Chiral intermediate for

By the radical pathway l, -diesters, -diketones, -dienes or -dihalides, chiral intermediates for synthesis, pheromones and unusual hydrocarbons or fatty acids are accessible in one to few steps. The addition of the intermediate radicals to double bonds affords additive dimers, whereby four units can be coupled in one step. By way of intramolecular addition unsaturated carboxyhc acids can be converted into five raembered hetero- or carbocyclic compounds. These radical reactions are attractive for synthesis because they can tolerate polar functional groups without protection. 

Takasago International Co. commercialized this hydrogenation method for the production of a chiral intermediate for the synthesis of carbapenem antibiotics (Equation (8)).29... 

A furanose-fused c/.,(3-unsaturated 8-lactone was also prepared from ester 11 as a key chiral intermediate for the synthesis of the enantiomer of (+ )altholactone, a natural product with cytotoxic and antitumor activities.18 A Reformatsky reaction with ethylbromoacetate or a Wittig... 

Although the hydrolysis of esters with lipases and esterases represents the most common process to obtain chiral intermediates for the synthesis of pharmaceuticals, proteases and other hydrolytic enzymes such as epoxide hydrolases and nitrilases have also been used for this purpose. We show here a few representative examples of the action of these biocatalysts that have been recently published. 

Roper H (1991) Selective oxidations of D-glucose chiral intermediates for industrial utilization. In Lichtenthaler FW (ed) Carbohydrates as organic raw materials. VCH Verlagsgesellschaf, Weinheim... 

Polymers derived from natural sources such as proteins, DNA, and polyhy-droxyalkanoates are optically pure, making the biocatalysts responsible for their synthesis highly appealing for the preparation of chiral synthetic polymers. In recent years, enzymes have been explored successfully as catalysts for the preparation of polymers from natural or synthetic monomers. Moreover, the extraordinary enantioselectivity of lipases is exploited on an industrial scale for kinetic resolutions of secondary alcohols and amines, affording chiral intermediates for the pharmaceutical and agrochemical industry. It is therefore not surprising that more recent research has focused on the use of lipases for synthesis of chiral polymers from racemic monomers. 

This unnatural acid is used as a chiral intermediate for the synthesis of a number of products. Chemical asymmetric synthesis was very difficult and so the stereoselective synthetic properties of enzymes were exploited to carry out a selective reduction reaction. The stereoselective hydrolysis of protein amino acid esters had already been commercialised by Tanabe in Japan using immobilised aminoacylase, and selective reduction reactions using whole yeast cells are already used in a number of processes, such as the selective reduction of the anti-cancer drag Coriolin. 

The Nntrasweet Corp. are now selhng L-phenylalanine, rather than just using it in-honse. They quote its potential as a chiral intermediate for the production of reimin inhibitors, HIV protease inhibitors, taxol and other pharmaceuticals. 

To overcome problems of poor acceptor substrate acceptance, high concentrations of aldehyde substrates are required to obtain synthetically useful product yields. Unfortunately, DERA shows rather poor resistance to such high aldehyde concentrations, especially toward CIAA, resulting in rapid, irreversible inactivation of the enzyme. Therefore, the organic synthesis of (3R,5S)-6-chloro-2,4,6-trideoxy-hexapyranoside 1 requires very high amounts of DERA. Thus, despite the synthetic usefulness of DERA to produce chiral intermediates for statin side chains, the large-scale application is seriously hampered by its poor stability at industrially relevant aldehyde concentrations. The production capacity for such 2,4,6-trideoxy-hexoses of wild-type E. coli DERA is rather low [15]. 

Application of Carbonyl Reductases to the Production of Chiral Intermediates for D-Pantothenate Synthesis... 

During the course of studies on the microbial production of chiral intermediates for D-pantothenic acid [2,134,135], Shimizu and co-workers found that several micro-organisms, such as Fusarium, Brevibacterium and so on, produce a novel enzyme that catalyzes the hydrolysis of aldonate lactones or aromatic lactones [136, 137],... 

NCIMB 9872, overexpressed in E. coli, as a whole cell biotransformation [167], The substrate, an oxabicycloketone, was successfully converted to the corresponding heterobicyclic lactone (Fig. 28) in 70% yield with an enantiomeric excess of 95%. This access to the chiral intermediate for several naturally occurring compounds, including (+)-frans-kumausyne and (+)-showdomycin, represents the first application of a whole cell biotransformation using recombinant E. coli with CPMO in natural product synthesis. 

Patel RN (2006) Biocatalysis synthesis of chiral intermediates for pharmaceuticals. Curr OrgChem 10 1289-1321... 

Patel RN (2001) Enzymatic synthesis of chiral intermediates for omapatrilat, an antihypertensive drug. Biomol Eng 17 167-182... 

A very recent example, which clearly shows the power and benefit of biocatalysis, is the synthesis of a chiral intermediate for the production of cholesterol-low-... 

Biocatalytic Syntheses of Chiral Intermediates for Antihypertensive Drugs... 

The S -(-)-a-[(acetylthio)methyl]phenylpropionic acid (21) is a key chiral intermediate for the neutral endopeptidase inhibitor (22) [48], We [44] have demonstrated the lipase-catalyzed stereoselective hydrolysis of thioester bond of racemic a-[(acetylthio)methyl]phenylpropionic acid (21) in organic solvent to yield A-(+)-a-[(mercapto)methyl]phenylpropionic acid (23) and Y-(-)-(21). Using lipase PS-30, the Y-(-)-(21) was obtained in 40% reaction yield (theoretical max. 50%) and 98% e.e. (Fig. 9). 

The 5 -(-)-2-cyclohexy 1-1,3-propanediol monoacetate (24) and the S-( )-2-phenyl-1,3-propanediol monoacetate (25) are key chiral intermediates for the chemoenzymatic synthesis of Monopril (26) (Fig. 10), a new antihypertensive drug which acts as an ACE inhibitor. The asymmetric hydrolysis of 2-cyclohexyl-1,3-propanediol diacetate (27) and 2-phenyl-1,3-propanediol diacetate (28) to the corresponding S-( - )-monoacetate (24) and S-( )-monoacetate (25) by porcine pancreatic lipase (PPL) and Chromobacterium viscosum lipase have been demon-... 

RN Patel, A Banerjee, L Chu, D Brzozowski, V Nanduri, LJ Szarka. Microbial synthesis of chiral intermediates for (3-3-receptor agonists. J Am Oil Chem Soc 75 1473-1488, 1998. 

Several new ligands that possess chirality at the phosphorus center have been developed and shown to be excellent catalysts for the asymmetric reduction of enamides to amino acids and chiral amines and P-enamides to P-amino esters. One ligand that shows great promise to be used at the manufacture scale is Trichickenfootphos, which has demonstrated high activity and enantioselectivity in the production of a chiral intermediate for Pregabalin. 

In the references cited earlier, numerous studies on the substrate specificities can be found for both (R)- and (S)-HNLs along with different processing conditions, which make these versatile enzymes amenable to preparing chiral intermediates for a wide variety of uses. 

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