Inclusion complexation, optical resolution

It is well known that spontaneous resolution of a racemate may occur upon crystallization if a chiral molecule crystallizes as a conglomerate. With regard to sulphoxides, this phenomenon was observed for the first time in the case of methyl p-tolyl sulphoxide269. The optical rotation of a partially resolved sulphoxide (via /J-cyclodextrin inclusion complexes) was found to increase from [a]589 = + 11.5° (e.e. 8.1%) to [a]589 = +100.8 (e.e. 71.5%) after four fractional crystallizations from light petroleum ether. Later on, few optically active ketosulphoxides of low optical purity were converted into the pure enantiomers by fractional crystallization from ethyl ether-hexane270. This resolution by crystallization was also successful for racemic benzyl p-tolyl sulphoxide and t-butyl phenyl sulphoxide271. 

A different non-classical approach to the resolution of sulphoxides was reported by Mikolajczyk and Drabowicz269-281. It is based on the fact that sulphinyl compounds very easily form inclusion complexes with /1-cyclodextrin. Since /1-cyclodextrin as the host molecule is chiral, its inclusion complexes with racemic guest substances used in an excess are mixtures of diastereoisomers that should be formed in unequal amounts. In this way a series of alkyl phenyl, alkyl p-tolyl and alkyl benzyl sulphoxides has been resolved. However, the optical purities of the partially resolved sulphoxides do not exceed 22% after... 

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]. 

When a mixture of methyl phenyl sulfide (69a) (1 g, 8.1 mmol), 30% H2O2 (1.84 g, 16.2 mmol), and water (10 ml) was stirred at room temperature for 24 h, rac-lOa was produced (Scheme 11). To the water suspension medium of rac-70a was added 10c (2 g, 4 mmol), and the mixture was stirred for 15 h to give a 1 1 inclusion complex of 10c with (+)-70a. Heating the filtered complex in vacuo gave (+)-70a of 57% ee (0.45 g, 82% yield). From the filtrate left after separation of the inclusion complex, (-)-70a of 54% ee (0.4 g, 73% yield) was obtained by extraction with ether. By the same procedure, optically active 70b-d were also prepared (Table 11). In the case of (+)-70b and (-)-70c,the efficiency of the enantiomeric resolution was very high. 

The possibility to resolve the two enantiomers of 27a (or 26) by crystalline complexa-tion with optically active 26 (or 27a) is mainly due to differences in topological complementarity between the H-bonded chains of host and guest molecules. In this respect, the spatial relationships which affect optical resolution in the above described coordination-assisted clathrates are similar to those characterizing some optically resolved molecular complexes S4). This should encourage additional applications of the lattice inclusion phenomena to problems of chiral recognition. 

The stereospecific conversion of sulfinates into sulfoxides of known chirality has been applied as a general method for determining the absolute configuration of a wide range of optically active sulfinic esters. For example, the absolute configurations of a series of alkyl alkanesulfinates obtained by asymmetric synthesis (107) or resolution via 3-cyclodextrin inclusion complexes (106) were determined by this method. 

Another variation of the enantioselective inclusion complexation procedure leading to optical resolution is the application of powdered host compounds in the... 

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... 

V-hexadecyltrimethylammonium bromide as a surfactant helped to prevent coagulation of the two substrates in aqueous suspension. It is interesting that, although bulky but small molecules of epoxides (8) easily penetrated the void space in crystals of 3b-c and underwent optical resolution, compounds 5a-b (with long aliphatic chains) and 7b did not form inclusion compounds. The application of suspension conditions resulted in a very efficient optical resolution, sometimes better than that achieved by the classic formation of complexes by recrystallization of host and guest from a common solvent. For comparison, optical resolution of 4c by co-crystallization with the host 6 after two recrystallizations gave the crude product at 100 % ee but only 35 % yield [21], in comparison with 57 % and 85 %, respectively, in hexane and water suspension [20],... 

Optically active 19a was previously obtained by inclusion complexation with N -benzylcinchon idi um chloride 21 [36], Compound 21 was also a very efficient resolving agent for rac-17 [37], Crystal structure analysis of a (1 1) complex of 21 and selectively included (+)-17 showed that the molecular aggregate was associated by formation of a Cl HO hydrogen bond. Racemic compound 20 could be efficiently resolved only by complexation with (R,R)-(—)-trans-2,3-bis(hydroxydiphenylmethyl)-l,4-dioxaspiro[4.4]nonane 3b. A crude inclusion complex of 1 1 stoichiometry of 3b was formed selectively with (+)-20 in a 2 1 mixture of dibutyl ether/hexane. One recrystallization from the above combination of solvents gave a 34 % yield of the pure complex. Optically active (+)-20 was obtained by dissolving the complex in 10% NaOH, followed by acidification with HC1 and then recrystallization. The optical purity determined by HPLC (Chiralpack As) was >99.9 %. As far as we know, this is the only report of the resolution of 4,4 -dihydroxybiphenyl derivatives. Conversely, an inclusion... 

Among the preparative methods used for obtaining P-chiral phosphorus compounds, there are procedures involving the use of optically pure auxiliaries like (—)-menthol [40], (—)-ephedrin [41,42], or more recently, the kinetic resolution of 1-hydroxymethylalkylphenylphosphine oxides using Pseudomonas or Candida antarctica lipases [43], It has been found that some [(alkyl-substituted)arene] phosphinates and phosphine oxides can also be resolved efficiently by inclusion complexation with optically active 2,2 -dihydroxy-1, 1 -binaphthyl (17) [44],... 

For example, when powdered host 27 was mixed with volatile rac-but-3-yn-2-ol (29) and left for 24 h, a 1 1 inclusion complex with (+1-29 was formed. The alcohol can be removed from the complex by heating in vacuo yielding 29 of 59 % ee and 77 % yield. A second complexation, followed by distillation in vacuo, gave (+)-29 of 99 % ee and 28 % yield. The best resolution of rac-29 reported to date was by enzymatic esterification, and gave chiral alcohol at 70 % ee and 31% yield [49], Host 27 could be used for optical resolution of rac-2-hexanol... 

The Optical Resolution of Reaction Intermediates by Inclusion Complexation... 

OPTICAL RESOLUTIONS BY INCLUSION COMPLEXATION WITH A CHIRAL HOST COMPOUND... 

This chapter consists mainly of two sections, 1) preparation of artificial chiral host compounds and 2) optical resolution of various racemic guest compounds by inclusion complexation with these hosts. 

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). 

Reason for the effective optical resolution by the inclusion complexation with a chiral host has been clarified by X-ray analysis of the complex formed. By the X-ray structural study of the host-guest complex, absolute configuration of the chiral guest resolved has also been elucidated easily, since absolute configuration of the chiral host is known. These X-ray data have been reported in the literature cited together with the detailed experimental procedure of the resolution. 

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. 

When a solution of 2 (243 g, 1 mol) and rac-2-methylpiperazine (21a, lOOg, 1 mol) in BuOH (50 ml) was kept at room temperature for 12 h, a 2 1 inclusion complex of 2 and (S)-(+)-2-methylpiperazine (21c) was obtained as colorless prisms, which upon three recrystallizations from BuOH gave pure complex crystals (60 g, 20%). Heating of the crystals in vacuo gave 21c of 100% ee by distillation (9.5 g, 19%).13 Optical resolution of 21a can also be accomplished by complexation with the host 3. 

Reaction of rac-1 -tert-buty l-3-chloroazetidin-2-one (28) with 25 gave the rac-phthalimide derivative (29). Optical resolution of rac-29 was accomplished efficiently by complexation with 15. When a solution of 15b and two molar equivalents of rac-29 in benzene-hexane (1 1) was kept at room temperature for 12 h, a crystalline 1 1 inclusion complex of 15b and (-)-29 was obtained. After one recrystallization from benzene-hexane, the crystals were chromatographed on silica gel to give pure complex consisting of (-)-29 of 100% ee in 63% yield. Decomposition of the complex with hydrazine gave optically pine (-)-3-amino- l-/m-butylazetidin-2-onc (30) in 44% yield.15 Mechanism of the precise chiral recognition between 15b and (-)-29 in their 1 1 complex was clarified by X-ray crystal structural analysis.15... 

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