stereospecificity in organic synthesisgjrowlan/stereo/lecture3.pdfadvanced organic me o o ome meme...
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Advanced organic
O
Me SiPhMe2
N3
MeO O
Me SiPhMe2
N3
MeO
N N N
O
Me SiPhMe2
OMs
MeO
NaN3
O
Me SiPhMe2
N3
MeO
NaN3
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
1
Ms = SO
OMe
Enantiospecific
Diastereospecific
Me
CH2OH
OsO4HO
HMe H
CH2OH
HO
MeH CH2OH
H
OH OH+
syn diastereoisomer
syn diastereoisomer
racemic mixture
X
Advanced organic
Me
H OH
Me
H OH
95.5% (S) 4.5% (R)
+
MeMe
HPh
HO PhMe
MeHPh
HO Ph
91.5% 8.5%
+MeMe
O
HPh
PhMgBr
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
2
Diastereoselective
Enantioselective H
O Me2Zn(–)-DAIB (2%)
MeOHNMe2
MeMe
(–)-DAIB
91% ee
Advanced organic
Me
O
O
OMe
Me Me
Li•H2N(CH2)2NH2O OMe
Me Me
Me
OHR
R
S
R
+>90%
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
3
Enantiospecific reactions
Me Me
TsO OTs KOHH2S
Me Me
HS OTs
SMe Me
Me Me
S S R SR R
MeMeMeMe
• SN2 reaction occurs with complete inversion - retain stereochemical information• Very useful if we already have incorporated stereochemistry
• 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)
no change in stereochemistry;
only name
inversion
Advanced organic
PhHBR2
O OH
PhHOH
HOO
retention of stereochemistry
PhHBR2
syn addition
Ph HBR2
PhH
PhH
Om-CPBA
syn
PhH
HPh
Om-CPBA
anti
Ph
HH
Ph(Z)
Ph
PhH
H(E)
Ph HPhH
OOOH
Ar
Stereospecific reactions II
• 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
4
A number of very useful reactions of alkenes are diastereospecific
Electrophilic epoxidation
Note: only controlling relative
stereocheimstry NOT absolute
stereochemistry
Note: only controlling relative
stereocheimstry NOT absolute
stereochemistry
Advanced organic
I
Me O Osyn
OOH
Me I2
(Z)
I
Me O O H
I
Me O OantiI
MeMe
Br
Brsyn
rotate central bond
Br2H
Me Me
HBrBr
Me
Br
MeBr
H
Me Me
H
(Z)
MeMe
Br
Branti
Br2Me
H Me
HBr
Br
Me
H Me
H
(E)
Stereospecific reactions IIIBromination
• 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
5
Iodolactonisation• Proceeds in an analogous fashion via an iodonium species• Geometry of alkene controls relative stereochemistry
Note: only controlling relative stereocheimstry NOT
absolute stereochemistry
OOHMe
I2
(E) OOHMe
I
Advanced organic
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
6
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
Advanced organic
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
7
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
Advanced organic
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
8
• 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
Advanced organic
Ph
Me
H
OH
Et
H
Ph
Me
H
OH
Et
H
PhEt
Me H
HO HPh
EtMe H
HO HPh
EtMe H
HO H
PhEt
Me H
HO HPh
Me
H H
O
PhH
O
Me H
EtMgBr
Felkin-Ahn model III
• Apply the Felkin-Ahn model to our example• Most problems seem to occur when swapping between different representations...
9
PhEt
Me H
HO HPh
H
O
Me H
EtMgBr 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?
PhEt
Me H
HO HPh
H
O
Me H
EtMgBr2. First, remember which parts of the molecule have not been effected by the reaction and draw them3. As the original stereogenic centre has not changed, we will compare the relative orientation of the substituents on the new centre to these
Ph
Me
H
H
HO
Et
PhEt
Me H
HO HPh
H
O
Me H
EtMgBr 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
Ph
Me
H
OH
Et
H
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.
Et
Ph
Me
H
OH
Et HPh
Me
H
OH
Et
H
rotate
Advanced organic
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 effect this...
10
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
Advanced organic
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
11
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
Advanced organic
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
12
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
Advanced organic
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 this effect is shown• But as always, chemistry not that simple...
13
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!
Advanced organic
Chelation control
• Chelation controlled additions are easy to predict• Normally do not need to draw Newman projection (yippee!)• Simple example shown below
14
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
Advanced organic
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
15
• 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