Zhengxu Han

RCM macrocyclization made practical: an efficient synthesis of HCV protease inhibitor BILN 2061.

We report here that dramatic improvement of the key RCM reaction in the synthesis of HCV protease inhibitor BILN2061 can be achieved by N-substitution of the diene substrate with an electron-withdrawing group. Mechanistic studies using 1H NMR spectroscopy showed an unprecedented switch of the initiation sites and the correlation between such switch and the results of RCM, from the unmodified to the modified substrates. We also provided theoretical evidence that such modification may also increase the thermodynamic preference of the macrocyclic product over the diene substrate.

Rapid access to enantiopure bupropion and its major metabolite by stereospecific nucleophilic substitution on an α-ketotriflate

Abstract A stereospecific method for the synthesis of enantiopure α-aminoketone from its corresponding α-hydroxy-ketone via the triflate intermediate is discussed. This strategy provides a rapid and efficient route for the preparation of either enantiomer of bupropion and its biologically active hydroxylated metabolite.

Asymmetric synthesis of cetirizine dihydrochloride

Abstract Practical route technology for the preparation of ( S )-cetirizine·2HCl via diastereoselective organometallic addition to N - tert -butanesulfinyl aldimines is disclosed.

Effective tuning of the arene and alkanesulfinamides for highly enantioselective synthesis of (S)-4-chlorophenylphenylmethylamine, a key intermediate for antihistamic (S)-cetirizine

High diastereoselectivity (>94%) has been achieved in the phenylMgBr addition process to chlorophenyl aldimine derived from the new and sterically hindered triisopropylbenzene sulfinamide (TIPBSA) in the synthesis of a key intermediate of (S)-Cetirizine. Surprisingly, under the same reaction conditions, toluenesulfinamide derived chlorophenyl aldimine provided only 10% ee.

Practical chemical and enzymatic technologies for (S)-1,4-benzodioxan-2-carboxypiperizine intermediate in the synthesis of (S)-doxazosin mesylate

Abstract ( S )-1,4-Benzodioxan-2-carboxypiperazine ( S )- 2 , the key chiral intermediate for the synthesis of ( S )-doxazosin, was prepared utilizing two approaches: (i) enzymatic resolution of ethyl 1,4-benzodioxan-2-carboxylate with an esterase ( Serratia ) followed by amide formation; (ii) direct resolution of 1,4-benzodioxan-2-carboxypiperazine 2 with d -tartaric acid. An efficient process for the conversion of ( S )- 2 to ( S )-doxazosin mesylate was developed (80% yield, 99.9% e.e.).

First preparation of enantiomerically pure sibutramine and its major metabolite, and determination of their absolute configuration by single crystal X-ray analysis

Abstract Racemic sibutramine was resolved with dibenzoyl- d -tartaric acid, and the absolute stereochemistry of sibutramine was determined by single crystal X-ray crystallography of its dibenzoyl d -tartrate. The major active metabolite (desmethylsibutramine) was obtained by demethylation of sibutramine with DEAD. Enantiomeric purity of sibutramine was determined by HPLC on an Ultron ES-OVM column.

First asymmetric synthesis of (R)-desmethylsibutramine ☆

Abstract A catalytic enantioselective addition of iBuLi to aldimine 3 derived from methyl amine and 1-(4-chlorophenyl) cyclobutanecarboxaldehyde is used as the key step in the asymmetric synthesis of (R)-desmethylsibutramine, a single enantiomer version of a pharmacologically active metabolite of anti-obesity drug sibutramine (Meridia®).

First practical synthesis of enantiomerically pure (R)- and (S)-desmethylsibutramine (DMS) and unambiguous determination of their absolute configuration by single-crystal X-ray analysis

A practical synthesis of enantiomerically pure (R)-desmethylsibutramine [(R)-DMS] and (S)-desmethylsibutramine [(S)-DMS] is outlined along with an improved synthesis of racemic desmethylsibutramine. This route was used for kilo-scale production of enantiomerically pure (R)- and (S)-DMS. Racemic desmethylsibutramine was resolved with either (R)- or (S)-mandelic acid, and the absolute stereochemistry of DMS was determined by single X-ray crystallography of its mandelate salt.

Synthesis of enantiomerically pure desmethylzopiclone and determination of its absolute configuration

Abstract Two synthetic methods have been established for the preparation of enantiomerically pure desmethylzopiclone, a metabolite of zopiclone. In Method A, (S)-desmethylzopiclone was prepared by demethylation of (S)-zopiclone with 1-chloroethyl chloroformate in high yield. Enantiomerically pure zopiclone (>99% ee) was obtained through a highly efficient resolution process in >36% overall yield. In Method B, racemic desmethylzopiclone was resolved with l -N-benzyloxycarbonyl phenylalanine ( l -ZPA) followed by recrystallization in good yield. The absolute stereochemistry of the (+)-enantiomer was first determined to be the (S)-configuration by X-ray crystallography.