Piperidine ring

In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

Fig. 1. Conformational representation of the piperidine ring of morphine (1) and analogues meperidine (7, R = H, R = COOC2H ) and alphaprodine (7, R = R = 0CC2H ). The chiral center of interest in stmcture (7) is starred (see text).

The replacement of the /V-methyl group on the nitrogen atom of the piperidine ring of morphine and analogues by aHyl, isopropyl, or methyl cyclopropyl, an isopropyl isostere, results in compounds which antagonize opioid responses, especially respiratory depression. Naloxone [465-65-6] C22H2 N04 (10... 

The action of anabasine is similar to that of nicotine. When the piperidine ring of anabasine is opened to produce 8-amino-8-3-pyridyl-n-valeric acid the activity is reduced, and this is also true of the corresponding lactam and the benzoyl derivative. According to De Eds myosmine is less toxic than nicotine but more active on isolated guinea-pig intestine. ... 

Formula (VI) has received support in two ways. The investigations of Winterfeld (with Ronsberg) on the oxidation of dehydrosparteine methoaeetate and of a-didehydrosparteine, indicated thatD was a piperidine ring and this was finally established by Clemo, Morgan and Raper a... 

Much interesting work has been done in the last ten years on the bridging of pyrrole and piperidine rings. Early in their work on this subject Clemo and Metcalfe (1937) prepared quinuclidine (V) by the reduction of 3-ketoquinuclidine (IV), the latter resulting from the hydrolysis and decarboxylation of the product (III) of a Dieckmann internal alkylation, applied to ethyl piperidine-l-acetate-4-carboxylate (II), itself made by condensing ethyl piperidine-4-carboxylate (I) with ethyl chloroacetate. 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

Gas-phase basity and proton affinity values for 3,4,6,7,8,9-hexahydro-2/f-pyrido[l,2-n]pyrimidine were determined and they were compared to other super bases, including its lower and higher piperidine ring homologs (94JP0725, 01JPO25). 

The wide structural latitude permitted for hypnotic activity is made particularly clear by the observation that the two carbonyl groups in the piperidine ring need not be disposed to form... 

Here the alcoholic hydroxyl is first protonated and then eliminated as water. The allylcarbenium ion (2) is initially stabilized by elimination of the proton at C-14. Then the ether link is opened after protonation of the ring oxygen with the formation of carbenium ion (3), whereby the neighboring C-C bond of the piperidine ring is cleaved with aromatization of the C ring. The carbenium ion (4) formed is stabilized by elimination of a proton and ring closure to apomorphine (5). 

Aldoximes can be oxidatively dehydrogenated to nitrile oxides using a variety of oxidants such as lead tetraacetate [16a], alkali hypohalites [lla],NBS in DMF followed by base treatment [16b], chloramine-T [11b], 1-chlorobenzotriazole [16c], mercuric acetate [ 16 d], etc. However, we employed either NaOCl or chloramine-T for most of our INOC reactions. For instance, a piperidine ring fused to an isoxazoline as in 14 was constructed using the INOC methodology (Scheme 3) [17]. Monoalkylation of N-tosylallylamine 10 with the bromoacetal... 

COSY, HMQC, HMBC, and HSQC-TOCSY NMR spectra. The relative stereochemistry of each of the piperidine rings in 21 was estabhshed by analysis of NMR and NOESY spectra. However, the authors have not obtained experimental data to relate the relative stereochemistry of each piperidine moiety to the other. They suggested the relative stereochemistry indicated in 21, based on the Baldwin and Whitehead biogenetic proposal [24] (see below) and also by comparison with data for haliclonacyclamine E (5) and arenosclerin A (14). 

The TS preference is influenced by avoidance of A1,3 strain between the a-methyl group and the piperidine ring. 

Reduction of the exocylic double bond and inclusion of the side chain nitrogen in a piperidine ring leads to a compound (19) which exhibits skeletal muscle relaxant activity. Its one step synthesis begins with reaction of thioxanthene (17) with phenyl sodium... 

Kibayashi and coworkers have used enantiometrically pure allylic silyl ethers obtained from amino acids in cycloaddition with nitrones (Eq. 8.49).71 Cyclic nitrone reacts with a chiral allyl ether to give selectively the exo and erythro isomer (de 90%). Optically active alkaloids containing a piperidine ring such as (+)-monomorine,71c (+)-coniine,71a and (-)-oncinotine71b have been prepared from the addition product. 

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