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Strategic Approaches in Multistep Syntheses

This chapter explores grouping chemical reactions, retrosynthetic analysis, and criteria for selecting the best synthetic route in complex molecule synthesis. It covers various functional group transformations and practical examples. Learn about protecting groups, oxidation-reduction reactions, and the importance of evaluating synthetic efficiency.

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Strategic Approaches in Multistep Syntheses

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  1. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Retrosynthetic Analysis • Reactions Requiring Both Functional-Group Transformation and Skeletal Construction • Extending the Retrosynthetic Approach: Alternative Routes for Synthesizing more Complex Molecules • Selecting the Best synthetic Route • Criteria for Evaluating Synthetic Efficiency • Real-World Synthetic Objectives • Protecting Groups • Practical Examples of Multistep Syntheses

  2. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Carbon-Carbon bond formation processes • R-MgBr with ketone forms alcohol • R-MgBr with epoxides form alcohols • Enolates with R-I • Enolates with ketones form -hydroxy ketones and ,-unsaturated ketones • Cyanide with RCH2X • Cyanide with ketones forms Cyanohydrin • Ylide and ketone forms alkene • Diene and Dienophile undergoes Diels-Alder cyclization • Alkyne and base with Alkylhalide forms alkylated alkyne

  3. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Oxidation-Reduction Reactions • Secondary alcohol to ketone with Cr-VI • primary alcohol to aldehyde with Cr-VI in Pyridine • Primary alcohol to aldehyde with Cr-VI in water • Alkene to 2 carbonyls with ozone followed by Zn/HOAc • Alkane to halo alkane with light and chlorine or bromine • Carbonyl -hydrogen with bromine to -bromo carbonyl • Alkene and OsO4 to vicinal di-alcohol • Alkene a per-acid to epoxide • Aldehyde and ketone to sec-alcohol with NaBH4 • Ester to pri-alcohol with LiAlH4

  4. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Oxidation-Reduction Reactions (continued) • Alkene to alkane with H2/Pt • Alkyne to cis-alkene with H2/Pd and Quinoline • Imine to amine with H2/Pt • Ketone to alkane with Zn(Hg), HCl or with NH2NH2, base • Amide to Amine with LiAlH4 • Alkyne with R2B-H followed by oxidation forms aldehyde • Alcohol to Alkene with sulfuric acid

  5. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Functional group transformation • Alcohol to alkyl halide with PX3 (x=Br, Cl, I) • alkyl halide to alcohol with NaOH Ketone to Ketal with acid/ROH • Ketal to Keone with acid/H2O • Ester to Acid with NaOH followed by acidification • Acid to Ester with acid and ROH • Nitrile to Amide with NaOH/H2O • Amide to Nitrile with POCl3 • Acid chloride to Acid with water • Acid to acid chloride with thionyl chloride • Acid Chloride to substituted amide or amide with HNR2 or NH3 • Acid chloride to Ester with ROH

  6. Chapter 15Multistep Syntheses • Grouping Chemical Reactions • Functional group transformation (continued) • Ketone to imine with pri-amine • Imine to ketone with acid/water • Ketone to enamine with sec-amine (needs alpha H on carbonyl • Alkene to Alcohol withBH3-hydroboration followed by H2O2-oxidation • Aryl-H to Aryl-Br with bromine/FeBr3

  7. Chapter 15 • Review Table 15.1, 15.2 15.3

  8. Chapter 15Multistep Syntheses • Retrosynthetic Analysis • Designing a synthesis by Working Backward • Synthesis requires analysis, insight, intuition and a sound knowledge of the reactivity of organic compounds • Many correct answers, the only incorrect one is one that fails to produce the desired compound • Need to have reactions and reagent combinations at your finger tips • Rational for Retrosynthetic Analysis • Basic changes during a synthesis • molecular skeleton: extend, connect, rearrange • functional groups: interchange or transpose • stereocenters: invert or transfer

  9. Chapter 15Multistep Syntheses • Extending the Retrosynthetic Approach: Alternative Routes for Synthesizing more Complex Molecules • Analyzing Individual Reactions in a Sequence • look for patterns or structures you have seen before • Order of Chemical Transformations • Order is important • May have to use protecting groups

  10. Chapter 15Multistep Syntheses • Selecting the Best synthetic Route • Number of Steps • Yield of each step • Reaction conditions • Ease of isolation and purification • Cost and availability of raw materials • Criteria for Evaluating Synthetic Efficiency • Linear synthesis • Convergent Synthesis • Logistical Factors

  11. Chapter 15Multistep Syntheses • Competing Reactions • Review Fox and Whitesell exercise 15.8 page 767 • good practice and problems for competing reactions • Protecting Groups • Protection of Aldehydes and Ketones • via acetal/ketal, regenerate with acid/water • Protection of Alcohols • via benzyl ether, regenerate with acid/water • via dihydropyran, regenerate with acid/water • via dimethyl-t-butyl-silylchloride, regenerate with fluoride • Protection of Carboxylates • with isobutylene to form t-butylester, regenerate with acid/water • Protection of Amines • via a urethane, regenerate with acid (decarboxylates)

  12. Chapter 15Multistep Syntheses • Practical Examples of Multistep Syntheses • 1.) cis-3-hexene • 2.) 2-heptanone • 3.) heptanal • 4.) 4-(3-ol-butyl)cyclohexanone from 4-vinylcyclohexanone • 5.) 2-methyl-6-one-heptanal from 2,6-dimethyl-methylenecyclohexane • 6.) heptane from cyclohexanol

  13. Chapter 15 Summary • Reactions classified as • Carbon-Carbon-bond-forming • Oxidation-Reduction • Functional group transformations • Analyze carefully by working backwards, develop an overall strategy • Utilize convergent synthesis to shorten overall sequence • Utilize protecting groups to control the order of the reactions • Study, Study, Study • Table 14.1 • Table 15.1, 15.2, 15.3 • Appendix: Summary of Synthetic Methods • Practice, Practice, Practice

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