New Access to Indolizidine and Pyrrolizidine Alkaloids from an Enantiopure Proline:  Total Syntheses of (−)-Lentiginosine and (1R,2R,7aR)-Dihydroxypyrrolizidine

Abstract

A new approach to the synthesis of indolizidine and pyrrolizidine skeletons is reported. (-)-Lentiginosine and (1R,2R,7aR)-dihydroxypyrrolizidine have both been synthesized in 13 steps from di-O-isopropylidene-d-mannitol. The common key intermediate is (-)-dihydroxyproline benzyl ester 10.

Applications of Mitsunobu Reaction in total synthesis of natural products

“…Interestingly, since 1965, over 100 members of polyhydroxylated alkaloids have been isolated from plants and living micro‐organisms and their biological potencies have been evaluated . As a result of the observed divers biological potencies such as being amyloglycosidase inhibitors, polyhydroxylated indolizidine alkaloids, for example (+)‐lentiginosine and its isomers, have stirred up the interest of synthetic organic chemists. Generally, these natural product sugar mimics were proven acting as impending therapeutic agents, towards numerous diseases for instance diabetes, cancer, or viral infections such as HIV .…”

“…Much attempt has been made for the total synthesis of lentiginosine. The total synthesis of such compounds is mainly based on the generation of the pyrrolidine or piperidine unit, in several steps, featuring the suitable functionalities being capable of securing the creation of the bicyclic skeleton . Initially, a synthetic pathway was designed for the synthesis of the diastereoisomer in which the indolizidine ring system was constructed using an intramolecular cyclization of readily accessible poly‐hydroxy compound 36 under Mitsunobu conditions in the presence of PPh 3 ‐DIAD in refluxing CH 3 CN, resulted in the construction of pyridinium salt 37 in excellent yield (92%) and in the pure form.…”

Pyrrolizidine alkaloids

“…Further investigations on a wider variety of analogues led to the discovery of a number of effective and selective ligands for the 5-HT 4 receptor and the interesting discovery that ent-SC-53116 does not show the same mutagenic toxicity. 72 7-Deoxycasuarine analogues 120-123 were designed as constrained analogues of the naturally-occurring chitin synthase inhibitor 6-deoxy-homo-DMDP (119). 73 The second ring was introduced in an effort to x the orientation of the hydroxyethyl group of 119 since this group had been shown to be important for binding affinity.…”

“…Building on a general method for the preparation of multifunctionalised pyrrolidines, Angle's group reported an enantiospecic synthesis of (1R,2R,7aR)-dihydroxypyrrolizidine from D-mannitol (297, Scheme 34). 119 An eightstep sequence was used to access isoserinal derivative 298, the substrate for the key step (step i). Lewis acid mediated Felkin-Anh mode addition of the diazoacetate into the aldehyde and stereoselective N-cyclisation gave trans,transdisubstituted pyrrolidine 299 along with some product of N 2 elimination (not shown).…”

Recent Developments in the Synthesis of Pyrrolidine‐Containing Iminosugars

“…For example, Angle et al [38] reported the use of a diazoacetate for the synthesis of a proline intermediate that proved useful in the synthesis of bicyclic iminosugars (Scheme 7). By making use of the C 2 symmetry of -mannitol-derived diamide 41, two molecules of the protected α-hydroxy aldehyde 42 were formed following the ozonolysis of alkene 41.…”