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Organic Chemistry Highlights

Total Synthesis

Monday, March 6, 2006
Douglass Taber
University of Delaware

Synthesis of the Potent FBBP12 Ligand Antascomicin B

The FK binding protein ligands that suppress the immune response, such as FK506 and rapamycin, have been thoroughly studied. FKBP ligands have also been shown to promote the regrowth of damaged neurons, both peripherally and in the central nervous system. To differentiate these two disparate activities, it is important to develop potent FKBP ligands that are not immune suppressive. The antascomicins, represented by antascomicin B (2), are such a class of natural products. Steven V. Ley of the University of Cambridge has described (Angew. Chem. Int. Ed. 2005, 44, 2732. DOI: 10.1002/anie.200500174) an elegant synthesis of 2, the key step of which was the ring-contracting transannular Dieckmann cyclization of 1.

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.

D. F. Taber, Org. Chem. Highlights 2006, March 6.