The Beatles - 1964

Massive Attack -

Oasis - 1992

Biography 2001-present: University of Bristol 1997-2000: Professor, Sheffield 1988-1997: Various Reader Positions 1986-1988: Post-doc with Gilbert Stork 1983-1986: PhD at University of Cambridge 1983: Undergrad at Cambridge University

Enantioselective Construction of Quaternary Stereogenic Centers fromTertiary Boronic Esters: Methodology and Applications–Ravindra P. Sonawane, Vshal Jheengut, Constantinos Rabalakos, Robin Larouche-Gauthier,Helen K. Scott, and Varinder K. Aggarwal*

Angew. Chem. Int. Ed. 2011, 50, Early View

Ar R1

BpinR2

>99:1 e.r.

M-Alk-LG

Ar R1

Alk-OHR2

>99:1 e.r.

Sounds cool, but how do you make chiral tertiary boronic esters?

Tertiary Boronic Esters Ar R1

BpinR2

Ar R1

OCbH

>99:1 e.r.

Ar R1

BpinR2

>99:1 e.r.

s-BuLi

R2Bpin

From secondary chiral carbamates of course!

Noyori Asymmetric Transfer Hydrogenation

Ar R1

O

Carbamate Formation

H

OCbArMe

sBuLi Li

OCbArMe

RB(OR')2

retention

B(OR')2

OCbArMe

R

Li

OArMe

O

NiPr2

R

B(OR')2ArMe

Δ

H2O2NaOH R

OHArMe

Aggarwal et al Nature, 2008, 456, 778-782

Ph Me

Et OH

91% (99:1)

Ph Me

OH

95% (1:99)

OHEt

69% (99:1)

Ph Me

OHO

94% (98:2)

Ph

Bpin

MeEt

a) LiCH2Br THF, –78 oC

b) H2O2, NaOH Ph MeEt

OH

83%

Ph

B

MeEtOO

Br

HH

Application of Matteson Homologation Conditions

D. S. Matteson Tetrahedron, 1998, 54, 10555-10607

MeEt

OH

83%, >99:1 e.r.

MeEt

OH

Cl

88%, >99:1 e.r.

MeEt

OH

MeO

62%, 99:1 e.r.

Me

OH

82%, >99:1 e.r.

Me

OH

37%, >99:1 e.r.

MePh

OH

MeO

41%, 98:2 e.r.

Extention to Vinylation of Boronic Esters

Ph

Bpin

MeEt

MgBr

(n equiv)

Ph

B

MeEtOO

Ph

B

MeEt

Ph

B

MeEt

I

I2

PhMe Et

BI

PhMe Et

NaOMe

Me Et MeEt

Me Et Me

66%, >99:1 e.r.

Cl

79%, >99:1 e.r.

MeO

62%, >99:1 e.r. 79%, >99:1 e.r.

Ph

Bpin

MeEtLi

OEta)

b) I2, NaOMePh Me

Et

OMe

66%, >99:1 e.r.a) LiCHCl2

b) H2O2, NaOH Ph MeEt

OH

68%, >99:1 e.r.

Applications

MeO

Me

OCb

a) s-BuLi

b) Bpin

c) MgBr2, MeOH

Ar

Me Bpin

MgBra)b) I2; NaOMe Ar

MeMeMgI, neat

180 oCMe

HO

98:2 e.r.69%

92%, 97:3 e.r.(+)-(S)-sporochnol

91%

Ph Me

OCb Bpin

a) s-BuLi

b) MgBr2 Ph Allyl

pinB Me

>99:1 e.r. 92% >99:1 e.r.

a) LCHCl2b) H2O2, NaOH Ph Allyl

MeOH

a) PhMgBr

b) PCC Ph Allyl

MeOPh

70% from boronic ester>99:1 e.r.

a) O3, Me2S

Ph

MeOPh

O

NN

OMePh

MePh

ON N Ar

NaBH(OAc)3

63% over two steps

serotonin antagonist

Biography 2001-present: University of Manchester 1992-1994: Post-doc with Prof Marc Julia 1989-1992: PhD at University of Cambridge 1968: Born: Kampala, Uganda

Enantioselective synthesis of tertiary thiols by intramolecular arylation ofLithiated thiocarbamates–Paul MacLellan and Jonathan Clayden*

Chem. Comm. 2011, 47, 3395-3397

R1

SH

R2R3 General Conundrum

R1

O

R2

NucleophileCoordinating Chiral Ligand

R1

OH

R2Nu

O

Me Me

O O

OMe

O

ZnEt2ZnMe2 EtMgBr

NH HNO2S SO2

OH HO

N

Me Ot-BuHN

O OTrtMe

NHnBu

OMeO

OH

Enantiofacial selectivity in nucleophilic attack on a

prochiral ketone

R1

S

R2

NucleophileCoordinating Chiral Ligand

R1

SH

R2Nu

"A synthesis of thioacetone in Freiburg in 1889 was abandoned after widespread public protest and the evacuation of whole sectors of the city" – J. Sulfur Chem. 2009, 30, 167

R1

S

R2 R1

SNu

R2H

Tet. Lett. 1976, 17, 4295-4296

NuMgX

H

OCbArMe

sBuLi Li

OArMe

O

NiPr2

General Strategy

If:

Then: R1 S

R2

N

OMe

Ar

aryl migration

R1

S

R2

N

O

Me

H

Ar

R1

SH

R2

Arbase

In Practice

S N

OMe

R2

R1 LDA, DMPU–78 oC S N

H

OMeR

1

R2

NaOEtSH

R1

R2

42-96%

works with electron rich as well as

deficient aromatics

S N

OMe

Me

Me

98:2 e.r.

LiTMP, THF–78 oC

S NH

OMe

Me

Me

83%

96:4 e.r.

S NMe

R2R1

OLi

NLi

MeMe

Me

Me

Substrates and Scope

SH

MeOMe

97%

SH

Me

Cl

97%

SH

Me

51%

SH

Me

89%

Ar1

R

OH

1. ClC=NMe2+Cl–2. MeCOSH3. LiAlH4

4.

N

O

NAr2

MeNMe

I–

Ar1 S N

OMe

Ar2

Me 1. LiTMP2.NaOEt

Ar1 SH

MeAr2

A general synthetic approach to the amnesic shellfish toxins: totalsynthesis of (–)-isodomoic acid B, (–)-isodomoic acid E and(–)-isodomoic acid F–Gilles Lemiere, Simon Sedehizadeh, Julie Toueg, Nadia Fleary-Roberts and Jonathan Clayden*

Chem. Comm. 2011, Advanced Article

NHt-BuO2C

H

H

CO2t-Bu

NH

Me

HO2CH

H

CO2H

R

R = E Isomers Z Isomers

HO2C

Me

HO2C

Me

HO2C

Me

isodomoicacid B

isodomoicacid A

isodomoicacid E

domoicacid

isodomoicacid F

isodomoicacid D

H kainic acid

(SiMe3)2CuCNLi2,N

O

O

Ph

H

H Ph

Me3Si

Single Diastereomer

86%

TMSCl NO

O

Boc

H

H

Me3Siacid;Boc2O

NO

O

Boc

H

H CO2t-Bu

Me3Si1. RuCl3 (10 mol%) NaIO4

2. t-BuOH, DCC

Sharpless et al J. Org. Chem. 1981, 46, 3936

NO

Boc

H

H CO2t-Bu

Me3Si

Reduction

Oxidation

N

O

H

CO2t-BuTMS

BocO

OO

Ar

O

mCPBA N

O

O

BocH

H CO2t-Bu

Me3Si

O83%

64%

MeO

N

O

Ph

PhNLi

Ph

Me

NO

O

Ph

H

H Ph67%

99:1 e.r.(after single

recryst.)

Clayden et al. Chem. Comm. 2002, 38-39 Org. Lett. 2000, 2, 4229-4231

Towards the Core

N

O

BocH

H CO2t-Bu

Me3Si

Ot-BuO2C

N BocH

H CO2t-Bu

1. TBAF

2. Boc2O, t-BuOH

70%

O3

t-BuO2C

N BocH

H CO2t-Bu

O

98%

"the use of NaOMe...allowed us to avoid the epimerisation of the sensitive aldehyde which resulted when potassium carbonate in methanolwas used a base."

t-BuO2C

N BocH

H CO2t-Bu

N2

PO

MeOMeO

O

Me

NaOMe89%

t-BuO2C

N BocH

H CO2t-Bu

MeBu3Sn

1. Bu3SnCu(Bu)CNLi22. MeI

HO2C

NH

H

H CO2H

Me

HO2CNH

H

H CO2H

Me

HO2C

NH

H

H CO2H

Me

HO2C

Me

HO2C

Me

HO2C Me

1. PdCl2(MeCN)2 allylbromide2. TFA

Pd; TFA

Pd; TFA

71%(–)-isodomoic acid B

51%(–)-isodomoic acid E

49%(–)-isodomoic acid F

HO2C

NH

H

H CO2H

MeH

TFA

(–)-kainic acid