Naturally piperidines

Halosaline was isolated from Haloxylon Salicornicum18 and is representative of a group of natural piperidine alkaloids that differ in the relative and absolute configuration at C2 and C8, as well as the length of the alkyl moiety at C8. 

Carpamic acid 74 is a member of natural piperidine alkaloids displaying important biological activity [61]. It has all-cis-configuration of its substituents and was made recently by CM of 72 and 73 with Grubbs catalyst 3 (Scheme 30) [62]. 

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 ... 

Marazano and co-workers have used the Zincke reaction extensively to prepare chiral templates for elaboration to substituted piperidine and tetrahydropyridine natural products and medicinal agents. For example, 3-picoline was converted to Zincke salt 40 by reaction with 2,4-dinitrochlorobenzene in refluxing acetone, and treatment with R- -)-phenylglycinol in refluxing n-butanol generated the chiral pyridinium 77. Reduction to... 

Likewise, a cis-2,6-disubstituted piperidine natural product, (-)-lobeline (98, Scheme 8.4.30) was synthesized from the chiral Af-alkyl pyridinium salt ent-80 via a sequence that included addition of a Reformatsky reagent to an intermediate oxazolidine. °... 

The effect of solvent on the rate, E, and dS can be derived from the data on haloquinolines and their A-oxides (Tables X and XI), on halonitronaphthalenes (Tables XII and XIII), and on halodinitro-naphthalenes (Table XVI). Depending on the nature of the reaction, the relative reactivity of two compounds can be substantially different in different solvents. For example, piperidination of 2-chloroquinoline (Table X, lines 3 and 4) compared to 2-chloroquinoxaline (Table XV,... 

Furthermore, as described by Mori and coworkers, the domino aldol/cyclization reaction of the 3-keto sulfoxide 2-422 with succindialdehyde (2-423) in the presence of piperidine at r.t. afforded the chromone 2-424 which, on heating to 140 °C, underwent a thermal syn-elimination of methanesulfenic acid to provide 2-426 in 22 % overall yield (Scheme 2.100) [227]. This approach was then used for the synthesis of the natural products coniochaetones A (2-425) and B (2-427) [228]. 

Stockman and coworkers [329] developed a straightforward synthesis of a tricyclic compound 2-636 which has some resemblance to the spirocyclic portion of the natural product halichlorine (2-637) [330]. On treatment of the symmetrical ketone 2-633, accessible in five steps from alcohol 2-632, with hydroxylamine hydrochloride the spiro piperidine 2-636 could be obtained in 62% yield (Scheme... 

An excellent example of a RCM/ROM domino process is shown in the total synthesis of the piperidine alkaloid (-)-halosaline (6/3-19) by Blechert and coworkers (Scheme 6/3.3) [231]. The key step is the reaction of the enantiopure cyclopentene derivative 6/3-17 to give 6/3-18 with 5 mol% of the catalyst 6/3-13. Further transformations of 6/3-18 led to the natural product 6/3-19. 

Naturally occurring and synthetic polyhydroxylated pyrrolidine and piperidines have recently received considerable attention due to their biological activities. Barco has used tandem Michael-Henry reactions to synthesize 2-hydroxymethyl-3-hydroxy-4-nitro-pyrrolidines, from which the nitro group is removed to give the natural product, trans 2-hydroxymethyl-3-hy-droxypyrrolidine (Eq. 7.72).91... 

Intramolecular nucleophilic attack of a pyridine or piperidine nitrogen atom onto an electrophilic function placed in the -position of a side chain is a common way to achieve quinolizidine compounds. These reactions are systematized below on the basis of the nature of the electrophile. 

The stereoselective total synthesis of (+)-epiquinamide 301 has been achieved starting from the amino acid L-allysine ethylene acetal, which was converted into piperidine 298 by standard protocols. Allylation of 297 via an. V-acyliminium ion gave 298, which underwent RCM to provide 299 and the quinolizidine 300, with the wrong stereochemistry at the C-l stereocenter. This was corrected by mesylation of the alcohol, followed by Sn2 reaction with sodium azide to give 301, which, upon saponification of the methyl ester and decarboxylation through the Barton procedure followed by reduction and N-acylation, gave the desired natural product (Scheme 66) <20050L4005>. 

The first example of this type of alkaloid, compound 535, known hitherto merely as 205B, has recently been isolated from the skin of the Panamanian frog Dendrobates pumilio. The absolute stereochemistry of the natural (—)-alkaloid was first established by the total synthesis of its (+)-enantiomer by a multistage route from the fused piperidine 536... 

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