Zaragozic acids Squalestatins

Zaragozic Acids The zaragozic acids (squalestatins) are a class of competitive inhibitors of mouse, rat, and HepG2 squalene synthases, which also display antifungal activity [104]. The characteristic structural feature of this family of natural products is its highly oxygenated core. 

The zaragozic acids (squalestatins) are not macrolides, but they are primarily acetate derived, and the central ring system is suggested to be... 

Nadin A and Nicolaou KC (1996) Chemistry and biology of the zaragozic acids (squalestatins). Angew Chem Int Ed Engl 35, 1623-1656. 

Zaragozic acids (squalestatins). Highly active, competitive inhibitors of squalene synthase (SQS) and thus of cholesterol biosynthesis. The different names are a result of the independent, simultaneous discovery of this class of natural products in various ascomycete strains (e. g., Phoma sp., Setosphaeria khartoumensis) by three research groups. All Z. possess a 4,6,7-tri-hydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarbox-ylic acid skeleton carrying acyl groups on the C-6 oxygen atom as lipophilic side chains and alkyl groups on the C-1 carbon atom. 

A review on the chemistry and biology of the zaragozic acids (squalestatins), including discussion of a number of approaches from sugars, has appeared this year [132 refs]. Heathcock s group have reported a complete total synthesis of zaragozic acid A via 195, prepared from carbohydrate precursor 194 (Scheme 15). ° The group had prepared 195 from the natural product and then reconverted it to the natural product to establish it as a viable relay compound for total synthesis. ... 

This year has seen several approaches to the core of the zaragozic acids/squalestatins from carbohydrate starting materials. D-Mannose was converted to the glycal 117, elaborated to precursor 118 by a-selective dioxirane oxidation and Cl epoxide ring opening by allyl alcohol, deallylation, oxidation and Grignard addition. Desilylation of 118 with concomitant intramolecular acetalation afforded the core analogue 119 (Schone 30). ... 

Medicinal chemistry has frequently drawn inspiration and important new leads from the examination of natural products, and this was proven to be the case once more. In 1992, researchers at Merck and Glaxo announced, almost simultaneously, the independent discovery of the same new class of natural products from two different fungi. As a consequence, the same family of natural products has two names - the zaragozic acids (Merck)4 or the squalestatins (Glaxo).5 A typical member of the family, zaragozic acid A (squa-lestatin SI) (1) was shown to have a tremendous affinity for squalene synthase (K, = 79 pM for rat microsomal squalene synthase) and could even lower serum cholesterol levels in vivo in a population of marmosets.6... 

Scheme 17. Retrosynthetic analysis of zaragozic acid A/squalestatin S1 (1).

Zaragozic Acid A/Squalestatin S1 35.3.4 Synthesis of the Side Chains... 

Coupling of Key Intermediates and Completion of the Total Synthesis of Zaragozic Acid A/Squalestatin SI... 

Zaragozic acid A (which is also called squalestatin SI and has been shown to lower serum cholesterol levels in test animals by inhibition of squalene biosynthesis) by K. C. Nicolaou (University of California San Diego, Scripps Research Institute) ... 

Stoermer, D, Caron, S, Heathcock, C H, Total synthesis of zaragozic acid A (squalestatin SI). Degradation to a relay compound and reassembly of the natural product, J. Org. Chem., 61, 9115-9125, 1996. 

Mann, R K, Parsons, J G, Rizzacasa, M A, Towards the synthesis of the squalestatins/zaragozic acids synthesis of an advanced intermediate and introduction of the C-1 sidechain, J. Chem. Soc., Perkin. Trans. 1, 1283-1293, 1998. 

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