ABSTRACT
An efficient enantioselective synthesis of the chiral polycyclic cholesteryl ester transfer protein (CETP) inhibitor 1 has been developed. The synthesis was rendered practical for large scale via the development of a modified Hantzsch-type reaction to prepare the sterically hindered pyridine ring, enantioselective hydrogenation of hindered ketone 6 utilizing novel BIBOP-amino-pyridine derived Ru complex, efficient ICl promoted lactone formation, and a BF3 mediated hydrogenation process for diastereoselective lactol reduction. This efficient route was successfully scaled to produce multikilogram quantities of challenging CETP drug candidate 1.
Subject(s)
Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Pyridines/chemical synthesis , Pyridines/pharmacology , Crystallography, X-Ray , Hydrogenation , Molecular Conformation , Molecular Structure , Pyridines/chemistry , StereoisomerismABSTRACT
For several decades, enamines and related compounds have been used as intermediates in organic synthesis and many methods are known for their preparation. Most of the synthetic protocols, however, require harsh reaction conditions. Recently, a new approach has emerged, inspired by the analogous arylation of amines catalysed by palladium or copper complexes (Buchwald-Hartwig reaction). Simultaneous and independent work from several research groups has led to the development of very powerful protocols for the preparation of enamines and their derivatives that require only readily available starting materials and proceed under very mild reaction conditions. Noteworthy is the fact that in less than five years an almost unknown reaction has reached such a high level of scope and generality that it is now very frequently applied in total syntheses of natural products.
Subject(s)
Alcohols/chemistry , Amides/chemical synthesis , Amines/chemical synthesis , Copper/chemistry , Ethers/chemistry , Palladium/chemistry , Vinyl Compounds/chemistry , Amides/chemistry , Amines/chemistry , Molecular StructureABSTRACT
New previously unavailable N-vinyl sulfoximines have been synthesized by intermolecular palladium-catalyzed coupling between sulfoximines and vinyl bromides in excellent yield. Hydrogenation of the vinyl moiety opens a novel way to alpha-branched N-alkyl sulfoximines.
Subject(s)
Palladium/chemistry , Sulfonamides/chemical synthesis , Vinyl Compounds/chemical synthesis , Bromides/chemistry , Catalysis , Molecular Structure , Stereoisomerism , Sulfonamides/chemistry , Vinyl Compounds/chemistryABSTRACT
Kinetic resolution of racemic mixtures is a well-established methodology for the preparation of optically active compounds. However, excellent enantioselectivities are required to obtain them in enantiopure form, due to the decrease in ee when conversion values are close to 50%. To overcome this limitation, a parallel (asymmetric) reaction can remove the disfavored enantiomer. In this review, several examples of this strategy showing its wide range of applicability are described, as well as their mathematical treatment and some new applications in combinatorial chemistry.
ABSTRACT
A series of fungi and yeasts have been tested for the stereoselective bioreduction of 2-oxocycloalkanecarbonitriles, 1. The yeast Saccharomyces montanus CBS 6772 yielded the corresponding cis-hydroxy nitriles, 2, in >90% ee and de and in high chemical yields. Through simple and efficient procedures, they were transformed into optically active 2-amino and 2-aminomethyl cycloalkanols.
ABSTRACT
Racemic 1-methyl-2-oxocycloalkanecarbonitriles have been subjected to bioreduction by the fungus Mortierella isabellina NRRL 1757 through a parallel kinetic-resolution process. The u and l alcohols thus obtained (up to >99% ee) were easily separated and oxidized to the R and S ketones, respectively. The process can be then repeated so that both enantiomers of the ketone and two epimers of the alcohol can be obtained in their enantiopure forms.