Stereoselective SynthesisDr Michael Perkins, Flinders UniversityReference Texts:“Stereochemistry of organic compounds” Ernest

L. Eliel New York : Wiley & Sons, c1994.Chapter 12 on stereoselective synthesis byLewis N. Mander.

“Stoichiometric Asymetric Synthesis”by Mark Rizzacasa and Michael Perkins,Sheffield Academic Press 2000

• Chiral Centre: older term, that for carbon correspondsto the asymmetric carbon of van't Hoff (1874)

• Diastereomers often contain two or more centres with 4different groups, but this is not necessarily the case. eg.the two diastereoisomers below are neither chiral norcontain “chiral” centres

Terminology

b

ca

d

Cl

H

H

ClCl

H

Cl

H

trans cis

• A Better term to use is– Stereogenic centre : (stereocentre) any centre

where interchange of two ligands (groups atoms etc)leads to a stereoisomer

TerminologyCl

H

H

ClCl

H

Cl

H

trans cis

Introduction of Stereogenic Centres• Introduction of new stereocentre into target

molecule is normally achieved by one oftwo fundamentally distinct processes:– either through addition to one or other

stereoheterotopic (enantiotopic ordiastereotopic) faces of a double bond

a

b

d

e

a

b

e

d

a

b

d

addition

– less commonly by selective modification orreplacement of stereoheterotopic (enantiotopicor diastereotopic) ligands

Introduction of Stereogenic Centres

a

b

d

e

a

b

e

d

a

b

d

additiona

b

d

d

sustitution

– another important group of processes is basedon the substitution of groups or ligands inmeso substrates

Introduction of Stereogenic Centres

a

b

d d

b

a

e

b

d d

b

a

a

b

d d

be

enantiomers(provided a, b, d, e not chiral)

Terminology• Enantioselectivity: one of two enantiomers is formed

preferentially. There may be an enantioselective step or anoverall enantioselective conversion over several steps. Thedegree of selectivity is indicated as enantiomeric excess (%ee)

• Diastereoselectivity: one of two or more diastereomers isformed preferentially. The degree of diastereoselectivity isgiven as % ds, the percentage of a certain diastereomer in amixture of two or more diastereomers

• Should not use the term de as often more than two isomers canbe produced in a reaction

Enantiomeric # moles major enantiomer – # moles minor enantiomer excess (% ee) = ––––––––––––––––––––––––––––––––––––– X 100 # moles of both isomers

Terminology• stereospecific– used when the configuration of the product is related to

that of the reactant and the reaction is mechanisticallyconstrained to proceed in a steroechemically definedmanner

– also different isomer of starting material givesdifferent product

• eg.

H

CH3H

H3C

CH3

CH3

HBr

HBr

trans - 2-butene meso only

Br2

Terminology• stereospecific• eg.

• via

CH3

HH

H3CCH3

CH3

BrH

HBr

CH3

CH3

HBr

BrH

cis - 2-butene(±) racemate

+Br2

H

CH3

CH3

HCH3

CH3

H

H

Br+

CH3

H

H

Br

Br

CH3

CH3

CH3

H

H

Br

Br

a

b

a

b

Terminology• stereoselective

– used to describe the stereochemical outcome of areaction when it is possible for more than one isomerto be formed, but one is formed in excess

}2BH

H

}2BH

H

or

not observed

Methyls shield top face

only product

BH3.S(CH3)2

That the Boron and H are added from the same side is stereospecific !

B

H

H

H

BH2 )2BH

Stereoselective Synthesis– stereochemical outcome is determined by

differences in free energy associated withdiastereomeric transition states (ΔΔG±)

– eg. for SM => Prod A or Prod B

E

!GA!GB

!!G = !GA – !GB

SM

A

B

Stereoselective Synthesis

• Three classes of diastereoselective reactions– stereochemically controlled synthesis of

achiral diastereomeric compounds– introduction of new stereogenic centres into

chiral substrates– coupling of two compounds at prostereogenic

centres with formation of two newstereocenters

Diastereoselective Synthesis• Synthesis of Achiral Diastereomers

– for example reduction of t-Butylcyclohexanone

– presence or lack of plane of symmetry has nobearing (provided the other reactant is achiral)

O

redn

OH

H

OH

H

+

Diastereoselective Synthesis

• Introduction of new stereogenic centresinto chiral molecules– diverse class of diastereoselective reaction– configuration of new stereocenters are

established in a relative relationship topreexisting stereocenters

– racemic substrates react with achiral reagentsto give the same relative relationship

Diastereoselective Synthesis• Introduction of new chiral centres into

chiral molecules (cont)

O

OH

OH

~ 90 : 10Racemate

O

HO

OH

Diastereoselective Synthesis• formation of two stereogenic centres• eg the aldol and Michael reaction

O

R

O

H

R

O OH1. LDA

R

O OH

R

O OH

R

O OHOLi

OLi

Enantioselective Synthesis– generally the substrates are achiral and

stereoselectivity in the formation of new stereogeniccentres will require reagents that are chiral

– potential for catalysed reactions!

– potential useful alternative is where a racemate isresolved into its individual enantiomers, which are thenutilised in the synthesis, either by recycling or use of acomplimentry sequence

– enantioselective synthesis depend on the avaliability ofenantiomerically pure compounds from biologicalsources

O

HN(CH3)2

OH

HO H

Et2Zn

8 Mole%(95 % ee)