Single-bond forming reactions Grignard reaction

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1 Appendix I: Named Reactions Covered in 235 / 335 Featured in 432 / 533 synthesis / problem set Single-bond forming reactions Grignard reaction various Radical couplings Conjugate addition / Michael reaction strychnine Stork enamine additions Aldol-type reactions (incl. Mukaiyama aldol) (aldol / Claisen / Knoevenagel / Mannich / Henry etc.) various Asymmetric aldol reactions: Evans / Carreira etc. Organocatalytic asymmetric aldol Pseudoephedrine glycinamide alkylation Prins reaction Prins-pinacol reaction Morita-Baylis-Hillman reaction problem set # 2 McMurry condensation Gabriel synthesis problem set #3 Double-bond forming reactions Wittig reaction Horner-Wadsworth-Emmons reaction Still-Gennari olefination general discussion Julia olefination and heteroaryl variants within the Corey-Winter olefination Peterson olefination synthesis Barton extrusion reaction Tebbe olefination / other methylene-forming reactions Selenoxide elimination / Burgess dehydration problem set # 3 Electrocyclic reactions and related transformations Diels-Alder reaction problem set # 1 Asymmetric Diels-Alder reaction Ene reaction problem set # 3 1,3-dipolar cycloadditions various [2,3] sigmatropic rearrangement various Cope rearrangement periplanone Claisen rearrangement Oxidations Also See Handout # 1 Swern-type oxidations (Swern / Moffatt / Parikh-Doering etc. Jones oxidation TPAP / NMO oxidation PCC oxidation Dess-Martin oxidation Allylic oxidations General epoxidation reactions Asymmetric epoxidations: Sharpless / Jacobsen / Shi etc. Sharpless asymmetric dihydroxylation Ozonolysis Lemieux-Von Rudloff oxidation Baeyer-Villiger oxidation progesterone dragmacidin periplanone / progesterone

2 Rubottom oxidation Phenol oxidation (quinone formation) Tamao-Fleming oxidation Reductions - Also See Handout # 3 CBS reduction Luche reduction Stryker reduction Barton-McCombie deoxygenation and tin-free variant Barton decarboxylation Diazene-mediated deoxygenation Reductive amination Hydrosilation reactions Radical dehalogenation Hydrogenation reactions Clemmensen reduction Woff-Kishner reduction Birch reduction Organometallic coupling reactions - Also See Handout # 2 Stille coupling Heck coupling Suzuki coupling Sonogashira coupling Negishi coupling Tsuji-Trost coupling Pd- Pt- & Au-mediated cycloisomerisations Buchwald-Hartwig coupling Olefin metathesis Pd-mediated carbonylation Carbene C-H insertion reactions Hydrozirconation Other key ring-forming reactions Robinson annelation Fischer indole synthesis Pictet-Spengler reaction Dieckmann condensation Other reactions at carbonyl groups Schiff base formation Shapiro reaction Bamford-Stevens reaction Other reactions at carboxylic acids, esters, or amides Fischer esterifications Amide couplings with DCC / EDC / HATU etc. Acid chloride / fluoride formation Iodolactonization / selenolactonization periplanone and handout # 3 see handout # 3 general discussion, illustrated by several syntheses virantmycin xanthatin xanthatin strychnine strychnine various problem set # 3 trivial virantmycin / Other reactions at alcohols or alkyl halides Metal-Halogen exchange reactions Reformatsky reaction problem set # 2 Mitsunobu reaction Finkelstein reaction Darzens condensation problem set # 3 Other reactions at aromatic rings Electrophilic aromatic substitution Nucleophilic aromatic substitution Sandmeyer reaction

3 Ring expansions and contractions Favorskii rearrangement Beckmann rearrangement / Photo-Beckmann Tiffeneau-Demjanov rerrangement Schmidt reaction Notable rearrangements Curtius rearrangement virantmycin Pinacol rearrangement problem set # 2 Gröb fragmentation [2,3] Wittig rearrangement problem set # 3 Nazarov reaction Bergman rearrangement Miscellaneous reactions Directed metallation reactions problem set # 3 Hydroboration Asymmetric hydroboration Oxymercuration / demurcuration Simmons-Smith cyclopropanation Carbene / carbenoid cyclopropanation Asymmetric cyclopropanation zincophorin zincophorin Krapcho decarboxylation virantmycin Ugi 4-component coupling problem set # 3 Strecker amino acid synthesis Corey-Fuchs reaction Glaser reaction Schmidt reaction Staudinger reaction problem set # 2

4 Appendix Ib: Other stuff you should be learning along the way. Protecting Groups see Greene for many others. TBS TBDPS (and selective removal in presence of TBS) TiPS (and selective removal in presence of TBS) TES TMS (and lability thereof) Bn Bz PMB (and removal under oxidative conditions) Ac MOM trimethylsilylethyl esters and carbamates CBZ Boc Fmoc (and gentle removal under basic conditions) acetal / ketal protecting groups thioacetal / thioketal protecting groups (and use as umpolung nucleophiles THP Esters as protected carboxylic acids Protected alcohols as good, unreactive precursors to aldehydes, esters or acids Pivalates Some other useful reagents DCC / EDC / HATU etc. Carbonyl diimidazole Weinreb amides (for mono-addition to carbonyls) Various ligands for Pd coupling (BINAP, DPPF, dba, etc.) Various bases (Hünig s base, DBU,etc.) Higher-order cuprates, Gilman reagents, etc. Lawesson s reagent AIBN Sulfur ylides for cyclopropanation DPPA for initiating Curtius rearrangements Cyanuric fluoride / oxalyl chloride, thionyl chloride, etc. for making acyl halides Grubbs catalysts Amino-acids as useful chiral building blocks Carbohydrates as useful chiral building blocks Hypervalent iodine reagents Admix α/β TBAF, buffered TBAF, HF-pyridine, etc. for removing silyl groups Nucleophilic catalysts (DABCO, DMAP) LiH 2 NBH 3 for reducing amides alcohols LiCl / LiBr as very gentle Lewis acids for enhancing reactivity Stryker reagent Vocabulary Key intermediate Synthetic equivalent Total synthesis vs. semi-synthesis Oxidative addition Reductive elimination Transmetallation Metathesis Migratory aptitude

5 Syn elimination Enantiselective Diastereoselective Epimerization Useful Concepts Retrosynthetic analysis Nucleophiles and electrophiles = HOMO + LUMO Hard and soft nucleophiles and electrophiles Woodward-Hoffmann rules Indole addition to 3- or 2-position Substructure recognition Formation of oxonium ions and synthetic utility thereof Formation of imines and synthetic utility thereof Catalytic cycles Electron counting Use of crown ethers in synthesis Ways you know to control relative stereochemistry Aldol reactions (E/Z enolate 1,2-anti/syn product) Local steric control (esp. approach of nucleophiles or enolates), particularly in rings Geometric approach of reacting groups (esp. with respect to nitrene insertion reactions) Stereospecific transformations from stereochemically fixed substrates (Curtius rrgmt, etc.) Inversion reactions (S N 2, Mitsunobu, epoxide opening, etc.) Tsuji-Trost couplings (double inversion = retention) Various ways to make E/Z olefins Chirality transfer in sigmatropic rearrangement reactions (esp. Ireland-Claisen) Ways you know to control absolute stereochemistry Asymmetric Diels-Alder CBS reduction Asymmetric epoxidations (Sharpless, Jacobsen, Shi) Asymmetric dihydroxylation (Sharpless) Asymmetric acylations (Evans, Carreira, organocatalytic) Asymmetric alkylation (Myers) Pd coupling strategies with chiral ligands (esp. Suzuki, Heck) Desymmetrization reactions (e.g. by enzymatic hydrolysis) Hydroboration with chiral boranes (e.g. IPC 2 BH) Asymmetric cyclopropanation (e.g. Charette, or diazo w/ chiral Ru)

6 Appendix II: Syntheses 1. Strychnine Woodward, 1954 Classics I, 21 (also see: J. Am. Chem. Soc. 2001, 123, 9324) Fischer indole synthesis Indole addition Dieckmann condensation Allylic rearrangement Retrosynthesis Substructure recognition 2. Progesterone Handout #1: Oxidation Marker, 1944 Oxidative degredations, including General metal oxide degradations Lemieux-Von Rudloff oxidation Ozonolysis Jones oxidation Semisynthesis Commercial synthesis 3. Prostaglandin E 2 Corey, 1969 and onward Classics I, 65 General discussion of olefin-forming reactions, including: Wittig reaction Horner-Wadsworth Emmons reaction Still-Gennari olefination Julia olefination Corey-Winter olefination Peterson olefination Barton extrusion reaction Asymmetric Diels-Alder reaction Baeyer-Villiger oxidation CBS reduction Iodolactonization

7 4. Periplanone B Still, 1979 Classics I, 211 Anionic oxy-cope Rubottom oxidation Selective epoxidations 5. Palladium-Mediated Coupling Strategies Handout #2: Palladium Coupling parts of various syntheses will be used to illustrate key transformations General discussion of: Stille coupling Heck coupling Suzuki coupling Sonogashira coupling Negishi coupling Tsuji-Trost coupling Pd- Pt- & Au-mediated cycloisomerizations Catalytic cycles oxidative addition, reductive elimination, etc. Increased synthetic efficiency using organometallic coupling strategies. 6. Virantmycin Back, 2004 Angew. Chemie Int. Ed , 43, 6493 Buchwald-Hartwig coupling Acid chloride / fluoride formation Curtius rearrangement Krapcho decarboxylation Stereodivergent synthesis 7. Xanthatin Martin, 2006 Tetrahedron 2006, 62, General discussion of olefin metathesis: Ring-opening metathesis polymerization Ring-closing metathesis Cross metathesis Ene-yne metathesis

8 8. The Ene-diynes: Nicolaou, 1992 Classics I, 523 Myers, 2006 J. Am. Chem. Soc. 2006, 128, Bergman cycloaromatization : Swern-type oxidations Asymmetric epoxidations Asymmetric dihydroxylations Amide couplings with DCC / EDC / HATU etc. Corey-Fuchs reaction Glaser reaction Synthetic planning 9. Tetrodotoxin Du Bois, 2003 J. Am. Chem. Soc. 2003, 125, (also see: Thienamycin; Classics I, 249) Carbene insertion reactions Oxidative degradations Methylene-forming reactions Selenoxide elimination TPAP/NMO oxidations Allylic oxidations 10. Hirstutene Handout #3: Reduction Curran, 1986 Classics I, 382 General discussion of Radical Cyclizations Luche reduction Stryker reduction Ireland-Claisen rearrangement Selenolactonization Radical deoxygenations & decarboxylations Barton-McCombie deoxygenation Tin-free variant of the Barton-McCombie Barton decarboxylation Diazene-mediated deoxygenation Baldwin s rules for radical cyclization

9 11. ent-sparteine Aubé, 2002 asymmetric Org. Lett. 2002, 4, General discussion of ring expansions and contractions: Beckmann rearrangement Favorskii rearrangement Tiffeneau-Demjanov rearrangement Schmidt reaction Finkelstein reaction Mitsunobu reaction 12. Zincophorin Meyer and Cossy, 2004 J. Org. Chem. 2004, 69, General discussion of hydroborations General discussion of cyclopropanation strategies 13. Saframycin A Myers, 1999 J. Am. Chem. Soc. 1999, 121, General discussion of auxiliary-controlled additions: Evans aldol Carreira aldol Pseudoephedrine glycinamide alkylation Pictet-Spengler reaction Strecker reaction Reductive amination 14. Endriandric Acids Nicolaou, 1982 Classics I, 264. Electrocyclic Ring-Closing reaction Woodward-Hoffmann rules