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Chem-GA 1311 Spring 2021 K, Diels-Alder

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Chem-GA 1311 Spring 2021 K, Diels-Alder Diels-Alder Reactions (and Some Other Cycloadditions) The Diels-Alder reaction the parent or “neutral” reaction (not very good): net addition (cycloaddition) diene ene (dienophile) cyclohexene a classical Diels-Alder reaction: Otto Diels and Kurt Alder Otto Diels (1876-1954) Kurt Alder (1902-1958) The 1950 Nobel Prize in Chemistry The nomenclature of cycloadditions counting the atoms in the perimeter (round brackets): COOMe COOMe (4 + 2) COOMe (3 + 2) COOMe + Bn N + Bn N COOMe COOMe COOMe COOMe counting the pi-electrons [square brackets]: COOMe COOMe [4 + 2] COOMe [4 + 2] COOMe + Bn N + Bn N COOMe COOMe COOMe COOMe adding the facial selectivitysubscript: COOMe [π4s + π2s] COOMe + MeOOC COOMe s = suprafacial (from the same side); a = antarafacial (from the opposite side); IUPAC Definition Thermodynamics of Diels-Alder reactions 3 + 1 σ-bonds 6 σ-bonds 2 + 1 π-bonds 1 π-bond ⇒ 2 new σ-bonds are made at the expense of 2 π-bonds. (2 x – 80) kcal/mol – (2 x – 66) kcal/mol = –28 kcal/mol (exothermic) Therefore: ΔH is usually strongly negative. But: ΔS is negative as well. And: ΔV is negative Remember: ΔG = ΔH – T ΔS (Gibbs-Helmholtz equation) The retro Diels-Alder reaction is more favorable at higher temperatures 200 °C biscyclopentadiene 2 cyclopentadiene ΔH > 0 (sigma bonds are broken) ΔS > 0 (two molecules out of one) –TΔS << 0 (at high temperatures) therefore: ΔG = ΔH – T ΔS < 0 (in the forward direction shown) The Diels-Alder reaction is more favorable at higher pressures Furan Diels-Alder reactions are enthalpically not particularly favorable because they break aromaticity: O O O 15 kbar O O + S O DV < 0 O O S Diastereoselectivties, which depend on DDG ‡ and DDV‡ , also improve at high pressures. Me OTBS H 10 kbar OTBS COOMe + N OTBS N COOMe O Bz O TBSO O OTBS Ph TBSO [Reference] Thermodynamics of Diels-Alder reactions ΔG ∂ΔG ΔG ∂ΔG = –ΔS = ΔV ∂T ∂P endergonic endergonic 0 0 exergonic exergonic T P ΔG = ΔH – T ΔS The Diels-Alder reaction is concerted In the transition state both σ-bonds are formed. –28 kcal/mol (exothermic) The diene needs to reside in an s-cis conformation The s-cis conformation is required. As a consequence, cyclic dienes generally react faster than acyclic ones: The Diels-Alder reaction is concerted The classical Diels-Alder reaction is concerted, i.e. there is only one transition state. The two bonds are more or less formed simultaneously. The Diels-Alder reaction is suprafacial with respect to both components. Six electrons are involved and 0 antarafacial components. As such, it abides to the Woodward-Hoffmann rules. COOMe [π4s + π2s] COOMe + COOMe COOMe The Woodward-Hoffmann rules in a nutshell A pericyclic process involving 4n+2 electrons is thermally allowed if the number of antarafacial components involved is even. note: 0 is an even number ‡ + ≡ [π4s + π2s] A pericyclic process involving 4n electrons is thermally allowed if the number of antarafacial components involved is odd. ‡ O O O O + ≡ [π2s + π2a] Generalized pericyclic selection rule. A ground-state pericyclic process involving N electron pairs and A antarafacial components is symmetry-allowed if and only if N + A is odd. This is reversed in photochemical processes. Orbital diagram of a “neutral” Diels-Alder reaction frontier orbitals of butadiene frontier orbitals (conformation ignored) of ethene E Y4 p* LUMO LUMO Y3 HOMO Y2 p HOMO Y1 Energy diagram of a “neutral” Diels-Alder reaction In the transition state both σ-bonds are formed. –28 kcal/mol (exothermic) Energy diagram of a “classical” Diels-Alder reaction Y2 An electron-withdrawing substituent narrows the HOMO-LUMO energy gap. Effect of EWG substituents (and catalysis) frontier orbitals of butadiene frontier orbitals of an (conformation ignored) electron poor alkene EWG E Y4 LUMO Y3 p* LUMO HOMO Y2 p HOMO Y1 Smaller HOMO-LUMO gap through “lowering the LUMO” translates to faster reactions. The Diels-Alder reaction is regioselective match the most stable resonance structures: + δ δ– + δ– δ + δ δ– + δ– δ The Diels-Alder reaction is stereospecific The configuration of the starting material is reflected in the configuration of the product. (E) trans (Z) cis (E) cis (E) The Diels-Alder reaction is stereoselective The endo product is generally preferred. This is a case of simple diastereoselection. formed as a racemate endo-product exo-product (preferred) EDG and EWG OAc H OAc cis OHC OAc CHO + ≡ [Reference] OHC Me endo-product formed as a racemate Secondary orbital interactions stabilize the endo TS Ψ2 (HOMO) ‡ O primary H orbital secondary interactions H orbital O O interactions endo product Ψ3 (LUMO of the “oxobutadiene”) Diels-Alder Reactions already covered in this course O O 160 °C O O + [Reference] MeO hydroquinone MeO MeO MeO [Reference] + cat. Cu(BF4)2 Cl CN Cl CN OH cat. TfOH OH + [Reference] OPiv O O PivO [Reference] Me OTBS H 10 kbar OTBS COOMe + N OTBS N COOMe Bz O TBSO Bz O OTBS TBSO The strategic value of the Diels-Alder Reaction The strategic value of the Diels-Alder reaction lies in making highly functionalized six membered rings. The reaction is very general and has a broad scope, i.e. many substitutions are possible. O O OH H H H Δ Al(Oi-Pr)3 Br2 Br + H H O i-PrOH H H H H H O COOMe O COOMe O O O O [Reference] Up to four stereocenters can be installed with with high fidelity: O N cat. t-Bu N H H Ph [Reference] CHO Me H CHO The reaction has found numerous applications in natural product synthesis [Nicoalou review] Cantharidin is a protein phosphatase inhibitor Cantharidin is produced by the “Spanish Fly” (really a beetle, Lytta vesicatoria) and was used as an “aphrodisiac”. It inhibits protein phosphatase 5 (PP5) as the dicarboxylate. Retrosynthetic analysis of cantharidin “We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems” Diels and Alder, 1930 The Stork synthesis of cantharidin [Reference] Me O O COOMe O O O ≡ O O Me O O COOMe cantharidin a classic in stereoselective synthesis that used Diels-Alder reactions twice to overcame the “dimethylmaleic anhydride issue” O Me O O O Me O 1 1) MeOOC COOMe key step: Diels-Alder reaction COOMe O COOMe with simple diastereoselection chemoselective hydrogenation of the more 2) Pd/C, H 2 2 electron rich and accessible double bond COOMe O COOMe 3 3) butadiene key step: diastereoselective Diels-Alder reaction COOMe O COOMe 4 4) LiAlH4 ehaustive ester reduction HO Me O O O O Me O OH 5 5) MsCl, py mesylation MsO O OMs 6 6) PhSNa displacement of mesylates with thiophenolate PhS O SPh 7 7) OsO4 dihydroxylation PhS OH O OH SPh Me O O O Me O 8 8) H2, Raney-Ni reductive desulfurization Me OH O OH Me 9 9) HIO4 glycol cleavage Me CHO O CHO Me 10 10) piperidine•HOAc intramolecular aldol condensation under Knoevenagel conditions Me O Me CHO 11, 12 11) PhLi addition of phenyllithium into the aldehyde 12) HCl, dioxane isomerization to the thermodyamically more stable product Me O OH Me Ph 13) stearic acid, H+ esterification 13, 14 14) Δ (240-300˚C) ester pyrolysis Me O Me Ph 15 15) O3 then H2O2 key step: ozonolysis and oxidative workup Me O O O Me O cantharidin The Dauben synthesis of cantharidin [Reference] A synthesis that beautifully exploited physicochemical principles and the logic of transient bonds to avoid steric clashes. O the anhydride can be made in 4 steps from: COOMe O + S O MeOOC S O key step: Diels-Alder reaction under 1 1) DCM, 15 kbar high-pressure conditions d.r. = 85:15 O O O O S + O O S O O 2 2) H , RaNi, EtOAc reductive desulfurization and 2 reduction of the double bond O O O O cantharidin Take-home message “If substituents clash sterically, put a transient bond between them” “Steric hinderance can be overcome with transient bonds” Twistane has D2 symmetry • E • one C2 axis • two C2 axes perpendicular • chiral [Wikipedia] The Whitlock synthesis of twistane [Reference] ≡ + COOMe COOMe twistane NaCN A classic in hydrocarbon chemistry. The opening Diels-Alder reaction was later modified by the Trauner group. O OMe 0 0) cat. SiMe3 0 °C 0) This reaction works N thermally but with much Tf Tf better yield when catalyzed. COOMe 1) LAH 1) Ester reduction 1, 2, 3 2) MeSO2Cl, py 2) Mesylation 3) NaCN 3) Substitution with cyanide NC 4) KOH, H O 4) Nitrile hydrolysis 4, 5 2 5) I2, NaHCO3 5) Iodolactonization, via I I O O O O I O O 6) H2, Pt 6) Reductive deiodination 6, 7, 8 7) LAH 7) Lactone reduction 8) MeSO2Cl, py 8) Selective mesylation of the primary alcohol OH OMs 9 9) CrO3, H2SO4 9) Oxidation O OMs 10 10) NaH 10) Intramolecular α-alkylation ≡ O O ≡ O O 11 11) H2NNH2, KOH 11) Wolff-Kishner reduction, via ≡ H N N twistane Dienes OMe OMe N OMe TMSO TBSO TBSO 1,3-butadiene isoprene Danishefsky diene Brassard diene Rawal diene O SO 2 O OMe α-pyrone cyclopentadiene Corey’s cyclopentadiene thiophene 1,1-dioxide cyclohexadiene O O N OMe O N O a cyclohexadienone ortho-quinone furan anthracene pyridazine The Danishefsky diene MeO O MeO O O Me Me + Δ H , H2O [Reference] TMSO TMSO O H H Danishefsky's diene endo product cis decalin compare with Robinson annulation: can be reduced to cis or trans decalin other examples: [Reference] [Reference] Highly reactive dienes [Reference] tetracyclone a cyclopentadieone (antiaromatic) O H Δ O H benzocyclobutene o-quinone aromatization dimethide [Reference] Dienophiles O O O O COOMe H H OMe COOMe acroleine methacroleine methyl acrylate a cycloalkenone acetylene dicarboxylate O O N Cl CN NO2 S PPh3 Ph acrylonitrile α-chloro nitroethene phenyl vinyl sulfone Schweitzer’s salt acrylonitrile O O O COOMe COOMe O NH MeOOC COOMe O O O dimethyl fumarate dimethyl maleate maleic anhydride maleimide para-benzoquinone Chiral dienophiles O O O O N OH O Ph N O S OPiv Bn O O O O O O N R O E 95:5 dr Me AlCl Bn 2 Me [Reference] O O N O O 93:7 dr i-Pr N Me AlCl 2 O O Note: the chiral auxiliary (e.g.
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