Olefination Reactions Lecture Notes OTBS OPMB O Key Reviews: O Me O Me XX Wittig Reaction K. C. Nicolaou and co-workers, Ann. 1997, 1283. Horner-Wadsworth-Emmons and Tebbe Olefinations S. E. Kelly, Comprehensive Org. Synth. 1991, Vol. 1, 729. Peterson Olefination D. J. Ager, Synthesis 1984, 384. Julia (Julia-Lythgoe) Olefination B. M. Trost, Bull. Chem. Soc. Jpn. 1988, 61, 107. Wittig Olefination: Background and Principles R1 n-BuLi, Ph P 3 O X LDA, R R1 LiHMDS PPh + 1 3 X Ph3P + R1 Ph3P pKa = 18-20 ylide when R = alkyl, H Ph Ph Ph Ph Ph R1 P Ph P -[Ph3P=O] O R1 O R strong bond 1 formation drives reaction oxaphosphatane betaine G. Wittig and G. Schollkopf, Chem. Ber. 1954, 87, 1318. Wittig Olefination: Background and Principles Stereoselectivity with non-stabilized ylides Me OMe Me Ph3P Ph3P Ph3P Me Ph3P Ph3P Not stable; must be made in situ and used immediately Wittig Olefination: Background and Principles Stereoselectivity with non-stabilized ylides Me OMe Me Ph3P Ph3P Ph3P Me Ph3P Ph3P Not stable; must be made in situ and used immediately Addition to carbonyl is an irreversible and concerted [2+2] cycloaddition such that the R groups on the aldehyde and the ylide are as far apart as possible PPh3 Ph3P O H H H O + Me Me Ph3P R O R H -[Ph3P=O] As the size of the R groups increases, selectivity for Z-alkene increases Me Nonpolar solvents favor initial addition Polar solvents favor the elimination Z-alkene Wittig Olefination: Background and Principles Stereoselectivity with stabilized ylides Me O O Ph P Ph3P 3 Ph3P Me OEt semistabilized Incredibly stable; not moisture sensitive, can be chromatographed Price for stability is lower reactivity: reacts well with aldehydes, slowly with ketones Wittig Olefination: Background and Principles Stereoselectivity with stabilized ylides Me O O Ph P Ph3P 3 Ph3P Me OEt semistabilized Incredibly stable; not moisture sensitive, can be chromatographed Price for stability is lower reactivity: reacts well with aldehydes, slowly with ketones Initial addition to carbonyl is reversible so the thermodynamic elimination product results. O Ph P O Ph P O 3 + 3 + OEt H Ph H H EtO C H O PPh3 2 EtO2C Ph minor kinetic product major kinetic product RDS Ph3P O H H Ph EtO2C EtO C Ph EtO2C Ph 2 thermodynamically most stable; rotation possible predominant or only product Wittig Olefination: Applications in Total Synthesis O OH 1. Ph2P=CH2, HO THF, -10 °C Me OH 2. AD-mix-β, HO HO H2N Me MeO OMe MeO OMe t-BuOH/H2O O OH (84% overall) O O (96% ee) O Cl Wittig reaction O O HO Cl OH O O O H H H H N N N N N N Me O H H N O H O Me 1. PCC, CH2Cl2 N NH N 2. Ph P=CH , O NH2 N 3 2 N Me THF, -20 °C N HO2C Br Br OH Br Br OH (86% overall) HO Wittig reaction vancomycin HO K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 1998, 37, 2708. Wittig Olefination: Applications in Total Synthesis BnO OTBDPS OTBDPS BnO PPh3 I BnO PPh3 I BnO BnO O O 1. TBAF BnO O BnO O BnO O 2. I2, PPh3 BnO OBn BnO 3. PPh3 BnOBnO BnOBnO nBuLi, THF, BnO O BnO BnO O HMPA, O -20 °C, 4 h BnO BnO (87%) BnO BnOBnO OMe Wittig reaction BnO O BnO O BnO BnO OMe OMe These researchers have made tetraoses and pentaoses via this technology A. Dondoni and co-workers, J. Org. Chem. 2002, 67, 4186. Wittig Olefination: Applications in Total Synthesis TBSO I TBSO PPh3 TBSO I OTBS Me Me Me Me Me Me Me NaHMDS; Me Me O then A PPh3 Me SEt Me Me -78 °C to rt Me Me THF Me Z/E = >49/1 Me TBSO Me Me Me (76%) Me O O Wittig O reaction Me PMP Me PMP Me PMP O O O PMP = p-methoxyphenyl O Me Me Me Me OTBS HO Me O O HO OH O O Me SEt Me Me Me O OH NH2 TBSO Me (+)-discodermolide A A. B. Smith and co-workers, J. Am. Chem. Soc. 2000, 122, 8654. Wittig Olefination: Applications in Total Synthesis Me O Me OMe Me Me OMe OMe OMe OH PPh3Br n-BuLi TBSO Me TBSO Me H Me H H OMe 0 → 25 °C OMe Me O Me Me (97%) Me H (3:1 E/Z) Me O Wittig reaction with colombiasin A semistabilized ylide K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 2001, 40, 2482. M. D. Shair and co-workers, J. Am. Chem. Soc. 2002, 124, 773. Wittig Olefination: Applications in Total Synthesis Me O Me OMe Me Me OMe OMe OMe OH PPh3Br n-BuLi TBSO Me TBSO Me H Me H H OMe 0 → 25 °C OMe Me O Me Me (97%) Me H (3:1 E/Z) Me O Wittig reaction with colombiasin A semistabilized ylide Me Me MeO OTBS OH 1. Dess-Martin [O] TIPS 2. Me , THF TIPS I Ph P I 3 O (47% overall) Wittig reaction fragment for longithorone A K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 2001, 40, 2482. M. D. Shair and co-workers, J. Am. Chem. Soc. 2002, 124, 773. Wittig Olefination: Applications in Total Synthesis Me Me H OTBS Me H O OTMS EtS H Me H Me H O O O + EtS O O O PPh I H H Me 3 O O O O H H H H OTPS H H H Me n-BuLi, HMPA, THF, -78 °C (75%) Wittig reaction TBSO Me H Me Me H EtS O Me H O OTMS OTPS H Me H O O EtS O O H O O H H H Me H O O H H H H Me HO Me Me O H H O O Me H Me H Me O O O H H O O H O H O O O H H H H H H O H Me Me brevetoxin B K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1995, 117, 1171. For a review, see: Classics in Total Synthesis I, Chapter 37. Wittig Olefination: Applications in Total Synthesis OTBDPS 1. DIBAL-H, THF, OTBDPS OTBDPS 1. Ph3P, DEAD, -78 °C, 5 h (PhO)2P(O)N3 2. OMe Ph3P , OH 2. 5 N HCl, THF/ N3 CH Cl (1:4) O O THF, 0 °C MeO 2 2 O (75% overall) (74% overall) Wittig Reaction This chain extension technique is usually + good yielding as long as the molecule is acid stable OMe OMe OMe THF, N -78 °C HO N3 (70%) OH OTBDPS H N N N (−)-quinine G. Stork and co-workers, J. Am. Chem. Soc. 2001, 123, 3239. Wittig Olefination: Applications in Total Synthesis Me Me O , CH Cl / H Me O 3 2 2 Me O O Ph3P Me O H MeOH (3:1), O -78 °C, 10 min; H toluene, O 110 °C, 3 h OMe Me2S, 20 °C, 16 h OMe OMe (98%) (84%) OMe Wittig reaction Me O Me Me HO HO OH Me Me O Me OMe O HO O O OH O MeO Me O Me Me HO OH OH Me Me O Me swinholide A OMe I. Paterson and co-workers, Tetrahedron 1995, 51, 9393. Wittig Olefination: Applications in Total Synthesis O NHBoc NH2 H , 1. (Boc)2O CHO NHBoc OTBDPS OH 2. TBDPSCl (69% overall) OTBDPS Br CO2Me (91%) (12:1 ratio of PPh3 Z/E isomers) CH2Cl2, Δ Wittig reaction N N H Br Br p-TsO H H OH CO2Me N CO2Me TMSOTf, 2,6-lutidine; NHBoc NH2 N then p-TsOH H OTBDPS OTBDPS (85%) manzamine A S. F. Martin and co-workers, J. Am. Chem. Soc. 1999, 121, 866. Wittig Olefination: Background and Principles Schlösser-modified Wittig Reaction: How to Get E-products with Non-stabilized Ylides Ph P O 3 H PhLi, THF, -78 °C H + Me IPh3P Me O M. Schlösser, Angew. Chem. Int. Ed. Engl. 1966, 5, 126. Wittig Olefination: Background and Principles Schlösser-modified Wittig Reaction: How to Get E-products with Non-stabilized Ylides Ph P O 3 H PhLi, THF, -78 °C H + Me IPh3P Me O PhLi (1 equiv), -30 °C, 5 min Ph3P O Ph3P O H HCl H Me Me Me H M. Schlösser, Angew. Chem. Int. Ed. Engl. 1966, 5, 126. Wittig Olefination: Applications in Total Synthesis Me O O O O PPh3I PPh Me PhLi, THF Me 3 Me + O O O O O PhLi (1 equiv); Schlösser- then MeOH, -30 °C modified (97:3 trans:cis) Wittig reaction Me O Me Me Me H O O Me H Me H H O O O progesterone W. S. Johnson and co-workers, J. Am. Chem. Soc. 1970, 92, 741. For a review, see: Classics in Total Synthesis I, Chapter 6. Wittig Olefination: Applications in Total Synthesis 1. EtPPh I/n-BuLi; OMe 3 O3, n-BuLi; acid O MeOH MeO 2. p-TsOH, acetone O Me (98%) (65% overall) Schlösser-modified Wittig reaction O O H O HO O OH Me O O O Me O O O O O O Me Me COOH COOH CP-225,917 (phomoidride A) CP-263,114 (phomoidride B) K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 1999, 38, 1669. Horner-Wadsworth-Emmons Olefination: Background and Principles O O O THF, O O + -78 °C Δ + P(OR) RO PX OEt RO P OEt 3 OEt neat RO RO Cl Cl Arbuzov X = Li, K, Na reaction Horner-Wadsworth-Emmons Olefination: Background and Principles O O O THF, O O + -78 °C Δ + P(OR) RO PX OEt RO P OEt 3 OEt neat RO RO Cl Cl Arbuzov X = Li, K, Na reaction Stereoselectivity Principles: Follows general rules of stabilized ylides O O O NaH (RO) P ONa 2 + (RO)2P ONa + OEt H Ph H H EtO C H O P(OR)2 2 EtO2C Ph O minor kinetic product major kinetic product O RDS (RO)2P O H H Ph EtO2C EtO C Ph EtO2C Ph 2 thermodynamically most stable; rotation possible predominant or only product Horner-Wadsworth-Emmons Olefination: Applications in Total Synthesis Me Me OTBDPS Pd2dba3, LiCl, Me Sn i-Pr NEt, NMP, 35 °C 3 + 2 Me OAc Me Me Me Me π-Allyl Stille Reaction Me OTBDPS (single stereoisomer) O (96%) O (92% 1.