Prochiral precursors

The strategy of the catalyst development was to use a rhodium complex similar to those of the Wilkinson hydrogenation but containing bulky chiral ligands in an attempt to direct the stereochemistry of the catalytic reaction to favor the desired L isomer of the product (17). Active and stereoselective catalysts have been found and used in commercial practice, although there is now a more economical route to L-dopa than through hydrogenation of the prochiral precursor. 

Fig. 4. Schematic representation of energy profiles for the pathways for the hydrogenation of a prochiral precursor to make L-dopa (19). The chiral...

Amino acid separations represent another specific application of the technology. Amino acids are important synthesis precursors - in particular for pharmaceuticals -such as, for example, D-phenylglycine or D-parahydroxyphenylglycine in the preparation of semisynthetic penicillins. They are also used for other chiral fine chemicals and for incorporation into modified biologically active peptides. Since the unnatural amino acids cannot be obtained by fermentation or from natural sources, they must be prepared by conventional synthesis followed by racemate resolution, by asymmetric synthesis, or by biotransformation of chiral or prochiral precursors. Thus, amino acids represent an important class of compounds that can benefit from more efficient separations technology. 

Asymmetric synthesis [2] [3], which involves the conversion of prochiral precursors into homochiral compounds, can be attained by means of ... 

Nevertheless, all these syntheses remain less important since they use expensive chiral or prochiral precursors that lead to costly p-BL, leading to high price PHB that cannot compete with poly(olefin) prices. 

Other similar lipase/esterase resolution processes have been developed such as the use of Bacillus that esterase to produce the substituted propanoic acids that are precursors of non-steroidal anti-inflammatory drags, snch as naproxen and ibuprofen etc., and the formation of chiral amines by Celgene. Other methods start from prochiral precursors and have the advantage that enantioselective synthesis allows the production of particular isomers in yields approaching 100%, rather than the 50% yields characteristic of resolution processes. For instance Hoechst have patented the production of enantiomers using Pseudomonas fluorescens lipase to either acylate diols or hydrolyse diacetate esters. 

Direct synthesis of atropisomeric benzamides and anilides from prochiral precursors has been reported using chiral-amide-mediated deprotonation of 2,6-dimethyl-substituted ben-zamide and anilide chromium complexes. A screening of amides revealed that (R,R) 3 was the most selective in the deprotonation of the benzylic methyl groups (Scheme 51)92 94. 

Enzymatic reduction, oxidation, ligase, or lyase reactions, especially, provide us with numerous examples in which prochiral precursor molecules are stereo-selectively functionalized. Ajinomoto s S-tyrosinase-catalyzed L-dopa process [112], the formation of L-camitine from butyro- or crotonobetaine invented by Lonza [113], and the IBIS naproxen route oxidizing an isopropylnaphthalene to an (S)-2-arylpropionic acid are representative, classic examples for many successful applications of enzymatic asymmetric synthesis on an industrial scale. A selection of recent industrial contributions in this field are summarized below. 

The accessibility of prochiral precursors is a key factor to a successful hydrogenation process from a practical point. There are several common and efficient methods for the formation of various enamides. An example is the preparation of N acyl a arylenamides as illustrated in Scheme 9.2. 

The demand to produce enantiomerically pure pharmaceuticals, agrochemicals, flavors, and other fine chemicals from prochiral precursors has advanced the field of catalytic asymmetric hydrogenation.1 In 2002 worldwide sales of single enantiomer pharmaceutical products approached 160 billion.2... 

Oxygen nucleophiles have not frequently been used as terminators in cascade car-bometallation reactions. The intramolecular carbopalladation starting with an iodo- or trifluoromethylsulfonyloxyalkenyl-substituted derivative in the presence of tetrabutylam-monium acetate led to a suitable precursor of the sesquiterpene (-)-A (i )-capneUene. In this case, desymmetrization of the prochiral precursor was achieved using (5)-BINAP as the ligand on the palladium catalyst (Scheme 32). ... 

Li WS, Li Y, Hill CM, Lum KT, Raushel EM (2002) Enzymatic synthesis of chiral organophosphothioates from prochiral precursors. J Am Chem Soc 124 3498-3499... 

The monoacetate phosphine oxide 158 was isolated in 92% yield and 72% ee. The absolute configuration was shown to be R by chemical correlation after preparing the known phosphine oxide 159. As in the previously described kinetic resolutions of phosphoryl derivatives, the sense of the chiral induction can be explained by the Jones model of the PLE active site. In the same report the enzyme-catalysed preparation of P-stereogenic phosphine oxide 156 from prochiral precursors was described (Scheme 6.62). 

In an idealistic sense, a chemical approach which uses a small amount of a chiral catalyst to produce either enantiomer, cleanly and efficiently from a prochiral precursor, is the preferred method. For such asymmetric catalysis the efficiency of chiral multiplication can be infinite. The use of chiral metal complexes as homogeneous catalysts has become one of the most powerful economically and environmentally sound strategies for the preparation of enantiopure compounds. An excellent comprehensive review of asymmetric catalysis in organic synthesis has recently been published by Noyori [30]. 

Chiral or asymmetric synthesis generates a single enantiomer from a prochiral precursor by using some chiral influence. This chiral influence is often added to the prochiral system first (chiral auxiliary) or it may already be present within the prochiral precursor as another chiral centre. The advantage of chiral synthesis is that like resolution it provides better, more suitable chiral materials but in addition the process is not wasteful because all of the material is converted into the desired single enantiomer (ideally). 

It is generally accepted that one of the remaining challenges in organic chemistry is to induce efficient asymmetric synthesis on a prochiral precursor, much as the enzyme does. One way to get around this problem is to use a chiral reagent that would produce diastereotopic interactions with a reactant molecule and lead to an asymmetric product. 

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