Chlorohydrin, diastereoselective

Chiral halohydrins epoxides.1 The esters (2) of the chiral alcohol 1 derived from camphor-10-sulfonic acid, are converted to a-chloro esters (3) by O-silylation and reaction with NCS with high diastereoselectivity. Reduction of 3 with Ca(BH4)2 results in the recovered auxiliary and the chlorohydrin 4 with clean retention. Cyclization of 4 to the terminal epoxide 5 proceeds with clean inversion. 

Addition of several lithium ester enolates to chiral 1-aminoalkyl choromethyl ketones gave the corresponding chlorohydrins which, when the solvent was completely evaporated to dryness at room temperature, underwent an intramolecular heterocyclization affording 3-hydroxyazetidinium salts 5 <02OL1299>. Azetidinium salts 5 were isolated in enantiomerically pure form, and with total or high diastereoselectivity. The degree of stereoselectivity was only moderately affected by the size of R1 in the a-amino-ketone and the substituents in the ester enolate. 

The earliest general method for the reductive deoxygenation of oxiranes to alkenes involved multistep procedures in which halohydrins were intermediates. Comforth, for example, used an oxirane deoxygenation in an early synthesis of squalene (Scheme 11). Diastereoselective double addition of ho-mogeranyllithium (23) to the dichloro diketone (24) gave the bis(chlorohydrin) (25), which was first converted to the diepoxide (26). Subsequent treatment with Nal and Zn in HOAc buffered with NaOAc gave squalene (27). 

Although chlorohydrins are obtained in good yield and with high diastereoselectivity by the reaction of the anion derived from 2-chloro-1,3-dithiane 1,3-dioxide with aromatic aldehydes, subsequent ring closure to the epoxide is prevented by a competing retro-aldol reaction <97JCS(P1)11>. 

Until the early 1990s, there was no practical use of the hydroxychlorination of alkenes. Recently, Dai and co-workers have enhanced the synthetic utility of this reaction by employing allylic amines and sulfides as the substrate. When a combination of DMF or THF with H2O is used as the solvent, the hydroxychlorination of these substrates proceeds smoothly and regioselectively to give chlorohydrins in high yields (Scheme 3). The product chlorohydrins serve as the precursors of epoxides. Unfortunately, with allyl amines bearing chiral moieties such as (/ )-phenethylamine, the diastereoselectivities of... 

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. 

---