Shimon Shatzmiller

REACTIONS OF α-CHLORONITRONES WITH UNSATURATED ETHERS

Abstract The Ag+ induced reaction of α-chloronitrones with unsaturated ethers goes in two parallel competitive directions. On the one hand cycloadducts like 3 are formed and on the other hand oxonium ions like 4. Formation of analogous oxonium compounds occurs also when α-alkoxynitrones are treated with Et3O+BF4− in 1,2-dichloroethane. Formation of oxonium compounds with the enol-ethers is practically irreversible and leads to enol-ether fragmentation. With the saturated ethers compounds like 25 were formed and were used as a potential source of N-alkyl-N-vinyl-nitrosonium ions.

Ionic and radical intermediates of 3-substituted 5,6-dihydro-1,4,2-dioxazines: a theoretical (AM1) study

Abstract Stable carbocations ( A ), carbanions ( B ) and free radicals ( C ) are expected to result from 3-substituted-5, 6-dihydro-1,4,2-dioxazine 1 or their 3- (1-bromoalkyl) derivative 2 , due to the presence of a CN double bond, adjacent to the active methylene group. However, experimental data indicate that while A and C could be obtained, B was apparently too unstable to act as an intermediate in alkylations. A theoretical study of the structures and stabilities of A - C resulting from 1 and 2 (R = CH 3 ), in the framework of a semiempirical all-valence electron molecular orbital approximation (AMI) is described. The results obtained indicate that A and C can be stabilized by delocalization and accommodation of the positive charge and unpaired electron respectively, by conjugation, hyperconjugation and field effects. Although B has a non-uniform distribution of the charge due to a less planar shape, it should be stabilized by delocalization. Calculated energies of reaction ( E r ) for the formation of B , and deprotonation enthalpy (DPE) of 1 (R = CH 3 ) in comparison with the deprotonation of 3-methyl-4H-5,6-dihydrooxazine ( 6 ), a structurally related compound proven to lead to carbanions ( B ′ and B ″), could not explain the failure to perform carbanion-mediated alkylations.

Structure design: An artificial intelligence-based method for the design of molecules under geometrical constraints

This study presents an algorithm that implements artificial-intelligence techniques for automated, and site-directed drug design. The aim of the method is to link two or more predetermined functional groups into a sensible molecular structure. The proposed designing process mimics the classical manual design method, in which the drug designer sits in front of the computer screen and with the aid of computer graphics attempts to design the new drug. Therefore, the key principle of the algorithm is the parameterization of some criteria that affect the decision-making process carried out by the drug designer. This parameterization is based on the generation of weighting factors that reflect the knowledge and knowledge-based intuition of the drug designer, and thus add further rationalization to the drug design process. The proposed algorithm has been shown to yield a large variety of different structures, of which the drug designer may choose the most sensible. Performance tests indicate that with the proper set of parameters, the method generates a new structure within a short time.

Implementation of artificial intelligence for automatic drug design. I: stepwise computation of the interactive drug-design sequence

In this article we represent the development of an artificial‐intelligence‐based method for the automatic design of valid chemical structures (AISD). The key feature of the proposed algorithm is its ability to mimic many decision‐making processes carried by the human drug designer during a design session. The manual drug‐design process is analyzed and transformed into a computerized form by associating a weight factor with each term. These weights enable the translation of the drug designers intution into probabilities that control the flow of the design process. The input required to initiate a design session might be as minimal as the geometry of a previously existed pharmacophoric model, up to the three‐dimensional geometry of the host receptor. A design application is demonstrated by the implementation of the proposed algorithm for the design of new potent sweeteners.

The generation and use of a masked α-acyl cation in aromatic substitution reactions; Ag+ induced reactions of 3-(bromomethyl)-5,6-dihydro-1,4,2-dioxazine derivatives

The Ag+ induced aromatic substitution reactions of 3-(1-bromomethyl)-5,6-dihydro-1,4,2-dioxazine derivatives via an α-acyl cation equivalent are described.

Ag+ induced cycloaddition of α-bromoacetone O-methyloxime to olefinic double bonds

The title reaction, which proceeds via the intermediacy of an N-alkoxyaza-allyl cation (2), was investigated.

Synthesis of model compounds for potential contrast agents containing phosphonate and peptide moieties

The synthesis of dimethyl 2-acetoxy-2-(2,4-diiodo-5-aminophenyl)ethylphosphonate and dimethyl 2-acetoxy-2-(2,4,6-triiodo-3,5-diaminophenyl)ethylphosphonate is described. Several amido and peptidic derivatives of these two compounds were prepared. These products are composed of a combination of structural/functional moieties which pave the way for their potential application as non-ionic selective X-ray contrast agents.

Localization and quantitative evaluation of potent local binding sites on the accessible Lennard–jones surface

This article presents a new method for topological analysis of molecular surfaces. Explicit representation of the van der Waals interaction according to the Lennard‐Jones potential enabled determination of the function of the maximum radius of a hypothetical atomic probe in any location, r, inside the hosts domain. The size of the spatial gradient of the maximal probes volume (named the ξ value) at that location was found to be a good descriptor of the local shape of the host. Consequently, mapping of the host domain according to the ξ value could be used as a quantitative tool for localization of potent local binding sites. The proposed method is illustrated by mapping an organic host (calix[4]arene) as well as an enzyme (HIV‐aspartic protease). Analysis of the calix[4]arene derivative revealed that the proposed method reproduces immediately the known binding site of conic calix[4]arenes. The second test case demonstrated how the catalytic site of the enzyme could be disassembled into many local binding sites. Some of these sites, located according to the proposed method, were found to follow the shape of a known inhibitor of the enzyme in a complementary manner.

Syntheses of α-Amino Phosphinic Acids via Oxo-iminium Salts

Abstract Nitrones 2a , 2b obtained from the aldehydes 1a , 1b , are used for the syntheses of the N-ethoxy iminium salts 4a and 4b . In the following procedure 4a and 4b react to several esters of phosphinic acids 6a - 6d .