Piperidine polyhydroxylated piperidines

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... 

On the nitrone side, high levels of selectivities have been reached using camphorsultam-derived nitrone 87 since hexahydro-isoxazolo[2,3- ]pyridine 88 en route to (—)-histrionicotoxin was obtained as a single regio- and diaster-eoisomer <1999JA4900> (Scheme 28). A polyhydroxylated hexahydro-isoxazolo[2,3- ]pyridine could also be obtained starting from a nitrone derived from a C2-symmetric piperidine <2002TL9357>. 

Preparation of polyhydroxylated 6-oxanortropane glycomimetics (e.g. 32), structurally related to the glycosidase inhibitor family of the calystegines, was reported. The synthetic strategy involves the furanose/piperidine... 

It has been shown that the Claisen rearrangement of lithium enolates of amino acid enynol esters allows the synthesis of very sensitive y, 5-unsaturated amino acids with conjugated enyne side chains.The chelate-enolate Claisen rearrangement has also been applied to the synthesis of unsaturated polyhydroxylated amino acids, polyhydroxylated piperidines, and unsaturated peptides. ... 

G. W. J. Fleet, An alternative proposal for die mode of inhibition of glycosidase activity by polyhydroxylated piperidines, pyrrolidines and indolizidines Implications for the mechanism of action of some glycosidases, Tetrahedron Lett., 26 (1985) 5073—5076. 

In the following paragraph the nucleophilic substitution of some of the activated lactones under aqueous conditions will be discussed in detail, namely the reactions with aqueous ammonia, thereby yielding polyhydroxylated pyrrolidines (azafuranoses) and piperidines (azapyranoses). 

Polyhydroxylated piperidines such as are of interest as glucosidase inhibitors. Antoni Riera, also of the University of Barcelona, has developed (J. Org. Chem. 2005, 70,2325) a route to 16 from the readily-available enantiomerically-pure epoxide 11. Condensation with ally isocyanate 12 followed by cyclization gave 13, which was further cyclized by a Grubb s catalyst (unspecified) to 14. Protection set the stage for face-selective dihydroxylation, to give 15. Several other piperidines having other polyhydroxylation patterns were also prepared from 14. 

The cyclic sulfate isoxazoline 53 was converted into the polyhydroxylated piperidine 54 through one-pot reduction and cyclisation reactions. The process was highly stereo- and regioselective and gave 54 as a single isomer in 82% yield <02SL1359>. 

Numerous examples of cyclizations by attack of a nitrogen nucleophile on an electrophilic carbon leading to piperidines have been reported in recent literature these examples are illustrated by the synthesis of polyhydroxylated indolizidine scaffold 60 <2004JOC3139> and the synthesis of azasugar type compounds 61 (Scheme 39) <2004JME1930>. 

Glycosidase-inhibiting alkaloids from plants are classified into five structural classes polyhydroxylated pyrrolidines, piperidines, indolizidines, pyrrolizidines, and nortropanes. Furthermore, they also occur as the glycosides. This review describes recent studies on isolation, characterization, glycosidase inhibitory activity, and therapeutic application of the sugar-mimicking alkaloids from plants. 

Figure 1. Diagram illustrating the common nomenclature for polyhydroxylated piperidine alkaloids, (a) 5-Amino-5-deoxy-D-glucopyranose has the trivial name nojirimycin, (b) 1-deoxynojirimycin (DNJ) is the trivial name for l,5-dideoxy-l,5-imino-D-glucitol and similarly (c) 1-deoxymannojirimycin (DMJ) is the common name for l,5-dideoxy-l,5-imino-D-mannitol.

Figure 4. Some naturally-occurring polyhydroxylated piperidine alkaloids.

Depazay and co-workers have described the synthesis of a series of polyhydroxylated pyrrolidine, piperidine and azepanes derived from D-mannitol as novel mimetics of somatostatin [8]. The synthesis of one piperidine 116 is shown in O Scheme 9. The authors used reaction of tr) tamine with the D-mannitol derived bis-epoxide 112 followed by protection of the indole nitrogen with a Boc group to prepare the L-gulo-piperidine 113, the azepane 114 also being formed. Selective protection of the primary alcohol followed by reaction with hydrazoic acid... 

Fleet, G. W. J. (1985) An Alternative Mechanism for the Mode of Inhibition of Glycosidase Activity by Polyhydroxylated Piperidines, Pyrrolidines, and Indolizidines The Mechanism of Action of Some Glycosidases, Tetrahedron Lett. 26, 5073-5076. 

The plant alkaloid castanospermine 155 and the related piperidine alkaloid 1-deox-ynojirimicin 160, like several other polyhydroxylated octahydroindolizidines, piperidines and pyrrolidines, are potent glycosidase inhibitors. These nitrogen bases are of considerable interest for the study of biosynthetic processes and, in addition, castanospermine and some of its derivatives may be of clinical value as antineo-plastic agents and as drugs in the treatment of AIDS. 

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