A Flexible Stereospecific Synthesis of Polyhydroxylated Pyrrolizidines from Commercially Available Pyranosides

Abstract

Nitrogen-containing sugar analogues, known as azasugars or iminosugars, such as polyhydroxylated piperdines, pyrrolidines, pyrrolizidines, and indolizidines, have the potential to become important therapeutic agents due to their ability to inhibit glycosidases. Synthetic pathways that are able to systematically produce a variety of these azasugars are eagerly sought after, since even minute structural or stereochemical changes often significantly alter the degree of inhibition. The synthesis of tetrahydroxylated pyrrolizidines 40 and 41 starting from methyl alpha-d-glucopyranoside is described and will be used as a template to develop syntheses of all the stereoisomers of polyhydroxylated pyrrolizidine 9 as well as other analogous bicyclic polyhydroxylated iminosugars. The key steps in this synthesis involve a one-pot conversion of a halopyranoside to a divinylamine by employing a simultaneous Zn reduction and reductive amination of the resulting aldehyde. After protection of the amine, a ring-closing metathesis results in a multifunctional eight-membered ring that then undergoes an internal S(N)2 cyclization to form an alkene-containing pyrrolizidine 33. Dihydroxylation of the alkene followed by hydrogenolysis of the benzyl protecting groups results in tetrahydroxylated pyrrolizidines 40 and 41.

An iodocyclization approach toward diastereoselective synthesis of highly functionalized tetrasubstituted tetrahydrofurans with 2,5-trans and 2,5-cis relationships from pyranoside derived acyclic oximes

“…16 Compound 2 on treatment with Zn dust in MeOH in the presence of a catalytic amount of cyanocobalamine 17 yielded cyclic hemiacetal 3 (an a-and b-mixture). Hemiacetal 3 on refluxing with O-benzylhydroxylamine hydrochloride 13 in DCM (Scheme 2) furnished an inseparable mixture of E-and Z-isomers of oxime 4 in an 84:16 ratio, as determined by 1 H NMR spectra, in very good yield ( To obtain the desired THF, oxime 4 was subjected to an iodocyclization reaction 18 (Scheme 3).…”

Regioselective reductive openings of 4,6-benzylidene acetals: synthetic and mechanistic aspects

“…The acetal can be completely removed by for example mild acidic hydrolysis (usually 80% acetic acid in water), 13 iodine in methanol, 14,15 or by hydrogenolysis (Pd/C in acetic acid or Pd(OH) 2 in ethanol). 16,17 The benzylidene acetals can also be regioselectively opened under oxidative conditions, for example, by N-bromosuccinimide in CCl 4 under basic conditions (usually BaCO 3 ) to give a 4-O-benzoate and bromine in position 6.…”

A Flexible Approach to Azasugars: Asymmetric Total Syntheses of (+)‐Castanospermine, (+)‐7‐Deoxy‐6‐epi‐castanospermine, and (+)‐1‐epi‐Castanospermine

“…[16] Numerous imaginative strategies have been developed for the enantioselective synthesis of castanospermine [16] and their stereoisomers. [14,17] However, novel, efficient, and flexiAbstract: The asymmetric total synthesis of natural azasugars (+ )-castanospermine, (+ )-7-deoxy-6-epi-castanospermine, and synthetic (+ )-1-epi-castanospermine has been accomplished in nine to ten steps from a common chiral building block (S)-8. The method features a powerful chiral relay strategy consisting of a highly diastereoselective vinylogous Mukaiyama-type reaction with either chiral or achiral aldehydes (!…”