Synthesis of a Library of 1,5,2-Dithiazepine 1,1-Dioxides. Part 2: Routes to Bicyclic Sultams.

Sultams have attracted attention recently due to their potent biological activity.1,2 In particular, a number of 7-membered thiazepane 1,1-dioxide-containing compounds have shown interesting bioactivities. Some representative examples include mitogen-activated protein (MAP) kinases inhibitor A,3 CCR2, CCR5, and/or CCR3 antagonist B,4 PKC-theta inhibitor C for the treatment of inflammatory diseases,5 thiadiazepinoindole D, an inhibitor of BACE-1 for treatment of Alzheimer's disease;6 platelet aggregation inhibitor E,7 derivatives of avermectin monosaccharide F and G with pesticidal properties,8 and HIV integrase inhibitor H (Figure 1).9 Figure 1 Bioactive thiazepanes. Despite the diverse biological activity of thiazepane 1,1-dioxides shown in Figure 1, the synthesis of bicyclic sultams incorporating this type of moiety is limited.10,11 The reported methodologies for other non-benzofused bicyclic sultams include Diels-Alder reaction,12 1,3-dipolar cycloaddition,13 Pauson Khand cyclization,14 RCM,15 Heck-type cyclization,16 oxa-Michael and Baylis-Hillman reaction,17 as well as oxidation from isothiazole.18 In this regard, we sought simple installation of an additional ring to the previously reported 1,5,2-dithiazepine 1,1-dioxide scaffolds in order to enrich our collection of sultam chemotypes. In previous work, we reported a one-pot sulfonylation/intramolecular thia-Michael protocol for the synthesis of 1,5,2-dithiazepine 1,1-dioxide scaffolds (Scheme 1). The reaction was carried out up to 40-gram scale (cysteine ethyl ester), and about 20 grams of the desired product 3b was obtained after recrystallization (CHCl3) in a single reaction step. With the large quantity of scaffold 3b in hand, we set out to utilize the free sulfonamide N-H and a nearby ester group for initial functional group manipulations, followed by additional cyclization. Scheme 1 The synthesis of core scaffolds 3 Initial coupling of sultam 3b and Boc-protected amino acids started investigations of secondary cyclization pathways to form fused sultams (Scheme 2). Subsequently, Boc removal from coupling product 4 with TFA and quenching with water enabled in situ cyclization to 5. Three amino acids, leucine, methionine, and isoleucine were used to generate the three corresponding (R)-hexahydropyrazino[1,2-b] [1,5,2]dithiazepine-6,9-dione 1,1-dioxides (5a–c) (Scheme 2). Scheme 2 Secondary cyclization strategies toward (R)-hexahydropyrazino[1,2-b][1,5,2]dithiazepine-6,9-dione 1,1-dioxides (5a–c) A number of N-substituted (R)-dihydro-2H-imidazo[1,5-b][1,5,2]dithiazepine-6,8(3H,7H)-dione 1,1-dioxides (6a–d) were synthesized by treatment of 3b with isocyanates under basic condition (K2CO3) in THF (Scheme 3). In this reaction, nucleophilic addition of sulfonamide to the isocyanate formed urea intermediates, which were shown to rapidly undergo in situ cyclization at room temperature with the neighboring ester group to afford the bicyclic product in good to excellent yields. Scheme 3 Secondary cyclization strategies toward (R)-dihydro-2H-imidazo[1,5-b][1,5,2]dithiazepine-6,8(3H,7H)-dione 1,1-dioxides (6a–d) Alternatively, the ester group in 3b was reduced and mesylated to generate 7, which could be further reacted with secondary amines in simple nucleophilic substitutions to form 8, while reaction with primary amines afforded 9, and thus providing additional cyclization manifolds to explore. To this end, sultams 9a–c were reacted with 1,1'-carbonyldiimidazole (CDI), 1,2-dibromoethane, and paraformaldehyde to provide bicyclic products 10, 11, and 12, respectively (Scheme 4). It should be mentioned that the yield for compounds 11a–c were generally low. We envisioned it is because the difficulty in the alkylation of the sulfonamide due to its low nucleophilicity. Scheme 4 Secondary cyclization strategies toward diverse bicyclic sultams In conclusion, we have successfully developed five different strategies for the production of different bicyclic sultams, namely (R)-hexahydropyrazino[1,2-b] [1,5,2]dithiazepine-6,9-dione 1,1-dioxides (5), (R)-dihydro-2H-imidazo[1,5-b][1,5,2]dithiazepine-6,8(3H,7H)-dione 1,1-dioxides (6), (R)-hexahydro-2H-imidazo[1,5-b][1,5,2]dithiazepine 1,1-dioxides (10), (R)-octahydropyrazino[1,2-b][1,5,2]dithiazepine 1,1-dioxides (11), and (R)-tetrahydro-2H-imidazo[1,5-b][1,5,2]dithiazepin-8(3H)-one 1,1-dioxides (12). To the best of our knowledge, these bicyclic systems containing the 1,5,2-dithiazepine 1,1-dioxide motif have not been previously reported. The compounds produced are under screening within the NIH Molecular Library Screening Network (NIH-MLSCN) and with other biological collaborators.