Master Course 2018-19 in Organic Chemistry

methods and design in organic synthesis

Pere Romea Rubik’s cube

4.2. Single & Double Bonds Non functional group R R disconnection Carbon-a Carbon-d R R ¿"?

Alkyl%d Alkyl%a

Li Potential precursors X Alkyl lithium Alkyl halide, X: Cl, Br, I MgBr RSO3 Alkyl magnesium halide Alkyl sulfonates

M + Y

M: Li, MgX M: halide, sulfonate

The reaction is plagued by many side reactions due to high pKa of Alkyl-d (pKa 45–50) OH

OMe O N O MeO H N O

(–) Hennoxazole A ?antiviral Smith, T. E. JOC 2008, 73, 142 Polyfibrospongia OH

OMe O N O MeO H N O

¿ FGA ? OPG

OMe TBS O N O MeO H N O

OPG

OMe TBS O N O Li Br MeO H N O Oxazole alkylation studies

O

Ph N

two potential reacting sites Oxazole alkylation studies

Li Li O base O O –78 °C Ph N Ph N Ph N

MeI MeI ratio 1:2 O Me Me O BuLi LDA LiNEt2 (14:86) (37:63) (99:1) Ph N Ph N 1 2

This reversal of regioselectivity is thought to arise from the ability of Et2NH to mediate the low-temperature equilibration of a kinetic mixture of otherwise noninterconverting lithiated intermediates

However, such a situation was dramatically modified in a model close to the TGT structure

TAKE-HOME MESSAGE: the model should be as similar as possible to the real system Oxazole alkylation studies single product Chelation could be the reason

O Li O Li O MeO OMe MeO OMe MeO OMe N base N N H N N N –78 °C H H O O O

three potential base: BuLi, LDA, LiNEt2 reacting sites These results suggest that deprotonation at the heterocycle is thermodynamically as well as kinetically favored

SOLUTION: BLOCKING THAT POSITION?

TBS TBS TBS O O Me O Me MeO OMe 1) base, –78 °C MeO OMe MeO OMe N N + N H N 2) 2 equiv MeI H N H N O O O ratio mono:di:SM Me BuLi LDA LiNEt2 (60:12:28) (43:8:48) (88:5:7) Alkylation of OTBS the real system OMe TBS N O O MeO H O N

1) LiNEt2, THF, –78 °C 2) Br

77% OTBS

OMe TBS N O O MeO H O N

TBAF, THF, rt 99%

OH

OMe TBS N O O MeO H (–) Hennoxazole A O N Alternative (I): Terminal

FGA

Alkynyl&d Alkyl&a

R H + n-BuLi R Li + n-BuH THF, –78 °C

pKa ca 25 pKa 50

R H + EtMgBr R MgBr + EtH THF, 0 °C Larva of Mexican bean beetle O

O NH Epilachnadiene defense agains ants Rao, B. V. TL 1995, 36, 147 ? O OH OH FGI O NH OH OH

Br OH OH OPG Alkyl%a Br Alkyl%a Alkynyl%d

OH O Alkynyl%d Alkyl%a Alkynyl%d

Rao, B. V. TL 1995, 36, 147 Alternative (II): Organocuprates

ORGANOCOPPER REAGENTS, easily prepared by transmetallation, are very selective

RLi + CuX RCu + LiX Monoorganocopper

2 RLi + CuX R2CuLi + LiX Homocuprates or Gilman’s reagents

RLi + CuCN RCu(CN)Li Heterocuprates

I

Me I Me2CuLi R Me R Et O, 0 °C to rt 90% 2 90%

Br I

81% 75% Me Me Cecropia moth

O

A classical synthesis OMe O

(±) Cecropia Juvenile Hormone Hormone involved in the development of larvae Corey, E. J. JACS 1968, 90, 5618 ? + I 1) TsCl, pyr 1) H3O OH OH 2) OTHP 2) LiAlH4, then i2 OTHP

Li2CuEt2

TMS PBr3 Br OH

TMS H

1) BuLi

2) CH2O

Me 1) LiAlH4, I2 OH OH 2) Li2CuMe2

O O

OMe OMe O Bacillus species

O OH

HO

Iedomycin D Maulide, N. OL 2015, 17, 4486 ? Strained bicycle CO H 2 H O OH OH O

HO O OH H 4π#Electrocyclic#transform

CO H OTIPS Activated Zn 2 Then CuCN, LiCl OTIPS I H O 1) H2SO4, MeOH 2) LiOH, MeOH O 98% H

CO H O OH 2 Δ OH HO 63% over three steps Alternative (III): Pd-Mediated Cross-Coupling Reactions

cat Pd(0) R1 X + R2 M R1 R2 + M X

GENERAL MECHANISM PdL2 R1 X R1: better no ß-H Pd(0) X: I, Br, (Cl), OTf Oxidative addition R1 R2

Reductive elimination

R1 R1 Pd(II) L2 Pd L2 Pd Pd(II) R2 X

M X R2 M R2: alkyl, alkenyl, alkynyl, aryl TRANSMETALATION

Fürstner, A. ACIE 2005, 44, 674

Reactants Pd-Mediated Cross-Coupling Reactions

TRANSMETALATION Transfer of an organic group from one metal center to another. The process involves no formal change in oxidation state for either metal.

For palladium-mediated cross-coupling reactions

R1 X + Pd R1 Pd X

R1Li, R1MgY Kumada

R1B(OR)2 SUZUKI

R1CuLn SONOGASHIRA R1ZnY Negishi

R1SnR3 STILLE

Mignani, G. CR 2006, 106, 2651 Magano, J.; Dunetz, J. R. CR 2011, 111, 2177

Reactants Suzuki Cross-Coupling Reaction

X 1 Csp2 X X: I > Br > OTf >> Cl R X

+ OH O O 2 2 2 2 Csp2 R B R B R B R : alkenyl, aryl OH O O R2 B

2 2 Csp3 R B R2 9-BBN R : alkyl

Pd(0) Base Pd(0): Pd(PPh3)4 Ph Ph P PdCl Pd(II): Pd(OAc)2 / PR3 or AsR3 Fe 2 1 2 P R R Ph Ph for Csp3–Csp2 dppf

Reactants Suzuki Cross-Coupling Reactions

0.2 mol% Pd(OAc)2 OH K2CO3 B + I NO2 NO2 OH Acetone / H2O, 65 °C 97%

2 mol% Pd(PPh ) OH I 3 4 B NaOEt + OH PhMe, 65 °C 98%

O B O OTHP 85%

OTHP 3 mol% Pd(PPh3)4, NaOEt Br PhMe, 85°C

OTHP 73%

O B O

Reactants Suzuki Cross-Coupling Reactions

H OMe B OMe OAc OMe OMe S Csp3–Csp2 Coupling OTBDPS OTBDPS N I THF, rt B OTBS OTBS PdCl2(dppf), AsPh3 71% Regioselective Cs2CO3

DMF, H2O OMe O OH O

OAc OMe O

S OTBDPS S OH N N OTBS O Epothilone A Danishefsky, S. ACIE 1996, 35, 2801 Csp2–Csp2 Coupling HO OMe B O HO O OMe OTBS EtO O I EtO O H H 5 mol % Pd(PPh3)4,Tl2CO3, THF/H2O, rt H H OTBS 91%

O OMe (+) Herboxidiene O HO O GEX 1A H H OH Romea P.; Urpí, F. OL 2011, 13, 5350; OBC 2017, 15, 1842 Reactants Sonogashira Cross-Coupling Reaction

X Csp2 X X: I > Br ≈ OTf >> Cl R1 X

+

pKa 25 pKa 12 CuX R3N 2 2 2 2 H R + CuX H R XCu R + R3NH XCu R

The acidity of Csp–H is enhanced via π-complexation

Pd(0) Pd(0): Pd(PPh3)4

Pd(II): PdCl 2(PPh3)2

R1 R2

Doucet, H.; Hierso, J.-C. ACIE 2007, 46, 834

Reactants Sonogashira Cross-Coupling Reactions

TBSO OH I 5 mol% PdCl2(PPh3)2 TBSO OH CO2Me CO Me CuI, Et3N 2 + N N CH3CN, –20 °C to rt MeO O MeO O 85%

Meyers, A. I. JOC 2001, 66, 6037

TBSO TBSO

O I O TBSO O O TBSO O O O O

N N 5 mol% PdCl2(PPh3)2 S CuI, Et3N S CO2Et CO2Et CH3CN, –20 °C to rt

74%

Kirschning, A. ACIE 2008, 47, 9134

Reactants Stille Cross-Coupling Reaction

X 1 Csp2 X X: I > Br > OTf >> Cl R X

+

2 2 R : alkynyl > alkenyl > aryl > benzyl ≈ allyl > alkyl R SnR3

Pd(0): Pd(PPh3)4, Pd2(dba)3 / PR 3 or AsR3 Pd(0)

Pd(II): Pd(OAc)2 / PR3 or AsR3

R1 R2

Reactants Stille Cross-Coupling Reactions

O O O SnBu3 O H OH H OH OMe O OMe O N Bu3Sn N I H 20 mol% PdCl2(MeCN)2, i-Pr2NEt H I O O DMF / THF, rt O O H H OMe OMe O OH 27% O OH O OH O OH OMe OMe Nicolaou, K. C. JACS 1993, 115, 4419

Extraordinary Functional Group Tolerance

O O Bu3Sn OTIPS OH O 20 mol% Pd2(dba)3, AsPh3 CuTC O I OTIPS OH NMP, 35 °C OH

OH 50% O O Williams, D. R. JACS 2001, 123, 765

Reactants Stille Cross-Coupling Reactions

A total synthesis of Chivosazole F shows the tremendous potential of the Stille coupling

Chivosazole F

MeO

OH O N O OH OH O OH

Paterson, I. ACIE 2017, 56, 645

Reactants Stille Cross-Coupling Reactions

A total synthesis of Chivosazole F 2 Stille coupling shows the tremendous potential of the Stille coupling MeO Br

Stille coupling O OTBS Me Sn N 3

O O O O Si MeO I O t-Bu t-Bu P OH O (OCH2CF3)2 N O OH OH O OH 3 SG olefination 1 Stille coupling Stille coupling

Bu Sn OH Bu3Sn H Stille coupling Still-Gennari olefination 3 OTES O

The Stille coupling were carried out using Pd(PPh3)4 and CuTC [copper thiophene-2-carboxylate] Paterson, I. ACIE 2017, 56, 645 See Fürstner, A. Chem Commun. 2008, 2873

Reactants Heck Reaction

cat Pd(0) R1 R1 X + R2 2 + HB X Base R

HX R1 X R1: no ß-H PdL2 L X: I, Br, (Cl), OTf Reductive elimination Oxidative addition R1 H Pd L L Pd L X X Pd(0): Pd(PPh3)4,

R1 Pd(dba)2+PR3 2 E olefin R Pd(II): Pd(OAc)2, R2 L PdCl 2(PR3)2,

PdCl2(CH3CN)2 R1 H R1 Pd L Pd L R2 X R2 X Base: R3N, R2NH

AcO–, CO32– β-Hydride elimination Olefin insertion R1 H H H H R1 R2 Pd L R2 Pd L H X H X Reactants Heck Reaction

The regioselectivity of the Heck reaction is not completely defined. Two pathways are available for the olefin insertion ...

R2 R1 R2 R1 R1 R1 Pd L Pd L versus Pd L Pd L 2 X X R2 X R X

Particularly important when R2: EDG

or the β-hydride elimination ... R1 – H H H R1 R1 R2 H Pd L Pd L H X X R1 R2 R2 – H

R2

Reactants Heck Reactions

0.02 mol% Pd(OAc) OMe I 2 Bu4NCl, K2CO3 + OMe O DMF, rt O 90%

O

OMe O O 2 mol% Pd(OAc) 1 mol% Pd(OAc) I 2 2 Et3N OMe P(o-Tol)3, Et3N OMe

Br CH3CN, Δ Br CH3CN, Δ 68% 63%

OMe 10 mol% Pd(PPh3)4 OMe OMe Et3N OMe TBSO O I + TBSO O H H DMF, Δ H H O O 69%

Reactants Alternative (IV): C=C Bond Forming Reactions

E- Wittig (stabilized ylides) HWE Julia- Kocienski FGA Metathesis

? Peterson olefination Tebbe olefination FGA Takai olefination

Z- Alkene Wittig (non-stabilized ylides) Still-Gennari, Ando

Reactants © Gareth Rowlands Reactants C=C Forming Reactions: Carbanions and Carbonyls

O X R2 R2 R3 R4 R1 R2 + R3 R4 R1 + R1 R4 R3

Regioselectivity is not a problem ... The only concern is stereoselectivity!

X: Si, Peterson Reaction C N O X: P, and variants Si P S R3P+, Wittig Reaction

R2P=O, Horner-Wittig

(RO)2P=O, Horner-Wadsworth-Emmons (HWE) X: S, Julia-Kocienski Reaction Georg Wittig N O O N N Nobel Prize in Chemistry 1979 S S N S O N O Ph …for the development of the use of phosphorus-containing compounds into important reagents in organic synthesis Reactants Wittig Reaction: Concept

Wittig reaction: addition of a phosphorus ylide to a carbonyl

R1 R3 R1 R3 O + R3P + O=PR3 R2 R4 R2 R4

Phosphorus Ylide Phosphine Oxide

O R P R2 R2 R1 H + 3 R1 + R1 H R2 E Z Thermodynamically favored

Non-stabilized ylides R2: alkyl minor MAJOR Semi-stabilized ylides R2: aryl mixtures (E > Z)

Stabilized ylides R2: CO 2R, CN MAJOR minor

Maryanoff, B. E. CR 1989, 89, 863 Nicolaou, K. C. Liebigs Ann. 1997, 7, 1283 Wittig Reaction: Mechanism

The mechanism of the Wittig reaction has been the subject of much debate. Initially, Wittig described this reaction as an addition to a carbonyl...

O PPh O O PPh 3 O PPh3 3 PPh R H H H R 3 R R Ylide Betaine Oxaphosphetane

PPh3 The thermodynamic force of the reaction relies on the P=O bond H H

... but the accepted picture in the absence of lithium salts is rather different nowadays

Ph Ph Ph O PPh3 O PPh3 O P Ph O P Ph + Ph R H H H R R R

Formal [2,2] Cycloaddition Pseudorotation Wittig Reaction: Mechanism

Wittig reactions carried out in the absence of lithium salts (salt-free Wittig reactions) are described as kinetically–controlled transformations...

R2 R2 Ph O O PPh3 Ph H Ph P H + Ph R1 R1 H H R2 P H Ph 2 1 H R : alkyl R2: CO 2R Ph O R

rds

O PPh3 O PPh3 cis-oxaphosphetane trans-oxaphosphetane H H H R2 R1 R2 R1 H

rds

O PPh3 O PPh3 + + R1 Vedejs, E. JACS 1989, 111, 5861 R2 Z alkene R1 E alkene R2 Aggarwal, V. K. & Harvey, J. N. JACS 2006, 128, 2394 Gilheany, D. G. JACS 2012, 134, 9225 For a review, Gilheany, D. G. CSR 2013, 42, 6670 Wittig Reaction in Synthesis

1) BuLi, THF-HMPA, –78 °C OTBS EtS H O EtS 2) H OTBDPS H O O O OTMS H H H H H H H O O O OTBDPS O O PPh3 H H O O H I TBSO H H H O H Through Non-stabilized ylide H O Et H RO S H O H H H S O O O Et H O O H H Z olefin O O H H H H R : TMS PPTS 75% over two steps R : H HO CHO

H O O H H H H Nicolaou, K. C. JACS 1995, 117, 10252 O O H H H H O O O H O O H H O O O H Brevetoxin B H H H Wittig Variants: Concept

Wittig variants: addition of phosphonate carbanions to carbonyls

O O R2 O + RO P EWG EWG + P R1 R2 R1 RO O RO RO R3 R3

Phosphonate Carbanion Phosphate salt

Phosphonate

(AlkylO)2POCH2CO2R2 Horner-Wadsworth-Emmons

(CF3CH2O)2POCH2CO2R2 Still-Gennari

(ArylO)2POCH2CO2R2 Ando HWE, Still-Gennari & Ando Reactions: Stereoselectivity

O O O P CO R2 1 + 2 1 2 + 1 R H (RO)2 OR R R 2 CO2R E Z Thermodynamically favored

Phosphonate

Horner-Wadsworth-Emmons (AlkylO)2POCH2CO2R2 MAJOR minor

Still-Gennari (CF3CH2O)2POCH2CO2R2 minor MAJOR

Ando (ArylO)2POCH2CO2R2 minor MAJOR Still-Gennari Reaction: Stereoselectivity

Still-Gennari reaction provides a reliable entry to Z olefines ...

O O 1) KHMDS, 18-crown-6, THF P R (CF3CH2O)2 OMe 2) RCHO CO2Me

CHO CHO CHO CHO

12:1 90% 4:1 74% > 50:1 87% > 50:1 95%

O O 1) KHMDS, 18-crown-6, THF P R (CF3CH2O)2 OMe 2) RCHO CO2Me

CHO CHO CHO CHO

46:1 88% 50:1 80% > 50:1 79% 30:1 95%

Still, W. C. & Gennari, C. TL 1983, 23, 4405 Ando Reaction: Stereoselectivity

Ando reaction also gives Z olefins ...

O O 1) NaH or R NOH, THF, –78 to –10 °C P 4 R (PhO)2 OEt 2) RCHO CO2Et

CHO CHO CHO CHO

90:10 100% 91:9 98% 89:11 97% 93:7 98%

O O O NaH, THF, –78 °C Bu H + P (PhO)2 OEt CO2Et Bu Z / E 95:5 85%

Ando, K. JOC. 1997, 62, 1934; JOC. 1998, 63, 8411 HWE & Variants: Mechanism

It is generally accepted that the stereoselectivity of the HWE reaction is a result of both kinetic and thermodynamic control upon the reversible formation of the erythro and threo adducts followed by the oxaphosphetane formation, pseudorotation, and decomposition to olefins.

H O O O O O H O O P P R (OR) + P R (OR) 2 R H (RO)2 OR 2 H CO2R RO2C H threo erythro

O O

O P (OR)2 O P (OR)2

R CO2R R CO2R

O R O Brandt, P. & Rein, T. JOC 1998, 63, 1280 R OR OR Ando, K. JOC. 1999, 64, 6817 E Z Wittig, HWE & Variants in Synthesis

O O P (CF CH O) 3 2 2 O KHMDS, 18-c-6 H O t-Bu O t-Bu THF, –78 °C O O O O O O O Z / E 20:1 80% Still-Gennari

O

Ph3P OEt O O CO2Et Wittig O H O O Stabilized ylide PhMe, 110 °C E / Z 10:1 87%

O O O P (EtO) O O 2 NaH O O O H O O O THF, 0 °C to rt O

E only 93% HWE OH O O O Yadav, J. S. JOC 2012, 77, 9628 N Tirandamycin C O H Wittig, HWE & Variants in Synthesis

Wittig O O O OTBS Ph PCH Br, BuLi O 3 2 EtO EtO H THF, –78 °C H 89% O O P Still-Genari OTBS OTBS MeO (OCH2CF3)2

KHMDS, 18-c-6, THF, –78 °C Z/E > 20:1 90% H O MeO O O O Still-Genari P OTBS OTBS MeO (OCH2CF3)2 Z/E > 20:1 96% O O

KHMDS, 18-c-6 EtO H THF, –78 °C

HO MeO O O P MeO OH O OTBS MeO (OMe)2

BuLi, DMPU, THF, 0 °C

HWE O E/Z > 20:1 98% H O O N R: N Archazolid F S O Menche, D. OL 2019, 21, 271 R Julia-Kocienski Reaction: Concept

[O] O O S Het-SH Het R S Het R RX (SN2)

or ROH, DEAD, Ph3P (Mitsunobu) Sulphone

N N N N N N SO2R SO2R SO2R SO2R S N N N N Ph t-Bu BT PT TBT PYR Julia,1991 Kocienski, 1998 Kocienski, 2000 Julia,1993

Julia-Kocienski reaction: addition of sulfone carbanions to

1 R O 1 + 2 R + SO + HetO HetSO2 R R2 2 H

Blakemore, P. R. JCS Perkin Trans 1 2002, 2563; Aïssa, C. EJOC 2009, 1831 Julia-Kocienski Reaction: Mechanism

Sulfone acidity

O O R H Me t-Bu Ph S R Ph pKa 29.0 31.0 31.2 23.4

O O 1 SO N S R 2 N RCHO, Base R2 O S 1 R S

B

O O O N 2 N S N S H R S N O O O S O S R1 S O O S O O O S R1 R2 R1 R2 R1 R2

For a computational analysis of the Julia Kocienski reaction, see Legnani, L.; Vidari, G. JOC 2015, 80, 3092 Julia-Kocienski Reaction: Stereoselectivity

O O O N S MN(SiMe3)3 H + –78 °C to rt S E

More E

M PhMe Et2O THF DME

Li 50 : 50 50 : 50 66 : 34 70 : 30 Na 54 : 46 50 : 50 62 : 38 75 : 25 K 54 : 46 50 : 50 54 : 46 76 : 24

O O O N S MN(SiMe3)3 H + N N N –78 °C to rt Ph E

More E

M PhMe Et2O THF DME

Li 51 : 49 61 : 39 69 : 31 72 : 28 Na 65 : 35 65 : 35 73 : 27 89 : 11 K 77 : 23 89 : 11 97 : 3 99 : 1 Kocienski, P. J. Synthesis 1998, 26 More E Julia-Kocienski Reaction: Stereoselectivity

O O O O Ph O O S S S N O O N N N N TBSO TBSO O O Ph O CHO O S N KHMDS, THF, –78 °C N N N TBSO TBSO E/Z > 20:1 83% OTMS OTMS

O O O H OBL O TBSO 2 O O OTBS

R O LiHMDS, THF, –75 °C, then HCl TBSO OTMS E/Z 12:1 65%

OTBS OH O O R: HO O O

HO O HO H Lasonolide A O O Hong, R. ACIE 2018, 57, 16200 H Stereoselectivity of Wittig, HWE & Variants

O X 1 2 + R + 1 R 1 2 R R H H R R2

Z olefin E olefin Regioselectivity Stereoselectivity (Z versus E) ?

Z olefin E olefin

X H Alkyl Wittig Julia-Kocienski

X H EWG Still-Gennari & Ando Wittig & HWE Synthesis of Natural Products

O O t-Bu O N S OTBDPS t-Bu O t-Bu O O N O O O O N N O O OTBDPS O O S N H Ph LHMDS, 5:1 THF-HMPA S –78 °C to rt O O O O O O E / Z 12:1 67%

O O MeO C O P CO Me 2 (CF CH O) 2 TBSO 3 2 2 TBSO H TBSO H H LDA, THF, –78 °C O H KHMDS,18-crown-6 O O E / Z 20:1 70% H THF, –78 °C H H t-Bu O I I I E / Z 1:15 85% O O

TBS OR1 O O O O O H R2 OR1 I O O O O O H R2 PPh 3 I O

O R1O KHMDS, O R1O R1O R1O H THF, –78 °C to rt H O O O O H Z 60% H R1: TBS R1: H R2: R1: TBS Lee, E. JACS 2002, 124, 384 Lasonolide A Other C=C Bond Forming Reactions:

R1 R1 O SiMe 3 SiMe SiMe + HO 3 + HO 3 R1 H H R2 R2 R2

acid acid base Remember elimination reactions to understand the mechanism 1 R2 R R1 R2

Nozaki-Hiyama-Kishi-type coupling

1) Br SiMe3 CHO CrCl2, THF, 15 °C

PMBO TBSO OPMB 2) KOH, MeOH/H2O PMBO TBSO OPMB

OTBS 81% OTBS

Novartis approach to Discodermolide. OPRD 2004, 8, 92, 101, 107, 113 & 122 Other C=C Bond Forming Reactions: Tebbe Olefination

Cl Ti + AlMe3 Ti AlMe2 + HCl Cl PhCH3, r t Cl

O CH2 + Ti AlMe2 R R Cl PhCH3 R R

From a mechanistic point of view, it looks like a metathesis

O

CH2 Ti AlMe Ti Ti Cl 2 O Other C=C Bond Forming Reactions: Tebbe Olefination

O O CH2 CH2 R H R R Ti CH Olefin R H 2 R R Olefin Ketone

Ester Amide O O CH CH 2 R OR R NR2 2 Vinyl ether Enamine O R OR R NR2 Acid chloride R Cl

CH2 Titanium(IV) enolate R OTiCp2Cl

The Tebbe-Petasis variant utilizes Cp2TiMe2

O CH2 Cp2TiMe2 R X R X Other C=C Bond Forming Reactions: Tebbe Olefination

Ø The Tebbe reagent is a non-basic reagent Ø Highly reactive in front of sterically hindered carbonyl groups Wittig Tebbe O 89% 97%

O 4% 77%

O Pine, S. H. Synthesis 1991, 165 Ph Ph 38% 63% Ph Ph

Ø The Tebbe reagent is generated and reacts at low temperature Ø The Tebbe reagent is a Lewis acid sensitive to moist and oxygen Ø The Tebbe reagent is limited to methylenation Other C=C Bond Forming Reactions:

I Cr(III) Cr(III) Cr(II) Cr(II) H H H I I I I I Cr(III)

O I H R H I O R Cr(III) Cr(III) R H

Iodoolefins are very useful intermediates for Pd-mediated couplings For an insightful analysis of the mechanism, see Anwander, R. JACS 2018, 140, 14334

Occasionally, it can be applied to bromo and chloroderivatives

Cl OH Cl Cl OH Cl CHCl , CrCl CHO 3 2 Cl THF, 65 °C Cl Cl Cl Cl Cl Cl

47%

Carreira, E. M. Nature 2009, 457, 573 Metathesis a key reaction beyond ionic analysis : A New Reaction?

Olefin Metathesis: the reaction of the 90s? The Nobel Prize in Chemistry 2005 … for the development of the metathesis method in organic synthesis

Yves CHAUVIN Robert H. GRUBBS Richard R. GRUBBS

Alkene metathesis in all its various guises has arguably influenced and shaped the landscape of synthetic organic chemistry more than any other single process over the last 15 years Nicolaou, K. C. ACIE 2005, 44, 4490

Robert H. Grubbs. The Development of Olefin Metathesis Catalysts: An Organometallic Success Story, in ACR 2001, 34, 18–29 Olefin Metathesis: Concept

Metathesis = Meta (change) & thesis (position)

AB + CD AC + BD

Olefin metathesis can be formally described as the intermolecular mutual exchange of alkylidene fragments between two olefins promoted by metal-carbene complexes

1 2 R R [M] R1 + + R2

Nicolaou, K. C. Classics in Total Synthesis II. p. 162

Grela K. Olefin Metathesis. Theory and Practice. Wiley For an analysis, see ACIE 2015, 54, 3856 Olefin Metathesis: Features & Mechanism

R1 M R1 + R2 R2 + Olefin metathesis is a reversible, catalytic process (1–5 mol%), with high levels of chemo-, regio-, and stereoselectivity

R1 Cycloaddition R2 M Except for the synthesis of small cycles, R1 the reversible character of olefin metathesis usually results in the formation of the thermodynamically most favorable E product. M M

R1 R2 R1 CURRENT CHALLENGE: KINETIC STEREOCONTROL

Fürstner, A, Science 2013, 341, 1357 R2 M Fischmeister, C. ChemCatChem 2013, 5, 3436 R1 Grubbs, R. H. Chem. Sci. 2014, 5, 501 Cycloaddition Olefin Metathesis: Catalysts

1 2 R R [M] R1 + + R2

Ruthenium carbenes, [M]=, the most common catalysts used in olefin methathesis so far

MesN NMes MesN NMes MesN NMes PCy3 Ph Cp i-Pr i-Pr Cl Cl Cl Cl Ru CHPh Ru CHPh Ru Ru W(CO)5 Ti N Ph R Cp Cl Cl Cl Cl Mo PCy PCy O O (F3C)2MeCO 3 3 NO2 (F3C)2MeCO

Katz 1976 Tebbe 1978 Schrock 1990 Grubbs I 1995 Grubbs II 1999 Hoveyda 2000 Grela 2002

Nicolaou, K. C. Classics in Total Synthesis II. p. 162 For an account of different ruthenium catalysts, Grela, K. ASC 2013, 355, 1997 For a perspective on Olefin Metathesis, Hoveyda, A. H. JOC 2014, 79, 4763

R N N R R O Ru More complex ruthenium based complexes are being developed N O O O to achieve high Z stereoselectivity Olefin Metathesis: A Powerful Synthetic Tool

Metathesis is widely considered as one of the most powerful synthetic tools in organic synthesis

C1 C2 Cat C1 C2 + Cross Metathesis C3 C4 C3 C4

C1 C2 Cat C1 C2 + Ring-Closing Metathesis (RCM) C3 C4 C3 C4

C1 C2 Cat C1 C2 + Ring-Opening Metathesis C3 C4 C3 C4

C1 C2 Cat C1 C2 Enyne Metathesis C3 C4 C3 C4

C1 C2 Cat C1 C2 + Metathesis C3 C4 C3 C4 Nicolaou, K. C. Classics in Total Synthesis II. p. 162 Blechert, S. ACIE 2003, 42, 1900; Nicolaou, K. C. 2005, 44, 4490 Schrodi, Y. & Pederson, R. L. Aldrichimica Acta 2007, 40, 45 Hoveyda, A. H. Nature 2007, 450, 243; Mori, M. ASC 2007, 349, 121 Grela, K. CR 2009, 109, 3708; Fürstner, A. CC 2011, 47, 6505; Fürstner, A. ACIE 2013, 52, 2 Sarabia, F. Synthesis 2018, 50, 3749 Cross Metathesis

Cross Metathesis has to face non-selective couplings ...

1 R1 R2 R + R2 2 R1 R

R1 R2

R1 R1 + EWG EWG R1 EWG

R1 EWG

The geometry of the resultant olefin turns to be E, the thermodynamically most stable isomer Cross Metathesis

SiMe3 SiMe3 SiMe3 O O O MesN NMes Cl O 69% + 25% O Ph3PMe Br O Ru CHPh BuLi 5 mol% Cl PCy3 Bn H THF, 0 °C Bn N O O 84% N O O O Wittig 2 equivalents O O 5 mol% CH2Cl2, 40 °C, 36 h MesN NMes Cl Ru CHPh Cl PCy3 SiMe3 O CH2Cl2 40 °C, 36 h

SiMe3 O O Bn O O O N O O N O O Bn O

O Me3Si

Ghosh, A. K. JACS 2003, 125, 2374 Cross Metathesis

MesN NMes Cl Ru Cl O NO2

(1–2.5 mol %) EWG EWG TBSO + TBSO CH2Cl2, rt, 30 min–16 h O E/Z 99:1 82% Grela, K. ACIE 2002, 41, 4038 TBSO O E/Z 95:5 95% TBSO OMe

SO Ph TBSO 2 E only 90%

CO2Et

MesN NMes Cl Ru 5 mol % OH OH OH Cl O OMe O O OBn HO O CH Cl , rt, 24 h H H OBn 2 2 HO OH EtO2C E/Z > 97:3 90% (+) Herboxidiene /GEX 1 A

Romea, P. & Urpí, F. OL 2011, 13, 5350; OBC 2017, 15, 1842 Ring-Closing Metathesis

OAc i-Pr i-Pr OAc OH AcO AcO HO O N Ph O O NHCbz NHCbz NH (F3C)2MeCO Mo 2

O (F3C)2MeCO O O O PhH, rt, 4 h O O

HN 92% HN HN

Hoveyda, A. H. JACS 1997, 119, 10302 Sch38516

1 mol% 1 mol%

EtO2C MesN NMes EtO2C Cl TsN EtO2C Ru CHPh TsN EtO C 2 CH2Cl2, rt, 1.5 h Cl CH2Cl2, rt, 1.5 h PCy3 99% 99%

1 mol% 2.5 mol% MesN NMes Cl Ph O R O O Ru Ph Cl R O O CH2Cl2, rt, 4 h O CH2Cl2, rt, 2 h O NO2 99% 99% Ring-Closing Metathesis

O O ROM & RCM H O

O H 25 mol% OPMB O 2 mol% MesN NMes PCy3 Cl Ru H H2C=CH2 Cl Ru CHPh Cl Cl O O PCy3 HO HO O HO CH Cl , rt PhMe, OH 2 2 O O Δ Ingenol 98% 76% PMBO Wood, J. L. JACS 2004, 126, 16300

MesN NMes TIPSO Cl TIPSO Ru O Cl OH O OH O HO 10 mol% HO O O O O OBn PhMe, 100 °C O O OBn OH 80% Streptolic acid

Kozmin, S. JACS 2011, 133, 12172 Ring-Closing Metathesis

For an insightful overview of the impact of RCM in the synthesis of pharmaceutical compounds see Yu M.; Lou, S.; Gonzalez-Bobes, F. OPRD 2018, 22, 918 HWE & Enyne & Cross Metathesis

TOTAL SYNTHESIS of DIHYDROXANTHAIN: synthesis of C=C in action

HWE O O O P O O OMe , BuLi O , Et3N, LiBr Me OMe H TBSO TBSO P OMe TBSO OMe THF, –78 °C OMe THF, 0 °C to rt

75% over two steps

5 mol% Enyne metathesis MesN NMes Cl H Ru CHPh H O Cl O PCy3 O TBSO O O CH2Cl2, rt H H 70%

Cross-Metathesis O MesN NMes Cl H H 5 mol% Ru CHPh H Cl O 1) LDA, THF, –78 °C O PCy3 O O O O O 2) MeI CH2Cl2, rt H H H dr 20:1 90% 66%

Morken, J. P. OL 2005, 7, 3371 Cross Metathesis: E/Z Diastereoselectivity

Angewandte. Minireviews R. H. Grubbs and M. B. Herbert

International Edition: DOI: 10.1002/anie.201411588 Olefin Cross Metathesis German Edition: DOI: 10.1002/ange.201411588 Z-Selective Cross Metathesis with Ruthenium Catalysts: Synthetic Applications and Mechanistic Implications Myles B. Herbert and Robert H. Grubbs*

cross metathesis · natural products · olefin metathesis · Z-

Olefin cross metathesis is a particularly powerful transformation that has been exploited extensively for the formation of complex products. Until recently, however, constructing Z-olefins using this methodology wasZ-Selective olefin cross metathesis can be achieved not possible. With the discovery and development of three families of ruthenium-based Z-selective catalysts, the formation of Z-olefins usingby using a new generation of ruthenium catalysts metathesis is now not only possible but becoming increasingly prevalent in the literature. In particular, ruthenium complexes containing cyclometalated NHC architectures developed in our group have been shown to catalyze various cross metathesis reactions with Schrock and Hoveyda, who synthe- high activity and, in most cases, near perfect selectivity for the sized monoaryloxide pyrrolide com- Z-isomer. The types of cross metathesis reactions investigated thus far plexes of tungsten and molybdenum that could promote a variety of Z- are presented here and explored in depth. selective metathesis reactions.[3] More recently, a series of ruthe- nium catalysts with cyclometalated N- 1. Introduction heterocyclic carbene (NHC) ligands capable of promoting Z- selective olefin metathesis has been reported. Catalysts 1–3 Olefin cross metathesis (CM) has been widely utilized for are three of the best-studied catalysts and are all derived from the formation of complex natural and nonnatural products, C H activation of the N-adamantyl substituent contained on À generally favoring formation of the more thermodynamically the NHC ligand (Figure 1).[5] Catalyst 1 features an N-mesityl stable E- (or trans) carbon–carbon double bond isomer.[1] Olefin metathesis reactions proceed through a [2+2] cyclo- addition reaction of an olefin with a metal alkylidene, generating a metallacyclobutane intermediate which can then undergo cycloreversion to produce a new olefin product (Scheme 1). Research into the structure and stability of

Ru-catalystsFigure 1.1–3Cyclometalated ruthenium catalysts for Z-selective olefin 2 R metathesis. R R + Grubbs, R. H. ACIE 2015, 54, 5018 THF, 35 °C (Mes) group as the nonchelated NHC substituent and is Scheme 1. Mechanism of olefin metathesis. substituted with a pivalate X-type ligand. This catalyst promoted the homodimerization of terminal olefins with ca. 90% selectivity for the Z-olefin at as low as 1 mol% catalyst substituted metallacyclobutanes has led to the development loading. Catalyst 2 was obtained by substitution of the of catalysts capable of producing Z- (or cis) olefins with high pivalate ligand with a nitrate ligand, to produce a catalyst stereoselectivity.[2] This was first realized by the groups of that showed a marked improvement in selectivity, exhibiting about 95% Z-selectivity across a broad range of homodime- rization reactions. When the nonchelating N-aryl NHC [*] Dr. M. B. Herbert, Prof. Dr. R. H. Grubbs substituent was changed to a bulkier N-DIPP (2,6-diisopro- Department of Chemistry and Chemical Engineering California Institute of Technology pylphenyl) group, a further improvement in Z-selectivity was Pasadena, CA, 91125 (USA) observed, as catalyst 3 exhibited > 98% Z-selectivity in E-mail: [email protected] analogous homodimerization reactions. Catalysts 2 and 3 also

5018 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2015, 54, 5018 – 5024 Cross Metathesis: E/Z Diastereoselectivity

Hoveyda, A. H. Science 2016, 352, 569

Thermodynamically disfavoured alkyl chlorides can also be prepared through cross metathesis Cross Metathesis: E/Z Diastereoselectivity

Grubbs, R. H. ACIE 2017, 56, 11024

Catalysts can nowadays provide kinetically controlled E and Z olefin metathesis Cross Metathesis: E/Z Diastereoselectivity

BocO i. CuBr·SMe2, LiCl, THF, –78 °C MgBr MsCl, DMAP

ii. H CH2Cl2 O O O OTBS OH OTBS 45%

OH HO OH

N N O Cl Ar Ar O OTBS S OTBS 5 mol% Ru S O

1) TPAP·NMO Cl 95% > 99:1 Z/E CH3CN THF, 40 °C 2) HF, CH3CN CO2H

89% ∆12-PGJ2 O OH

Xu, C., Stoltz, B. & Grubbs, R. H. JACS 2018, XXX, XXX Diels-Alder a key reaction beyond ionic analysis

See Chapter 6 & 7 Ring-Closing Metathesis

Diels-Alder and Ring-Closing Metathesis: two approaches to cyclohexenes

+

Diels-Alder RCM

+ 2 C–C & – 1 C=C 0 C–C & 0 C=C

(Catalytic) process Catalytic process

Inter or intramolecular process Intramolecular process

Reversible Reversible

Up to four new stereocenters No new stereocenters