichloromethane (50 mL), 7-octenoic acid (1.54 mL, 10.0 mmol), and pyridine (80.7 μL, 1.00 mmol). Oxalyl chloride (1.00 mL, 11.8 mmol) was added dropwise, and the reaction was stirred overnight. The solvents were removed under vacuum. Dichloromethane (20 mL) and pyridine (0.81 mL, 10.0 mmol) were added, subsequently, cis-4-hexenol (1.09 mL, 9.3 mmol) was added dropwise at 0° C. After bringing the reaction to room temperature, it was stirred for an additional 4 h. The reaction mixture was extracted with 1M aq. HCl (200 mL) and sat. aq. NaHCO3 (200 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were removed under vacuum. The product was purified by column chromatography on silica gel (5:95 Et2O: pentane) to yield a colorless oil (1.58 g, 76% yield).
1H NMR (400 MHz, CDCl3) δ 5.79 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 5.49 (dddd, J=10.7, 8.2, 6.7, 5.2 Hz, 1H), 5.42-5.29 (m, 1H), 4.99 (dq, J=17.1, 1.7 Hz, 1H), 4.93 (ddt, J=10.2, 2.3, 1.2 Hz, 1H), 4.06 (t, J=6.6 Hz, 2H), 2.30 (t, J=7.5 Hz, 2H), 2.16-1.98 (m, 4H), 1.73-1.55 (m, 7H), 1.46-1.28 (m, 4H).
13C NMR (101 MHz, CDCl3) b 174.00, 138.94, 129.24, 125.03, 114.53, 63.89, 34.45, 33.70, 28.74, 28.66, 28.56, 24.98, 23.31, 12.85.
HRMS (FAB+): [M]+ C14H24O2 Calculated—224.1776, Found—224.1745.
Example 2 Synthesis of (Z)-hex-3-en-1-yl dec-9-enoate (7)
To a 100 mL round-bottom flask charged with a stir bar were added dichloromethane (50 mL), 9-decenoic acid (1.85 mL, 10.0 mmol), and pyridine (80.7 μL, 1.00 mmol). Oxalyl chloride (1.00 mL, 11.8 mmol) was added dropwise, and the reaction was stirred for overnight. The solvents were removed under vacuum. Dichloromethane (20 mL) and pyridine (0.81 mL, 10.0 mmol) were added, subsequently, cis-3-hexenol (1.10 mL, 9.3 mmol) was added dropwise at 0° C. After bringing the reaction to room temperature, it was stirred for an additional 4 h. The reaction mixture was extracted with 1M aq. HCl (200 mL) and sat. aq. NaHCO3 (200 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were removed under vacuum. The product was purified by column chromatography on silica gel (5:95 Et2O: pentane) to yield a colorless oil (2.02 g, 86% yield).
1H NMR (400 MHz, CDCl3) δ 5.79 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 5.64-5.37 (m, 1H), 5.37-5.14 (m, 1H), 5.02-4.94 (m, 1H), 4.92 (ddt, J=10.2, 2.3, 1.2 Hz, 1H), 4.05 (t, J=6.9 Hz, 2H), 2.43-2.32 (m, 2H), 2.28 (t, J=7.5 Hz, 2H), 2.12-1.89 (m, 4H), 1.67-1.50 (m, 2H), 1.42-1.19 (m, 8H), 0.96 (t, J=7.5 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 174.01, 139.22, 134.61, 123.90, 114.31, 63.88, 34.46, 33.89, 29.23, 29.21, 29.04, 28.97, 26.89, 25.07, 20.73, 14.37.
Example 3 Synthesis of (Z)-hex-3-en-1-yl undec-10-enoate (8)
To a 100 mL round-bottom flask charged with a stir bar were added dichloromethane (20 mL), undecenoyl chloride (2.37 mL, 11.0 mmol), and pyridine (0.89 mL, 11.0 mmol). Cis-3-hexenol (1.18 mL, 10.0 mmol) was then added dropwise at 0° C. The reaction mixture was brought to room temperature and stirred for 4 h. The reaction mixture was extracted with 1M aq. HCl (200 mL) and sat. aq. NaHCO3 (200 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were removed under vacuum. The product was purified by column chromatography on silica gel (5:95 Et2O: pentane) to yield a colorless oil (2.53 g, 95% yield).
1H NMR (400 MHz, CDCl3) δ 5.80 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 5.55-5.45 (m, 1H), 5.36-5.26 (m, 1H), 4.99 (dq, J=17.1, 1.7 Hz, 1H), 4.92 (ddt, J=10.2, 2.3, 1.2 Hz, 1H), 4.06 (t, J=6.9 Hz, 2H), 2.43-2.31 (m, 2H), 2.32-2.24 (m, 2H), 2.04 (dddd, J=14.8, 7.9, 5.0, 1.5 Hz, 4H), 1.67-1.54 (m, 2H), 1.42-1.33 (m, 2H), 1.33-1.24 (m, 8H), 0.97 (t, J=7.5 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 174.06, 139.32, 134.63, 123.92, 114.28, 63.89, 34.49, 33.94, 29.43, 29.35, 29.26, 29.20, 29.04, 26.90, 25.11, 20.75, 14.39.
To a 100 mL round-bottom flask charged with a stir bar were added dichloromethane (50 mL), 9-decenoic acid (1.85 mL, 10.0 mmol), and pyridine (80.7 μL, 1.00 mmol). Oxalyl chloride (1.00 mL, 11.8 mmol) was added dropwise, and the reaction was stirred overnight. The solvents were removed under vacuum. Dichloromethane (20 mL) and pyridine (0.81 mL, 10.0 mmol) were added, subsequently, cis-4-hexenol (1.09 mL, 9.3 mmol) was added dropwise at 0° C. After bringing the reaction to room temperature, it was stirred for an additional 4 h. The reaction mixture was extracted with 1M aq. HCl (200 mL) and sat. aq. NaHCO3 (200 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were removed under vacuum. The product was purified by column chromatography on silica gel (5:95 Et2O: pentane) to yield a colorless oil (2.05 g, 87% yield).
1H NMR (400 MHz, CDCl3) δ 5.80 (ddt, J=13.2, 10.0, 7.2 Hz, 1H), 5.60-5.44 (m, 1H), 5.44-5.32 (m, 1H), 5.12-4.96 (m, 1H), 4.93 (ddd, J=10.2, 2.3, 1.2 Hz, 1H), 4.07 (t, J=6.5 Hz, 2H), 2.30 (t, J=8.0 Hz, 2H), 2.20-1.96 (m, 4H), 1.81-1.58 (m, 7H), 1.49-1.24 (m, 8H).
13C NMR (101 MHz, CDCl3) b 174.12, 139.29, 129.27, 125.05, 114.34, 63.89, 34.53, 33.92, 29.26, 29.07, 29.00, 28.59, 25.14, 23.34, 12.88.
HRMS (FAB+): [M+H] C16H29O2 Calculated—253.2158, Found—253.2168.
Example 5 Synthesis of (Z)-hex-4-en-1-yl undec-10-enoate (10)
To a 100 mL round-bottom flask charged with a stir bar were added dichloromethane (20 mL), undecenoyl chloride (2.37 mL, 11.0 mmol), and pyridine (0.89 mL, 11.0 mmol). Cis-4-hexenol (1.17 mL, 10.0 mmol) was added dropwise at 0° C. The reaction mixture was brought to room temperature and stirred for 4 h. The reaction mixture was extracted with 1M aq. HCl (200 mL) and sat. aq. NaHCO3 (200 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were removed under vacuum. The product was purified by column chromatography on silica gel (5:95 Et2O: pentane) to yield a colorless oil (2.45 g, 92% yield).
1H NMR (400 MHz, CDCl3) δ 5.80 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 5.49 (dddd, J=10.7, 8.2, 6.7, 5.2 Hz, 1H), 5.36 (dtq, J=10.7, 7.3, 1.7 Hz, 1H), 4.99 (dq, J=17.2, 1.8 Hz, 1H), 4.92 (ddt, J=10.2, 2.3, 1.2 Hz, 1H), 4.06 (t, J=6.6 Hz, 2H), 2.29 (t, J=7.5 Hz, 2H), 2.11 (qt, J=7.2, 1.2 Hz, 2H), 2.07-1.99 (m, 2H), 1.73-1.64 (m, 2H), 1.60 (ddt, J=6.7, 1.8, 0.9 Hz, 6H), 1.36 (dt, J=8.3, 4.8 Hz, 2H), 1.28 (q, J=4.1, 3.3 Hz, 7H).
13C NMR (101 MHz, CDCl3) b 174.12, 139.33, 129.26, 125.04, 114.28, 63.89, 34.54, 33.94, 29.44, 29.36, 29.28, 29.21, 29.04, 28.58, 25.15, 23.33, 12.86.
Example 6 Synthesis of (Z)-oct-5-en-1-yl undec-10-enoate (11)
To a 100 mL round-bottom flask charged with a stir bar were added dichloromethane (20 mL), undecenoyl chloride (2.37 mL, 11.0 mmol), and pyridine (0.89 mL, 11.0 mmol). Cis-5-octenol (1.51 mL, 10.0 mmol) was added dropwise at 0° C.; the reaction mixture was brought to room temperature and stirred for 4 h. The reaction mixture was extracted with 1M aq. HCl (200 mL) and sat. aq. NaHCO3 (200 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were removed under vacuum. The product was purified by column chromatography on silica gel (5:95 Et2O: pentane) to yield a colorless oil (2.82 g, 96% yield).
1H NMR (400 MHz, CDCl3) δ 5.82 (ddt, J=16.9, 10.1, 6.7 Hz, 1H), 5.46-5.37 (m, 1H), 5.36-5.25 (m, 1H), 5.01 (dq, J=17.1, 1.8 Hz, 1H), 4.94 (ddt, J=10.2, 2.4, 1.2 Hz, 1H), 4.08 (t, J=6.7 Hz, 2H), 2.31 (t, J=7.6 Hz, 2H), 2.06 (dddd, J=10.9, 9.5, 5.3, 1.6 Hz, 6H), 1.72-1.61 (m, 4H), 1.47-1.27 (m, 12H), 0.97 (t, J=7.5 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 173.99, 139.17, 132.16, 128.49, 114.14, 64.22, 34.39, 33.80, 29.31, 29.22, 29.14, 29.07, 28.90, 28.23, 26.63, 26.05, 25.02, 20.54, 14.36.
Example 7 Synthesis (Z)-non-6-en-1-yl undec-10-enoate (12)
To a 100 mL round-bottom flask charged with a stir bar were added dichloromethane (20 mL), undecenoyl chloride (2.37 mL, 11.0 mmol), and pyridine (0.89 mL, 11.0 mmol). Cis-6-nonenol (1.67 mL, 10.0 mmol) was then added dropwise at 0° C. The reaction mixture was brought to room temperature and stirred for 4 h. The reaction mixture was extracted with 1M aq. HCl (200 mL) and sat. aq. NaHCO3 (200 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvents were removed under vacuum. The product was purified by column chromatography on silica gel (5:95 Et2O: pentane) to yield a colorless oil (2.74 g, 89% yield).
1H NMR (400 MHz, CDCl3) δ 5.80 (ddt, J=16.9, 10.2, 6.7 Hz, 1H), 5.50-5.16 (m, 2H), 5.04-4.94 (m, 1H), 4.94-4.88 (m, 1H), 4.05 (t, J=6.7 Hz, 2H), 2.35-2.22 (m, 2H), 2.13-1.96 (m, 6H), 1.61 (dt, J=11.8, 4.1 Hz, 4H), 1.36 (dt, J=6.5, 2.2 Hz, 6H), 1.32-1.25 (m, 8H), 0.95 (t, J=7.5 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 174.14, 139.32, 131.99, 128.96, 114.28, 64.47, 34.54, 33.94, 29.48, 29.44, 29.36, 29.28, 29.21, 29.03, 28.70, 27.07, 25.70, 25.15, 20.66, 14.52.
Synthesis of Z-Macrocyclic products Example 8 Synthesis of (Z)-oxacyclododec-8-en-2-one (Z-6)
To a 150 mL Schlenk tube equipped with a stir bar were added diene (6) (21.0 mg, 0.0938 mmol) in DCM (30.3 mL) and a solution of catalyst 5 (4.8 mg, 0.00563 mmol) in DCM (1 mL). The tube was sealed and taken out of the glovebox. After one freeze, pump, thaw cycle, the reaction flask was heated at 40° C. for 1 h and quenched with butyl vinyl ether (1 mL). The solvents were removed under vacuum, and the product was purified by column chromatography on silica gel (1:49 Et2O: pentane) to yield a colorless oil (12.0 mg, 70% yield).
1H NMR (400 MHz, CDCl3) δ 5.45-5.21 (m, 2H), 4.10-−3.96 (m, 2H), 2.49-2.28 (m, 4H), 2.18 (q, J=6.3 Hz, 2H), 1.89-1.81 (m, 2H), 1.68 (ddq, J=8.2, 4.0, 2.0 Hz, 2H), 1.47-1.40 (m, 2H), 1.26-1.18 (m, 2H).
13C NMR (101 MHz, CDCl3) b 174.18, 131.37, 128.57, 62.31, 35.73, 26.80, 26.30, 25.14, 24.18, 23.08, 22.42.
Example 9 Synthesis of (Z)-oxacyclotridec-10-en-2-one (Z-7)
1H NMR (400 MHz, CDCl3) δ 5.50-5.32 (m, 2H), 4.30-4.15 (m, 2H), 2.43 (q, J=5.0 Hz, 2H), 2.35-2.25 (m, 2H), 2.15-2.04 (m, 2H), 1.73-1.64 (m, 2H), 1.49 (q, J=6.3 Hz, 2H), 1.41-1.33 (m, 2H), 1.22-1.15 (m, 2H).
13C NMR (101 MHz, CDCl3) b 174.89, 132.41, 127.26, 64.34, 35.54, 29.86, 27.66, 27.41, 26.15, 26.02, 24.73, 23.67.
HRMS (EI): C12H21O2 Calculated—197.1542, Found—197.1536.
Example 10 Synthesis of (Z)-oxacyclotetradec-11-en-2-one (Z-8)
1H NMR (400 MHz, CDCl3) δ 5.55 (dtt, J=11.1, 7.7, 1.7 Hz, 1H), 5.45-5.33 (m, 1H), 4.28-4.11 (m, 2H), 2.50-2.40 (m, 2H), 2.40-2.29 (m, 2H), 2.10-1.99 (m, 2H), 1.66 (ddt, J=6.3, 4.5, 2.5 Hz, 2H), 1.43-1.30 (m, 10H).
13C NMR (101 MHz, CDCl3) δ 174.13, 132.47, 127.22, 63.89, 33.46, 27.85, 27.65, 26.25, 26.14, 25.67, 25.56, 25.34, 23.65.
To a 150 mL Schlenk tube equipped with a stir bar were added a solution of diene (9) (23.7 mg, 0.0938 mmol) in DCM (30.3 mL) and a solution of catalyst 5 (4.8 mg, 0.00563 mmol) in DCM (1 mL). The tube was sealed and taken out of the glovebox. After one freeze, pump, thaw cycle, the reaction flask was heated at 40° C. for 1 h and then quenched with butyl vinyl ether (1 mL). The solvents were removed under vacuum, and the product was purified by column chromatography on silica gel (1:49 Et2O: pentane) to yield a colorless oil (14.2 mg, 72% yield).
1H NMR (400 MHz, CDCl3) δ 5.48 (dtt, J=10.5, 7.6, 1.5 Hz, 1H), 5.33 (dtt, J=10.5, 7.6, 1.3 Hz, 1H), 4.22-4.02 (m, 2H), 2.51-2.37 (m, 2H), 2.25 (qd, J=7.5, 1.4 Hz, 2H), 2.14-1.95 (m, 2H), 1.79-1.65 (m, 4H), 1.49-1.28 (m, 8H).
13C NMR (101 MHz, CDCl3) b 173.98, 131.23, 128.50, 62.84, 33.57, 29.11, 27.00, 26.77, 26.03, 25.23, 25.04, 24.63, 23.73.
Example 12 Synthesis of (Z)-oxacyclopentadec-11-en-2-one (Z-10)
To a 150 mL Schlenk tube equipped with a stir bar were added a solution of diene (10) (25.0 mg, 0.0938 mmol) in DCM (30.3 mL) and a solution of catalyst 5 (4.8 mg, 0.00563 mmol) in DCM (1 mL). The tube was sealed and taken out of the glovebox. After one freeze, pump, thaw cycle, the reaction flask was heated at 40° C. for 1 h and quenched with butyl vinyl ether (1 mL). The solvents were removed under vacuum, and the product was purified by column chromatography on silica gel (1:49 Et2O: pentane) to yield a colorless oil (15.6 mg, 70% yield).
1H NMR (400 MHz, CDCl3) δ 5.57-5.38 (m, 1H), 5.30 (dt, J=10.9, 6.9 Hz, 1H), 4.18-3.95 (m, 2H), 2.46-2.32 (m, 2H), 2.23 (qd, J=7.1, 1.7 Hz, 2H), 2.02 (q, J=7.1 Hz, 2H), 1.72 (dtd, J=8.9, 6.9, 4.3 Hz, 4H), 1.36 (dt, J=8.7, 5.9 Hz, 10H).
13C NMR (101 MHz, CDCl3) b 174.45, 131.47, 128.85, 63.36, 34.51, 28.81, 28.24, 27.96, 27.12, 27.05, 27.01, 26.35, 24.63, 23.75.
Example 13 Synthesis of (Z)-oxacyclohexadec-11-en-2-one (Z-11)
To a 150 mL Schlenk tube equipped with a stir bar were added a solution of diene (11) (27.6 mg, 0.0938 mmol) in DCM (30.3 mL) and a solution of catalyst 5 (4.8 mg, 0.00563 mmol) in DCM (1 mL). The tube was sealed and taken out of the glovebox. After one freeze, pump, thaw cycle, the reaction flask was heated at 40° C. for 1 h and quenched with butyl vinyl ether (1 mL). Solvents were removed under vacuum, and the product was purified by column chromatography on silica gel (1:49 Et2O: pentane) to yield a colorless oil (17.7 mg, 79% yield).
1H NMR (400 MHz, CDCl3) δ 5.53-5.20 (m, 2H), 4.14 (t, J=6.3 Hz, 2H), 2.43-2.27 (m, 2H), 2.03 (qd, J=7.0, 3.1 Hz, 4H), 1.63 (dq, J=9.2, 6.3 Hz, 4H), 1.45-1.37 (m, 2H), 1.30 (q, J=5.5, 4.6 Hz, 10H).
13C NMR (101 MHz, CDCl3) δ 174.09, 130.24, 129.71, 64.24, 34.01, 29.28, 28.54, 28.31, 28.07, 27.76, 27.32, 27.25, 26.73, 26.61, 25.38.
Example 14 Synthesis of (Z)-oxacycloheptadec-11-en-2-one (Z-12)
1H NMR (400 MHz, CDCl3) δ 5.39-5.22 (m, 2H), 4.19-4.01 (m, 2H), 2.38-2.22 (m, 2H), 2.06 (dq, J=18.6, 6.1 Hz, 4H), 1.71-1.52 (m, 4H), 1.47-1.17 (m, 14H).
13C NMR (101 MHz, CDCl3) b 174.57, 130.37, 130.29, 64.75, 34.43, 29.45, 28.88, 28.84, 28.79, 28.76, 28.19, 27.73, 27.32, 26.57, 26.22, 25.57.
Synthesis of E/Z-Macrocyclic Products
For determining the selectivity of the synthesized Z-macrocyclic products, E/Z mixtures of unsaturated lactones were synthesized using catalyst C823 (PCy3)2Cl2Ru═CHPh as references for GC and 13C NMR studies for comparison.
Example 15 Synthesis of (E/Z)-oxacyclotetradec-10-en-2-one (E/Z-9)
To a 150 mL Schlenk tube equipped with a stir bar were added a solution of diene (9) (23.7 mg, 0.0938 mmol) in DCM (30.3 mL) and a solution of catalyst C823 (4.6 mg, 0.00563 mmol) in DCM (1 mL). The tube was sealed and taken out of the glovebox. After one freeze, pump, thaw cycle, the reaction flask was heated at 40° C. for 4 h and quenched with butyl vinyl ether (1 mL). The solvents were removed under vacuum, and the product was purified by column chromatography on silica gel (1:49 Et2O: pentane) to yield a colorless oil (13.0 mg, 67% yield).
1H NMR (400 MHz, CDCl3) δ 5.68-5.42 (m, 1H), 5.42-5.24 (m, 1H), 4.29-3.98 (m, 2H), 2.53-2.18 (m, 4H), 2.14-2.05 (m, 2H), 1.79-1.64 (m, 4H), 1.49-1.20 (m, 12H).
13C NMR (101 MHz, CDCl3) δ 174.28, 173.86, 131.11, 130.62, 130.40, 128.38, 64.81, 62.72, 33.45, 33.01, 31.42, 30.91, 28.98, 28.18, 27.06, 26.88, 26.65, 26.53, 25.91, 25.11, 24.98, 24.92, 24.51, 24.08, 23.61.
Example 16 Synthesis of (E/Z)-oxacyclopentadec-11-en-2-one (E/Z −10)
To a 150 mL Schlenk tube equipped with a stir bar were added a solution of diene (10) (25.0 mg, 0.0938 mmol) in DCM (30.3 mL) and a solution of catalyst C823 (4.6 mg, 0.00563 mmol) in DCM (1 mL). The tube was sealed and taken out of the glovebox. After one freeze, pump, thaw cycle, the reaction flask was heated at 40° C. for 4 h and quenched with 1 mL butyl vinyl ether (1 mL). The solvents were removed under vacuum, and the product was purified by column chromatography on silica gel (1:49 Et2O: pentane) to yield a colorless oil (11.7 mg, 52% yield).
1H NMR (400 MHz, CDCl3) δ 5.50-5.20 (m, 2H), 4.19-4.04 (m, 2H), 2.40-2.29 (m, 2H), 2.20 (qd, J=7.4, 6.3, 1.6 Hz, 2H), 2.09-1.96 (m, 2H), 1.85-1.54 (m, 5H), 1.45-1.22 (m, 11H).
13C NMR (101 MHz, CDCl3) b 174.48, 174.45, 131.97, 131.48, 129.87, 128.85, 64.30, 63.36, 35.01, 34.51, 31.02, 30.32, 28.81, 28.24, 27.96, 27.85, 27.56, 27.13, 27.05, 27.03, 27.01, 26.82, 26.63, 26.35, 25.03, 24.63, 24.57, 23.75.
Example 17 Synthesis of (E/Z)-oxacyclohexadec-11-en-2-one (E/Z-11)
To a 150 mL Schlenk tube equipped with a stir bar were added a solution of diene (11) (27.6 mg, 0.0938 mmol) in DCM (30 mL) and a solution of catalyst C823 (4.6 mg, 0.00563 mmol) in DCM (1 mL). The tube was sealed and taken out of the glovebox. After one freeze, pump, thaw cycle, the reaction flask was heated at 40° C. for 4 h and quenched with butyl vinyl ether (1 mL). The solvents were removed under vacuum, and the product was purified by column chromatography on silica gel (1:49 Et2O: pentane) to yield a colorless oil (16.8 mg, 75% yield).
1H NMR (400 MHz, CDCl3) δ 5.52-5.15 (m, 2H), 4.22-4.01 (m, 2H), 2.45-2.22 (m, 2H), 2.03 (ddt, J=9.1, 6.8, 3.8 Hz, 4H), 1.61 (dtd, J=15.7, 7.1, 4.0 Hz, 4H), 1.42-1.11 (m, 12H).
13C NMR (101 MHz, CDCl3) b 174.09, 174.07, 131.95, 130.46, 130.24, 129.71, 64.24, 64.08, 34.89, 34.01, 32.16, 32.12, 29.28, 28.54, 28.47, 28.41, 28.34, 28.31, 28.14, 28.07, 27.76, 27.34, 27.32, 27.25, 26.73, 26.68, 26.61, 25.60, 25.38, 25.30.
Example 18 Synthesis of (E/Z)-oxacycloheptadec-11-en-2-one (E/Z −12)
To a 150 mL Schlenk tube equipped with a stir bar were added a solution of diene (12) (28.9 mg, 0.0938 mmol) in DCM (30.3 mL) and a solution of catalyst C823 (4.6 mg, 0.00563 mmol) in DCM (1 mL). The tube was sealed and taken out of the glovebox. After one freeze, pump, thaw cycle, the reaction flask was heated at 40° C. for 4 h and quenched with butyl vinyl ether (1 mL). The solvents were removed under vacuum, and the product was purified by column chromatography on silica gel (1:49 Et2O: pentane) to yield a colorless oil (16.4 mg, 69% yield).
1H NMR (400 MHz, CDCl3) δ 5.39-5.22 (m, 2H), 4.19-4.02 (m, 2H), 2.40-2.25 (m, 2H), 2.04 (ddt, J=14.3, 11.9, 4.8 Hz, 4H), 1.68-1.56 (m, 4H), 1.48-1.22 (m, 14H).
13C NMR (101 MHz, CDCl3) δ 173.38, 129.79, 129.71, 129.18, 129.10, 63.87, 63.56, 33.64, 33.24, 31.57, 30.70, 28.66, 28.26, 28.19, 28.14, 27.71, 27.68, 27.65, 27.60, 27.57, 27.38, 27.14, 27.00, 26.94, 26.91, 26.54, 26.13, 25.93, 25.38, 25.02, 24.96, 24.38, 24.30, 24.28.
General Procedure for Catalyst Initiation Experiments
A solution of catalyst (0.003 mmol) in CD2Cl2 (0.6 mL) was added to a NMR tube and the tube was sealed with a rubber septum. The tube was taken out of the glovebox and placed in a dry ice/acetone bath. Butyl vinyl ether (12 μL, 0.090 mmol) was injected into the tube, and the reaction was monitored by observing the disappearance of the benzylidene signal by 1H NMR using an array at the appropriate temperature. FIG. 4 captures the results.
1. A method for producing at least one Z-macrocyclic product represented by Formula (VI):
comprising: subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (III):
wherein in Formulae (I), (III), and (VI): n is 1, 2, 3, or 4; m is 4, 5, 6, or 7; the Z-macrocyclic product of Formula (VI) is a twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95, or 98, or 99; R and R0 are independently nil, H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently H, methyl, ethyl, propyl, iso-propyl, iso-propoxy, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano; R15, R16, R17, and R18 are independently H or methyl; X1, X2, X3, and X4 are independently H, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; and Y is oxygen, sulfur, nitrogen, or iodo;
or wherein in Formulae (I), (III), and (VI): R′ is methyl; n is 2; m is 6; the Z-macrocyclic product of Formula (VI) is a sixteen-membered ring with a Z-selectivity of 98; R is nil, iso-propyl, or butyl; R0 is nil; R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are H, methyl, iso-propyl, or fluoro; R11, R12, R13, and R14 are H, phenyl, iso-propoxy, nitro, or dimethylaminosulfonate; R15, R16, R17, and R18 are H or methyl; X1, X2, X3, and X4 are H, fluoro, or chloro; and Y is oxygen, sulfur, or iodo;
or wherein in Formulae (I), (III), and (VI): R′ is methyl or ethyl; n is 2; m is 4 or 7; the Z-macrocyclic product of Formula (VI) is a twelve or fifteen-membered ring with a Z-selectivity of 99; R is nil, iso-propyl, or butyl; R0 is nil; R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are H, methyl iso-propyl, or fluoro; R11, R12, R13, and R14 are independently H, phenyl, iso-propoxy, nitro, or dimethylaminosulfonate; R15, R16, R17, and R18 are H or methyl; X1, X2, X3, and X4 are H, fluoro, or chloro; and Y is oxygen, sulfur, or iodo;
or wherein in Formulae (I), (III), and (VI): R is iso-propyl; R0 is nil; R1, R5, R6, and R10 are iso-propyl; R2, R3, R4, R7, R8, and R9 are H; R11, R12, R13, and R14 are H; R15, R16, R17, and R18 are H; X2 and X3 are H; X1 and X4 are chloro; Y is oxygen; and wherein in Formulae (III) and (VI): R′ is methyl or ethyl; n is 1, 3, or 4; m is 6 or 7; and the Z-macrocyclic product of Formula (VI) is a thirteen, fourteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95; or wherein in Formulae (III) and (VI): R′ is methyl; n is 2; m is 6; and the Z-macrocyclic product of Formula (VI) is a fourteen-membered ring with a Z-selectivity of 98; or wherein in Formulae (III) and (VI): R′ is methyl or ethyl; n is 2; m is 4 or 7; and the Z-macrocyclic product of Formula (VI) is a twelve or fifteen-membered ring with a Z-selectivity of 99; or wherein in Formulae (III) and (VI): R′ is ethyl; n is 1; m is 6; and the Z-macrocyclic product of Formula (VI) is a thirteen-membered ring with a Z-selectivity of 95.
2. The method of claim 1, wherein in Formulae (I), (III), and (VI):
R′ is methyl or ethyl;
n is 1, 3, or 4;
m is 6 or 7;
the Z-macrocyclic product of Formula (VI) is a thirteen, fourteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95;
R is nil, iso-propyl or butyl;
R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are H, methyl, iso-propyl, or fluoro;
R11, R12, R13, and R14 are independently H, phenyl, iso-propoxy, nitro, or dimethylaminosulfonate;
R15, R16, R17, and R18 are H or methyl;
X1, X2, X3, and X4 are H, fluoro, or chloro; and
3. The method of claim 1, wherein the stereoretentive Ru-based catalyst represented by Formula (I) is selected from the group consisting of:
4. The method of claim 1, wherein the stereoretentive Ru-based catalyst represented by Formula (I) is selected from the group consisting of
5. The method of claim 1, wherein in Formula (I):
R1, R3, R5, R6, R8, and R10 are independently H, methyl, or iso-propyl;
R2, R4, R7, and R9 are H;
R11, R12, R13, and R14 are independently H or nitro;
Y is oxygen.
wherein: n is 1, 2, 3, or 4; m is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VI) is a twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z selectivity of 95, or 98, or 99; comprising: subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (III):
wherein: R′ is methyl, ethyl, or propyl; n is 1, 2, 3, or 4; and m is 4, 5, 6, or 7; to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (II):
wherein: R and R0 are independently nil, H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently H, methyl, ethyl, propyl, iso-propyl, iso-propoxy, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano; R15, R16, R17, and R18 are independently H or methyl; Z1 and Z2 are independently cyano or nitro; and Y is oxygen, sulfur, nitrogen, or iodo.
7. The method of claim 6, wherein the stereoretentive Ru-based catalyst represented by Formula (II) is selected from the group consisting of:
8. A method for producing at least one Z-macrocyclic product represented by Formula (VII):
wherein: q is 1, 2, 3, or 4; p is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VII) is a twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z selectivity of 95, or 98, or 99; comprising: subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (IV):
wherein: R″ is methyl, ethyl, or propyl; q is 1, 2, 3, or 4; p is 4, 5, 6, or 7; to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (I):
wherein: R and R0 are independently nil, H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently H, methyl, ethyl, propyl, iso-propyl, iso-propoxy, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano; R15, R16, R17, and R18 are independently H or methyl; X1, X2, X3, and X4 are independently H, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; and Y is oxygen, sulfur, nitrogen, or iodo.
10. The method of claim 8, wherein the stereoretentive Ru-based catalyst represented by Formula (I) is selected from the group consisting of
11. The method of claim 8, wherein in Formula (I):
12. A method for producing at least one Z-macrocyclic product represented by Formula (VII):
wherein: R″ is methyl, ethyl, or propyl; q is 1, 2, 3, or 4; p is 4, 5, 6, or 7; to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (II):
wherein: R and R0 are independently nil, H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, or phenyl; R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14 are independently H, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl, phenyl, fluoro, chloro, bromo, iodo, nitro, dimethylaminosulfonate, diethylaminosulfonate, or cyano; R15, R16, R17, and R18 are independently H or methyl; Z1 and Z2 are independently cyano or nitro; and Y is oxygen, sulfur, nitrogen, or iodo.
13. The method of claim 12, wherein the stereoretentive Ru-based catalyst represented by Formula (II) is selected from the group consisting of:
14. A method for producing at least one Z-macrocyclic product represented by Formula (VIII):
wherein: s is 1, 2, 3, or 4; t is 4, 5, 6, or 7; and the Z-macrocyclic product of Formula (VIII) is an eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen-membered ring with a Z-selectivity of 95, or 98, or 99; comprising: subjecting a diene substrate bearing a Z-olefin moiety represented by Formula (V):
wherein: R″′ is methyl, ethyl, or propyl; s is 1, 2, 3, or 4; t is 4, 5, 6, or 7; to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (I):
15. The method of claim 14, wherein the stereoretentive Ru-based catalyst represented by Formula (I) is selected from the group consisting of:
16. The method of claim 14, wherein the stereoretentive Ru-based catalyst represented by Formula (I) is selected from the group consisting of
17. The method of claim 14, wherein in Formula (I):
wherein: R″′ is methyl, ethyl, or propyl; s is 1, 2, 3, or 4; t is 4, 5, 6, or 7; to a macrocyclic ring-closing metathesis reaction in the presence of a stereoretentive Ru-based catalyst represented by Formula (II):
Applicant: CALIFORNIA INSTITUTE OF TECHNOLOGY (Pasadena, CA)
Inventors: Tonia S. AHMED (Pasadena, CA), Robert H. GRUBBS (South Pasadena, CA)
International Classification: C07D 313/00 (20060101); B01J 31/22 (20060101);


text:
The Killers deliver a killer at Little Caesars…
The Killers deliver a killer at Little Caesars Arena
The Killers' Brandon Flowers performs Saturday night, Oct. 8, at Detroit's Little Caesars Arena (Photo courtesy of The Killers)
PUBLISHED: October 9, 2022 at 10:39 a.m. | UPDATED: October 9, 2022 at 10:39 a.m.
A week before the Killers' concert Saturday night, Oct. 8, at Little Caesars Arena the band was joined onstage by Bruce Springsteen for encores at New York's Madison Square Garden.
That's tough to top, but seven days later Brandon Flowers and his Las Vegas troupe still managed to deliver an abundantly eventful night, nearly two hours filled with energy, exuberance and high spirits in what was the Killers' biggest show to date in the metro area.
"We've been coming to Detroit since probably 2003," Flowers noted at the action-packed 23-song concert's halfway point. (It was actually 2004, at the Shelter and then Saint Andrew's Hall.) "The bars to clubs, theaters, Masonic lodges. Here we are in this beautiful arena. It's wild to have everyone grow with us."
Little Caesars was, in fact, nearly full the show, which Flowers also noted was the Killers' last Saturday date in North America on its latest tour. "We're gonna play like it's our last Saturday night on Earth!" he promised and just about made good on that with a whiplash fervor and a musical mix that had one foot in 90s British New Wave and the other in the Americana arena rock of Springsteen, Bon Jovi and Bryan Adams (ok, he's Canadian, but still…).
"It's a super spreader event!" Flowers proclaimed early on. "We're spreading peace! We're spreading love! We're spreading rock 'n' roll! Come get some!"
There was indeed plenty to be had, and a needle drop at any point of the Killers show yielded a highlight — up to and including a, well, killer opening set by Johnny Marr, the former Smiths guitarist whose quartet lit up Little Caesars with his own material, including "Armatopia" and "Easy Money" and the Britpop history of his old band ("Panic," "There is a Light That Never Goes Out," "How Soon is Now?" and the "Manchester disco" of his other band Electronica's "Getting Away With It."
The Killers, meanwhile, didn't waste any time getting to the Big Moments, opening the show with "My Own Soul's Warning" and the first of three major confetti blasts into the general admission arena floor. The group — which featured as many as eight musicians on stage behind Flowers — deftly balanced old favorites with recent material and offering a full-career sampling weighted, not surprisingly, in favor of its platinum-and-better first two albums and oddly playing just one track ("Cody") from its latest release 2021's "Pressure Machine" — with the new single, "Boy," also in the mix.
You'd have been hard-pressed to find any complaints, though, as the group pounded through anthemic favorites such as "When We Were Young," "Somebody Told Me" "Human," "Read My Mind," "Spaceman" and the singalong "All These Things I've Done," with the charismatic Flowers ping-ponging around the stage, occasionally stopping to play at his mid-stage bank of keyboards. He and guitarist Ted Sablay also gave Motown a musical shout-out with a bit of the Temptations' "My Girl.
For "For Reasons Unknown," Flowers brought a well-prepared fan from Grand Rapids named Scotty Rock on stage to play drums, with the frontman stropping on a bass while drummer Ronnie Vannucci Jr. switched to guitar. And Flowers brought "Dying Breed" to a halt in order to call out a fan in the pit who had punched another, ordering that the offender be removed and not starting the song again until he was assured the attack victim was alright.
During the encores Flowers honored a sign request for "Miss Atomic Bomb" by a group of "next generation Killer fans" sitting at the side of the stage, and while there was no Springsteen in sight Marr joined the Killers to wrap the show with the Smiths' hit "This Charming Man" and the headliners' "Mr. Brightside," the latter's choruses sung almost entirely by the Little Caesars crowd.
It was, ultimately, a night that lived up to the occasion, a mark of how far the Killers have come since that first basement bar show in Detroit — and how ready Flowers and his group was for the arena ranks.

redpajama_set_name: RedPajamaCommonCrawl


Stand close to the 'cone'. Have your dog on your left or right side (parallel to you). You your leg (toe to line) to cue your dog to move forward and turn around the cone. Make sure you're using the dog-side leg. Reward with your opposite (non-dog side) hand. Throw your reward ahead of the dog to encourage speed out of the turn. Gradually build distance from your cone (or what ever you're using as a post) to build obstacle commitment.


text:
Home News Custom farming rates going up, but so are the costs
Custom farming rates going up, but so are the costs
By Chris Kick -
SALEM, Ohio — If you're paying someone else to plant or harvest your crop — known as custom work — you'll probably pay a little more this year than usual.
Rates are up for everything from planting to harvesting, according to a survey conducted by Ohio State University, with results released in July.
The survey is conducted every two years, and this year included 256 participants.
Compared to 2012, the cost for custom planting is up about 10.4 percent on average, grain harvesting is up 10.5 percent and hay/straw harvesting is up 15.4 percent.
Rates normally do go up, according to ag economist Barry Ward, a business management leader with OSU Extension, who coordinates the survey. But this year's increase is noticeably higher, partly due to the profitable conditions for farmers the past few years.
"We've seen a very profitable period in grain production that has allowed some of these rates to go higher," he said, adding that it amounts to inflation.
Questionable year
Of course, farmers already know that this year could be a difficult year to be profitable — as prices for crop commodities have been falling all year, and are approaching and dipping below the break-even point.
But Ward said it will likely take more time and sustained low prices, before those factors begin to factor into the price of custom work.
See our custom farming infographic here.
Even with the price increases, he said many custom operators probably are not covering all of their costs. Custom operators usually cover their cash costs, he said, but may not figure in all of their variable costs, like depreciation of equipment or the amount of time spent doing the custom work.
Part of the reason, Ward said, is because a lot of custom work is done within a neighborhood or a family — and those custom operators may not be in it for profit — as would an operator who travels or does custom work full-time.
Many factors
There's a wide variety of scenarios, depending on the custom operator and the farm that hires the work done. That's why Ward's survey includes average prices, as well as the range of prices. The survey lists prices for dozens of field operations, but should not be considered the market standard.
The average cost to harvest corn with a combine and grain cart, for example, is $34.65 per acre, but the range is from $25-$68 per acre. Similarly, the average price for harvesting soybeans is $32, with a range of $23-$50.
"Hopefully, it's not setting the market," Ward said, suggesting instead that farmers should use the survey results as a "starting point" and a reference.
Covering costs
Even with the increases, custom operators say their own costs are becoming harder to cover.
Jon Orr, of Orrson Custom Farming in Apple Creek, harvests forages in Ohio, Michigan, Georgia and Florida. He is also vice president of U.S. Custom Harvesters — a nationwide association of custom harvesters.
The two biggest challenges Orr has had in recent years are the cost of good labor, and the price for good equipment.
"We're having to up the ante on what we pay employees to be able to maintain employees," he said, noting that government regulations have made it too difficult to get foreign workers.
His company had previously relied on workers from South Africa who were dependable and responsible farm hands. He's also finding himself in competition with the oil and gas industry, which has spurred employment.
At the same time, equipment prices are going up at unprecedented levels, with the price of new forage choppers sometimes increasing 6-10 percent a year. Orr said he's also seeing an increase in the price of tandem-axle trucks, which he believes is tied to new demand, resulting from the oil and gas industry.
"Our overhead is going up continually, our labor is getting harder, we've got to charge more if we want the quality," he said.
Advantages of going custom
Ward said he's unsure how many farmers in Ohio may be hiring custom field work, but if he had to guess, he said he would guess the trend has decreased slightly in recent years, because more farmers have invested in their own equipment following years of good grain prices.
There are advantages both ways, and those who hire the work done usually do so to increase efficiency and free up their time to do other tasks.
Orr said he sees custom harvesting as Henry Ford once saw the auto industry — with a focus on specialization and quality.
'"We know these machines — we run these machines the whole year," Orr said. "This is our specialty."
And experience is important, considering the new machines are ever-evolving and more complex and costly than ever.
Jerome Rhoads, who custom harvests forages in and around Lancaster County, Pa., said farmers may only need to use certain equipment, like harvesters, twice a year. It often doesn't make sense to own the equipment year-round.
The advantage of hiring the work done is "a consistent job. We get it done when it needs done, with up-to-date equipment," he said.
Rhoads admits, though, that being consistent can be stressful during harvest season — especially when the weather isn't cooperating.
"That can be very challenging," he said. "You can't guarantee it. You do the best that you can."
If things get too bad, he hires custom harvesters himself — to help share the load and make sure the farmers get what is promised.
Orr said he tries hard not to over-book himself and, like Rhoads, he sometimes turns to other custom harvesters to help get the job done. He harvests between 7,000-8,000 acres of forages each year — a huge responsibility.
"In general, we (custom operators) try to work together," he said. "Our goal is to get the work done."
Part of a custom operator's concern, he said, is retaining customers and making sure veteran harvesters don't lose out to a new competitor. Orr said it's not uncommon for a new custom harvester to emerge during the busy season — with offers of cheap labor and cheap harvest.
But, he said, such harvesters usually find out in a few years' time what it's like to stay in business — and many end up exiting.
Orr's own family has been custom harvesting since 1949, and on a traveling, commercial scale since 1997. Rhoads has been custom harvesting since 1982.
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Chris Kick
http://www.farmanddairy.com
Chris Kick served Farm and Dairy's readership as a reporter for nearly a decade before accepting a job at Iowa State University Extension. An American FFA Degree recipient, he holds a bachelor's in creative writing from Ashland University.


Not long ago, the idea of finishing a 5K race would have never occurred to Larry Smith, 58. The retired civil rights director for the UAW walked for an hour several times a week. He also monitored his blood sugar regularly to keep his diabetes in check. At 5 feet 9 inches and 210 pounds, Larry knew his doctor wanted him to lose weight. But despite a healthy diet, Larry just hadn't been able to shed the excess pounds.
Today, Larry has a new waistline to go with his new identity as a runner. The Beverly Hills resident runs 15 to 18 miles a week and has completed two 5K races.
His inspiration? HAP's 5K Challenge. Here's how this innovative program propelled Larry from walker to runner in just nine weeks – and how you can, too.
Larry accepted the challenge but, honestly, wasn't sure at first whether he'd complete it. "The first two weeks, I wanted to quit. I thought there was no way I would be able to do the program," says Larry. "I couldn't run for 30 seconds!" He started by alternating brief periods of running with walking. Four weeks in, he ran a quarter mile without stopping and continued to increase the length of his runs.
While Larry trained alone, he says support from the program kept him going. "The weekly communication from HAP was phenomenal," he says. "The weekly emails encouraged you and let you know what you should be doing." He and the other participants – about 300 signed up for the 5K – also used an online training program to log their miles, ask questions about training and connect with other runners.
"It became a friendly competition – you didn't want to lag behind anybody," he says. "That was a huge key to my success." Inspired, he ramped up to training five days a week. He walked and ran countless steps and placed in the top five of participants at the end of the program. And in June 2016, Larry ran his first 5K race.
He's impressed his doctor. "I'm finally in my normal weight range. I've always tried to eat right but the running was the missing piece." Larry's doctor also is changing his medication to reflect his improved health.
Input from Larry's doctor was critical as Larry set off on this lifestyle change. While we know it might be low on your to-do list, it's important to see your doctor regularly – even when you feel perfectly healthy. Conditions like high blood pressure, high cholesterol and high blood sugar often have no symptoms. Checkups every year or two can spot these silent health issues. That way, you can address and treat them before they develop into more serious health problems.
For more information and training resources, go to hap.org/5K.
3.	View the list of races and discount codes.
4.	Sign up for a race.