Transition-Metal-Free Total Synthesis and Revision of the Absolute Configuration of Pipermethystine

Abstract

Starting from 3-hydroxy piperidines, a novel transition-metal-free strategy to 5-hydroxy-5,6-dihydro-2­(1H)­pyridones is reported. This unprecedented approach, which provides a practical, economical, and ecofriendly alternative to either the classical ring-closing metathesis of N-homoallyl-unsaturated amides or the dehydrogenation of amides, occurs by means of a triple C–H functionalization of three unreactive piperidine sp3 carbons. The completion of the total synthesis revealed that the natural levo-isomer possesses the R absolute configuration, not S.

Transition‐Metal‐Free Methods for the Remote C−H Bond Functionalization of Cyclic Amines

“…When compound 35 is used as the substrate, a Grignard reagent conjugate addition‐electrophile trapping reaction sequence affords versatile 4‐substituted and 3,4‐disubstituted 2‐piperidones such as compound 36 . This method is applicable to the synthesis of a few drug molecules including vesamicol, paroxetine and femoxetine, and later to the total synthesis and revision of the absolute configuration of bioactive alkaloid pipermethystine [37] . The series of work developed by the Sartillo‐Piscil group for the C−H bond functionalization of cyclic amines under transition metal‐free conditions mediated by NaClO 2 was later reviewed by Sartillo‐Piscil and co‐workers themselves in 2021 [38] .…”

“…This method is applicable to the synthesis of a few drug molecules including vesamicol, paroxetine and femoxetine, and later to the total synthesis and revision of the absolute configuration of bioactive alkaloid pipermethystine. [37] The series of work developed by the Sartillo-Piscil group for the CÀ H bond functionalization of cyclic amines under transition metal-free conditions mediated by NaClO 2 was later reviewed by Sartillo-Piscil and co-workers themselves in 2021. [38] In 2019, Fan and co-workers developed an oxidative β-nitration of N-aryl cyclic amines (Scheme 16).…”

Organic Synthesis Using Nitroxides

“…Upon heating 78 to 140 °C, the C–O bond is homolytically cleaved and subsequent hydrogen abstraction by TEMPO delivers dihydropyridinone 79 in a formal TEMPOH elimination (Scheme b) . This sequence was successfully applied to the total synthesis of pipermethystine (not shown) . Oxidation of lactam 78 with m CPBA leads to the α-ketoamide 80 , which readily reacts via Baeyer–Villiger oxidation and subsequent decarboxylation to the γ-lactam 82 (Scheme c) .…”

Transition-Metal-Free Functionalization of Saturated and Unsaturated Amines to Bioactive Alkaloids Mediated by Sodium Chlorite

“…The shortcoming of the synthesis of glycidic amides was the poor diastereoselectivities when chiral auxiliaries such as (S)--methylbenzylamine, (S)-4-methoxy--methylbenzylamine, and (R)-2-phenylglycinol were used. In an attempt to address this drawback, the chiral auxiliary derived from L-prolinol (40) was prepared and tested under the established reaction conditions; however, cinnamic acid and prolinol 42 were obtained instead of the glycidic amide 41. 33 Wondering if free-radical intermediates are formed during this reaction; it was decided to trap them by adding a radical scavenger (Scheme 9a).…”

“…Acetylation of (R)-63 employing acetic anhy-dride and a Mitsunobu reaction with AcOH generated the stereoisomers (R)-64 and (S)-64, respectively, which were debenzylated with CAN and acylated with 3-phenylpropionyl chloride producing (+)-and (-)-pipermethystine (Scheme 17). 40 The total synthesis of both enantiomers of pipermethystine from 3-hydroxipiperidine (R)-62 permitted also the revision of the configurational assignment of the natural product.…”