Diastereomeric recrystallization

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 ... 

Meyers has also reported the use of chiral oxazolines in asymmetric copper-catalyzed Ullmann coupling reactions. For example, treatment of bromooxazoline 50 with activated copper powder in refluxing DMF afforded binaphthyl oxazoline 51 as a 93 7 mixture of atropisomers diastereomerically pure material was obtained in 57% yield after a single recrystallization. Reductive cleavage of the oxazoline groups as described above afforded diol 52 in 88% yield. This methodology has also been applied to the synthesis of biaryl derivatives. 

The final two stages are very straightforward. Oxidative scission of the C3-C5 double bond in 6 with ozone provides triketone 5 which, without purification, is subjected to a base-induced intramolecular aldol/dehydration reaction. The crystalline product obtained from this two-step sequence (45 % overall yield) was actually an 85 15 mixture of ( )-progesterone and a diastereomeric substance, epimeric at C-17. Two recrystallizations afforded racemic progesterone [( )-(1)] in diastereomerically pure form. 

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. 

The synthesis of key intermediate 6 begins with the asymmetric synthesis of the lactol subunit, intermediate 8 (see Scheme 3). Alkylation of the sodium enolate derived from carboximide 21 with allyl iodide furnishes intermediate 26 as a crystalline solid in 82 % yield and in >99 % diastereomeric purity after recrystallization. Guided by transition state allylic strain conformational control elements5d (see Scheme 4), the action of sodium bis(trimethylsilyl)amide on 21 affords chelated (Z)-enolate 25. Chelation of the type illustrated in 25 prevents rotation about the nitrogen-carbon bond and renders... 

The products 4 are formed as racemic mixtures, but can be resolved by recrystallization of diastereomeric salts.23 - 25 Syntheses starting from optically active biphenyl compounds are also known.26 -28 l,l -Binaphthyl-2,2 -diamine(5) can be transformed to the dinaphtho[1,4]di-azocine 6 by melting with benzil.29... 

A related palladium(O)-catalyzed epimerization of y-aziridinyl-a,P-enoates 244 was also reported by Ibuka, Ohno, Fujii, and coworkers (Scheme 2.60) [43]. Treatment of either isomer of 244 with a catalytic amount of Pd(PPh3)4 in THF yielded an equilibrated mixture in which the isomer 246 with the desired configuration predominated (246 other isomers = 85 15 to 94 6). In most cases the isomer 246 could be easily separated from the diastereomeric mixture by a simple recrystallization, and the organocopper-mediated ring-opening reaction of 246 directly afforded L,L-type (E)-alkene dipeptide isosteres 243. 

Results of nucleophilic addition reactions to various a-oxo 4,5-dihydrooxazoles are summarized in Table 24. In general, the diastereoselectivity of these reactions is low to moderate, although an increased selectivity is found in the presence of triethylamine or N,N,N, N -te-tramethylethylenediamine, which slow down the rate of reaction. Nevertheless, enantiomerical-ly pure 2-hydroxy carboxylic acids can be prepared by this method, since the diastereomeric addition products are separable either by recrystallization or HPLC21. 

A solution of 0.11 mol of 1.5M butyllithium in hexane is added to 30 mL of THF under a layer of argon or nitrogen at —78 C, followed by 0.10 mol of (4S,5/ )-1-allyl-3,4-dimcthyl-5-phenyl-2-imidazolidinone in 75 mL of THF. After 25 min, a solution of 0.11 mol of chlorotris(diethylamino)titanium in 30 mL of THF is introduced. The mixture is stirred at — 20 °C for 45 min, then 0.11 mol of the aldehyde or ketone in 10 mL of THF is added. After 2 h. 20 mL of water and 200 mL of diethyl ether are added. The ethereal solution is separated, washed with 20 mL of 10% aq NaHS03 followed by 20 mL of water, dried over Na2S04 and concentrated, whereupon the product crystallizes. Diastereomerically pure samples are prepared by recrystallization from hexane or hexane/ethyl acetate. 

The lithium cnolate generated by deprotonation of 2-/m-butyl-6-methyl-l,3-dioxan-4-onc, readily available from polyhydroxybutyric acid (PHB), predominantly affords the diastereo-mers 7 when reacted with aldehydes. The diastereomeric ratios of aldol adducts 7/8, produced by reactions with aliphatic aldehydes, range from 87.5 12.5 to >99 1. Pure diastereoiners7are obtained by recrystallization in 25-74% yield116-118. Only marginal diastereoselectivities with respect to the carbinol center are obtained with aromatic aldehydes111-119. Benzoylation of the dioxanones 7, followed by reduction with lithium aluminum hydride, affords enan-tiomerically and diastereomerically pure triols 9 in >85% yield 11. ... 

Optically pure (S)-benzyl methyl sulfoxide 139 can be converted to the corresponding a-lithio-derivative, which upon reaction with acetone gave a diastereomeric mixture (15 1) of the /S-hydroxysulfoxide 140. This addition reaction gave preferentially the product in which the configuration of the original carbanion is maintained. By this reaction, an optically active epoxy compound 142 was prepared from the cyclohexanone adduct 141181. Johnson and Schroeck188,189 succeeded in obtaining optically active styrene oxide by recrystallization of the condensation product of (+ )-(S)-n-butyl methyl sulfoxide 143 with benzaldehyde. 

The reaction of chiral sulfones 161, derived from (lS)-( + )-10-camphorsulfonyl chloride, with cyclopentadiene gives predominantly the endo adduct in a diastereomeric ratio of 91 9 from which one diastereomer 162 can be isolated in pure form by recrystallization (equation 115)109. 

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. 

The isolation of 73 was then fully optimized. Upon completion of the etherification reaction, the insoluble trichloroacetamide 68 was filtered, leaving a 17 1 mixture of 18 and 19 as a DCE/heptane solution, together with starting material 10. The solvent was switched to MeOH and the esters were saponified with KOH. The carboxylic acid was isolated after neutralization and the addition of NEt3 which gave the highly crystalline triethylamine solvate 73 as a 40 1 mixture of diastere-omers. Recrystallization from MTBE/heptane gave a 109 1 diastereomeric mixture of 73 in 54% overall yield from 10. This final process was successfully implemented in the pilot plant without incident. 

Other methylphenyl(2-phenylpropyl)stannyl-transition metal complexes are oily compounds 18). Fractional recrystallization could therefore not be applied to separate those diastereomers. For the irondicarbonylcyelopentadienyl compound (77), the diastereomeric ratio (77)A/(77)B = 45/55 could be reached by the standard route (see Fig. 9) but could not be modified by column chromatography. 

Reaction of 3-ketoester 2-97 and acrolein 2-98 in presence of stoichiometric amounts of 2-103 led to the desired product 2-100 in 45 % yield. A transition-state model 2-99 may be postulated assuming an ion-pairing mechanism as reported for similar asymmetric transformations [37]. The diastereomeric mixture of 2-100 was transformed into 2-101 by mesylation and subsequent elimination. Despite the moderate 64% ee determined for 2-101, it was possible to obtain optically pure 2-101 by recrystallization from hexane. 

Diastereomerically pure (2W,5.V)-l,3-diaza-2-(2-methylphenyl)-3-phenyl-2-phosphabicyclo[3.3.0]octane (.S )-202] was formed in the thermal reaction of (S)-2-(anilinomethyl)pyrrolidines (197a) with o-TolP(NMe2)2 and isolated in 27% yield after recrystallization (Scheme 56) [87], Its cyclopalladation with palladium diacetate followed by anion metathesis gave dimer (5,5)-203 (Scheme 56) [87],... 

A useful method for large-scale synthesis of diastereomerically pure (2R,5S)-3 -phenyl-2-(8-quinolinoxy)-1,3-diaza-2-phosphabicyclo[3.3.0]octane (205) was based on a similar reaction of tris(dimethylamino)phosphine with (5)-197a generating the intermediate 204 which, by addition of 8-hydoxyquinoline followed by additional refluxing gave the final product. Recrystallization of the crude reaction mixture afforded diastereomerically pure 205 as a solid, stable to air and moisture in 98% yield (Scheme 57) [88], It was converted to complex 206 by mixing with... 

Chiral sulfonium ylides have been known for some 30 years, and their stereochemistry and properties have been studied.15 Optically active selenonium ylides were obtained by reacting selenoxides with 1,3-cyclohexanedione under asymmetric conditions by Sakaki and Oae in 1976 for the first time,16 and also optically resolved by fractional recrystallization of the diastereomeric mixtures in the early 1990s.17 In 1995, optically active selenonium ylides 6 were obtained in over 99% de by nucleophilic substitution of optically active chloroselenurane or selenoxide with active methylene compounds with retention of configuration.18 The absolute configurations were determined by X-ray analysis of one... 

Optically active telluronium ylides were not obtained for a long time. Optically active diastereomeric telluronium ylides 7 were obtained for the first time in 1995 by fractional recrystallization of the diastereomeric mixture.19 The absolute configurations of the chiral telluronium ylides were determined by comparing their specific rotations and circular dichroism spectra with those of the corresponding selenonium ylide with known absolute configuration. The telluronium ylides were found to be much more stable toward racemization than the sulfonium and selenonium ylides (Scheme 4). 

In summary, boryl enolate 38 can be obtained via in situ O-borylation of N-propionylsultam 37 and converted to aldol product 40 upon treatment with aliphatic, aromatic, or a,/l-unsaturatcd aldehdyes at - 78°C in the presence of TiCU- As aldol product 40 can normally be obtained in crystalline form, in most cases diastereomerically pure anti- Ao 40 can also be obtained after the recrystallization. 

The procedure that Kuhn and Baschang99 had reported for the synthesis of NeuAc was extended by Hershberger and Binkley100 to a synthesis of KDO, as follows. Condensation of di-ter -butyl oxalacetate (85 see Scheme 25) with D-arabinose gave the epimeric mixture of lactone esters, 86 and 87, which was separated by fractional recrystallization. When 86 was heated in aqueous solution, the enol lactone, 88, was produced from 87, an enol lactone diastereomeric with 88 was obtained under these conditions. Compound 88 was converted into ammonium KDO by treatment with aqueous ammonia. 

In principle, separation of resonances of diastereomeric compounds (such as dl and meso isomers) may be increased simply through use of an appropriate achiral solvent. Chiral solvents may in some cases be especially effective in producing a separation, particularly if the diastereomers differ in configuration about a center that is amenable to analysis by the CSA method. Kaehler and Rehse (89) give a detailed account of conditions necessary for measurement of the ratio of meso- and dZ-tartaric acid employing A,N-dimethyl PEA. Bomyl acetate used as solvent for l,2-difluoro-l,2-dichloroethane (90) allows measurement of the diastereomeric composition. Paquette and co-workers (91,92), using TFAE, were able to determine the diastereomeric purity of the recrystallized adducts 47 of... 

Isolated yield of pure product after recrystallization or flash chromatography Diastereomeric ratio 1.1 1... 

SimplePHOX 7a proved a useful tool to force the diastereomeric reduction of olefin 31a to pseudopteroxazole precursor 31b in perfect diastereoselectivity and 90% yield with only trace amounts of over-reduced product. NeoPHOX catalyst from ligand 14b, a closely related system to 7a, furnished product 32b in 93% ee, which was then easily recrystallized to enantiopure material with 58% recovery. The R enantiomer of 33b was synthesized by the use of catalyst from ligand 8a in 90% ee and 98% yield with the fully aromatized naphthalene as 2% byproduct. A higher catalyst loading of 2 mol% of catalyst from 7a was used to produce the... 

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