Abstract
Iminosugars have attracted increasing attention as chemical probes, chaperones and leads for drug discovery. Despite several clinical successes, their de novo synthesis remains a significant challenge that also limits their integration with modern high-throughput screening technologies. Herein, we describe a unique synthetic strategy that converts a wide range of acetaldehyde derivatives into iminosugars and imino-C-nucleoside analogues in two or three straightforward transformations. We also show that this strategy can be readily applied to the rapid production of indolizidine and pyrrolizidine iminosugars. The high levels of enantio- and diastereoselectivity, excellent overall yields, convenience and broad substrate scope make this an appealing process for diversity-oriented synthesis, and should enable drug discovery efforts.
Highlights
Iminosugars have attracted increasing attention as chemical probes, chaperones and leads for drug discovery
A growing number of unnatural analogues of these compounds have been reported as leads for drug discovery, including the imino-C-nucleosides developed by Schramm5,6 and b-hexosaminidase inhibitors developed by Wong7,8
The incorporation of pyrrolidine iminosugars into chemical screening libraries or diversity-oriented synthesis (DOS) campaigns is problematic, as their syntheses are often lengthy, low-yielding, cost-intensive and limited by reliance on carbohydrate building blocks9
Summary
Iminosugars have attracted increasing attention as chemical probes, chaperones and leads for drug discovery. Considering the spatial relationship between the chloromethine and carbonyl functions in 9, these aldol adducts may serve as building blocks for the synthesis of polyhydroxypyrrolidines via a reductive amination–annulation sequence (see grey box, Fig. 2) Such a strategy would allow for the conversion of virtually any acetaldehyde derivative 6 into an iminosugar 10 in two straightforward transformations from commodity chemicals, enabling their integration with modern high-throughput screening technologies. This unique two- or three-step process requires no cryogenic, anhydrous or otherwise complicated experimental conditions The demonstration of this strategy in several short syntheses of biologically active imino-C-nucleoside analogues, and indolizidine and pyrrolizidine iminosugars highlights its adaptability for DOS and the rapid preparation of iminosugar-based screening libraries
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
