Resolution of Diastereomeric Mixtures

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. 

The resolution of mixtures of steroidal diastereomers using Eu(dpm)3 has been reported by Joseph-Nathan et al. (1972). More recently DePuy et al. (1976) demonstrated that Eu(fod)3 resolves not only the diastereomers of 2-methoxy-3-methyl-pentane but also the additional pairs of diastereomers obtained by monodeuteration at position 4. It should be emphasized that spectral resolution of diastereomeric mixtures by achiral shift reagents may occur by two possible mechanisms different shifts in the adducts and different association constants. If the latter is the dominant mechanism the chemical shift difference induced by the reagent will have a maximum at certain reagent concentration and will decrease with increasing the concentration. 

Another route to enantiomcrically pure iron-acyl complexes depends on a resolution of diastereomeric substituted iron-alkyl complexes16,17. Reaction of enantiomerically pure chloromethyl menthyl ether (6) with the anion of 5 provides the menthyloxymethyl complex 7. Photolysis of 7 in the presence of triphenylphosphane induces migratory insertion of carbon monoxide to provide a racemic mixture of the diastereomeric phosphane-substituted menthyloxymethyl complexes (-)-(/ )-8 and ( + )-( )-8 which are resolved by fractional crystallization. Treatment of either diastereomer (—)-(/J)-8 or ( I )-(.V)-8 with gaseous hydrogen chloride (see also Houben-Weyl, Vol 13/9a, p437) affords the enantiomeric chloromethyl complexes (-)-(R)-9 or (+ )-(S)-9 without epimerization of the iron center. 

The resolution of racemic mixtures through fractional crystallization of diastereomeric salts is traditionally used for organic acids and bases (19). Often the separation requires multiple recrystallizations and, in addition to the desired product, results in the production of the unwanted isomer... 

Resolution of Racemic Mixtures ofAllylic Alcohols.An important application of the SAE reaction is the kinetic resolution of racemic mixtures of secondary allylic alcohols. In this case, the chiral catalyst reacts faster with one enantiomer than with the other since the two transition states are diastereomeric. Thus, using 0.5 mole of r-BuOOH for each mole of racemic allylic alcohol, the faster-reacting enantiomer will consume the r-BuOOH to furnish the epoxide. This leaves behind the unreacted slower-reacting allylic alcohol in high enantiomeric excess, which is then separated from the epoxide via chromatography. 

Section 2.2 deals with the classical resolution of racemic mixtures via formation of diastereomeric adducts with chiral auxiliaries or by chromatographic methods. 

Profens are an important group of NSAIDs. The biological activity of these drugs resides exclusively in the (S)-enantiomer, so considerable effort has been invested in developing efficient routes for their preparation. For instance, (S)-naproxen has been prepared via recrystallization of diastereomeric mixtures. The carboxylesterase-catalyzed kinetic resolution of R/S)-naproxen methyl ester achieves excellent optical purity of the product. Nevertheless, the AMDase-catalyzed as5unmetrizahon of prochiral a-aryl-a-methylmalonates gives rise to a 100% theoretical 5deld of profens, a clear improvement from kinetic resolution (50%). Unfortunately, wild-type AMDase produces only the undesirable (R)-enantiomers. 

Aryl analogs of threonine 94 (Fig. 32) are of interest for their occurrence as constituents of a number of antibiotics (e.g., vancomycin). Because of often unfavorable equilibrium constants [43], synthetic reactions usually lead to stereoisomer mixtures due to thermodynamic control [152,153]. Resolution of diastereomeric material (93/94) by retroaldolization under kinetic control is more successful, as has been demonstrated by the preparation of enantiopure p-substituted (2i ,35)-phenylserines 94 [154] and (2R,3R)-3-hetarylserines [155] using a threonine aldolase from Streptomyces amakusaensis that is selective for aromatic threo substrates. 

In the resolution of 1 phenylethylamine using (-) malic acid the compound obtained by recrystallization of the mixture of diastereomeric salts is (/ )... 

In the resolution of 1-phenylethylamine using (-)-malic acid, the compound obtained by recrystallization of the mixture of diastereomeric salts is (/ )-1-phenylethylammonium (S)-malate. The other component of the mixture is more soluble and remains in solution. What is the configuration of the more soluble salt ... 

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. 

Since the addition of dialkylzinc reagents to aldehydes can be performed enantioselectively in the presence of a chiral amino alcohol catalyst, such as (-)-(1S,2/ )-Ar,A -dibutylnorephedrine (see Section 1.3.1.7.1.), this reaction is suitable for the kinetic resolution of racemic aldehydes127 and/or the enantioselective synthesis of optically active alcohols with two stereogenic centers starting from racemic aldehydes128 129. Thus, addition of diethylzinc to racemic 2-phenylpropanal in the presence of (-)-(lS,2/ )-Ar,W-dibutylnorephedrine gave a 75 25 mixture of the diastereomeric alcohols syn-4 and anti-4 with 65% ee and 93% ee, respectively, and 60% total yield. In the case of the syn-diastereomer, the (2.S, 3S)-enantiomer predominated, whereas with the twtf-diastereomer, the (2f ,3S)-enantiomer was formed preferentially. 

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... 

Wudl and Lee (96,97) reported the first preparation and resolution of the cyclic diastereomeric amidosulfites 58, which have been successfully used in the synthesis of chiral sulfoxides. A mixture of diastereomeric menthyl dimethylamidosulfites (100) was obtained in the reaction of racemic dimethylaminosulfinyl chloride (101) with menthol in the presence of pyridine (149). The degree of asymmetric... 

In contrast, electrophilic additions to the double bond of acetal 70 (derived from 64 ) gave adduct mixtures 71/72 with regioselectivities opposite to those of reactions 64 + EX — 68 + 69, 72 being the major adducts. Tests were carried out to confirm that adducts 68 + 69 and 71+72 were formed under conditions of kinetic control. Acetal 70 was obtained optically pure via resolution of lactol 73 by medium pressure chromatographic (silica gel) separation of the diastereomeric acetals 74 derived from (-)-menthol. ... 

It has been reported that Horeau s method can be applied to micromolar quantities of secondary alcohols, if the enantiomeric composition of the remaining 2-phenylbutanoic anhydride is determined by means of gas chromatography. To the acylation mixture an optically active amine [(+)-(R)-l-phenylethanamine] is added which reacts rapidly with the excess of 2-phenylbutanoic anhydride. The resulting diastereomeric amides are then characterized by GLC. The amine salts of 2-phenylbutanoic acid do not interfere. Success is dependent upon rapid amide formation (without significant resolution of the anhydride by the amine)236. The application of this method to (+)-(A/)-binaphthol (9) is shown237. 

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. 

Sertraline is the active pharmaceutical ingredient (API) in Pfizer s antidepressant Zoloft [25]. The developed commercial process employs an SMB chromatographic resolution of tetralone (Scheme 13.10) in >99% ee followed by diastereoselective reductive amination to give 95% sertraline (cis-isomer) and 5% trans-isomer the (4R)-tetralone can be racemized with an alkoxide base [8]. Asymmetric processes to sertraline have been described [26]. Our studies started with the original patented process involving palladium-catalyzed reductive amination of a tetralone to give a mixture of 80% racemic-cis and 20% racemic-trans diastereomers [27]. The cis-diastereomer can be purified by selective crystallization from toluene followed by diastereomeric crystallization of the (lS,4S)-enantiomer using (R)-... 

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