Syntheses of 2,3-Dihydro-1,4-Benzodioxins and Bioisosteres as Structural Motifs for Biologically Active Compounds

Abstract

The 2,3-dihydro-1,4-benzodioxin ring system is present in a large number of structures of therapeutic agents possessing important biological activities. Some of them are antihypertensive agents. Others are involved in nervous breakdown and schizophrenia or represent an attractive therapeutic target for the treatment of glaucoma. The 2,3-dihydro-1,4-benzodioxin core has also been developed for the synthesis of inhibitors of 5-lipoxygenase and accordingly, these 2,3-dihydro-1,4-benzodioxins are useful for the treatment of inflammatory diseases such as asthma and arthritis. The synthesis and reactivity of several bioisosteres of the non-aromatic ring will be discussed. The occurrence of the 2,3-dihydro-1,4-benzodioxin structure in various naturally abundant compounds is also known. The total synthesis of angustureine (a novel 1,2,3,4-tetrahydroquinoline alkaloid with a n-pentyl side chain at position 2) will be presented. The bioisosteric replacement of benzene by pyridine in compounds containing the 2-substituted-2,3-dihydro-1,4-benzodioxin core has yielded derivatives of biological interest in diverse therapeutic areas such as central nervous system and cardiovascular diseases. These promising results have prompted interest in the area of 1,4-dioxino-[2,3-b]pyridine analogues. Several modifications on both the aromatic and the non-aromatic rings will be reviewed, including several transformations of the new heterocycles, such as the Smiles rearrangement. Moreover, the enantiomers of 2-and 3-hydroxymethyl-2,3-dihydro-1,4-dioxino-[2,3-b]pyridines, important chiral building blocks for the preparation of several biologically active compounds, have been synthesized. We have made an attempt to take into account the largest possible number of original papers, including our research and others. Publications of the last eleven years are included in this review.

Efficient enzymatic synthesis of chiral 2,3-dihydro-1,4-benzodioxane motif using engineered Candida antarctica lipase B

“…The chiral motif of 2,3-dihydro-1,4 benzodioxane is widely used in various biologically active natural products and therapeutic agents with crucial biological activity. [1][2][3][4] It has been proven that the absolute conguration of the C 2 stereo centroid of benzodioxane greatly inuences its biological activity. 5 Several 1,4benzodioxanes have displayed intriguing characteristics as aor b-blocking agents, exhibiting antihypertensive properties.…”

Synthesis, unambiguous chemical characterization, and reactivity of 2,3,4,5-tetrahydro-1,5-benzoxazepines-3-ol

“…1 We have recently reviewed the chemistry of 2,3-dihydro-1,4 benzodioxins and bioisosteres as structural motifs for biologically active compounds. 2 We used the bioisosteres 3,4-dihydro-2H-1,5-benzoxathiepine-3-ol 2 and 2,3-dihydro-1,4-benzoxathiine-2-methanol 3 (Fig. 1) as intermediates to obtain a series of substituted-9-(2,3-dihydro-1,4-benzoxathiine-3-and -2-ylmethyl) purine derivatives with notable antiproliferative activities.…”