First Generation Synthesis of the Acyl Domain

Synthesis of the Cl-Cll domain of the epothilones at first appeared quite forbidding because of the need to gain facile control over the stereocenters at C3, C6, C7, and C8. Indeed, this region has been the scene of many variations in strategy and synthetic design. [12] Our first generation synthesis of the Cl-Cll acyl domain, al- 

Investigation of C9-C10 Bond Construction Through Ring Closing Metathesis. 

Our second approach involved condensation of the lithium enolate of acetate 32 with aldehyde 28. In the event, the aldol reaction afforded an 85 % yield of a ca. 5 1 mixture of C3 epimers with the desired diastereomer (35) comprising the major product. 

Initial efforts in the ring-dosing metathesis approach were attempted with substrates 34 and 35. However, after employing a variety of catalysts and experimental conditions, no cydized systems (36 or 37) were obtained. Other substrates were prepared to further probe this unexpected failure however, no observable reaction was realized. Model systems later suggested that die dense functionality between C3 and C8 was the culprit for lack of macrocycle formation. Eventually a second generation Cl2-03 RCM (not shown here) approach was developed [26] which yielded mixtures of C12-C13 Z/E isomers that were used in early SAR studies. [26b] However, since the separation of products was so difficult, we did not seriously pursue this route for total synthesis. 

With the appropriate vinyl iodide in hand, we sought to prepare the polypropionate moiety suitable for eventual Suzuki merger. Thus, we envisioned merger of 

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