Host compound, optically active

Enantioselective bromination of cyclohexene (11) in an inclusion complex with the optically active host compound, (i, i )-(-)-trans-4,5-bis(hydroxy-diphenylmethyl)-2,2-dimethyl-l,3-dioxacyclopentane (10a) was accomplished. 

The question that emerges at the climax of this survey relates to the possibility of using crystalline inclusion phenomena for optical resolutions of molecular species. Can this be done effectively with suitably designed host compounds The definitely positive answer to this question has elegantly been demonstrated by Toda 20) as well as by other investigators (see Ch. 2 of Vol. 140). An optically active host compound will always form a chiral lattice. Therefore, when an inclusion type structure is induced, one enantiomer of the guest moiety should be included selectively within the asymmetric environment. 

When guest molecules are arranged together in the channel of a host-guest inclusion complex, intermolecular reactions of the guest compound may proceed stereoselec-tively and efficiently. An enantioselective reaction is expected when optically active host compounds are used. 

When an optically active host compound is used instead of 4, formation of an optically active pinacolone is expected by an enantioselective pinaeol rearrangement in the solid state. 

An enantioselective photoreaction of a guest compound is expected when an inclusion complex of the guest with an optically active host compound is irradiated in the solid state. 

In order to control both the stereochemistry and enantioisomerism of the photocyclization product, design of a good host compound is necessary. It seems adequate to design an optically active 2,2-biphenyldicarboxamide derivative, since 4 is very useful for the control of stereochemistry of the photocyclization of 74. 

The most exciting enantioselective photochemical conversion of a a-oxoamide to a P-lactam has been found in the case of N,N-diisopropylbenzoylformamide (96) which gives P-lactam 97. In the photocyclization of plain 96 in the solid state, optically active P-lactam 97 of high optical purity was obtained in high chemical yield. Thus no optically active host compound is necessary for the enantioselective reaction 48>. 

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... 

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 called 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 42 partially to resolve the racemic amine salt 43.121 When an aqueous solution of 43 was mixed with a solution of optically active 42 in chloroform, and the layers separated, the chloroform layer contained about... 

Certain chiral organic compounds create crystalline environments and act as enantio-controlling media (7) even though they do not function as true catalysts. Natta s asymmetric reaction of prochiral trans-1,3-pentadiene, which was included in the crystal lattice of chiral perhydro-triphenylene as a host compound, to form an optically active, isotactic polymer on 7-ray irradiation, is a classic example of such a chiral molecular lattice (Scheme 1) (2). Weak van der Waals forces cause a geometric arrangement of the diene monomer that favors one of the possible enantiomeric sequences. 

When a mixture of thiocoumarin 4 and optically active host compound (R,R)-(-)-l in butyl ether was kept at room temperature for 12 h, a 1 1 inclusion complex (mp 106-108 °C) was obtained as colorless needles. The 1 1 complex gave anti-head-to-head dimer (+)-5 (mp 254—255 °C) of 100% ee ([a]D+182 °, c 0.02 in CHC13) in 73% yield upon photoirradiation in the solid state. The optical purity of 5 was determined by HPLC on the chiral stational phase Chiralpak AS with using hexane-EtOH (95 5) as an eluent. 

Even for the oxoamides which do not form chiral crystals, enantioselective photoconversion to optically active (3-lactams can easily be accomplished by photoirradiation in their inclusion crystals with an optically active host compound. For example, irradiation of a 1 1 inclusion complex crystal of 9 with 11 [8] gave (-)-10 of 100% ee in a quantitative yield [9], The host compound 11 is recovered and can be used again. The chiral arrangement of 9 molecules in the inclusion complex was studied by x-ray analysis [9], A schematic stereoview of the inclu-... 

Intramolecular [2 + 2] photocyclization reactions of 2- /V-(2-propcnyl)amino]cy-clohex-2-enones (67) are also controlled enantioselectively by carrying out irradiation in inclusion complex with a chiral host compound. When inclusion crystals of 67 with 12 are irradiated in the solid state, optically active 9-azatricyclo[5.2.1.0]-decan-2-ones (68) were obtained in the chemical and optical yields indicated in Table 3 [30],... 

Photoirradiation of inclusion crystals of 3-oxo-2-cyclohexanecarboxamide derivatives (69b-69d) with the optically active host compound 12b as a water suspension for 4 hr gave optically almost pure 2-aza-l, 5-dioxaspiro[3,5]nonane derivatives (70b-70d) [38], Optically pure 70b and 70c were prepared by the... 

Enantioselective photocyclization of /V-al lyl furan-2-carboxanilidc (78) in its inclusion crystals with the optically active host compound 12b was accomplished successfully. More interestingly, ( )-79 and (+)-79 were obtained selectivity... 

Photoirradiation of inclusion crystals of the 4-(3-butenyl)cyclohexa-2,5-dien-l-ones (83) with the optically active host compounds (12c) in the solid state gave optically active l-carbomethoxytricyclo[4.3.1.0]dec-2-en-4-ones (84). For... 

Optically active oxazolidinones (91a-91d) of 95-100% ee were obtained by irradiation of the 1 1 inclusion complex crystals of nitrones (90a-90d) and optically active host compound 11 in the solid state in the chemical and optical yields indicated (Table 10) [48],... 

The enantioselective photodimerization of thiocoumarin (102) to optically pure (+)-a ft -head-to-head dimer (103) in the 1 1 inclusion complex of 102 with 12b was also found to proceed in a single-crystal to single-crystal manner. For example, when a mixture of thiocoumarin (102) and optically active host compound 12b in butyl ether was kept at room temperature for 12 hr, a 1 1 inclusion complex of 103 with 12b was obtained as colorless needles. Photoirradiation of a 1 1 inclusion complex in the solid state (400-W high-pressure Hg lamp, Pyrex filter, room temperature, 2 hr) gave a 2 1 complex of 12b with 103,... 

Some of the first, and most versatile hosts are compounds 3a-c, which can be prepared from optically active tartaric acid. It has been found that they work as chiral selectors in solution [17], and in a powdered state [18], In the crystal structure of the free host compound (R,R)-(—)-fra s-bis(hydroxydiphenylmethyl)-l, 4-dioxaspiro[4.5]decane (3c), only one hydroxyl group is intramolecularly hydrogen bonded (Figure 1). As long as no suitable guest molecules are present, the other OH-group remains unbonded in both media. 

For example, when a suspension of powdered optically active host 3a was mixed with racemic 1-phenylethanol (4a) in a 1 1 molar ratio and stirred at room temperature for 6 h, a 2 1 inclusion complex was formed. When the filtered solid complex was heated in vacuo, it gave (—)-4a (95 % ee, 85 % yield). For the host compounds 3a-c, approximately the same ee (78-99.9 %) and high yield (75-93 %) could be achieved in the resolution of alcohols of the 4 and 5 series in water and hexane. It has been found that introducing... 

Among the different types of compounds whose complexation properties have been studied are various amides linear oxoamide 9 [22], fumaramide 10 [23,24] and methanetricarboxamide 11 [25], biphenyl derivatives 12 [26], and derivatives of tartaric acid 13-16, that can also be prepared in an optically active form [27], The above-mentioned chiral hosts have been found to form inclusion complexes with chiral guests 17 and 18. Molecular recognition between chiral hosts and... 

The design of host compounds for optical resolution has received much attention. Toda [23,24] has reviewed the subject, and has used a number of novel techniques to effect efficient optical separation. He has demonstrated the possibility of resolving a racemic oil by stirring in a water suspension of a chiral host [25], and has applied fractional distillation techniques at different temperatures to separate a variety of racemic guests in the presence of chiral hosts [26]. An overview of the industrial applications and production of optically active materials is given in the book Chirality in Industry [27],... 

When chemical reactions are carried out in inclusion complexes, reactions can proceed selectively due to template control effects caused by the host compound. In some cases, reaction occurs only in the inclusion complex, but not in solution, since molecules can be arranged in the appropriate positions for reaction in an inclusion crystal. When an optically active host compound is used, enantiose-lective reactions can be accomplished. For some time we have been studying such selective reactions in inclusion complex crystals in the solid state. However, these reactions have already been published in the book Organic Solid State Reactions [1], In this present chapter, some representative topics and some recent new results of selective thermochemical and photochemical reactions in inclusion crystals are briefly summarized. 

When a mixture of powdered ketone and NaBH4 is kept at room temperature, reduction of the ketone occurs to give the corresponding alcohol [2], When the reaction is carried out in inclusion crystals containing a chiral host compound, the optically active alcohol can be obtained by enantio-control of the reaction by the chiral host. For example, treatment of inclusion crystals of acetophenone (2a) or o-methylacetophenone (2b) and (S,S)-(-)-1,6-bis(o-chlorophenyl)-1,6-diphenylhexa-2,4-diyne-l,6-diol (1) [3] with powdered BH3-ethylenediamine complex (3) in the solid state gave 4a of 44 % ee (96 % yield) or 4b of 59 % ee (57 % yield), respectively [4],... 

Wittig reactions of cyclohexanone derivatives in their inclusion compounds with the chiral host 5 gave optically active reaction products. For example, when a mixture of finely powdered 1 1 inclusion compound of 5b with 4-methyl-(15a) or 4-ethylcyclo-hexanone (15b) and phosphorane (16) was kept at 70 °C, the Wittig reaction in the solid state was completed within 4 h. To the reaction mixture was added diethyl ether-petroleum ether (1 1), and then the precipitated triphenylphos-phine oxide was removed by filtration. The crude product left after evaporation of solvent from the filtrate was distilled in vacuo to give (-)-4-methyl- (17a) of 42% ee (73 % yield) or (-)-4-ethyl-l-(carboethoxymethylene)cyclohexane (17b) of 45 % ee (57 % yield), respectively [9], Similar reaction of the 1 1 inclusion compound of 5c and c /. v - 3,5 - dime th y I c y c I o h e x a n o n e (18) with 16 gave 19 of 57 % ee in 58 % yield [9],... 

Some amide derivatives have been reported to form inclusion complex with a wide variety of organic compounds.9 Optically active amide derivatives are expected to include one enantiomer of a racemic guest selectively. According to this idea, some amide derivatives of tartaric acid (11-13) were designed as chiral hosts.10 As will be described in the following section, these amide hosts were found to be useful for resolution of binaphthol (BNO) (14) and related compounds (15,16). 

Optical resolution of some hydrocarbonds and halogeno compounds by inclusion complexation with the chiral host (9a) has been accomplished.11,12 Preparation of optically active hydrocarbons is not easy and only a few example of the preparation of optically active hydrocarbons have been reported. For example, optically active 3-phenylcyclohexene has been derived from tartaric acid through eight synthetic steps.11 Although one-step synthesis of optically active 3-methylcyclohexene from 2-cyclo- hexanol by the Grignard reaction using chiral nickel complex as a catalyst has been reported, the enantiomeric purity of the product is low, 15.9%.11 In this section, much more fruitful results by our inclusion method are shown. 

Although some kinds of optically active compounds can be prepared by an asymmetric synthesis using a chiral catalyst, this method is not applicable for preparation of all kinds of compounds. Furthermore, optical yields of the product are not always very high. On the contrary, optical resolution method by inclusion complexation with a chiral host is applicable to various kinds of guest compounds as described in this chapter. When optically pure product cannot be obtained by one resolution procedure, perfect resolution can be accomplished by repeating the process, although asymmetric synthetic process cannot be repeated. Especially, optical resolutions by inclusion complexation with a chiral host in a water suspension medium and by fractional distillation in the presence of a chiral host are valuable as green and sustainable processes. 

Toda, F., Tanaka, K., Infantes, L., Forces-Forces, C., Claramunt, R. M., and Elguero, J. (1995), Optical Resolution of 1,3-Dimethyl-5-phenyl-V2-pyrazoline by Diastereo- isomeric Complex Formation with an Optically Active Host Compound X-Ray and Molecular Structure of the Complex, J. Chem. Soc., Chem. Commun., 1453-1454. 

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