Chiral templates, preparation

Marazano and co-workers have used the Zincke reaction extensively to prepare chiral templates for elaboration to substituted piperidine and tetrahydropyridine natural products and medicinal agents. For example, 3-picoline was converted to Zincke salt 40 by reaction with 2,4-dinitrochlorobenzene in refluxing acetone, and treatment with R- -)-phenylglycinol in refluxing n-butanol generated the chiral pyridinium 77. Reduction to... 

Preparation of chiral mesoporous materials has become a great interest for material scientists. Normally chiral property is introduced into chiral mesoporous material via an organic chiral templating component. But, by using a sonochemical method, Gabashvili et al. [36] have prepared mesoporous chiral titania using a chiral inorganic precursor and a non-chiral dodecylamine as a template. Size of the pores was 5.5 nm. 

Last year, a short enantioselective total synthesis of herbarumin III (42) in 11% overall yield was published the approach applied uses Keck s asymmetric allylation and Sharpless epoxidation to build the key fragment. Esterification with 5-hexenoic acid and a RCM was used to yield 42. Finally, another asymmetric synthesis of herbarumin III (42) was carried out using (R)-cyclohexylidene glyceraldehyde as the chiral template. The key steps of the synthesis were the enantioselective preparation of the... 

The number of synthetic routes to the natural 1-hydroxymethyl-pyrrolizidines continues to increase. Robins and Sakdarat have achieved the first synthesis of these necines in optically active form, using natural (-)-4-hydroxy-L-proline as a chiral template.2 The dihydropyrrolizine ester (2) was prepared by regiospecific 1,3-dipolar cycloaddition of ethyl propiolate to the N,0-diformyl derivative (1) of (-)-4-hydroxy-L-proline, followed by deformylation (Scheme 1). Addition... 

This class of compounds serves as a chiral template rather than a chiral auxiliary because the original stereogenic center is destroyed in the reaction sequence. Dehydromorpholinones have been prepared from the amino alcohol by a rather extended reaction sequence that uses expensive reagents,9 but it has now been shown that the heterocycles can be made simply and cheaply in a one-pot reaction (Scheme 2.2).9 10... 

Thus, with proper choice of chiral template and aldehyde, all four possible syn- and anti-aldol products can be prepared with predictable stereochemistry. Both boron and titanium enolate methodologies have been successfully applied to the stereoselective syntheses of several biologically active compounds66-69 and natural product synthons.61-70-71... 

Chiral (helical) Lewis acids for asymmetric Diels-Alder catalysis are prepared from titanium tetraisopropoxide 5 and a chiral binaphthol ligand 4 [13]. The titanium reagent 6 plays an important role as chiral template for the fixation of a,fi-unsaturated aldehydes and thereby for the enantioface recognition of substrates. The asymmetric Diels-Alder reaction, e. g., of cyclopentadiene 7 and acrolein 8, is effected in the presence of catalytic (P)-6 (10 mol%), producing the endo adduct 9 (R =R2=H) in 88% ee (Scheme 1). 

A novel series of chiral grass herbicides based on the benzyloxy substituted tetrahydrofuran ring system has been prepared. These compounds are readily accessible synthetically from diacetone-D-glucose which serves as a chiral template possessing the appropriate stereochemistry for elaboration to the active herbicides. The degree of herbicidal activity is related to the molecular shape of these compounds and especially to the orientation of the substituents around the tetrahydrofuran ring. The chemistry and empirical structure-activity relationships of these compounds will be discussed. 

Molecular modelling has also played an important role in the design of novel reagents. Skidmore showed recently that cholic acid 26 provides an excellent chiral template for stannane-based reagents. Indeed, computational data recommended 27 and 28 as the reagents of choice for enantioselective reduction these stannanes were subsequently prepared from cholic acid and lithocholic acid (Scheme 6). ... 

McCarthy and coworkers126 229 reported a template-guided synthesis of water-soluble chiral PAn nanocomposites. The nanoparticles were prepared by the physical adsorption of aniline monomer onto a templating poly(acrylic acid) in the presence of (+)- or (-)-CSA, followed by chemical oxidation. Using this approach, optically active nanocomposites of approximately 100 nm diameter were formed. Earlier work by Sun and Yang230 using polyelectrolytes produced similar nonchiral dispersions in which the PAn chain is interwound with a water-soluble polymer by electrostatic forces.231 Similar work by Samuelson and coworkers utilized DNA as a chiral template for PAn.232... 

An alternative approach for the preparation of chiral APIs is the use of chiral raw materials. The increased availability of functionalized chiral raw materials from both synthetic as well as natural sources has made this a more viable option in recent years. In the event that the desired chiral precursors are not commercially available, asymmetric synthetic techniques may be employed to introduce one or more stereogenic centers into the molecule. Many elegant techniques have been developed using chiral induction, chiral templates, and chiral catalysts to produce enantio-merically enriched drug substances, and this area of research continues to be at the forefront of organic chemistry. 

The aqueous rate-enhanced Claisen rearrangement of glycoorganic compounds was shown to proceed in excellent yields [57]. The water solubility of the reactants was induced by grafting a free sugar onto the allyl vinyl ether moiety moreover, the sugar functioned as a chiral template and gave highly crystalline diastereomers which were easily separable to yield pure enantiomers after enzymic hydrolysis. This method allows the preparation of either enantiomerically pure (R)- or (S)-l,3-diol (Scheme 1). 

F.nantiomcrically pure A -protected /i-amino alcohols arc prepared using (I )-2,3-0-isopropyli-deneglyceraldehvde as the chiral template by the reaction sequence shown, thereby allowing the chiral template to be recovered351. 

Rac-N-(3,5-dinitro- benzoyl)-oc-methyl- benzylamine (S)-(-)-Methacryloyl-l-naphthylethylamine EDMA toluene Chiral separation prepared with racemic template [80]... 

In order to examine the stereochemical implications in the synthesis of (largely) phosphinic acids (but also tertiary phosphine oxides), Inch and coworkers " employed carbohydrate frameworks as chiral templates. As primary substrates, the cyclic phospho-rochloridate 161 and the corresponding phosphorofluoridate 162 were prepared from methyl 1,2,3-di-O-methyl-a-D-glucopyranoside, each phosphoryl halide being obtained as a mixture of diastereoisomers, anomeric at phosphorus, and from which, in each case, the major component (thought to have an equatorial P=0 bond) was isolated. Configurations in both substrates and reaction products were assigned with the aid of proton and NMR... 

As an example for a one-dimensional property transfer, the preparation of optically active co-polymers using chiral template molecules is described. In this case, the optical activity in the polymer arises from the chirality of the configurational arrangement of the main chain (main chain chirality). Symmetry considerations show that there are several possible structures both for stereoregular homo- and for co-polymers in which this type of chirality can be expected [4]. 

A.ii. Preparation of Chiral Sulfoxides. The sulfur atom in a sulfoxide has four different groups (R, R1, O, and the lone pair electrons). There is virtually no inversion at sulfur (in contrast to nitrogen) so the sulfur can be a stereogenic center under these circumstances, which raises two points when using unsymmetrical sulfoxides. The first is the presence of diastereomers that can complicate separation and identification. The second is the ability to resolve the enantiomeric sulfoxides or produce one enantio-selectively, and use this material as a chiral auxiliary or as a chiral template (sec. 10.9). 

The last approach to chiral synthesis begins with a chiral precursor whose components will be integrated into the final product, which is the chiral template approach (sec. 10.9). The examples of asymmetric syntheses involving Diels-Alder templates are as varied as the targets. One typical example is by Oppolzer, who reported an asymmetric synthesis of pumiliotoxin C via Diels-Alder cyclization of 303, prepared from (/ )-norvaline, to give 304.248... 

Carbohydrates are efficient chiral templates and have been used in the Diels-Alder reaction. Sherbum used L-ascorbic acid as a template to synthesize 305.249 Heating this compound in refluxing toluene led to a 96 4 mixture of 306 and 307 (68% yield). The chirality inherent in the carbohydrate precursor provides the needed facial selectivity that is transferred to the cycloadduct product. The use of chiral templates for preparing Diels-Alder precursors will undoubtedly increase in importance. As the need for enantiomerically pure material increases, the chiral template approach coupled with the power of the Diels-Alder reaction will be an effective combination. 

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