Regio- and Enantioselective Synthesis of Novel Functionalized Pyrano­pyrrolidines by 1,3-Dipolar Cycloaddition of Carbohydrates

Abstract

A new methodology is described for the rapid enantiomeric synthesis of a novel series of pyranopyrrolidines from readily available and inexpensive carbohydrate compounds. The major feature of the method is a highly selective [3+2] cycloaddition reaction of different azomethine ylides with a chiral carbohydrate-derived enone. The reaction proved to be extremely regio-and stereoselective, giving rise to single enantiomeric compounds in all cases. Moreover, the method is totally atom-efficient and amenable to diversity, since structural diversity of the new compounds is dictated by the choice of the starting materials employed.Pyrrolidinic bicyclic systems are constituents of many biologically active compounds, such as, for example, antagonists of neuroexcitatory amino acids, 1 which intervene in disorders like epilepsies or Huntington's chorea. They are also useful as intermediates for total synthesis of more complex therapeutic molecules. 2 As such, it is of interest to develop the synthesis of such target molecules, using methods allowing control of stereochemistry and permitting diversity.One of the most versatile methods for the synthesis of pyrrolidines is the [3+2] cycloaddition reaction involving azomethine ylides derived from a-aminoesters, an aldehyde and a suitable dipolarophile. 3 The generation of azomethine ylides from imines by formal 1,2-prototropy, metal salt-tertiary amine combinations provides a simple, regio-and stereospecific process for the synthesis of polysubstitued pyrrolidines. 4 We describe herein a novel and potentially widely adaptable methodology for the synthesis of pyranopyrrolidines from carbohydrate derivatives using azomethine ylides (Scheme 1). The method is atom-economical, with no loss of chiral inducing fragments. Indeed, the carbohydrate moiety maintains its specific stereochemistry and induces regio-and stereoselectivity to the cycloaddition reaction, providing the new pyranopyrrolidines in a controlled manner.By this approach, we considered that an easily accessible common key intermediate would provide diversely substituted fused pyrrolidines when treated with a variety of 1,3-dipolar azomethine ylides. As such, our strategy uses commonly available carbohydrates and a short and flexible sequence of reactions, leading to the final key step.Thus, the synthesis of the chiral enone 5 5 was undertaken as indicated in Scheme 2, in which the required compound was prepared in few steps using commonplace reactions, the judicious choice of which led to a relatively high overall yield. This key intermediate then underwent cycloaddition reaction in a stereo-and regiocontrolled manner to afford the required compounds. In each case, a single isomer was obtained, indicating the excellent induction conferred during the cyclization.As an example starting material, we used the commercially available and inexpensive 1-bromo-tetra-O-acetyl glucose (1), which was firstly submitted to reductive elimination 6 using zinc/aqueous acetic acid to afford glycal 2 in 78% yield. Treatment with catalytic...

A Survey of Recent Synthetic Applications of 2,3-Dideoxy-Hex-2-enopyranosides

“…Oxidative transformations of hex-2,3-enopyranosides are also of synthetic value since they might lead to unsaturated enones, unsaturated lactones, or 6-formyl derivatives, depending on the conditions employed. Oxidation of diols 94 can be attained regioselectively at either O -4, or O -6, to give enones, e.g., 95 [96,97,98,99,100,101], or aldehydes, e.g., 96 [102], respectively (Scheme 22). For example, ethyl 2,3-dideoxy-α- d -erythro-hex-2-enopyranoside ( 94 , R=Et) undergoes chemoselective allylic oxidation upon treatment with manganese dioxide or pyridinium dichromate to give hex-2-enopyranoside-4-ulose 95 , whereas selective oxidation of the primary hydroxyl group can be effected by a modification of the Corey-Kim procedure [103], as recommended by Fraser-Reid and co-workers, leading to aldehyde 96 [104,105,106].…”

Regio- and Stereoselectivity in the Titanium-Mediated Cyclopropanation of ω-Alkenoic Diesters: Application in the Diastereoselective Synthesis of Pyrrolidinone

“…Thus, after esterification of L-aspartic acid (isopropanol, thionyl chloride), first allylation 14 then subsequent benzylation 15 allowed the diester 10 16 to be obtained in 75% yield. Alternatively, the same succinate derivative could be synthesized with comparable yields through imine 11 according to the literature, 17 followed by reduction 18 and allylation 14 (Scheme 4).…”

Cycloaddition Reactions

“…68 The products 152 were formed in 59-66% yield as single diastereoisomers (Scheme 2.41). 68 The products 152 were formed in 59-66% yield as single diastereoisomers (Scheme 2.41).…”