Dianions, alkylation

The 5yn-directed deprotonation of arylhydrazones can be used to reverse the normal preference of the less-substituted vinyllithium. By employing a one-flask dianion alkylation procedure, the formation of an almost exclnsive stereoisomer of acyclic vinyllithinms... 

Good yields and high to excellent diastereoselectivities have been realized by the dianion alkylation of cyclic /1-hydroxy esters (see Table 5). Because of the cyclic structures these results correspond to the creation of quaternary carbon centers. 

It is worth noting that the relative configurations of products from dianion alkylations in the open-chain and in the lactone cases are different. Attack of the electrophile in the open-chain dianion is on a chelated species and will result in an anri-product, whereas in a /Z-hydrox-ylactone the dianion has a different geometry and will give a. vyu-product upon alkylation. 

As described previously [63], P-ketoester 111 [Fig. (31)] was subjected to Baker s yeast reduction to afford the optically active P-hydroxyester 112 (60-80% yield). Dianion alkylation of 112 with (E)-3-methyl-4-(0-tert-butyldimehtylsilyl)-2-butene afforded the desired a-alkyl product 113 in 58-70% isolated yield. 

In this chemistry, pivotal final steps in the sequence are a dianion alkylation of the side-chain carboxylic acid, leading to erythro products only. Second, ozonolysis of this product is followed by silyl migration, hydrolysis to a hydroperoxyaldehyde, and, finally, after acidification, cyclization to product. 

Several useful variations of the tetracarbonyliron dianion-alkyl halide reactions are known. These employ the iron complex stoichiometrically, however. Since the dianion is much more nucleophilic than the alkyliron monoanion, the reaction can easily be stopped at the monoalkylated stage. Carbonylation or addition of another good ligand such as triphenylphos-phine to the monoalkylated complexes produces monoacyliron anions. Pro-... 

In summary, a stereoselective 10-step total synthetic route to the antimalarial sesquiterpene (+)-artemisinin (1) was developed. Crucial elements of the approach included diastereoselective trimethylsilylanion addition to a,p-unsaturated aldehyde 16, and a tandem Claisen ester-enolate rearrangement-dianion alkylation to afford the diastereomerically pure erythro acid 41. Finally, acid 41 was converted in a one-pot procedure involving sequential treatment with ozone followed by wet acidic silica gel to effect a complex process of dioxetane formation, ketal deprotection, and multiple cyclization to the natural product (+)-artemisinin (1). The route was designed for the late incorporation of a carbon-14 label and the production of a variety of analogues for structure-activity-relationship (SAR) studies. We were successful in preparing two millimoles of l4C-l73 which was used for conversion to I4C-arteether for metabolism75 and mode of action studies.76,77... 

Recently Avery et al [94] have developed a stereoselective total synthesis of (+)-artemisinine starting from (R)-(+)-pulegone (92). Elaboration of 92 gives the known sulphoxide 93, which was allowed to undergo dianion alkylation and desul-phurisation to yield disubstituted-cyclohexanone (95). Homologation of the latter afforded the aldehyde % in two steps. This product was then converted into the silyl acetate (97), which underwent Tandem Claisen ester-enolate rearrangement to give the vinylsilane 98. Ozonolysis and cyclisation of 98 provided 7 (Scheme 10). 

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