Intermolecular cycloadditions enantioselective synthesis

Diastereoselective intermolecular nitrile oxide—olefin cycloaddition has been used in an enantioselective synthesis of the C(7)-C(24) segment 433 of the 24-membered natural lactone, macrolactin A 434 (471, 472). Two (carbonyl)iron moieties are instrumental for the stereoselective preparation of the C(8)-C(ii) E,Z-diene and the C(i5) and C(24) sp3 stereocenters. Also it is important to note that the (carbonyl)iron complexation serves to protect the C(8)-C(ii) and C(i6)-C(i9) diene groups during the reductive hydrolysis of an isoxazoline ring. 

It took another 35 years until the first (and still the only known) enantioselective total synthesis of (/ )-ochratoxin a (326), and therefore of ochratoxins A and B, was published by Gill et al. in 2002 (264, 265). Scheme 6.1 shows six steps of the nine-step synthesis, which was achieved with 10% overall yield. The first three steps of the procedure are not shown and comprise the preparation of 327 from (/ )-2-methyloxirane according to ref. (266). Ketene dimethyl acetal and acetylenic ester 327 react in an intermolecular cycloaddition to give 328. This diene undergoes a Diels-Alder reaction with methyl propiolate to yield 329. Lactonization ( 330), demethylation ( 331), chlorination ( 332), and methyl ester cleavage finally furnished enantiomerically pure ochratoxin a (326) (267). 

The MacMillan group reported recently (Scheme 53) a nine-step synthesis of the complex Strychnos alkaloid (+)-minfiensine (224) starting from commercially available compounds 194). The key step in this elegant approach was an intermolecular highly enantioselective [4 + 2] cycloaddition between 225 and propynal... 

The critical step in the enantioselective and stereocontrolled total synthesis of eunicenone A by E.J. Corey et al. was the highly efficient chiral Lewis acid catalyzed intermolecular Diels-Alder cycloaddition reaction The diene component was mixed with 5 equivalents of 2-bromoacrolein and 0.5 equivalents of the chiral oxazaborolidine catalyst in CH2CI2 at -78 °C for 48h. The reaction gave 80% of the desired cycloadduct in 97% ee and the endolexo selectivity was 98 2. 

Enantioselective intermolecular [2-F2-F2] cycloadditions of 1,6-diynes with a,fS-unsaturated carbonyl compounds are valuable methods for the synthesis of chiral cyclohexadienes in a single step [36]. The intramolecular Diels-Alder reaction (IMDA) is known to be a powerful strategy for the construction of complex multicyclic skeletons [37]. Tanaka reported an efficient enantioselective domino intermolecular [2-F2-F2]/IMDA cycioaddition reaction occurring between 1,6-diyne 106 and amide-linked 1,5-diene 107 bearing two sterically and/or electronically... 

The phosporic acid (261) catalysed three component reaction involving asymmetric 1,3-dipolar cycloaddition of electron-deficient azomethine ylides (327), aromatic aldehydes (328) and 2-aminomalonates (329) to provide to novel 2,5-dihydropyrrole derivatives (330) with potential bioactivities with enantioselectivities of up to >99% ee (Scheme 86). The Bronsted acids (253) catalysed intermolecular enantioselective alkylation of indoles (332) with cx,p-unsaturated y-lactams (331) thus providing a highly enantioselective method for the synthesis of chiral pyrroli-dinones (333) containing indole moieties, with enantioselectivity (up to 95% ee), has been described by Huang et al. (Scheme 87). " ... 

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