Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpene 1,3-Aminoalcohol Regioisomers
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of Key Intermediate β-Keto Alcohol 4
2.2. Synthesis of 1,3-Aminoalcohol Derivatives 6–17
2.3. Synthesis of 1,3-Aminoalcohol Regioisomers 22–30 and Preparation of 1,2,3-Triazole Derivatives via a Click Reaction
2.4. In Vitro Antiproliferative Studies of Steviol-Based Aminoalcohols and Structure–Activity Relationship
3. Materials and Methods
3.1. General Methods
3.2. Starting Materials
3.2.1. (2’S,4R,4aS,6aS,11aR,11bS)-Methyl 9-hydroxy-4,11b-dimethyldodecahydro-1H-spiro [6a,9-methanocyclohepta[a]naphthalene-8,2’-oxirane]-4-carboxylate (3)
3.2.2. (4R,4aS,6aR,9S,11aR,11bS)-Methyl 9-(hydroxymethyl)-4,11b-dimethyl-8-oxotetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (4)
3.2.3. (4R,4aS,6aR,9R,11aR,11bS,E)-Methyl 8-(hydroxyimino)-9-(hydroxymethyl)-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (5)
3.3. Hydrogenation of Oxime 5
3.3.1. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 8-amino-9-(hydroxymethyl)-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (6)
3.3.2. (4R,4aS,6aR,8S,9R,11aR,11bS)-Methyl 8-amino-9-(hydroxymethyl)-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (7)
3.4. General Procedure for the Preparation of Aminoalcohols Using Primary Amines from β-keto Alcohol 4
3.4.1. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 8-(benzylamino)-9-(hydroxymethyl)-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (8)
3.4.2. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 8-((4-fluorobenzyl)amino)-9-(hydroxymethyl)-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (9)
3.4.3. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 9-(hydroxymethyl)-8-((4-methoxybenzyl)amino)-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (10)
3.4.4. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 9-(hydroxymethyl)-4,11b-dimethyl-8-(((S)-1-phenylpropyl)amino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (11)
3.4.5. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 9-(hydroxymethyl)-4,11b-dimethyl-8-(((R)-1-phenylpropyl)amino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (12)
3.4.6. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 9-(hydroxymethyl)-4,11b-dimethyl-8-(((R)-1-(naphthalen-1-yl)ethyl)amino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (13)
3.4.7. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 9-(hydroxymethyl)-4,11b-dimethyl-8-(((S)-1-(naphthalen-1-yl)ethyl)amino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (14)
3.4.8. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 9-(hydroxymethyl)-4,11b-dimethyl-8-((naphthalen-1-ylmethyl)amino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (15)
3.4.9. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 9-(hydroxymethyl)-4,11b-dimethyl-8-(((S)-1-(naphthalen-2-yl)ethyl)amino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (16)
3.4.10. (4R,4aS,6aR,8R,9R,11aR,11bS)-Methyl 9-(hydroxymethyl)-4,11b-dimethyl-8-(((R)-1-(naphthalen-2-yl)ethyl)amino)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (17)
3.5. (4R,4aS,6aR,9S,11aR,11bS)-Methyl 4,11b-dimethyl-9-(((methylsulfonyl)oxy)methyl)-8-oxotetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (18)
3.6. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 8-hydroxy-4,11b-dimethyl-9-(((methylsulfonyl)oxy)methyl)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (21)
3.7. General Procedure for Azide Synthesis of 18 and 21 for Preparation of 19 and 20
3.7.1. (4R,4aS,6aR,9S,11aR,11bS)-Methyl 9-(azidomethyl)-4,11b-dimethyl-8-oxotetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (19)
3.7.2. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 9-(azidomethyl)-8-hydroxy-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (20)
3.8. General Procedure for Preparation of Aminoalcohol Regioisomers with Primary Amines from Hydroxy-Mesylate 21
3.8.1. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 9-((benzylamino)methyl)-8-hydroxy-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (22)
3.8.2. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 9-(((4-fluorobenzyl)amino)methyl)-8-hydroxy-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (23)
3.8.3. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 8-hydroxy-4,11b-dimethyl-9-((((R)-1-phenylpropyl)amino)methyl)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (24)
3.8.4. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 8-hydroxy-4,11b-dimethyl-9-((((S)-1-phenylpropyl)amino)methyl)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (25)
3.8.5. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 8-hydroxy-4,11b-dimethyl-9-(((naphthalen-1-ylmethyl)amino)methyl)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (26)
3.8.6. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 8-hydroxy-4,11b-dimethyl-9-((((S)-1-(naphthalen-1-yl)ethyl)amino)methyl)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (27)
3.8.7. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 8-hydroxy-4,11b-dimethyl-9-((((R)-1-(naphthalen-1-yl)ethyl)amino)methyl)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (28)
3.8.8. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 8-hydroxy-4,11b-dimethyl-9-((((R)-1-(naphthalen-2-yl)ethyl)amino)methyl)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (29)
3.8.9. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 8-hydroxy-4,11b-dimethyl-9-((((S)-1-(naphthalen-2-yl)ethyl)amino)methyl)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (30)
3.9. (4. R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 9-(aminomethyl)-8-hydroxy-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (31)
3.10. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 8-hydroxy-9-(((4-methoxybenzyl)amino) methyl)-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (32)
3.11. General Procedure for Click Reaction of 19 and 20 for the Preparation of 33–36
3.11.1. (4R,4aS,6aR,9S,11aR,11bS)-Methyl 4,11b-dimethyl-8-oxo-9-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (33)
3.11.2. (4R,4aS,6aR,9S,11aR,11bS)-Methyl 9-((4-benzyl-1H-1,2,3-triazol-1-yl)methyl)-4,11b-dimethyl-8-oxotetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (34)
3.11.3. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 8-hydroxy-4,11b-dimethyl-9-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)tetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (35)
3.11.4. (4R,4aS,6aR,8R,9S,11aR,11bS)-Methyl 9-((4-benzyl-1H-1,2,3-triazol-1-yl)methyl)-8-hydroxy-4,11b-dimethyltetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate (36)
3.12. Determination of the Antiproliferative Activities
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Entry | Product | R | Yield [%] |
---|---|---|---|
1 | 8 | benzyl | 43 |
2 | 9 | 4-fluorobenzyl | 48 |
3 | 10 | 4-methoxybenzyl | 70 |
4 | 11 | (R)-α-ethylbenzyl | 65 |
5 | 12 | (S)-α-ethylbenzyl | 60 |
6 | 13 | (R)-1-(1-naphthyl)ethyl | 41 |
7 | 14 | (S)-1-(1-naphthyl)ethyl | 38 |
8 | 15 | 1-naphthylmethyl | 78 |
9 | 16 | (R)-1-(2-naphthyl)ethyl | 60 |
10 | 17 | (S)-1-(2-naphthyl)ethyl | 56 |
Entry | Product | R | Yield [%] |
---|---|---|---|
1 | 22 | benzyl | 22 |
2 | 23 | 4-fluorobenzyl | 41 |
3 | 24 | (R)-α-ethylbenzyl | 40 |
4 | 25 | (S)-α-ethylbenzyl | 36 |
5 | 26 | 1-naphthylmethyl | 44 |
6 | 27 | (R)-1-(1-naphthyl)ethyl | 29 |
7 | 28 | (S)-1-(1-naphthyl)ethyl | 21 |
8 | 29 | (R)-1-(2-naphthyl)ethyl | 19 |
9 | 30 | (S)-1-(2-naphthyl)ethyl | 15 |
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Bai, D.; Schelz, Z.; Boncz, M.F.; Zupkó, I.; Szakonyi, Z. Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpene 1,3-Aminoalcohol Regioisomers. Molecules 2023, 28, 7962. https://doi.org/10.3390/molecules28247962
Bai D, Schelz Z, Boncz MF, Zupkó I, Szakonyi Z. Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpene 1,3-Aminoalcohol Regioisomers. Molecules. 2023; 28(24):7962. https://doi.org/10.3390/molecules28247962
Chicago/Turabian StyleBai, Dorottya, Zsuzsanna Schelz, Mária Fanni Boncz, István Zupkó, and Zsolt Szakonyi. 2023. "Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpene 1,3-Aminoalcohol Regioisomers" Molecules 28, no. 24: 7962. https://doi.org/10.3390/molecules28247962
APA StyleBai, D., Schelz, Z., Boncz, M. F., Zupkó, I., & Szakonyi, Z. (2023). Stereoselective Synthesis and Antiproliferative Activity of Steviol-Based Diterpene 1,3-Aminoalcohol Regioisomers. Molecules, 28(24), 7962. https://doi.org/10.3390/molecules28247962