Resolution diastereomeric mixtures

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. 

In another approach, the alcohol moiety, formed by an enzymatic hydrolysis of an ester, can act as a nucleophile. In their synthesis of pityol (8-37a), a pheromone of the elm bark beetle, Faber and coworkers [17] used an enzyme-triggered reaction of the diastereomeric mixture of ( )-epoxy ester 8-35 employing an immobilized enzyme preparation (Novo SP 409) or whole lyophilized cells of Rhodococcus erythro-polis NCIMB 11540 (Scheme 8.9). As an intermediate, the enantiopure alcohol 8-36 is formed via kinetic resolution as a mixture ofdiastereomers, which leads to the diastereomeric THF derivatives pityol (8-37a) and 8-37b as a separable mixture with a... 

The optical resolution of the rigid racemic 1,2,3-trimethylcyclooctatetraene 277a, which exists in equilibrium with a small amount of the valence isomer 277b, was accomplished by means of (—)-ewdo-bornyl-l,2,4-triazoline-3,5-dione 278. The diastereomeric mixture... 

If a diastereomeric mixture of (S,S)-2,5-dimethyl-3.4-hexanediol esters 2 and 3 reacts with methylmagnesium bromide, the result is kinetic resolution, as verified for R1 = Bn. The diastereomeric mixture was prepared from the racemic ethylene glycol a-chloro boronic ester via transesterification with chiral diol. The products isolated were (S,S)-2,5-dimethyl-3,4-hexanediol [(/ )-2-phcnyl-l-methylethyl]boronate, diastereomeric ratio >95 5 as indicated by the rotation of the (/ )- -phenyl-2-propanol derived by deboronation with hydrogen peroxide, and (S,S)-2,5-dimethyl-3.4-hexanediol methylboronate. Phenylacetaldehyde was identified by 1H NMR4. 

The use of 0.75 mol% Yb(fod)3 (27) at 50 °C offered more reproducible results (Scheme 6). A diastereomeric mixture (65 35) of cis-11 to trans-11 was isolated in 60-65% yields as racemic materials. This process, however, required an oxidation (TEMPO, NaOCl) followed by NaBH4 reduction, protection as acetate derivative and lipase resolution (PS-C, amino-I) to afford the bis-THF alcohol in 97-98% ee and 28-35% yields. 

A patented synthesis by Doan et al. at GlaxoSmithKline used a Patemo-Buchi photochemical reaction to obtain acetal 33 in 96% yield, as shown in Scheme 8.35 Hydrogenation followed by acid-catalyzed cyclization resulted in a diastereomeric mixture of bis-THF alcohol ( )-ll. Formation of acetate 15, followed by lipase resolution resulted in the formation of the acetyl bis-THF, which was subsequently deprotected to afford the desired product (-)-ll in 98% ee.35... 

Early studies from the Pfizer laboratories had revealed that compounds from a series of mzn.s-l-amino-4-phenyl-tetralins possessed potent norepinephrine (NE) uptake blocking activity. The activity was highly specific for the (1/ , 4S)-enantiomer and was confined to the trans derivatives. The corresponding (IS, 4/ )-enantiomer was much less active and the diastereomeric cis racemates were inactive at blocking NE uptake. It was subsequently shown that many compounds from the diastereomeric cis senes were unexpectedly potent and selective inhibitors of serotonin (5-HT) uptake, thus differentiating these compounds from the trans compounds. One of these compounds, sertraline (5), was originally discovered as a racemic mixture. Resolution showed that the (+)-enantiomer was several times more selective for 5-HT uptake blocking activity than the (-)-isomer. The (+)-enantiomer was subsequently shown to possess the in vivo behavioral effects expected of a potent and selective 5-HT blocker. Thus, as opposed to... 

Resolution of the racemic 7-/i-tolyldinaphtho[2,l-4 T,2 -optically active palladium complexes (with O.Sequiv of dimeric optically active di-p.-chlorobis (4)-2-[T(dimethylamino)-ethyl]phenyl-(7,M dipalladium(n)) 29 is a rare example of a reaction giving a product with CN 4 (Equation 6). The diastereomeric mixture thus produced could not be separated by fractional recrystallization from a variety of solvents or by column chromatography, because the optically active 7-A-tolyldinaphtho[2,l-4 l, 2 -palladium complex 48. Also the complex prepared from enantiomerically pure R-(-)-stibole 16 racemizes due to fluxionality (NMR estimated at elevated temperatures) <2001TL441, 2003YZ577>. 

An efficient method of resolution of diastereomeric mixtures of 5-substituted 2-oxazolidinones, utilizing commercially available (S)-l-phenylethylamine as the optically active portion of the molecule, has been developed16. Thus, the Ar-benzyloxycarbonyl derivative of (S)-TV-(l-phen-ylethyl)-2-propen-1-amine (1), treated with iodine in chloroform, affords the diastereomeric products as a 50 50 mixture which is easily separated by chromatography on silica gel. 

Furthermore, Kamigata and co-workers have shown an example of the conversion of a chiral selenoxide, obtained by the optical resolution of a diastereomeric mixture, into the corresponding enantiomerically pure selenimide, ascertaining the detailed stereochemistry of this compound [39] (Scheme 23). The transformation of the selenoxide into the selenimide proceeded with an overall retention of configuration at the selenium center in the presence of dicy-clohexylcarbodiimide (DCC). 

In some cases (3), the addition of a chiral shift reagent (Eu(hfc)3) is necessary to obtain baseline separation of the signals corresponding to the p-proton of both diastereomers by H NMR. Diastereomeric mixtures derived from secondary alcohols have also been analyzed by HPLC. The resolution of a secondary alcohol (4) could be achieved by a selective crystallization of one of the two diastereomeric camphorsulfonate esters. ... 

Fig. 9.26). In general, the MaNP esters of less polar aliphatic alcohols, such as 2-hexadecanol, are more effectively separated by HPLC on sihca gel than fhe MaNP esters of polar alcohols, as discussed above. Therefore it was very surprising to us to find that the diastereomeric mixture of MaNP esters 81a/81b composed of polar groups was clearly separated by HPLC on silica gel (hexane/EtOAc = 5 1) as shown in Fig. 9.26 separation factor a = 1.72 resolution factor Rs = 2.52. It should be emphasized that a mixture (50 mg) of these two esters was separable even with a HPLC silica gel column of 10 cm length. The first-eluted ester (-i-)-81a (45%, [ajn -1-23.0 (c 1.215, Cl I Cl, )) and the second one (-)-81b (50%, [ajo -77.3 (c 1.255, CHCl-J) were obtained. 

Subsequently, the absolute configuration of the natural lineatin was determined as (lR,4S,5R,7R)-77 by our second synthesis, as shown in Figure 4.16.35 The first step was the cycloaddition of dichloroketene to isoprene to construct a cyclobutane ring. The symmetrical cyclobutanone A was then converted to ( )-bicyclic lactone B. Enantiomer separation (optical resolution) of ( )-B was executed as follows. Reaction of ( )-B with the resolving agent C (derived from chrysanthemic acid) yielded a diastereomeric mixture... 

Dibenzoylation of 76 can be also realized by using a combination of benzoyl chloride and DMAP in 88% yield. The resultant benzoate 78 was converted to the optically active menthoxyacetate 83 by successive decyclohexylidenation, selective acylation at C-l, and optical resolution (Scheme 3-11). A diastereomeric mixture of 83... 

The reduction of a diastereomeric mixture of enantiomerically pure /3-keto sulfoxides (7) furnished one of the four possible isomers with good overall stereoselectivity (90%), when carried out under conditions which favor epimerization of the a chiral center (eq 16). This outcome derives from a chelation-controlled reduction (involving the sulfoxide oxygen) coupled with a kinetic resolution of the two diastereoisomers of (7). ... 

The vindoline synthesis required prior preparation of the amine coupling partner, the 2,4-dinitrobenzenesulfonamide 713, which was prepared from the pent-anal 710, as shown in Scheme 43. A notable feature of this route was the enzyme-mediated resolution of the cyanohydrin acetate 711, via enzymatic hydrolysis to selectively afford a diastereomeric mixture of only the (5)-cyanohydrins 712. 

This chapter describes the preparation of optically pure phosphines and derivatives by resolution of racemic/diastereomeric mixtures or by taking advantage of additional stereogenic elements in the scaffold of the phosphine. 

Resolution of Racemic and Diastereomeric Mixtures Table 2.1 Continued). 

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