wBackground

Isolated from the listhid sponge Leiodermatium sp$.$ in $2008.{?}^1$

Exhibits potent and selective antiproliferative activity against a range of cancer

cell lines. $2$

Interacts with tubulin via an unknown mode of action but one distinct to that of

other tubulin binding compounds such as taxol and discodermolide

Structure of macrocyclic core and side chain reassigned by NMR analysis and

DP$4$ methodology in $2010?$

We aimed to develop a synthesis that could produce further material for

biological testing and provide easy access to a variety of analogues for

structure$-$activity relationship studies.

$2$ C$\mathrm{.}1\_$C$\mathrm{.}11$ Wactarn Franmant

Completion of the Synthesis

Retrosynthesis

Convergent strategy based on introduction of the dienes via palladium$-$

catalysed cross$-$coupling of three key fragments.

Allows for easy generation of structural modifiation.

Anti$-$selective boron$-$mediated aldol reactions set up the three stereoclusters. ${?}^3$

C$12-$C$25$ Eastern Fraqment

Conclusions

The total synthesis of $(-)-$leiodermatolide has been achieved in $23$ steps LLS

$(35$ steps overall$)$ from a known Roche ester$-$derived Weinreb amide."

Three highly diastereoselective boron$-$mediated anti$-$aldol reactions are used

to set up $6$ of the $9$ stereocentres.

Three different palladium$-$catalysed cross$-$coupling reactions are used to form

the diene regions and trisubstituted double bond with high geometrical purity

A site$-$selective macrolactonisation closes the $16-$membered macrolactone in

high yield.

Future work wilof both modified and simplified

analogues for structure$-$activity relationship studies with the aim of probing

the mode of action.suynthesis steps.