A General Strategy for the Stereoselective Synthesis of Pyrrole‐Fused Chiral Skeletons: [3+2] Cycloaddition with 2‐Nitro‐2,3‐Unsaturated Glycosides

Abstract

In this study, a two-step methodology was developed for the synthesis of chiral pyrroles from 2-nitroglycals via Ferrier rearrangement and Barton-Zard reaction under mild conditions without transition metal catalysts. The Ferrier rearrangement reaction of 2-nitro-glycals and a series of O-nucleophiles proceeded smoothly in the presence of N-heterocyclic carbene (NHC) catalyst and K 2 CO 3 which allowed the highly stereoselective synthesis of the diverse 2-nitro-2,3-unsaturated glyco-sides in excellent yields. Subsequently, the rearrangement products were conveniently transformed into the desired chiral pyrroles by [3 + 2] cycloaddition (Barton-Zard reaction) with isocyanoacetate in the presence of Cs 2 CO 3 . One-pot strategy was also successfully demonstrated for the gram-scale synthesis of one chiral pyrrole. This is the first report of stereoselective conversion from 2-nitroglycals to chiral pyrrole.

Synthesis of 2-Nitro-2,3-Unsaturated Glycosides by a Nanomagnetic Catalyst Fe3O4@C@Fe(III)

“…Not only that, the glycosyl acceptor (entry 9) could be well-applied to the reaction system, and the yield could reach 83%. Moreover, isopropanol gave a fairly good yield in our system compared with that in the reported methods ( Jiang et al, 2021 ). From entry 10 and entry 11, for complex natural alcohols, such as menthol and cholesterol, the reaction time was prolonged, and the yield was obtained with 71–73%.…”

“…From entry 10 and entry 11, for complex natural alcohols, such as menthol and cholesterol, the reaction time was prolonged, and the yield was obtained with 71–73%. Phenolic acceptors, a type of difficult acceptors in the previous Ferrier rearrangement research, such as phenol and p -methoxyphenol, could also produce the corresponding phenolic glycosides with excellent yield at 0.1 equivalent ( Dharuman et al, 2013 ; Jiang et al, 2021 ). Compared with the literature studies, the yield of the corresponding product 3m (entry 13) was also increased by 10% ( Dharuman et al, 2013 ).…”

“…The structure and stereochemistry of the rearrangement products were elucidated by NMR and mass spectroscopy and were subsequently compared with the reported data ( Dharuman et al, 2013 ; Lafuente et al, 2019 ; Jiang et al, 2021 ). It was noteworthy that the stereoselectivity of 2-nitro-2,3-unsaturated glycoside compounds was confirmed as α: β > 19:1 by 1 H NMR.…”

“…Based on the experimental results and literature studies, a reaction mechanism may be proposed as follows ( Figure 3 ). ( Dharuman et al, 2013 ; Lafuente et al, 2019 ; Jiang et al, 2020b ; Jiang et al, 2021 ): As we know, a halogen substituent at the C-2 position of the glycals has a remarkable effect, and those electron-withdrawing groups would reduce the electron density of the oxocarbenium intermediate, which is commonly assumed as the intermediate cation in the Ferrier rearrangement ( Dong et al, 2019 ). Thus, under the nanocatalysis of Fe 3 O 4 @C@Fe(III), C3 site deacylation in 2-nitro-glucal would occur very slowly and electron transfer would occur in a different way, with the aid of the nucleophiles.…”

“…However, the preparation process of the Cu–Fe spinel catalyst was complicated, and the conditions were very harsh, so the number of suitable substrates was only eight. Recently, we published an article in which N-heterocyclic carbenes (NHCs) catalyzed Ferrier rearrangement smoothly with the aid of potassium carbonate ( Jiang et al, 2021 ). The reaction conditions were mild, and the range of alcoholic substrates was wide, but the reaction was time-consuming and suffered deacylation as well.…”