A Mechanistically Inspired Halenium Ion Initiated Spiroketalization: Entry to Mono‐ and Dibromospiroketals

Abstract

Employing halenium affinity (HalA) as a guiding tool, the weak nucleophilic character of alkyl ketones was modulated by the templating effect of a tethered 2‐tetrahydropyranyl(THP)‐protected alcohol towards realizing a bromenium ion initiated spiroketalization cascade. Addition of ethanol aided an early termination of the cascade by scavenging the THP group after the halofunctionalization stage, furnishing monobromospiroketals. Alternatively, exclusion of ethanol from the reaction mixture biased the transient oxocarbenium towards α‐deprotonation that precedes a second bromofunctionalization event thus, furnishing dibrominated spiroketals. The regio‐ and stereoselectivity exploited in the current methodology provides a novel and rapid access to the dibrominated spiroketal motifs exhibited by several natural products.

Photoexcited Palladium-Initiated Remote Desaturation of N-Alkoxypyridinium Salts

“…1 H NMR (400 MHz, Chloroform-d) δ 7.34–7.29 (m, 2H), 7.02–6.96 (m, 2H), 6.46 (d, J = 15.9 Hz, 1H), 6.12 (dt, J = 15.8, 7.1 Hz, 1H), 3.77–3.74 (m, 2H), 2.50–2.45 (m, 2H), 1.52 (s, 1H); 13 C­{ 1 H} NMR (101 MHz, Chloroform-d) δ 162.1 (d, J = 247.1 Hz), 133.4 (d, J = 3.4 Hz), 131.6, 127.5 (d, J = 8.0 Hz), 126.1­(d, J = 2.3 Hz), 115.4 (d, J = 21.5 Hz), 62.0, 36.3; 19 F NMR (376 MHz, Chloroform-d) δ −115.1. The spectroscopic properties were consistent with the data available in the literature …”

“…The spectroscopic properties were consistent with the data available in the literature. 24 (E)-4-(4-Chlorophenyl)but-3-en-1-ol (2e). Prepared according to General Procedure A, corresponding N-alkoxypyridinium salt 1e (0.1 mmol) was employed.…”

Structure Guided Design of VANOL-Imidodiphosphorimidate Catalysts for the Catalytic Enantioselective Bromospiroketalization Reaction

“…These results suggest the catalyst's structural bias toward trans-olefins for optimum stereoinduction. Unlike the intramolecular halocyclizations of cis-olefins, 23,26,52 we did not observe any 5-exo products arising from the catalytic spiroketalization of 4m and 4n, suggesting a requisite structural preorganization of the catalyst-substrate complex. Intriguingly, the EWG p-CF 3 in substrate 4o (Scheme 2) furnished a 1:1 mixture of 6-endo and 5-exo products.…”

“…Returning to the transformation depicted in Figure 2b, the weak nucleophilic character of alkenyl ketones such as 4a (HalA(Br) 138.7 kcal/mol) was modulated by the templating effect of a tethered THP-protected alcohol as in structure 4a′ (HalA(Br) 141.6 kcal/mol) toward realizing a bromenium atom initiated spiroketalization cascade. 23 The addition of ethanol aided an early termination of the cascade by scavenging the THP group after the halofunctionalization stage, furnishing monobromospiroketals 5.…”

“…With an excellent diastereoselective spiroketalization reaction in hand, our next goal was to develop the enantioselective version of this transformation. We had previously shown the exceptional performance of cinchona alkaloid dimers in delivering enantioenriched halogenated products, both intra- and intermolecularly .…”