This document summarizes MacMillan's total synthesis of callipeltoside C, which employs organocatalysis and several interesting chemical transformations. The retrosynthesis splits the molecule into three fragments - the macrocyclic lactone core, carbohydrate, and a third segment prepared using organocatalysis. The forward synthesis couples these fragments in a convergent manner, with key steps including a Negishi carbometallation, organocatalytic hydroxylation, Semmelhack reaction to form the tetrahydropyran ring, and glycosidation to join the sugar moiety. The synthesis highlights the utility of retrosynthesis in simplifying complex targets and total synthesis in confirming the structure of natural products.

1. This lecture covers MacMillan’s synthesis of
callipeltoside C, a molecule with potential
anti-viral and anti-carcinogenic properties.
Other groups (Evans, Trost, Patterson &
Panek … all names you should become
familiar with) have synthesised other
members of this family of compounds.
This synthesis employs some of
MacMillan’s organocatalysis chemistry as
well as a number of other interesting (and
in one case challenging) chemical
transformations.
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2. So let us start the retrosynthesis …
As always it is important to remove
sensitive/reactive functionality as quickly
as possible so a C–O disconnection allows
the sugar to be removed.
This also splits the molecule into two
readily prepared fragments, the
macrocyclic lactone core and the
carbohydrate.
To simplify formation of the macrolide, first
disconnect the lactone. This removes the
macrocycle.
2

3. C–C disconnection breaks the molecule into
two fragments.
In the forward sense this reaction can be
achieved by a simple Grignard reaction or
equivalent.
We now have three segments to prepare.
Hopefully you can see how this has
simplified the problem greatly.
The whole molecule may look daunting but these
smaller sections seem readily achievable.
The advantages of breaking a molecule into
fragments instead of attempting a long, linear
synthesis should be obvious …
• Each block can be made simultaneously
without effecting the others (so when you drop
one in the rotary evaporator bath …)
• Less concerns about chemoselectivity
• The mathematics of a convergent synthesis
favour higher yields than with a linear synthesis.
3

4. You need to remember that a good
retrosynthesis is a road map to preparing
the molecule but it is not a definitive
instruction manual. Reality may necessitate
changing the order of some steps and a
complete rethink … chemistry is easy on
paper. It is not always so easy in reality.
The bottom half of the molecule can be
further dismantled.
C=C disconnection halves the molecule
once more. The forward equivalent is a
standard HWE reaction.
The right hand fragment was made during
an earlier synthesis by Evans.
The left hand fragment will be formed
using organocatalysis.
4

5. Disconnection of the tetrahydropyran is
slightly more tricky (but the synthetic
equivalent is elegant).
C–O disconnection allows ring opening to
give a linear molecule. But the
disconnection actually involves a great deal
of simplification as it involves C–C and two
C–O disconnections.
Disconnections such as these are hard to
see and it is a matter of experience, a good
working knowledge of the chemical
literature and an even better knowledge of
how to search databases effectively.
Practice allows you to spot opportunities
and exposes you to more chemistry.
5

6. But what a great simplification that
cyclisation was …
Now all we are left with is a 1,3-diol. As
soon as you see this pattern you should be
thinking about the aldol reaction …
(there are many other efficient ways of introducing this
functionality but until you gain more experience the aldol
reaction is a great starting point)
6

7. The aldol reaction is a reliable method to
prepare β-hydroxyketones or β-
hydroxylaldehydes.
These in turn offer functionality for either
more C–C bond forming reactions (an
electrophilic carbonyl group) or can be
selectively reduced using Evans chemistry.
C–C disconnection removes the propargyl
group. Substrate control should allow the
reaction to be achieved with high
diastereoselectivity (remember Cram
Chelation and Felkin-Anh will give different
diastereomers).
C–C aldol disconnection (1,3-diX
disconnection) permits two stereocentres
to be controlled …
7

8. All we are left with is the synthesis of the
sugar moiety.
When looking at a target such as this there
are two starting points:
1) an existing carbohydrate (boring)
2) ring-open the hemiacetal and synthesis
the open chain form. As there are plenty of
hydroxyl groups you might want to consider
…
… the aldol reaction.
Here is one 1,3-diX disconnection.
8

9. Here is another 1,3-diX disconnection. Thus one retrosynthetic route would be:
• C–C disconnection to remove methyl
group.
• C–O disconnection (not shown) using the
open chain form of the carbohydrate.
• C–C disconnection aldol reaction installs
two carbon atoms with control of
stereocentre.
9

10. The remaining oxygenated fragment can be
formed from yet another aldol reaction and
the dimerisation of this simple aldehyde.
Having finished the retrosynthesis lets
address the synthesis (as most people find
this easier to visualise and we need to
known that MacMillan’s plan actually
works!)
10

11. Starting with the bottom half of the
molecule …
The first step is a Negishi carbometallation-
iodination. This permits the stereospecific
addition of a carbon fragment and a metal
to an alkyne (or alkene). The addition
invariably gives the cis-product.
The mechanism of the Negishi
carbometallation is complex and almost
certainly there are three competing
mechanisms. Which one is operating will
depend on the aluminum reagent and the
solvent (amongst other things).
A simplified version is given on the next
slide …
11

12. There is an interaction between the
zirconocene dichloride and the
trimethylaluminium, which creates a highly
reactive aluminum species. This forms a π-
complex with the alkyne. The nucleohilic
alkyne attacks the electron deficient
aluminium. Simultaneously the nucleophilic
methyl group attacks the polarised alkyne
(regioselectivity can be explained by the
more stable cation).
The simultaneous nature of this addition
leads to syn addition and the
stereospecificity of the reaction.
Once the organoaluminium species has
been formed it is an example of simple
metal-halogen exchange (effectively
transmetallation) to give the iodide with
retention of stereochemistry.
phew …
12

13. With the vinyl iodide in place the terminal
alcohol was oxidised under standard Swern
conditions to give the aldehyde necessary
for the …
… organocatalytic hydroxylation reaction
that will introduce the necessary
stereocentre to this fragment.
13

14. Proline-catalysed asymmetric hydroxylation
occurs as outlined in lecture 6.
Condensation of the proline and aldehyde
results in the formation of an enamine.
Hydrogen bonding between the carboxylic
acid and nitrosobenzene delivers the
electrophile to the top face.
Standard functional group manipulation
prepares this small fragment for coupling
to the rest of the molecule.
1) reduction of the aldehyde to primary
alcohol
2) reduction of the O-alkyl hydroxylamine
3) chemoselective protection of the
primary (less sterically demanding) alcohol
4) orthogonal protection of the secondary
alcohol.
14

15. Synthesis of the central tetrahydropyran.
This involves reagent control catalytic direct
aldol reaction as covered in lecture 6.
Condensation of the proline with the more
reactive, less sterically demanding aldehyde
creates the enamine that attacks the chiral
aldehyde.
It might be interesting for you to work out if this is a case of
matched or mis-matched substrate-catalyst control … or to
look up what this means!
Addition of the organozinc reagent occurs
with good diastereoselectivity. The reaction
is under …
15

16. … substrate control with the standard
Felkin-Anh (apologies for the spelling
mistake).
Remember. The largest substituent is
perpendicular to the carbonyl group. There
are two conformations that fulfil this
criterion. The nucleophile then approaches
along the Bürgi-Dunitz angle attacking
through the conformation that has it
passing the smallest substituent.
Now the scene is set for the Semmelhack
reaction …
This is a palladium-mediated reaction that
closes the ring while inserting carbon
monoxide to furnish the ester above.
16

17. The mechanism is a little bit of a
nightmare (see what I did there!).
The Pd(II) is a π Lewis acid. It activates the
alkyne towards nucleophilic attack. The
oxygen cyclises onto the alkyne (6-exo-trig
for those that remember Baldwin’s
guidelines) to give the cyclic enol ether. The
carbon monoxide adds to the Pd and then
participates in migratory insertion to give
the acyl palladium species.
The methanol then reacts to give the ester
and Pd(0) …
17

18. … the Pd(0) is oxidised by the
benzoquinone so that it can rejoin the
catalytic cycle.
The reaction of the enoate does not stop
here. It too can be activated by the Lewis
acidic Pd(II) and this permits formation of
an oxonium species which is trapped by
more methanol as the ketal.
Lovely reaction …
Standard FGI prepare the THP for the
subsequent coupling reactions:
1) Orthogonal protection of the secondary
alcohol
2) Selective deprotection of the primary
alcohol with DDQ (electron acceptor - oxidises
the para-methoxybenzyl protecting group and
thus cleaves it).
3) Parikh-Doering oxidation (like the Swern
oxidation this is an activated DMSO
oxidation).
18

19. Conversion of the vinyl iodide into a
Grignard reagent permits the coupling of
the two fragments formed so far.
The stereochemistry is an example of Cram
chelation control. If you do not believe me
you should draw out the reaction for
yourself (you should probably do this any
way as good practice).
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20. The resulting allylic alcohol is methylated.
DDQ deprotection of the para-
methoxybenzyl protected alcohol is
followed by a second Parikh-Doering
oxidation.
1) Horner-Wadsworth-Emmons coupling
then joins the last part of the southern
hemisphere onto the molecule. The HWE
reaction is more reactive than the Wittig
reaction and the side product is more
readily removed during an aqueous work-
up.
2) TBAF removes the silicon protecting
group.
3) Barium hydroxide hydrolyses the ester.
20

21. Yamaguchi esterification forms the
macrolactone. This reaction involves
formation of a highly reactive mixed
anhydride, which is then attacked by the
DMAP (N,N’-dimethyl-4-aminopyridine).
The resulting activated ester is attacked by
the alcohol to give the lactone.
Unfortunately, under the reaction
conditions the ketal undergoes elimination
…
… luckily it can be reintroduced as the
desired hemiacetal (with the correct
stereochemistry - anomeric effect and
bulky group equatorial) by treatment with a
mild acid.
The strong acid then removes the silyl
protecting group.
21

22. And finally we are onto the synthesis of the
sugar fragment.
Here the MacMillan group had a little
trouble. They prepared the reported
molecule but found that the nmr did not
match the published data.
22

23. It turns out that the stereochemistry of the
sugar had been miss-assigned when the
molecule was isolated. The correct sugar
was actually the enantiomer of the
reported structure.
This highlights another use of Total
Synthesis … structural elucidation.
The synthesis of the sugar moiety starts
with a proline-catalysed aldol reaction.
This is a dimerisation of the TIPS
protected aldehyde (TIPS = triisopropylsiyl
or iPr3Si).
23

24. Substrate controlled (Felkin-Anh) Lewis
acid-mediated aldol reaction of the silyl
enol ether gives the sugar with excellent
diastereoselectivity (but not fantastic yield).
Even though there is a Lewis acid present
…
… it is not an example of Cram chelation
control as the TIPS group prevents
chelation.
Like many sugars the molecule is an
equilibrium of the open and closed chain
forms.
24

25. 1) A mixture of acetyl chloride and benzyl
alcohol generates HCL in situ. This is mild
enough to deprotect the primary silyl ether (but
leave the less reactive secondary silyl ether
alone) and form the acetal at the anomeric
position.
2) The alcohol is then converted into a xanthate
to allow …
3) The Barton-McCombie radical deoxygenation
reaction.
4) Oxidation with Dess-Martin periodinane
(DMP) gives the ketone (See oxidation lectures)
1) Grignard addition gives one
diastereomer with the nucleophile
approaching axially. This is probably a
result of the equatorial approach being
blocked by the methoxy ether.
2) Hydrogenation removes the benzyl
protecting group from the anomeric
position.
3) Activation of the anomeric oxygen as
Schmidt’s trichloroacetimidate prepares
the sugar for glycosidation.
25

26. 1) Schmidt glycosidation joins the two
fragments together and then …
2) the final protecting group is removed.
The synthesis is fairly convergent and this allows
an increased yield compared to some of the
earlier syntheses (of callopeltoside A not C).
Longest linear sequence is 18 steps an the
overall yield is 12% (although this may be based
on recovered starting material, some of the
supplementary information is a little
ambiguous).
But, overall it is a neat synthesis that
demonstrates the value of organocatalysis.
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