Total Synthesis Highlights

The enantiomerically-pure fragments 8, 12 and 17 were coupled to prepare the macrolide 1. The
preparation of 8 started with the commercially-available enantiomerically-pure bromide 3.
Protection and halide exchange set the stage for homologation with allylmagnesium chloride.
Ozonolysis followed by condensation with the acyl oxazolidinone 6 set the last two stereogenic
centers of 8.
The starting point for 12 was the commercially-available enantiomerically-pure Roche ester (9).
Protection, reduction and oxidation gave 10, which was homologated to the ester 11. Reduction to
the allylic alcohol followed by conversion to the chloride and coupling with TMS acetylene led to
12. Addition to 8 of the alkenyl zirconium derived from 12 then gave 13.
Professor Ley used his elegant tartrate method to assemble the carbocyclic fragment 17.
Condensation of two inexpensive components, dimethyl D-tartrate and biacetyl, followed by
reduction and monoprotection delivered the aldehyde 14. Diastereoselective addition of the allyl
stannane 15 led to diene 16, setting the stage for cyclization with the Grubbs second-generation
Ru catalyst.
The sulfone anion derived from 13 added smoothly to 17, to give, after reduction and acylation,
the ester 1. The templating effect of the arene ring of 1 facilitated macrolide formation. The
Dieckmann cyclization then could proceed via a 6-membered ring transition state, leading to the
ring-contracted product 18. In addition to establishing the β-keto amide, this cyclization left
residual oxygenation at the α-carbon, allowing direct elaboration of the 1,2,3-tricarbonyl system of
2.