Synthesis of Phosphomuramyl Pentapeptide

The initial target for our chemical synthesis of lipid I was phosphomuramyl pentapeptide 9. At the outset, we were confident in our ability to prepare the monosaccharyl pentapeptide core structure, but were unsure of our ability to install the anomeric phosphate with the desired a-stereochemistry. We were also concerned about the timing for introduction of the anomeric phosphate since solubility and anomeric selectivity could be strongly influenced by the presence or absence of the peptapeptide side chain. In addition, we had not settled on a method for 

Our premise for the selection of a phosphitylation/oxidation sequence derived from its successful application during the course of the Park nucleotide synthesis.14 Hitchcock reported the phosphitylation/oxidation of lactol 17, existing predominantly as the a-anomer, provided the desired a-phosphate, albeit with a modest 2.5 1 preference.15 In related work, the Walker group reported a similar phosphitylation/oxidation sequence applied to lactol 19 provided a-phosphate 20 as the exclusive product in very good chemical yield.16 

At this point, we had achieved access to an orthogonally protected phosphomuramyl pentapeptide derivative poised to enable completion of our lipid I total synthesis. The technical hurdles that remained to be addressed were 1) identification of a mild method for installation of the lipid diphosphate linkage, 2) global deprotection, and 3) final purification of our synthetic lipid I. Our solutions to these problems are addressed in the following section. 

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