Appendix I: Named Reactions 235 / 335 432 / 533 synthesis / / synthesis Covered in Covered Featured in problem set problem Single-bond forming reactions Grignard reaction various Radical couplings hirstutene Conjugate addition / Michael reaction strychnine Stork enamine additions Aldol-type reactions (incl. Mukaiyama aldol) various (aldol / Claisen / Knoevenagel / Mannich / Henry etc.) Asymmetric aldol reactions: Evans / Carreira etc. saframycin A Organocatalytic asymmetric aldol saframycin A Pseudoephedrine glycinamide alkylation saframycin A Prins reaction Prins-pinacol reaction problem set # 2 Morita-Baylis-Hillman reaction McMurry condensation Gabriel synthesis problem set #3 Double-bond forming reactions Wittig reaction prostaglandin Horner-Wadsworth-Emmons reaction prostaglandin Still-Gennari olefination general discussion Julia olefination and heteroaryl variants within the Corey-Winter olefination prostaglandin Peterson olefination synthesis Barton extrusion reaction Tebbe olefination / other methylene-forming reactions tetrodotoxin hirstutene / Selenoxide elimination tetrodotoxin Burgess dehydration problem set # 3 Electrocyclic reactions and related transformations Diels-Alder reaction problem set # 1 Asymmetric Diels-Alder reaction prostaglandin Ene reaction problem set # 3 1,3-dipolar cycloadditions various [2,3] sigmatropic rearrangement various Cope rearrangement periplanone Claisen rearrangement hirstutene Oxidations – Also See Handout # 1 Swern-type oxidations (Swern / Moffatt / Parikh-Doering etc. N1999A2 Jones oxidation progesterone TPAP / NMO oxidation tetrodotoxin PCC oxidation dragmacidin Dess-Martin oxidation Allylic oxidations tetrodotoxin General epoxidation reactions periplanone Asymmetric epoxidations: Sharpless / Jacobsen / Shi etc. N1999A2 Sharpless asymmetric dihydroxylation Ozonolysis tetrodotoxin / Lemieux-Von Rudloff oxidation progesterone Baeyer-Villiger oxidation prostaglandin Rubottom oxidation periplanone Phenol oxidation (quinone formation) saframycin A Tamao-Fleming oxidation sparteine Reductions - Also See Handout # 3 CBS reduction prostaglandin Luche reduction hirstutene Stryker reduction hirstutene Barton-McCombie deoxygenation and tin-free variant hirstutene and Barton decarboxylation handout # 3 Diazene-mediated deoxygenation Reductive amination saframycin A Hydrosilation reactions sparteine Radical dehalogenation Hydrogenation reactions Clemmensen reduction see handout # 3 Woff-Kishner reduction Birch reduction Organometallic coupling reactions - Also See Handout # 2 Stille coupling Heck coupling general Suzuki coupling discussion, Sonogashira coupling illustrated by Negishi coupling several syntheses Tsuji-Trost coupling Pd- Pt- & Au-mediated cycloisomerisations Buchwald-Hartwig coupling virantmycin Olefin metathesis xanthatin Pd-mediated carbonylation xanthatin Carbene C-H insertion reactions tetrodotoxin Hydrozirconation N1999A2 Other key ring-forming reactions Robinson annelation Fischer indole synthesis strychnine Pictet-Spengler reaction saframycin A Dieckmann condensation strychnine Other reactions at carbonyl groups Schiff base formation various Shapiro reaction problem set # 3 Bamford-Stevens reaction Other reactions at carboxylic acids, esters, or amides Fischer esterifications trivial Amide couplings with DCC / EDC / HATU etc. N1999A2 Acid chloride / fluoride formation virantmycin prostaglandin / Iodolactonization / selenolactonization hirstutene Other reactions at alcohols or alkyl halides Metal-Halogen exchange reactions Reformatsky reaction problem set # 2 Mitsunobu reaction sparteine Finkelstein reaction sparteine Darzens condensation problem set # 3 Other reactions at aromatic rings Electrophilic aromatic substitution Nucleophilic aromatic substitution Sandmeyer reaction
Ring expansions and contractions Favorskii rearrangement Beckmann rearrangement / Photo-Beckmann sparteine 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 N1999A2 Miscellaneous reactions Directed metallation reactions problem set # 3 Hydroboration Asymmetric hydroboration zincophorin Oxymercuration / demurcuration Simmons-Smith cyclopropanation Carbene / carbenoid cyclopropanation zincophorin Asymmetric cyclopropanation Krapcho decarboxylation virantmycin Ugi 4-component coupling problem set # 3 Strecker amino acid synthesis saframycin A Corey-Fuchs reaction N1999A2 Glaser reaction N1999A2 Schmidt reaction sparteine Staudinger reaction problem set # 2
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) LiH2NBH3 for reducing amides Æ 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 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 Æ 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 (SN2, 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. IPC2BH) Asymmetric cyclopropanation (e.g. Charette, or diazo w/ chiral Ru) Appendix II: Syntheses
1. Strychnine Woodward, 1954 Classics I, 21 (also see: J. Am. Chem. Soc. 2001, 123, 9324)
Reactions: · Fischer indole synthesis · Indole addition · Dieckmann condensation · Allylic rearrangement
Concepts: · Retrosynthesis · Substructure recognition 2. Progesterone Handout #1: Oxidation Marker, 1944
Reactions: · Oxidative degredations, including · General metal oxide degradations · Lemieux-Von Rudloff oxidation · Ozonolysis · Jones oxidation
Concepts: · Semisynthesis · Commercial synthesis
3. Prostaglandin E2 Corey, 1969 and onward Classics I, 65
Reactions: · 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
4. Periplanone B Still, 1979 Classics I, 211
Reactions: · 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
Reactions: · General discussion of: · Stille coupling · Heck coupling · Suzuki coupling · Sonogashira coupling · Negishi coupling · Tsuji-Trost coupling · Pd- Pt- & Au-mediated cycloisomerizations
Concepts: · Catalytic cycles – oxidative addition, reductive elimination, etc. · Increased synthetic efficiency using organometallic coupling strategies. 6. Virantmycin Back, 2004 Angew. Chemie Int. Ed.. 2001, 43, 6493
Reactions: · Buchwald-Hartwig coupling · Acid chloride / fluoride formation · Curtius rearrangement · Krapcho decarboxylation
Concepts: · Stereodivergent synthesis 7. Xanthatin Martin, 2006 Tetrahedron 2006, 62, 11437
Reactions: · General discussion of olefin metathesis: · Ring-opening metathesis polymerization · Ring-closing metathesis · Cross metathesis · Ene-yne metathesis 8. The Ene-diynes: N1999A2 Nicolaou, 1992 – Classics I, 523 Myers, 2006 – J. Am. Chem. Soc. 2006, 128, 14825.
Reactions: · Bergman cycloaromatization
N1999A2: · Swern-type oxidations · Asymmetric epoxidations · Asymmetric dihydroxylations · Amide couplings with DCC / EDC / HATU etc. · Corey-Fuchs reaction · Glaser reaction Concepts: · Synthetic planning
9. Tetrodotoxin Du Bois, 2003 J. Am. Chem. Soc. 2003, 125, 11510 (also see: Thienamycin; Classics I, 249)
Reactions: · 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
Reactions: · 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 Concepts: · Baldwin’s rules for radical cyclization 11. ent-Sparteine Aubé, 2002 asymmetric Org. Lett. 2002, 4, 2577.
Reactions: · 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, 4626.
Reactions: · General discussion of hydroborations · General discussion of cyclopropanation strategies
13. Saframycin A Myers, 1999 J. Am. Chem. Soc. 1999, 121, 10828.
Reactions: · 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.
Reactions: · Electrocyclic Ring-Closing reaction Concepts: · Woodward-Hoffmann rules