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STEREOSELECTIVE SYNTHESIS NOTES
Definitions
Chemoselectivity –
We can envisage two modes:
a) Substrate selectivity. Preferential reaction of one of several functional groups in the
molecule with the reagent. In general the less reactive the reagent the more selective the
reaction of chemically similar functional groups that can be achieved.
b) Product selectivity. In the case where reaction of a functional group can lead to several
chemically distinct products, this occurs when a non-statistical ratio of products is
observed.
Regioselectivity –
Preferential formation of one structural isomer over any others.
Stereoselectivity –
Preferential formation of one stereoisomer over any others. Obviously a diastereoselective
reaction leads to the preferential formation of one diastereoisomer and an enantioselective
reaction leads to the preferential formation of one enantiomer.
The term stereospecific is used in two instances:
(i) For a reaction where a single stereoisomer is converted completely to a single
product stereoisomer. Textbook definitions define a process as being stereospecific
only when starting materials differing only in their configuration are converted to
stereoisomerically different products.
(ii) Can also be applied to a process that is completely stereoselective.
Topicity
Groups or faces of a molecule may display topicity. Strict definitions refer to whether such groups
/ faces are interchangeable by particular types of symmetry operations, but it is more useful to
consider the concept in relation to the outcome of possible “future” reactions.
Prochirality
When replacement of one of a pair of groups or reaction on one of two molecular faces leads to
the formation of a chiral material then these groups / faces are termed prochiral. Prochirality
descriptions to both groups and faces can be assigned by the use of the standard Cahn-Ingold-
Prelog rules. These are very useful, particularly when considering addition reactions.
Faces:
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, -2-
Groups:
Give the group under consideration priority over the other enantiotopic group, and then rank as
normal with the CIP rules:
Umpolung Chemistry
Polarity reversal. Some common examples follow:
Dithianes:
Enol Ethers:
Wittig Reagents:
Silicon Reagents:
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
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, -3-
Alcohol Carbanion Equivalents:
Cyanide:
Selectivity of Enolate Formation
(More on this can be found further on)
Kinetic Control – enolate composition is governed by the relative rates of proton abstraction.
Thermodynamic Control – enolate composition is governed by the relative stabilities of the
enolates.
Kinetic Enolates
Usually the less substituted enolate.
Favoured by rapid irreversible deprotonation at low temperatures. Use of bulky bases favours
kinetic deprotonation at the least hindered site, e.g. LDA, ButLi. Li is usually used as the
counterion since the higher covalent character prevents equilibration.
Thermodynamic Enolates
Usually the more substituted enolate.
Former at higher temperature under conditions of reversible deprotonation, e.g. in the presence
of a weak acid. Judged as the more stable enolate by consideration as an olefin: increased
substitution increases the stability.
Diastereoselectivity in Additions to Acyclic RCHO and R2CO
1,2 Asymmetric Induction
The influence of a chiral centre α to the carbonyl group.
Cram’s Rule and Modifications
A purely empirical rule. The three substituents on the α carbon are ranked L (large), M (medium),
and S (small) in terms of steric bulk. The carbonyl compound is presumed to react in a
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
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, -4-
conformation where the largest (L) of the substituents on the α carbon is eclipsed with the
carbonyl substituent R (hydrogen in the case of aldehydes). The direction of nucleophilic attack is
then predicted to be the same side of the carbonyl as the small substituent, S, rather than attack
form the side of the medium substituent M.
Although this rule has great utility there are significant exceptions to it. The following points are
notable:
(a) No distinction is made between ground state and reactive conformations. The postulate
that conformation A makes a significant contribution to the ground state conformation is
unlikely.
(b) In view of the low rotational barriers around C-C bonds then more than one reactive
conformation may be involved (by the Curtin-Hammett Principle). The likelihood that
amongst thermally available conformations that conformation A makes a significant
contribution is small since conformation A leads to fully eclipsed conformations B and C.
(c) The substituents on the α carbon are classified merely with respect to their steric bulk;
any dipolar effects are ignored.
Modifications:
(i) Cornforth’s dipolar model suggests that any electronegative substituent on the α
carbon will preferentially occupy the L position – due to favourable dipolar
interactions. Nucleophilic addition then occurs from the less hindered face.
(ii) Chelation Model is used in the case of an α substituent that is capable of binding to
the metal (itself complexed with the carbonyl group), e.g. α alkoxy, hydroxy and
amino carbonyls. Chelate formation occurs prior to addition of the organometallic to
the carbonyl group. This subsequently occurs to the less hindered face of the chelate
– this may result in induction that is opposite to that predicted by the simple Cram’s
Rule.
Chelation (a) enhances the electrophilic nature of the carbonyl and (b) prevents
rotation about the C-C bond and compels the nucleophile to add from the least
hindered face.
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
STEREOSELECTIVE SYNTHESIS NOTES
Definitions
Chemoselectivity –
We can envisage two modes:
a) Substrate selectivity. Preferential reaction of one of several functional groups in the
molecule with the reagent. In general the less reactive the reagent the more selective the
reaction of chemically similar functional groups that can be achieved.
b) Product selectivity. In the case where reaction of a functional group can lead to several
chemically distinct products, this occurs when a non-statistical ratio of products is
observed.
Regioselectivity –
Preferential formation of one structural isomer over any others.
Stereoselectivity –
Preferential formation of one stereoisomer over any others. Obviously a diastereoselective
reaction leads to the preferential formation of one diastereoisomer and an enantioselective
reaction leads to the preferential formation of one enantiomer.
The term stereospecific is used in two instances:
(i) For a reaction where a single stereoisomer is converted completely to a single
product stereoisomer. Textbook definitions define a process as being stereospecific
only when starting materials differing only in their configuration are converted to
stereoisomerically different products.
(ii) Can also be applied to a process that is completely stereoselective.
Topicity
Groups or faces of a molecule may display topicity. Strict definitions refer to whether such groups
/ faces are interchangeable by particular types of symmetry operations, but it is more useful to
consider the concept in relation to the outcome of possible “future” reactions.
Prochirality
When replacement of one of a pair of groups or reaction on one of two molecular faces leads to
the formation of a chiral material then these groups / faces are termed prochiral. Prochirality
descriptions to both groups and faces can be assigned by the use of the standard Cahn-Ingold-
Prelog rules. These are very useful, particularly when considering addition reactions.
Faces:
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -2-
Groups:
Give the group under consideration priority over the other enantiotopic group, and then rank as
normal with the CIP rules:
Umpolung Chemistry
Polarity reversal. Some common examples follow:
Dithianes:
Enol Ethers:
Wittig Reagents:
Silicon Reagents:
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -3-
Alcohol Carbanion Equivalents:
Cyanide:
Selectivity of Enolate Formation
(More on this can be found further on)
Kinetic Control – enolate composition is governed by the relative rates of proton abstraction.
Thermodynamic Control – enolate composition is governed by the relative stabilities of the
enolates.
Kinetic Enolates
Usually the less substituted enolate.
Favoured by rapid irreversible deprotonation at low temperatures. Use of bulky bases favours
kinetic deprotonation at the least hindered site, e.g. LDA, ButLi. Li is usually used as the
counterion since the higher covalent character prevents equilibration.
Thermodynamic Enolates
Usually the more substituted enolate.
Former at higher temperature under conditions of reversible deprotonation, e.g. in the presence
of a weak acid. Judged as the more stable enolate by consideration as an olefin: increased
substitution increases the stability.
Diastereoselectivity in Additions to Acyclic RCHO and R2CO
1,2 Asymmetric Induction
The influence of a chiral centre α to the carbonyl group.
Cram’s Rule and Modifications
A purely empirical rule. The three substituents on the α carbon are ranked L (large), M (medium),
and S (small) in terms of steric bulk. The carbonyl compound is presumed to react in a
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
, -4-
conformation where the largest (L) of the substituents on the α carbon is eclipsed with the
carbonyl substituent R (hydrogen in the case of aldehydes). The direction of nucleophilic attack is
then predicted to be the same side of the carbonyl as the small substituent, S, rather than attack
form the side of the medium substituent M.
Although this rule has great utility there are significant exceptions to it. The following points are
notable:
(a) No distinction is made between ground state and reactive conformations. The postulate
that conformation A makes a significant contribution to the ground state conformation is
unlikely.
(b) In view of the low rotational barriers around C-C bonds then more than one reactive
conformation may be involved (by the Curtin-Hammett Principle). The likelihood that
amongst thermally available conformations that conformation A makes a significant
contribution is small since conformation A leads to fully eclipsed conformations B and C.
(c) The substituents on the α carbon are classified merely with respect to their steric bulk;
any dipolar effects are ignored.
Modifications:
(i) Cornforth’s dipolar model suggests that any electronegative substituent on the α
carbon will preferentially occupy the L position – due to favourable dipolar
interactions. Nucleophilic addition then occurs from the less hindered face.
(ii) Chelation Model is used in the case of an α substituent that is capable of binding to
the metal (itself complexed with the carbonyl group), e.g. α alkoxy, hydroxy and
amino carbonyls. Chelate formation occurs prior to addition of the organometallic to
the carbonyl group. This subsequently occurs to the less hindered face of the chelate
– this may result in induction that is opposite to that predicted by the simple Cram’s
Rule.
Chelation (a) enhances the electrophilic nature of the carbonyl and (b) prevents
rotation about the C-C bond and compels the nucleophile to add from the least
hindered face.
These Notes are copyright Alex Moss 2003. They may be reproduced without need for permission.
www.alchemyst.f2o.org
