stereoselectivity in organic synthesis - massey …gjrowlan/stereo2/lecture3.pdf ·...
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123.702 Organic Chemistry
Stereoselectivity 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! e.g. SN2 reactions
• 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 predominates.
• Diastereoselective reactions - a stereogenic centre is introduced into a molecule in such a way that diastereoisomers are produced in unequal amounts
1
MeMe
HPh
HO PhMe
MeHPh
HO Ph
91.5% 8.5%
+MeMe
O
HPh
PhMgBr
• Enantioselective reactions - a reaction that produces two enantiomers of a...product in unequal amounts
MeOHNMe2
MeMe
(–)-DAIB
Me
H OH
Me
H OH
95.5% (S) 4.5% (R)
+H
O Me2Zn(–)-DAIB (2%)
91% ee
123.702 Organic Chemistry
view from this face HPh
O
2 3
1
anti-clockwiseSi faceH Ph
O
23
1
H Ph
O
23
1
Stereoselective reactionsNucleophilic addition to C=O
• Reaction of a nucleophile with a chiral substrate gives two possible diastereoisomers• Reaction is stereoselective if one diastereoisomer predominates
2
MeR
O
H Ph
LiAlH4H3O+
MeR
H Ph
H OHMe
RH Ph
H OH+
R = MeR = t-Bu
75% (50% de)98% (96% de)
25%2%
::
O
PhH
view from this face
clockwiseRe face
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
% de = diastereisomeric excess = [major] – [minor]
[major] + [minor]
= %major – %minor
123.702 Organic Chemistry
Ph
Me
H H
O
Ph
Me
H H
O
Ph
H
MeH
O
Ph
H
MeH
O
PhH
O
Me H
PhH
O
Me H
Ph
HMe H
O≡ two substituents (C=O & Ph) are eclipsed - unfavoured
Felkin-Ahn model
• 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
3
PhH
O
Me H
EtMgBr PhEt
Me H
PhEt
Me H
H OH HO H
25% 75% (50% de)
+
• Rotate around central bond so that substituents are staggered
• Two favoured as largest substituent (Ph) furthest from O & H• Continue to rotate around central bond and find 6 possible conformations
Me
Ph
HH
O
Me
H
Ph H
O
H
Me
PhH
O
H
Ph
Me H
O
largest substituent (Ph) furthest from O & H
largest substituent (Ph) furthest from O & H
123.702 Organic Chemistry
C ORR
C ORR
Nu
C ORR
C ORR
Nu
Felkin-Ahn model II
• 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
4
• Nucleophiles attack the carbonyl group along the Bürghi-Dunitz angle of ~107°
maximum overlap with π* - nucleophile attacks at
90° to C=O
C ORR
Nu
C ORR
repulsion from full π orbital - nucleophile
attacks from obtuse angle
compromise, nucleophile attacks π* orbital at angle
of 107°
Ph
H
MeH
O
Ph
Me
H H
O
Nu NuNu Nu
Bürghi-Dunitz angle: 107°
Ph
H
MeH
O
Ph
Me
H H
O
Nu NuNu Nu
close to Ph
close to Ph
close to Me
unhindered approach
X X X
• Favoured approach passed smallest substituent (H) when molecule in most stable...conformation
123.702 Organic Chemistry
Felkin-Ahn model IV
• 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 affect this...
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LR
O
M S
L
M
S R
O
Nu
L
M
S
OH
Nu
R
LR
M S
Nu OH
L = large group, M = medium group, S = small group
123.702 Organic Chemistry
Diastereoselective addition to carbonyl group
• 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
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PhR
Me H
HO HPh
H
O
Me H
RMgBr
R = MeR = EtR = Ph
40% de50% de60% de
PhMe
Me H
HO HPh
H
O
Me H
Me(metal)
Me(metal) = MeMgIMe(metal) = MeTi(OPh)3
33% de86% de
MeR
O
H Ph
MeR
H Ph
H OH
R = MeR = EtR = i-PrR = t-Bu
50% de50% de66% de96% de
LiAlH4
123.702 Organic Chemistry
Effect of electronegative atoms
• 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
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Me
EtNBn2
O
H
OLi
OMeMe
EtNBn2
OH
OMe
O
>92% de
Bn2N
HH
OMe
EtOLi
OMeBn2N
H
HO
H
MeEt
CO2Me
• Overlap results in a new, lower energy orbital, more susceptible to nucleophilic attack• Thus if electronegative group perpendicular, C=O is more reactive
ZY
X
O
RNu
Z = electro-negative group
• When an electronegative group is perpendicular to the C=O it is possible to get an...overlap of the π* orbital and the σ* orbital
Z
Y
X
O
RNu
C=O π*
C–Z σ*
nucleophile interacts with π* orbital
C=O π*
C–Z σ*
new π*+σ* LUMO
Z
Y
X
O
RNu
new π*+σ* LUMO
new low energy orbital formed from C=O & C-Z anti-bonding orbitals favours nucleophilic attack at carbonyl
123.702 Organic Chemistry
Et
MeS
H Ph
OZn
rotate to allow
chelationMeS
Et
HPh
O
PhEt
O
SMe
ZnPh
Et
SMe
H OHBH4
PhEt
O
SMe
Li R3BHPh
Et
SMe
HO H
Effect of electronegative atoms II
• A good example of the previous effect is shown on the left hand-side• But as always, chemistry not that simple...
8
MeS
Et
HPh
O
H BR3
MeS
Et
H
HO
H
Ph
Felkin-Ahn attack
Cram-chelation control
Et
MeS
H
OH
H
PhHH3B
• 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!
123.702 Organic Chemistry
Chelation control
• Chelation controlled additions are easy to predict• Normally do not need to draw Newman projection (yippee!)• Simple example shown below
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LR
Nu OH
Z S
MR
OZ
M
S L
LR
O
Z S
Z = heteroatom capable of coordination; M = metal capable of coordinating to more than one heteroatom
NuNucleophile attacks
from least hindered face
O
H
O
Me PhMgI
O
HMe
HO Ph96% de
123.702 Organic Chemistry
Me
Me
Ph2PO
H OH
NaBH4, CeCl3EtOH, –78°C
Me
OMe
Ph2POMe
Me
Ph2PO
H OH
NaBH4MeOH, 20°C
Chelation control II
• Example shows normal Felkin-Ahn selectivity gives one diastereoisomer• Electronegative and bulky phosphorus group in perpendicular position
10
• Chelation control gives opposite diastereoisomer• Chelation can occur through 6-membered ring• Lower temperature typical of activated, chelated carbonyl
P
Me
H
O
Me
O
PhPh
H BH3 Me
P
H
O
HH3BMe
O
PhPh
Ce
123.702 Organic Chemistry
Felkin-Ahn control in total synthesis
• An example of the Sakurai reaction from the synthesis of preswinholide A• Preswinholide A is effectively the monomer of swinholide A (the dimer), a compound
displaying potent cytotoxic activity that was isolated from a Red Sea sponge• Ian Paterson, Richard A. Ward, Julian D. Smith, John G. Cumming and Kap-Sun
Yeung, Tetrahedron, 1995, 51, 9437
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OMe
OMe
Me
OSiO
Me
MeH
Ot-Bu
t-Bu
Me3Si Me+
TiCl4, DCM, –90°C
94%95% d.e.
OMe
OMe
Me
OSiO
Me
Me
OHt-Bu
t-BuMe
Me
HH
OCl3TiH
O
SiMe3MeOMe
OMe
Me
HO
HOMe
Me
OH OHMe
MeO
OOH
MeHO
O
preswinholide
123.702 Organic Chemistry
n-C4H9
BnO
H H
OTiCln
BnO
n-C4H9
HH
O
n-C4H9 H
O
OBn
+OMe
OSiMe3 n-C4H9
OH
OBnOMe
OTiCl4, –78°C, DCM
77%100% de
Chelation control in total synthesis
• An example of the Mukaiyama aldol reaction• Comes from the synthesis of canadensolide, a fungicidal agent• Yung-Son Hon & Cheng-Han Hsieh, Tetrahderon, 2006, 62, 9713
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O
O
O
On-C4H9
H H
canadensolide
n-C4H9
BnO
H
OH
HMe3SiO
MeOO
MeO