Regio- and Stereodivergent Allylic Reductions of Bicyclic Piperidine Enecarbamate Derivatives

Abstract

The particular nature of tetrahydropyrido[4,3- e]-1,4,2-dioxazines of type 1 allows the regio- and stereoselective obtainment of substituted N-carbamoyl tetrahydropyridines by common reducing agents. A completely novel, biologically active, bicyclic 1,3-diaza-4-oxa-[3.3.1]-nonene scaffold can be generated by the use of lithium triethylborohydride through unprecedented cascade syn-S2' reduction/carbamate reduction/cyclization reactions. The remarkable regioselectivity switches in the allylic reduction process have been rationalized with the aid of computational studies.

Nitroso Diels-Alder Cycloadducts Derived From N-Acyl-1,2-dihydropyridines as a New Platform to Molecular Diversity

“…It is also likely that the concomitant reduction of the carbamate moiety of species 44 gives rise to a zwitterionic iminium ion 45 that undergoes intramolecular trapping by N-alkylation to deliver the bicyclic framework 43. In accordance with the proposed mechanism, the formation of such a bicyclic framework necessarily requires the presence of a carbamate protecting group on the endocyclic piperidine nitrogen [45].…”

“…To our knowledge, the first and unique example of a reductive manipulation of a bicyclic 1,4,2-dioxazine have been described in the previous paragraph for the synthesis of iminosugars (see Scheme 14) [39]. Basically, twenty-eight years later, Pineschi and co-workers chanced upon a diversification on the behavior of dioxazines in the presence of different combinations of hydride sources and/or metal catalysts [45]. Some preliminary unpublished results had already shown the different behavior of dioxazines in diverse catalyzed reductive protocols.…”

“…Interestingly, 2,3-disubstituted piperidine scaffolds (type 39) represent a pharmaceutically interesting molecular skeleton, since this motif is included into non-peptidic human neurokinin-1 (NK1) substance P receptor antagonists, natural products, antiprotozoal agent and potential chemotherapeutic agents [48][49][50]. The use of common reducing agents, with or without palladium catalysts, provided selectively ∆ 2,3 -or ∆ 3,4 -piperidine derivatives 41 and 42 with unconventional substitution patterns [45]. In particular, NaBH 4 or LiBH 4 in presence of 5 mol % of (CH 3 CN)PdCl 2 gave selectively compound 42.…”

“…Furthermore, with Pd(dba) 2 , a 63/37 mixture of 42 and 43 was detected. Importantly, it was noticed that the selective formation of compound 43 can be also achieved in moderate to good yields without any palladium-based catalysts starting from carbamate-protected dioxazines [45]. The attainment of compound 43 having a novel 1,3-diazo-4-oxa-bicyclic-[3.3.1]-nonene architecture has been fully rationalized by means of a cascade reaction (Scheme 22).…”

Recent Progresses in the Catalytic Stereoselective Dearomatization of Pyridines

“…Nonaromatic six-membered azaheterocycles are privileged structures present in a variety of natural compounds, small molecule drugs, and agrochemicals [3]. In this context, the synthesis and applications of dihydropyridines continue to attract considerable interest di per se and also due to the presence of two double bonds that can be further elaborated in a regio-and stereoselective fashion to give highly substituted tetrahydropyridines and piperidines [4] or to impart molecular diversity in a DOS approach [5][6][7]. N-Substituted 2-pyridones are also important compounds found in many natural products and medicinally relevant molecules [8,9] that can be obtained in a stereoselective fashion by the use of dearomative asymmetric procedures.…”