Total Synthesis of Solandelactones A, B, E, and F Exploiting a Tandem Petasis−Claisen Lactonization Strategy

Abstract

Solandelactones A, B, E, and F were synthesized using Nozaki-Hiyama-Kishi coupling of iododiene 13 with aldehydes 14 and 99 obtained by oxidation of alcohols 92 and 94. Key steps in the synthesis of 92 and 94 were (i) a Nagao asymmetric acetate aldol reaction of aldehyde 77 with thionothiazolidine 78 to set in place an alcohol that becomes the (7 S) lactone center of solandelactones, (ii) a Simmons-Smith cyclopropanation of 80 directed by this alcohol, and (iii) Petasis methylenation of cyclic carbonate 90 in tandem with a Claisen rearrangement that generates the octenalactone portion of solandelactones. Synthesis of solandelactones A, B, E, and F confirmed their gross structure and absolute configuration at C7, 8, 10, and 14 but showed that alcohol configuration at C11 must be reversed in pairs, A/B and E/F, from the previous assignment made to these hydroid metabolites. Thus, solandelactones A and B are correctly represented by 2 and 1, respectively, whereas solandelactones E and F are 6 and 5. A biogenesis of solandelactones is proposed for these C 22 oxylipins that parallels a hypothesis put forward previously to explain the origin of C 20 cyclopropane-containing algal products.

Asymmetric Total Synthesis of Solandelactone E: Stereocontrolled Synthesis of the 2‐ene‐1,4‐diol Core through a Lithiation–Borylation–Allylation Sequence

“…This was achieved by utilizing the directing effect of the homoallylic alcohol with Ti(OiPr) 4 / tBuOOH [24] which, after acid-catalyzed rearrangement, gave solandelactone E as a single diastereoisomer in 68 % yield over two steps (Scheme 6). The spectroscopic data matched exactly with those of natural and synthetic solandelactone E. [1,[4][5][6] In conclusion, we have completed a short (13 steps, longest linear sequence) and highly selective synthesis of solandelactone E. The key steps included Sharpless epoxidation, Taber cyclopropanation, chemoselective reduction of a nitrile to an aldehyde, and our own lithiation-borylationallylation sequence on a highly functionalized substrate. Not only does the completed synthesis establish the method for application to complex targets, it also solves the problem of poor stereocontrol at C11 that had dogged many previous syntheses of this class of molecules.…”

“…[3] Initial assignment of structure and absolute stereochemistry was based primarily on NMR studies, which led to two sets of compounds depending on their configuration at C11: R configuration for A, C, E, and G; S configuration for B, D, F, and H. However, the experimental data for synthetic solandelactone "F", which had been synthesized by Martin and coworkers, [4] matched the data for solandelactone E, thus indicating that the two sets of compounds had been incorrectly assigned. Further syntheses by White et al [5] as well as Pietruszka and Rieche [6] confirmed that the configuration at C11 in all of the solandelactones A-H should be depicted as in Scheme 1.…”

“…Attempts using diisobutylaluminum hydride led to a mixture of products but Raney-nickel with sodium hypophosphite [18] gave 2 as a single product in high yield. Although aldehyde 2 had previously been synthesized, our route represents a significant decrease in the number of steps (10 steps vs. 13 steps [5,19] or 14 steps [6] ), with high stereocontrol and only a single protecting-group manipulation.…”

Chiral Pool Synthesis of N-Cbz-cis-(3R,4R)-3-methylamino-4-methylpiperidine from L-Malic acid

“…Our experiments showed that with borane methyl sulfide (BMS)-NaBH 4 , the chemoselective reduction of ester 3 could be achieved and gave the diol 4 in good yield, according to the literature precedents. [27][28][29][30][31] The reason for the chemoselectivity was discussed by Moriwake et al 54 The best ratio for BMS: NaBH 4 :ester 3 was 1:0.1:1. Excess BMS could lead to over-reduction and thus lower yield was obtained.…”

Asymmetric Domino Reactions Based on the Use of Chiral Substrates

“…117 As shown in Scheme 1.76, Petasis methylenation of an enantiopure cyclic carbonate in tandem with a Claisen rearrangement generated the corresponding chiral octenalactone portion of solandelactones as a single stereoisomer in 60-65% yield. This chiral product was further converted into a mixture of expected solandelactones A, B, E and F.…”