Transition‐Metal‐Free Deconstructive Lactamization of Piperidines

Abstract

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.

Selective Deconstructive Lactamization of the Indolo[2,3‐a]quinolizine Skeleton for the Total Synthesis of (+) and (−)‐Cuscutamine

“…Having in hand both indolo[2,3‐ a ]quinolizine precursors 1 a and 1 b , we proceeded to transform them into their corresponding hexahydroindolizin‐3‐ones 6 a and 6 b , respectively, via the title reaction. Under reported reaction conditions, [4] in which the TEMPO + salt is formed in situ by TEMPO oxidation, [8] the dual C−H oxidation of 1 a and 1 b to 5 a and 5 b , respectively, occurred in low and moderate chemical yield, depending on the substrate stereochemistry (Table 1). For instance, whereas precursor 1 a gave low yield under standard reaction conditions, precursor 1 b gave much better results under the same reaction conditions (Table 1, entries 1 and 2).…”

“…Completion of the deconstructive lactamization of 1 a and 1 b was achieved when diastereomeric indolo[2,3-a]quinolizines 5 a and 5 b were transformed into hexahydroindolizin-3-ones 6 a and 6 b in 45 % and 50 % yields, respectively, by employing 5 equivalents of m-CPBA (Scheme 3). [4] We next proceeded to complete the synthesis of naturally occurring cuscutamine, which has been isolated from three different natural sources. First from Clerodendron trichotomum thunb by Irikawa and coworkers; however, they did not report NMR and optical rotation data.…”

“…The residue was purified by column chromatography [SiO 2 , hexanes/EtOAc; 6 : 1 until TEMPO came out of the column, then 3 : 1] to give 0.113 g (50 %) of 6 b as a white solid. [4]…”

“…[3b,c] In this regard, we recently reported a new way for accessing to γ-lactams by means of the deconstruction of tertiary piperidines through the following sequence: alkoxyaminolactam!α-ketolactam!N-carboxyanhydride (Scheme 1, reaction 1). [4] Additionally, this transition-metal-free deconstructive lactamization (TMFDL) reaction was employed to prepare some relevant lactams such as the indole γ-lactam, which provided the synthesis of (+)-harmicine after the application of the Bischler-Napieralski reaction (Scheme 1, reaction 2). Accordingly, we decided to challenge this sequential transformations in a more complicated structural system such as the 11carboxylate-indolo[2,3-a]quinolizine, from which, we would get access into hexahydroindolizin-3-one skeleton of the naturally occurring (+)-cuscutamine, in a straightforward and unprecedented manner (Scheme 1, reaction 3).…”

“…In this regard, we recently reported a new way for accessing to γ‐lactams by means of the deconstruction of tertiary piperidines through the following sequence: alkoxyaminolactam→α‐ketolactam→ N ‐carboxyanhydride (Scheme 1, reaction 1) [4] . Additionally, this transition‐metal‐free deconstructive lactamization (TMFDL) reaction was employed to prepare some relevant lactams such as the indole γ‐lactam, which provided the synthesis of (+)‐harmicine after the application of the Bischler‐Napieralski reaction (Scheme 1, reaction 2).…”