Pyrrolo oxazine-1,4-diones

Snyder DS, Tradtrantip L, Yao C, Kurth MJ, Verkman AS (2011) Potent, metaboUcaUy stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease. J Med Chem 54 5468-5477... 

The 3,5-diphenylmorpholine-2-one 161 was used to prepare bicyclic lactams 162 by reaction with the cesium fluoride/tetramethoxysilane system and different Michael acceptors. The adducts were rapidly obtained as a mixture of diastereoisomers that could be separated by column chromatography just after TFA-mediated cyclization to the 8-substituted-4,8a-diphenyltetrahydro-l//-pyrrolo[2,l-r1[l,4]oxazine-l,6(7//)-diones 62 and 163 <1997SL935>. These compounds were then reduced to give substituted prolines as described in Section 11.11.6.1. 

A series of enantiomerically pure tetrahydro-l//-pyrrolo[2,l-c][l,4]oxazine-l,4(3//)-diones 86a-d have been prepared by bromolactonization of acrylamides derived from proline mediated by NBS (Equation 5). These compounds... 

The 3-chloro-l,7-dimethylpyridazino[3,4-(7][l,3]oxazine-4,5-dione (149) was prepared in a four-step synthesis starting with (Z)-methyl-3-(3,6-dichloro-l-methyl-4-oxo-l,4-dihydropyridazin-5-yl)-2-methylacrylate (146) which is converted with sodium azide into the 6-azido compound (147). Heating in o-dichlorobenzene at 150°C results in cyclization to methyl 3-chloro-l,6-dimethyl-4-oxo-1,4-dihydro(7//)pyrrolo[2,3-c]pyridazine-5-carboxylate (148) via a nitrene intermediate. Ozonolysis effects ring-enlargement of the pyrrole ring into the 3-chloro-l,7-dimethylpyridazino[3,4-d][l,3]oxazine-4,5-dione (149) (Scheme 26) <79JHC1213>. 

---