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Asymmetric Synthesis of 1,3-anti-Diol Containing Subunits using Phosphorus-Based Tethers: Application in the Total Synthesis of Dolabelide C
Thomas, Christopher Daniel
Thomas, Christopher Daniel
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Abstract
The focus of this dissertation is the desymmetrization of C2-symmetric 1,3-anti-diols through the construction of pseudo-C2-symmetric phosphorus heterocycles, bearing a chirotopic, non-stereogenic center at phosphorus. Diastereotopic differentiation is achieved through cyclization via ring-closing metathesis (RCM), affording a chiral, non-racemic bicyclic P-heterocycle, which is stereogenic at phosphorus. This strategy is central to building skeletally diverse polyol subunits, which are commonly seen in polyketide-based natural products. Terminus differentiation and chain elongation through selective transformations on the previously reported bicyclo[4.3.1]phosphate (both antipodes), e.g. cross-metathesis, regioselective olefin reduction and regio- and diastereoselective allylic phosphate displacements, provide a rapid protocol to accessing the aforementioned motifs. The development of this methodology advanced into an application toward the total synthesis of dolabelide C (bearing two separate 1,3-anti-diol containing fragments), which exhibits cytotoxicity against cervical cancer HeLa-S3 cells with an IC50 value of 1.9 μg/mL. A route to this target was devised, where the final step was amending the 24-membered marcocycle through RCM. The result provided a diastereomeric mixture of E and Z isomers, which proved to be difficult to separate during initial efforts. However, LC-MS analysis of the mixture showed the contaminants were by-products arising from isomerization events occurring prior to RCM. Other reports coincide with this observation, mainly in the synthesis of medium to larger sized rings. Scale-up was required after this initial study to provide ample material for final characterization and the re-synthesis provided a copious amount of the RCM precursor. The large amount of material allowed for optimization studies and finally resulted in 14 mgs of analytically pure dolabelide C and 10 mgs of the non-natural Z-isomer, which to the best of our knowledge is the first synthesis of both compounds and the most synthetic material available of each to date.
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Date
2010-12-16
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University of Kansas
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Keywords
Organic chemistry, Chain elongation, Diastereotopic differentiation, Dolabelide c, Phosphorus, Terminus differentiation