The presence of the alpha-beta unsaturated ketone functionality (see note
to the right) suggests the use of an aldol condensation to form the
This would simplify our target to A. In the forward sense,
formation of the enolate of the methyl ketone at the top, subsequent
attack of the ketone in the lower left, and loss of water would result in
the desired molecule.
Remember: when performing retrosynthetic analysis, it is important to
consider the merit of the reactions in the forward sense. In this case,
while one may worry about possible side reactions
(by formation of another enolate), these aldols are in equilibrium, and
the thermodynamic stability of the six-membered ring would
favor the desired product. This step is indeed feasible in the forward
Examining A, one observes a 1,5 diketone relationship embedded in
the structure. This suggests that a Michael reaction could be used to
form A from B and C. Note: This retrosynthetic step
would be a more sensible choice than the one shown below.
Why is this? Think about it and then check the answer...
B is a beta keto ester, which calls to mind the Claisen
...and C is an alpha beta unsaturated ketone which can be easily
formed in an aldol reaction.
Again, remember to consider what is happening in the forward sense. In
this case, this mixed aldol reaction is acceptable since even though there
are two different
aldehydes involved, only one has acidic protons, and only one enolate can
I leave the forward synthesis to you. If you have any
problems determining what reaction conditions to use, consult your notes
and Professor Wintner's problems.
Question: The combination of B and C to
form the desired
target of question four in two steps is an example of a special, named
sequence of reactions. What is the name for this Michael addition and
subsequent intramolecular aldol condensation? The answer
found in the solutions to question 6 (near the bottom of the
One last thought on problem 4. If the target was just like the one
given, except without the ester group next to the ketone at the top of
the molecule, the synthetic pathway would be the same, with the added
last step of hydrolysis of the ester and subsequent decarboxylation.
Retrosynthetically, the first step would be the installation of this
ester (since this allows us to perform the Michael reaction using the
stable enolate derived from B). Be able to recognize when it is
appropriate to retrosynthetically add this ester group! (Another example
is alkylations of enolates.)