Synthesis Study Of Pyranose Sugar Ring Pyrrole Spiroketal Alkaloids

The pyrrole spiroketal alkaloids,which have been found in traditional Chinese herbs,natural drugs and pollen in succession,attracted the attention of pharmaceutical chemistry specialists both here and abroad due to the special morpholine moiety and good antioxidant activity.Since 2011,there have been 10 different total synthesis routes of these alkaloids.Throughout the existing synthetic routes,N-substituted-5-hydroxymethyl-pyrrole-2-carbaldehyde was a key intermediate for the synthesis of these alkaloids and one of the main reasons for the complexity of the synthetic routes.In this paper,we focused on two pyrrole spiroketal alkaloids with pyranose sugar ring,Pyrrolopyrroside A and Shensongine A.We used the Maillard condensation reaction of amino sugars and sugar to construct the key intermediate structure of N-substituted 5-hydroxymethyl-pyrrole-2-carbaldehyde.We designed three synthetic schemes of the key intermediate.Synthetic Scheme 1: Amino sugar compound of 1,3-dideoxy-1-amino fructose was designed as a substrate of the Maillard reaction.Using D-glucose as raw material,With Dglucose as raw material,3-deoxy-D-glucose was prepared via isopropylidene protection,xanthate of 3-hydroxyl group,Barton-McCombie dehydroxylation and hydrolysis deprotection.Then,3-deoxy-D-glucose reacted with dibenzylamine through Amadori rearrangement reaction.However,1,3-dideoxy-1-amino fructose was not obtained in a single configuration.Synthetic Scheme 2: Amino sugar compound of 1-deoxy-1-amino fructose was designed as a substrate of the Maillard reaction.The D-glucose reacted with dibenzylamine to produce fructose dibenzylamine.1-deoxy-aminofructose was prepared from fructose dibenzylamine in two steps including isopropylidene protection and hydrogenation catalyzed by Pd/C.The Maillard reaction conditions of reducing sugars and 1-deoxy-1-amino fructose were explored.No key intermediate structures were obtained in proton acid/DMSO system,Lewis acid/dioxane system,ionic liquid system and deep eutectic solvent system.Synthetic Scheme 3: Maillard reaction between fructose active intermediate dihydropyrone and 1-deoxy-1-amino fructose was designed.D-fructose was used as the raw material and dehydrated resulting in the formation of 5-HMF.The dihydropyranone intermediate was obtained from the peroxidation of the reduced product of 5-HMF,catalyzed by m-CPBA.Maillard reaction between dihydropyrone and amino sugar was completed.The key intermediate 2-11 was prepared in a total yield of 53%.The target compounds were obtained in 4 steps,including spirocyclization,Barton-McCombie dehydroxylation,and removal of isopropylidene.The synthetic route consisted of 11 steps to form the pyrrole spiroketal alkaloids with pyranose sugar ring.Pollenopyrroside A and Shensongine A were gotten in total yield of 11.1% and 5.5%,respectively.The derivatives of Pollenopyrroside A and Shensongine A were seperately prepared in total yield of 15.7% and 7.9%.