Polyhydroxylated 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. 

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>. 

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.

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. 

Polyhydroxylated piperidines from natural sources, which have structures and shapes resembling monosaccharides have been found as a -glycosidase inhibitors. They competitively inhibit glycosidases whose substrates they most closely resemble. 1-Deoxynojirimycin (moranoline) (98 1), was isolated from Mori Cortex (root bark of the mulberry tree, Morus bombycis (Moraceae)), leaves of Jacobinia suberecta (Acanthaceae)... 

Pharmacol, 1, 1004-1011 (1955). Cited in Perrin 2862 ref. C27. NB The study used measurements of pH witti a glass electrode. See also Jensen HH, Lyngbye L, Jensen A and Bols M, Stereoelectronic substituent effects in polyhydroxylated piperidines and hexahydropyridazines, Chem. Eur. /., 8(5), 1218-1226 (2002). This paper reported pJmethyl ecgonine (9.1), along witti more than 60 other piperidines or closely related compounds. 

Syntheses of peptidomimetics based on pyranose and polyhydroxylated piperidine scaffolds 06COS403. 

Stereoelectronic Effects of Substituents Polyhydroxylated Piperidines and Sugars... 

Jensen HH, Lyngbye L, Jensen A, Bols M (2002) Stereoelectronic substituent effects in polyhydroxylated piperidines and hexahydropyridazines. Chem Eur J 8 1218-1226... 

Johnson and coworkers [47] have synthesized (l->6)-, (l->4)-, and (1->1)-linked aza-C-disaccharides D-azaMan- -Jl->6)-D-Man(8), D-azaMan-(3-(1->6)-d-G1c(9), D-azaMan-(3-(l->4)-D-Talo(10) and D-azaMan-P-(l-> 1)-D-P-Glc(ll). The polyhydroxylated piperidine ring is constructed employing vinylbromide, (3R,4R,5S,6S)-3-[(N-benzyloxycarbonyl)amino]-l-bromo-4-[(tert-butyldimethylsilyl)oxy]-5,6-(0-isopropylidenedioxy)cyclohex-l-ene(12), as a common intermediate for these sugars. Vinylbromide (12) required for Suzuki coupling is synthesized de novo from 3-bromocyclohex-3,5-dien-l,2-diol as outlined in Scheme 31.12 [47]. 

The products presented in scheme 5 show that it should be possible by subsequent introduction of amino groups through halogen or oxirane functionalities, to get an efficient entry into a series of polyhydroxylated piperidines (azasugars) [6,7,30] by intramolecular reductive amination. This class of compounds gained much interest recently because of its biological activity as potential glycosidase inhibitors [31-33]. In scheme 8 novel substitution patterns of polyhydroxy piperidines (boxed), which we synthesized stereoselectively by our own new procedures [34], are compared with known compounds derived from natural sources. 

Scheme 8. Novel polyhydroxylated piperidines (azasugars) as potential glycosidase inhibitors [34]...

Scheme 9. Flexible, diastereo- and enantioselective synthesis of novel polyhydroxylated piperidines (oxirane azide ring opening variant) [15]...

An example of the use of SAMP/RAMP methodology to prepare polyhydroxylated piperidines is illustrated in Scheme 7. Other examples are also described. 

Species belonging to the genera Alexa from Amazonia and Castanospermum from Australia contain polyhydroxylated piperidines, pyrrolidines, indolizines and pyrrolizidines. The presence of this related series of alkaloids suggests the original derivation of both genera from a common ancestor thriving on the old South Panagean continent. 

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