Chiral host

This chapter provides (i) a brief review of the chemistry involved in chiral host-chiral guest recognition involving primary amines (ii) a description of a nonchromatographic (equilibrium or bind-release based) separation process devel-... 

Chiral Recognition. The use of chiral hosts to form diastereomeric inclusion compounds was mentioned above. But in some cases it is possible for a host to form an inclusion compound with one enantiomer of a racemic guest, but not the other. This is caUed chiral recognition. One enantiomer fits into the chiral host cavity, the other does not. More often, both diastereomers are formed, but one forms more rapidly than the other, so that if the guest is removed it is already partially resolved (this is a form of kinetic resolution, see category 6). An example is use of the chiral crown ether (53) partially to resolve the racemic amine salt (54). " When an aqueous solution of 54 was... 

A regio- and stereoselective Beckmann rearrangement utilized diastereose-lective host guest interactions of the inclusion complexes 225 and 228 in a solid state reaction. Initially, a 1 1 mixture of the chiral host 223 and the racemic oximes 224 and 227, respectively, was treated with ultra sound in the solid state to induce the optical resolution. Then H2SO4 was added to start the Beckmann rearrangement, the corresponding c-caprolactams 226 and 229 were isolated in 68 % and 64 % yields and ee of about 80 % and 69 % (determined by HPLC analysis on chiracel OC) (Scheme 43) [46]. 

Complexation with a Chiral Host in a Water Suspension Medium... 

Some solid-solid reactions were shown to proceed efficiently in a water suspension medium in Sect. 2.1. When this reaction, which gives a racemic product, is combined with an enantioselective inclusion complexation with a chiral host in a water suspension medium, a unique one-pot preparative method of optically active product in a water medium can be constructed. Some such successful examples are described. 

An enantioselective Michael addition reaction was also accomplished in an inclusion complex with a chiral host compound. Treatment of a 1 1 complex of 10c and 66b with 2-mercaptopyridine (137) in the solid state gave (+)-138 of 80% ee in 51% yield. By a similar method, 3-methyl-3-buten-2-one (139) gave (+)-140 of 49% ee in 76% yield [30]. 

It is not easy to control the steric course of photoreactions in solution. Since molelcules are ordered regularly in a crystal, it is rather easy to control the reaction by carrying out the photoreaction in a crystal. However, molecules are not always arranged at an appropriate position for efficient and stereoselective reaction in their crystals. In these cases inclusion chemistry is a useful technique, as it can be employed to position molecules appropriately in the host-guest structure. Chiral host compounds are especially useful in placing prochiral and achiral molecules in suitable positions to yield the desired product upon photoirradiation. Some controls of the steric course of intramolecular and intermolelcular photoreactions in inclusion complexes with a host compound are described. 

Enantiocontrol of the photocyclization of Ar-methyl-AT-phenyl-3-amino-2-cyclohexen-l-one (151a,b) to the corresponding AT-methylhexahydro-4-car-bazolones (153a,b) via the dipolar ionic intermediate (152a,b) (Scheme 22) was also accomplished by photoirradiation of 1 1 inclusion complexes of 151 a,b with the chiral hosts lOa-c. Of the complexes prepared, 10a-151a, 10a-151b,... 

Photoirradiation of both neat and benzene solutions of 2-cyclohexenone (66b) gives a complex mixture of photodimers [40]. However, photoirradiation of a 1 1 complex of 66b with the chiral host (S,S)-(-)-l,4-bis[3-(o-chlorophenyl)-3-hydroxy-3-phenylprop-l-ynyl]benzene (167) in the solid state (Scheme 24) gave (-)-anf/-head-to-head dimer 168 of 46% ee in 75% yield [40]. This reaction was found to proceed in a single crystal-to-single crystal manner. The mechanism of the reaction was studied by X-ray crystal structural analysis [41]. 

Control of Enantioselective Photoreactions in Inclusion Complexes with Chiral Host Compounds... 

X-Ray crystal structural studies32) (Fig. 13 and Scheme 8 which refers to the crystal structure) showed that one molecule of 93 is held in a fixed conformation determined by two hydrogen bonds and by neighboring host molecules which prevent free rotation about the CO—CO single bond in 93. Free rotation about this bond would enable the production of the two possible enantiomers. The fixed conformation of the guest molecule by the chiral host molecule causes the least molecular motion during the photocyclization reaction and the high enantioselectivity. 

Systems exhibiting chiral recognition. Complexation of an optically active guest molecule (+)G or (-)G by a chiral host (—)H may be represented as follows ... 

Chirality has also been introduced into crown hosts using optically-active functional groups other than bis-/ -naphthol. For example, the crown (233) derived from L-tartaric acid is a chiral host showing much less... 

Many optically active hypervalent chalcogen compounds, particularly sulfur compounds, have been synthesized and proposed as important key intermediates in various reactions of the chalcogen compounds.46 Since the synthesis of spirosulfurane by Kapovits and Kalman,47 many optically active spir-osulfuranes were isolated in the last decade. Spirosulfurane 28 was separated into enantiomers by kinetic resolution using a chiral host molecule and found to be optically stable by Drabowicz and Martin.48 Spirosulfurane 29 was separated into enantiomers by chromatographic method by Allenmark and Claeson, and characterized by chiroptical methods.49 Optically active... 

Toda and Akai49 reported that compound 48 reacted with the stable solid state inclusion compound of chiral host 46 and meso-ketone 47, providing alkene 49 in 57% ee. 

Only Cram (36) has published a rationale for the very high (99%) enantiomeric excess achieved in the reaction of methyl vinyl ketone and the hydrindanone in the presence of the chiral crown ether. This mechanism envisions a bimolecular complex comprising the potassium cation and chiral host as one entity and the enolate anion of the hydrindanone as the counterion. Methyl vinyl ketone lies outside this complex. The quinine-catalyzed reaction appears to have a termo-lecular character, since the hydroxyl of the alkaloid probably hydrogen bonds with the methyl vinyl ketone—enhancing its acceptor properties—while the quin-uclidine nitrogen functions as the base forming the hydrindanone—alkaloid ion pair. 

In principle, the approach outlined above for the a-oxoamides can be applied to any reaction, ground or excited state, which converts an achiral reactant into a chiral product, and Toda, Tanaka, and coworkers have investigated a wide variety of such processes [ 15,16]. A complete discussion of their work is beyond the scope of this review, and we illustrate the general approach taken with one final example. As shown in Scheme 4, irradiation of crystalline complexes of ene-diones 20a-f with chiral host (R,R)-(-)-9b led to cyclized products 21a-f in the variable yields and ee values indicated in Table 1 [22]. Remarkably, for reasons that were not clear (there was no accompanying X-ray crystallography), the R=n-propyl derivative 20g was found to give a completely different photoproduct, spiro compound 22 (69% yield, 97% ee, stereochemistry unknown), a result that once again illustrates the rather capricious nature of the use of chiral hosts for asymmetric induction. 

We turn now to a presentation of our own research on the use of built-in or internal chiral auxiliaries for asymmetric induction in photochemical reactions in the crystalline state [28]. This work is a natural outgrowth of the work of Toda and coworkers on the use of external chiral host compounds for the same purpose discussed in Sect. 2.2. In both cases, the primary role of the chiral auxiliary is to guarantee the presence of a chiral space group for the ensuing solid-state photochemical reaction. 

When the analyte is chiral, however, the stereochemical issues evolve to how a chiral host interacts with a chiral guest. The nature and magnitude of these diastereomeric interactions ultimately control the DCL evolution and what types of hosts are amplified. 

A general overview of the molecular modeling techniques applied to chiral hosts can be found in papers by Lipkowitz (77,78). Some special aspects of molecular modeling techniques related to chiral CE and earlier studies on the subject are summarized in Refs. 3, 17, 79, and 80. 

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