Ionomycin stereoselectivity

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). 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

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. 

The C-17 to C-22 subunit of ionomycin (937) is synthesized by regioselective fragmentation of an appropriately substituted tetrahydrofuran (935), which is readily accessible from (R)-malic acid (Scheme 137) [205]. Alkylation of the dianion of diethyl (7 )-malate (897) with methyl iodide provides anti-929 in 69% yield with 10 1 stereoselectivity. Reduction of the esters, acetal formation, oxidation of the primary alcohol of 930 to an aldehyde, and Wittig olefination furnishes a,j -unsaturated ester 931. 

Marshall and coworkers reported that the internal trisubstituted alkene of 69 was stereoselectively epoxidized with ketone 42 in 80% yield, and the resulting epoxide (70) was transformed into the bistetrahydrofuran C17-C32 segment (72) of antibiotic ionomycin (Scheme 3.25) [55]. 

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... 

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). ... 

The applications of oxazolidinone auxiliaries 114-116 in stereoselective enolate bond constructions are countless. A classic example that showcases their general synthetic utility in enolate alkylations is documented in Evans total synthesis of the antibiotic ionomycin (111, Scheme 3.22) [79]. Throughout this synthetic endeavor, no fewer than nine of the 14 stereogenic centers were installed through auxiliary-based enolate chemistry. Eight of these were accomplished through the use of oxazolidinones, with the two examples that involve diastereoselective enolate alkylations depicted in Scheme 3.22. The... 

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