Iterative alkylation

The 6-methylacetylamino-l,2,3,4-tetrahydroquinoline, after nitration and separation of isomers, following reduction and deprotection, gave the 7-amino-6-methylamino derivative, which cyclized with cyanogen bromide. Alkylation of the cyclization products afforded inhibitors of thymidylate synthase, 5-substituted 2-amino-l//-l-methyl-5,6,7,8-tetrahydroimidazo[4,5-g]quinolines 136, designed for use in iterative protein crystal analysis (Scheme 42) (92JMC847). 

The OPLS parameters (charges and Lennard-Jones terms) were obtained primarily via Monte Carlo simulations with particular emphasis on reproducing the experimental densities and heats of vaporization of liquids. Those simulations were performed iteratively as part of the parametrization, so better agreement with experiment is obtained than in previous studies where the simulations were usually carried out after the parametrization. Once the OPLS parametrization was completed, further simulations were also performed in order to test the new set of parameters in the calculation of other thermodynamic and structural properties of the system, besides its density and its heat of vaporization. Parameters have now been generated, among others, for water, alkanes, alkenes, alcohols, amides, alkyl chlorides, amines, carboxylic esters and acids, various sulfur and nitrogen compounds, and nitriles. A protein force field has been established as well. 

This first reaction sequence on the exposed dendron (Figure 1.14) creates G = 0 (i.e. the core branch cell), wherein the number of arms (i.e. dendrons) anchored to the core is determined by Nc. Iteration of the alkylation/amidation sequence produces an amplification of terminal groups from 1 to 2 with the in situ creation of a branch cell at the anchoring site of the dendron that constitutes G = 1. Repeating these iterative sequences (Scheme 3), produces additional shells (generations) of branch cells that amplify mass and terminal groups according to the mathematical expressions described in the box opposite. 

One astute way to obtain macrocyclic systems with TTF is the stepwise method of deprotection/alkylation of cyanoethyl-protected TTF-thiolates. With this method molecular units can be built but with the precaution of preserving one cyanoethyl group in order to be able to iteratively proceed with the oligomerization. Combining such units, larger units can be produced. An example of a TTF dendrimer containing 21 TTFs is shown in Fig. 2.15 (Christensen et al, 1998). Here only the main philosophy of the synthesis is discussed. 

Iron-acyl complex 47 illustrates the diastereoselective a-alkylation of the 3-methyl-l-oxobutyl-substituted enolate 46, prepared by two iterations of the elimination-Michael addition sequence three alkylations are conducted in a single reaction vessel44. 

In this chapter we describe a partial synthesis of the C-l through C-21 fragment of l devised by Armstrong One striking feature is the iterative use of a method by which functionalized alkyl chains arc constructed stereoselectively. 

The relatively mild synthetic conditions during iterative growth of poly(benzyl ether) dendrons are tolerated by many peripheral groups (e.g. cyano, bromide functionality, alkyl ester, alkyl ether, perfluoroalkyl ether, oligo(ethylene glycol)... 

Scheme 4.47. Iterative synthesis of dendrimers using tetrahedral alkyl ammonium moieties as branching centers.

After debenzylation (Pd-C, cyclohexene) of the hypercores (e.g., 25) by transfer hydrogenation, they were treated with aryl branched, benzyl ether dendrons (Scheme 5.6) that were prepared by similar iterative transformations,1271 i.e., benzylic bromination and phenolic O-alkylation (See Section 5.4.2). Thus, hexaphenol core 27 was reacted with six equivalents of the benzylic bromide building block 28 to give the benzyloxy terminated dendrimer 29. Key features of these dendrimers include cores with flexible alkyl spacers and a three-directional, quaternary carbon branching center. 

SCHEME 5.23 Oligothiosialoside synthesis by iterative alkylation of a sialic acid-based anomeric thiolate. DIPEA, diisopropylethylamine. 

Rychnovsky and his group have recently developed new synthetic methods that lead to the total syntheses of the polyene macrolides roxaticin [2], roflamycoin [3], and filipin III [4]. The polyol chains of all three natural products were constructed by iterative, stereoselective alkylation of lithiated cyanohydrin acetonides and subsequent reductive decyanation, illustrated here by the synthesis of the polyol framework of filipin III (1) (Scheme I). The bifunctional cyanohydrin acetonide 2, prepared by ruthenium/BINAP catalyzed enantioselective hydrogenation of the corresponding ) -keto ester (BINAP = [ 1,1 -binaphthyl]-2,2 -diylbis(diphenylphosphane)), is deprotonated with LiNEt2 and alkylated with 2-benzyloxy-l-iodoethane. The alkylation product 3 is converted by a Finkelstein reaction into the iodide 4, which is used to alkylate a second... 

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