SYNTHESIS OF THE CARBON FRAMEWORK:
ELECTROPHILES
INTRODUCTION• Fundamental to the synthesis of any molecule is the formation of the carbon skeleton
• Not possible to just connect two molecules
+
✘
• Need functional groups to aid bond formation
• Polarisation of the bonds provides an idea of how to bring the pieces together
• Idealistically we perform the following +
• This implies that we react an electrophile with a nucleophile
• Lets look at each in turn....
ELECTROPHILES Alkylating Agents
• Consideration of the polarisation of a molecule often indicates how they will behave
• Compounds that have δ+ve are often electrophiles Haloalkanes
R X + Nuc R Nuc + X
simple SN2 displacement
X = normally Br or I
From the synthesis of (+)-thienamycin, a potent antibacterial
NTBS I H
O S
S Li
SiMe3 N
TBS H
O
S S SiMe3
+ LiI
N
S CO2H O
OH
H H H2N
• Diagrams in boxes are just examples
• I don't expect you to remember the structures but you should know what is happening and be able to draw mechanism / curly arrows
(Nuc )
Epoxides
• Useful electrophiles as allow the introduction of stereochemistry with complete control
R O δ+
δ+ δ–
+ Nuc
R Nuc
O H
O H
R Nuc
OH
+ OH H2O
electrons attracted to electronegative oxygen
aqueous work-up
• Which δ+ve carbon is attacked?
• Normally the least substituted end of epoxide on steric grounds (easier approach for SN2 attack)
• Advantage of epoxides is that there are a number of reliable ways of making them
δ+ δ–
electrons attracted to electronegative halide
• The differences in reactivity have very important consequences when we consider the addition of nucleophiles such as Grignard reagents
R H
O 1. EtMgBr
2. H2O
R Et OH
R OR
O 1. EtMgBr
R Et
O OH
R Et Et ketone more reactive than ester!
Stereoselectivity in Nucleophilic addition to Carbonyls
R O
H
1. NucMgBr 2. H2O
R
H Nuc OH
R
H Nuc HO
R
H Nuc HO
R
H OH Nuc
• When a nucelophile reacts with a chiral carbonyl compound diastereoisomers are generated
• If the starting material is racemic (stereochemistry not defined) then a mixture of 4 diastereoisomers is produced
• Remember that a planar sp2 carbon is becoming tetrahedral sp3
enantiomers
enantiomers
stereochemistry not defined
racemate
diastereoisomers
Nuc R OH H H
O R
Nuc
H H
O R
Nuc
new stereocentre diastereotopic
favoured disfavoured
only passing small hydrogen group
Nuc
R OH
• If the chiral centre is close enough to the carbonyl moiety then it may effect the stereo- chemical outcome, resulting in a diastereoselective reaction
• If the substrate contains a chiral centre α to the carbonyl group we can predict the outcome with the Felkin-Anh Model
• Believed to be a "realistic" representation of the transition state 1. EtMgBr 2. H2O
M L
S L
M
S O
R L
S
M O
R
R Nuc
OH
M L
S
Nuc R
OH
Nuc Nuc
minor major minor major
place largest substituent perpendicular to carbonyl
nucleophile will attack along Bürgi-Dunitz angle
passed smallest group
• If there is a chelating group (Lewis basic) then Cram-Chelation control can be used to predict the outcome
L PO
S O
R Met
R O
OP L S
≡
Nuc
L PO
S R Nuc
OH chelating metal
or Lewis acid
again attacks passed smallest group
From Still's synthesis of monensin
Reaction proceeds via Cram-chelation control
OTMS O
(Nuc )
O O OBn
1. MgBr2 2. Nuc 3. H2O
OBn O
OTMS OH O
Electrophilic Alkenes
• Alkenes attached to electron withdrawing groups such as SO2Ph, CN or C(O)R can be attacked by nucleophiles
O R
δ+
δ–
δ– δ+
Nuc
Nuc O
R
Nuc O
R H
O H
1,4-Addition
• Problem of selectivity; carbonyl also electrophilic 1,2-Addition
O
R Nuc
1 2
3 R
Nuc O H
O H
R Nuc OH
• The nature of the nuceleophile has a strong effect on the position of attack
• Soft nucleophiles (charge spread out / diffuse) attack 1,4
• Hard nucleophiles (charge concentrate at one point) attack 1,2
• Next lecture we will start to look at different nucleophiles...
What have we learnt?
• There is a large range of electrophiles (many we haven't covered)
• The carbonyl group is one of the most important
• Additions to the carbonyl group can be stereoselective
• Additions to enones can result in selectivity problems
