The synthesis of a unique isoindoline- and tetrahydroisoquinoline (THIQ)-containing tricyclic sultam library, utilizing a Heck-aza-Michael (HaM) strategy is reported. Both isoindoline and THIQ rings are installed through a Heck reaction on a vinylsulfonamide, followed by one-pot deprotection and intramolecular aza-Michael reaction. Subsequent cyclization with either paraformaldehyde condensation or 1,1'-carbonyldiimidazole coupling generates a variety of tricyclic sultams. Overall, a 160-member library of these sultams, together with their isoindolines/THIQ and secondary sulfonamides precursors, were constructed using this strategy.
The construction of a 225-member (3 × 5 × 15) library of thiadiazepan-1,1-dioxide-4-ones was performed on a Chemspeed Accelerator (SLT-100) automated parallel synthesis platform, culminating in the successful preparation of 184/225 sultams. Three sultam core scaffolds were prepared based upon the utilization of an aza-Michael reaction on a multifunctional vinyl sulfonamide linchpin. The library exploits peripheral diversity in the form of a sequential, twostep [3 + 2] Huisgen cycloaddition/Pd-catalyzed Suzuki-Miyaura coupling sequence.
Applications of silica-ROMP
reagents in a one-pot, sequential protocol
have been developed for the synthesis of a variety of diverse benzoxathiazepine
1,1-dioxides. This protocol includes sulfonylation, intramolecular
SNAr, alkylation with silica-supported oligomeric benzyl
(Si-OBPn) and triazole (Si-OTPn) phosphates, and intermolecular SNAr
addition with a number of secondary amines in one-pot to afford a
variety of unique benzoxathiazepine 1,1-dioxides sultams in good to
excellent yields.
A one-pot, sequential protocol is reported that involves complementary ambiphile pairing (CAP) of a vinyl sulfonamide with a variety of unprotected amino acids via aza-Michael addition and subsequent intramolecular amidation. The method generates diverse, sp3-rich mono- and bicyclic acyl sultams in a highly scalable manner. Modular pairing of stereochemically rich building blocks allows quick access to all possible isomers. Extension to include one-pot, sequential 3-, 4- and 5-multicomponent protocols is also discussed.
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