Optical resolution recrystallization

Cr(CO)3 coordinates from either the top or bottom side of aromatic rings, bearing two different substituents in ortho or meta position, so that the enantiomers 285 and 286 are obtained. Optical resolution of the enantiomers is carried out by recrystallization, or column chromatography. The racemic complex of benzyl alcohol derivative 287 was separated to 288 and 289 by lipase-catalysed acetylation [68]. Enzymes recognize Cr(CO)3 as a bulky group. Chiral Cr(CO)3-arene complexes are used for asymmetric synthesis [68a]. 

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],... 

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... 

In 1986, Minami and his coworkers described the optical resolution of the oxide of tram-his-1,2-(diphcnylphosphino)cyclobutanc (20, Scheme 10.) with stoichiometric amount of DBTA in methanol solution. [30] In the same year, Noyori and his coworkers published the synthesis of optically active BINAP via resolution of BINAP oxide (21) with DBTA. [31] In this process, hot chloroformic solution of racemic 21 was mixed with a molar equivalent amount of DBTA previously solved in ethyl acetate. Optically pure -21 was isolated in 79 % yield from the recrystallized diastereoisomeric complex by... 

Preparative Methods (i) preparation of racemic DPEN and its optical resolution Reaction of benzil and cyclohexanone in the presence of ammonium acetate and acetic acid at reflux temperature gives a cyclic bis-imine (1) (eq 1). Stereoselective reduction of the bis-imine with lithium in THF-liquid ammonia at —78 °C followed by addition of ethanol, then hydrolysis with hydrochloric acid and neutralization with sodium hydroxide produces the racemic diamine (2). Recrystallization of the l-tartaric acid salt from a 1 1 water-ethanol mixture followed by neutralization with sodium hydroxide, recrystallization from hexane results in (5,5)-DPEN (3) as colorless crystals. 

Optical Resolution. This reagent is commonly used for the optical resolution of various compounds. Racemic spiro[4.4]nonane-1,6-dione was the first compound to be resolved (55% overall yield). The corresponding semioxamazone was obtained in optically active pure form in two or three recrystallizations and hydrolyzed to (—)-(5)-spiro[4.4]nonane-l,6-dione in a refluxing methanol-water mixture in the presence of Iodine (eq 2). 

A nice complement to the Haller-Bauer reaction (Section II.B) is the decarbonylation of aldehydes with (Ph3P)3RhCl (Wilkinson s catalyst) A recent example comes from the work of Baldwin and Barden and is shown in Figure 5. Interestingly, partial optical resolution was achieved in this synthesis by use of an optically active copper catalyst for the preparation of the labeled phenylcyclopropane carboxylic acid. The resolution to optical purity was then accomplished by recrystallization of the quinine salt of the acid. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the p/eso-cydoacid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cydoacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitativdy yidd the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystallization. Acid hydrolysis of the amide thenyidds the desired < lactone (17). A similar approach uses rhiral alcohols to form diastereomic half-esters stereosdectivity. These are reduced and directly converted to < lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

If the molecule is indeed bent out of a plane the nitro substituent should produce the potentiality for molecular asymmetry. Hence the nitro derivative was treated with p-boronobenzoic acid in benzene under a water separator to yield the cyclic boronate ester carboxylic acid (8). a derivative directly suitable for optical resolution. As a carboxylic acid. (8) gave a crystalline salt with quinine which, after four recrystallizations (aD — 37.4°), liberation of the organic acid, and hydrolysis gave optically active nitroglycol (6), X = NO,. Lead tetraacetate cleavage of the dextrorotatory (6), X = N02. gave optically active (5), X = NO,. the racemization of polarimetry in a chloroform solution. 

To our knowledge, no such effective optical resolution by inclusion formation with an optically active channel-type host compound has been reported so far. 1,2-Bis(2-methyl-1-naphthyl)-l,2-bis(2,4,6-trimethylphenyl)ethane (80) yields a 1 1 crystal inclusion with (+)-a-pinene, but successive recrystallization of 80 from (-i-)-a-pinene gives only a partial optical resolution... 

P-chiral phosphines, which are potential ligands for transition metal-catalyzed reactions, were synthesized through hpase-catalyzed optical resolution of the corresponding racemic phosphine oxide compounds (Fig. 10.29). For example, lipase from C. rugosa (CRL) was used for the enantioselective hydrolysis of acetoxynaphthyl phosphine oxide (Fig. 10.29(a)). The P-enantiomer was hydrolyzed selectively, leaving the (S)-acetoxy compound, which was further subjected to chemical hydrolysis. Both enantiomeric phosphine oxides were obtained in >95% after recrystallization. Methylation followed by reduction with triethyl amine/trichlorosilane, with inversion of configuration, yielded the desired chiral phosphine. 

Applications for optical resolution of racemic mixture. Since conventional methods of resolution of racemic mixtures by fractional recrystallization of their corresponding diastermeric salts is often laborious, generates low yields, and does not always produce high optical purity, a direct chromatographical optical resolution method was desired. During the past decade, extensive research has been carried out in an effort to prepare novel chiral adsorbents based on silica gel for liquid... 

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

Recrystallization of a 1 1 molecular complex formed from several sulfoxides and (R)-( + )-2,2 -dihydroxy-l, l -binaphthyl (7) allowed resolution of the former22. Conversely, using the optically pure sulfoxide, it was possible to resolve racemic bis-naphthol 7. 

A new approach to the resolution of sulphoxides 242 was recently reported by T oda and coworkers282. It takes advantage of the fact that some sulphoxides form crystalline complexes with optically active 2,2 -dihydroxy-l, 1-binaphthyl 243. When a two-molar excess of racemic sulphoxide 242 was mixed with one enantiomeric form of binaphthyl 243 in benzene-hexane and kept at room temperature for 12 h, a 1 1 complex enriched strongly in one sulphoxide enantiomer was obtained. Its recrystallization from benzene followed by chromatography on silica gel using benzene-ethyl acetate as eluent gave optically pure sulphoxide. However, methyl phenyl sulphoxide was poorly resolved by this procedure and methyl o-tolyl, methyl p-tolyl, s-butyl methyl and i-propyl methyl sulphoxides did not form complexes with 243. 

Our approach for chiral resolution is quite systematic. Instead of randomly screening different chiral acids with racemic 7, optically pure N-pMB 19 was prepared from 2, provided to us from Medicinal Chemistry. With 19, several salts with both enantiomers of chiral acids were prepared for evaluation of their crystallinity and solubility in various solvent systems. This is a more systematic way to discover an efficient classical resolution. First, a (+)-camphorsulfonic acid salt of 19 crystallized from EtOAc. One month later, a diastereomeric (-)-camphorsulfonic acid salt of 19 also crystallized. After several investigations on the two diastereomeric crystalline salts, it was determined that racemic 7 could be resolved nicely with (+)-camphorsulfonic acid from n-BuOAc kinetically. In practice, by heating racemic 7 with 1.3equiv (+)-camphorsulfonic acid in n-BuOAc under reflux for 30 min then slowly cooling to room temperature, a cmde diastereomeric mixture of the salt (59% ee) was obtained as a first crop. The first crop was recrystallized from n-BuOAc providing 95% ee salt 20 in 43% isolated yield. (The optical purity was further improved to -100% ee by additional recrystallization from n-BuOAc and the overall crystallization yield was 41%). This chiral resolution method was more efficient and economical than the original bis-camphanyl amide method. 

A method for determining optical purities of less than one percent for secondary alcohols has been published, and Mislow has observed a partial resolution which may serve to distinguish between a meso and a racemic host product when a derived inclusion compound is recrystallized from an enantiomerically enriched guest solvent. ... 

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