Rearrangements, Claisen dianions

In this contribution, we describe work from our group in the development and application of alternatives that allow the explicit inclusion of environment effects while treating the most relevant part of the system with full quantum mechanics. The first methodology, dubbed MD/QM, was used for the study of the electronic spectrum of prephenate dianion in solution [18] and later coupled to the Effective Fragment Potential (EFP) [19] to the study of the Claisen rearrangement reaction from chorismate to prephenate catalyzed by the chorismate mutase (CM) enzyme [20]. 

Claisen rearrangementThe allyl ether 1 when heated rearranges and cyclizes slowly and in low yield to the dihydrobenzofuran 2. However, the dianion (NaH) of 1 rearranges in refluxing DMF mainly to the isomeric dihydrobenzofuran 3, a precursor to the antibiotic ( )-atrovenetin (4). 

Z)-.S -Allylic ketene aminothioacetals underwent thio-Claisen rearrangement at room temperature to give iVjV-dimethyl /1-hydroxy a-allylic thioamides96. /3-I Iydroxy-/V,/V,-dimethylthioamides were deprotonated with LDA to afford a chelated dianion with Z-configuration. Alkylation of this dianion gave the corresponding Z a-hydroxy S-allylic... 

Most recently, our total synthesis was streamlined further. Since the Claisen rearrangement which provided 32 required excess base, and was followed in a separate step by dianion formation, it seemed reasonable that the two steps could be combined. For example, treatment of acetate 30 with several equivalents of base should lead directly to the dianion of 32, which could then be alkylated in situ to provide the homologated acid 41. Indeed, treatment of 30 with four equivalents of LDEA (-78 to 50 °C) provided the desired dianion of 32, which upon cooling and admission of methyl iodide, gave the acid 41 in 57% yield. 

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). 

Dianionic Claisen rearrangements of (E)- and (Z)-butenyl jS-hydroxy esters afford acyclic systems I and 2 containing three stereogenic centers. The reactions proceed with remote stereocontrol (see Section 1.6.3.1.1,5.1.1. p 3481)50S-509. 

The dianionic /i-hydroxy ester Claisen rearrangements of E- or Z-configurated substrates 1 and 2 have shown to proceed with high a,/ - (1,2-relative) asymmetric induction, but moderate a, -selectivity (internal asymmetric induction) resulting in only two products 3 a and b or 4 a and bin each case508 509 584-587. 

Diastereoselective asymmetric thio-Claisen rearrangement has been carried out by the reaction of thioamides with allyllic bromide (Scheme 37). Thioamide dianions (generated by the highly efficient reaction of A -benzyl thioamides with 2 equiv. of BuLi) take place alkylation, allylation and silylat-ion selectively at the carbon atom adjacent to the nitrogen atom of the thioamide dianions (Scheme 38). ... 

Dianionic Claisen rearrangements of 3-hydroxy-esters (129) give largely the substituted esters (130), although only in moderate yields (ca. 40%)Despite this, the method is brief and should find many applications, as such highly functionalized esters can be used as precursors to a wide variety of compounds. 

Whitesell and Helbling [49] reported on a conversion of allylic alcohols into jS,y-unsaturated esters based on a Claisen rearrangement/oxidative degradation (Scheme 5.2.25). Thus, Claisen rearrangement of ester 92 as the lithium enolate or as the silylenolether afforded a-methoxycarboxylate 93 as a diastereomeric mixture. Degradation by one carbon was effected by the sequence of Wasserman [50] wherein the dianion 94 formed, by subsequent deprotonation with additional LDA, was oxidized with molecular oxygen. 

As anticipated on the basis of steric bulk in the allyl moiety, the dianionic Claisen rearrangement of 207b was slightly less selective than that of207a, but much... 

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