Multi-step Organic Synthesis

1 8 Lecture Supplement: Multi-step Organic SynthesisMulti- step Organic SynthesisConversion of existing molecules into other useful sources: petroleum natural gas natural productsCommercial sourcesEtc. PharmaceuticalsPolymersGasolineTextilesE tc. Little molecules ----> big molecules Synthesis of unnatural products Modification of existing structures Synthesis of rare and useful natural productsExample: Paclitaxel (taxol): anticancer drug and rare natural productOHOOOOOOOHHHOHOHONHHOPhOHOE xample #2: Synthesis of indynaprost from cyclopentadieneintoOHHHOHOHO2 CCyclopentadieneIndynaprost(Experimental platelet aggregation inhibitor)Lecture Supplement: Multi-step Organic Synthesis 9 Fundamental Synthesis Operations C-C bond formation functional group interconversions (FGI): oxidation reduction substitution elimination addition others skeletal rearrangements protection /deprotectionKeys to Doing Synthesis Problems Use reactions you know (flash cards) Keep an eye on the requirements of the problem: Can I solve the problem in one stepfrom where I am?

2 Think backwards: retrosynthesis ( Corey, Harvard, Nobel Prize in Chemistry,1990)Retrosynthesis (Corey s definition): a problem solving technique for transforming thestructure of a synthetic target molecule to a sequence of progressively materials along apathway which ultimately leads to a simple or commercially available starting materialfor chemical Synthesis Practice Practice Practice PracticeSample Problem #1 HOfromTarget moleculeStarting materialHint: Unless otherwise specified, any other reagents can also be Lecture Supplement: Multi-step Organic SynthesisCan the target molecule be made from the starting materialin one reaction?Phone step ???PhOHAnalysis:No change in carbon countFGI: alkene aldehydeHow to make an aldehyde? Alkene ozonolysis (alters carbon count) Oxidation of a primary alcohol (carbon count unchanged)Hint: Flash cards may suggest reactions to carry out the desired : "thinking backwards" "the molecule on the left could be made from the molecule on the right by the reaction above the arrow"Can the new target molecule (the alcohol) be made in one step from the starting alkene?

3 PhOHPhhydroborationComplete Retrosynthesis:PhhydroborationPhOHoxidat ionPhOHForward Direction: Fill in the reaction details Carefully check each step : stereochemistry, carbocation rearrangements, Supplement: Multi-step Organic Synthesis 11 PhhydroborationPhOHoxidationPhOHPCC1. BH32. H2O2, NaOHOr:PhPhOHPhOHPCC1. BH32. H2O2, NaOHSample Problem #2 PhCH3 SOCH2CH3fromPhHOCan the target molecule be made from the starting material in one reaction?Analysis: Target has three more carbons than starting material, but no new C-C : Alcohol thioetherAlkene etherHow to make an ether? SN2 with CH3CH2O- SN2 with RO- and CH3CH2I AlkoxymercurationPhCH3 SOCH2CH3 WilliamsonPhCH3 SOHCan the target molecule be made from the new starting material in one reaction?How to make an alcohol? SN2 with HO- Alkene hydration Nucleophilic addition to epoxidePhCH3 SOHoxymercurationPhCH3S12 Lecture Supplement: Multi-step Organic SynthesisCan the target molecule be made from the new starting material in one reaction?

4 How to make a thioether? SN2 with RS- (Must first convert OH into LG)PhCH3 SCH3S- SN2 PhTsOTsClPhHOComplete RetrosynthesisPhCH3 SOCH2CH3 WilliamsonPhCH3 SOHoxymercurationPhCH3 SCH3S- SN2 PhTsOTsClPhHOForward DirectionPhHOTsClpyridinePhTsONa SCH3 PhCH3S1. Hg(OAc)2, H2O2. NaBH4 PhCH3 SOH1. NaH2. CH3CH2 IPhCH3 SOCH2CH3 Shorter Forward Direction: Alkoxymercuration achieves the alkene ether conversion injust one stepPhHOTsClpyridinePhTsONa SCH3 PhCH3S1. Hg(CF3CO2)2, CH3CH2OH2. NaBH4 PhCH3 SOCH2CH3 Hint: Thorough reaction knowledge increases flexibility and simplifies synthesisproblems. Some problems might not be doable without good mastery of reactions!Lecture Supplement: Multi-step Organic Synthesis 13 Sample Problem #3intoOCNCan the target be made in one step from the given starting material?Analysis:New C-C bond between ring and nitrilesFGI: Alkene ether + nitrile + another alkene, with trans stereochemistryHow to make a nitrile?

5 SN2 with -CN and alkyl halide, alkyl sulfonate, or epoxideHow to make an ether? SN2 with RO- oxymercuration with ROH Williamson ether synthesisSeveral routes to consider. Pick one and explore it! The trans relationship of the ether andnitrile groups suggests an epoxide (SN2)OCan the new target molecule (the epoxide) be made from the original starting material(alkene) in one step ?ORCO3 HComplete RetrosynthesisOCNOHCNOW illiamson-CN (SN2)RCO3 HForward NaHCH3OH