147220-48-2Relevant articles and documents
Synthesis of solandelactone F, constanolactone A and an advanced intermediate towards solandelactone e from a common synthetic intermediate
Yalla, Raju,Raghavan, Sadagopan
, p. 4572 - 4592 (2019/05/16)
The stereoselective synthesis of solandelactone F, constanolactone A and an advanced intermediate towards solandelactone E, from a common synthetic intermediate, is disclosed. The propargylic sulfide stereocenter is created stereoselectively via carbon-carbon bond formation in the reaction of α-chloro sulfides with alkynylzinc reagents via 1,2-asymmetric induction by a β-siloxy group. The characteristic 1,4-diol motif of the natural products is introduced by a [2,3] sigmatropic rearrangement of an allylic sulfoxide or by the Mislow-Evans-Braverman rearrangement of a propargylic sulfoxide followed by stereoselective reduction of the ensuing α,β-unsaturated ketone. Unlike earlier reports, the C11/C9 carbinol center is created with excellent stereocontrol and derivatives of natural products differing at C14/C12 can be readily obtained. Catalytic asymmetric protocols and substrate-controlled asymmetric induction are utilized for the efficient introduction of the stereogenic centers.
Total synthesis of (-)-zampanolide and structure-activity relationship studies on (-)-dactylolide derivatives
Zurwerra, Didier,Glaus, Florian,Betschart, Leo,Schuster, Julia,Gertsch, Jürg,Ganci, Walter,Altmann, Karl-Heinz
supporting information, p. 16868 - 16883 (2013/03/14)
A new total synthesis of the marine macrolide (-)-zampanolide (1) and the structurally and stereochemically related non-natural levorotatory enantiomer of (+)-dactylolide (2), that is, ent-2, has been developed. The synthesis features a high-yielding, selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction to close the 20-membered macrolactone ring of 1 and ent-2. The β-keto phosphonate/aldehyde precursor for the ring-closure reaction was obtained by esterification of a ω-diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent-2. THP ring formation was accomplished through a segment coupling Prins-type cyclization. Employing the same overall strategy, 13-desmethylene-ent-2 as well as the monocyclic desTHP derivatives of 1 and ent-2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with nM IC50 values, while ent-2, which lacks the diene-containing hemiaminal-linked side chain of 1, is 25- to 260-fold less active. 13-Desmethylene-ent-2 as well as the reduced versions of ent-2 and 13-desmethylene-ent-2 all showed similar cellular activity as ent-2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1. Oxidation of the aldehyde functionality of ent-2 gave a carboxylic acid that was converted into the corresponding N-hexyl amide. The latter showed only μM antiproliferative activity, thus being several hundred-fold less potent than 1. It's the side chain that matters: The marine macrolide (-)-zampanolide (1) has been synthesized via (-)-dactylolide (ent-2), the non-natural enantiomer of the marine natural product (+)-dactylolide (2), employing a high-yielding intramolecular Horner-Wadsworth-Emmons reaction to close the macrolactone ring. While the hemiaminal-linked side chain in 1 is crucial for nanomolar antiproliferative activity, the methylene group and the aldehyde functionality in ent-2 are dispensable. A monocyclic destetrahydropyran derivative of 1 shows equal activity as ent-2. Copyright
Synthesis of (-)-dactylolide and 13-desmethylene-(-)-dactylolide and their effects on tubulin
Zurwerra, Didier,Gertsch, Juerg,Altmann, Karl-Heinz
supporting information; experimental part, p. 2302 - 2305 (2010/08/05)
An efficient new synthesis has been elaborated for non-natural (-)-dactylolide ((-)-2) and its 13-desmethylene analogue 4, employing a HWE-based macrocyclization approach with β-keto-phosphonate/aldehyde 19 and the respective 13-desmethylene derivative as the key intermediates. Both (-)-2 and 4 as well as the corresponding C20 alcohols inhibit human cancer cell proliferation with IC50 values in the sub-micromolar range and induce the polymerization of tubulin in vitro.
