[reaction: see text] A new, robust tert-butyldiarylsilyl (TBDAS) linker has been developed for solid-phase organic synthesis. This linker is stable to both protic and Lewis acidic reaction conditions, overcoming a significant limitation of previously reported silyl linkers. Solid-phase acetal deprotection, olefination, asymmetric allylation, and silyl protecting group deblocking reactions have been demonstrated with TBDAS-linked substrates.

A unified synthetic approach to diverse polycyclic scaffolds has been developed using transition metal-mediated cycloaddition and cyclization reactions of enynes and diynes. The t-butylsulfinamide group has been identified as a particularly versatile lynchpin in these reactions, with a reactivity profile uniquely suited for efficient, stereoselective substrate synthesis and downstream transformations. This approach provides ten distinct, functionalized scaffold classes related to common core structures in alkaloid and terpenoid natural products.Polycyclic alkaloid and terpenoid natural products exhibit a tremendous array of chemical scaffolds and biological activities. 1,2 Accordingly, these structures are attractive targets for the synthesis of natural product-based libraries. 3 Ideally, a concise, unified synthetic route would provide an array of distinct, polycyclic scaffolds for use in discovery screening against a wide range of targets. The synthesis of such multiscaffold libraries remains a major challenge in diversity-oriented synthesis. 4,5 We envisioned that the modern arsenal of transition-metal mediated cycloaddition and cyclization reactions 6,7 would provide a powerful means to generate such libraries from simple tethered enyne and diyne substrates. We report herein the development of a unified synthetic approach leading to ten classes of polycyclic scaffolds, and the emergence of the t-butylsulfinamide moiety 8 as a versatile lynchpin for these reactions, affording uniquely suited reactivity and a novel motif for biological evaluation.To identify transition metal-mediated cycloaddition and cyclization reactions suitable for diversity-oriented synthesis, we set out to evaluate candidate reactions systematically across a panel of substrates having electronically and sterically distinct groups at sites expected to influence reactivity. This would also provide broad insights into the scope and efficiency of these reactions.To assemble the requisite enyne and diyne substrates, we initially investigated ether, carbamate (N-Boc), and sulfonamide (N-Ts, N-Ns) tethers. After extensive experimentation, the t- butylsulfinamide 8 emerged as a uniquely suited lynchpin. This group provides asymmetric induction during substrate assembly, can be readily deprotonated and N-alkylated, does not exhibit rotamers on the NMR timescale, and can be deprotected or oxidized under mild conditions. The t-butylsulfinamide is also a novel motif for biological evaluation, related to sulfonamides in synthetic drugs and natural products. Notably, although a picture of compatibility of the t-butylsulfinamide with metal catalysts is beginning to emerge, 9 its stability and reactivity in transition metal-mediated cycloadditions and cyclizations has not yet been explored in detail.Thus, synthesis of enynes 4 and diynes 5 began with condensation of aldehyde 1 and (R)-tbutylsulfinamide (Scheme 1). The R 1 sidechain was designed with a TPDPS-protected alcohol as a potential handle for later functionalization and as a mimic of ou...

Alkaloid and terpenoid natural products display an extensive array of chemical frameworks and biological activities. However such scaffolds remain underrepresented in current screening collections and are, thus, attractive targets for the synthesis of natural product-based libraries that access underexploited regions of chemical space. Recently, we reported a systematic approach to the stereoselective synthesis of multiple alkaloid/terpenoid-like scaffolds using transition metal-mediated cycloaddition and cyclization reactions of enyne and diyne substrates assembled on a tert-butylsulfinamide lynchpin. We report herein the synthesis of a 190-membered library of alkaloid/terpenoid-like molecules using this synthetic approach. Translation to solid-phase synthesis was facilitated by the use of a tert-butyldiarylsilyl (TBDAS) linker that closely mimics the tert-butyldiphenysilyl protecting group used in the original solution-phase route development work. Unexpected differences in stereoselectivity and regioselectivity were observed in some reactions when carried out on solid support. Further, the sulfinamide moiety could be hydrolyzed or oxidized efficiently without compromising the TBDAS linker to provide additional amine and sulfonamide functionalities. Principal component analysis of the structural and physicochemical properties of these molecules confirmed that they access regions of chemical space that overlap with bona fide natural products and are distinct from areas addressed by conventional synthetic drugs and drug-like molecules. The influences of scaffolds and substituents were also evaluated, with both found to have significant impacts on location in chemical space and three-dimensional shape. Broad biological evaluation of this library will provide valuable insights into the abilities of natural product-based libraries to access similarly underexploited regions of biological space. diversity-oriented synthesis | multiscaffold library | asymmetric synthesis | cheminformatics A major goal in the field of diversity-oriented synthesis is the efficient production of small-molecule libraries that address underexploited regions of biologically relevant chemical space to enable the discovery of new biological probes and potential therapeutic lead compounds (1). A key approach to addressing this challenge is to emulate natural products and other biogenetic molecules, which have coevolved with macromolecular biological targets (2). Toward this end, a variety of natural product-based libraries have been synthesized, with promising early results (3). These libraries can be validated initially by evaluation of their structural and physicochemical properties using principal component analysis (PCA) to determine the regions of chemical space that are accessed. Subsequently, screening across a wide range of biological assays provides direct biological validation of the functional capabilities of these libraries.Alkaloids and terpenoids have long served as important small-molecule drugs and leads for drug discovery (4, ...