The document provides information about various carbon-carbon bond forming reactions including the aldol reaction, Claisen condensation, Dieckmann cyclization, Robinson annulation, and the Hajos-Parrish-Eder-Sauer-Wiechert reaction. It discusses how to control the chemoselectivity of reactions and outlines strategies like choosing the correct nucleophile or pre-forming enolates. Functional groups in specific arrangements like a 1,3-diol relationship indicate certain reaction types. The key message is that retrosynthesis involves recognizing underlying patterns in molecular structures.

1. 123.312FUNCTIONALGROUP enolates as nucleophile...
INTERCONVERSIONS
previously, we had looked
functional group at enolates...
CHAPTER 11
interconversions
Li O
O
R X Li X
CHAPTER eleven R
the aldol reaction &
conjugate additions
E
the carbonyl as electrophile... combine
the two...
previously, we had
looked attack on the
carbonyl group
O HO Cnuc
Cnuc “the aldol reaction”
R1 R2 R1 R2
©marvel/sony pictures
©Anchor Bay Entertainment
The aldol reaction The aldol reaction
O O NaOH OH O O O NaOH OH O
it can go further in a
O
this is the original/simplest reaction known as the aldol O
aldol reaction condensation & generate an
enone
THE ALDOL REACTION IS THE KING
OF C-C BOND FORMING REACTIONS

2. mechanism of the aldol reaction mechanism of the aldol condensation
O
O H H O HO O
enolisation OH O
HO
H
O the problem
H
you should know the HO elimination
with the aldol
mechanism by now!
reaction
O O
OH O H H O O this is the base-mediated
elimination. It can also be achieved
under acidic conditions
©caro wallis@flickr
how do we control chemoselectivity? & that number
increases if we consider
enantiomers
OH O O OH
O
O
O OH OH O
possible solutions
if we have two different carbonyl
compounds we can form four different products
(two homo-coupling & two cross coupling
products) ©kevin steele@flickr
correct choice of nucleophile correct choice of nucleophile correct choice of electrophile
O esters are more reactive
O O
enolates, so will preferentially
act as nucleophiles
aldehydes are most
R R R1 R2 electrophilic
enolate nucleophilicity enolate nucleophilicity carbonyl electrophilicity
O O O O O O O O O
> > > > > >
EtO C H EtO C H C1 H C1 C2 C1 OEt

3. correct choice of reagents (no pre-form enolate...
choice of reaction)
O O O OH O O
EtO EtO Et H Li
O LDA O
only one
aldehyde better NaOH
enolisable
carbonyl
R2 R2
electrophile than R1 R1
bulky ketone
OH O
correct choice allows another solution is to form the enolate first,
selective transformations. performing the reaction at low temperature to
alternatively... slow/prevent self-condensation
©fe ilya@flickr
...then add Electrophile Synthesise an enolate equivalent add Electrophile
O O OH Me3SiCl SiMe3
Li O SiMe3 O O OH
O Et3N O O
R2 R1 R2 R2 R1
R1 R1 R2 R1
R3 R2 R3 R1 R3 R2 R3
simple to previous strategy...make often require acid or lewis
the enolate equivalent first then... acid to promote addition
Synthesise an enolate equivalent add Electrophile Me Me
Me
Me
H
Cy2BCl BCy2 BCy2 O O
B Me
O O O O OH H
O Me
Et3N R
Me Me
R2 R1 R1 R1
R1 R3 R2 R3
R2
R2
boron enolates are incredibly
useful in the aldol reaction, I really wish I had
more time to go into their use (look it up in a
book, its worth it) allows us to control stereochemistry

4. the claisen condensation the dieckman cyclisation
O O
O O O O O
NaOEt NaOEt
EtO O
“aldol-like chemistry” OEt
OEt
OEt OEt OEt
this is the reaction of two
a lot of chemistry gets lumped esters to give a !-ketoester
mechanism involves
together with the aldol reaction as a enolate formation before addition to this is the intramolecular version
lot of chemistry shares the same a carbonyl with a leaving group of the claisen condensation
principles (hence ketone formed)
many other examples... aldol reaction in total synthesis
!"##$%&'
Darzens ()"%*$+# (+)-Ipc2BO
reaction enamine
Me
H
O
H
CO2Me
Me
O
OH OPMB
OTBS
H
O
OH CO2Me
O H H H
reaction
O Me
O OTBS
H
enamine Darzens
H O
86%
Me OH O O O OPMB
62%de
reaction
H H
O Me Me
Mannich reaction reaction look at the synthesis of
this carcinogen
(–)-laulimalide
(fijianolide B)
here the aldol reaction is used
to join the two halves together by C-C
bond formation
aldol reaction in total synthesis conjugate addition also known as
Michael Addition or 1,4-addition
(+)-Ipc2BO
Nuc O Nuc O
Meeven better it CO2Me
controls OTBS
H
the stereochemistry of the
H H
R1 R2
O O O
R1 R2
new alcohol Me OH OPMB
“michael Additions”
ipc=pinene derived chiral H H
CO2Me
(conjugate additions
OTBS O Me H
H
H
borane (see O7 slides ago) 1,4-additions)
86%
62%de this is the general
O OPMB
de=diastereomeric excess reaction - addition of a nucleophile Nuc O
means Me have only 19% of the
we to an activated alkene (numbering
wrong diastereoisomer starts with o=1 for the name)
R1 R2

5. potential problem: 1,2-addition the details about why we Solution: change nucleophile
can get both additions etc
can be found...
Nuc O Nuc OH
R1 R2 R1 R2 Cu Li
2 x H3C Li CuI
H3C CH3
there are a number of
methods to avoid 1,2-addition. The
all about the interplay of two most common is the use of
nucleophile can add factors depending on the nucleo- organocuprates
directly to the carbonyl group phile & the conditions: kinetic vs
(numbering starts with o=1 for the these are readily prepared from
thermodynamic & Hard vs soft other organometallic reagents
name)
page 230 onwards
Solution: change nucleophile cuprates can be made from organocoprates are soft nucleophiles
grignard reagents
O two possible reasons for the
O
Cu Li
H
!– !+
exclusive 1,4-attack. Cuprates are soft
nucleophiles so attack soft electrophile (the
H3C CH3 O O C Licuprates are soft
alkene not the hard carbonyl)
CH3 CuClcat because copper is less
organocuprates always
H3C MgBr
!+
!– electropositive than lithium or
magnesium, thus C-Cu bond is
undergo 1,4-addition (in fact they
only react with highly activated O CH3
C Mgless polarised
carbonyl compounds such as acyl
chlorides)
only need a sub-stoichiometric !– !+
CH3
quantity of a copper(I) salt to
achieve this C Cu
Addition of 1,3-dicarbonyl compounds
Text
O O O
OEt OEt
NaOEt
C•
personally, i think the
as an aside, why should
two negatively charged electrons ever
O O
OEt
another solution is to
reaction is probably radical & radicals add travel as a pair? doesn’t really make
reversibly to c=O bonds so we observe 1,4 use a 1,3-dicarbonyl-based
sense enolate. these invariably
addition instead EtO O
©kathybragg@flickr
undergo 1,4-addition

6. 1,3-dicarbonyls are soft nucleophiles the robinson annulation
Text
if we combine
conjugate addition &
O O aldol condensation we
O O O O
get... O O
OEt O
OEt OEt NaOH
!
O O
O O
OEt
soft nucleophiles because charge combining these two reactions gives us
is spread over 5 atoms so add to the soft a ‘one-pot’ route to 6-membered rings
electrophile (the alkene)
Mechanism of the robinson annulation Mechanism of the robinson annulation
the next reaction has a
O O O O wonderful name. you don’t
H OH need to know it but...
O O O
O O O
the robinson annulation O
starts with a conjugate and ends with an H2O
addition aldol condensation
O O O O
H2O
HO OH
O O O O O O the next one is a bit
OH
of a tongue twister...
the Hajos-Parrish-Eder-Sauer-
Wiechert reaction
O
O
N CO2H
H
retrosynthesis, the next part
O O of this course is all about recognising
O these patterns
OH
99%
93% ee
synthesis is about synthesis is about
proline catalysed intramolecular
aldol reaction with exquisite control finding the hidden finding the hidden
of stereochemistry patterns ©moominsean@flickr
patterns ©moominsean@flickr

7. C-C at !position 1,3-di-O relationship 1,3-di-O relationship
O O OH O O
R2
R1 R1 R2 R1 R2
if we want to make a if there are two
bond adjacent to a oxygens in a 1,3-relationship or at least
carbonyl group think (regardless of oxidation aldol-like
enolate state), think aldol chemistry
O O O O O
R2 X
R1 R1 R2 R1 EtO R2
enone relationship 1,4-di-O relationship 1,5-di-O relationship
O O O O
R2
R1 R2 R1 R1 R2
even an enone can be changing the electrophile OH
made from an aldol allows different patterns to and repeat...
i told you the be accessed
reaction aldol was good!
O O O O O O
R1 R2 R1 R2 R1 R2
Text
learn to recognise
patterns