Anomeric phosphates

Synthesis of anomeric phosphates of aldoses and 2-ulosonic acids 71... 

Glycosyl halides as glycosyl donors in the synthesis of anomeric phosphates... 

Phosphoramidite approach for the instalment of oc-anomeric phosphate in lipid A synthesis... 

The mild conditions offered by the approach of phosphitylation of the anomeric hemiacetals and subsequent oxidation of phosphites to phosphates suggest a very attractive alternative to the 1-0-lithiation method used in lipid A synthesis considering the complexity of the substrates. Indeed, an application of the phosphoramidite methodology was reported to be effective for the stereoselective instalment of the a-anomeric phosphate... 

To make an appropriate choice of the procedure for the instalment of anomeric phosphate the following criteria are of considerable importance ... 

Fig. 3.—Chemical structure of the major component of Campylobacter jejuni lipid A. For details see the text. See also the legend to Fig. 2. For substituents of the phosphate groups see Table I. The a-anomeric phosphate has been tentatively assigned (97).

Our first disconnection revealed glycosyl monophosphate 7 and undecaprenyl monophosphate 8.11 This disconnection was chosen because previous work, directed toward the synthesis of the Park Nucleotide 3, had shown it possible to introduce an anomeric phosphate with anomeric selectivity in favor of the desired a-anomer. A second reason for choosing this disconnection was that undecaprenyl monophosphate was available for purchase from a commercial source. Thus, if we could identify a mild method for joining these two fragments, only a global deprotection step would be required to arrive at lipid I. 

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... 

Ultimately, we settled on a protocol that relied on in situ generation of a carbohydrate-derived phosphorimidazolidate for coupling with a lipid monophosphate [Scheme 9]., 24 The procedure involved activation of an anomeric phosphate by exposure to carbonyldiimidazole (CDI) followed by quenching of the CDI with methanol. The activated intermediate is then exposed to a lipid phosphate salt and was reported to provide the lipid diphosphate in quantitative yield for the coupling step. Coward has successfully applied this protocol toward the construction of dolichyl-linked lipid diphosphates (see below),23 but the basic reaction conditions... 

In model reactions employing a glucosamine-derived anomeric phosphate, we found that we were able to monitor the appearance of the phosphoroimidazolidate intermediate by mass spectrometry. Similarly, we were able to monitor its disappearance upon slow addition of a famesyl monophosphate salt added via syringe. 

In summary, we were able to develop a chemically robust synthetic route to lipid I, the penultimate intermediate utilized in bacterial cell wall biosynthesis. The identification of a method for stereoselective introduction of the anomeric phosphate and a protocol to enable diphosphate coupling were pivotal to our success and ultimately provided the precedent for our chemical synthesis of lipid II detailed in the sections that follow. 

Not surprisingly the procedures described in Section 3.7.2 for the phosphorylation of nonanomeric hydroxyl groups, that is, the phospho-triester, phosphite triester, and 77-phosphonate approaches, have been applied to the preparation of anomeric phosphates.103d,e 110... 

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