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 OsO₄/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.

Keywords: 1,2-aminoalcohol; antimicrobial activity; chiral catalyst; neoisopulegol; octahydrobenzofuran.

Figure 1

Synthesis of (–)-isopulegol-based methylenetetrahydrofuran 3: (i) PCC (2 equivalents), DCM (Dichloromethane), 25 °C, 48 h, 80% than L-selectride (1.5 equivalents) dry THF, −78 °C, 1 h, 90% [48,49,50,51]; (ii) Ca(OCl)₂, DCM, rt 25 °C, 3 h, 70% than NaH (2 equivalents), dry THF, 50 °C, 6 h [52,53,54,55]; (iii) CrO₃ (3 equivalents), DCM/pyridine, reflux, 1.5 h, 84% [55,56].

Figure 2

Proposed reaction pathway of allylic oxidation of 3.

Scheme 1

(i) mCPBA (2 equivalents), Na₂HPO₄. 2H₂O (3 equivalents), 25 °C, 2 h, 23%; (ii) RNH₂ (2 equivalents), LiClO₄ (1 equivalent), MeCN, 70–80 °C, 6 h, 65–85%; (iii) 5% Pd/C, H₂ (1 atm), MeOH, 25 °C, 24 h, 70–75%; (iv) 35% HCHO, Et₂O, 25 °C, 1 h, 50–90%; (v) 2% OsO₄/t-BuOH, 50% NMO/H₂O, acetone, 25 °C, 24 h, 50%.

Figure 3

Determination of relative configuration of aminoalcohols 7–10 and diol 6.

Scheme 2

Model reaction for enantioselective catalysis.