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Skeletal Reorganization Divergence of N-Sulfonyl Ynamides ✉ Linwei Zeng1, Yuxin Lin 1, Jiaming Li1, Hironao Sajiki 2, Hujun Xie3 & Sunliang Cui 1

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Skeletal Reorganization Divergence of N-Sulfonyl Ynamides ✉ Linwei Zeng1, Yuxin Lin 1, Jiaming Li1, Hironao Sajiki 2, Hujun Xie3 & Sunliang Cui 1 ARTICLE https://doi.org/10.1038/s41467-020-19467-5 OPEN Skeletal reorganization divergence of N-sulfonyl ynamides ✉ Linwei Zeng1, Yuxin Lin 1, Jiaming Li1, Hironao Sajiki 2, Hujun Xie3 & Sunliang Cui 1 Skeletal reorganization is a type of intriguing processes because of their interesting mechanism, high atom-economy and synthetic versatility. Herein, we describe an unusual, divergent skeletal reorganization of N-sulfonyl ynamides. Upon treatment with lithium dii- N 1234567890():,; sopropylamine (LDA), -sulfonyl ynamides undergo a skeletal reorganization to deliver thiete sulfones, while the additional use of 1,3-dimethyl-tetrahydropyrimidin-2(1H)-one (DMPU) shifts the process to furnish propargyl sulfonamides. This skeletal reorganization divergence features broad substrate scope and scalability. Mechanistically, experimental and computa- tional studies reveal that these processes may initiate from a lithiation/4-exo-dig cyclization cascade, and the following ligand-dependent 1,3-sulfonyl migration or β-elimination would control the chemodivergence. This protocol additionally provides a facile access to a variety of privileged molecules from easily accessible ynamides. 1 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, 310058 Hangzhou, China. 2 Laboratory of Organic Chemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. 3 School of Food Science and Biotechnology, Zhejiang Gongshang ✉ University, 310018 Hangzhou, China. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:5639 | https://doi.org/10.1038/s41467-020-19467-5 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19467-5 keletal reorganization is a type of process involving multiple investigated in C–H functionalization to establish axially chiral bond cleavage and formation for molecule framework molecules and macrocyclic compounds25,26. However, the con- S 1,2 reassembly (Fig. 1a) . Owing to the intriguing reaction ventional synthesis of thiete sulfones relies on multi-step routes mechanism, high atom-economy property and capability of and also suffers from narrow scope27–32. Therefore, it would be accessing complex and synthetically challenging molecules, the interesting to explore a distinct and efficient approach to func- skeletal reorganization process has attracted considerable attention tionalized thiete sulfones. and also been widely applied in organic synthesis toward diverse Ynamides are a type of N-substituted electron-rich alkynes that carbocyclic and heterocyclic compounds3–5. For example, a variety exhibit unique chemical properties and serve as versatile synthons of transition-metal-catalysed skeletal reorganizations of enynes in organic synthesis33–42. For example, ynamides could act as have been explored for efficient synthesis of polycyclic com- flexible cyclization partners in heterocycle synthesis43–45, carbene pounds6–10. Recently, Sun and co-workers discovered an unusual precursors46–49 and enamide precursors50,51, racemization-free skeletal reorganization of oxetane for the synthesis of 1,2-dihy- coupling reagents for peptide and macrolide synthesis52–54 and C2 droquinolines (Fig. 1b)11. Meanwhile, Liu and co-workers estab- building blocks of multicomponent reactions)55–57. In recent lished a skeletal reorganization protocol of olefine via a radical- years, the intramolecular cyclizations of ynamides, including initiated cyclization/1,n (n = 3, 4, 5) vinyl migration cascade for transition-metal-catalysed and Brønsted acid-catalysed nucleo- accessing medium- and large-sized cycles, which are ubiquitous philic cyclizations, anionic cyclizations and radical cyclizations, structural motifs in natural products and pharmaceutical agents have been extensively investigated for the synthesis of N-hetero- (Fig. 1c)12. Very recently, Zhu and co-workers reported a novel cycles (Fig. 3a)58–61. However, the skeletal reorganization of skeletal reorganization of kojic acid- or maltol-derived alkynes ynamides is rarely reported. In 2012, Evano and co-workers under Indium catalysis, which provided an expeditious access to reported an s-BuLi-mediated skeletal reorganization of N-Boc valuable hydroxylated benzofurans (Fig. 1d)13. Despite these ynamides for de novo synthesis of 1,4-dihydropyridines and advances, the investigation of skeletal reorganizations toward pyridines, which invoked a process of carbonyl-directed depro- synthetically challenging and biologically interesting molecules tonation and anionic 6-endo-dig cyclization (Fig. 3b)62. Encour- remains continuously interesting and important. aged by these, we hypothesized that the deprotonation at the α- The four-membered sulfur-containing heterocycles, such as position of sulfonyl moiety of N-sulfonyl ynamides might initiate thiete sulfones, thietane sulfones and thietanes, are strained small an anionic 4-exo-dig or 5-endo-dig cyclization to deliver cyclic ring compounds that have found wide applications in the dis- sulfonamides, which are privileged structures in medicinal covery of dye, drug and pesticide (Fig. 2)14–19. Typically, the chemistry (Fig. 3c)63,64. In continuation of our interests in yna- unsaturated thiete sulfones showed valuable synthetic utility in mide chemistry55–57,65, herein we would like to report a skeletal organic synthesis. For example, thiete sulfones could be used as reorganization divergence of N-sulfonyl ynamides for selective dienophiles in the Diels–Alder reaction with tetraphenyl cyclo- entry to thiete sulfones and propargyl sulfonamides (Fig. 3d). pentadienones or isobenzofurans for accessing bridged and fused- – ring compounds20 22. Moreover, they could participate in [3 + 2] Results cycloadditions with diazo compounds or nitrile oxides for the Reaction optimization. We commenced our study by using N- synthesis of heterocycles23,24. Recently, thiete sulfones have been sulfonyl ynamide 1a and lithium base to investigate this reaction. a Bond cleavage and formation Molecule framework reassembly b c R 2 R2 R R 8-14 Rf • N HO O N In(OTf) O 3 Xn R1 R1 Xn R3 Rf 3 R X = C, O; n = 1~3 d 4 1 5 R O R O R O HO 4 O 5 R In(OTf)3 R R1 R6 R3 R6 R3 O R2 O OH R2 Kojic acid derived Maltol derived Hydroxylated benzofurans O • • O • Aldol reaction 5-endo-dig • H2O O • Aromatization O • • In O • In Fig. 1 Skeletal reorganization. a Scheme of a skeletal reorganization in molecules. b In-catalysed skeletal reorganization of oxetanes. c Radical-initiated skeletal reorganization of olefines. d In-catalysed skeletal reorganization of kojic acid- or maltol-derived alkynes. 2 NATURE COMMUNICATIONS | (2020) 11:5639 | https://doi.org/10.1038/s41467-020-19467-5 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19467-5 ARTICLE Et Me O N O Me N O S S S O S OCF2H O O N Me S O OMe Et O Cyanine dye Antidepressant agent Phosphodiesterase inhibitor HO O OH HO O S O Boc Boc Cl Me Me N NH O NH O H Ph Ph O S O S H H Cl HO HO OBz HO HO OBz N CF O 3 Taxol derivatives Pesticide Fig. 2 Sulfur-containing four-membered ring in useful molecules. Some representative cases are listed. a R Nu Transition metal Nu Radical cyclization Nu R or 1 1 1 N R N R N N R Brønsted acid 1 N 1 EWG EWG R EWG R EWG EWG (EWG = electron-withdrawing group) b Boc t-BuO O t-BuO O t-BuO O Boc N N N s-BuLi N Li N N or 1 1 2 R 1 1 1 R R 2 R R Li R Li 1 2 R TMEDA 2 2 2 R R R R R R3 3 3 R R3 R3 R3 R 6-endo-dig c O R3 S O N 1 3 R R2 R3 R O O 4-exo-dig H S Deprotonation S O R1 N R1 N O R3 R2 R2 5-endo-dig O R1 S O N R2 d O O 2 Skeletal reorganization divergence S SO2NHR O S LDA O LDA R1 N Unusual outcome 2 1 2 R DMPU R NHR Broad substrate scope R1 Fig. 3 Skeletal reorganization of ynamides. a Intramolecular cyclizations of ynamides. b Skeletal reorganization of N-Boc ynamides. c Our initial hypothesis. d This work: Skeletal reorganization divergence of N-sulfonyl ynamides. As shown in Table 1, we initially treated 1a with n-BuLi at −40 °C occurrence of skeletal reorganization. This unexpected outcome for 1 h and then quenched with MeOH; a new major product 2a prompted us to optimize the reaction. The next survey of lithium and a minor product 3a were isolated (entry 1). The standard bases showed that lithium diisopropylamine (LDA) was superior analysis, including 1H nuclear magnetic resonance (NMR), 13C to give 2a in 72% yield (entry 2), while the utilization of lithium NMR and mass spectroscopy, was not able to identify these bis(trimethylsilyl)amide would decrease the yield to 31% (entry 3). compounds. Gratifyingly, the X-ray analysis showed that 2a was a The use of sodium bis(trimethylsilyl)amide and potassium bis thiete sulfone and 3a was a propargyl sulfonamide (for more (trimethylsilyl)amide as base could only give 3a in very low yield details, see Supplementary Figs. 8 and 9), indicating an unusual (entries 4–5). Using NaH, 1,8-diazabicyclo[5.4.0]undec-7-ene or NATURE COMMUNICATIONS | (2020) 11:5639 | https://doi.org/10.1038/s41467-020-19467-5 | www.nature.com/naturecommunications 3 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-19467-5 Table 1 Reaction optimizationa. Me O Me Me SO NHn-Pr O 2 O S Me Me S Reaction condition Me O + Ph N n-Pr Ph NHn-Pr Ph 1a 2a 3a Entry Base Additive Solvent T (°C) Yield of 2a (%)b Yield of 3a (%)b 1 n-BuLi None THF −40 60 19 2 LDA None THF −40 72 18 3 LiHMDS None THF −40 31 0 4 NaHMDS None THF −40 0 14 5 KHMDS None THF −40 0 16 6 NaH None THF 25 0 0 7 DBU None THF 25 0 0 8 TEA None THF 25 0 0 9 LDA None THF 0 68 19 10 LDA None THF −78 65 21 11 LDA TMEDA THF −40 63 16 12 LDA DMPU THF −40 Trace 82 LDA lithium diisopropylamine, LiHMDS lithium bis(trimethylsilyl)amide, NaHMDS sodium bis(trimethylsilyl)amide, KHMDS potassium bis(trimethylsilyl)amide, DBU 1,8-diazabicyclo[5.4.0]undec-7-ene, TEA trimethylamine, TMEDA N,N,N’,N’-tetramethylethylenediamine, DMPU 1,3-dimethyl-tetrahydropyrimidin-2(1H)-one.
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