Enol esters, structure-activity

Regression Approaches to Structure-Activity Relationships in Miticidal 2-Aryl-l cycloalkanediones and Enol Esters... 

Optimization of biological properties in a series of miticidal and mite ovicidal 2-aryl-l,3-cycloalkanediones, Ia,b, and enol esters, II, was achieved through analog synthesis and testing supported by the development of quantitative structure/ activity trends during the course of the project. QSAR equations developed during an initial phase provided the basis for both... 

In the early 1970 s potent acaricidal activity in 3-aryl-4-hy-droxy-coumarins. III, and 2-aryl-l,3-indanediones, IV, and their enol esters was discovered at Union Carbide (1,2). Extensive synthesis and screening of analogs in the dione and enol ester series led to the field test candidates Va and Vb, active against both motile forms (mite) and eggs. Va and Vb embodied certain structural and physicochemical features shown by published QSAR studies (2,3) to be important in determining the level of activity in the 1,3-indanedione series (1) the dimension D2 across the aryl ring must be near 7A and symmetry is preferred (2) the... 

Overview of the Databank. A profile of the Phase I databank of compounds is presented in Tables II-IV 202 of the 2652 permutations possible from 12 dione moieties, 13 aryl substitution patterns, and 17 different enol ester acyl groups constituted the Phase I dataset. The structures and data given below exemplify how activity varied with structure throughout the dataset. 

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... 

Also for side chain variations, clear - and in this case quantitative - structure-activity relationships have been established at the target level. In a series of oximino esters of type 4, we obtained a curve (Fig. 13.2.7) in accordance with a bilinear equation [7, 9]. Similar correlations have been deduced for enol ethers, oximino amides, crotonic esters and methoxycarbamates [66]. 

Previously, the use of activated esters such as enol esters, especially VinOAc, has been shown for the classical KR of alcohols. Nevertheless, since the leaving acetaldehyde can react in the DKR with the racemization catalyst, other acyl donors must be considered, like IPA ( PrOAc) or p-chlorophenyl acetate (PCPA), the structures of which are shown in Figure 9.10. IPA is a very interesting acyl donor as its byproduct in acylation reactions is acetone, which is a less reactive carbonyl compound that usually does not caused biocatalyst deactivation, its lower atom economy being the only drawback for synthetic purposes. 

The models become more complex when they take the structure of the base into account. A simple and very popular hypothesis was proposed for esters by Ireland and coworkers in pioneering work23. This model supposes that a monomeric LDA is the active species and that the lithium-carbonyl interaction leads to a six-membered cyclic Zimmerman-Traxler chair-like transition state24, at which a more-or-less concerted proton transfer occurs. The resulting preference for the E enolate observed in THF and the Z preference in THF-HMPA mixtures, an issue discussed in more detail below, could even be accounted through steric considerations (Scheme 4). 

Lithium ester enolates are extremely important in polymer chemistry as initiators and active centers of the anionic polymerization of acrylic and methacrylic monomers in polar solvents. Thus, HF-SCF studies, comparable to those mentioned above, were undertaken on monomeric methyl isobutyrate (MIB) enolate210,211. The overall conclusions on the aggregation and solvation trends are exactly the same, the bent rj3-0,C mode being preferred over the rj1-O planar one by ca 3.3 kcalmol-1. While the dimeric MIB enolate solvated by four molecules of THF was found to be the enthalpically most stable aggregate, the prismatic S6 unsolvated MIB hexamer was computed as the preferred structure in non-polar solvents (Scheme 55)212. In the latter case, the supplementary oxygen of the ester acting as a side-chain ligand for the lithium seems to explain this remarkable stability. 

Ester enolates can be used as molecular models of the active centers in the anionic polymerization of acrylates and methacrylates. Thus, knowledge of the structure of these models in polar and nonpolar solvents is important for the understanding of the polymerization processes. Earlier C and Li NMR smdies by Wang and coworkers of methyl... 

Zune and coworkers studied the structure of the species propagating the anionic polymerization of tBMA by NMR spectroscopy . The spectrum of the lithium ester enolate was perturbed by LiCl, as result of an equilibrium established between free lithium chloride and complexed active end-groups. The structure of the chain-end was not modified by a large excess of LiCl. 

The classical example of the selective activation of a reaction site in a substrate with more than one reactive center is acetoacetic ester 168 (Scheme 2.80). Its reactive form is the enolate 169, which reacts with a variety of electrophiles selectively at the central carbon atom. A subsequent hydrolysis and decarboxylation of the product 170 leads to the formation of ketone 171. The structure of 171 corresponds to the coupling of the electrophile with the carbanion 172, or, in other words, with deprotonated acetone. Thus acetoacetic ester is actually employed in this sequence as a synthetic equivalent to 172. 

This method can be effectively applied to the preparation of /S-lactam compounds. The ester enolate-imine condensation approach to j8-lactam formation has been developed over the past decade. Thienamycin and related carbapenems have been the focus of particular attention because of their structural uniqueness and potent antibacterial activity. 

Activation of C=N double bonds by copper Lewis acids for nucleophilic addition has also been reported (Sch. 37) [73]. The a-imino ester 157 undergoes alkylation at the imine carbon with a variety of nucleophiles when catalyzed by copper Lewis acids. The presence of the electron-withdrawing ester group increases the reactivity of the imine and also assists in the formation of a stable five-membered chelate with the Lewis acid. Evidence for Cu(I) Lewis-acid catalysis and a tetrahedral chelate was obtained by FTIR spectroscopy, from the crystal structure of the catalyst, and from several control experiments. The authors rule out the intermediacy of a copper enol-ate in these transformations. The asymmetric alkylation of A,0-acetals with enol silanes mediated by a copper Lewis acid proceeding with high selectivity has been reported [74],... 

Sodium enolates of ketones and disodium enediolates of substituted phenylacetic acids reacted with activated aziridines to afford 7-amido ketones and 7-amidobutyric acids, respectively (Scheme 72). Aziridine-2-carboxylic acid esters can be utilized as versatile precursors for amino acid derivatives. Although the product distribution resulting from the reaction of activated aziridine-2-carboxylates with amines depends on the structure of the reactants, the reactions with alcohols or thiols in the presence of acidic cabilysts generally gave the a-amino acid derivatives (Scheme 73). ° On the other hand, free 3-methyl-2-aziridinecarboxylic acids (168) reacted with thiophenol, cysteine and glutathione to afford P-amino acid derivatives with sulfur substituents at the a-position as the main product (Scheme 73). ... 

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