Total Synthesis of Zaragozic Acid A (Squalestatin S1). Degradation to a Relay Compound and Reassembly of the Natural Product

Abstract

Zaragozic acid A (squalestatin S1) (1) was converted into the simpler derivative 2, which was reconverted into the natural product, thus establishing 2 as a viable relay compound for total synthesis of 1. The degradation (Scheme 1) consisted of formation of the tri-tert-butyl ester (3), from which the two side chains were sequentially removed to obtain 8. Aldehyde 8 was converted into dimethyl acetal 2 in standard fashion. The C6 acyl side chain 14 was prepared from (S)-2methylbutanol ("active amyl alcohol"), and the desired 4S configuration was obtained by use of Evans asymmetric enolate methylation (Scheme 2). The C1 alkyl side chain was prepared as stannane 23a from (R)-2-methyl-3-phenylpropanol (21) as shown in Scheme 5. For conversion of 2 back into zaragozic acid A, the dimethyl acetal was first converted into the cyclic acetal 17, thus protecting the C7 hydroxyl group. The remaining hydroxyl group was then acylated with acid 14 to obtain 18, which was transformed into aldehyde 20 (Scheme 4). The C1 alkyl chain was elaborated by the addition of a chiral R-alkoxyorganocerium reagent, obtained from 23a, to aldehyde 20. The resulting mixture of diastereomeric secondary alcohols was converted into zaragozic acid A (1) in six steps (Scheme 6).

An efficient and general route to reduced polypropionates via Zr-catalyzed asymmetric C—C bond formation

“…The results suggested that the formation of (2S,4S)-7 is mildly favored by the preexisting 4-methyl group, whereas that of (2R,4S)-7 is either essentially unaffected or slightly disfavored. To probe the extent of internal asymmetric induction, (S)-4-methyl-1-hexene was methylaluminated by using 5 mol% of (Ind) 2 ZrCl 2 or (2-MeInd) 2 ZrCl 2 , where Ind is indenyl and 2-MeInd is 2-methylindenyl. These reactions produced nearly racemic mixtures of (2S,4S)-7 and (2R,4S)-7 in 1.03:1.0 to 1.10:1.0 ratios with a slight preference for the formation of (2S,4S)-7.…”

“…In one synthesis of compound 2, (2S,4S)-7 was prepared from compound 4 in Ϸ40% yield in six to seven steps via stoichiometric ␣-methylation of a chiral amide (2). Thus, even at the current stage of development, the three-step synthesis of (2S,4S)-7 via Zr-catalyzed asymmetric methylalumination offers a higher level of efficiency and catalysis in chiral auxiliary as advantageous features.…”

“…The latter includes those reduced polypropionates that contain (i) two methylbranched asymmetric carbon centers, such as zaragozic acid A (compound 2 in Fig. 1) (2), and (ii) three methyl-branched asymmetric carbon centers, such as antibiotics TMC-151 A-F (compound 3 in Fig. 1) (3).…”

“…Another earlier asymmetric route to reduced polypropionates involved diastereoselective conversion of chirons derived from natural sources (8). However, the methods most frequently used now involve either ␣-alkylation of chiral enolates (2,(9)(10)(11)(12) and related nucleophiles (13) or conjugate addition to chiral ␣,␤-unsaturated carboxamides (14,15). Despite the fact that these methods require at least one, and often more than one, equivalent of chiral reagents, some of them, in particular the protocol of Myers et al (11,12), may be viewed as the current benchmarks.…”

Total Synthesis of the Squalene Synthase Inhibitor Zaragozic Acid C

“…Since then the Evans 30) and Armstrong 31,32) groups have accomplished the total syntheses of zaragozic acid C, while the efforts of the groups of Heathcock, 33,34) and Tomooka and Nakai 35) culminated in successful total syntheses of zaragozic acid A. These approaches are summarized in Chart 1.…”