The tert-Butylsulfinamide Lynchpin in Transition-Metal-Mediated Multiscaffold Library Synthesis

Abstract

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...

Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library

“…Notably, the TBDAS linker withstood these strongly basic reaction conditions, and the reactions proceeded in good yields, comparable to those previously obtained in solution phase (3a, 87% vs. 98%; 3b, 72% vs. 76%; 3c, 88% vs. 80%; 3d, 81%; 4a, 86% vs. 82%; 4b, 82% vs. 90%; 4c, 85% vs. 82%; 4d, 79%) (12). Because the terminal alkynes (3d, 4d) were more broadly effective substrates compared to the trimethylsilyl (TMS)-alkynes (3c, 4c) in the original solution-phase studies (12), and afford identical products after desilylation, the former were used in most of the subsequent transition metal-mediated cycloaddition and cyclization reactions. With the enyne and diyne substrates 3 and 4 in hand, we were poised to investigate the key transition metal-mediated solid-phase cycloaddition and cyclization reactions (Scheme 2).…”

“…We were gratified to find that these reactions proceeded with complete diastereoselectivity [≥95∶5 diastereomeric ratio (DR), 1 H-NMR] and in yields comparable to those observed in the corresponding solution-phase reactions (2a, 91% vs. 85%; 2b, 69% vs. 80%; 2c, 85% vs. 77%) (12). Subsequent desilylation of 2c with K 2 CO 3 in MeOH also provided the terminal alkyne 2d in 78% yield.…”

“…We recently reported a systematic approach to the synthesis of multiple polycyclic scaffolds related to structures found in diverse alkaloid and terpenoid natural products (12). Our synthetic approach was designed to emulate divergent biosynthetic strategies used in nature by converting a small number of relatively simple, acyclic starting materials into a diverse array of polycyclic scaffolds (13).…”

Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

“…Th e goal of these methods is not to provide an absolute measure of diversity, but a relative measure that also agrees to a good extent with chemical intuition 3 . For example, some groups have used a computational process for diversity assessment based around the calculation of molecular descriptor values followed by principal component analysis 3,53,62 . In essence, this provides a measure of total chemical space coverage.…”

Diversity-oriented synthesis of macrocyclic peptidomimetics

“…We have utilized a computational process for diversity assessment based around the calculation of various shape-and charge-based molecular surface descriptors followed by principal component analysis (PCA) (6,9,70,71). Essentially this provides a measure of overall chemical space coverage (9).…”