WO2016014954A1 - Métathèse/dihydroxylation tandem à sélectivité z - Google Patents

Métathèse/dihydroxylation tandem à sélectivité z Download PDF

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WO2016014954A1
WO2016014954A1 PCT/US2015/042013 US2015042013W WO2016014954A1 WO 2016014954 A1 WO2016014954 A1 WO 2016014954A1 US 2015042013 W US2015042013 W US 2015042013W WO 2016014954 A1 WO2016014954 A1 WO 2016014954A1
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cross
metathesis
dihydroxylation
olefin
reaction
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PCT/US2015/042013
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English (en)
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Robert H. Grubbs
Peter K. DORNAN
Zachary K. WICKENS
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California Institute Of Technology
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2265—Carbenes or carbynes, i.e.(image)
    • B01J31/2278—Complexes comprising two carbene ligands differing from each other, e.g. Grubbs second generation catalysts
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/50—Redistribution or isomerisation reactions of C-C, C=C or C-C triple bonds
    • B01J2231/54—Metathesis reactions, e.g. olefin metathesis
    • B01J2231/543—Metathesis reactions, e.g. olefin metathesis alkene metathesis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/821—Ruthenium

Definitions

  • This invention relates generally to C-H activated ruthenium olefin metathesis catalyst compounds and the use of such catalysts in the metathesis of olefins and olefin compounds, such as, in the use of such catalysts in Z-selective olefin metathesis reactions, such as tandem Z-selective cross- metathesis / stereospecific dihydroxylation.
  • the invention has utility in the fields of catalysis, organic synthesis, and industrial and fine chemicals chemistry.
  • anti-diols see for representative examples of anti 1,2-diol synthesis: a) H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483–2547; b) H. C. Brown, G. Narla, J. Org. Chem. 1995, 60, 4686–4687; c) A. B. Northrup, D. W. C. MacMillan, Science 2004, 305, 1752–1755; d) S. M. Lim, N. Hill, A. G. Myers, J. Am. Chem. Soc. 2009, 131, 5763–5765; e) S. B.
  • 1,2-Diols are a common structural motif found in numerous classes of natural products, including carbohydrates and polyketides, as well as chiral ligands.
  • Stereospecific dihydroxylation is a powerful method to access stereodefined diols from olefins (H. C. Kolb, M. S. Van Nieuwenhze, K. B. Sharpless, Chem. Rev. 1994, 94, 2483–2547; C. J. R. Bataille, T. J. Donohoe, Chem. Soc. Rev. 2010, 40, 114–128).
  • the diastereopurity of the resulting diol is largely dependent on the geometrical purity of the olefin substrate.
  • Blechert developed the first tandem metathesis-dihyroxylation, employing a variation of Plietker’s oxidation conditions with YbCl 3 (S. Beligny, S. Eibauer, S. Maechling, S. Blechert, Angew. Chem. Int. Ed. 2006, 45, 1900–1903).
  • the authors examined RCM- dihyroxylation, as well as three examples of cross-metathesis / dihydroxylation. Snapper and co-workers subsequently reported a similar tandem process for RCM-dihydroxylation and cross-metathesis / dihydroxylation (A. A. Scholte, M. H. An, M. L. Snapper, Org. Lett.
  • Plietker s oxidation conditions with CeCl3 were used.
  • the cross-metathesis products led to syn-diol products, due to the stereospecific nature of the ruthenium dihydroxylation.
  • Plietker has developed a chiral auxiliary directed diastereoselective cross-metathesis / dihydroxylation that also leads to syn-diols (N. M.Neisius, B. Plietker, J. Org. Chem. 2008, 73, 3218–3227).
  • the invention is directed to addressing one or more of the aforementioned concerns and relates to tandem Z-selective cross-metathesis / stereospecific dihydroxylation. More particularly, the invention relates to C-H activated ruthenium olefin metathesis catalyst compounds and the use of such catalysts in tandem Z-selective cross-metathesis /stereospecific dihydroxylation.
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross- metathesis reaction to form a cross-metathesis mixture; and contacting the cross-metathesis mixture with an oxidizing agent under conditions to promote a dihydroxylation reaction to form at least one compound comprising a vicinal diol, wherein the vicinal diol has anti stereochemistry.
  • the invention provides an assisted tandem catalysis procedure for the Z-selective cross-metathesis / dihydroxylation of terminal olefins, containing electron withdrawing groups at the allylic position, to yield anti-diols.
  • Ruthenium catalyzes both transformations, and the Z- selectivity observed in the cross-metathesis is translated to anti-selectivity via the stereospecific dihydroxylation.
  • Densely functionalized anti-diols with four contiguous heteroatom substituted carbon atoms can be synthesized from simple allyl alcohol and allyl amine derivatives.
  • the invention provides a C-H activated catalyst compound composed of a Group 8 transition metal complex and a chelating ligand structure formed from the metal center M, a neutral electron donor ligand L 1 , and a 2-electron anionic donor bridging moiety Q*.
  • a general structure of catalyst compounds according to the invention is shown below:
  • M is a Group 8 transition metal (e.g., Ru or Os);
  • X 1 is an anionic ligand;
  • L 1 is a neutral two electron ligand, where L 1 may connect with R 2 ;
  • R 1 and R 2 are independently selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups, and wherein R 1 may connect with R 2 and/or L 1 ;
  • Q* is a 2-electron anionic donor bridging moiety (e.g., alkyl, aryl, carboxylate, alkoxy, aryloxy, or sulfonate, etc.);
  • Q is a linker, typically a hydrocarbylene linker, including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene linkers, wherein two or more substituents on adjacent atoms within Q may also be linked to form an additional cyclic structure, which may be similarly substituted to provide a fused polycyclic structure of two to about five cyclic groups.
  • Q is often, although again not necessarily, a two-atom linkage or a three-atom linkage;
  • X is an atom selected from C, N, O, S, and P. Since O and S are divalent, n is necessarily zero when X is O or S. Similarly, when X is N or P, then n is 1, and when X is C, then n is 2; and
  • R 3 and R 4 are independently selected from hydrocarbyl, substituted hydrocarbyl, heteroatom- containing hydrocarbyl, and substituted heteroatom-containing, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 24 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, etc.), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 24 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 - C 20 alkynyl, C 5 -
  • the invention is directed to a stereoselective synthesis of anti-1,2-diols, developed using a multitasking Ru-catalyst in an assisted tandem catalysis protocol.
  • a cyclometalated ruthenium complex catalyses first a Z-selective cross-metathesis of two terminal olefins followed by a stereospecific dihydroxylation. Both steps are catalyzed by Ru, as the Ru-complex is converted to a dihydroxylation catalyst upon addition of NaIO4 (Scheme 4) and the stereocontrol of the cross-metathesis is translated via high stereospecificity in the dihydroxylation step to diastereoselectivity for the 1,2-anti-diol.
  • Scheme 4 Z-selective catalysts lead to anti-diols
  • the invention provides an assisted tandem catalysis procedure for the Z- selective cross-metathesis / dihydroxylation of terminal olefins to yield anti-diols.
  • Ruthenium catalyzes both transformations, and the Z-selectivity observed in the cross-metathesis is translated to anti- selectivity via the stereospecific dihydroxylation.
  • Densely functionalized anti-diols with four contiguous heteroatom substituted carbon atoms can be synthesized from simple allyl alcohol and allyl amine derivatives.
  • the behaviour of the in situ generated Ru-based oxidation catalyst was probed with unfunctionalized electron rich alkenes, and these were found to inhibit dihydroxylation.
  • the invention provides a tandem Z-selective metathesis / dihydroxylation reaction, which is effective for substrates containing electron withdrawing groups at the allylic position.
  • a variety of olefins were transformed into valuable highly functionalized and stereodefined molecules. Mechanistic experiments are performed to probe the nature of the oxidation step and catalyst inhibition pathways. These experiments point the way to more broadly applicable tandem catalytic transformations. It has been demonstrated that Z-selective catalysts lead to anti-diols in a catalyst controlled fashion via the Z-olefin.
  • the tandem Z-selective metathesis– dihydroxylation reaction
  • allylic functional groups could either be acting as electron withdrawing groups to render the Ru center more electrophilic, or as directing groups.
  • T. J. Donohoe Synlett 2002, 1223-1232.
  • Schem 1 inhitibs the dihydroxylation of cis-butenyldiacetate 3.
  • allyl acetate 1 was subjected to cross-metathesis conditions under static vacuum, and then the reaction mixture was added to a mixture of NaIO4 and CeCl 3 in MeCN:EtOAc:H 2 O (3:3:1).
  • the anti diol 2 was isolated in 60% yield, and spectroscopic data was consistent with literature values (T. K. M. Shing, E. K. W.Tam, V. W.-F. Tai, I. H. F. Chung, Q. Jiang, Chem.– Eur. J. 1996, 2, 50–57), thus confirming the anti-stereochemistry.
  • N-tosyl allyl amine 4 was also a competent substrate, undergoing homodimerization and dihydroxylation to give 5 in 66% yield.
  • cross-metathesis is possible if an excess of one of the alkene partners is used.
  • N-tosyl allyl amine 4 was subjected to cross-metathesis with an excess of allyl butyrate 6 (5 eq).
  • the resulting diol 7 was isolated after dihydroxylation in 63% yield.
  • olefins that lack an electron withdrawing group at the allylic position can undergo Z-selective metathesis, but do not undergo dihydroxylation.
  • terminal olefin 8 was homodimerized and then subjected to oxidation conditions in the presence of diacetate 3. Interestingly, neither olefin is dihydroxylated in this case. Considering that diacetate 3 is a competent dihydroxylation substrate under these conditions, this result indicates that olefin 10 is not only unreactive towards but actually inhibits catalytic dihydroxylation. It was hypothesized that a stable ruthenate ester is formed with olefin 10, thus sequestering the catalytic species.
  • alkyl refers to a linear, branched, or cyclic saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, preferably 1 to about 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 12 carbon atoms.
  • lower alkyl intends an alkyl group of 1 to 6 carbon atoms
  • specific term“cycloalkyl” intends a cyclic alkyl group, typically having 4 to 8, preferably 5 to 7, carbon atoms.
  • substituted alkyl refers to alkyl substituted with one or more substituent groups
  • heteroatom-containing alkyl and heteroalkyl refer to alkyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms“alkyl” and“lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl and lower alkyl, respectively.
  • alkylene refers to a difunctional linear, branched, or cyclic alkyl group, where“alkyl” is as defined above.
  • alkenyl refers to a linear, branched, or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like.
  • Preferred alkenyl groups herein contain 2 to about 12 carbon atoms.
  • lower alkenyl intends an alkenyl group of 2 to 6 carbon atoms
  • specific term“cycloalkenyl” intends a cyclic alkenyl group, preferably having 5 to 8 carbon atoms.
  • substituted alkenyl refers to alkenyl substituted with one or more substituent groups
  • heteroatom-containing alkenyl and“heteroalkenyl” refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms“alkenyl” and“lower alkenyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl and lower alkenyl, respectively.
  • alkenylene refers to a difunctional linear, branched, or cyclic alkenyl group, where“alkenyl” is as defined above.
  • alkynyl refers to a linear or branched hydrocarbon group of 2 to about 24 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like. Preferred alkynyl groups herein contain 2 to about 12 carbon atoms.
  • the term“lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms.
  • substituted alkynyl refers to alkynyl substituted with one or more substituent groups, and the terms“heteroatom-containing alkynyl” and
  • heteroalkynyl refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the terms“alkynyl” and“lower alkynyl” include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.
  • alkoxy intends an alkyl group bound through a single, terminal ether linkage; that is, an“alkoxy” group may be represented as -O-alkyl where alkyl is as defined above.
  • A“lower alkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms.
  • alkenyloxy” and“lower alkenyloxy” respectively refer to an alkenyl and lower alkenyl group bound through a single, terminal ether linkage
  • “alkynyloxy” and“lower alkynyloxy” respectively refer to an alkynyl and lower alkynyl group bound through a single, terminal ether linkage.
  • aryl refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety).
  • Preferred aryl groups contain 5 to 24 carbon atoms, and particularly preferred aryl groups contain 5 to 14 carbon atoms.
  • aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like.
  • “Substituted aryl” refers to an aryl moiety substituted with one or more substituent groups
  • the terms“heteroatom-containing aryl” and“heteroaryl” refer to aryl substituents in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra.
  • aryloxy refers to an aryl group bound through a single, terminal ether linkage, wherein“aryl” is as defined above.
  • An“aryloxy” group may be represented as -O-aryl where aryl is as defined above.
  • Preferred aryloxy groups contain 5 to 24 carbon atoms, and particularly preferred aryloxy groups contain 5 to 14 carbon atoms.
  • aryloxy groups include, without limitation, phenoxy, o-halo-phenoxy, m-halo-phenoxy, p-halo-phenoxy, o-methoxy-phenoxy, m- methoxy-phenoxy, p-methoxy-phenoxy, 2,4-dimethoxy-phenoxy, 3,4,5-trimethoxy-phenoxy, and the like.
  • alkaryl refers to an aryl group with an alkyl substituent
  • aralkyl refers to an alkyl group with an aryl substituent, wherein“aryl” and“alkyl” are as defined above.
  • Alkaryl groups contain 6 to 24 carbon atoms, and particularly preferred alkaryl and aralkyl groups contain 6 to 16 carbon atoms.
  • Alkaryl groups include, for example, p-methylphenyl, 2,4- dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctylnaphthyl, 3-ethyl-cyclopenta- 1,4-diene, and the like.
  • aralkyl groups include, without limitation, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4- phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like.
  • alkaryloxy and aralkyloxy refer to substituents of the formula -OR wherein R is alkaryl or aralkyl, respectively, as just defined.
  • acyl refers to substituents having the formula -(CO)-alkyl, -(CO)-aryl, or -(CO)- aralkyl
  • acyloxy refers to substituents having the formula -O(CO)-alkyl, -O(CO)-aryl,or - O(CO)-aralkyl, wherein“alkyl,”“aryl,” and“aralkyl” are as defined above.
  • cyclic and“ring” refer to alicyclic or aromatic groups that may or may not be substituted and/or heteroatom containing, and that may be monocyclic, bicyclic, or polycyclic.
  • alicyclic is used in the conventional sense to refer to an aliphatic cyclic moiety, as opposed to an aromatic cyclic moiety, and may be monocyclic, bicyclic, or polycyclic.
  • halo and“halogen” and“halide” are used in the conventional sense to refer to a chloro, bromo, fluoro, or iodo substituent.
  • Hydrocarbyl refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including linear, branched, cyclic, saturated, and unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like.
  • lower hydrocarbyl intends a hydrocarbyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms
  • hydrocarbylene intends a divalent hydrocarbyl moiety containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species.
  • lower hydrocarbylene intends a hydrocarbylene group of 1 to 6 carbon atoms.“Substituted hydrocarbyl” refers to hydrocarbyl substituted with one or more substituent groups, and the terms “heteroatom-containing hydrocarbyl” and“heterohydrocarbyl” refer to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Similarly,“substituted hydrocarbylene” refers to hydrocarbylene substituted with one or more substituent groups, and the terms“heteroatom-containing hydrocarbylene” and heterohydrocarbylene” refer to hydrocarbylene in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term“hydrocarbyl” and
  • hydrocarbylene are to be interpreted as including substituted and/or heteroatom-containing
  • heteroatom-containing hydrocarbyl group refers to a hydrocarbon molecule or a hydrocarbyl molecular fragment in which one or more carbon atoms is replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur.
  • heteroalkyl refers to an alkyl substituent that is heteroatom-containing
  • heterocyclic refers to a cyclic substituent that is heteroatom- containing
  • heteroaryl and“heteroaromatic” respectively refer to“aryl” and“aromatic” substituents that are heteroatom-containing, and the like.
  • a“heterocyclic” group or compound may or may not be aromatic, and further that“heterocycles” may be monocyclic, bicyclic, or polycyclic as described above with respect to the term“aryl.”
  • heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylated amino alkyl, and the like.
  • heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., and examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, etc.
  • substituted as in“substituted hydrocarbyl,”“substituted alkyl,”“substituted aryl,” and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, alkyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents.
  • substituents include, without limitation:
  • Fn functional groups referred to herein as“Fn,” such as halo, hydroxyl, sulfhydryl, C 1 -C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 24 aryloxy, C 6 -C 24 aralkyloxy, C 6 -C 24 alkaryloxy, acyl (including C 2 -C 24 alkylcarbonyl (-CO-alkyl) and C 6 -C 24 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl, including C 2 - C 24 alkylcarbonyloxy (-O-CO-alkyl) and C 6 -C 24 arylcarbonyloxy (-O-CO-aryl)), C 2 -C 24 alkoxycarbonyl (-(CO)-O-alkyl), C 6 -C 24 aryloxycarbonyl (-(CO)-aryl),
  • dialkylaminosulfonyl (-SO2-N(alkyl)2), C 5 -C 24 arylsulfonyl (-SO2-aryl), boryl (-BH2), borono (- B(OH)2), boronato (-B(OR)2 where R includes without limitation alkyl or other hydrocarbyl), phosphono (-P(O)(OH) 2 ), phosphonato (-P(O)(O ⁇ ) 2 ), phosphinato (-P(O)(O ⁇ )), phospho (-PO 2 ), and phosphino (-PH2); and the hydrocarbyl moieties C 1 -C 24 alkyl (preferably C 1 -C 1 2 alkyl, more preferably C 1 -C 6 alkyl), C 2 -C 24 alkenyl (preferably C 2 -C 1 2 alkenyl, more preferably C 2 -C 6 alkenyl), C 2 -C 24 alkynyl (
  • “functionalized olefin,”“functionalized cyclic olefin,” and the like, is meant that in the hydrocarbyl, alkyl, olefin, cyclic olefin, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more functional groups such as those described hereinabove.
  • the term “functional group” is meant to include any functional species that is suitable for the uses described herein.
  • the term“nil” as used herein means nonexistent or absent.
  • the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties such as those specifically enumerated above.
  • the above-mentioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties such as those specifically enumerated.
  • the term“internal olefin” as used herein means an olefin wherein each of the olefinic carbons is substituted by at least one non-hydrogen substituent.
  • the internal olefin may be di- substituted, tri-substituted, or tetra-substituted.
  • The“internal olefin” may have an E-configuration or a Z-configuration.
  • terminal olefin as used herein means an olefin wherein one of the olefinic carbons is substituted by at least one non-hydrogen substituent.
  • the terminal olefin may be di- substituted or mono-substituted.
  • The“reactant internal olefin” may be di-substituted, tri- substituted, or tetra-substituted.
  • The“reactant internal olefin” may have an E-configuration or a Z- configuration.
  • The“product internal olefin” may be di-substituted, tri-substituted, or tetra-substituted.
  • The“product internal olefin” may have an E-configuration or a Z-configuration.
  • the“product internal olefin” has a Z-configuration.
  • the“product internal olefin” is di-substituted.
  • the“product internal olefin” has a Z-configuration and is di-substituted.
  • ruthenium species refers to RuCl 3 as a hydrate but also to anhydrous RuCl 3 , RuO 4 , or Ruthenium salts such as Ru(III)(acetylacetonate), RuI 3 , Dichloro(p- cymene)ruthenium(II) dimer Ru(O) precursors, such as triruthenium dodecacarbonyl.
  • Ruthenium salts such as Ru(III)(acetylacetonate), RuI 3 , Dichloro(p- cymene)ruthenium(II) dimer Ru(O) precursors, such as triruthenium dodecacarbonyl.
  • the“ruthenium species” can also refer to Grubbs-type Ru-alkylidenes 1 st or 2 nd generation catalysts.
  • the“ruthenium species” may also refer to an in situ generated Ru-based oxidation catalyst, wherein the in situ generated Ru-based oxidation catalyst is derived from a C-H activated catalyst complex as described and used herein.
  • an in situ Ru-based oxidation catalyst is thought to be generated upon subjecting a C-H activated catalyst complex (or a cross- metathesis mixture comprising a C-H activated catalyst complex) to oxidation conditions and/or oxidizing agents and/or dihydroxylation conditions.
  • the term“multitasking Ru-catalyst” refers to a cyclometalated ruthenium complex which catalyses first a Z-selective cross-metathesis of two terminal olefins followed by a stereospecific dihydroxylation. Both steps are catalyzed by the ruthenium Ru, as the Ru-complex is converted to a dihydroxylation catalyst upon addition of NaIO 4.
  • the term“enantioenriched,” refers to mirror images, when one chiral center is present or when 2 or more chiral centers are present and the enantiomeric or diastereomeric ratio is greater than 50:50 but less than 100:1.
  • enantiopure refers to mirror images, when one chiral center is present or when 2 or more chiral centers are present and the enantiomeric or diastereomeric ratio is greater than 95%.
  • “Optional” or“optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
  • the phrase“optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non- hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
  • Functional groups may be protected in cases where the functional group interferes with the metathesis catalyst, and any of the protecting groups commonly used in the art may be employed.
  • C-H activated refers to the cleavage of a carbon-hydrogen (C-H) bond of a ligand by the metal in a transition metal complex to form a resultant transition metal complex having a metal-carbon (M-C) bond.
  • This reaction type is also called cyclometallation. See C. Elschenbroich in “Organometallics” 1989 VCH page 439; ACS Symposium Series, Vol. 485“Organometallic C—H Bond Activation: An Introduction” A. Goldman and K. Goldberg, publication date July 12, 2004, Copyright ⁇ 2004 American Chemical Society; and Janowicz, A. H. & Bergman, R. G. J. Am. Chem. Soc.1982, 104, 352-354.
  • the terms“C-H activated” and“cyclometalated” are used interchangeably herein.
  • the olefin metathesis catalyst complex is preferably a Group 8 transition metal complex may be represented by the structure of Formula (I):
  • L 1 is a neutral electron donor ligand
  • Q* is a 2-electron anionic donor bridging moiety linking R 3 and Ru; and may be hydrocarbylene (including substituted hydrocarbylene, heteroatom-containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene, such as substituted and/or heteroatom-containing alkylene) or - (CO)-;
  • Q is a linker, typically a hydrocarbylene linker, including substituted hydrocarbylene, heteroatom- containing hydrocarbylene, and substituted heteroatom-containing hydrocarbylene linkers, wherein two or more substituents on adjacent atoms within Q may also be linked to form an additional cyclic structure, which may be similarly substituted to provide a fused polycyclic structure of two to about five cyclic groups.
  • Q is often, although again not necessarily, a two-atom linkage or a three-atom linkage;
  • X is an atom selected from C, N, O, S, and P. Since O and S are divalent, n is necessarily zero when X is O or S. Similarly, when X is N or P, then n is 1, and when X is C, then n is 2;
  • R 1 and R 2 are independently selected from hydrogen, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 24 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, etc.), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 24 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 24 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl,
  • R 1 and R 2 may also be linked to form a cyclic group, which may be aliphatic or aromatic, and may contain substituents and/or heteroatoms. Generally, such a cyclic group will contain 4 to 12, preferably 5, 6, 7, or 8 ring atoms;
  • R 3 and R 4 are independently selected from hydrocarbyl, substituted hydrocarbyl, heteroatom- containing hydrocarbyl, and substituted heteroatom-containing, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 24 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, etc.), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 24 aryl, C 6 -C 24 alkaryl, C 6 -C 24 aralkyl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -
  • X 1 is a bidentate anionic ligand.
  • X 1 is nitrate, C 1 -C 20 alkylcarboxylate, C 6 -C 24 arylcarboxylate, C 2 -C 24 acyloxy, C 1 -C 20 alkylsulfonato, C 5 -C 24 arylsulfonato, C 1 -C 20 alkylsulfanyl, C 5 - C 24 arylsulfanyl, C 1 -C 20 alkylsulfinyl, or C 5 -C 24 arylsulfinyl.
  • X 1 is benzoate, pivalate, nitrate, an N-acetyl amino carboxylate, O-methyl mandelate, or a carboxylate derived from 2- phenylbutyric acid. More specifically, X 1 may be is CF 3 CO 2 , CH 3 CO 2 , CH 3 CH 2 CO 2 , CFH 2 CO 2 , (CH3)3CO2, (CH3)2CHCO2, (CF3)2(CH3)CO2, (CF3)(CH3)2CO2, benzoate, naphthylate, tosylate, mesylate, or trifluoromethane-sulfonate. In one embodiment, X 1 is nitrate (NO - 3 ).
  • R 1 is hydrogen and R 2 is selected from C 1 -C 20 alkyl, C 2 -C 20 alkenyl, and C 5 -C 24 aryl, more preferably C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 5 -C 14 aryl. Still more preferably, R 2 is phenyl, vinyl, methyl, isopropyl, or t-butyl, optionally substituted with one or more moieties selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and phenyl.
  • Any two or more (typically two, three, or four) of X 1 , L 1 , R 1 , and R 2 can be taken together to form a cyclic group, including bidentate or multidentate ligands, as disclosed, for example, in U.S. Patent No. 5,312,940 to Grubbs et al.
  • X 1 , L 1 , R 1 , and R 2 are linked to form cyclic groups, those cyclic groups may contain 4 to 12, preferably 4, 5, 6, 7, or 8 atoms, or may comprise two or three of such rings, which may be either fused or linked.
  • Suitable functional groups include carboxyl, C 1 -C 20 alkoxy, C 5 -C 24 aryloxy, C 2 -C 20 alkoxycarbonyl, C 5 -C 24 alkoxycarbonyl, C 2 -C 24 acyloxy, C 1 -C 20 alkylthio, C 5 -C 24 arylthio, C 1 -C 20 alkylsulfonyl, and C 1 -C 20 alkylsulfinyl, optionally substituted with one or more moieties selected from C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 5 -C 14 aryl, hydroxyl, sulfhydryl, formyl, and halide.
  • R 11 , R 12 , R 13 , and R 14 are preferably independently selected from hydrogen, C 1 -C 12 alkyl, substituted C 1 -C 12 alkyl, C 1 -C 12 heteroalkyl, substituted C 1 -C 12
  • any two of R 11 , R 12 , R 13 , and R 14 may be linked together to form a substituted or unsubstituted, saturated or unsaturated ring structure, e.g., a C4- C 1 2 alicyclic group or a C 5 or C 6 aryl group, which may itself be substituted, e.g., with linked or fused alicyclic or aromatic groups, or with other substituents.
  • any one or more of R 11 , R 12 , R 13 , and R 14 comprises one or more of the linkers.
  • R 3 and R 4 may be alkyl or aryl, and may be independently selected from alkyl, aryl, cycloalkyl, heteroalkyl, alkenyl, alkynyl, and halo or halogen- containing groups. More specifically, R 3 and R 4 may be independently selected from C 1 -C 20 alkyl, C 5 -C 14 cycloalkyl, C 1 -C 20 heteroalkyl, or halide.
  • Suitable alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like;
  • suitable cycloalkyl groups include cyclopentyl, cyclohexyl, adamantyl, pinenyl, terpenes and terpenoid derivatives and the like;
  • suitable alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like;
  • suitable alkynyl groups include ethynyl, n-propyn
  • R 3 or R 4 are aromatic, each may be independently composed of one or two aromatic rings, which may or may not be substituted, e.g., R 3 and R 4 may be phenyl, substituted phenyl, biphenyl, substituted biphenyl, or the like. In a particular embodiment, R 3 and R 4 are independently an
  • any substituents present are hydrogen C 1 -C 1 2 alkyl, C 1 -C 1 2 alkoxy, C 5 -C 1 4 aryl, substituted, C 5 -C 1 4 aryl, or halide. More particularly, R 3 and R 4 may be independently substituted with hydrogen, C 1 -C 4 alkyl, C 1 - C4 alkylcarboxylate, C 1 -C4 alkoxy, C 5 -C 1 4 aryl, substituted C 5 -C 1 4 aryl, or halide.
  • R 3 and R 4 are selected from cyclopentyl, cyclohexyl, adamantyl, norbonenyl, pinenyl, terpenes and terpenoid derivatives, mesityl, diisopropylphenyl or, more generally, cycloalkyl substituted with one, two or three C 1 -C 4 alkyl or C 1 -C 4 alkoxy groups, or a combination thereof.
  • C-H activated catalysts are C-H activated Grubbs-Hoveyda metathesis-active metal carbene complexes
  • C-H activated Grubbs-Hoveyda metathesis-active metal carbene complexes of the invention may be represented by the structure of Formula (II):
  • X 1 , Q, Q*, R 3 , and R 4 are as previously defined for Formula (I);
  • Y is a heteroatom selected from N, O, S, and P; preferably Y is O or N; more preferably O;
  • R 5 , R 6 , R 7 , and R 8 are each, independently, selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroatom containing alkenyl, heteroalkenyl, heteroaryl, alkoxy, alkenyloxy, aryloxy, alkoxycarbonyl, carbonyl, alkylamino, alkylthio, aminosulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonyl, nitrile, nitro, alkylsulfinyl, trihaloalkyl, perfluoroalkyl, carboxylic acid, ketone, aldehyde, nitrate, cyano, isocyanate, hydroxyl, ester, ether, amine, imine, amide, halogen- substituted amide, trifluoroamide, sulfide, disul
  • X is an atom selected from C, N, O, S, and P. Since O and S are divalent, n is necessarily zero when X is O or S. Similarly, when X is N or P, then n is 1 , and when X is C, then n is 2; preferably X is N and n is 1;
  • n 1 or 2, such that m is 1 for the divalent heteroatoms O or S, and m is 2 for the trivalent heteroatoms N or P;
  • Z is a group selected from hydrogen, alkyl, aryl, functionalized alkyl, functionalized aryl where the functional group(s) may independently be one or more or the following: alkoxy, aryloxy, halogen, carboxylic acid, ketone, aldehyde, nitrate, cyano, isocyanate, hydroxyl, ester, ether, amine, imine, amide, trifluoroamide, sulfide, disulfide, carbamate, silane, siloxane, phosphine, phosphate, or borate; methyl, isopropyl, sec-butyl, t-butyl, neopentyl, benzyl, phenyl and trimethylsilyl; and wherein any combination or combinations of X 1 , Q*, Y, Z, R 5 , R 6 , R 7 , and R 8 may be linked to a support.
  • Z is selected from C 1 -C 6 alkyl, functionalized C 1 -C 6 alkyl, aryl, and functionalized aryl. In another embodiment, Z is selected from C 1 -C 6 alkyl and aryl. In another embodiment, Z is selected from C 1 -C 6 alkyl and phenyl. In another embodiment, Z is selected from methyl, ethyl, n-butyl, n-propyl, iso-butyl, iso-propyl, and sec-butyl. In another embodiment, Z is isopropyl.
  • C-H activated catalyst complexes represented by the structure of Formula (I) or Formula (II), as well as any specific C-H activated catalyst complexes shown herein or incorporated herein by reference may be used in racemate (racemic) form or in enantioenriched (enantiomerically enriched) form or in enantiopure (enantiomerically pure) form or in diastereoenriched (diastereomerically enriched) form or in diastereopure (diastereomerically pure) form.
  • Examples of C-H activated catalyst complexes represented by the structure of Formula (I) or Formula (II) include the following:
  • Examples of C-H activated catalyst complexes represented by the structure of Formula (I) or Formula (II) include the following:
  • Examples of C-H activated catalyst complexes represented by the structure of Formula (I) or Formula (II) include the following:
  • Examples of C-H activated catalyst complexes represented by the structure of Formula (I) or Formula (II) include the following:
  • xes represented by the structure of Formula (I) or Formula (II) include the following:
  • C-H activated catalyst complex represented by the structure of Formula (I) or Formula (II) includes the following:
  • [ ] p es of C-H activated catalyst complexes represented by the structure of Formula (I) or Formula (II) include the following: .
  • Examples of C-H activated catalyst complexes represented by the structure of Formula (I) or Formula (II) include the following: )
  • Examples of C-H activated catalyst complexes represented by the structure of Formula (I) or Formula (II) include the following:
  • C-H activated catalyst complexes represented by the structure of Formula (I) or Formula (II) for use in the present invention include those mentioned above and those further disclosed in International Pat. App. No. PCT/US2012/021609, the contents of which are incorporated herein by reference.
  • C-H activated catalyst complexes represented by the structure of Formula (I) or Formula (II) for use in the present invention include those mentioned above and those further disclosed in International Pat. App. No. PCT/US2013/074783, the contents of which are incorporated herein by reference.
  • tandem Z-selective cross-metathesis / stereospecific dihydroxylation reaction comprises a cross-metathesis reaction comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product
  • at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration
  • an oxidation reaction comprising contacting the cross-metathesis mixture with an oxidizing agent under conditions to promote a dihydroxylation reaction to form at least one compound comprising a vicinal diol, wherein the vicinal diol has anti stereochemistry.
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture, wherein the cross-metathesis reaction is performed under static vacuum; and
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture; and reacting the cross-metathesis mixture under dihydroxylation conditions to promote a stereospecific dihydroxylation reaction to form at least one compound comprising a vicinal diol, wherein the vicinal diol has anti stereochemistry.
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture, wherein the cross-metathesis reaction is performed under static vacuum; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture, wherein the cross-metathesis mixture comprises at least one cross-metathesis product; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture, wherein the cross-metathesis mixture comprises at least one cross-metathesis product; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture, wherein the cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture, wherein the cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture, wherein the cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture, wherein the cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture, wherein the cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture, wherein the cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration, wherein the cross-metathesis reaction is performed under static vacuum;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • cross-metathesis mixture comprises at least one cross-metathesis product, wherein the at least one cross-metathesis product comprises a product internal olefin, wherein the product internal olefin is in a Z-configuration;
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • a Br ⁇ nsted acid selected from H2SO4, HOAc, H 3 PO 4 , TFA, benzoic acid, citric acid, MeSO 3 H, p-toluene sulfonic acid, HCl, and HNO 3.
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation, the method comprising:
  • contacting the cross-metathesis mixture with an oxidizing agent wherein the oxidizing agent comprises a ruthenium species, under conditions to promote a dihydroxylation reaction to form at least one compound comprising a vicinal diol, wherein the vicinal diol has anti stereochemistry.
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • a Lewis acid is selected from CeCl3 and YbCl 3 or La(OTf) 3.
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • a first olefin reactant comprising a reactant terminal olefin with a second olefin reactant in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture; and contacting the cross-metathesis mixture with an oxidizing agent under conditions to promote a dihydroxylation reaction to form at least one vicinal diol, wherein the vicinal diol has anti stereochemistry.
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising: contacting a first olefin reactant comprising a reactant internal olefin with a second olefin reactant comprising a reactant terminal olefin in the presence of a C-H activated catalyst under conditions to promote a cross-metathesis reaction to form a cross-metathesis mixture; and
  • the invention provides a method for tandem Z-selective cross- metathesis / stereospecific dihydroxylation, the method comprising:
  • a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation comprising:
  • a method for tandem Z-selective cross-metathesis / stereospecific dihydroxylation comprising:
  • any of the embodiments described herein may be optionally performed under any conditions that remove any inhibitory bi-products (e.g., ethylene, or any bi-product that inhibits dihydroxylation) from a reaction (e.g., a cross-metathesis reaction, or a dihydroxylation reaction).
  • a reaction e.g., a cross-metathesis reaction, or a dihydroxylation reaction
  • the reaction may be optionally performed under inert gas purge (e.g., argon purge, nitrogen purge, helium purge), under vacuum (vacuum conditions), for example static vacuum (static vacuum conditions) or dynamic vacuum (dynamic vacuum conditions).
  • the cross-metathesis reaction is performed under static vacuum.
  • any inhibitory bi-products e.g., ethylene, or any bi-product that inhibits dihydroxylation
  • inert gas purge e.g., argon purge, nitrogen purge, helium purge
  • vacuum vacuum conditions
  • static vacuum static vacuum conditions
  • dynamic vacuum dynamic vacuum conditions
  • any set of conditions suitable for performing the cross-metathesis reaction may be utilized in the present invention.
  • the cross-metathesis reactions utilized herein may be homo-metathesis reactions or hetero-metathesis reactions.
  • the term“homo-metathesis” as used herein refers to a cross-metathesis reaction between a first olefin reactant and a second olefin reactant, wherein the first olefin reactant and the second olefin reactant are the same.
  • hetero-metathesis refers to a cross-metathesis reaction between a first olefin reactant and a second olefin reactant, wherein the first olefin reactant and the second olefin reactant are different.
  • Those of ordinary skill in the art would understand the meaning of terms“cis- configuration” or“trans-configuration” or“Z-configuration” or“E-configuration” as used within the context of the invention.
  • the first olefin reactant and the second olefin reactant selected for the cross-metathesis reaction can both be reactant terminal olefins, both can be reactant internal olefins, or one can be a reactant terminal olefin and the other can be a reactant internal olefin, where the term reactant terminal olefin and reactant internal olefin are described herein. Moreover, those of ordinary skill in the art would understand the meaning of the terms terminal olefin and internal olefin.
  • the two reactant terminal olefins may be the same or different.
  • the two reactant internal olefins may be the same or different.
  • the reactant terminal olefin may be a single reactant terminal olefin or mixture of different reactant terminal olefins
  • the reactant internal olefin may be a single reactant internal olefin or a mixture of different reactant internal olefins.
  • the cross-metathesis reaction may be performed in the presence or absence of solvent. Any solvent that does not interfere with the metathesis catalyst or the cross-metathesis reaction and/or the dihydroxylation reaction may be used in the present invention.
  • An example of solvents for use in the cross-metathesis reaction include, without limitation, THF, dioxane, diethyl ether (Et 2 O), CH 2 Cl 2 , ethyl acetate (EtOAc), or mixtures thereof.
  • the cross-metathesis reaction may be optionally performed under inert gas purge (e.g., argon purge, nitrogen purge, helium purge), under vacuum (vacuum conditions), for example static vacuum (static vacuum conditions) or dynamic vacuum (dynamic vacuum conditions).
  • inert gas purge e.g., argon purge, nitrogen purge, helium purge
  • vacuum conditions vacuum conditions
  • static vacuum static vacuum conditions
  • dynamic vacuum dynamic vacuum conditions
  • the cross-metathesis reaction is performed under vacuum.
  • the cross-metathesis reaction is performed under static vacuum.
  • the cross-metathesis reaction is performed under static vacuum.
  • any inhibitory bi-products may be removed from a cross-metathesis mixture during a cross-metathesis reaction or subsequent to performing a cross-metathesis reaction using any known technique including without limitation inert gas purge (e.g., argon purge, nitrogen purge, helium purge), under vacuum (vacuum conditions), for example static vacuum (static vacuum conditions) or dynamic vacuum (dynamic vacuum conditions).
  • inert gas purge e.g., argon purge, nitrogen purge, helium purge
  • vacuum vacuum
  • static vacuum static vacuum
  • dynamic vacuum dynamic vacuum conditions
  • Any set of oxidation conditions suitable for performing the dihydroxylation reaction of a cross-metathesis product may be utilized in the present invention. More particularly, any set of oxidation conditions suitable for performing a dihydroxylation reaction of a compound comprising a product internal olefin, wherein the product internal olefin is in the Z-configuration, to provide at least one compound comprising a vicinal diol, wherein the vicinal diol has anti stereochemistry, may be utilized in the present invention.
  • ruthenium catalyzed dihydroxylation conditions include contacting a compound comprising a product internal olefin (e.g., a compound comprising a product internal olefin in the Z-configuration) with a mixture of NaIO 4 and CeCl 3 in MeCN:EtOAc:H 2 O in the presence of a ruthenium species (see B. Plietker, J. Org. Chem. 2005, 70, 2402-2405).
  • a product internal olefin e.g., a compound comprising a product internal olefin in the Z-configuration
  • ruthenium catalyzed dihydroxylation conditions include contacting a compound comprising a product internal olefin (e.g., a compound comprising a product internal olefin in the Z-configuration) with a mixture of NaIO4 and YbCl3 in MeCN:EtOAc:H2O in the presence of a ruthenium species (see S. Blechert, Angew. Chem. Int. Ed. 2006, 45, 1900-1903).
  • Lanthanide based Lewis acids may also be suitable for use, such as La(OTf) 3 .
  • ruthenium catalyzed dihydroxylation conditions include contacting a compound comprising a product internal olefin (e.g., a compound comprising a product internal olefin in the Z-configuration) with a mixture of NaIO 4 and H 2 SO 4 in MeCN:EtOAc:H 2 O in the presence of a ruthenium species (see B. Plietker, Org. Lett. 2003, 5, 3353-3356).
  • a product internal olefin e.g., a compound comprising a product internal olefin in the Z-configuration
  • ruthenium catalyzed dihydroxylation conditions include contacting a compound comprising a product internal olefin (e.g., a compound comprising a product internal olefin in the Z-configuration) with a mixture of NaI0 4 and acid in MeCN:EtOAc:H 2 0 in the presence of a ruthenium species, wherein the acid was selected from HOAc, H3PQ4, TFA, Benzoic acid, citric acid, MeSOsH, p-toluene sulfonic acid, HC 1 , or HNOs (see B. Plietker, Org. Biomol. Chem. 2004, 5, 1 116).
  • a product internal olefin e.g., a compound comprising a product internal olefin in the Z-configuration
  • a ruthenium species wherein the acid was selected from HOAc, H3PQ4, TFA, Benzoic acid, citric acid, MeSOsH
  • phase transfer catalyst such as tetrabutylammonium iodide or chloride may also be used in addition to the other reagents.
  • solvents such as THF, Et 2 0, dioxane, and CH2CI2 may be used in place of or in conjunction with EtOAc.
  • nucleophilic or basic additives such as NEtiCl, NEt.40H, NBIMOAC, and methane sulfonamide may be used in place or in conjunction with the acid.
  • oxidizing agents other than NaI0 4 include N-methylmorpholine N-oxide, K3(Fe(CN) 6 ), HIO4,
  • Olefin Reactant Comprising a Reactant Terminal Olefin
  • an olefin reactant comprising a reactant terminal olefin may be represented by the structure of Formula (III):
  • D 1 and D 2 are independently selected from nil, C 2, O, or S; and E 1 and E 2 are independently selected from hydrogen, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), substituted hydrocarbyl (e.g., substituted C 1 -G.0 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), heteroatom-containing hydrocarbyl (e.g., Ci-C 2 o heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing C 5 -C 30 aralkyl, or heteroatom-containing C 5 -C 30 alkaryl), and substituted heteroatom-containing hydrocarbyl (e.g., substituted Ci-C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing C 5
  • the functional groups may be selected from electron withdrawing groups.
  • electron withdrawing groups may include, but are not limited to, aldehyde (-COH), ketone (-COR), acyl (-COR), carbonyl (-CO), carboxylic acid (-COOH), ester (-COOR), ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO2R), epoxide (e.g., epoxybutadiene), halides (-Cl, -F, -Br, -I), fluoromethyl (-CF n ), fluroaryl (e.g., -C 6 F 5 , p-CF 3 C 6 H 4 ), cyano (-CN), sulfoxide (-SOR), sulfonyl
  • n 1, 2, or 3
  • R is a hydrogen, methyl, substituted C 2 - C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-OCOR), sulfonamide (-NRSO 2 Ar), carbamate (-NCO2R), sulfonyl (-SO2R), fluoromethyl (-CFn), fluroaryl (e.g., -C 6 F5, p-CF3C 6 H4), epoxide (e.g., epoxybutadiene), or cyano (-CN), wherein n is 1, 2, or 3, and R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-COOR), ketone (-COR), aldehyde (-COH), halides (-Cl, -F, -Br, -I), carboxylic acid (-COOH), sulfonic acid (-SO3H), 1°, 2°, and 3° ammonium (-NR +
  • an olefin reactant comprising a reactant terminal olefin may be represented by the structure of Formula (IV):
  • D 3 is selected from nil, CH2, O, or S; and E 3 is selected from hydrogen, hydrocarbyl (e.g., C 1 - C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), heteroatom-containing hydrocarbyl (e.g., C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing C 5 -C 30 aralkyl, or heteroatom-containing C 5 -C 30 alkaryl), and substituted heteroatom-containing hydrocarbyl (e.g., substituted C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing C 5 -C 30 aralky
  • the functional groups may be selected from electron withdrawing groups.
  • electron withdrawing groups may include, but are not limited to, aldehyde (-COH), ketone (-COR), acyl (-COR), carbonyl (-CO), carboxylic acid (-COOH), ester (-COOR), ester (-OCOR), sulfonamide (-NRSO 2 Ar), carbamate (-NCO 2 R), epoxide (e.g., epoxybutadiene), halides (-Cl, -F, -Br, -I), fluoromethyl (-CFn), fluroaryl (e.g., -C 6 F5, p-CF3C 6 H4), cyano (-CN), sulfoxide (-SOR), sulfonyl (-SO 2 R),
  • n 1, 2, or 3
  • R is a hydrogen, methyl, substituted C 2 - C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO 2 R), sulfonyl (-SO 2 R), fluoromethyl (-CF n ), fluroaryl (e.g., -C 6 F 5 , p-CF 3 C 6 H 4 ), epoxide (e.g., epoxybutadiene), or cyano (-CN), wherein n is 1, 2, or 3, and R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 - C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-COOR), ketone (-COR), aldehyde (-COH), halides (-Cl, -F, -Br, -I), carboxylic acid (-COOH), sulfonic acid (-SO 3 H), 1°, 2°, and 3° ammonium (-NR +
  • an olefin reactant comprising a reactant terminal olefin may be represented by the structure of Formula (IV): wherein, D 3 is CH 2 , or substituted heteroatom-containing hydrocarbyl and E 3 is a functional group (“Fn”) such as: acyloxy (-O-acyl, including C 2 -C 24 alkylcarbonyloxy (-O-CO-alkyl) and C 6 -C 24 arylcarbonyloxy (-O-CO-aryl)), C 2 -C 24 alkylcarbonato (-O-(CO)-O-alkyl), C 6 -C 24 arylcarbonato (-O-(CO)-O-aryl), carbamido (-NH-(CO)- NH2),–NH-(CO)-NHR,–NH-(CO)-NR 2 , C 2 -C 24 alkylamido (-NH-(CO)-alkyl), C 6 -C
  • an olefin reactant comprising a reactant terminal olefin may be represented by the structure of Formula (IV): wherein, D 3 is CH 2 , and E 3 is an electron withdrawing group such as: ester (-OCOR), sulfonamide (-NRSO 2 Ar), carbamate (-NCO 2 R), sulfonyl (-SO2R), sulfonic acid (-SO3H), phthalamide, or nitro (-NO 2 ), wherein R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • One or more olefin reactants comprising a reactant terminal olefin may be used with the invention described herein, wherein the one or more olefin reactants comprising a reactant terminal olefin may be the same or different.
  • Olefin Reactant Comprising a Reactant Internal Olefin
  • One or more olefin reactants comprising a reactant internal olefin may be used with the invention described herein, wherein the one or more olefin reactants comprising a reactant internal olefin may be the same or different.
  • the reactant internal olefin may be in the Z- or E-configuration. In one embodiment, in the one or more olefin reactants comprising a reactant internal olefin, the reactant internal olefin is in the Z-configuration. In one embodiment, in the one or more olefin reactants comprising a reactant internal olefin, the reactant internal olefin is in the E-configuration.
  • an olefin reactant comprising a reactant internal olefin may be represented by the structure of Formula (V): E 6 D 6 D4 E4 5
  • D 4 , D 5 , D 6 , and D 7 are independently selected from nil, CH2, O, or S; and E 4 , E 5 , E 6 , and E 7 are independently selected from hydrogen, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 - C 30 alkaryl), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), heteroatom-containing hydrocarbyl (e.g., C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom- containing C 5 -C 30 aralkyl, or heteroatom-containing C 5 -C 30 alkaryl), and substituted heteroatom- containing hydrocarbyl (e.g., substituted C 1 -C
  • the functional groups may be selected from electron withdrawing groups.
  • electron withdrawing groups may include, but are not limited to, aldehyde (-COH), ketone (-COR), acyl (-COR), carbonyl (-CO), carboxylic acid (-COOH), ester (-COOR), ester (-OCOR), sulfonamide (-NRSO 2 Ar), carbamate (-NCO 2 R), epoxide (e.g., epoxybutadiene), halides (-Cl, -F, -Br, -I), fluoromethyl (-CFn), fluroaryl (e.g., -C 6 F5, p-CF3C 6 H4), cyano (-CN), sulfoxide (-SOR), sulfonyl (-SO 2 R),
  • n 1, 2, or 3
  • R is a hydrogen, methyl, substituted C 2 - C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-OCOR), sulfonamide (-NRSO 2 Ar), carbamate (-NCO 2 R), sulfonyl (-SO 2 R), fluoromethyl (-CF n ), fluroaryl (e.g., -C 6 F 5 , p-CF 3 C 6 H 4 ), epoxide (e.g., epoxybutadiene), or cyano (-CN), wherein n is 1, 2, or 3, and R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-COOR), ketone (-COR), aldehyde (-COH), halides (-Cl, -F, -Br, -I), carboxylic acid (-COOH), sulfonic acid (-SO 3 H), 1°, 2°, and 3° ammonium (-NR +
  • an olefin reactant comprising a reactant internal olefin may be represented by the structure of Formula (VI):
  • D 8 , D 9 , and D 10 are independently selected from nil, CH 2 , O, or S; and E 8 , E 9 , and E 10 are independently selected from hydrogen, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 - C 30 alkaryl), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), heteroatom-containing hydrocarbyl (e.g., C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom- containing C 5 -C 30 aralkyl, or heteroatom-containing C 5 -C 30 alkaryl), and substituted heteroatom- containing hydrocarbyl (e.g., substituted C 1 -C 20 heteroalkyl,
  • the functional groups may be selected from electron withdrawing groups.
  • electron withdrawing groups may include, but are not limited to, aldehyde (-COH), ketone (-COR), acyl (-COR), carbonyl (-CO), carboxylic acid (-COOH), ester (-COOR), ester (-OCOR), sulfonamide (-NRSO 2 Ar), carbamate (-NCO 2 R), epoxide (e.g., epoxybutadiene), halides (-Cl, -F, -Br, -I), fluoromethyl (-CFn), fluroaryl (e.g., -C 6 F5, p-CF3C 6 H4), cyano (-CN), sulfoxide (-SOR), sulfonyl (-SO2R),
  • n 1, 2, or 3
  • R is a hydrogen, methyl, substituted C 2 - C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO 2 R), sulfonyl (-SO 2 R), fluoromethyl (-CF n ), fluroaryl (e.g., -C 6 F 5 , p-CF 3 C 6 H 4 ), epoxide (e.g., epoxybutadiene), or cyano (-CN), wherein n is 1, 2, or 3, and R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-COOR), ketone (-COR), aldehyde (-COH), halides (-Cl, -F, -Br, -I), carboxylic acid (-COOH), sulfonic acid (-SO 3 H), 1°, 2°, and 3° ammonium (-NR +
  • an olefin reactant comprising a reactant internal olefin may be represented by the structure of Formula (VII):
  • D 11 and D 12 are independently selected from nil, CH 2 , O, or S; and E 11 and E 12 are independently selected from hydrogen, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), heteroatom-containing hydrocarbyl (e.g., C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing C 5 -C 30 aralkyl, or heteroatom-containing C 5 -C 30 alkaryl), and substituted heteroatom-containing hydrocarbyl (e.g., substituted C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing
  • the functional groups may be selected from electron withdrawing groups.
  • electron withdrawing groups may include, but are not limited to, aldehyde (-COH), ketone (-COR), acyl (-COR), carbonyl (-CO), carboxylic acid (-COOH), ester (-COOR), ester (-OCOR), sulfonamide (-NRSO 2 Ar), carbamate (-NCO 2 R), epoxide (e.g., epoxybutadiene), halides (-Cl, -F, -Br, -I), fluoromethyl (-CF n ), fluroaryl (e.g., -C 6 F 5 , p-CF 3 C 6 H 4 ), cyano (-CN), sulfoxide (-SOR), sulfonyl
  • n 1, 2, or 3
  • R is a hydrogen, methyl, substituted C 2 - C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO2R), sulfonyl (-SO2R), fluoromethyl (-CFn), fluroaryl (e.g., -C 6 F5, p-CF3C 6 H4), epoxide (e.g., epoxybutadiene), or cyano (-CN), wherein n is 1, 2, or 3, and R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-COOR), ketone (-COR), aldehyde (-COH), halides (-Cl, -F, -Br, -I), carboxylic acid (-COOH), sulfonic acid (-SO 3 H), 1°, 2°, and 3° ammonium (-NR +
  • an olefin reactant comprising a reactant terminal olefin may be represented by the structure of Formula (VII): wherein D 11 and D 12 are CH 2, and E 11 and E 12 are independently functional groups (“Fn”) such as: acyloxy (-O-acyl, including C 2 -C 24
  • an olefin reactant comprising a reactant terminal olefin may be represented by the structure of Formula (VII): wherein D 11 and D 12 are CH 2, and E 11 and E 12 are independently electron withdrawing groups such as: ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO 2 R), sulfonyl (-SO 2 R), sulfonic acid (-SO 3 H), phthalamide, or nitro (-NO 2 ), wherein: R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • an olefin reactant comprising a reactant internal olefin may be represented by the structure of Formula (VIII):
  • D 13 and D 14 are indepen , or S; and E 13 and E 14 are independently selected from hydrogen, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), heteroatom-containing hydrocarbyl (e.g., C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing C 5 -C 30 aralkyl, or heteroatom-containing C 5 -C 30 alkaryl), and substituted heteroatom-containing hydrocarbyl (e.g., substituted C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing C 5 -C 30 alka
  • the functional groups may be selected from electron withdrawing groups.
  • electron withdrawing groups may include, but are not limited to, aldehyde (-COH), ketone (-COR), acyl (-COR), carbonyl (-CO), carboxylic acid (-COOH), ester (-COOR), ester (-OCOR), sulfonamide (-NRSO 2 Ar), carbamate (-NCO 2 R), epoxide (e.g., epoxybutadiene), halides (-Cl, -F, -Br, -I), fluoromethyl (-CF n ), fluroaryl (e.g., -C 6 F 5 , p-CF 3 C 6 H 4 ), cyano (-CN), sulfoxide (-SOR), sulfonyl
  • n 1, 2, or 3
  • R is a hydrogen, methyl, substituted C 2 - C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-OCOR), sulfonamide (-NRSO 2 Ar), carbamate (-NCO2R), sulfonyl (-SO2R), fluoromethyl (-CFn), fluroaryl (e.g., -C 6 F5, p-CF3C 6 H4), epoxide (e.g., epoxybutadiene), or cyano (-CN), wherein n is 1, 2, or 3, and R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-COOR), ketone (-COR), aldehyde (-COH), halides (-Cl, -F, -Br, -I), carboxylic acid (-COOH), sulfonic acid (-SO3H), 1°, 2°, and 3° ammonium (-NR +
  • One or more cross-metathesis products comprising a product internal olefin, wherein the product internal olefin is in the Z-configuration may be used with the invention described herein, wherein the one or more cross-metathesis products comprising a product internal olefin may be the same or different.
  • an at least one cross-metathesis product comprising a product internal olefin, wherein the product internal olefin is in the Z-configuration may be represented by the structure of
  • D 15 , D 16 , D 17 , and D 18 are independently selected from nil, CH 2 , O, or S; and E 15 , E 16 , E 17 , and E 18 are independently selected from hydrogen, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), heteroatom-containing hydrocarbyl (e.g., C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing C 5 -C 30 aralkyl, or heteroatom-containing C 5 -C 30 alkaryl), and substituted heteroatom-containing hydrocarbyl (e.g., substituted C 1 -C
  • the functional groups may be selected from electron withdrawing groups.
  • electron withdrawing groups may include, but are not limited to, aldehyde (-COH), ketone (-COR), acyl (-COR), carbonyl (-CO), carboxylic acid (-COOH), ester (-COOR), ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO2R), epoxide (e.g., epoxybutadiene), halides (-Cl, -F, -Br, -I), fluoromethyl (-CFn), fluroaryl (e.g., -C 6 F 5 , p-CF 3 C 6 H 4 ), cyano (-CN), sulfoxide (-SOR), sulfonyl (
  • n 1, 2, or 3
  • R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-OCOR), sulfonamide (-NRSO 2 Ar), carbamate (-NCO 2 R), sulfonyl (-SO 2 R), fluoromethyl (-CF n ), fluroaryl (e.g., -C 6 F5, p-CF3C 6 H4), epoxide (e.g., epoxybutadiene), or cyano (-CN), wherein n is 1, 2, or 3, and R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-COOR), ketone (-COR), aldehyde (-COH), halides (-Cl, -F, -Br, -I), carboxylic acid (-COOH), sulfonic acid (-SO3H), 1°, 2°, and 3° ammonium (-NR +
  • an at least one cross-metathesis product comprising a product internal olefin, wherein the product internal olefin is in the Z-configuration may be represented by the structure of
  • D 19 , D 20 , and D 21 are independently selected from nil, CH 2 , O, or S; and E 19 , E 20 , and E 21 are independently selected from hydrogen, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 - C 30 alkaryl), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), heteroatom-containing hydrocarbyl (e.g., C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom- containing C 5 -C 30 aralkyl, or heteroatom-containing C 5 -C 30 alkaryl), and substituted heteroatom- containing hydrocarbyl (e.g., substituted C 1 -C 20 heteroalkyl,
  • the functional groups may be selected from electron withdrawing groups.
  • electron withdrawing groups may include, but are not limited to, aldehyde (-COH), ketone (-COR), acyl (-COR), carbonyl (-CO), carboxylic acid (-COOH), ester (-COOR), ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO 2 R), epoxide (e.g., epoxybutadiene), halides (-Cl, -F, -Br, -I), fluoromethyl (-CF n ), fluroaryl (e.g., -C 6 F5, p-CF3C 6 H4), cyano (-CN), sulfoxide (-SOR), sulfonyl (-SO
  • n 1, 2, or 3
  • R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO2R), sulfonyl (-SO2R), fluoromethyl (-CFn), fluroaryl (e.g., -C 6 F 5 , p-CF 3 C 6 H 4 ), epoxide (e.g., epoxybutadiene), or cyano (-CN), wherein n is 1, 2, or 3, and R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-COOR), ketone (-COR), aldehyde (-COH), halides (-Cl, -F, -Br, -I), carboxylic acid (-COOH), sulfonic acid (-SO 3 H), 1°, 2°, and 3° ammonium (-NR +
  • an at least one cross-metathesis product comprising a product internal olefin, wherein the product internal olefin is in the Z-configuration may be represented by the structure of
  • D 22 and D 23 are independently selected from nil, CH 2 , O, or S; and E 22 and E 23 are independently selected from hydrogen, hydrocarbyl (e.g., C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), substituted hydrocarbyl (e.g., substituted C 1 -C 20 alkyl, C 5 -C 20 aryl, C 5 -C 30 aralkyl, or C 5 -C 30 alkaryl), heteroatom-containing hydrocarbyl (e.g., C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing C 5 -C 30 aralkyl, or heteroatom-containing C 5 -C 30 alkaryl), and substituted heteroatom-containing hydrocarbyl (e.g., substituted C 1 -C 20 heteroalkyl, C 5 -C 20 heteroaryl, heteroatom-containing
  • the functional groups may be selected from electron withdrawing groups.
  • electron withdrawing groups may include, but are not limited to, aldehyde (-COH), ketone (-COR), acyl (-COR), carbonyl (-CO), carboxylic acid (-COOH), ester (-COOR), ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO 2 R), epoxide (e.g., epoxybutadiene), halides (-Cl, -F, -Br, -I), fluoromethyl (-CF n ), fluroaryl (e.g., -C 6 F 5 , p-CF 3 C 6 H 4 ), cyano (-CN), sulfoxide (-SOR), sulfony
  • n 1, 2, or 3
  • R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO2R), sulfonyl (-SO2R), fluoromethyl (-CFn), fluroaryl (e.g., -C 6 F5, p-CF3C 6 H4), epoxide (e.g., epoxybutadiene), or cyano (-CN), wherein n is 1, 2, or 3, and R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or unsubstituted aryl.
  • Examples of electron withdrawing groups of various embodiments include ester (-COOR), ketone (-COR), aldehyde (-COH), halides (-Cl, -F, -Br, -I), carboxylic acid (-COOH), sulfonic acid (-SO3H), 1°, 2°, and 3° ammonium (-NR +
  • an at least one cross-metathesis product comprising a product internal olefin, wherein the product internal olefin is in the Z-configuration, may be represented by the structure of Formula (XI): wherein, D 22 and D 23 are CH2, and E 22 and E 23 are independently functional groups (“Fn”) such as: acyloxy (-O-acyl, including C 2 -C 24 alkylcarbonyloxy (-O-CO-alkyl) and C 6 -C 24 arylcarbonyloxy (-O-CO-aryl)), C 2 -C 24 alkylcarbonato (-O-(CO)-O-alkyl), C 6 -C 24 arylcarbonato (-O-(CO)-O-aryl), carbamido (-NH-(CO)-NH2),–NH-(CO)-NHR, etcNH-(CO)- NR 2 , C 2 -C 24 alkylamido (-NH-(XI): wherein, D 22 and
  • an at least one cross-metathesis product comprising a product internal olefin, wherein the product internal olefin is in the Z-configuration, may be represented by the structure of Formula (XI): wherein, D 22 and D 23 are CH 2, and E 22 and E 23 are independently electron withdrawing groups such as: ester (-OCOR), sulfonamide (-NRSO2Ar), carbamate (-NCO 2 R), sulfonyl (-SO 2 R), sulfonic acid (-SO 3 H), phthalamide, or nitro (-NO 2 ), wherein R is a hydrogen, methyl, substituted C 2 -C 6 alkyl, unsubstituted C 2 -C 6 alkyl, substituted aryl, or
  • PCy 3 tricyclohexylphosphine P(C 6 H 11 ) 3
  • the mixture was vigorously stirred at 0 °C for 20 min and then quenched with 2 mL of a saturated Na 2 S 2 O 3 aqueous solution.
  • the mixture was extracted with ethyl acetate (4 x 2.5 mL), and then concentrated under reduced pressure.
  • the anti-diol product was purified by column chromatography.
  • iyl dibenzoate (6c) Synthesized according to the general procedure B for homodimerization under static vacuum followed by the general procedure D for dihydroxylation. The title compound was purified by column chromatography (60-80% ethyl acetate in hexanes). This material was then triturated with ether to afford a white solid (23.4 mg, 71%) which was sparingly soluble in CDCl 3 but soluble in DMSO.
  • yl benzoate (13) In a nitrogen filled glove box, 1-pentene 12 (35.1 mg, 0.5 mmol, 5 eq) was added to allyl benzoate 5c (16.2 mg, 0.1 mmol, 1 eq) using Ru-4 (0.003 mmol, 3 mol%, 150 ⁇ L, 0.02 M in THF) to quantitatively transfer to a Schlenk tube. The tube was capped, and then brought to a Schlenk line where it was evacuated using one freeze-pump-thaw cycle, capping the flask under static vacuum. The solution was then heated in an oil bath with stirring at 40 °C for 4 hr. Subsequently, the volatiles were removed with a high vacuum for 5 minutes.

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Abstract

La présente invention concerne d'une manière générale des composés catalyseurs de métathèse d'oléfines à base de ruthénium activés par C-H, et l'utilisation desdits catalyseurs dans la métathèse croisée tandem à sélectivité Z/la dihydroxylation stéréospécifique. L'invention concerne une procédure de catalyse tandem assistée pour la métathèse croisée à sélectivité Z/la dihydroxylation d'oléfines terminales contenant des groupes accepteurs d'électrons en position allylique, afin d'obtenir des anti-diols. Le ruthénium catalyse les deux transformations, et la sélectivité Z observée dans la métathèse croisée est traduite en sélectivité anti' par la dihydroxylation stéréospécifique. Il est possible de synthétiser des anti-diols densément fonctionnalisés ayant quatre atomes de carbone à substitution hétéroatome à partir de simples dérivés d'alcool allylique et d'amine allylique.
PCT/US2015/042013 2014-07-25 2015-07-24 Métathèse/dihydroxylation tandem à sélectivité z WO2016014954A1 (fr)

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