Reductions ketoester

This synthesis of the pyrrole ring system, due to Knorr, consists in the condensation of an a-aminoketone with a 1,3-diketone or the ester of a p-keto-acid, a-Aminoketones are unstable in the free state, readily undergoing self-condensation consequently they must be prepared, by the reduction of an a-nitroso (or oximino) ketone, in the presence of the 1,3-diketone or p-ketoester, to ensure rapid interaction. 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

A limitation of this approach was the fact that the cyclization could not be accomplished on the resin. This would preclude further functionalization of the core. Therefore an alternate approach was to link the resin to the core via an aminoalcohol spacer as in 93. Furthermore, since linkage was conducted through the P-ketoester component rather than through the nitrogen atom, dihydropyridines 94 could now be formed on the solid support. When the 4-aryl substituent of 94 was nitro, on-resin reduction to the corresponding amine was possible. This allowed for further addition of diversity elements to the core scaffold before cleavage from the resin. 

Under the conditions used for the reductive cleavage of the O—N bond in isoxazoles, a similar reaction readily occurs with isoxa-zolines, e.g. on treatment with organomagnesium compounds and on catalytic hydrogenation.- Hydrogenolysis of the O—N bond (180 181 182 183) was used to elucidate the structure of isoxa-zolones from -ketoesters. -... 

SYNTHESIS AND RU(II)-BINAP REDUCTION OF A KETOESTER DERIVED FROM HYDROXYPROLINE 2(S)-(p tert-BUTOXYCARBONYL-a-(S) and a-(R)-HYDROXYETHYL)-4(R)-HYDROXYPYRROLIDINE-1 -CARBOXYLIC ACID, tert-BUTYL... 

A full account has appeared of the reactions of the ester phosphoranes (30 R = H) with acyl chlorides. Equimolecular proportions gave the salts (31) from which /8-ketoesters were obtained on electrolytic reduction. A 2 1 excess of phosphorane gave the allenic esters (32), presumably via the betaines (33). 

Many enantioselective catalysts have been developed for reduction of functional groups, particularly ketones. BINAP complexes of Ru(II)C12 or Ru(II)Br2 give good enantioselectivity in reduction of (3-ketoesters.49 This catalyst system has been shown to be subject to acid catalysis.50 Thus in the presence of 0.1 mol % HC1, reduction proceeds smoothly at 40 psi of H2 at 40° C. 

The enantioselective reduction of a-ketoester was carried out using the cell suspension of Aureobasidium pullulans SC 13 849 to produce the corresponding (R)-alcohol in 94% isolated... 

Two interesting yeast carbonyl reductases, one from Candida magnoliae (CMCR) [33,54] and the other from Sporobolomyces salmonicolor (SSCR) [55], were found to catalyze the reduction of ethyl 4-chloro-3-oxobutanoate to give ethyl (5)-4-chloro-3-hydroxybutanoate, a useful chiral building block. In an effort to search for carbonyl reductases with anti-Prelog enantioselectivity, the activity and enantioselectivity of CMCR and SSCR have been evaluated toward the reduction of various ketones, including a- and /3-ketoesters, and their application potential in the synthesis of pharmaceutically important chiral alcohol intermediates have been explored [56-58]. 

The carbonyl reductase from Candida magnoliae catalyzed the enantioselective reduction of a diversity of ketones, including aliphatic and aromatic ketones and a- and /3-ketoesters (Figure 7.17), to anti-Prelog configurated alcohols in excellent optical purity (99% ee or higher) [56]. 

Figure 7.18 Reduction of a-ketoesters by a carbonyl reductase from Sporobolomyces salmonicolor (SSCR)...

Zhu, D., Mukherjee, C., Rozzell, J.D. et al. (2006) A recombinant ketoreductase tool-box. Assessing the substrate selectivity and stereoselectivity toward the reduction of beta-ketoesters. Tetrahedron, 62 (5), 901-905. 

Engelking, H., Pfaller, R., Wich, G. and Weuster-Botz, D. (2006) Reaction engineering studies on /3-ketoester reductions with whole cells of recombinant Saccharomyces cerevisiae. Enzyme and Microbial Technology, 38, 536-544. 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

A Knorr-type pyrrole synthesis involving the condensation between a-amino-P-ketoesters and P-ketonitriles provided P-cyanopyrroles <06OPRD899>. The former amine substrates were prepared by reduction of the corresponding a-isonitroso-P-ketoesters with Zn/HOAc. 

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of p-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>. 

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

Much the same situation pertains to the asymmetric reduction of diketones and ketoesters. Thus, some years ago, a yeast reduction of the diketone (12) formed a key step in the preparation of important steroids (Scheme 9). Work in... 

---