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. Ch. Soc. Jpn. 1988, 61, 107 The reduction step is not stereospecific.

OH OAc BuLi Ac O Na(Hg) R SO Ph R 2 R R 2 R' R' R' O MeOH SO2Ph SO2Ph H R' This elimation produces the +e- thermodynamic product.

OAc +e- OAc R R Evans: JACS 1990, 112, 5290 R' R' Ionomycin Synthesis

PhO2S Li Me O O OTBDPS H Me H Me Me OTBS Me Me O 1) add RCHO, -78 °C Me add AC2O, -78 °C to R.T. O Me O O 2) Na(Hg), H Me H Me Me OTBS EtOAc/MeOH, O -30 °C OTBDPS Me O Me Me 70% yield H O 86:14 olefin mixture -Peterson Olefination: O

(R1)3Si (R1)3Si (R1)3Si OH RLi R4 R5 R3 R3 R R R2 R4 2 2 R R H Li 3 5 Peterson: JOC 1968, 33, 780 Ager: Synth 1984, 384 base acid Conditions control the stereospecificity of the elimination reaction, but the initial stereochemistry of the addition to the carbonyl must also be controlled to produce E or Z olefins specifically.

Tetrahedron 1994, 50, 6643 H2O Me (R1)3Si (R1)3Si O R2 R5 N R2 R4 R3 R4 R3 R5 OH O 2

1) KN(SiMe3)2, <50 °C N O 2) OTMS Me TMSO O SiMe Me 3 N Me O Me R R R R O 2 4 2 5 OTMS O + 3) H , THF/H O R3 R5 R3 R4 2 N O OTMS TMSO Me For practice: What is the required Me O Me stereochemistry for each O step of the mechanism? OTMS 90% yield 13:1 E:Z

Claisen Rearrangement: (more at the end) Recall: Enolate geometry arguments •Esters + LDA → E-enolates •Esters + LDA + (HMPA or DMPU) → Z-enolates Ireland-Claisen: very powerful reaction

O OTMS OH O LDA/TMSCl O R R' R R R' R' R' O R OTMS H

O Equatorial in TS! trans olefin R' O TMSO R R R' OTMS H trisubstituted if R' ≠ H

Of Note: OTMS R R R 1 1 1 R4 R4 O H R O O 3 O R R R 2 R 2 R2 R3 R3 TMSO R R R 3 TMSO TMSO H R H H H 2 R4 R4 Subst. at R Z-enolate Two new stereocenters 1 → and Subst. at R2 → E-enolate trisubstituted olefin

R H Trisubstituted Olefins Still a serious stereochemical problem. R'' R''' I 2,3 and 3,3 rearrangements (eg Wittig, Claisen, Cope, etc.) In fact 3,3 rearrangements are among the best methods. OTMS OTMS

O O

R' R' R R

II Wittig Rxns: Typically not very selective (if R' and R'' are different). some examples with stabilized reagents: Kishi TL 1981, 37, 3873 JACS 1979, 101, 259 O O P RO OEt O 2 O + H OEt KOtBu, THF CO2Et R= Me 95 : 5 iPr 5 : 95 CH2CF3 1 : 50

III From acetylenes by metalation reactions

Acetylenes/Propargyllic alcohols Corey: -With aluminum reagents: JACS 1967, 89, 4245 JACS 1970, 92, 6314 JACS 1968, 90, 5618

Must be freshly Reduces the Lewis acidity prepared! of any Al species. 1) LAH, NaOMe (1:2) R H R R

R Et2O or THF R'2CuLi OH 2) I Al → 2 O I OH R' OH

-If there is a small amount of Lewis acid present:

1) LAH, AlCl (60:1) R OH R OH R 3 R'2CuLi

OH 2) I2 H I R'

Maybe ???

R R O O H Al Cl H Al Cl Cl Cl Cl

-With organocopper reagents:

terminal acetylenes: Org. Synth. VII 236-240

EtMgBr "EtCu" R R O CuI R E Br E = H , I , R H , Et Cu Et E 2 Et2O

Negishi Protocol: JOC 1980, 45, 2526 JACS 1981, 103, 1276 JACS 1981, 103, 4985

R R Me3Al E or R Cp2ZrCl2 Me AlMe O Me R CH Cl or ClCH CH Cl 2 2 2 2 2 R H HO Cp Cl Zr Cp Me R R Cp R Cp Cp Cp R Cl Zr Zr Zr Zr Me Me Cp Me Cp Me Cp Cp Cl

Me2Al Cp Zr Cl Cp Me Al Me Catalytic 2 E Product R

-Schwartz Hydrozirconation Reaction: TL 1987, 28, 3895 Jeffrey Swartz (Princeton) TL 1990, 31, 7257

LAH Cp Cl Cp2ZrCl2 Zr Will not react with olefins! Cp H Swartz's Reagent

Hydroboration is not as selective between olefins and alkynes.

RL Me RL Me Swartz's Reagent I2 RL Me Cp H Zr I Cl Cp

Enol Triflates: JOC 1986, 3405 McMurray TL 1980, 21, 4313 Pd(0) Me3Sn Me3Sn O OTf 1) LDA, Tf NPh O 2 O 2) Pd(0) Me Sn O O 3 Et SiH O O 3 Pd(0) H or Bu3SnH

O O

Also: JACS 1993, 115, 9293

R OTIPS Pd(0) OTIPS RI OTIPS TfO Bu3Sn O Bu3SnSnBu3 CO LiCl Pd(0) OtBu OtBu OtBu

O OTf Pd(0) Ph CO PhSnBu3

Shapiro Reaction Ex: Pacquette JOC 1980, 45, 3017 O Also: Sorenson S Ar Li O N2 SO2Ar O Li N Li Li E H N N N S nBuLi (2 equiv) N E N Li O -78 °C warm

golden yellow •trisyl group: prevents o-lithiation solution and nucleophilic attack at S

-Also acyclic examples: TL 1997, 38, 8915 Corey and Roberts TL 1997, 38, 8919

OMe SO2Ar SO Ar Li H 2 Li N N SO trisyl nBuLi Li N SO Ar N 2 N Br 2 nBuLi N N N (2 equiv) Li Li OMe golden yellow Ar solution warm - N2 - LiSO Ar OMe 2 Li I

Ar Ar 64% yield Tetrasubstituted Olefins

-Z-enol Silyl Ethers: Corey TL 1997, 38, 5771 JACS 1996, 118, 8765

O Li 1) Brook Li O Si Si TBS O Rearrangement Et2O, -78 °C Ar 2) BaI2 Ph 3) R-X Acyl silane Li

OTBS OTBS TBSO Li R-X BaI2 R Ph BaI - I Ph

Applications of Olefin Synthesis: The Bamford-Stevens Reaction

Ph Ph N2 N RhLn O H2N N N 1,2-Hydride N Ph N R R R' R' R R' R R shift R' R' HH Rh2(OAc)4

Results in the lab: Can this reaction be made more powerful?

entry Substrate Product Yield Z:E

Ph N N 1 70 1:0 O Ph O Ph NR 2 OBn Ph OBn 81 1:0 Ph NR 3 OBn 63 1:0 Ph Ph OBn

NR O 4 O O 69 1:0 Ph O Ph O O JACS 2002, 124, 12426

Coupling of the Bamford-Stevens reaction to a Claisen Reaction

Δ or O R4 R5

Me2AlCl H R2 Ph R -45 °C N 5 R1 R3 N R3 R4 O R4 Δ O R R 1 R2 1 Rh2(OAc)4 R3 R4 R5 R2 R5 (iBu)2AlH -15 °C HO R2 -allyloxy α R R substituent 1 3

R1 = Ar, vinyl, or alkyl Yields: 63-87% de: 75-99% Mono, Di, and Trisubstituted olefins are accesible

As seen previously, aldehydes offer access to many transformations:

Ph N I N Bamford- O [O] Stevens O O H Ph Claisen iodolactonization Ph O

Coupling of the Bamford-Steves Claisen to the Cope and Ene Reactions:

Bamford-Stevens/Claisen/Ene

H NR O OH O BS Claisen Ph Ene Ph

68 % yield >20:1 dr

Bamford-Stevens/Claisen/Cope

O Ph O Ph NR BS Claisen Cope O Ph H H

68 % yield one isomer for both olefins