Acyloin Research Articles

Reduction of activated carbonyl groups by alkyl phosphines: formation of α-hydroxy esters and ketones

Reduction of activated carbonyl groups such as alpha-keto esters, benzils, 1,2-cyclohexanedione, and alpha-ketophosphonates by alkyl phosphines afforded the corresponding alpha-hydroxy esters or ketones in good to excellent yields in THF at room temperature. The mechanism of the proton transfer and intramolecular hydrolysis has been studied on the basis of deuterium and 18O labeling experiments.

One-pot, high yield synthesis of α-ketols from Δ 5-steroids

α-Hydroxy ketones (α-ketols) are present in many compounds with biological activity. Several methods are available for the preparation of α-ketols but only a few of them describe the synthesis of steroid α-ketols from olefins. In this work, a new system consisting of KMnO 4/Fe(ClO 4) 3· nH 2O was used in order to achieve the direct conversion of Δ 5-steroids to their corresponding α-ketols, in high yields. Consideration of the probable reaction mechanism is provided. 2D homo- and heteronuclear correlation NMR spectroscopic techniques were used to assign 1H and 13C resonances of some synthesized compounds. This method has potential for the preparation of α-hydroxy ketones of biological interest.

Chemoenzymatic Dynamic Kinetic Resolution of Acyloins

[Reaction: see text]. Acyloins (alpha-hydroxy ketones) are important building blocks in organic synthesis, e.g., for the total synthesis of epothilones. Optically pure acyloins can be obtained by lipase-catalyzed kinetic resolution (KR) of the racemate with, for example, Burkholderia cepacia lipase, but this process suffers from a yield limitation of 50%. To devise a dynamic kinetic resolution (DKR), we studied the racemization of two different acyloins and corresponding esters with various amine bases and ion exchangers. No combination of base and solvent was found that could selectively racemize the acyloin or corresponding ester under the conditions needed for a DKR. In contrast to bases, acidic resins (ARs) were found to racemize the acyloins selectively in n-hexane and in water. Unfortunately, the AR deactivated the lipase, preventing a one-pot DKR. Minor side reactions involving the AR, the substrate acyloin, and the vinyl ester acyl donor were also observed. However, an efficient DKR was made possible by the spatial separation of lipase and ion exchanger, with enzymatic transesterification and AR-catalyzed racemization taking place simultaneously in two compartments connected by a pump loop. The conversion of substrate alcohol was 91%, the selectivity toward the product butyrate ester 90%, and the enantiomeric excess of the (S)-product 93% ee.

Electroreductive Acylation of Aromatic Ketones with Acylimidazoles

[Reaction: see text]. The intermolecular reductive coupling of aromatic ketones with acylimidazoles was effected by electroreduction in the presence of chlorotrimethylsilane and gave alpha-trimethylsiloxy ketones and esters. The best result was obtained using Bu4NPF6 as a supporting electrolyte and a Pb cathode in THF. The alpha-trimethylsiloxy-containing products were transformed to the corresponding alpha-hydroxy ketones and esters by treatment with TBAF in THF. This method was also effective for the intramolecular reductive coupling of delta- and epsilon-keto acylimidazoles.

Asymmetric dihydroxylation of disubstituted allenes

Asymmetric dihydroxylation of 1,1-disubstituted and 1,3-disubstituted allenes can be used to synthesize chiral α-hydroxy ketones. We have also obtained α,α′-dihydroxy ketones with high enantioselectivity from 1,3-disubstituted allenes. Low conversion of the dihydroxylation of chiral allenes can be used as a kinetic resolution of sterically hindered allenes.

Synthesis of three carbon atom bridged 2,4-diaminopyrrolo[2,3-d]-pyrimidines as nonclassical dihydrofolate reductase inhibitors

A series of seven nonclassical three carbon atom bridged 2,4-diamino-5-substituted-pyrrolo[2,3-d]-pyrirnidines 1a-g were synthesized as potential inhibitors of dihydrofolate reductase. Selective oxidation of diols 7a-g affords α-hydroxy ketones 8a-g. Subsequent condensation with malononitrile gave the requisite 2-amino-3-cyano-4-substituted furan precursors 9a-g. Cyclocondensation with guanidine in refluxing ethanol in one step affords the three carbon atom bridged 2,4-diamino-5-substituted-pyrrolo[2,3-d]-pyrimidines 1a-g. Preliminary biological results indicated that these compounds showed moderate inhibitory activities against dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium and rat liver with IC50 values in the 0.66 μM - 70.1 μM range and some compounds had marginal selectivity for T. gondii dihydrofolate reductase.

A Mild and Efficient Procedure for the Oxidation of Epoxides and Aziridines Using Cerium(IV) Ammonium Nitrate and NBS.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Investigations into the Selective Oxidation of Vicinal Diols to α‐Hydroxy Ketones with the NaBrO3/NaHSO3 Reagent: pH Dependence, Stoichiometry, Substrates and Origin of Selectivity.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An Alkyne Hydrosilylation-Oxidation Strategy for the Selective Installation of Oxygen Functionality

Alkynes bearing propargylic, homopropargylic, and bishomopropargylic hydroxyl groups are shown to serve as precursors for ketone or alpha-hydroxy ketone functionality. The approach hinges on the intermediacy of vinylsilanes created through regioselective hydrosilylation catalyzed by the complex [Cp*Ru(MeCN)3]PF6. Several oxidative pathways of linear and cyclic vinylsilanes are studied, and the possibility of diastereoselective epoxidation of cyclic vinylsilanes is demonstrated. The sequences constitute the equivalent of stereoselective aldol, homo-aldol, and bishomo-aldol type processes. The method is applied to a short synthesis of the piperidine alkaloid, spectaline.

A mild and efficient procedure for the oxidation of epoxides and aziridines using cerium(IV) ammonium nitrate and NBS

The CAN and NBS combination has been used for the first time for the synthesis of versatile α-hydroxy ketones and α-amino ketones from oxiranes/aziridines, respectively, in excellent yields. This method is a direct, one-pot, synthesis under mild conditions using acetonitrile–water (9:1) as solvent.

Investigations into the selective oxidation of vicinal diols to α-hydroxy ketones with the NaBrO 3/NaHSO 3 reagent: pH dependence, stoichiometry, substrates and origin of selectivity

The NaBrO 3/NaHSO 3 reagent is one of the few oxidizing agents that chemoselectively oxidizes vicinal diols to α-hydroxy ketones with little overoxidation to the corresponding vicinal-dione or dicarboxylic acid. Oxidation reactions performed with this reagent showed strong pH dependence. cis-Vicinal diols reacted faster than trans-vicinal diols to the α-hydroxy ketone product. Hydroxy functional groups at axial ring positions were more readily oxidized than equatorial hydroxy groups. The application of the NaBrO 3/NaHSO 3 reagent for the chemoselective oxidation of vicinal diols was limited to simple systems and failed with more complex monosaccharide compounds probably due to acid catalyzed dehydrogenation reactions. Despite the simple reaction set-up and good selectivity towards the α-hydroxy ketone product, the actual oxidation reaction mechanism is highly complex and postulated to involve at least six different equilibria with a plethora of bromine containing species. A possible oxidation reaction mechanism is discussed.

Quinoxaline Synthesis from α-Hydroxy Ketones via a Tandem Oxidation Process Using Catalysed Aerobic Oxidation

The direct conversion of α-hydroxy ketones into quinoxalines via metal-catalysed aerobic oxidation followed by in situ trapping with aromatic 1,2-diamines is reported. Catalyst screening indicated that these transformations could be carried out efficiently using 2 mol% Pd(OAc)2 or RuCl2(PPh3)3-TEMPO; the palladium system was utilised for a range of transformations.

The RuO4‐Catalyzed Ketohydroxylation. Part 1. Development, Scope, and Limitation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Alcohol oxidation with dioxygen mediated by oxotitanium porphyrin and related transition metal complexes

Oxotitanium porphyrin ( TTP ) Ti = O and related transition metal complexes were shown to catalyze the oxidation of alcohols using dioxygen as the oxidant. Vicinal diols were cleaved to carbonyl compounds in the presence of catalytic amounts of ( TTP ) Ti = O , ( TTP ) V = O or ( Saldach ) V = O . α-Hydroxy ketones were oxidized to α-diketones with ( TTP ) Ti = O . Benzyl alcohol was converted to benzaldehyde in modest to high yields by a number of high valent transition metal complexes. Reaction pathways for the transformations mediated by ( TTP ) Ti = O are discussed. Formation of diolato and enediolato complexes is believed to be the key step in the diol cleavage and α-hydroxy ketone oxidation, respectively.

Highly Stereoselective Oxy‐Michael Additions to α,β‐Disubstituted Nitro Olefins: Asymmetric Synthesis of Pseudo‐Norephedrine Derivatives and THP* Protected α‐Hydroxy Ketones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Hydron Transfer Catalyzed by Triosephosphate Isomerase. Products of Isomerization of (R)-Glyceraldehyde 3-Phosphate in D2O

The product distributions for the reactions of (R)-glyceraldehyde 3-phosphate (GAP) in D(2)O at pD 7.5-7.9 catalyzed by triosephosphate isomerase (TIM) from chicken and rabbit muscle were determined by (1)H NMR spectroscopy. Three products were observed from the reactions catalyzed by TIM: dihydroxyacetone phosphate (DHAP) from isomerization with intramolecular transfer of hydrogen (49% of the enzymatic products), [1(R)-(2)H]-DHAP from isomerization with incorporation of deuterium from D(2)O into C-1 of DHAP (31% of the enzymatic products), and [2(R)-(2)H]-GAP from incorporation of deuterium from D(2)O into C-2 of GAP (21% of the enzymatic products). The similar yields of [1(R)-(2)H]-DHAP and [2(R)-(2)H]-GAP from partitioning of the enzyme-bound enediol(ate) intermediate between hydron transfer to C-1 and C-2 is consistent with earlier results, which showed that there are similar barriers for conversion of this intermediate to the alpha-hydroxy ketone and aldehyde products (Knowles, J. R., and Albery, W. J. (1977) Acc. Chem. Res. 10, 105-111). However, the observation that the TIM-catalyzed isomerization of GAP in D(2)O proceeds with 49% intramolecular transfer of the (1)H label from substrate to product DHAP stands in sharp contrast with the <or=6% intramolecular transfer of the (3)H label from substrate to product GAP reported for the TIM-catalyzed reaction of [1(R)-(3)H]-DHAP in H(2)O (Herlihy, J. M., Maister, S. G., Albery, W. J., and Knowles, J. R. (1976) Biochemistry 15, 5601-5607). The data show that the hydron bound to the carboxylate side chain of Glu-165 in the TIM-enediol(ate) complex is not in chemical equilibrium with those of bulk solvent.

Enantioselective C–C bond synthesis catalysed by enzymes

The enantioselective synthesis of C-C bonds is often the pivotal step of a synthesis. Nature has made a variety of versatile enzymes available that catalyse this type of reaction very selectively under mild conditions. Cyanohydrins, acyloins (alpha-hydroxy ketones), alpha-hydroxy acids and aldols (beta-hydroxy ketones) are very efficiently synthesised enantioselectively with the aid of C-C bond forming enzymes, which we discuss in this tutorial review. In the case of the alpha-hydroxy acids the applications of nitrilases in a synthetic dkr even allows a disconnection that has no enantioselective chemical equivalent.

Prebiotic carbohydrate synthesis: zinc–proline catalyzes direct aqueous aldol reactions of α-hydroxy aldehydes and ketones

Zn-proline catalyzed aldolisation of glycoladehyde gave mainly tetroses whereas in the cross-aldolisation of glycoladehyde and rac-glyceraldehyde, pentoses accounted for 60% of the sugars formed with 20% of ribose.

Substrate range of acetohydroxy acid synthase I from Escherichia coli in the stereoselective synthesis of α‐hydroxy ketones

Acetohydroxy acid synthase I appears to be the most effective of the AHAS isozymes found in Escherichia coli in the chiral synthesis of phenylacetyl carbinol from pyruvate and benzaldehyde. We report here the exploration of a range of aldehydes as substrates for AHAS I and demonstrate that the enzyme can accept a wide variety of substituted benzaldehydes, as well as heterocyclic and heteroatomic aromatic aldehydes, to produce chiral carbinols. The active site of AHAS I does not appear to impose serious steric constraints on the acceptor substrate. The influence of electronic effects on the reaction has been probed using substituted benzaldehydes as substrates. The electrophilicity of the aldehyde acceptor substrates is most important to their reactivity, but the lipophilicity of substituents also affects their reactivity. AHAS I is an effective biosynthetic platform for production of a variety of alpha-hydroxy ketones, compounds with considerable potential as pharmacological precursors.

Optical Resolution of Acyclic α-Hydroxy Ketone Derivatives by Inclusion Complexation

Abstract A new method for the preparation of optically active acyclic α-hydroxy ketone derivatives by thermodynamic resolution using a chiral host compound is described. We examined the resolution of racemic 2-benzyloxy-3-pentanone with chiral host compounds in various solvents. After optimization of the reaction conditions, it has become apparent that the optical resolution could occur only under certain strict conditions about solvents, host compounds, and the concentration of the substrate. Stirring the suspension of the ketone with (−)-TADDOL bearing a cyclohexyl ring, derived from ethyl l-tartrate, in MeOH–H2O (1:1) at room temperature produces the inclusion complex with high enantioselectivity to give (S)-ketone with up to 99% ee. On the other hand, the ee of (R)-ketone obtained from the filtrate could be improved by the same procedure using (+)-TADDOL; finally, both enantiomers of the ketone as an almost optically pure form were afforded. Analysis of the formed complex by ESI-TOFMS supposed that the host–guest ratio would be 1:1. This resolution procedure was also applied to other substrates to afford the corresponding optically active ketones.