Design and Synthesis of Biotin Analogues Reversibly Binding with Streptavidin

Abstract Two new biotin analogues, biotin carbonate 5 and biotin carbamate 6 , have been synthesized. These molecules were designed to reversibly bind with streptavidin by replacing the hydrogen‐bond donor NH group(s) of biotin’s cyclic urea moiety with oxygen. Biotin carbonate 5 was synthesized from L ‐arabinose ( 7 ), which furnishes the desired stereochemistry at the 3,4‐ cis ‐dihydroxy groups, in 11 % overall yield (over 10 steps). Synthesis of biotin carbamate 6 was accomplished from L ‐cysteine‐derived chiral aldehyde 33 in 11 % overall yield (over 7 steps). Surface plasmon resonance analysis of water‐soluble biotin carbonate analogue 46 and biotin carbamate analogue 47 revealed that K D values of these compounds for binding to streptavidin were 6.7×10 −6 M and 1.7×10 −10 M , respectively. These values were remarkably greater than that of biotin ( K D =10 −15 M ), and thus indicate the importance of the nitrogen atoms for the strong binding between biotin and streptavidin.