Organic synthesis Kamil Paruch Masaryk University, Brno (-)-oseltamivir phosphate Tamiflu Angew. Chem. Int. Ed. 2009, 48, 1070. Kamil Paruch Organic Synthesis C4450 2 1 : 5 one-pot (Michael + Wittig) (epimerization + addition of RSH) Kamil Paruch Organic Synthesis C4450 3 one-pot overallyield:57% Angew. Chem. Int. Ed. 2009, 48, 1304.. one-pot Kamil Paruch Organic Synthesis C4450 4 Pericyclic reactions • Highest Occupied Molecular Orbital (HOMO) LowestUnoccupied Molecular Orbital (LUMO) • bonding interactions: overlap of MO parts with the same sign of the wave function HOMO LUMO HOMO LUMO Kamil Paruch Organic Synthesis C4450 5 Woodward-Hoffmann rules • describe the course of pericyclic reactions, based on the symmetryof molecular orbitals suprafacialinteractions: same side of the p system antarafacialinteractions: oppositesides of the p system allowed reactions: thermal: number of components (4m+2)s + (4n)a : odd number photochemical: number of components (4m+2)s + (4n)a : even number Diels-Alderreaction: (4p+2p)s + (0)a : 1 (6): 4m+2 (14p+2p)s + (0)a : 0 (16): 4m (14p+0p)s + (2p)a : 1 (14): 4m+2 thermal reaction: Pericyclic reactionsKamil Paruch Organic Synthesis C4450 6 Electrocyclic reactions • pericyclic closure and opening of rings thermal: HOMO (correspondsto double bonds in the structure) conrotation disrotation conrotation (4p)a : 1 (6p)s : 1 (8p)a : 1 photochemical: 4p 6p 8p disrotation conrotation disrotation Pericyclic reactionsKamil Paruch Organic Synthesis C4450 7 J. Am. Chem. Soc. 1982, 104, 5560. endiandric acid A Pericyclic reactionsKamil Paruch Organic Synthesis C4450 8 Cope rearrangement J. Org. Chem. 1989, 54, 930. • equilibrium reaction • in some cases, the equilibrium is significantly shifted to the more stable isomer (or the isomer that is converted to more stable product) Tetrahedron Lett. 1988, 29, 2773. Pericyclic reactionsKamil Paruch Organic Synthesis C4450 9 oxy-Cope rearrangement • newly formed enol tautomerizes to ketone (irreversible process) anionic oxy-Cope rearrangement • substrate: 1,5-diene alkoxide • fast reactions, often at 25 °C J. Am. Chem. Soc. 1980, 102, 774. Pericyclic reactionsKamil Paruch Organic Synthesis C4450 10 J. Am. Chem. Soc. 1979, 101, 2493. J. Am. Chem. Soc. 2002, 124, 9199. Pericyclic reactionsKamil Paruch Organic Synthesis C4450 11 Claisen rearrangement E, E anti E, Z syn • reliable method for introduction of double bond in combination with defined stereochemistry at C atoms bearing R1 and R2 Pericyclic reactionsKamil Paruch Organic Synthesis C4450 12 Angew. Chem. Int. Ed. 2001, 40, 4264. biomimeticsynthesis of 1-O-methylforbesione: Pericyclic reactionsKamil Paruch Organic Synthesis C4450 13 Johnson-Claisen rearrangement (of ketene acetals) Claisen: • preparation of g,d-unsaturated esters Pericyclic reactionsKamil Paruch Organic Synthesis C4450 14 J. Am. Chem. Soc. 1978, 100, 4274. Pericyclic reactionsKamil Paruch Organic Synthesis C4450 15 progesterone Note: Schlossermodificationof Wittig reaction J. Am. Chem. Soc. 1978, 100, 4274. • preparation of (E)- olefins using nonstabilized ylides Pericyclic reactionsKamil Paruch Organic Synthesis C4450 16 Ireland-Claisen rearrangment (of allyl ester enolates) Pericyclic reactionsKamil Paruch Organic Synthesis C4450 17 J. Org. Chem. 2004, 69, 112. Pericyclic reactionsKamil Paruch Organic Synthesis C4450 18 dipole dipolarophile dipolarophile:esentially any double/triple bond dipole: nitriloxides azides nitrones azomethine ylides regioselectivity:HOMO – LUMO interaction (overlap of MO parts on atoms with larger coefficients) LUMO HOMO HOMO LUMO DE1 DE2 • typically DE1 < DE2 • if DE1 ~ DE2 : mixture of regioisomers Dipolar cycloadditionsKamil Paruch Organic Synthesis C4450 19 J. Am. Chem. Soc. 2002, 124, 2137. click reaction: Cu(I) catalyzed triazole formation frequently used in biology;can be done in the cell (in vivo) nitrile oxides:frequently used dipoles Kamil Paruch Organic Synthesis C4450 20 Dipolar cycloadditions Angew. Chem. Int. Ed. 2017, 56, 12586. forskolin Kamil Paruch Organic Synthesis C4450 21 Dipolar cycloadditions Kamil Paruch Organic Synthesis C4450 22 Dipolar cycloadditions Strain-promoted azide-alkyne cycloadditions Chem. Eur. J. 2021, 27, 5057. Kamil Paruch Organic Synthesis C4450 23 Dipolar cycloadditions Inverse electron-demand Diels-Alder reaction • click reactions with trans-cyclooctene • widely used in chemical biology(protein labelling and imaging) Chem. Soc. Rev. 2017, 46, 4895.