Pyrrolo-benzothiadiazepines

Reduction of nitro glyoxylic ester 334 with iron powder in acetic acid into pyrrolo-benzothiadiazepine 335 represents a type (i) intramolecular cyclization (Equation (39) (1996JHC2019)). 

Another example of type (iii) intramolecular cyclization is the final step of a multistep synthesis of a series of substituted pyrrolo-benzothiadiazepines 344 

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As with pyrrolo-benzodiazepine (1992JHC1005), 0x0 derivative of pyrrolo-benzothiadiazepine 203 (X = SO2) can be synthesized by the thermal cyclization of intermediate 205 (Scheme 42, Section 3.1.1.2 (1992SC1433)). 

Fusion of the imidazole ring to pyrrolo-benzothiadiazepine 340 can be achieved by straightforward TosMIC cycloaddition approach (Scheme 72, Section 4.2 (1994JHC1033)). An alternative sequence starts with the addition of nitromethane to the C-N double bond on the thiadiazepine ring, nitro group reduction and manganese oxide oxidation of the intermediate dihydroimidazole derived from amine 342 and tiiethyl ortho formate. 

Oxidation on the sulfur atom of pyrrolo-benzothiazepine 175 (Scheme 34, Section 2.3.1 (1994MI283)), indolo benzothiazepine (Scheme 65, Section 3.3.1.2 (1998MI139)) and pyrrolo-benzothiadiazepine (Scheme 74, Section 4.2 (1994SC2685)) proceeds smoothly with hydrogen peroxide in acetic acid or with MCPBA to afford cyclic sulfones in good yields. 

Type (ii) cyclizations are more common. Thus, acid derivatives of pyrrolo[l,2-f>]-[l,2,5]benzothiadiazepine 5,5-dioxide 346 and 347 have been prepared from amino sulfonyl pyrrole 345 with acetal (2006JMC5840) or the semiacetal (1994JHC867) of ethyl glyoxalate or ethyl 2,2-diethoxy propionate (1996FES425) in the presence of PTSA catalyst in boiling absolute ethanol by a Pictet-Spengler type of reaction (Scheme 73). 

Lithium hydroxide hydrolysis of the ester of pyrrolo[l,2-l7][l,2,5]benzothia-diazepine 5,5-dioxide 346 afforded the acid, subsequently reduced with lithium aluminum hydride-aluminum chloride to alcohol 348 (Scheme 73, Section 4.2 (2006JMC5840)). Pyrrolo[l,2- 7][l,2,5]benzothiadiazepine acid 347 gives easy access to a variety of esters and amides 407, while treatment with TFAA produces fused lactam 408 (Scheme 85 (1996FES425)). 

Pyrrolo[l,2- >]-l,2,5-benzothiadiazepine 1,1-dioxide (105) has been obtained by cyclization of the A(-formamide derivative (104), derived from l-(2-aminobenzenesulfonyl)pyrrole (103) and acetic formic anhydride, with phosphorus oxychloride via a Bischler-Napieralski reaction in 47% yield, or by iron powder-acetic acid reduction of the nitro-aldehyde derivative (106) and subsequent ring closure of the resulting aminoaldehyde intermediate in 92% yield <94JHC1033>. The reaction of (103) with ethyl glyoxylate hemiacetal via a Pictet-Spengler type condensation afforded the benzo-thiadiazepine (107) in a high yield (94%) <94JHC867> (Scheme 17). 

A series of sulfamide benzodiazepines 204 have been prepared and their p5 3-murine double minute 2 (MDM2) inhibitory activity and in vitro antitumor activity were evaluated (14MI15741). These heterocycles demonstrated moderate inhibition of p53 MDM2 protein—protein interaction. Intramolecular 1,3-dipolar cycloaddition of a l-(azidoarylsulfonyl)-2-alke-nyl pyrrolidine yielded aziridino-fused pyrrolo[l,2,5]benzothiadiazepine 205 as the only isolable product this system and other henzodiazepines are under investigation for antitumor and antibiotic potential (14MOL16737). 

The same authors reported further use of the intramolecular 1,3-dipolar cycloaddition method to prepare tetrazolo-fused pyrrolo[l,2,5]benzothia-diazepine 206 from an azide-nitrile cycloaddition reaction in 100% yield (14T7306). Another series of pyrrolo[l,2,5]benzothiadiazepines containing a previously unknown oxadiazolopyrrolobenzothiadiazepine nucleus 207 were also reported in the same paper, accessed by an alternative strategy. Future work will involve exploring the use of such tetracyclic systems as Glut-1 transporter inhibitors, which would indicate potential anticancer activity (14T7306). 

Chiral disulfonimides of the general structure 236 have been used as highly efficient catalysts for reactions such as an asymmetric Mannich reaction of silyl ketene acetals with A/-Boc-amino sulfones (13JA15334) as well as an asymmetric three-component synthesis of homoaUylic amines (13AGE2573). Analogs of pyrrolo[l,2,5]benzothiadiazepine 237a and the... 

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