Solid phase reactions II -- ReductionReduction,, oxidationoxidation,, formationformation ofof carbonylcarbonyl compoundscompounds andand derivatesderivates thereofthereof Formation of carbonyl compounds Formation of carbonyl compounds Ozonolysis Hydroformylation Reduction of carboxylic acids (Weinreb amide) Oxidation of alcohols ... Reduction of carboxylic acids Oxidation of polymer-bound alcohols to aldehydes/ketones Swern-oxidation Dess-Martin-periodinane + - TPAP (Pr4N RuO4 ) Cr-reagents (PCC,...) IBX (o-Iodoxybenzoic acid) SO3/pyridine ... Oxidation of a secondary alcohol with TPAP Oxidation of carbonyl compounds Oxidation of polymer-bound carbonyl compounds Oxidation of alcohols and carbonyl groups to carboxylic acids: Cr-reagents (PDC, Jones Oxidation) KMnO4 Oxidation of carbonyl compounds to carboxylic acids: NaClO2 Oxidation sequence in the synthesis of sarcodictyins Reduction of carbonyl compounds Reduction of polymer-bound carbonyl compounds reduction to alcohol (NaBH4, LiBH4,...) diastereoselective reductions (Evans-Tishchenko SmI2, Zn(BH4)2,...) reductive amination (NaCNBH3, NaBH(OAc)3, Me4NBH(OAc)3) Reductive amination with Me4NBH(OAc)3 Carbonylderivates Formation of acid halogenides problemproblem:: SOCl2 or POCl3 are incompartible with acid-sensitive linkers as well as with the resin itself solutionssolutions:: PPh3/CCl4 combination (Apple) oxalyl chloride formation of acid fluorides using cyanuric fluoride Formation of acid flourides Esterification of carboxylic acids lack of methods for acide chloride formation mainly two procedures Steglich: DIC/DMAP Yamaguchi: TCBC (2,4,6-trichlorobenzoylchloride) Esterhydrolysis: addition of solvents with better swelling properties Yamaguchi esterification Reduction of esters using DIBALH in solution: ability to stop the reaction at the aldehyde oxidation state solid phase: stopping at the aldehyde oxidation state not possible, as excess of the reagent is needed to drive the reaction to completion Formation of amides introduction of a suitable leaving group instead of the OH group prior to the reaction with an amine two principle ways: (1) replacement of the OH group (e.g. acid halogenides) (2) transformation into a suitalbe leaving group (e.g. active esters, anhydrides) best conditions highly dependent on the steric and electronic nature of amine and carboxylic acid Different coupling methods Carbodiimide-mediated couplings (DIC or DCC) Carbodiimide/HOBt (activating base: NMM or DIEA) HBTU or TBTU (activating base: NMM or DIEA) HATU or HOAt/DIC (activating base: NMM or DIEA) Literature Bannwarth W. and Felder E. (eds.): Combinatorial chemistry:A Practical Approach, Wiley-VCH, Weinheim, 2000 Jung G. (ed.): Combinatorial chemistry, Synthesis,Analysis, Screening, Wiley-VCH, Weinheim 1999 Nicolaou K., Hanko R., Hartig W. (eds.): Handbook of combinatorial chemistry, Wiley-VCH, Weinheim 2002.