Solubility, diastereomers

Arenesulfinate esters are usually prepared from an arenesulfinyl chloride and an alcohol in ether and pyridine. The arenesulfinyl chloride is usually prepared from the sodium arenesulfinate which is made by reduction of the arenesulfonyl chloride, preferably by aqueous sodium sulfite. After the crystalline sulfinate epimer has been removed by filtration, the equilibrium between the epimers remaining in the mother liquor may be reestablished by the addition of hydrogen chloride as shown by Herbrandson and Cusano . In this way the yield of the least soluble diastereomer may be increased beyond that which exists in the original reaction mixture (Scheme 1). Solladie prepared sulfinate ester 19 in 90% yield using this technique and published the details of his procedure. Estep and Tavares also published a convenient recipe for this method, although their yields were somewhat lower than Solladie s. 

Compound (+ )-(53) has been made from one of the diastereomers of the (—)-menthyl ester of 3-(p-anisylmethyl-l-naphthylstannyl)propionic acid, (54) ([a]p°° — 24) which could be obtained from the mixture of diastereomers because it is much less soluble in -pentane at low temperature than the other one. Their separation could be followed by NMR, both diastereomers differing by the position of their methoxy signal. The pure less soluble diastereomer (54) reacts with methylmagnesium iodide to give a tetraorganotin compound containing only one chiral center, the asymmetric tin atom 36> 87>. 

The less soluble diastereomer (S,S)-57 was obtained in >96% diastereomeric purity by six step-by-step crystallizations of this mixture from hexane or by three crystallizations, when a sample of (S,S)-57 was used as a crystallization seed (Scheme 20) <2003MC121, B-2003MI97>. 

Compound (6) contains 3 centers of dissymmetry, and its resolution into separated enantiomers could effected using ( )-mandelic acid [7]. The least soluble diastereomer was found to be the (-)-mandelate salt (m.p. 164.5-164.8°C). Formation of the hydrochloride salts of both enantiomers gave (-i-)-isoxsuprine HCl (m.p. 196-196°C) and (-)-isoxsuprine HCl (m.p. 195-196°C). The two asymmetric centers at C-1 and C-2 were correlated with those of the erythro (p-OH-C6H4-CH(OH)-CH(CH3)-NH-) residue. 

The practical difficulty with carrying out a crystalhzation DTR process is the need to operate under conditions that allow selective crystalhzation of the least soluble diastereomer while permitting the racemization to take place. Amine racemization catalysts, such as SCRAM , Shvo, Pd/C, and Adam s, are more active at higher temperatures, which runs counter to the conditions required for crystaUization. A solution to this problem is to separate the diastereomeric resolution and racemization steps but couple them with a flow engineering design. In this way each reaction can be operated under optimal conditions for example, temperature, concentration and solvent, via an intermediary solvent exchange unit Since the racemization catalyst itself may affect the crystalhzation (or indeed the crystalhzation may affect the catalyst), it is preferred to keep them separate. This can be achieved by having the catalyst or product either permanently or temporarily in a different phase by immobilization, extraction, precipitation, distil-... 

Table 36 Electronic and Optical Spectra of m-[Rh(en),XYj4 Complexes (Less Soluble Diastereomer)...

Sodium ethylphenylarsenide with carbon dioxide yields crystalline ethylphenylarsino-formic acid (52) after treatment with dilute sulphuric acid . The arsinoformic acid was resolved with (—)-quinine. The less-soluble diastereomer, after three recrystallizations from chloroform, was decomposed with dilute sulphuric acid into (— )-52, which required purification by extraction into benzene to separate it from arsine oxide (Table 2). 

Specific rotations [a] to nearest 0.1° measured at specified concentrations and temperatures ca 20°C). Reference 127 gives [a]o 45.7° (CHCI3) for the less soluble diastereomer of this compound. 

Filtrate B-1, containing the more-soluble diastereomer, is stirred at 60° and 5.0 g of NH4Br is added, whereupon crystallization of (-)s89-[Co(C204)(en)2]-Br H20 begins. After the NH4Br dissolves, the mixture is cooled in ice to 30° and then filtered. The red crystals are washed with 80% methanol, pure methanol, and diethyl ether and dried by suction on the filter. The yield (Aes2o = -1.99) is 8.4 g. The bromide salt is then stirred in 165 mL of water at 75° for about 10 minutes, allowed to cool in ice to 15°, and filtered and washed as before. The yield (Aejao = -2.61, [a]p = 820°)is 6.5 g or 71% of theoretical. 

We also felt that the relative solubilities of the diastereomeric amides (or their crystal lattice energies) might be related to the sense of steric bulk disymmetry about that central backbone. If one could perform a chemical reaction, such as addition to the double bond, that could alter the distribution of steric bulk, one could hope to invert diastereomer solubility. Addition of a symmetrical reagent, such as bromine, avoids positional isomerism and the stability of the bromonium ion ensures stereoselectivity. Thus each diastereomeric amide gave only one bromine adduct. The solubilities were indeed dramatically altered and, since bromine is easily removed (Zn, acetic acid) it became possible to use the amide mixture that had been recovered from purification to claim the more soluble diastereomer as its bromine adduct. A process was established to obtain both enantiomeric cyclohexene acids using only one chiral amine. 

Treatment of racemic methoxysilane 30 with (-)-menthol afforded a mixture of diastereomeric menthoxysilanes 31. Fractional crystallization from pentane gave the less soluble diastereomer ([a]D -53.9°) in 46% yield. Lithium aluminum hydride reduction led to (+)-l-naphthylphenylmethylsilane (4, [a]D +33.4°). The more soluble diastereomer similarly gave rise to (-)-l-NpPhMeSiH ([a]D -32.8°). The absolute configuration of (+)-l-NpPhMeSiH was shown to be R by X-ray diffraction studies (45). 

The theoretical and synthetic interest of difunctional organosilicon compounds prompted the resolution of several other compounds, shown in Figure 2. The configuration and properties in each case refer to the less soluble diastereomer. Chemical correlations were used to establish the relative configuration... 

The chlorosilane 50 undergoes rapid racemization, which is faster than alcoholysis. The menthoxysilane diastereomers 39 are obtained quantitatively in a ratio 1 2 close to that of the rate constants ky-.k. Fractional crystallization of the mixture of diastereomeric menthoxysilanes 39 allowed isolation of the less soluble diastereomer (-)-(-)-39 ([o]D -66.2°, m.p. 72°C) in almost 70% recovery. 

Attempts to resolve the racemic potassium salt by the usual method of the less soluble diastereomer formation were unsuccessful. In the following procedure, one enantiomer of the lithium salt of the complex is obtained in excess of 50% yield. 

The cyclosilane which was obtained from a Friedel-Crafts-type reaction was converted to the ( —)-menthoxy derivatives. After fractional crystallization, lithium aluminium hydride reduction of the less soluble diastereomer afforded the optically active R- -I- )-hydrosilane whose configuration was correlated to that of the fluoro derivative of S configuration as determined by X-ray diffraction20. 

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