Natural product synthesis Zaragozic Acid

FIGURE 2 Examples of the variety of structures obtained in natural product screens. I, zaragozic acid A, is an inhibitor of mammalian and fungal sterol synthesis, obtained from fungi (48) II, L-696,474, is an inhibitor of the HIV protease, obtained from fungi (51) III, dehydrosoyasaponin I, is an agonist of the calcium-activated potassium channel, obtained from a medicinal plant (58) IV, tetrandrine, is an inhibitor of L-type calcium channels, obtained from a plant (78). 

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. 

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. ... 

The first two completed total syntheses of zaragozic acids have been reported this year. Carreira s synthesis of zaragozic acid C 122 commenced from D-erythronolactone.52 The synthesis of zaragozic A/squalestatin SI 123 by the Nicolaou group was based on sequential asymmetric dihydroxylations of the achiral diene 126, prepared by Sdlle coupling of 124 and 125 (Scheme 32).S3,54 The dihydroxylation was not completely diastereoselecdve, and elaboration led to the two epimeric pyranose derivative intermediates 127 and 128 en route to the natural product. 

In comparison with ketone-based SAMP/RAMP hydrazones, the use of aldehyde-derived SAMP/RAMP hydrazones in natural product syntheses is much more prevalent. For instance, Nicolaou et al. synthesized the side chain of zaragozic acid A 49 using two successive SAMP hydrazone alkylations (Scheme 1.1) The zaragozic acid class of natural products inhibits squalene synthase, the enzyme responsible for the biosynthesis of cholesterol. Inhibition of this enzyme has implications in the treatment of coronary artery disease. The synthesis of the side chain of zaragozic acid began with the formation of 42, which... 

Finally, this new asymmetric reaction (and more particularly the diastereoselective version) has been appHed to the synthesis of natural products. First, rapid access to 2-methyldecanol and undecanol 40 and 41, two insect pheromones, has been performed. The P.y-unsaturated esters have been hydrogenated over catalytic amounts of PtOj and then reduced without epimerization to the chiral 2-methylalkanols. 2 According to a similar approach, the side chain of Zaragozic acid C 42 has been prepared in high EE, while access to curcumanoHde A 43 and its analogs has been developed (Scheme 23). 

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