1
Stereospecificity in organic synthesis • Stereospecific reactions - a reaction where the mechanism means the
• • • •
stereochemistry of the starting material determines the stereochemistry of the product; there is no choice. Occasionally, the term may be used with chiral reagents or catalysts if the configuration of the product depends uniquely on the configuration of the catalyst or reagent. If the reaction starts with a chiral material the reaction will be enantiospecific If the reaction forms only one diastereoisomer (control of relative stereochemistry not absolute stereochemistry) it is diastereospecific A typical example is substitution by a SN2 reaction The reaction must proceed with inversion Me
Enantiospecific
O
SiPhMe2 N3
O
X
Me
SiPhMe2
NaN3 O
Me NaN3
OMs
O
Me
SiPhMe2
O
Me
N3
O Me
N N N Me
Diastereospecific
OsO4 CH2OH
HO Me
OH
H H CH2OH syn diastereoisomer
HO +
OH
H Me
CH2OH H syn diastereoisomer
O Ms =
S Me O
racemic mixture
Advanced organic
2
Stereoselectivity in organic synthesis • Stereoselective reactions - a reaction where one stereoisomer of a product is • •
formed preferentially over another. The mechanism does not prevent the formation of two or more stereoisomers but one does predominate. If a stereogenic centre is introduced into a molecule in such a way that diastereoisomers are produced in unequal amounts the reaction is diastereoselective If a chemical reaction produces the two enantiomers of a chiral product in unequal amounts it is as an enantioselective reaction O
Diastereoselective
HO Ph PhMgBr
Me
Me
+
Me
Ph H 91.5%
Ph H
O
Enantioselective
Me
HO Ph
H
Me2Zn (–)-DAIB (2%)
Me
Me
Ph H 8.5%
H OH
H OH
Me
+
95.5% (S) Me
Me
Me 4.5% (R)
91% ee NMe2 OH
Me
(–)-DAIB
Advanced organic
3
Stereospecific reactions • Initially, we will look at the general principles of stereo-specific and -selective reactions • This is intended to familiarize the terminology we have just covered and to instill a number of the basic principles we will be utilising in the rest of the course • In future lectures we will look at ‘asymmetric’ synthesis or various strategies for enantioselective synthesis
Enantiospecific reactions TsO Me Me S
Me OTs
KOH H2S
S Me
HS Me
Me
Me OTs
Me R
S Me
Me
R
Me
S
R
Me
• SN2 reaction occurs with complete inversion - retain stereochemical information • Very useful if we already have incorporated stereochemistry R Me
inversion
no change in stereochemistry; only name
Me R
O Li•H2N(CH2)2NH2
+
R O Me
OMe Me
>90%
S OH O OMe Me
Me
• Epoxides are excellent candidates for enantiospecific reactions • Highlights area of potential confusion: (R,S) nomenclature is independent of the
...chemical process occurring (stereochemistry at Me (R) inverted yet still (R)
Advanced organic
4
Stereospecific reactions II A number of very useful reactions of alkenes are diastereospecific Electrophilic epoxidation H
Ph
Ar O O
O
H Ph
Ph
O
m-CPBA H Ph
H (E)
H H Ph H
H
Ph
H anti
Ph
O
m-CPBA H Ph
Ph
Note: only controlling relative stereocheimstry NOT absolute stereochemistry
H Ph
syn
(Z)
• Epoxidation with peracids occurs via a concerted process • Results in conservation of alkene geometry • • •
Hydroboration Again occurs via a concerted reaction (bonds made & broken at same time) Observe syn addition of hydrogen and boron Further stereospecific transformations possible Ph
H BR2
Ph
Ph H BR2
syn addition
HOO
Ph H
H
BR2 O OH retention of stereochemistry
OH
Note: only controlling relative stereocheimstry NOT absolute stereochemistry
Advanced organic
5
Stereospecific reactions III • • •
Bromination Bromination of alkenes proceeds with the anti addition of Br2 across the double bond This is the result of the formation of a bromonium cation followed by SN2 attack The geometry of the starting material controls the stereochemistry of the product Me
H
H
Br2
Me
H
H
Me
Me H
Br
(E)
Br anti
Me
Br
Br Br
Br
(Z)
Me
Note: only controlling relative stereocheimstry NOT absolute stereochemistry
Me
H Br H
Br2
Me
Br
Me Br H
Me
Me
Me Me Me rotate central bond Br syn
Iodolactonisation • Proceeds in an analogous fashion via an iodonium species • Geometry of alkene controls relative stereochemistry O Me
O
O
H
Me
(E)
Me
I2
O O (Z)
H
I
I
I2
O
H
Me
I O
O
H I
Me
O anti
O
I Me
O syn
O
Advanced organic
6
Stereoselective reactions • •
Nucleophilic addition to C=O Reaction of a nucleophile with a chiral substrate gives two possible diastereoisomers Reaction is stereoselective if one diastereoisomer predominates LiAlH4 H3O+
O Me
H OH Me
R
H Ph 25% 2%
H Ph R = Me R = t-Bu
R
H OH +
Me
: :
H Ph 75% (50% de) 98% (96% de)
R
% de = diastereisomeric excess = [major] – [minor] = %major – %minor [major] + [minor]
Prochiral Nomenclature • Trigonal carbons that are not stereogenic centres but can be made into them are prochiral • Each face can be assigned a label based on the CIP rules
• If the molecule is chiral (as above) the faces are said to be diastereotopic • If the molecule is achiral (as below) the faces are enantiotopic O
clockwise Re face H 3
1 Ph 2
1
O
view from this face
H
view from this face Ph
Ph 2
O
anti-clockwise Si face H 3
Advanced organic
7
Felkin-Ahn model O
H OH EtMgBr
Ph
H
Ph
Et
HO H +
Me H 25%
Me H
Ph
Et
Me H 75% (50% de)
• The diastereoselectivity can be explained and predicted via the Felkin-Ahn model • It is all to do with the conformation of the molecule... • Easiest to understand if we look at the Newman projection of the starting material Ph O
O Ph
two substituents (C=O & Ph) are eclipsed - unfavoured
H
Me H
Me
H
H
• Rotate around central bond so that substituents are staggered • Continue to rotate around central bond and find 6 possible conformations • Two favoured as largest substituent (Ph) furthest from O & H Ph O
O H H
Me H
H O
Ph
O Me Me
H Me
largest substituent (Ph) furthest from O & H
Ph H
Me O
O Ph Ph
H H Ph
H H
largest substituent (Ph) furthest from O & H
Me H H
Advanced organic
8
Felkin-Ahn model II • Nucleophiles attack the carbonyl group along the Bürghi-Dunitz angle of ~107° Nu
R R
Nu
Nu R
C O
R
maximum overlap with π* - nucleophile attacks at 90° to C=O
R
C O
R
repulsion from full π orbital - nucleophile attacks from obtuse angle
C O
compromise, nucleophile attacks π* orbital at angle of 107°
• As a result of the Bürghi-Dunitz (107°) angle there are four possible trajectories for • •
the nucleophile to approach the most stable conformations Three are disfavoured due to steric hindrance of Ph or Me Therefore, only one diastereoisomer is favoured Bürghi-Dunitz angle: 107° O H close to Ph Nu
Ph
X
H Me
Me O
X
close to Me
Ph
unhindered approach H H
Nu
Nu
X
close to Ph Nu
• Favoured approach passed smallest substituent (H) when molecule in most stable ...conformation
Advanced organic
9
Felkin-Ahn model III Me O
O
Me OH
EtMgBr
Ph
Ph
H
Me H
Et H
H H
Et
rotate Ph H
Me
OH
HO H Ph
Et H
H
Ph
Et
Me H
• Apply the Felkin-Ahn model to our example • Most problems seem to occur when swapping between different representations... O
HO H EtMgBr
Ph
Ph
H
O
HO H EtMgBr H
Ph
Et
Me
O
HO H EtMgBr H
Ph Me H
Me H Me
H
Et
Me
OH
Et H
OH
H
Ph
4. Remember, we prefer to draw the main carbon chain in the plane of page, therefore, align Ph and Et in Newman projection as well
H HO H
Ph
Et H
Et
Ph
2. First, remember which parts of the molecule have not been effected by the reaction and draw them 3. As the original stereogenic centre has not changed, we will compare the relative orientation of the substituents on the new centre to these
H
HO
Me H
Me H
Ph
Et
Me H
Me H
Ph
1. So, assuming we have used the Felkin-Ahn model and Newman projections to predict the product, how do we draw the correct ‘zig-zag’ representation?
Ph Me H
Et
5. Me and OH on same side, therefore, as Me not effected by reaction & is ‘up,’ OH must be ‘up.’ This leaves both H down.
Advanced organic
10
Felkin-Ahn model IV M O
O L M S
M L
R Nu
S R
OH
Nu OH L
Nu S
L
R
R
M S
L = large group, M = medium group, S = small group
• To explain or predict the stereoselectivity of nuclophilic addition to a carbonyl group • •
with an adjacent stereogenic centre, use the Felkin-Ahn model Draw Newman projection with the largest substituent (L) perpendicular to the C=O Nucleophile (Nu) will attack along the Bürghi-Dunitz trajectory passed the least sterically demanding (smallest, S) substituent Draw the Newman projection of the product Redraw the molecule in the normal representation
• • • Whilst the Felkin-Ahn model predicts the orientation of attack, it does not give any information about the degree of selectivity • Many factors can effect this...
Advanced organic
11
Diastereoselective addition to carbonyl group O Ph
HO H RMgBr H
Me H R = Me R = Et R = Ph
Ph
O Me(metal)
Ph
R
Me H 40% de 50% de 60% de
H
HO H Ph
Me
Me H Me(metal) = MeMgI 33% de Me(metal) = MeTi(OPh)3 86% de
Me H
• The size of the nucleophile greatly effects the diastereoselectivity of addition • Larger nucleophiles generally give rise to greater diastereoselectivities • Choice of metal effects the selectivity as well, although this may just be a steric effect • The size of substituents on the substrate will also effect the diastereoselectivity • Again, larger groups result in greater selectivity • Should be noted that larger substituents normally result in a slower rate of reaction O Me H Ph R = Me R = Et R = i-Pr R = t-Bu
LiAlH4 R
H OH Me
R
H Ph 50% de 50% de 66% de 96% de
Advanced organic
12
Effect of electronegative atoms Me
OLi
O
Et
Me
OH
Me O
O
OMe
H
Et
OMe
NBn2
Me Et OLi
Bn2N
NBn2
H H
>92% de
Et
HO
OMe
Bn2N H
H
CO2Me
• It is hard to justify the excellent selectivity observed above using simple sterics • The Bn2N group must be perpendicular to C=O but a second factor must explain why •
the selectivity is so high (& the reaction much faster than previous examples) There is an electronic effect O Nu
O Y
Y Z
R
O
X
Nu Z
R X
Z = electronegative group
C=O π*
C–Z σ*
nucleophile interacts with π* orbital
new π*+σ* LUMO Y
Nu Z
R X
C–Z σ* C=O π* new π*+σ* LUMO
new low energy orbital formed from C=O & C-Z antibonding orbitals favours nucleophilic attack at carbonyl
• When an electronegative group is perpendicular to the C=O it is possible to get an
of the π* orbital and the σ* orbital • Overlap results in a new, lower energy orbital, more susceptible to nucleophilic attack • Thus if electronegative group perpendicular, C=O is more reactive Advanced organic ...overlap
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Effect of electronegative atoms II O Li R3BH
Et
O
HO H Ph
Et
Ph SMe
SMe
H OH Zn BH4
Et
H BR3
H Ph
O Et
Et
MeS Ph H
Ph SMe
Zn HO
MeS
Cram-chelation control
SMe
Felkin-Ahn attack O Et
Et
Ph
H
MeS
rotate to allow chelation
Ph H
H3B H
MeS O
MeS Et
H Ph
OH Et
H H
Ph
• A good example of this effect is shown • But as always, chemistry not that simple...
• If heteroatom (Z) is capable of coordination and...
...a metal capable of chelating 2 heteroatoms is present we observe chelation control • Metal chelates carbonyl and heteroatom together • This fixes conformation • Such reactions invariably occur with greater selectivity • Reactions are considerably faster • The chelating metal acts as a Lewis acid and activates the carbonyl group to attack • As shown, chelation can reverse selectivity! Advanced organic
14
Chelation control M
O M
L Z
L
Z
R S
Nu OH
O
R
R
S
Z
L
S
Nu Nucleophile attacks from least hindered face Z = heteroatom capable of coordination; M = metal capable of coordinating to more than one heteroatom
• Chelation controlled additions are easy to predict • Normally do not need to draw Newman projection (yippee!) • Simple example shown below
H Me O
O
PhMgI
H Me O HO Ph 96% de
Advanced organic
15
Chelation control II Me Ph2PO
NaBH4 MeOH, 20°C
Me Ph2PO
NaBH4, CeCl3 EtOH, –78°C
Me Ph2PO
Me
Me H OH
Me H OH
O
Ce O
O Me
O
Ph P O Ph
P
Ph Ph
H BH3 H Me
H3B H
H
Me Me
• Example shows normal Felkin-Ahn selectivity gives one diastereoisomer • Electronegative and bulky phosphorus group in perpendicular position • Chelation control gives opposite diastereoisomer • Chelation can occur through 6-membered ring • Lower temperature typical of activated, chelated carbonyl
Advanced organic
