Olefination Reactions Lecture Notes OTBS OPMB O

Key Reviews: O Me O Me XX 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 when R = , 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

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] such that the R groups on the 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- 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 , slowly with 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. Ph P OMe 2. 5 N HCl, THF/ 3 , OH N CH Cl (1:4) 3 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

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 Me OTBDPS (single stereoisomer) O (96%) O

(92% 1. HIO , NaIO , THF/H O NMP = N-methyl-2-pyrrolidinone 4 4 2 overall) 2. O Me HWE P t-BuOK, THF EtO O Olefination EtO

Me Me Me O Me OTBDPS

Me Me Me Me H Me OTIPS O Me OH palominol (E-isomer only)

S. A. Snyder, E. J. Corey, J. Am. Chem. Soc. 2006, 128, 740. Horner-Wadsworth-Emmons Olefination: Applications in Total Synthesis

OH 1. TMSCl, imid OTMS TESO Me 4-DMAP, CH2Cl2 TESO Me 2. O Me N O Li P OMe O OMe MeO OMe P THF, -78 °C MeO O

(83%) O Ba(OH)2, THF; A THF/H O (40:1), 0 °C HWE 2 olefination I H Me A

OTMS H Me O Me HO Me O H H HO H OH H O O H I H Me Me Me (−)-FR182877

E. J. Sorensen and co-workers, J. Am. Chem. Soc. 2003, 125, 5393. Horner-Wadsworth-Emmons Olefination: Applications in Total Synthesis

OBn OBn NaOH, t-BuOCl, 1. BnBr, K CO , OH 2 3 BnOCONH2, HO KI, DMF, 25 °C (DHQD)2AQN, O 2. KOH, K2OsO2(OH)4, O OEt NHCbz O n-PrOH/H2O (1:1), O P OEt OEt 25 °C, 12 h OEt OEt O (45%, 87% ee) (93% overall) Sharpless asymmetric HWE olefination aminohydroxylation

TBSOTf, 2,6-lutidine, (98%) CH2Cl2, 0 °C, 30 min Cl OH OH OBn H2, TBSO TBSO TBSO SO2Cl2, Pd(OH)2/C,

O Et2O/CH2Cl2 O MeOH, 25 °C O NH2 (1:10), 0 °C, 1 h NH2 (97%) NHCbz OEt (80%) OEt OEt vancomycin fragment

K. C. Nicolaou and co-workers, Angew. Chem. Int. Ed. 1998, 37, 2708. Horner-Wadsworth-Emmons Olefination: Applications in Total Synthesis

Me Me OH 1. Br Me O 1. DIBAL-H, O CO Et CHO CHO K2CO3, acetone 2 CH2Cl2 2. O 2. Swern [O] EtO P CO2Et (90% overall) EtO OMe OMe OMe NaH, THF (91% overall) HWE olefination ZnCl , CH Cl , (60%) 2 2 2 Diels-Alder 25 °C, 3 days reaction Me H H CO H HO O HN 2 O O Me OMe H H CHO

HO O HO OMe dynemicin A

S. J. Danishefsky and co-workers, J. Am. Chem. Soc. 1996, 118, 9509. Horner-Wadsworth-Emmons Olefination: Applications in Total Synthesis

O O O O P(OMe)2 N Pd(dppf)Cl2, N P(OMe)2 Cbz Cbz Br O K2CO3, DME, OTBS N N + OTBS 90 °C O (60%) Suzuki NMOM N MeO coupling MeO O O MOM B O O 1. HF, MeCN, 0 °C 2. 2,2-DMP (70%) Sterics dictates 3. Dess-Martin [O] O this product O O NH N N P(OMe)2 Cbz Me Me Cbz N N N O N Me Me O O LiCl, DMF, 70 °C NMOM (60%) NMOM MeO O HWE MeO O Macrocyclization diazonamide A core K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 2002, 126, 10162. For a related use of 1,1,3,3-TMG, see: S.J. Danishefsky, et al. J. Am. Chem. Soc. 2001, 123, 1890. Horner-Wadsworth-Emmons Olefination: Applications in Total Synthesis

CO Me CO2Me 2 NaH, benzene, O 15-crown-5 P Me Me 25 °C, 5 h MeO OMe MeO OMe HO OH (55%) HWE dimerization HO OH Me O CO2Me

Me HO Me HO OH

HO OH Me OH Me (–)-cylindrocyclophane A

T. R. Hoye and co-workers, J. Am. Chem. Soc. 2000, 122, 4982. Horner-Wadsworth-Emmons Olefination: Applications in Total Synthesis

1. EtO Me OTHP Me OTHP EtO P CO2Et O LDA, THF TBSO TBSO Me 2. DIBAL-H Me O O 3. MnO2 Me (86% overall) Me HWE olefination EtO EtO P CO2Et HWE olefination O LDA, THF

Me OH Me OTHP 1. PPTS, RO MeOH RO Me 2. DIBAL-H Me O Me 3. MnO2 Me CO2Et R = TBS (48% overall) R = TBS

K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1988, 110, 4672. For a review, see: Classics in Total Synthesis I, Chapter 24. Horner-Wadsworth-Emmons Olefination: Applications in Total Synthesis

OTBS OMe Me OH HO OTBS

TBSO O O O O O O Me + CO2Me Me Me Me Me O Me (MeO)2P O O

1. DCC, 4-DMAP (70% overall) 2. DBU, LiCl, CH3CN, 25 °C HWE macrocyclization

OTBS OMe Me O OTBS

TBSO O OR OR OR OR O Me CO2Me Me O core architecture of amphotericin B

K. C. Nicolaou and co-workers, J. Am. Chem. Soc. 1988, 110, 4672. For a review, see: Classics in Total Synthesis I, Chapter 24. Horner-Wadsworth-Emmons Olefination: Background and Principles

Me Me Me CO2R BnO O BnO BnO CO2R

E-alkene Z-alkene

O Ph3P CH2Cl2, 0 °C 7 1 OMe

MeO O MeO P LiHMDS, THF, -78 °C 3 1 O OMe Use of non-hindered i-PrO phosphonate, O 1 i-PrO P LiHMDS, THF, -78 °C 19 low temp., and KOt-Bu O OEt can favor Z-olefin MeO O Enhances rate of elimination MeO P 3 KOt-Bu, THF, -78 °C 1 relative to O OMe equilibration

Y. Kishi and co-workers, Tetrahedron 1981, 37, 3873. Horner-Wadsworth-Emmons Olefination: Background and Principles

Me Me Me CO2R BnO O BnO BnO CO2R

E-alkene Z-alkene

O Ph3P CH2Cl2, 0 °C 7 1 OMe

MeO O MeO P LiHMDS, THF, -78 °C 3 1 O OMe Use of non-hindered i-PrO phosphonate, O 1 i-PrO P LiHMDS, THF, -78 °C 19 low temp., and KOt-Bu O OEt can favor Z-olefin MeO O Enhances rate of elimination MeO P 3 KOt-Bu, THF, -78 °C 1 relative to O OMe equilibration

Y. Kishi and co-workers, Tetrahedron 1981, 37, 3873. 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: Still-Gennari Modification

First Method to Use Phosphonates and Get E-

O O KHMDS, KOt-Bu, KH, or K CO F CH CO P 2 3 3 2 OEt with 18-Crown-6 F3CH2CO

W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405. Horner-Wadsworth-Emmons Olefination: Still-Gennari Modification

First Method to Use Phosphonates and Get E-Alkenes

O O KHMDS, KOt-Bu, KH, or K CO F CH CO P 2 3 3 2 OEt with 18-Crown-6 F3CH2CO

Stereoselectivity Principles: Changes the RDS from the elimination to the initial addition

O O O K base (RO) P ONa 2 + (RO)2P ONa + OEt H Ph H H RDS EtO C H EtO C Ph O P(OR)2 2 2 O minor kinetic product major kinetic product

Ph EtO C 2 EtO2C Ph predominant or only product

W. C. Still, C. Gennari, Tetrahedron Lett. 1983, 24, 4405. Still-Gennari Modified HWE Olefination: Applications in Total Synthesis

KHMDS, O O 18-Crown-6, toluene CO2Me F CH CO P CO2Me + 3 2 Me F3CH2CO (89%) Me OTHP Still-Gennari OTHP modified HWE olefination

K2CO3, O 18-Crown-6, TBS O TBS O P CO Bn N toluene F3CH2CO 2 + N (65%) F3CH2CO BnO C O Still-Gennari 2 modified HWE olefination

S. V. Ley and co-workers, J. Chem. Soc., PT 1 1999, 1917. E. J. Thomas and co-workers, J. Chem. Soc., PT 1 1999, 1083. Still-Gennari Modified HWE Olefination: Applications in Total Synthesis

O P CO Me F3CH2CO 2 F3CH2CO sugarO Me KHMDS,18-Crown-6, sugarO Me THF, -78 °C O O TBSO (57%) TBSO O Still-Gennari modified Br HWE olefination Br MeO2C

What reaction was used sugarO H to make the TBSO H core?

Br Me H O MeO2C tricyclic core of spinosyn A

W. R. Roush and co-workers, Org. Lett. 2002, 4, 3157. Still-Gennari Modified HWE Olefination: Applications in Total Synthesis

OTBDPS OTBDPS O O K CO , N O 2 3 18-Crown-6 N O toluene, O -40 °C, 5 h O Me Boc O O Me (77%) Boc O O N Z:E = 4:1 O O N Still- O O Me Me P Gennari O O Me Me F3CH2CO modified F3CH2CO HWE olefination core structure of phorboxazole A

C. J. Forsyth and co-workers, J. Am. Chem. Soc. 1998, 120, 5597. Julia-Lythgoe Olefination: A Versatile Method for Forming E-Alkenes

O O O Ph Ph Ph O S Base O S R + 2 O S (usually LDA R Li O R2 R1 or LiHMDS) 1 R1 OH

Ac2O

O Ph O S R R 2 1 H OAc

M. Julia, J.-M. Paris, Tetrahedron Lett. 1973, 4833. Julia-Lythgoe Olefination: A Versatile Method for Forming E-Alkenes

O O O Ph Ph Ph O S Base O S R + 2 O S (usually LDA R Li O R2 R1 or LiHMDS) 1 R1 OH

Forms the most stable radical prior to quenching, which ultimately affords E-alkene products Ac2O

O O Ph Ph Na/Hg O S O S in MeOH R2 R R R1 2 2 R1 R2 R1 R1 H OAc

OMe

M. Julia, J.-M. Paris, Tetrahedron Lett. 1973, 4833. Tebbe Olefination: Background and Principles

Me THF THF Me (Cp)2Ti Al (Cp)2Ti CH2 (Cp)2Ti Cl Me 0 °C 60 °C Me Tebbe Reagent Petasis Reagent

Tebbe reagent is commercially available ($454.50 for 100 mL of a 0.5 M solution in toluene) By contrast, simple ylide sells for pennies per gram

Reacts with virtually every carbonyl (which other methods do not do at all).

F. N. Tebbe, J. Am. Chem. Soc. 1978, 100, 3611. N. A. Petasis, J. Am. Chem. Soc. 1990, 112, 6392. Tebbe Olefination: Applications in Total Synthesis

OTBS OTBS O Me Cp2Ti(Me)2 Me (5.0 equiv) N N O Boc toluene, 70 °C O Boc O (81%) O Me Me

I. Martinez, A. H. Howell, Tetrahedron Lett. 2000, 41, 5607. Tebbe Olefination: Applications in Total Synthesis

OTBS OTBS O Me Cp2Ti(Me)2 Me (5.0 equiv) N N O Boc toluene, 70 °C O Boc O (81%) O Me Me

General Trend of Reactivity Acids can sometimes survive; but tend not to be tolerated. Aldehydes Functional group Ketones reactivity Note: Surprises are sometimes observed Amides in highly functionalized cases.

I. Martinez, A. H. Howell, Tetrahedron Lett. 2000, 41, 5607. Deoxygenation of Sulfoxides Using Tebbe Reagent: Discovery of a Novel Titanocene-Methylidene Mediated Process

O O O

N N N Cbz Cbz Cbz PPh O 3 O H2C=PPh3 THF, -78 °C, (99%) 1 min BnO BnO BnO O O O PhS Br PhS Br Br O O

K.C. Nicolaou, A.E. Koumbis, S.A. Snyder, K.B. Simonsen, Angew. Chem. Int. Ed. 2000, 39, 2529. Deoxygenation of Sulfoxides Using Tebbe Reagent: Discovery of a Novel Titanocene-Methylidene Mediated Process

O O O

N N N Cbz Cbz Cbz PPh O 3 O H2C=PPh3 THF, -78 °C, (99%) 1 min BnO BnO BnO O O O PhS Br PhS Br Br O O

O O O

N N Cp N Cbz Tebbe Cbz Cp Cbz Reagent Ti O O (2.2 equiv) - O Ti(Cp)2 THF, -20 °C, (73%) 0.5 h BnO BnO BnO O O O PhS Br PhS Br PhS Br O O

K.C. Nicolaou, A.E. Koumbis, S.A. Snyder, K.B. Simonsen, Angew. Chem. Int. Ed. 2000, 39, 2529. Tebbe Olefination: Applications in Total Synthesis

H N O O H Cp2Ti(Me2), N O THF, Δ, 24 h O O N (87%) O N Me Tebbe-Petasis O olefination Me

H N O Wittig reaction did not succeed with the substrate N O Me gelsemine

D. J. Hart and co-workers, J. Am. Chem. Soc. 1997, 119, 6226. Tebbe Olefination: Applications in Total Synthesis

Tebbe reagent, THF, 4-DMAP, -40 °C TMSO TMSO O (71%) O O OTBS Tebbe olefination OTBS

1. TBAF Intramolecular 2. (HSiMe ) NH, NH Cl 2 2 4 hydrosilation 3. Pt(DVS)2; H2O2

Br O HO O OH OH Me OH laurencin

A. H. Holmes and co-workers, J. Am. Chem. Soc. 1993, 115, 10400. Oops, I Made the Wrong Alkene: Olefin Inversion Reactions

OLi O H Ph Ph mCBPA H Ph Ph2PLi Ph Ph H Ph H PPh2

E. Vedejs and co-workers, J. Am. Chem. Soc. 1971, 93, 4070. Oops, I Made the Wrong Alkene: Olefin Inversion Reactions

OLi O H Ph Ph mCBPA H Ph Ph2PLi Ph Ph H Ph H PPh2

MeI

Me OLi Ph -[Ph2MePO] H Ph Ph2P O Ph Ph (95%, 99% cis) Ph Ph PPh H H 2 H Me

E. Vedejs and co-workers, J. Am. Chem. Soc. 1971, 93, 4070. Oops, I Made the Wrong Alkene: Olefin Inversion Reactions

OLi O H Ph Ph mCBPA H Ph Ph2PLi Ph Ph H Ph H PPh2

1. mCPBA 2. Ph2PLi MeI 3. MeI

Me OLi Ph -[Ph2MePO] H Ph Ph2P O Ph Ph (95%, 99% cis) Ph Ph PPh H H 2 H Me

E. Vedejs and co-workers, J. Am. Chem. Soc. 1971, 93, 4070. Oops, I Made the Wrong Alkene: Olefin Inversion Reactions

OLi O H Ph Ph mCBPA H Ph Ph2PLi Ph Ph H Ph H PPh2

1. mCPBA 2. Ph2PLi MeI 3. MeI

Me OLi Ph -[Ph2MePO] H Ph Ph2P O Ph Ph (95%, 99% cis) Ph Ph PPh H H 2 H Me

1. mCPBA Me Me 1. mCPBA 2. Ph2PLi 2. Ph2PLi 3. MeI 3. MeI Me Me OTHP (85%) (90%) OTHP

E. Vedejs and co-workers, J. Am. Chem. Soc. 1971, 93, 4070. Oops, I Made the Wrong Alkene: Olefin Inversion Reactions

O O OH KH, Oxy-Cope OTBS rearrangement OPMB 18-Crown-6 Me Me Me O (75%) Me H Me O Me Me O Me O 175 °C, toluene XX O O 4π-conrotatory (82%) electrocyclic O O ring opening O 18-crown-6 O O O O + Me Me O Me Me Me Me periplanone B hν Olefin isomerization

S. L. Schreiber, C. Santini, J. Am. Chem. Soc. 1984, 106, 4038. For a review, see: Classics in Total Synthesis I, Chapter 21 Julia-Lythgoe Olefination: Applications in Total Synthesis

O OTBS SO Ph O OTBS 2 Li N H N Me Me Teoc H Teoc THF, -78 °C; SO2Ph Ac2O AcO O Me Me Teoc = (2-trimethylsilyl)ethoxycarbonyl Na/Hg (77%) O OH O OTBS

1. HIO4 N N H 2. TPAP H 3. TBAF Teoc (22% overall)

Me Me Me Me indolizomycin S. D. Danishefsky and co-workers, J. Am. Chem. Soc. 1993, 115, 30. Julia-Lythgoe Olefination: Applications in Total Synthesis

TESO Me t-Bu Me HO O Si t-Bu H O O O Me Me OTroc OMe + DEIPSO O TESO Me O O O Me Me OTES H Me TBSO PhO S 2 OTES OPMB OH 1. LiNEt2 2. Ac O Me O 2 (66%) 3. NaHCO3, MeOH-THF; H O OH OTES Na/Hg O Me Me O ODEIPS Me t-Bu Julia-Lythgoe Me Si olefination Me H t-Bu TESO O TBSO OPMB O OMe Me O OTES Me fragment en route OTES to cytovaricin D. A. Evans and co-workers, J. Am. Chem. Soc. 1990, 112, 7001. Kocienski-Modified Julia-Lythgoe Olefination: A One Step Procedure

N N N N O N N N O N Base O N O S N + R2 O S N N Ph (usually LDA O S R2 Ph R or LiHMDS) Ph O 1 R 1 R1 Li OLi altered piece

S Also a viable aryl grouping N

Affords E-alkene products only in one-pot; kinetically controlled, irreversible addition gives anti-β-alkoxysulfones

P. Kochienski and co-workers, Synlett. 2000, 365. Kocienski-Modified Julia-Lythgoe Olefination: A One Step Procedure

N N N N O N N N O N Base O N O S N + R2 O S N N Ph (usually LDA O S R2 Ph R or LiHMDS) Ph O 1 R 1 R1 Li OLi altered piece

S Smiles Also a viable aryl rearrangement sulfone grouping N

N N LiO N O S N O Ph R1 R2

Affords E-alkene products only in one-pot; kinetically controlled, irreversible addition gives anti-β-alkoxysulfones

P. Kochienski and co-workers, Synlett. 2000, 365. Kocienski-Modified Julia-Lythgoe Olefination: A One Step Procedure

N N N N O N N N O N Base O N O S N + R2 O S N N Ph (usually LDA O S R2 Ph R or LiHMDS) Ph O 1 R 1 R1 Li OLi altered piece

S Smiles Also a viable aryl rearrangement sulfone grouping N

N N N N N LiO + N O S N R2 + SO3 O R1 N Ph Ph R1 R2

Affords E-alkene products only in one-pot; kinetically controlled, irreversible addition gives anti-β-alkoxysulfones

P. Kochienski and co-workers, Synlett. 2000, 365. Julia-Lythgoe Olefination: Applications in Total Synthesis OTBS N N Me OTBS N + N O S O O Ph O O Me Me Me OTBDPS Me LiHMDS, DMF, -35 to 0 °C (30:1 E/Z) Kocienski modified Julia-Lythgoe olefination OTBS OTBS Me

O O OTBDPS Me Me Me Me OH OH Me

O O CO2H Me Me Me Me (+)-ambruticin

E. N. Jacobsen and co-workers, J. Am. Chem. Soc. 2001, 123, 10772. Julia-Lythgoe Olefination: Applications in Total Synthesis OTBS N N Me OTBS N + N O S O O Ph O O Me Me Me OTBDPS Me LiHMDS, DMF, -35 to 0 °C (30:1 E/Z) Kocienski modified Julia-Lythgoe olefination OTBS OTBS Me

O O OTBDPS Me Me Me Me OH ? OH Me

O O CO2H Me Me Me Me (+)-ambruticin

E. N. Jacobsen and co-workers, J. Am. Chem. Soc. 2001, 123, 10772. Julia-Lythgoe Olefination: Applications in Total Synthesis

N N Me O N Me TESO O S N NaHMDS, Ph TESO HMPA, DME, -78 °C Me + Me (35%) O Kocienski modified O Julia-Lythgoe olefination OMe O OMe Me Me Me Me Me

OH O

Me Me

O

callystatin A OMe

A. B. Smith and co-workers, Org. Lett. 2001, 3, 1685. Julia-Lythgoe Olefination: Applications in Total Synthesis

N N Me O N Me TESO O S N NaHMDS, Ph TESO HMPA, DME, -78 °C Me + Me (35%) O Kocienski modified O Julia-Lythgoe olefination OMe O OMe Me Me Me Me Me

OH O

Also made by a similar Me olefination Me

O

callystatin A OMe

A. B. Smith and co-workers, Org. Lett. 2001, 3, 1685. : Background and Principles

R1 R2 Me3Si R1 acid base (anti) (syn)

Me3Si R1 Me3Si R1

Me3Si R1 HO R2 HO R2 acid O base (syn) R2 (anti) R1 R2

Me3Si R1 Nonstabilized Peterson reagents usually add with no HO R2 diastereoselectivity, so hard to get E- and/or Z-selectivity; stabilized Peterson reagents are more controlled and typically give Z-olefins under basic reaction conditions

D. J. Peterson and co-workers, J. Org. Chem. 1968, 33, 780. D. J. Peterson and co-workers, J. Am. Chem. Soc. 1975, 97, 1464. Peterson Olefination: Applications in Total Synthesis

(i-Pr)3Si Si(i-Pr) TBSO 3 TBSO O n-BuLi, -74 °C to 25 °C, 8 h O Me Me (83%) O Peterson (i-Pr)3Si olefination

TBAF, THF (93%)

Cl HO O CCl4, PPh3 O Me Me toluene, 65 °C, 12 h (92%) brasilenyne

S. E. Denmark, S.-M. Yang, J. Am. Chem. Soc. 2002, 124, 15196. Peterson Olefination: Applications in Total Synthesis

Me Me Me Me TBSO Me3Si CO2Me TBSO Me Me (Cy)2NLi, THF, -78 °C to -25 °C O CO Me Peterson 2 olefination

Me Me TBSO No other method Me gave the Z-alkene needed for the synthesis Me

Me lancifolol

H. Monti and co-workers, Tetrahedron Lett. 2001, 42, 6125. Peterson Olefination: Applications in Total Synthesis

O Me O CN DMSO, H O, MeO C 2 2 155 °C, 4 h Me CN O Transannular H Diels-Alder O Me reaction H Me Me Me

B(Oi-Pr)2 THF, Peterson Boron serves to mask -78 °C olefination the anionic species Me3Si CN (71%) Me OH CN CN

Me Me

H H HO H O H Me Me Me Me maritimol

A. Toro, P. Nowak, P. Deslongchamps, J. Am. Chem. Soc. 2000, 122, 4526. Peterson Olefination: Applications in Total Synthesis

O OH TMS Me Me O O Me Me H O TMS Li H O H H O THF, -78 °C, O 10 min OBz Me OH Me (48%) OTMS OTMS O O No other procedure 49% aq. HF, Peterson olefination worked for MeCN, 25 °C (83% overall) this olefination Me

O Me Me H O O H Me O H O Me O OMe H O OH O O Me OH resiniferatoxin OH OTMS O P. A. Wender and co-workers, J. Am. Chem. Soc. 1997, 119, 12976.