One of the major challenges in organic synthesis is the activation or deconstructive functionalization of unreactive C(sp3)–C(sp3) bonds, which requires using transition or precious metal catalysts. We present here an alternative: the deconstructive lactamization of piperidines without using transition metal catalysts. To this end, we use 3‐alkoxyamino‐2‐piperidones, which were prepared from piperidines through a dual C(sp3)–H oxidation, as transitory intermediates. Experimental and theoretical studies confirm that this unprecedented lactamization occurs in a tandem manner involving an oxidative deamination of 3‐alkoxyamino‐2‐piperidones to 3‐keto‐2‐piperidones, followed by a regioselective Baeyer–Villiger oxidation to give N‐carboxyanhydride intermediates, which finally undergo a spontaneous and concerted decarboxylative intramolecular translactamization.
In recent years, several six-membered ring phosph(on)ates and phosphonamides have been reported as potent prodrugs against liver diseases such as hepatitis B and C and also as antitumor agents. Apparently, the success for their biological activity depends on the selective cleavage of the C4-O3 bond within the respective P-heterocyclic ring. Empirical observations have suggested that the group attached to the C4 position (aryl or pyridyl group) is responsible for the selective cleavage. In this regard, we show in the present work that the configuration at the P-atom, the conformation of the P-heterocyclic ring, and particularly, the anomeric effect are involved in the spontaneous and selective cleavage of the C4-O3 bond in cyclic phosph(on)ates. We arrived at this assumption based on the conformational and configurational study of simple model phosphates and phosphonates, where it was observed that the spontaneous conversion of unstable six-membered ring phosphates to their most stable six-membered ring phosphate (4d, 6d and 7d to 5d), by a selective C4-O3 bond cleavage, depends on both: the stereochemistry of the aryl group at C4 and the electronic nature of the substituent attached to the P-atom. Thus, we postulated that the anomeric effect weakens the C4-O3 bond within the 1,3,2-dioxaphosphorinane ring, favoring thus their selective cleavage and spontaneous conversion, similarly to the proposed mechanistic mode of action of six-membered ring P-heterocyclic prodrugs.
The
stereocontrolled synthesis of naturally occurring products
containing a 5,5-spiroketal molecular structure represents a major
synthetic problem. Moreover, in a previous work, the stereocontrolled
synthesis of cephalosporolide E (ceph E), which presumably was obtained
from its epimer congener (ceph F) through an acid-mediated equilibration
process, was reported. Consequently, we performed a theoretical investigation
to provide relevant information regarding the title question, and
it was found that the higher thermodynamic stability of ceph E, relative
to ceph F, is caused by an n → π* interaction between
a lone electron pair of the oxygen atom of the spiroketal ring (nO) and the antibonding orbital of the carbonyl group (π*C=O). Although similar stereoelectronic interactions have been
disclosed in other molecular structures, its presence in ceph E, and
very likely in other related naturally occurring products, represents
a novel nonanomeric stabilizing effect that should be introduced into
the chemical literature.
One of the major challenges in organic synthesis is the activation or deconstructive functionalization of unreactive C(sp 3 )-C(sp 3 )b onds,w hich requires using transition or precious metal catalysts.W ep resent here an alternative:t he deconstructive lactamization of piperidines without using transition metal catalysts.T ot his end, we use 3-alkoxyamino-2-piperidones,w hich were prepared from piperidines through adual C(sp 3 )-H oxidation, as transitory intermediates.Experimental and theoretical studies confirm that this unprecedented lactamization occurs in at andem manner involving an oxidative deamination of 3-alkoxyamino-2-piperidones to 3keto-2-piperidones,f ollowed by ar egioselective Baeyer-Villiger oxidation to give N-carboxyanhydride intermediates, which finally undergo aspontaneous and concerted decarboxylative intramolecular translactamization.
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