Chiral Pyridin-3-ones and Pyridines: Syntheses of Enantiopure 2,4-Disubstituted 6-Hydroxy-1,6-Dihydro-2H-Pyridin-3-ones, 2,3-Disubstituted 4-Iodopyridines, and Enantiopure 2,3-Disubstituted 4-Pyridinemethanols

Abstract

The development of an innovative method to access enantiopure 2,4-disubstituted 6-hydroxy-1,6-dihydro-2H-pyridin-3-ones starting from D-glucal via the aza-Achmatowicz transformation has been described. These highly functionalized pyridin-3-ones have been utilized for the synthesis of contiguously substituted pyridines through a rapid and efficient Et(3)N/Ac(2)O promoted cyclo-elimination, aromatization cascade, allowing the facile assembly of important pyridine-based building blocks like 2-substituted 3-acetoxy-4-iodopyridines and enantiopure 2-substituted 3-acetoxy-4-pyridinemethanols possessing benzylic stereogenic centers, whose synthesis otherwise would be tedious. The utilization of commercially available sugars as starting materials, mild reaction conditions, catalytic transfer hydrogen (CTH) of α-furfuryl azide derivatives, transfer of chiral aryl/alkyl methanols from enulosides to pyridin-3-ones and pyridines, high yields, and short reaction times are key features of this method. The utility of the method has been further exemplified by demonstrating the usage of the 2-substituted 3-acetoxy-4-iodopyridine for the construction of biologically significant molecules like 2,7-disubstituted furo[2,3-c]pyridines and 7,7'-disubstituted 2,2'-bifuro[2,3-c]pyridines.

Conjugation‐Driven Cascade Approach to Enantiopure Pyrano‐Fused 1,5‐Benzodiazepines by Tandem Condensation/[3,3]‐Sigmatropic Rearrangement/Aza‐Michael Addition–Elimination

“…To further explore the scope and generality of above method, two more previously synthesized MBH acetates 7a and 7b were tested. The MBH acetates 7a and 7b were prepared by acetylation of their respective adducts reported earlier from our laboratory (see the representative procedure for the synthesis of compounds 4b – f from 3b – f in the Experimental Section) 17,21. MBH acetate 7a was allowed to react with 4,5‐dimethyl‐1,2‐benzenediamine ( 5b ) at room temperature to obtain benzodiazepines 8a and 8b as a column‐separable diastereomeric mixture (2:1) in 66 % overall yield 22.…”

“…This prompted us to exploit the sugar‐based MBH acetates 4b – f for the construction of pyrano‐fused 1,5‐benzodiazepines. The synthesis of the acetate 4a and its utilization as precursor for the synthesis of molecules of biological significance was reported from our laboratory 15–17…”

The Aza‐Achmatowicz Reaction: Facile Entry into Functionalized Piperidinones

“…Closely related to the work by Nelson, Shaw and co‐workers unexpectedly obtained pyridines 224a – d while investigating the acetylation of aza‐Achmatowicz products 221a – d (Scheme ) 56. Recognizing this unexpected reaction as a novel approach to 2,4‐disubstituted 3‐acetoxypyridines, the authors extended the scope by preparing 4‐iodopyridine 225 starting from piperidinone 223 , which was readily obtained by treatment of 222 with iodine and base.…”

Palladium‐Catalyzed Asymmetric Hydrogenation of α‐Acyloxy‐1‐arylethanones

“…The azide species 3 was prepared from 2 i in 71 % yield and 95 % ee , and then converted into 4 according to a literature procedure 1h. Similarly, the chiral 1,6‐dihydro‐2 H ‐pyridin‐3‐one 6 (an intermediate which can be used to prepare chiral pyridine‐3‐ones and pyridines species) was prepared from the intermediate 2 s via 5 (Scheme ) 2f…”