MINIMALISTS Sculimbrene (left) and Miller find a short, practical approach to phosphorylation. PHOTO BY JARRED BLANK

Phosphorylated natural products are ubiquitous in nature. Their biological function depends on where and to what extent they are phosphorylated. Complex proteins called kinases catalyze reactions that put phosphate groups on specific sites of a substrate.

Often the substrate offers not only multiple reactive sites, but also the possibility of enantiomeric products for each reactive site. Preparing the desired enantiomer in the lab usually involves elaborate protecting-group strategies; use of chiral auxiliaries; or laborious isolation by, for example, selective recrystallizations or enzymatic resolutions. Synthesis would benefit greatly from a small molecule that mimics the action of the complex kinases.

Now, by screening a library of small peptides, graduate student Bianca Sculimbrene and associate chemistry professor Scott J. Miller have found a pentapeptide that asymmetrically phosphorylates a derivative of myo-inositol [J. Am. Chem. Soc., 123, 10125 (2001)].

"This paper demonstrates that it is now possible to go from 'nothing' in a given reactivity regime--in this case, asymmetric phosphorylation of hydroxyl groups--to a practical catalyst in a logical and efficient manner," comments Samuel H. Gellman, a chemistry professor at the University of Wisconsin, Madison.

Miller's group had been using combinatorial techniques to search for small-peptide catalysts of acylation reactions. They found that the most promising small peptides were those that adopt well-defined structures. Reasoning that acylation and phosphorylation likely have mechanistic similarities, they focused screening for phosphorylation catalysts on peptides that could assume well-defined secondary structures in nonpolar solvents.

The best catalyst to emerge from those screenings is a pentapeptide that phosphorylates the myo-inositol derivative in 65% yield and with greater than 98% excess of the desired enantiomer. Total synthesis of d-myo-inositol-1-phosphate from myo-inositol is achieved in five steps.

One previous synthesis involves only four steps, but relies on a chiral auxiliary and a precipitation-driven equilibrium, Miller notes [Tetrahedron Lett., 32, 4031 (1991)]. "I believe our catalyst-dependent approach may be more efficient than that one," he says.

The Boston synthesis is "exceptionally short and practical," Gellman says. Inositol phosphates, he notes, have broad importance and are difficult to synthesize in good quantities.

Protecting groups still are used in the synthesis, because the small peptides need a nonpolar environment to adopt a defined secondary structure, Miller explains. Myo-inositol is poorly soluble in a nonpolar medium, however, so protecting groups are used to increase its solubility in nonpolar solvents. At the same time, they reduce the number of reactive sites.

"We see this synthesis as a partial solution," Miller says. "What we'd love to be able to do is to take substrates like myo-inositol and in one step selectively phosphorylate them. We can't do that yet, but we're moving toward that direction."

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Copyright © 2001 American Chemical Society