Stereoselective synthesis and application of isopulegol-based bi- and trifunctional chiral compounds

Abstract

A new family of isopulegol-based bi- and trifunctional chiral ligands was developed from commercially available (-)-isopulegol. Nucleophilic addition of primary amines towards (+)-α-methylene-γ-butyrolactone was accomplished, followed by reduction of the obtained β-aminolactones to provide aminodiols in highly stereoselective reactions. Epoxidation of (-)-isopulegol and subsequent oxirane ring opening with primary amines resulted in N-substituted aminodiols. The regioselective ring closure of these aminodiols with formaldehyde was also investigated. Benzylation of isopulegol furnished O-benzyl-protected isopulegol, which was transformed into aminoalcohols via epoxidation and ring opening of the corresponding epoxides. First benzyl-protected isopulegol was subjected to hydroxylation and epoxidation, then aminolysis of the served oxiranes delivered aminodiols. On the other hand, (-)-isopulegol was oxidised to diol, which was again converted into both dibenzyl- and monobenzyl-protected diol derivatives. The products were transformed into aminoalcohols and aminodiols, respectively, by aminolysis of their epoxides. The ring opening of epoxides, derived from diols with primary amines was also performed producing aminotriols. Dihydroxylation of (-)-isopulegol or derivatives with OsO₄/NMO gave isopulegol-based di-, tri- and tetraols. The antimicrobial activity and antioxidant property, measuring DPPH˙ free radical scavenging activity of aminodiol and aminotriol derivatives as well as di-, tri- and tetraols were also explored. In addition, structure-activity relationships were examined from the aspects of substituent effects and stereochemistry on the aminodiol and aminotriol systems.

Fig. 1. Synthesis of (−)-isopulegol-based (+)-α-methylene-γ-butyrolactone.

Scheme 1. Synthesis of (−)-isopulegol-based aminodiols. Reaction conditions: (i) RNH₂ (1 equiv.), dry EtOH, 25 °C, 20 h, 65–75%; (ii) LiAlH₄ (2 equiv.), dry Et₂O, 25 °C, 4 h, 50–70%; (iii) 5% Pd/C, H₂ (1 atm), MeOH, 25 °C, 24 h, 50–67%; (iv) 35% HCHO, Et₂O, 25 °C, 1 h, 64–74%; (v) 2% OsO₄/t-BuOH, 50% NMO/H₂O, acetone, 25 °C, 24 h, 28%; (vi) RNH₂ (4 equiv.), dry THF, 60 °C, 24–72 h, 35–56%.

Fig. 2. Determination of the structure of diol 18 by NOESY.

Scheme 2. Synthesis of (−)-isopulegol-based aminodiols. Reaction conditions: (i) 2% OsO₄/t-BuOH, 50% NMO/H₂O, acetone, 25 °C, 24 h, 33% (22a), 33% (22b); (ii) mCPBA (2 equiv.), Na₂HPO₄·12H₂O (3 equiv.), CH₂Cl₂, 25 °C, 2 h, 29% (23a), 43% (23b); (iii) RNH₂ (2 equiv.), LiClO₄ (1 equiv.), MeCN, 70–80 °C, 8 h, 75–95% (23a), 50–90% (23b); (iv) 5% Pd/C, H₂ (1 atm), MeOH, 25 °C, 24 h, 87–95% (28a), 85–90% (28b); (v) 35% HCHO, Et₂O, 25 °C, 1 h, 89–97% (29a–32a), 85–90% (29b–32b).

Scheme 3. Synthesis of (−)-isopulegol-based aminodiol derivatives. Reaction conditions: (i) NaH (1.5 equiv.), BnBr (1.5 equiv.), KI (1.5 equiv.), dry THF, 60 °C, 12 h, 70%; (ii) mCPBA (2 equiv.), Na₂HPO₄·12H₂O (3 equiv.), CH₂Cl₂, 25 °C, 2 h, 43% (34a), 25% (34b); (iii) RNH₂ (2 equiv.), LiClO₄ (1 equiv.), MeCN, 70–80 °C, 20 h, 31–45%; (iv) 5% Pd/C, H₂ (1 atm), MeOH, 25 °C, 24 h, 65–70%; (v) 5% Pd/C, H₂ (1 atm), n-hexane : EtOAc = 9 : 1, 25 °C, 24 h, 53%.

Scheme 4. Synthesis of (−)-isopulegol-based diols. Reaction conditions: (i) 2% OsO₄/t-BuOH, 50% NMO/H₂O, acetone, 25 °C, 24 h, 88%; (ii) triphosgene (0.5 equiv.), pyridine (4 equiv.), dry CH₂Cl₂, 25 °C, 2 h, 36% (40a), 36% (40b); (iii) LiAlH₄ (2 equiv.), dry Et₂O, 0 °C, 4 h, 95% (39a), 56% (39b); (iv) 5% Pd/C, H₂ (1 atm), MeOH, 25 °C, 24 h, 95% (39a), 91% (39b).

Scheme 5. Synthesis of (−)-isopulegol-based aminotriol derivatives. Reaction conditions: (i) SeO₂ (0.24 equiv.), 70% t-BuOOH (4 equiv.), CHCl₃, 60 °C, 20 h, then LiAlH₄ (3 equiv.), dry Et₂O, 0 °C, 6 h, 60%; (ii) mCPBA (2 equiv.), Na₂HPO₄·12H₂O (3 equiv.), CH₂Cl₂, 25 °C, 2 h, 64% (42a), 15% (42b); (iii) RNH₂ (2 equiv.), LiClO₄ (1 equiv.), MeCN, 70–80 °C, 6 h, 46–58% (42a), 14% (42b); (iv) NMO/H₂O, 2% OsO₄/t-BuOH, acetone, 25 °C, 24 h, 60%; (v) 5% Pd/C, H₂ (1 atm), MeOH, 25 °C, 24 h, 87–95% (47a), 86% (48).

Scheme 6. Synthesis of (−)-isopulegol-based aminotriol derivatives. Reaction conditions: (i) NaH (1.5 equiv.), BnBr (3.0 equiv.), KI (1.5 equiv.), dry THF, 60 °C, 12 h, 40% (50b), 19% (50a); (ii) mCPBA (2 equiv.), Na₂HPO₄·12H₂O (3 equiv.), CH₂Cl₂, 25 °C, 2 h, 38% (51a), 28% (51b); (iii) RNH₂ (2 equiv.), LiClO₄ (1 equiv.), MeCN, 70–80 °C, 6 h, 25–40% (51a), 29–42% (51b); (iv) NMO/H₂O, 2% OsO₄/t-BuOH, acetone, 25 °C, 24 h, 50% (56a), 15% (56b); (v) 5% Pd/C, H₂ (1 atm), MeOH, 25 °C, 24 h, 95–98% (47a–b), 83% (56a).

Scheme 7. Synthesis of (−)-isopulegol-based aminotriol derivatives. Reaction conditions: (i) mCPBA (2 equiv.), Na₂HPO₄·12H₂O (3 equiv.), CH₂Cl₂, 25 °C, 2 h, 38% (57a), 15% (57b); (ii) RNH₂ (2 equiv.), LiClO₄ (1 equiv.), MeCN, 70–80 °C, 6 h, 39–50% (57a), 16–21% (57b); (iii) 5% Pd/C, H₂ (1 atm), MeOH, 25 °C, 24 h, 90–93% (47a–b), 97% (62a), 95% (62b); (iv) NMO/H₂O, 2% OsO₄/t-BuOH, acetone, 25 °C, 24 h, 59% (62a), 29% (62b).

Scheme 8. Synthesis of (−)-isopulegol-based aminotriols. Reaction conditions: (i) mCPBA (2 equiv.), Na₂HPO₄·12H₂O (3 equiv.), CH₂Cl₂, 25 °C, 2 h, 33% (63a), 7% (63b); (ii) RNH₂ (2 equiv.), LiClO₄ (1 equiv.), MeCN, 70–80 °C, 6 h, 62–77% (63a), 87–93% (63b); (iii) 5% Pd/C, H₂ (1 atm), MeOH, 25 °C, 24 h, 67–75%; (iv) NMO/H₂O, 2% OsO₄/t-BuOH, acetone, 25 °C, 24 h, 53%.

Scheme 9. Determination of the structure of (−)-isopulegol-based aminotriol as well as triol derivatives. Reaction conditions: LiAlH₄ (2 equiv.), dry THF, 25 °C, 6 h, 70%; (ii) 5% Pd/C, H₂ (1 atm), n-hexane : EtOAc = 9 : 1, 25 °C, 24 h, 90% (42a), 78% (51a), 90% (57a); (iii) 3 M NaOH, DMSO, 25 °C, 2–24 h, 33% (56b), 57% (62b); (iv) LiAlH₄ (2 equiv.), dry THF, 25 °C, 6 h then 5% Pd/C, H₂ (1 atm), n-hexane : EtOAc = 9 : 1, 25 °C, 24 h, 87%.