Optically pure trans -1-benzyl-4-aminopiperidin-3-ols. Synthesis and absolute configuration

Enantiomerically pure trans -( 3R,4R )-4-aminopiperidin-3-ols, which are convenient precursors for making natural and synthetic aminohydroxylated piperidine alkaloid analogs, were efficiently synthesized through the reaction of enantiomerically pure ( 3R,4S )-3,4-epoxypiperidine with amines in the presence of LiClO 4 in CH 3 CN at room temperature. The absolute stereochemistry of the resultant amino alcohols was determined by the stereochemical correlation method and single-crystal X-ray analysis


Introduction
Numerous amino-and hydroxysubstituted piperidine derivatives constitute a subclass of hydroxylated piperidine alkaloids, also referred to as iminosugars, and are known as potent inhibitors of glycosidases and related enzymes.
Pseudodistomins A-F, novel potent antineoplastic aminohydroxylated piperidine alkaloids with calmodulin antagonistic and antitumor activities, have recently become of great interest (Figure 1). 1,2

Figure 1
The presence of an amino group in the iminosugar structure leads to selective inhibition of some kinds of glycosidases and hexoaminidases.For example, aminodihydroxypiperidine 2, which is an amino analog of isofagomine 1, exhibits selective inhibition activity toward βglucosidase. 3The acetylamino derivative of 1-deoxynojirimycin 3 is a selective inhibitor of β-Nacetylaminoglucosaminidase. 4 Cisapride, a potent gastric prokinetic agent with reduced dopamine D2 receptor antagonist activity, 5 is a cis-4-amino-3-hydroxypiperidine derivative (Fig. 2).

Figure 2
Nowadays aminohydroxylated piperidine alkaloids and their synthetic analogs have drawn significant attention owing to their ability to mimic sugars and selectively inhibit glycosidases and glycoprotein-processing enzymes. 6,7he high therapeutic potential of these inhibitors for treatment of a variety of carbohydratemediated diseasessuch as diabetes, cancer, and viral infections including HIVhas evoked considerable efforts aimed at their structural modifications and synthesis of their analogs.
After standard treatment of reaction mixtures, individual amino alcohols (-)-5 to (-)-7 were isolated in the form of dihydrochlorides or dihydrobromides.Their chemical individuality was confirmed by elemental analysis. 1H and 13 C NMR spectra confirmed formation of only one diastereomer of amino alcohols (-)-5 to (-)-7 in each reaction.
For N-salicylidene derivatives of chiral alkylamines, the planar sector rule predicts that the negative sign of the Cotton effects near 315 and 250 nm corresponds to negative chirality ((R) configuration).We have analyzed the circular dichroism (CD) data of both derivatives 9a and 9b in CHCl3 (room temperature).As it is shown in Figure 3, three Cotton effects in the CD curve of derivative 9anegative at 322 and 250 nm and positive at 276 nmare attributed to transitions of the salicylidenimino chromophore with an intramolecular hydrogen bond. 16For the Nsalicylidenimino derivative 9a, the observable negative Cotton effects at 322 and 250 nm correspond to the negative sign of chirality; thus, derivative 9a has the (3R,4R) configuration.
The CD spectrum 9b in CDCl3 exhibits an almost mirror image of the 9a spectrum: there are less intense positive Cotton effects at 322 and 250 nm (room temperature), which correspond to positive chirality (Fig. 3).Thus 9b has to have the (3S,4S) configuration.
There is no change in the absolute stereochemistry of the 3-and 4-centers of the piperidine core during the synthesis of enantiomers 9a, 9b; therefore, the absolute configuration of parent (-)-6a should also be (3R,4R).

Conclusions
Our results showed that various optically pure trans-(3R,4R)-4-aminopiperidin-3-ols can be conveniently prepared through trans ring opening of optically pure (3R,4S)-epoxide 4 with various amines.We hope that our results may be useful in directed chiral synthesis of natural and synthetic aminohydroxylated piperidine alkaloid analogs with the required biological activities.

Experimental Section
The NMR spectra were recorded on Varian VXR-400 spectrometer using chloroform-d as solvent.Chemical shifts are given in δ (ppm) relative to ТМS as internal standard.Elemental analysis was performed with a Perkin-Elmer 2400 CHNS elemental analyzer.Silica gel 60 was used for column chromatography.Merck Kieselgel 60 and Silufol were used for TLC.Optical rotations were measured on Perkin-Elmer 14.The CD spectra were registered on a Jasco-720 instrument using a 0.1 cm optical-path length cuvette.

Table 1 .
Selected coupling constants for amino alcohols 5

Table 2 .
Characteristic properties of amino alcohols 5