Synthesis ionomycin

Similar 5-exo cyclization procedures have been widely utilized by Evans in his total syntheses of complex natural compounds, such as the synthesis of ionomycin [12a] and polyether antibiotic X-206 [12b]. A 5-exo cyclization of a y-epoxy alcohol has also been observed under basic conditions [12c]. 

Lautens also used this nickel-catalyzed hydroalumination methodology in the total synthesis of ionomycin 145. The starting compound was a [3.2.1]oxabicyclic alkene 143.144 Their rigid bicyclic structures can be used to introduce functional groups in a highly stereoselective manner. The synthesis of the key intermediate 144 involves the slow addition of DIBAL to the oxabicyclic alkene and the Ni(COD)2/(6T)-BINAP in toluene to afford 144 in 95% yield and 93-95% ee. (Scheme 18). 

SCHEME 72. Iterative one-pot homologation of reduced polypropionates viaZACA-Pd-catalyzed vinylation and its application to highly efficient catalytic and asymmetric synthesis of key intermediates of ionomycin and borrelidin... 

Applications in Total Synthesis. Two recent examples of directed hydrogenations employing (1) in the total synthesis of complex molecules are illustrated. In eq I a simultaneous diastereoselective reduction of the trisuhstituted alkene and the a,p-unsaturated ester afforded the illustrated advanced intermediate in the asymmetric total synthesis of ionomycin. In addition, a two-directional application has been utilized in an asymmetric synthesis FK-506 (eq 2). ... 

Attention is drawn to the synthesis the oxygenated linalool oxide 896. This compound (and other stereoisomers) is not a naturally occurring monoterpenoid, but a fragment required in the synthesis of a calcium ion-selective ionophore, ionomycin, and was made from hydroxygeranyl acetate (113, R = Ac), then Sharpless conditions for introducing a chiral epoxide were used. The vital step is the cyclization of 897 by epoxidizing again under Sharpless conditions (titanium tetraisopropoxide and diethyl tartrate) when the product 896 is obtained. ... 

The in vitro development of bovine cloned embryos was significantly improved by delayed activation with an electrical pulse for 4—6 h after fusion [18]. Other materials, including a calcium inducer (calcium iono-phore or ionomycin), a protein kinase inhibitor [6-dimethyl aminopurine (DMAP)] or a protein synthesis inhibitor (cyclohexa-mide or puromycin) were known oocyte activators. In cattle, incubation with cyclo-hexamide following exposure of the embryo to ionomycin or electrical pulses resulted in embryo development to term [19,... 

The aldol addition reaction, and the related crotyl metal additions (section 5.1), have figured prominently in the total synthesis of a number of complex natural products (reviews [48,140-142]). Figure 5.8 illustrates those mentioned in the preceding discussion, along with others selected from the recent literature, with the stereocenters formed by stereoselective aldol addition indicated ( ). For the Prelog-Djerassi lactone and ionomycin, recall (Figure 3.8) that most of the other stereo-centers were formed by asymmetric enolate alkylation. 

Studies towards the synthesis of a fragment of the antibiotic ionomycin involving branched-chain sugar intermediates are referred to in Chapter 14. 

Natural product synthesis, can lead to the discovery of new reactions by chance, by open-eyed serendipity, or by design. Our total synthesis of ionomycin (Scheme 6) [45] led us in fact to consider a design-based approach for the construction of deoxypropionate, and propionate subunits which are the natural building blocks for a large number of macrolide and ionophore-type antibiotics [46]. 

In a synthesis of the C(2) - C(9) fragment (64) of the polyether ionomycin (Scheme 13), enone (63), produced by intramolecular Wadsworth-Emmons reaction, underwent stereoselective introduction of a methyl group by use of a higher-order cuprate.49... 

In an improved procedure, the deprotonation with potassium hydride and LDA was shown to lead to higher diastereoselectivity, in particular with chiral iodides. Based thereupon, the amide 16 was obtained by alkylation with the enantiomer-ically pure iodide 15 in a diastereomeric ratio of 97 3. It served, after cleavage from the auxiliary, under the form of carboxylic acid 17, as a building block in a total synthesis of the polyether antibiotic ionomycin [12b]. 

In the synthesis of ionomycin published in 1990, the Evans group provided a convincing acid test of their auxiharies in several alkylation and aldol addition steps. Just one of those, the preparation of the alcohol 72, that was required as C-13 to C-16 fragment of ionomycin, may serve as an Ulustrative example, shown in Scheme 4.13. The hthium enolate of imide 48 was alkylated with cinnamyl bromide in a highly diastereoselective manner. The a-branched imide 71 thus obtained was reduced to the alcohol 72 that, after conversion into the primary iodide 15 (Scheme 4.3), served as electrophile in Evans prolinol procedure for chain elongation en route to ionomycin [12b]. 

Scheme 4.13 Application of Evans auxiliary for a synthesis of alcohol 72, a building block for ionomycin.

The methodology of nucleophilic addition to ri -allyliron complexes has also been applied for natural product synthesis. Thus, the regioselective and stereoselective addition of an organocopper reagent to a neutral Tl -allyl(dicarbonyl)(nitrosyl)iron complex is the key step in the total synthesis of the Cl-Cl 6 fragment of ionomycin (Scheme 4-90). ... 

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