Enantioselectivity chlorohydrin synthesis

The studies described in the last section provided the background for the development of a new asymmetric chlorohydrin synthesis. If the neutral ligand that encourages chlorohy-drin formation is made chiral, there is the possibility of forming chiral chlorohydrins. First, pyridine was replaced with chiral monodentate ligands such as (5)-(-)-Af, Af-dimethyl-l-phenethylamine.f f Scheme 23 shows the general reaction sequence. As might be expected the enantioselectivities were low 10-15% for propene. The Wacker oxidation product, acetone, was a side product in the reaction. 

These observations resulted in the development of a new asymmetric chlorohydrin synthesis. Mono- and bimetallic Pd(ll) catalysts containing bidentate chiral ligands gave good to excellent enantioselectivities. 

The asymmetric deprotonation of l-(benzothiazol-2-yl)-l-chloroethane followed by carbonyl addition served as a tool for the enantioselective synthesis of chlorohydrins and... 

Hydrodehalogenation. A synthesis of chiral epoxides from trichloromethyl ketones is through enantioselective reduction to the trichloromethyl carbinols and tinhydride-mediated conversion to the chlorohydrins before base treatment to close the three-membered ring. Dehalogenation of halocarboxylic acids in water is apparently a method that deserves wide application. 

Umani-Ronchi adapted the Furstner protocol to achieve the first catalytic, enantioselective variant of this reaction. The chiral chromium salen complex was prepared from the in situ reduction of the anhydrous CrCb to CrCl2 with an excess of manganese metal, followed by complexation with the salen ligand 8 in the presence of catalytic triethylamine." Then the addition of allylic chloride (9) to aldehydes 10 to give the allylic alcohols 11 in moderate yields and in up to 95% ee. The same groups employed the same conditions for the addition of 2-butenyl bromides to aldehydes to achieve up to 83 17 syn/anti of allylic alcohol products and for the addition of 1,3-dichloropropene to aromatic aldehydes to obtain the syn chlorohydrin adduct in modest yield which were further converted to optically active vinyl epoxides. The [Cr(salen)]-catalyzed addition of propargyl halides to aromatic aldehydes allowed the synthesis of enantiomerically enriched homopropargyl alcohols in moderate yields with up to 56% ee. ... 

Evans aldol reaction between the functionalized 4-phenyl-oxazohdinone 6 and 5-chloropentanal 7, securing the 1,2-syn stereochemistry " in the resultant chlorohydrin 9. The diastereoselectivity of this process is governed by the preferential formation of a (Z)-enolate and dipole minimization in the Zimmerman-Traxler transition state 8. Conversion of the aldol adduct into the corresponding mesylate was followed by reductive removal of the auxiliary to provide the hydroxymesylate 10, an advanced intermediate in the enantioselective synthesis of (-l-)-methylphenidate hydrochloride 11. The active pharmaceutical ingredient was produced in >99% ee after lecrystaUization. 

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