Crystallization acid monoesters

Application of Crystallization Technique for the Lipase-Catalyzed Solid-Phase Synthesis of Sugar Fatty Acid Monoesters... 

The early experimental efforts to separate enantiomeric forms of simple derivatives of phosphono-thioic or -selenoic acids concentrated on the fractional crystallization of quinine, brucine or strychnine salts of the acid monoesters 69 (Z = S or Se) the early work in this area has been summarized It was not long before this tedious procedure, which did not always provide the best results, was superseded by a modification devised by Boter and Platenberg which utlized enantiomers of 1-phenylethylamine. Essentially, (+)-l-phenylethylamine (0.5 mol) is added to the acid monoester in ether and the (+),(+)-salt is allowed to crystallize out, although this does not generally occur quantitatively. The excess... 

Succinic acid is absorbed from aqueous solutions by anion-exchange resins or active carbon (9—11). Succinic anhydride forms rhombic pyramidal or bipyramidal crystals. It is relatively insoluble in ether, but soluble in boiling chloroform and ethyl acetate. Succinic anhydride reacts with water and alcohols, giving the acid and monoesters, respectively. 

The procedure described here for compound 1 is a scaleup of a published method.6 Phase-transfer catalysis7 and concentrated alkali are used to effect a one-pot conversion of diethyl malonate to the cyclopropane diacid, which is easily obtained by crystallization. Apparently alkylation of the malonate system occurs either at the diester or monocarboxylate, monoester stage since the method fails when malonic acid itself is used as the starting material. This method of synthesizing doubly activated cyclopropanes has been extended to the preparation of 1-cyanocyclopropanecar-boxylic acid (86%) by the use of ethyl cyanoacetate and 1-acetyl-cyclopropanecarboxylic acid (69%) by use of ethyl acetoacetate.6... 

Simple alcohols with only one hydroxy function and one asymmetric carbon atom are classical chiral chemicals. While they are often commercially available, they are relatively expensive. Until recently, they were obtained mainly by resolution of the racemates using a reliable but not very convenient technique. Reaction of the racemic alcohol with phthalic acid anhydride gave the monoester of phthalic acid, which was resolved by salt formation with a chiral base, usually brucine, or occasionally also strychnine or cinchonidine. The methyl carbinols from 2-butanol 1 to 2-tridecanol were first obtained by this method1,2 and this was later extended to 3,3-dimethyl-2-butanol3. When crystallization of the diastereomeric salts was performed in the presence of triethylamine, some other methyl carbinols could also be resolved, such as... 

Sorbitan is derived from sorbitol by dehydration and then esterified with fatty acids as described for PGME. Depending on the amount of fatty acids used for esterification the equilibrium reaction mixture may contain primarily sorbitan monoesters or triesters. Sorbitan esters of palmitic or stearic acid crystallize from melt in a stable a-like crystal form. 

The diol 4 had never been described in the literature before we used it in the synthesis of 1. Initially, we tried to synthesize it using an enantioselective Diels-Alder reaction between a chiral fumarate equivalent 5 (Scheme 10.1) and butadiene 6, followed by double-bond dihydroxylation [41]. However, a more effective protocol for large-scale synthesis could finally be based on the procedure shown in Scheme 10.2, leading to enantiomericaUy pure (lS,2S)-cyclohex-4-ene-1,2-dicarboxylic acid 7 [42]. Here, a Bolm desymmetrization of tetrahydrophthahc anhydride 8 using quinine leads to monoester 9 in 89% ee. The monoester 9, in turn, can be epimerized to the trans isomer 10 which is hydrolyzed to obtain 7, after crystallization. This intermediate is the starting material for the synthesis of 4 and of other conformationally constrained DCCHD to be used as monosaccharide mimics [43, 44]. Our current best protocol for the large-scale synthesis of 7 is reported at the end of this chapter. 

EHsubstituted (—)-a-methyl-a-ethyl-]3-thiolactone (IX) was synthesized by Jerman and Fles [7 ] from (+)-methyl-ethylmalonic acid monoethyl ester (V), which was prepared by fractional crystallization of diastereomeric quinine salt for the (+)-antipode and cinchonidine salt for the (—)-antipode. Monoester (V) was converted to a-methyl-a-ethyl-/3-bromopropionic acid (VI) using essentially the method described by Sweeney and Casey [4] for the racemic compound. Optically active a-methyl-a-ethyl-j3-fiiiolactone (IX) was synthesized either via the dehydration of the /3-mercapto derivative (VII) or by debenzylation of the jS-benzyl-... 

Ye and Hayes have employed solvent-free media 10-100 jm-sized suspensions of saccharide (fructose, glucose, sucrose, or xylose) in crystalline form dispersed in mixtures of acyl donor (e.g., oleic, myristic, lauric, or caprylic acid) and the main reaction product, monoester, with the latter being present initially at 5-25 wt-% (depending on the nature of the acyl acceptor crystals) (Ye et al 2010 Ye and Hayes, 2011). The presence of monoester greatly increased the solubility of saccharide crystals in the solvent-free media. For instance, for the reaction between fructose and oleic acid, the maximum fructose concentration increased from 0.7 wt-% up to 2.5 wt-% as the ester concentration increased from 5 wt-% (initially) to 93 wt-% (Ye and Hayes, 2011). 

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