Organic synthesis Kamil Paruch Masaryk University, Brno Metathesis of alkenes • catalytic amount of Mo or Ru carbene • mild reaction conditions; various functional groups (OH, COOR, CHO…) tolerated all steps are reversible  rxn can be pushed to conversion e.g. by removal of ethene Kamil Paruch Organic Synthesis C4450 2 catalysts: R. R. Schrock R. H. Grubbs RCM (ring closing metathesis) ROM (ring opening metathesis) ROMP (ring opening metathesis polymerization) Kamil Paruch Organic Synthesis C4450Metathesis of alkenes 3 J. Am. Chem. Soc. 2001, 123, 12432. J. Am. Chem. Soc. 2002, 124, 7061. J. Org. Chem. 2002, 67, 6456. Kamil Paruch Organic Synthesis C4450Metathesis of alkenes 4 Norsorex process: polymerization of norbornene (45 000 tons/year) Angew. Chem. Int. Ed. 1997, 36, 2036. Kamil Paruch Organic Synthesis C4450Metathesis of alkenes 5 catalysts: • tolerated: esters, aldehydes, double bonds, acetals, nitriles… (not terminal) J. Am. Chem. Soc. 2010, 132, 11045. stable Kamil Paruch Organic Synthesis C4450Metathesis of alkynes 6 Chem. Eur. J. 2001, 7, 5299. Synthesis 2003, 2535. Kamil Paruch Organic Synthesis C4450Metathesis of alkynes 7 Mo-catalyzed RCM of the diyne 28 to the bis lactone 29 proceeded efficiently even in the presence of air. Nature Commun. 2021, 12, 1136. synthesis of epothilones A B C RCM esterification aldol Kamil Paruch Organic Synthesis C4450Metathesis of alkenes 8 A B C Kamil Paruch Organic Synthesis C4450Metathesis of alkenes 9 A B Chem. Commun. 2001, 1057. J. Am. Chem. Soc. 1997, 119, 7960.. epothilone C Z-selective RCM: Angew. Chem. Int. Ed. 2017, 56, 11213. Kamil Paruch Organic Synthesis C4450Metathesis of alkenes 10 (terminal) Angew. Chem. Int. Ed. 2012, 51, 13019. • metathesis of internal and terminal alkynes • compatible with esters, OMe, SMe Kamil Paruch Organic Synthesis C4450Metathesis of alkynes 11 • nucleophilic carbene complex • methylenation of carbonyl under mild conditions Tebbe reagent Synthesis 1991, 165. • conversion of esters to enol ethers & amides to enamines (in contrast to the Wittig reaction!) J. Am. Chem. Soc. 1980, 102, 3270. J. Org. Chem. 1985, 50, 1212. Kamil Paruch Organic Synthesis C4450Tebbe reagent 12 • methylenation of C=O under very mild conditions J. Org. Chem. 1991, 56, 3207. • methylenation of aldehydes and ketones is typically faster than methylenation of esters J. Org. Chem. 1993, 58, 5918. (Tebbe reagent cleaved the bicyclic system) Kamil Paruch Organic Synthesis C4450dimethyltitanocene (Petasis reagent) 13 electrons moving in a concerted fashion, cyclic transition state, no intermediates • cycloadditions (Diels-Alder reaction, dipolar cycloadditions) • sigmatropic reactions (Claisen, Cope, Wittig rearrangement) • ene reactions • cheletropic reactions Kamil Paruch Organic Synthesis C4450Pericyclic reactions 14 Diels-Alder reaction diene dienophile • one of the most important reactions in organic synthesis • formation of 2 new C-C (C-N, C-O) bonds & up to 4 new stereogenic centers in one step • stereochemistry of products is determined by the configurations of the diene and dienophile • can be done in intramolecular fashion -> construction of polycyclic systems • (enantioselective) catalysis normal electron-demand D-A rxn R1-R4: donors (typically OR, OSiR3, alkyl etc.) R5, R6: acceptors (typically NO2, CN, COR, CO2R etc.) inverse electron-demand D-A rxn R1-R4: acceptors R5, R6: donors Kamil Paruch Organic Synthesis C4450 15 regioselectivity J. Chem. Soc. Perkin Trans. 1, 1987, 1929. J. Org. Chem. 1966, 31, 1121. d+ d- d- d- d- d- d+ d+ d+ J. Org. Chem. 1979, 44, 1180. • unsymetrical/ diene/dienophile major Kamil Paruch Organic Synthesis C4450Diels-Alder reaction 16 Kamil Paruch Organic Synthesis C4450Diels-Alder reaction • intramolecular variants can be done with electronically sub-optimal dienes & dienophiles Angew. Chem. Int. Ed. 2017, 56, 6280. J. Am. Chem. Soc. 2019, 141, 19589. Org. Lett. 2017, 19, 858. 17 The dienophile and the diene do not have to be covalently attached for a Diels-Alder reaction to be intramolecular. addition of methyl acrylate 16 to the sorbic acid-derived alcohol 15 proceeded well only in the presence of the magnesium salt 17, which is presumably serving to complex the diene and the dienophile prior to cycloaddition: 18 Kamil Paruch Organic Synthesis C4450Diels-Alder reaction Angew. Chem. Int. Ed. 2006, 45, 3256. stereoselectivity endo exo • stereochemistry of the product is dictated by the configuration (E vs. Z) of the diene and dienophile • endo-diastereomer usually predominates (Alder endo-rule) s-cis Kamil Paruch Organic Synthesis C4450Diels-Alder reaction 19 Kamil Paruch Organic Synthesis C4450Dienes • a,b-unsaturated enones do not react as dienes in their enol form, but can be converted into silyl enol ethers Angew. Chem. Int. Ed. 2015, 54, 13630.Diels-Alder & hydrolysis or enamines (can be done in organocatalysis mode) 20 Danishefsky‘s diene J. Am. Chem. Soc. 1974, 96, 7807. • reactive, universal diene unreactive dienophile J. Am. Chem. Soc. 1978, 100, 7098. Kamil Paruch Organic Synthesis C4450Dienes 21 Kamil Paruch Organic Synthesis C4450Dienes 22 J. Am. Chem. Soc. 1979, 101, 6996. • construction of the central benzene ring in 39 by the D-A reaction of the diene 37 with the dienophile 38, leading to 39: Angew. Chem. Int. Ed. 2021, 60, 9439. o-quinonedimethane • very reactive diene, prepared in situ J. Am. Chem. Soc. 1982, 104, 7609. Kamil Paruch Organic Synthesis C4450Dienes 23 benzyne • very reactive dienophile • generated in situ Angew. Chem. 1955, 67, 348. Org. Synth. 1979, 59, 71. Chem. Ber. 1958, 91, 895. Organic Synthesis C4450DienophilesKamil Paruch 24 Organic Synthesis C4450DienophilesKamil Paruch 25 • preparation of the reactive dibenzocyclooctyne 29 by the carbodiimide-mediated dehydration of the tetrazole 28 J. Am. Chem. Soc. 2021, 143, 9489. Organic Synthesis C4450DienophilesKamil Paruch strain-promoted reactions of 1,2,3-cyclohexatriene and its derivatives: Nature 2023, 618, 748. Hetero Diels-Alder reaction • dienes and dienophiles contain heteroatoms (O, N) • electron-deficient dienes: inverse electron-demand Diels-Alder reaction (electron-rich dienophile) heterodienes: heterodienophiles: Kamil Paruch Organic Synthesis C4450 27 Helv. Chim. Acta 1981, 64, 1247. Tetrahedron Lett. 1982, 23, 3261. Tetrahedron Lett. 1984, 25, 2119. J. Org. Chem. 1985, 50, 5377. Kamil Paruch Organic Synthesis C4450Hetero Diels-Alder reaction 28 Tetrahedron Lett. 1969, 1527. J. Org. Chem. 1984, 49, 1955. Kamil Paruch Organic Synthesis C4450Hetero Diels-Alder reaction 29 interesting example of hetero Diels-Alder: cyclopentadiene as dienophile Adv. Synth. Catal. 2022, 364, 4347. J. Am. Chem. Soc. 1987, 109, 2717. Kamil Paruch Organic Synthesis C4450Hetero Diels-Alder reaction 30