Ionic chiral auxiliaries synthesis

The first reported use of ionic chiral auxiliaries in asymmetric synthesis was the work of Gudmundsdottir, Scheffer, and Trotter on the di-Tt-methane photorearrangement of the dibenzobarrelene system 33 [31]. Of a number of chiral auxiliaries tested,best results were obtained with prohne fert-butyl ester, which led to dibenzosemibullvalene derivative 34 in an enantiomeric excess of 95% at 40% conversion following diazomethane workup. By determining the ab-... 

A second example of the use of ionic chiral auxiliaries for asymmetric synthesis is found in the work of Chong et al. on the cis.trans photoisomerization of certain cyclopropane derivatives [33]. Based on the report by Zimmerman and Flechtner [34] that achiral tmns,trans-2,3-diphenyl-l-benzoylcyclopropane (35a, Scheme 7) undergoes very efficient (0=0.94) photoisomerization in solution to afford the racemic cis,trans isomer 36a, the correspondingp-carboxylic acid 35b was synthesized and treated with a variety of optically pure amines to give salts of general structure 35c (CA=chiral auxiliary). Irradiation of crystals of these salts followed by diazomethane workup yielded methyl ester 36d, which was analyzed by chiral HPLC for enantiomeric excess. The results are summarized in Table 3. 

It is important to mention again at this point that a general feature of the solid-state ionic chiral auxiliary approach to asymmetric synthesis is that not all chiral auxiliaries lead to high enantiomeric excesses. A case in point is found in the work of Natarajan et al. on the a-oxoamide-containing salts 43 (Scheme 10) [29]. Like the nonionic a-oxoamides discussed previously (Sect. 2.2), these compounds undergo photocyclization to p-lactam derivatives, and while the prolinamide salt behaves perfectly, leading to p-lactam 44 in 99% ee at 99% conversion, the corresponding 1-phenylethylamine salt affords nearly racemic photoproduct (3% ee at 99% conversion). The reason for this difference is... 

Comparison of the Solid-State Ionic Chiral Auxiliary Method of Asymmetric Synthesis with the Pasteur Resolution Procedure... 

Fig. 4 Comparison of the solid-state ionic chiral auxiliary method of asymmetric synthesis with the Pasteur resolution procedure...

Like other methods of asymmetric synthesis, the solid-state ionic chiral auxiliary procedure has an advantage over Pasteur resolution in terms of chemical yield. The maximum amount of either enantiomer that can be obtained by resolution of a racemic mixture is 50%, and in practice the yield is often considerably less [47]. In contrast, the ionic chiral auxiliary approach affords a single enantiomer of the product, often in chemical and optical yields of well over 90%. Furthermore, either enantiomer can be obtained as desired by simply using one optical antipode or the other of the ionic chiral auxiliary. 

Abstract After a brief introduction and summary of various methods of asymmetric induction in organic photochemistry, the main part of the review covers the solid-state ionic chiral auxiliary approach to asymmetric photochemical synthesis. Application of this technique to the Norrish type II reaction, as well as to the di-n-methane and oxa-di-n-methane photorearrangements, and the cis,trans-photoisomerization of diarylcyclopropane derivatives is presented and discussed. 

To this point, all the examples presented have been ones in which the origin of the asymmetric induction has been unimolecular in nature, that is, the molecules adopt homochiral conformations in the solid state that favor the formation of one enantiomer over the other, usually through the close intramolecular approach of reactive centers bimolecular crystal packing effects appear to play little or no role in governing the stereochemical outcome of such reactions. This raises the interesting question of whether the soUd-state ionic chiral auxiliary approach to asymmetric synthesis could be made to work for conformationally unbiased reactants, i.e., those possessing symmetrical, conformationally locked structures. Two such cases are presented and discussed below. 

For a variety of conceptual and practical reasons, we have chosen to carry out most of our asymmetric synthesis work employing the ionic chiral auxiliary method. Conceptually, the idea was attractive because, as far as we were aware, i it represents a new approach to asymmetric synthesis [8]. Furthermore, from the practical point of view, ionic solids have a number of advantages over purely... 

In principle, any of the photoproducts shown in Table 4 could have been prepared in enantiomerically pure form by irradiating their achiral precursors in solution to form a racemate and then separating the enantiomers by means of the classical Pasteur resolution procedure [36]. This sequence is shown in the lower half of Fig. 3. The top half of Fig. 3 depicts the steps involved in the solid-state ionic chiral auxiliary method of asymmetric synthesis. The difference between this approach and the Pasteur method is one of timing. In the ionic chiral auxiliary method, salt formation between the achiral reactant and an optically pure amine precedes the photochemical step, whereas in the Pasteur procedure, the photochemical step comes first and is followed by treatment of the racemate with an optically pure amine to form a pair of diastereomeric salts. The two methods are similar in that the crystalline state is crucial to their success. The Pasteur resolution procedure relies on fractional crystallization for the separation of the diastereomeric salts, and the ionic chiral auxiliary approach only gives good ees when the photochemistry is carried out in the crystalline state. 

The reports in the organic sections of this review are now considered. Irradiation of valerophenone is well known to yield both acetophenone and cyclobutanols by a Norrish Type II process but Zepp et al. report that the latter product (cis trans ratio 2.4 1) is more efficient in aqueous systems than hydrocarbons. Such ketones as 1 readily undergo the Type II process in the solid phase and from a detailed study involving the use of chiral auxiliaries as counter ions of its carboxylate derivative, Leibovitch et al. conclude that the ionic chiral auxiliary approach is a viable general method for asymmetric synthesis. Crystals of the ketone 2 are apparently photostable at room temperature but when finely ground or at elevated temperatures intramolecular hydrogen abstraction and formation of the benzocyclobutene 3 occurs (Ito et al), and the same workers also note that irradiation of S-4 at 4 °C in the solid state and at 34% conversion gives the SS product 5 with a diastereoselectivity of 99%. 

Upon was the use of chiral auxiliaries as counter ions of the carboxylate examples in (38a) and (39a). The authors conclude that the ionic chiral auxiliary approach is a viable general method for asymmetric synthesis. The irradiation of the biphenyl ketoamide (40) at 340 nm affords the two products (41) and (42) via the conventional Norrish Type II hydrogen abstraction process. When the reaction is carried out in the presence of an antibody microenvironment the reaction follows a different route and yields the tetrahy-dropyrazine derivative (43). The authors reason that there is interplay between conformational control and chemical catalysis that results in this high specificity. 

Table 4 Photochemical Asymmetric Synthesis Using the Solid -State Ionic Chiral Auxiliary Method... 

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