反应详情

The synthesis of homochiral pyrrolizidine (1) requires joining by nitrogen of C-1, C-4 and C-7 of the diacetonide (2). A stereochemical feature of the pyrrolizidine (1), is that it possesses a chirotopic, non-stereogenic center at C-7a and is pseudo C2 symmetric (i.e. the molecule would possess C2 symmetry other than for the center at C-7a). C-7a in (1) is derived from C-4 of the sugar lactone, so that the introduction of nitrogen at this carbon with inversion or retention of configuration will still result in the synthesis of (1). Esterification of the primary alcohol in (2) with trifluoromethanesulphonic anhydride in the presence of pyridine, followed by displacement of the triflate with sodium azide in dimethylformamide, gave the fully protected azide (7) [89% yield]. Reduction of the lactone (7) with sodium borohydride in ethanol afforded the diol (8) [84% yield] which, on treatment with methanesulphonyl chloride in pyridine, was converted to the dimesylate (9) [82% yield]. Hydrogenation of the azide (9) in the presence of palladium black in ethanol gave the corresponding amine which, with sodium acetate, cyclized to the diisopropylidene pyrrolizidine (10) [81% yield]. Removal of the acetonides from (10) with aqueous trifluoroacetic acid gave the target pyrrolizidine (1) in 84% yield [42% overall yield from lactone (2)]. ##STR5## An alternative approach to the synthesis of the pyrrolizidine (1) can involve initial introduction of azide at C-4 of the sugar, followed by subsequent cyclization of the nitrogen onto leaving groups at C-1 and C-7. Reduction of the silyl ether (11) with sodium borohydride in ethanol gave the diol (12) [86% yield] which with tert-butylchlorodiphenylsilane gave the secondary alcohol (13) [77% yield]. Reaction of (13) with methanesulphonyl chloride in pyridine in the presence of DMAP gave the mesylate (14) [78% yield], suitable for introduction of nitrogen at C-4. Strong confirmatory evidence for the structure of the alcohol (13) was obtained by pyridinium chlorochromate oxidation to the corresponding ketone (15). Both the alcohol (13) and mesylate (14) are pseudo C2 symmetric and have complex 1H and 13C NMR spectra; in contrast, the ketone (15) is C2 symmetric with very much simpler NMR spectra. ##STR6## The symmetry features of compounds such as (13), (14) and (15) can be exploited in two methods of elaboration of the basic carbon skeleton. For acyclic molecules of this symmetry type, the method of two directional chain synthesis has been pioneered by Schrieber, Chem. Scr.27 563 (1987), in the synthesis of precursors of biologically active compounds. However in this case, an alternative strategy of one and two carbon chain extension reactions at the non-stereogenic center would allow the synthesis of analogues of the pyrrolizidine structure, such as (16) and (17), which retain the C2 pseudo symmetry. Furthermore a three carbon chain extension at C-4, coupled with the diasteroselective incorporation of two hydroxyl groups, can provide a synthetic route to (18), an extremely highly functionalized chiral tertiary amine possessing a C3 axis of symmetry. At present there is considerable interest in, and some differing views about the mechanism of, the asymmetric dihydroxylation of olefins by osmium tetroxide in the presence of chiral amines; [Jacobsen et al, J. Am. Chem. Soc. 110, 1968, (1988); Wai et al, J. Am. Chem. Soc. 111, 1123, (1989); Svendsen et al, J. Org. Chem. 54, 2264, (1989); Tomioka et al, J. Am. Chem. Soc. 109, 6213 (1987); Tomioka et al, Tetrahedron Lett. 29, 573, (1988); Corey et al, J. Am. Chem. Soc. , 111, 9243, (1989); Corey et al, Tetrahedron Lett. 31, 2665 (1990); Kim et al, Tetrahedron Lett. 31, 3003, (1990)]; such bicyclic amines as (1), (16), (17), and (18) may provide interesting probes on the course of this reaction. ##STR7## As part of a program to study the effect of polyhydroxylated pyrrolizidines and related compounds as inhibitors of glycosidases, [Collin et al, Cabohydr. Res., 202, 105, (1990)] the effect of the tetrahydroxylated pyrrolizidine (1) on the activity of 15 human liver glycosidases, [Winchester et al, Biochem. J. 265, 277, (1990)] was investigated. Although (1) is a moderate inhibitor of α-L-fucosidase (76%) and β-D-galactosidase (53%) at a concentration of 1 mM, it is a very weak inhibitor of the different forms of α-D-mannosidase. This behavior is in marked contrast to the very potent inhibition of these activities by DIM, 1,4dideoxy-1,4-imino-D-mannitol, (19), a nitrogen analogue of the aza-furanose form of mannose. A comparison of the relative inhibitory properties of a series of analogues of (19) and the pyrrolizidine (1) provides some insight into structural features affecting the relative potency of such structures as mannosidase inhibitors (Figure). N-Methylation of DIM, to give (20), [Al Daher et al, Biochem. J. 258, 613, (1989)] virtually abolishes inhibition of lysosomal α-D-mannosidase at the enzyme's pH optimum and also greatly decreases the inhibition of other α-mannosidases. The pyrrolizidine (1) is related to DIM (19) by an additional methylene bridge between the ring nitrogen and the carbon bearing the primary hydroxyl function, and is related to N-methyl DIM by elimination of hydrogen between the N-methyl and primary alcohol methylene groups. In contrast, 6-deoxy DIM (20), [Stevens et al., J. Am. Chem. Soc. 92, 3160, (1970)] a potent inhibitor of Jack bean α-mannosidase, [Eis et al, Tetrahedron Lett. 26, 5397, (1985)] is an even more potent inhibitor of the human liver α-D-mannosidases than is DIM itself; accordingly, it is probable that the loss of freedom in regard to the side chain hydroxyl groups in (1) is an unimportant feature in its lack of glycosidase inhibition. The trihydroxypyrrolizidine (22), [Carpenter et al, Tetrahedron Lett. 30, 7261, (1989)] a cyclized analogue of 6-deoxy DIM (20) and a ring contracted form of swainsonine (24), is a better inhibitor of the α-mannosidases than the tetrahydroxylated pyrrolizidine (1); in contrast, the trihydroxypyrrolizidine (23), the C-7 epimer of (22) is inactive towards the enzymes. This behavior parallels the behavior observed in the stereoisomers of swainsonine itself [Cinci de Bello et al, Biochem. J. 259, 255 (1989)]. ##STR8##