Epoxides, hydrolysis crystallization

Davies and Reider (1996) have given some details of the HIV protease inhibitor CRDCIVAN (INDINAVIR) for which (lS,2R)-c -amino indanol is required. Indene is epoxidized enantioselectively, using the lacobsen strategy (SS-salen Mn catalyst, aqueous NaOH and PiNO), to (lS,2/ )-indene oxide in a two-phase system, in which the OH concentration is controlled. Indene oxide was subjected to the Ritter reaction with MeCN, in the presence of oleum, and subsequent hydrolysis and crystallization in the presence of tartaric acid gives the desired amino indanol. 

XLVII was speculated as being formed by the debromination of a 9epoxidation process, whereas the 21-cathylate XLVIII was believed to have arisen due to occlusion in the relatively insoluble crystals of desired epoxide (XLIV) formed during the hydrolysis of this 21-cathylate in methanol/tetrahydrofuran. 

The reaction mechanism catalysed by sEH has been recently elucidated from experiments using heavy isotopes, protein, mass spectrometry, site-directed mutagenesis, and has been supported by the recent crystal structure determination at 2.8-A resolution (Fig. 31.28). This two-step reaction mechanism involves a catalytic nucleophile (aspartic acid 333) which can attack the polarized epoxide ring by two tyrosyl residues (tyrosines 381 and 465) leading to the ring opening and the formation of an acyl-enzyme intermediate. The second step corresponds to hydrolysis of this intermediate by a water molecule activated by a histidine 523-aspartic acid 495 pair." ... 

The a-epoxide (XVI, 120 mg) is refluxed in acetic acid (20 ml) for 3.5 hr. The solution is diluted with water and extracted with ether. The product (methyl 3a,6 -diacetoxy-7a-hydroxy-5p-cholanate) is purified on a silica gel column and is eluted by 20 % ether in benzene. After hydrolysis by methanolic KOH (2%, 20 ml) at room temperature overnight, a-muricholic acid is obtained after acidification and extraction with ether. It forms crystals from an acetic acid solution after the addition of water. These crystals contain... 

TiCl4 in oxygen [11], hydrolysis of titanium alkoxides in different conditions [12], photo-assisted sol-gel method from titanium tetrabutoxide [13], hydrothermal oxidation of metallic titanium powder [14], hydrothermal hydrolysis of titanium tetraethoxide [15], oxysulfate [16,17] and tetrabutylammonium [18], solvothermal synthesis from titanium butoxide in 2-butanol [19], crystallization of amorphous Ti02 in hydrothermal condition [20], vapor hydrolysis of titanium tetraisopropox-ide [21], destabilization of titanium lactate [22], decomposition of titania-hydrate [23], epoxide sol-gel process to aerogel of Ti02 [24], hydrolysis of aqueous solution of TiCl4 in the presence of polyethyleneglycol [25], and so forth. 

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