Executive Summary : | Natural products (NPs) are quintessential source of modern medicine and many of them have deep roots in the traditional system of medicine practised worldwide for centuries. An analysis of currently used drugs and pharmacophores indicates that over 50% of the approved first-in-class drugs are derived either directly from NPs or semisynthetic NPs. During the development of semi-synthetic therapeutic agents, the initial NPs are invariably modified by late-stage functionalization to achieve final products with desired pharmacokintetic (PK) profile, efficacy and safety. Despite many recent advances, a challenge common to late-stage NP derivatization is to design new diversity oriented “site-selective” reactions having much larger chemical space that enables the structure activity relationship studies to explore their full potential as drug leads. One way to deal with this problem is to devise a comprehensive panel of reactions from ubiquitous functional group present in all classes of NPs that manage to obtain large ensembles of previously inaccessible late-stage transformations with spatial and functional diversity.1-3 Recently, metal (Rh2+ or Ni2+) imino-carbene precursors derived from N-sulfonyl- or N-perfluoroalkyl-1,2,3-triazole have unlocked a new avenue in carbenoid chemistry. The latter compound can be readily obtained via copper(1)-catalyzed azide-alkyne cycloaddition reaction and function as more stable, safer alternatives to diazo compounds. The experimentally simple, slow liberation of carbene (as acceptor or donor/acceptor carbene) works well for many typical stereoselective carbene reactions, such as 1,2-alkyl migration, cyclopropanation, O-H, C-H, or N-H insertion, [2,3] sigmatropic rearrangement, and others.4-6 This chemistry has now become a reliable synthetic tool and has led to the discovery of a diverse range of products. Applying this chemistry to complex NPs would be a worthy endeavour to give semisynthetic NPs having important pharmaceutical properties. Recently, the versatile usefulness of organocatalytic reactions to synthesize various fused 1,2,3-triazole heterocycles from enolizable ketones via enolate or enamine pathway has been successfully investigated. Since enolizable ketones are very abundant in all classes of NPs, these remarkable organocatalysed reactions would be a lead transformation for the fast and easy access to functionalize N-sulfonyl/(per)fluoroalkyl-1,2,3-triazole on the basic skeleton of NPs having great synthetic and biological importance.7-13 Enolizable ketones could thus function as intermediates for the site-selective introduction of α-imino diazo species on the basic skeleton of NPs for generation of transient metallocarbenes. This would thus permit the chemists to rationally plan the placement of nitrogen-containing functional groups on NP skeleton with regio and stereochemical control to afford previously inaccessible semisynthetic modifications. |