A novel synthetic approach to the construction of the zaragozic acids, which was used for the asymmetric synthesis of zaragozic acid A/squalestatin S1 (l), is described. Fragment 5, representing the tricarboxylic acid core portion, is assembled in three key steps: 1) Stille coupling to establish the carbon framework; 2) enantioselective dihydroxylation to introduce the absolute stereochemistry ; and 3) diastereoselective dihydroxylation to complete the required carbon -oxygen event acid-catalyzed rearrangement yieldconnectivity. The convergency of this syn-ed the zaragozic acid core 86, which was thesis is demonstrated by the dithiane ad-converted to an intermediate obtained dition of a variety of C 1 side chains (e.g., from degradation of zaragozic acid A. A 78) to advanced intermediate 5. A multi-second-generation synthesis of the core of the zaragozic acids is also described. When aldehyde 90 was used instead of 5, both the yield and diastereoselectivity of the dithiane addition reaction were improved, although the degree ofconvergency was slightly lower.
Step by step the first total synthesis was approached: of the zaragozic acids/ squalestatins showing potential therapeutic value for lowering the serum cholesterol concentration, zaragozic acid A/squalestatin SI (1), the most abundant member of a new class of naturally occurring products, has now been synthesized via the key intermediates 2 and 3. Initially the projected final sequence (2 → 1) was achieved, and the side chains attached to C1 and C6 were prepared through efficient asymmetric syntheses. The first synthesis of the highly oxygenated “core”, which is characteristic of this class of natural products, was achieved from a simple prochiral diene via intermediate 3. Finally the synthetic route 3 → 2 was developed to successfully complete the total synthesis. Bn benzyl, PMB para‐methoxybenzyl, TMS trimethylsilyl.
The reactions of chiral nitro enamines 2a-c with zinc enolates 4-6 of a-substituted &lactones afforded a,a-disubstituted &lactones with a high ee through an addition-elimination process. The best results were obtained with the reaction of 2c with 5. Michael-type addition of the enolate onto the nitro enamine is kinetically controlled and decides the absolute stereochemistry of the product. A cyclic transition model is proposed to rationalize the S-selectivity.
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