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CHEM3115
Synthetic Medicinal
Chemistry
Lecture 2
Dr Chris McErlean
Rm 518a
C.McErlean@chem.usyd.edu.au
Lecture 19 Carbonyl Chemistry. Reducing reagents: Chemo and diatseteroselectivity;
Introduction to Felkin-Anh model.
Lecture 20 Carbonyl Chemistry. Organometallics: formation and reactivity; 1,2 vs 1,4
addition; Felkin-Anh vs Chelation control
Lecture 21 Carbonyl Chemistry. Enolates: formation, regioselectivity; silylenol ethers:
thermodynamic vs kinetic control; enolate geometry with LDA
Lecture 22 Carbonyl Chemistry. Enolates: Aldol reactions; diastereoselectivity via
Zimmerman Traxler transition states. Auxillary approach to enantioselectivity.
Lecture 23 Chemistry of other sp2 centres. Alkenes: synthesis via Wittig, Julia and
Metathesis (RCM and cross metathesis).
Lecture 24 Chemistry of other sp2 centres. Palladium in Contemporary Synthesis:
general mechanism, Suzuki, Stille, Negeshi, Sonogashira and Heck reactions.
Lecture 25 Workshop problems; Recap and review.
Lecture outline
Reminder
In lecture 1 we discussed selectivity.
•Chemoselectivity in the hydride reduction of carbonyls;
•Different hydride sources have different levels of reactivity
Lithium aluminium
hydride
LiAlH4
Lithium
borohydride
LiBH4
Sodium
borohydride
NaBH4
Diisobutyl aluminium
hydride
DiBAl-H ®
DiBAl
Reminder
In lecture 1 we discussed selectivity.
•Chemoselectivity in the hydride reduction of carbonyls;
•Different hydride sources have different levels of reactivity
•Diastereoselectivity in hydride reduction of carbonyls;
•Nucleophiles approach at 107o (Burgi-Dunitz angle);
•Small nucleophiles approach 5 and 6 membered rings from the axial direction,
(large nucleophiles approach from the equatorial direction);
•Nucleophiles approach bridged bicyclic compounds from the least hindered face;
•Diastereomeric outcome of nucleophilic attack on acyclic carbonyls bearing an a stereogenic centre
can be predicted using the Felkin-Anh model.
Felkin Anh Model.
If there is a stereogenic centre a to the carbonyl then:
•Draw the Newman projection with the stereogenic centre at the rear of the diagram;
•Rotate the group at the rear so that the large group is perpendicular to the carbonyl group
(there will be two possible conformations);
•The nucleophile will approach at the Burgi-Dunitz trajectory (107o) over the small group
(i.e. one conformation will react preferentially);
•Draw the product Newman projection;
•Draw the product in the standard fashion along the longest carbon chain.
Reminder
Organometallics: introduction
Other nucleophiles are capable of reacting with carbonyl groups, i.e. organometallic species.
RMgX R2CuLi RLi
Organomagnesium
„Grignard‟ reagents
Reactivity is determined by nature of organometallic species;
Both carbanion and metal parts contribute to reactivity.
Organocuprate
„Gilman‟ reagents
Organolithium
reagents
Organometallics: carbanion part
For organometallics with the same metal component, reactivity increases with decreasing “s” character.
If the orbital containing the lone pair (negative charge) has a lot of “s” character, then the
negative charge is held closer to the positively charged nucleus and is thus stabilised.
Alkyne: sp hybridized
50% “s” character
pKa ~ 26 pKa ~ 50
Alkane: sp3 hybridized
25% “s” character
Organometallics: carbanion part
Reactivity can mean:
Acting as a nucleophile
Or act as a base
Because alkyl groups are slightly electron donating (hyperconjugation)
they destabilise the carbanion; therefore they increase reactivity.
N.B. this is why tert-butyllithium is a stronger base than n-butyllithium
Organometallics: carbanion part
Electron withdrawing groups help to stabilise the negative charge therefore decrease reactivity.
Organometallics: carbanion part
Organometallics: metal part
Reactivity is determined by
nature of organometallic
species;
Both carbanion and metal parts
contribute to reactivity.
The larger the difference in
electronegativity between
the metal and the organic
parts, then the less
covalent (more ionic) is the
bond and the greater the
reactivity.
Order these organometallic species from most reactive to least reactive.
Order these organometallic species from most reactive to least reactive.
Organometallics: metal part
Organometallics: Formation
There are four main ways to make organometallics:
•Reductive replacement – e.g. Grignard synthesis
(Oxidative addition of the metal)
There are four main ways to make
organometallics:
•Reductive replacement – e.g. Grignard
synthesis
(Oxidative addition of the metal)
•Metal – hydrogen exchange (deprotonation;
because lots of organometallics are
commercially available)
Organometallics: Formation
Chelating/ directing group
ortho lithiation
There are four main ways to make
organometallics:
•Reductive replacement – e.g. Grignard
synthesis
(Oxidative addition of the metal)
•Metal – hydrogen exchange (deprotonation;
because lots of organometallics are
commercially available)
•Metal – halogen exchange
Organometallics: Formation
There are four main ways to make
organometallics:
•Reductive replacement – e.g. Grignard
synthesis
(Oxidative addition of the metal)
•Metal – hydrogen exchange (deprotonation;
because lots of organometallics are
commercially available)
•Metal – halogen exchange
•Metal – metal exchange
Organometallics: Formation
Organometallics: Regioselectivity
Organometallics: Regioselectivity
Resiniferatoxin
(Potent analgesic)
Paul Wender
Stanford University
Organometallics: Diastereoselectivity
Diastereoselective nucleophilic additions to some cyclic compounds:
Most organometallics can be
regarded as large
nucleophiles, therefore they
approach carbonyl on six
membered rings from the
equatorial direction
Large nucleophiles approach
carbonyl on five membered
rings from the pseudo-
equatorial direction, but
selectivity is bad to due
flexibility of ring.
Due to steric clash,
nucleophiles must approach
bridged bicyclic compounds
from the least hindered face.
Organometallics: Diastereoselectivity
Organometallics: Diastereoselectivity
Felkin Anh Model.
If there is a stereogenic centre a to the carbonyl then:
•Draw the Newman projection with the stereogenic centre at the rear of the diagram;
•Rotate the group at the rear so that the large group is perpendicular to the carbonyl group
(there will be two possible conformations);
•The nucleophile will approach at the Burgi-Dunitz trajectory (107o) over the small group
(i.e. one conformation will react preferentially);
•Draw the product Newman projection.
•Draw the product in the standard fashion along the longest carbon chain.
Organometallics: Diastereoselectivity
The effect of electronegative atoms.
The electronegative NBn2 group appears to be acting as the L substituent
Organometallics: Diastereoselectivity
There is more than sterics operative here (notice the dr is very high).
Conformations of a-chiral carbonyl compounds that place an electronegative atom perpendicular to
the C=O bond will be more reactive.
This is an electronic effect
Organometallics: Diastereoselectivity
•Acyclic carbonyl with an a-stereogenic centre:
Felkin Anh
•Atom at the a position is an electronegative element:
It must be considered as the large group.
Organometallics: Diastereoselectivity
Organometallics: Diastereoselectivity
Chelation can reverse selectivity
In this example the selectivity
follows normal Felkin-Anh control (justify
it to yourself)
If the counter ion is changed to one that can
interact with sulfur we get the alternative
daistereoisomer.
Two things are needed for chelation to occur.
- A heteroatom with lone pairs available for coordination to a metal
- A metal atom that prefers to coordinate to more than one heteroatom at once.
These are mainly more highly charged ions.
- Usually only 5- or 6-membered chelates are formed.
Organometallics: Diastereoselectivity
Other pertinent examples
Note a higher diastereoselectivity with chelation control versus Felkin Anh control.
Chelation controlled diastereoselectivity is higher due to a cyclic transition state.
As the size of R increases, chelation is more difficult. Thus diastereoselectivity is affected and the rate of
the addition reaction becomes slower. Chelation increases the rate of reaction at the carbonyl group.
Organometallics: Diastereoselectivity
Explain why two different reducing agents give diastereomeric products.
Organometallics: Diastereoselectivity
Organometallics: Diastereoselectivity
Organometallics: Diastereoselectivity
Al3+ can chelate;
6-membered ring.
Explain why two different reducing agents give diastereomeric products.
Under Felkin-Anh control
Under chelation control
Organometallics: Diastereoselectivity
Summary
Organometallics:
•Relative reactivities as a consequence of carbanion and metal fragment.
•Carbanion : sp3 > sp2 > sp
•sp3 carbanions : more electron donating groups increase reactivity, more electron
withdrawing groups decrease reactivity.
•Metal : reactivity Li > Mg > Cu due to electronegativity differences.
•Regioselectivity as a consequence of nature of the carbon-metal bond.
•organocuprates react in a 1,4-manner.
•Organomagnesium and organolithitiums react in a 1,2- manner.
•Diastereoselectivity on cyclic and acyclic systems:
•Equatorial attack of nucleophile on 5 and 6 membered rings.
•Attack form least hindered face on bridged bicyclic compounds.
•Felkin-Anh control on acyclic systems.
•Felkin-Anh model expanded to cover electronegative elements at the a-position and
chelation control
Next time
The exciting world of enolate chemistry
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