Download ADVANCED SYNTHESIS Stereochemistry

Lecture 1
ADVANCED SYNTHESIS
Stereochemistry
Introduction
• One of the most important issues in modern organic synthesis
• Most natural compounds are enantiomerically pure
• Frequently different enantiomers have different biological properties
O
• two possible
compounds
N
O
O
N
H
O
(S)-thalidomide
• Only one stereocentre so two possible compounds
OH
HO
OH
HO
O
OH
D-glucose
• Glucose has four stereocentres so 24 = 64 possible diastereoisomers
• So need effective means of isolating the one compound we want
Resolution
• The separation of enantiomers
• Can be achieved by chiral chromatography
• Can be achieved by selective recrystallisation (although this requires luck)
• Can be achieved by derivatisation
• Convert enantiomers into diastereoisomers
• 2 enantiomers can not be separated
by standard chromatography
• Equivalent by nmr and all physical
data except optical rotation
CO2Me
F 3C
OMe
HN
+
NH2
O
O
CO2Me
Ph
+
Cl
CO2Me
F 3C
OMe
F 3C OMe
• Diastereoisomers, physically different
and seperable by chromatography
HN
Ph
O
• Biggest disadvantage with such a route is the waste
• Maximum yield of 50 % as the wrong enantiomer is discarded
• So various methods have been developed for stereoselective synthesis
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis
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Lecture 1
Stereoselective Organic Chemistry
• There a five broad strategies for the synthesis of optically pure compounds
• Over the next few lectures we will look at:
1. The Chiral Pool (chiral starting materials) (1/2 lecture)
2. Substrate Control (1/2 lecture)
3. Chiral Auxiliaries (1 lecture)
4. Chiral Reagents (1 lecture)
5. Chiral Catalysis (2 lectures)
The Chiral Pool
(Chiral Starting Materials)
Substrate
do chemistry
Functionality
• use existing
stereochemistry
Substrate
Modified
• Use the stereochemistry available in readily available natural materials
• Most commonly used materials used are amino acids and carbohydrates
• Remember you can destroy stereocentres by oxidation, reduction and displacement
• Wasteful but sometimes useful
-Amino Acids
NHBoc
NH2
NHBoc
NH
CO2H
O
Cl
DCC
Ph
N
Cl
O
Ph
HBr-AcOH
O
N
Cl
Ph
C N
• a coupling reagent
that activates /
dehydrates acids
• Synthesis of the pharmaceutically important benzodiazepines
• Incorporate stereocentre from alanine
• Amino acids used to prepare chiral auxiliaries and chiral ligands (the use
of which should become apparent)
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis
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O
H
N
Lecture 1
Carbohydrates
• Carbohydrates are (frequently) cheap, readily available materials
• Contain up to 5 stereocentres so offer plently of opportunity
• Ideally use all stereocentres
• Swern oxidation
OH
3
HO 2
1. TBS-Cl, base
2. acetone, H+
4 OH
O
O
OH
OH
BnO 1 O 5
1. DMSO, (COCl)2
then Et 3N
2. NaBH4
3. Ms-Cl, Et3N
4. NaN3
BnO
O
N3
• SN2
OTBS
O
O
BnO
OTBS
O
benzyl D-mannose
• acetal formation (2nd year)
• Swern & Wittig
(2nd year)
1. TBAF
2. DMSO, (COCl)2 then Et3 N
3. Br–Ph 3P+ CHCHO
• deprotection
CHO
O
O
O
1. Pd / black, H2,
AcOH
H
N
O
H H
N
O
1. Pd / C, H 2
O
N3
H
BnO
HO
O
BnO
H
O
CHO
• acetal hydrolysis
HO
1
O
+
1. H3 O
O
3
2
N
HO
N
4
H
H
HO
5
HO
swainsonine
• Due to the ready availability of carbohydrates and their low cost frequently destroy chirality
to get desired compound
• Glyceraldehyde intermediate derived from D-mannitol (open chain form of mannose)
• Used in preparation of Tomolol, a potent β-adrenergenic blocking agent
OH
O
MeO
O
O
SnCl2
O
OH
HO
OH
NaIO4
D-mannitol
OH
OH
tBuHN
O
O
OH
OH
O
O
OH
OMe
tBuHN
O
O
O
N
N
N
S
• only one of the 5 stereocentres remains
• yet a profitable synthesis
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis
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Lecture 1
• Carbohydrate used in the synthesis of a fragment of indanomycin antibiotic
• Destroy 2 chiral centres
• But use one of the remaining centres to form two new ones
• Transfer / induction of chirality
OH
HO
OH
O
O
OH
O
TsO
O
O
O
O
laevoflucosan
• Ireland-Claisen rearrangement
OTMS
O
O
H
CO2H
O
OTMS
O
OTMS
O
OTMS
O
• Which brings us nicely on to....
Substrate Control
New chirality
Substrate
do chemistry
Substrate
Existing chirality
Existing chirality
• Use of chirality present within the substrate to control the introduction of new chirality
• This is a diastereoselective reaction
• If the starting material is enantiopure then the product will be enantiomerically pure
• Last year you would have briefly met:
Felkin-Ahn Model
O
Nuc–
L
R
M
Nuc
OH
L
R
M
S
S
• place largest substituent
perpendicular to carbonyl
S
O
O
L
Nuc
M
OH
M
OH
L
M
L
M
Nuc
R
R
Nuc
L
S
R
R
minor
major
Nuc
S
S
minor
major
• nucleophile will attack
along Bürgi-Dunitz angle
passed smallest group
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis
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Lecture 1
• Stereochemistry of the substrate influences the face of the carbonyl the nucleophile adds to
• If there is chelating heteroatom:
Cram-Chelation Control
• chelating metal
or Lewis acid
Met
OH
PO O
O
OP
R
S
L
≡
L
Nuc S
• again attacks passed
smallest group
PO
L
Nuc
R
S
R
• There are many other directing effects
• In Steve Caddick's course last year you would have seen conjugate (Michael) additions
O
O
• nucleophile
approaches from
least hindered
face
1. LiCuMe2
Epoxidation
• Allylic alcohols undergo diastereoselective epoxidation
• If we use a free hydroxyl group then the peracid hydrogen bonds to the hydroxyl group
• Results in a pseudo-intramolecular reaction
• If alcohol is protected then epoxidation occurs from least hindered face
OH
OR
mCPBA, R = H
OAc
mCPBA, R = Ac
O
O
O
H
H
O
O
O
Ar
What have we learnt?
• It is very important to perform stereoselective synthesis
• It can be achieved in a number of ways
• Resolution is (normally) wasteful
• Utilising the chiral pool allows incorporation of stereochemistry
• Substrate control allows diastereoselective reactions
As you may have noticed there are some gaps in the notes. A fully annoted
version will be placed on the Web at the end of course.
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Advanced Synthesis
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