Olefin Synthesis Chem 6352 Jeremy May -Plethora of references in the literature on olefin synthesis: see Larock 2nd ed. p. 215-562 -These can be catagorized by reaction type: -Or categorized by the olefinic product: Elimination Reactions - Larock p. 251-315 Terminal Olefins (see other handout) X Y reagent R R R R R R R R R R Wittig-type Reactions - Larock p. 327-350 1,2-Disubstituted Olefins R R'' R R'' R R O + R3P R R R' R''' R' R''' E Z Metathesis Reactions - Grubbs group Tri & Tetrasubstituted olefins (see other handout) R' R R R R Catalyst + R R' R R R R Note: these are much more difficult because of E/Z issues! 1,2-Disubstituted Olefins •Z-olefins -From Acetylenes: by reduction R R R R I Lindar's Catalyst, H2 Pd/BaSO4, Quinoline (partially poisons catalyst) II Diimide reduction H N N H III CO Cr CO , H2 (JOC 1985, 30, 1147) CO IV Hydroboration/Acidic Quench R R R R HBR2 AcOH R R H BR2 H H -From Rings: OMe CO Me O3, NaBH4 2 OH -From Wittig Reaction: O R' H R R PPh PPh3 3 R R' preparation of ylide: Δ R PPh X base 3 R R X + PPh3 PPh3 Polar Solvent alkyl halide (THF, acetone, H H EtOH, MeCN) pKa ~22 O- mechanism of the Wittig reaction: + Chem. Rev. 1989, 863 S - JACS 1989, 6861 Vedejs Base: nBuLi, LDA, KHMDS, NaHMDS, LiHMDS, tBuOK, , etc. JACS 1981, 2823 (DMSO, NaH) Antiperiplanar R R R R R' C H C H Ph3P Ph3P O H Ph3P H R Ph P R' R' O 3 H O O H H H Kinetic Reaction Preference Betaine Ph Ph R R H Ph P H + Ph3P O R' O R' H H Oxaphosphetaine -Salt Effect: Li O Activation of the carbonyl by a Lewis acidic salt can increase the reaction rate and lower the selectivity. Also, it leads to a more open transition state (ie. there are fewer steric effects). R H -To counter the effect: N Additives: HMPA, TMEDA → these break up and sequester lithium ions N Li N Freeze/filter salts: becomes difficult preparatively. N -Examples: (Stork TL 1989, 30, 2173) O H + Ph P Very useful for Stille/Heck reactions. 3 R I We will see this again later! R H I + + I I PPh3 base -Phosphine effect: Synlett 1990, 605 Ar O Ph P + + Ar Z form is slightly favored 3 R Ar R H R H Z E Ar O + + Ar Z:E = 96:4 P R Ar R H R H 3 Z E O MeO -The Reaction of Lactols: (Corey, JACS 1969, 91, 5675) OH CO H HO O 2 Ph3P CO H I 2 DMSO NaH THPO OTHP THPO OTHP The Schlosser Modification of the Wittig: reversal of selectivity for non-stabilized ylides. ACIEE 1966, 5, 126 O Synth. 1971, 29 Liebigs Ann. 1967, 708, 35 1) R +PPh PhLi R R' H 3 PPh3 R' - R Br 2) PhLi (-70 → -30 °C) 3) MeOH or tBuOH (-30 °C) warming (-30 °C) + H H Ph-Li+ H R' H H R' R R' R R' H + - + - + - + - (MeOH) + - + - Li O PPh3 Br Li O PPh3 Br Li O PPh3 Br W. S. Johnson, Progesterone Synth. JACS 1971, 93, 4332 O O 1) O O PPh 3 o H 97:3 trans:cis 2) PhLi, then MeOH, O O -30 °C O O More Z-olefin formation: -Carbometallation: R R'' R R'' R E R'' M + M R' E R' R' -Copper/Magnesium: H 1) CuBr•DMS R H + Et2O, -20 °C There will be more examples with the R Li trisubstituted olefin section. 2) E E H H O O E=I2, , H H -Zirconium/Aluminum: Me AlMe2 Me I Me3Al I2 R H or Cp2ZrCl2 R E R TL 1981,22,315 TL 1986,27,4351 Org. Rxn. Vol. 41 (Lipschutz) -Hydrometallation/Halogenation: R H Br Et3SiH 2 R H R Br PtCl2 H SiEt Hydrosilylation Br2 Br Br H Br Br R H SiEt3 H R R H SiEt Br 3 H Br H SiEt3 Further reaction of the vinyl bromide: Pd mediated R R' reactions R Br R Me Me2CuLi "Gilman Reagent" R Note: treatment with I2 gives I . -Hydroboration/Alkyl transfer: R H R R' I2 R H + R'2 BH NaOH H BR'2 H H I2 Note: One R' group will be wasted! I I R R' R H H H H BR' 2 B OH R' HO HO I I R H R H OH H B H B OH R' R' R' R' •E-olefins: 1,2-disubstituted olefins continued From Olefins: Olefin Metathesis Grubbs Acc. Chem. Res. 2000, 34, 18 Schrock JACS 990, 112, 3875 N N PCy3 Cl i-Pr i-Pr Cl N Ru Ru Ph Cl Ph Cl Ph Mo PCy CH3C(CF3)2O CH3 PCy3 3 CH3 CH3C(CF3)2O Diene Metathesis Reactions Terminal Olefin Intermolecular Reactions X X n X ROM R R' R' R - RCM 4 C H 2 ADMET 2 H C 4 - R 1 CM R2 X R1 X ROMP - C2H4 n R2 n -Mechanism of Olefin Metathesis: R1 R R [M] [M] R1 R1 + R2 R2 R2 R [M] R [M] R [M] = Metal Alkylidene R1 R1 R2 R2 R [M] [M] + R1 R2 R1 R2 R1 Typically a thermodynamic equilibrium process. The reaction produces a new carbon-carbon double bond. Examples: Ring closing for meduim reings: Furstner JOC 1996, 61, 8746 O ClMg HO HO Mixture of diastereomers Dactylol Macrocycle formation: Cross Metathesis: Meyers ACIEE 2000, 9, 1664 Grubbs ACIEE 2002, 41, 3174 H Ar Me Ar Substituted O R styrenes O H O H H N S H CHO CHO Unsaturated H R O N aldehydes O NH H H R H H Si(OR') Vinyl 3 Si(OR')3 OH OH R silanes Griseoviridin H H B(OR')2 B(OR') Vinyl R 2 boronates H Olefin Categorizing for Selective Cross Metathesis N N PCy3 Cl i-Pr i-Pr Cl N Ru Ru Ph Cl Ph Cl Ph Mo Olefin type CH3C(CF3)2O CH3 PCy3 PCy3 CH3 1 2 CH3C(CF3)2O 3 Term inal olefins, 1° allylic alcohols, esters Terminal olefin Type 1 Allylboronate esters, Allylic halides Allylsilanes Terminal olefins Styrenes (no large ortho substit.) 1° allylic alcohols, ethers, esters (fast Allylsilanes homodimerization) Allyl phosphonates, phosphine oxides, Allylboronate esters sulfides, protected am ines Allylhalides Styrenes (large ortho substit.) Acrylate esters, amides, acids, Styrene aldehydes, and vinylketones 2° allylic alcohols Styrene Type 2 2 o allylic alcohols Vinyl dioxolanes (slow Unprotected 3° allylic alcohols Allylstannanes homodimerization) Vinyl epoxides Vinyl boronates Perfluorinated alkane olefins 1,1-Disubstituted olefins Vinylphosphonates Tertiary allylamines Type 3 Phenyl Vinyl Sulfone Vinylsiloxanes o Acrylonitrile (no homodimerization) 4 allylic carbons (all alkyl substituents) 3o allylic alcohols (protected) 1,1-disubstituted olefins Type 4 Vinyl nitro olefins Disubstit. α,β-unsaturated carbonyls 1,1-disubstituted olefins 4o allylic carbon containing olefins Trisubstituted allylic alcohols (protected) (spectators to CM) Perfluorinated alkane olefins 3o allylam ines (protected) From Acetylenes: Li, NH 3(l) R R R R H LAH R H2O R R OH dioxane OH 100 °C Al → O From Aldehydes: JACS 1978, 100, 1942 Wittig Reaction: Modifications to give E-selectivity Corey Ch. 11 - Prostanoids Ch. 12 - Leukotrienes & Eicosanoids -Internal basic group promotes E-selectivity Nicolaou ACIEE 1991, 30, 1100 O CO2Me CO2Me H PhMe + HMPA -78 → -10 °C HO Ph3P Li O -Electron Withdrawing Group (EWG) on Wittig Reagent: EWG H Consider the mechanism: PPh3 Normally Kinetic Ph3P R' H R' Z-olefin O H R R equilibration Stabilization of this anion by EWG as R' will favor the Ph P R' R' ultimate thermodynamic 3 H H product. R' Ph3P E-olefin O H O H R R R Vedejs Examples: JOC 1984, 49, 210 Synth. 1988, 911 Corey and Lazerwith O H H CN H R' JACS 1998, 12777 H or PPh OR PPh 2 PPh3 Me 2 PPh3 also: Phosphine oxides: S. Warren JCSPT1 1985, 2307 (Horner) 10% NaOH O 1)BuLi R Br Ph3P R R' Ph P R H2O 2) O Ph R' H + 100 °C -Horner-Emmons-Wadsworth Modification Arbuzov Rxn: O R Br O P(OR)3 O Br RO P CO2R OR RO P CO2R RO RO Phosphonate HEW Rxn: O RO OR O RO OR CO R O O P CO R 2 O R H, base 2 P H H O OR + RO P CO2R H RO P RO O RO O M O H R equilibrium R R Also: O O THF O O + P -78 → 0 °C P RO CH RO R RO 2 RO R 96% RO see Nicolaou amphotericin synthesis in Classics of Total Synthesis (many other examples). -Still Modification of the HEW reaction: TL 1983, 24, 4405 O O O R H OR Z-selective enoate synthesis P CO2Me F3CH2CO KHMDS 2 18-crown-6 R THF >95% >50:1 M O O RO P irreversible, and a late transition state RO OR O M M O O R H O O O O fast H P OCH2CF3 R OCH CF R OR R OR 2 3 RO C H P OCH CF P OCH CF 2 O 2 3 O 2 3 OCH2CF3 OCH2CF3 syn-aldol product RO RO P O P O RO R RO R O O H H O M O M H H OR OR Transition state that leads to the syn-aldol stereochemistry. -Takai Reaction: JACS 1986, 108, 6048 JACS 1987, 109, 951 H CHI (Iodoform) 3 I many uses R R O CrCl2 THF/dioxane 4:1 >20:1 stereoselectivity Nicolaou - Rapamycin Synthesis CrII I proposed active H intermediate CrII Also: R 1) I2 R' N R 2) CrCl2, Zn, DMF H NH2 95:5 E/Z 3) O R' H II R I CrCl2 R Cr H I H CrII -Julia Olefination: Phosphorus & Sulfur 1985, 24, 97 JCSPK1 1978, 834 Bull.