Five-membered ring analogues of shikimic acid

Shikimate and other intermediates of the shikimate-chorismate pathway are densely functionalized structures that seem to offer limited options for skeletal modification. We designed and synthesized cyclopentylidenes 1 and 2, as well as cyclopentenes 3 and 4, as novel ring-contracted analogues of shikimic acid. Enzymatic studies showed that analogues 1-3 are indeed processed by shikimate kinase to give phosphates 1-P, 2-P, and 3-P as five-membered ring analogues of shikimate-3-phosphate. In particular, analogue 1 is converted by the enzyme at a rate only 3.5-fold slower than that of the native substrate, while analogue 3 binds to shikimate kinase with an apparent K_m of 1.7 mM, compared to 0.14 mM for shikimate.