Synthesis and Application of 1,2-Aminoalcohols with Neoisopulegol-Based Octahydrobenzofuran Core

Abstract

A library of 1,2-aminoalcohol derivatives with a neoisopulegol-based octahydrobenzofuran core was developed and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The allylic chlorination of (+)-neoisopulegol, derived from natural (-)-isopulegol followed by cyclization, gave the key methyleneoctahydrobenzofuran intermediate. The stereoselective epoxidation of the key intermediate and subsequent oxirane ring opening with primary amines afforded the required 1,2-aminoalcohols. The ring closure of the secondary amine analogues with formaldehyde provided spiro-oxazolidine ring systems. The dihydroxylation of the methylenetetrahydrofuran moiety with OsO 4 /NMO (4-methylmorpholine N-oxide) resulted in the formation of a neoisopulegol-based diol in a highly stereoselective reaction. The antimicrobial activity of both the aminoalcohol derivatives and the diol was also explored. Molecules 2020, 25, 21 2 of 14 antimalarial [26-28], and antileishmanial [29] agents. The 1,2-aminoalcohol function is found in a broad range of β-adrenergic blockers that are used extensively in the management of cardiovascular disorders [30], including hypertension, angina pectoris and cardiac arrhythmias, and other disorders that are related to the sympathetic nervous system [31,32]. 1,2-aminoalcohols have also been demonstrated to be excellent chiral auxiliaries and chiral catalysts in asymmetric synthesis [33]. To achieve new, efficient, and commercially available chiral catalysts, natural chiral terpenes, such as α-pinene [34-38], β-pinene [34,39], (-)-3-carene [39,40], (-)-verbenone [41,42], (-)-fenchone [43,44], (+)-camphor [43,45,46], and (-)-menthone [47] have proven to be excellent sources for the synthesis of bifunctional chiral compounds and heterocycles.In the present work, we set out to create a compound library with a (+)-neoisopulegol-based octahydrobenzofuran core and 1,2-aminoalcohol moieties. The synthesis started from commercially available (-)-isopulegol and then utilizing the resulting 1,2-aminoalcohol derivatives as chiral catalysts in the enantioselective addition of diethylzinc to benzaldehyde. Furthermore, the antimicrobial activities of the synthesized compounds were also tested on multiple bacterial and fungal strains. Results Synthesis of Key Intermediate 3Key intermediate (-)-3-methylenetetrahydrofuran 3 was prepared from commercially available (-)-isopulegol 1 by oxidizing its hydroxyl function, followed by the stereoselective reduction of the resulting carbonyl group, thus providing (+)-neoisopulegol 2 [48][49][50][51]. The allylic chlorination of (+)-neoisopulegol 2 was followed by the cyclization-produced (-)-methylenetetrahydrofuran 3 [52-55], which was transformed into (−)-methylenetetrahydrofuran 4 by allylic oxidation after applying the literature method [55,56] (Figure 1).

Enantiomeric Isopulegol as the Chiral Pool in the Total Synthesis of Bioactive Agents

“…[89] 1,2-Aminoalcohols containing additional moieties between the 1,2-aminoalcohol unit [84] and the octabenzohydrofuran core were synthesized by Bamou et al in 2019 starting from (+)-neoisopulegol 3. [90] Allylic chlorination of (+)-3 followed by cyclisation produced (À )-methylenetetrahydrofuran 147 b. [91]…”

Synthesis of Hierarchical Silicoaluminophosphate (SAPO) Molecular Sieves by Post‐Synthetic Modification and Their Catalytic Application

“…[36,37] βamino alcohols are produced from the asymmetric ring opening reaction of epoxides with amines [38][39][40] and have recently gained popularity in organic synthesis and pharmaceutical development. [41][42][43][44][45] The purpose of this work is to generate mesoporosity in SAPO-34 and SAPO-5 catalysts by post-synthetic acid and alkali treatment and use the modified materials in epoxide ring opening reaction to check the effectiveness of the materials. To the best of our knowledge, no thorough study on using both acid and alkali treated SAPO-34 and SAPO-5 materials and their catalytic application on epoxide ring opening reaction is available.…”

Antimicrobial activity of novel 1-[(2,4-(di-tert-butylphenoxy))-3-dialkylamino-2-propanol] derivativesy

“…The microbial biofilm-forming ability is one of the major aspects of the emerging issue of antibiotic resistance, which makes them tolerant to antibiotics and host defence systems and other external stresses, thus contributing to persistent chronic infections (5). Several studies confirmed the high efficiency of aminopropanol derivatives as potential antibacterial and antifungal agents, which actually drew our interest to compounds of this group (6,7,8).…”