Zaragozic Acid A/Squalestatin S1
In 1992, a family of structurally related natural products was isolated from various fungal cultures by researchers at Glaxo and Merck. This chemical family is known as the squalestatins and the zaragozic acids, named after Province of Zaragoza, where the fungi were found. One of the members of the zaragozic acids/squalestatins family is zaragozic acid A/squalestatins 1.
Zaragozic acids/squalestatins have a unique structure which is based on a highly-oxygenated bicyclic 4,6,7-tridhydroxy-2,8-dioxobicyclo-[3.2.1]-octane-3,4,5-tricarboxylic acid and differ only at C1 alkyl chain and C6 ester.
The first ever total synthesis of zaragozic acid 1 was done by Nicolaou's group in 1994 and the synthesis consists of 3 main reaction:
Diene 8 was synthesised via Stille coupling reaction of vinylstannane 4 and vinyl iodide 7. The hydroxylation of 8 was done by using a mixture of reagents called AD-mix β containing 1% K2OsO2(OH)2 and 5% chiral ligand (DHQD)2PHAL. Despite the yield of this hydroxylation is moderate (around 40%), it can be run conveniently on a large scale. It is noteworthy to point out that the formation of triol via OsO4/NMO produce a single diastereomer which then protected by tert-butyldiphenylsilyl (TBDS) group.
The synthesis of key aldehyde 14 was achieved by protection of the alcohol at C4 as TMS followed by Dess-Martin periodinane. In overall, 22 steps is needed to synthesise key aldehyde 14.
The alkyl chain on C1 of zaragozic acid 1 was attached via addition of dithiane 15 followed by hydrolysis to give lactol 17.
Then, exposing 17 with HCl/MeOH triggered rearrangement reaction to give 18 with several minor products, but these minor products are slowly converted into 18. This conversion shows that 18 is the thermodynamically most stable skeleton of then central region of the molecule. The use of di-tert-butylmethylsilyl (DTBMS) is preferable, despite very rarely used, as common protecting groups PMB and TBDS are failed withstand in the rearrangement condition.
The total synthesis of zaragozic acid A was completed by esterification of 21 (the synthesis of acid 29 is outlined below), acetylation on alkyl side chain, and deprotection of the protecting groups. Benzyl protecting groups are removed by transfer hydrgenolysis and TBAF was used to removed TES group.
Ester 21 can be synthesised using esterification of 29 with benzyl alcohol.
The chemistry of the total synthesis of zaragozic acid A demonstrates cascade rearrangement reactions and asymmetric hydroxylation to access the complex structure of zaragozic acid A and the rest of the zaragozic acids and squalestatins.
Furthermore, zaragozic acid A shows a moderately high affinity for Ca2+ ions and it is speculated to be the cause of its biological activity, a potent inhibitor of S. cervisiae, fungal and mammal squalene synthase and therefore inhibitor of sterol synthesis. Zaragozic acid A produces lower plasma cholesterol levels in primate and treatment of rats with zaragozic acid A causes an increase in hepatic LDL receptor mRNA levels.
References
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| Zaragozic acid A and coat of arm of Province of Zaragoza |
Zaragozic acids/squalestatins have a unique structure which is based on a highly-oxygenated bicyclic 4,6,7-tridhydroxy-2,8-dioxobicyclo-[3.2.1]-octane-3,4,5-tricarboxylic acid and differ only at C1 alkyl chain and C6 ester.
- ester formation at C6,
- C1-C7 bond formation, and
- internal ketalization.
The alkyl chain on C1 of zaragozic acid 1 was attached via addition of dithiane 15 followed by hydrolysis to give lactol 17.
Then, exposing 17 with HCl/MeOH triggered rearrangement reaction to give 18 with several minor products, but these minor products are slowly converted into 18. This conversion shows that 18 is the thermodynamically most stable skeleton of then central region of the molecule. The use of di-tert-butylmethylsilyl (DTBMS) is preferable, despite very rarely used, as common protecting groups PMB and TBDS are failed withstand in the rearrangement condition.
The total synthesis of zaragozic acid A was completed by esterification of 21 (the synthesis of acid 29 is outlined below), acetylation on alkyl side chain, and deprotection of the protecting groups. Benzyl protecting groups are removed by transfer hydrgenolysis and TBAF was used to removed TES group.
The chemistry of the total synthesis of zaragozic acid A demonstrates cascade rearrangement reactions and asymmetric hydroxylation to access the complex structure of zaragozic acid A and the rest of the zaragozic acids and squalestatins.
Furthermore, zaragozic acid A shows a moderately high affinity for Ca2+ ions and it is speculated to be the cause of its biological activity, a potent inhibitor of S. cervisiae, fungal and mammal squalene synthase and therefore inhibitor of sterol synthesis. Zaragozic acid A produces lower plasma cholesterol levels in primate and treatment of rats with zaragozic acid A causes an increase in hepatic LDL receptor mRNA levels.
References
- J. D. Bergstrom, M. M. Kurtz, D. J. Rew, A. M. Amend, J. D. Karkas, R. G. Bostedor, V. S. Bansal, C. Dufresne, F. L. van Middlesworth, O. D. Hensens, J. M. Liesch, D. L. Zink, K. E. Wilson, J. Onishi, J. A. Milligan, G. Bills, L. Kaplan, M. Nallin Omstead, R. G. Jenkins, L. Huang, M. S. Meinz, L. Quinn, R. W. Burg, Y. L. Kong, S. Mochales, M. Mojena, I. Martin, F. Pelaez, M. T. Diez, and A. W. Alberts, Proc. Natl. Acad. Sci. USA, 1993, 90, 80.
- K. C. Nicolaou, E. W. Yue, Y. Naniwa, F. de Riccardis, A. Nadin, J. E. Leresche, S. la Greca, and Z. Yang, Angew. Chem. Int. Ed. Engl., 1994, 33, 2184.
- K. C. Nicolaou, A. Nadin, J. E. Leresche, S. la Greca, T. Tsuri, E. W. Yue, and Z. Yang, Angew. Chem. Int. Ed. Engl., 1994, 33, 2187.
- K. C. Nicolaou, A. Nadin, J. E. Leresche, E. W. Yue, and S. la Greca, Angew. Chem. Int. Ed. Engl., 1994, 33, 2190.
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