Silaborative carbocyclization of 1,6-enynes catalyzed by Pd-PEPPSI-IPr {PEPPSI = pyridine-enhanced precatalyst preparation stabilization and initiation; IPr = N,N-bisA C H T U N G T R E N N U N G [2,6-(diisopropyl)phenyl]imidazolium} employing either (dimethylphenylsilyl)pinacolborane or (chlorodimethylsilyl)pinacolborane provides access to densely functionalized five-membered rings as single diastereomers in excellent yields. The vinylboronate functions were employed in palladium-catalyzed Suzuki cross-coupling reactions with a range of aryl bromides, containing electron-withdrawing as well as electron-donating substituents, furnishing arylated exo-methylenecyclopentanes or exo-methylenepyrrolidines in good yields. Subsequent oxidation of the isopropoxydimethylsilyl function generated via addition of (chlorodimethylsilyl)-pinacolborane provided access to hydroxymethyl derivatives of the arylated compounds. Use of a chiral ester, bismenthyl (2-propenyl)(2-propynyl)malonate, afforded two diastereomeric products which could be separated, thereby giving access to the cyclized compounds as single isomers, with opposite absolute configurations at the newly formed stereocenter.

This work reports the possibility of controlling the sense of enantio-and diastereoinductions in the sequential hydroformylation and aldol reactions via the judicious combination of a chiral metal catalyst with a chiral organocatalyst. The diastereoselectivity of the reaction between styrene, syngas and acetone can be increased by using a matched pair of catalysts, [rhodium/A C H T U N G T R E N N U N G (2S,4S)-Chiraphite]/(S)-organocatalyst and decreased, but not inverted, by using a mismatched pair of catalysts,Keywords: aldol reaction; asymmetric catalysis; hydroformylation; organocatalysis; tandem reactions In order to achieve the highest possible efficiency in enantioselective chemical transformations, the number of steps must be kept to a minimum and the yield, regio-, enantio-and diastereoselectivities of each step should approach 100%. To meet this enormous challenge, several reactions can be combined in tandem reaction sequences.[1] Moreover, multiple chiral catalysts operating simultaneously could circumvent the time and yield losses associated with the isolation and purification of stereoisomers in multistep sequences.In contrast to the major progress made in asymmetric multicatalysis using multimetallic, [2] multiorganocatalytic [3] or metal-enzyme systems, [4] very few reports exist on the combination of metal with organocatalysts to accomplish an asymmetric reaction.[5] Recently, achiral metal catalyst/chiral organocatalyst [6] and chiral metal catalyst/achiral organocatalyst catalytic systems have been reported. [7] However, a methodology where the absolute configuration of one stereogenic center in the product is controlled by a chiral metal-ligand complex and the configuration of another stereogenic center is controlled by a chiral organocatalyst has not been very successful so far.[6g] Considering the multitude of enantioselective reactions catalyzed by either metal catalysts (reductions, oxidations, s-bond insertions, p-bond activation, Lewis acid reactions) [8] or organocatalysts (enamine, iminium, hydrogen-bonding, SOMO, counter ion catalysis) [9] we envision a tremendous potential for the creation of unique multicatalytic systems to influence chirality in reaction products.In this report we present the combination of a chiral rhodium catalyst with a chiral organocatalyst in an enantioselective sequential hydroformylation followed by an aldol reaction (Scheme 1).The sequential conversion of styrene with syngas and acetone to aldol product 3 was chosen as a model reaction. We presumed that exposure of styrene to a chiral Rh catalyst under hydroformylation conditions would generate an enantioenriched aldehyde 2, which can be intercepted in the second catalytic cycle by the chiral enamine derived from acetone and (S)-proline. We envisioned that control of the sense of enantioand diastereoinductions (e.g., S vs. R, anti vs. syn) could be achieved via judicious selection of the chiral catalysts involved in each catalytic cycle. The synthetic plan relied on finding optimal conditions for ...

No abstract

This work reports the feasibility of recently developed industrial viable process for eltrombopag olamine starting from 2-bromo-6-nitro phenol and reports the identification of four potential impurities related to eltrombopag olamine, namely eltrombopag olamine ester (1), 2-aminophenol analogue of eltrombopag (2), 3,3′-(2-amino-3-oxo-3H-phenoxazine-4,6-diyl dibenzoic acid (3), 2′-hydroxy[1,1- biphenyl]-3-carboxylic acid (4). These impurities are the crucial components in determining the quality of the drug substance, eltrombopag olamine during its manufacturing. These impurities have impact on the quality of eltrombopag olamine and controlled these impurities results excellent yields of active pharma ingredient of eltrombopag olamine