Article

Chemoenzymatic synthesis of rivastigmine via dynamic kinetic resolution as a key step.

Department of Chemistry and Bionanotechnology Center, Pohang University of Science and Technology, San-31 Hyojadong, Pohang 790-784, Korea.
The Journal of Organic Chemistry (Impact Factor: 4.56). 03/2010; 75(9):3105-8. DOI: 10.1021/jo9027374
Source: PubMed

ABSTRACT A practical and efficient procedure for the synthesis of rivastigmine was developed. This procedure includes dynamic kinetic resolution using a polymer-bound ruthenium complex and a lipase in combination as a key step. Enantiopure (-)-rivastigmine was obtained from commercially available 3'-hydroxyacetophenone via five steps in overall 57% yield.

0 Bookmarks
 · 
290 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Secondary alcohols having bulky substituents on both sides of the hydroxy group are inherently poor substrates for most lipases. In view of this weakness, we redesigned a Burkholderia cepacia lipase to create a variant with improved enzymatic characteristics. The I287F/I290A double mutant showed a high conversion and a high E value (>200) for a poor substrate for which the wild-type enzyme showed a low conversion and a low E value (5). This enhancement of catalytic activity and enantioselectivity of the variant resulted from the cooperative action of two mutations: Phe287 contributed to both enhancement of the (R)-enantiomer reactivity and suppression of the (S)-enantiomer reactivity, while Ala290 created a space to facilitate the acylation of the (R)-enantiomer. The kinetic constants indicated that the mutations effectively altered the transition state. Substrate mapping analysis strongly suggested that the CH/π interaction partly enhanced the (R)-enantiomer reactivity, the estimated energy of the CH/π interaction being -0.4 kcal mol(-1). The substrate scope of the I287F/I290A double mutant was broad. This biocatalyst was useful for the dynamic kinetic resolution of a variety of bulky secondary alcohols for which the wild-type enzyme shows little or no activity.
    Organic & Biomolecular Chemistry 06/2012; 10(31):6299-308. · 3.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dynamic kinetic resolution of various homoallylic alcohols with the use of Candida antarctica lipase B and ruthenium catalyst 2 afforded homoallylic acetates in high yields and with high enantioselectivity. These enantiopure acetates were further transformed into homoallylic acrylates after hydrolysis of the ester function and subsequent DMAP-catalyzed esterification with acryloyl chloride. After ring-closing metathesis 5,6-dihydropyran-2-ones were obtained in good yields. Selective hydrogenation of the carboncarbon double bond afforded the corresponding δ-lactones without loss of chiral information.
    Chemistry - A European Journal 08/2013; · 5.93 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A highly efficient and convenient procedure for the enantioselective synthesis of (S)-Rivastigmine, a cho-linergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson’s disease, is accomplished by the treatment of versatile, readily accessible (S)-(-)-2-methyl- 2-propanesulfinamide with 3-hydroxyacetophenone. This protocol provides high yield and excellent enan-tiomeric excess in short step synthesis.
    International Journal of Organic Chemistry. 01/2011; 1:30-36.

Full-text (2 Sources)

Download
47 Downloads
Available from
May 17, 2014