Stereoselective Synthesis and Investigation of Isopulegol-Based Chiral Ligands
Abstract
:1. Introduction
2. Results
2.1. Synthesis of (−)-α-methylene-γ-butyrolactone 4
2.2. Synthesis of Isopulegol-based Aminodiols
2.3. Synthesis of Isopulegol-based Aminotriols
2.4. Application of Aminodiol Derivatives and Aminotriols as Chiral Ligands for Catalytic Addition of Diethylzinc to Benzaldehyde
2.5. Antimicrobial Effects
3. Discussion
4. Materials and Methods
4.1. General Methods
4.2. Starting Materials
(3S,3aS,6R,7aS)-3-((Isopropylamino)methyl)-6-methylhexahydrobenzofuran-2(3H)-one (8)
4.3. General Procedure for Reduction with LiAlH4
4.3.1. (1S,2S,5R)-2-((S)-1-(Benzylamino)-3-hydroxypropan-2-yl)-5-methylcyclohexanol (9)
4.3.2. (1S,2S,5R)-2-((S)-1-Hydroxy-3-(((R)-1-phenylethyl)amino)propan-2-yl)-5-methylcyclohexanol (10)
4.3.3. (1S,2S,5R)-2-((S)-1-Hydroxy-3-(((S)-1-phenylethyl)amino)propan-2-yl)-5-methylcyclohexanol (11)
4.3.4. (1S,2S,5R)-2-((S)-1-Hydroxy-3-(isopropylamino)propan-2-yl)-5-methylcyclohexanol (12)
4.4. General Procedure of Epoxidation
4.4.1. (1S,2R,5R)-5-Methyl-2-((S)-2-methyloxiran-2-yl)cyclohexanol (19)
4.4.2. (1S,2R,5R)-2-((R)-2-(Hydroxymethyl)oxiran-2-yl)-5-methylcyclohexanol (31)
4.5. General Procedure for Ring-Opening of Epoxide with Primary Amines
4.5.1. (1S,2R,5R)-2-((S)-1-(Benzylamino)-2-hydroxypropan-2-yl)-5-methylcyclohexanol (20)
4.5.2. (1S,2R,5R)-2-((S)-2-Hydroxy-1-(((R)-1-phenylethyl)amino)propan-2-yl)-5-methylcyclohexanol (21)
4.5.3. (1S,2R,5R)-2-((S)-2-hydroxy-1-(((S)-1-phenylethyl)amino)propan-2-yl)-5-methylcyclohexanol (22)
4.5.4. (1S,2R,5R)-2-((S)-2-Hydroxy-1-(isopropylamino)propan-2-yl)-5-methylcyclohexanol (23)
4.5.5. (S)-3-(Benzylamino)-2-((1R,2S,4R)-2-hydroxy-4-methylcyclohexyl)propane-1,2-diol (32)
4.5.6. (S)-2-((1R,2S,4R)-2-Hydroxy-4-methylcyclohexyl)-3-(((R)-1-phenylethyl)amino)propane-1,2-diol (33)
4.5.7. (S)-2-((1R,2S,4R)-2-Hydroxy-4-methylcyclohexyl)-3-(((S)-1-phenylethyl)amino)propane-1,2-diol (34)
4.5.8. (S)-2-((1R,2S,4R)-2-Hydroxy-4-methylcyclohexyl)-3-(isopropylamino)propane-1,2-diol (35)
4.6. General Procedure for Ring Closure with Formaldehyde
4.6.1. (1S,2S,5R)-2-((S)-3-Benzyl-1,3-oxazinan-5-yl)-5-methylcyclohexanol (14)
4.6.2. (1S,2S,5R)-5-Methyl-2-((S)-3-((R)-1-phenylethyl)-1,3-oxazinan-5-yl)cyclohexanol (15)
4.6.3. (1S,2S,5R)-5-Methyl-2-((S)-3-((S)-1-phenylethyl)-1,3-oxazinan-5-yl)cyclohexanol (16)
4.6.4. (1S,2S,5R)-2-((S)-3-Isopropyl-1,3-oxazinan-5-yl)-5-methylcyclohexanol (17)
4.6.5. (1S,2R,5R)-2-((S)-3-Benzyl-5-methyloxazolidin-5-yl)-5-methylcyclohexanol (25)
4.6.6. (1S,2R,5R)-5-Methyl-2-((S)-5-methyl-3-((R)-1-phenylethyl)oxazolidin-5-yl)cyclohexanol (26)
4.6.7. (1S,2R,5R)-5-Methyl-2-((S)-5-methyl-3-((S)-1-phenylethyl)oxazolidin-5-yl)cyclohexanol (27)
4.6.8. (1S,2R,5R)-2-((S)-3-Isopropyl-5-methyloxazolidin-5-yl)-5-methylcyclohexanol (28)
4.7. General Procedure for Debenzylation
4.7.1. (1S,2S,5R)-2-((S)-1-Amino-3-hydroxypropan-2-yl)-5-methylcyclohexanol (13)
4.7.2. (1S,2R,5R)-2-((S)-1-Amino-2-hydroxypropan-2-yl)-5-methylcyclohexanol (24)
4.7.3. (S)-3-Amino-2-((1R,2S,4R)-2-hydroxy-4-methylcyclohexyl)propane-1,2-diol (36)
4.8. General Procedure for Dihydroxylation
4.8.1. (3R,3aR,6R,7aS)-3-Hydroxy-3-(hydroxymethyl)-6-methylhexahydrobenzofuran-2(3H)-one (18)
4.8.2. (R)-2-((1R,2S,4R)-2-Hydroxy-4-methylcyclohexyl)propane-1,2-diol (29)
4.8.3. 2-((1R,2S,4R)-2-Hydroxy-4-methylcyclohexyl)propane-1,2,3-triol (37)
4.9. (S)-4-((1R,2S,4R)-2-Hydroxy-4-methylcyclohexyl)-4-methyl-1,3-dioxolan-2-one (30)
(R)-2-((1R,2S,4R)-2-Hydroxy-4-methylcyclohexyl)propane-1,2-diol (29)
4.10. General Procedure for the Reaction of Benzaldehyde with Diethylzinc in the Presence of Chiral Catalysts
4.11. Antimicrobial Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
Et2O | Diethyl ether |
EtOH | Ethanol |
HCHO | Formaldehyde |
EtOAc | Ethyl acetate |
t-BuOOH | tert-Butyl hydroperoxide |
VO(acac)2 | Vanadyl aceatylacetonate |
NMO | 4-Methylmorpholine N-oxide |
MeCN | Acetonitrile |
THF | Tetrahydrofuran |
LiAlH4 | Lithium aluminum hydride |
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Entry | Ligand | Yield a (%) | eeb (%) | Configuration c |
---|---|---|---|---|
1 | 9 | 90 | 18 | (R) |
2 | 10 | 92 | 60 | (R) |
3 | 11 | 95 | 43 | (R) |
4 | 12 | 95 | 17 | (R) |
5 | 22 | 97 | 18 | (R) |
6 | 25 | 93 | 37 | (R) |
7 | 32 | 86 | 19 | (S) |
8 | 34 | 87 | 28 | (S) |
9 | 35 | 80 | 16 | (S) |
Inhibitory Effect (%) ± RSD (%) | |||||||
---|---|---|---|---|---|---|---|
Yeast | Gram-negative | Gram-positive | |||||
Analogue | Conc. (µg/mL) | C. albicans | C. krusei | E. coli | P. aeruginosa | B. subtilis | S. aureus |
9 | 10 | − | 38.2 ± 4.2 | − | − | − | − |
100 | − | 41.8 ± 1.2 | 24.8 ± 1.3 | − | − | − | |
10 | 10 | − | − | 21.1 ± 8.0 | − | − | − |
100 | − | − | 25.8 ± 10.1 | 19.5 ± 0.5 | − | − | |
11 | 10 | 0.2 ± 0.9 | 0.9 ± 0.5 | − | 22.6 ± 2.1 | 18.4 ± 0.7 | 8.5 ± 0.6 |
100 | 2.2 ± 2.3 | 3.3 ± 4.7 | 0.2 ± 1.8 | 41.6 ± 12.2 | 21.0 ± 7.5 | 9.8 ± 4.0 | |
12 | 10 | − | − | − | 5.4 ± 0.3 | − | 8.5 ± 6.3 |
100 | − | − | − | 14.3 ± 4.5 | − | 9.4 ± 5.4 | |
13 | 10 | − | − | − | − | 26.1 ± 8.3 | 24.5 ± 15.6 |
100 | − | 40.4 ± 2.4 | − | − | 42.9 ± 20.0 | 25.2 ± 1.1 | |
14 | 10 | − | 8.4 ± 4.1 | − | 3.2 ± 7.1 | − | − |
100 | − | 6.7 ± 2.0 | 25.6 ± 2.1 | 4.4 ± 5.8 | − | 12.6 ± 4.5 | |
15 | 10 | − | 1.9 ± 0.7 | − | 8.6 ± 2.5 | − | 3.6 ± 1.4 |
100 | − | 2.8 ± 4.2 | 18.0 ± 1.8 | 20.1 ± 0.2 | − | 10.4 ± 1.5 | |
16 | 10 | − | − | − | 4.4 ± 5.8 | − | − |
100 | − | 48.9 ± 0.1 | 15.7 ± 1.7 | 8.4 ± 5.1 | 4.6 ± 12.5 | − | |
17 | 10 | − | − | − | 15.2 ± 10.4 | − | − |
100 | − | 33.1 ± 0.4 | 8.5 ± 2.06 | 16.7 ± 7.2 | − | − | |
18 | 10 | − | − | − | − | 16.9 ± 17.7 | 34.4 ± 11.7 |
100 | − | − | − | − | 27.1 ± 16.0 | 34.2 ± 2.6 | |
20 | 10 | − | − | − | 2.0 ± 0.9 | 10.6 ± 6.4 | − |
100 | 4.1 ± 1.6 | − | 35.4 ± 0.8 | 19.9 ± 4.8 | 11.5 ± 1.3 | 19.7 ± 7.2 | |
24 | 10 | − | 34.6 ± 3.3 | − | − | 47.6 ± 10.6 | 30.0 ± 2.0 |
100 | 23.6 ± 1.2 | 37.8 ± 3.6 | − | − | 55.1 ± 19.9 | 33.9 ± 4.0 | |
29 | 10 | − | − | − | − | − | 32.4 ± 4.1 |
100 | − | − | − | − | 21.2 ± 5.2 | 34.7 ± 6.6 | |
32 | 10 | − | − | − | − | − | − |
100 | − | − | − | − | − | 24.6 ± 11.9 | |
10 | − | − | − | − | 14.9 ± 13.8 | 31.2 ± 7.9 | |
36 | 100 | 39.9 ± 4.1 | − | − | 43.1 ± 2.6 | 33.3 ± 2.1 | |
37 | 10 | − | − | − | − | − | 31.6 ± 15.1 |
100 | − | 26.8 ± 7.9 | − | − | 40.9 ± 16.6 | 32.8 ± 8.2 |
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Le, T.M.; Szilasi, T.; Volford, B.; Szekeres, A.; Fülöp, F.; Szakonyi, Z. Stereoselective Synthesis and Investigation of Isopulegol-Based Chiral Ligands. Int. J. Mol. Sci. 2019, 20, 4050. https://doi.org/10.3390/ijms20164050
Le TM, Szilasi T, Volford B, Szekeres A, Fülöp F, Szakonyi Z. Stereoselective Synthesis and Investigation of Isopulegol-Based Chiral Ligands. International Journal of Molecular Sciences. 2019; 20(16):4050. https://doi.org/10.3390/ijms20164050
Chicago/Turabian StyleLe, Tam Minh, Tamás Szilasi, Bettina Volford, András Szekeres, Ferenc Fülöp, and Zsolt Szakonyi. 2019. "Stereoselective Synthesis and Investigation of Isopulegol-Based Chiral Ligands" International Journal of Molecular Sciences 20, no. 16: 4050. https://doi.org/10.3390/ijms20164050