Α-keto Amides Research Articles

New Ugi/Pictet-Spengler Multicomponent Formation of Polycyclic ­Diketopiperazines from Isocyanides and α-Keto Acids

A new four-component 1,4-diketopiperazine formation is described via an Ugi/Pictet-Spengler two-step procedure. The use of α-ketocarboxylic acids and homoveratryl isocyanide allows the formation of α-keto amides along with cyclised 6-hydroxypiperazines. The mixtures are not separated but directly treated with trifluoroactic acid to afford a tricyclic 2,5-diketopiperazine in a Pictet-Spengler-type cyclisation.

Toward the total synthesis of Scleritodermin A: preparation of the C 1–N 15 fragment

The synthesis of the C 1–N 15 fragment of the marine natural product Scleritodermin A has been accomplished through a short and stereocontrolled sequence. Highlights of this route include the synthesis of the novel ACT fragment and the formation of the α-keto amide linkage by the use of a highly activated α,β-ketonitrile.

Photochemical Cleavage and Release of Para-Substituted Phenols from α-Keto Amides

In aqueous media alpha-keto amides 4-YC6H4OCH2COCON(R)CH(R')CH3 (5a, R = Et, R' = H; 5b, R = iPr, R' = Me) with para-substituted phenolic substituents (Y = CN, CF3, H) undergo photocleavage and release of 4-YC6H4OH with formation of 5-methyleneoxazolidin-4-ones 7a,b. For both 5a,b quantum yields range from 0.2 to 0.3. The proposed mechanism involves transfer of hydrogen from an N-alkyl group to the keto oxygen to produce zwitterionic intermediates 8a-c that eliminate the para-substituted phenolate leaving groups. The resultant imminium ions H2C=C(OH)CON+(R)=C(R')CH3 9a,b cyclize intramolecularly to give 7a,b. The quantum yields for photoelimination decrease in CH3CN, CH2Cl2, or C6H6 due to competing cyclization of 8a,b to give oxazolidin-4-one products which retain the leaving group 4-YC6H4O- (Y = H, CN). A greater tendency to undergo cyclization in nonaqueous media is observed for the N,N-diethyl amides 5a than the N,N-diisopropyl amides 5b. With para electron releasing groups Y = CH3 and OCH3 quantum yields for photoelimination significantly decrease and 1,3-photorearrangment of the phenolic group is observed. The 1,3-rearrangement involves excited state ArO-C bond homolysis to give para-substituted phenoxyl radicals, which can be observed directly in laser flash photolysis experiments.

Diastereoselective Cyanation of α-Keto Amides Derived fromN-Phenyl Camphorpyrazolidinone and Camphorsultam

The diastereoselective cyanation of α-keto amides using trimethylsilyl cyanide in the presence of a Lewis acid is described. The corresponding O-acetylated cyanohydrins are obtained in good to high levels of stereoselectivities. The predominance of products with the S absolute configuration at the newly generated stereogenic center was deduced from single crystal X-ray analysis. 13 C NMR data suggest that a preferential s-cis conformation was formed by the chelation of a Lewis acid to the dicarbonyl oxygen atoms.

A One‐Pot Synthesis of Nitrogen‐Containing Heteroaryl α‐Keto Amides from Heteroaryl Halides.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Photochemical Cleavage and Release of Carboxylic Acids from α-Keto Amides

In aqueous media, alpha-keto amides LGCH(2)COCON(R)CH(R')CH(3) (1a, R = Et, R' = H; 1b, R = (i)()Pr, R' = Me; 1c, R = Ph, R' = H) with various carboxylate leaving groups (LG) at the C-3 position undergo photocleavage and release of carboxylic acids with formation of diastereomeric 5-hydroxyoxazolidin-4-ones 2a,c in the cases of 1a,c or 5-methyleneoxazolidin-4-ones 3b in the case of 1b. For 1a,b, Phi(photocleavage) = 0.24-0.38, whereas Phi(photocleavage) = ca. 0.05 for 1c. The proposed mechanism involves transfer of hydrogen from an N-alkyl group to the keto oxygen to produce zwitterionic intermediates 4a-c that eliminate carboxylate anions. The resultant imminium ions, H(2)C=C(OH)CON(+)(R)=C(R')CH(3) 5a-c, cyclize intramolecularly to 3b or undergo intermolecular addition of water followed by tautomerization and cyclization to give 2a,c. These inter- or intramolecular trapping reactions of 5 release protons that decrease the pH and cause bleaching of the 620 nm band of the pH indicator, bromocresol green. Determination of the bleaching kinetics by laser flash photolysis methods in the case of 1a gives time constants of 18-137 mus, depending on the leaving group ability of the carboxylate anion, whereas amides 1b show only a small leaving group effect. For 1a, the large leaving group effect is consistent with rate-limiting carboxylate elimination from 4a, whereas the proton release step would be largely rate determining for 1b. Photolyses of 1a (LG = CH(3)CO(2)(-), PhCH(2)CO(2)(-)) in neat CH(3)CN results in carboxylate elimination to form imminium ion 5a, followed by internal return to give aminals.

A one-pot synthesis of nitrogen-containing heteroaryl α-keto amides from heteroaryl halides

The S NAr-type reaction of the piperidine amide of cyanoacetic acid with a series of heteroaryl halides followed by in situ oxidation of the resultant anion with peracetic acid provided a convenient, one-pot protocol for preparative access to heteroaryl α-keto amides. In this procedure, the amide of cyanoacetic acid functions as an Umpolung-type synthon of the α-keto amide moiety.

Time-resolved pH jump study of photochemical cleavage and release of carboxylic acids from α-keto amides

Time-resolved pH jump experiments, using laser flash photolysis and bromocresol green as an indicator, showed that photochemical cleavage and release of carboxylic acids from various α-keto amides derivatives in aqueous media occurs on the microsecond timescale (18–136μs), depending on carboxylate leaving group ability.

The Chemistry of Vicinal Tricarbonyls and Related Systems

AbstractFor Abstract see ChemInform Abstract in Full Text.

Substituent Effects on Competitive Release of Phenols and 1,3‐Rearrangement in α‐Keto Amide Photochemistry.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Substituent effects on competitive release of phenols and 1,3-rearrangement in alpha-keto amide photochemistry.

[reaction: see text] Photolysis of alpha-keto amides bearing 4-YC(6)H(4)O leaving groups at the position alpha to the keto group efficiently produces high yields of phenols when Y is an electron-withdrawing group or H. The photoelimination likely involves cleavage of zwitterionic intermediates produced via excited-state hydrogen transfer. When Y is an electron-donating group, competing excited-state ArO-C(alpha) bond scission to radicals occurs, followed by recombination to give 1,3-photorearrangment products.

Purification and Characterization of α-Keto Amide Reductase fromSaccharomyces cerevisiae

An NADPH-dependent alpha-keto amide reductase was purified from Saccharomyces cerevisiae. The molecular mass of the native enzyme was estimated to be 33 and 36 kDa by gel filtration chromatography and SDS-polyacrylamide gel electrophoresis, respectively. The purified enzyme showed a reducing activity not only for aromatic alpha-keto amides but also for aliphatic and aromatic alpha-keto esters. The internal sequence of the enzyme was identical with that of a hypothetical protein (ORF YDL 124w) coded by yeast chromosome IV.

Alpha-keto amides as inhibitors of histone deacetylase.

Alpha-keto ester and amides were found to be potent inhibitors of histone deacetylase. Nanomolar inhibitors against the isolated enzyme and sub-micromolar inhibitors of cellular proliferation were obtained. The alpha-keto amide 30 also exhibited significant anti-tumor effects in an in vivo tumor model.

Application of acyl cyanophosphorane methodology to the synthesis of protease inhibitors: poststatin, eurystatin, phebestin, probestin and bestatin

Full details are given for the syntheses of the protease inhibitors, poststatin and eurystatin by the acyl cyanophosphorane coupling procedure used for the formation of α-keto amides. We have also extended this methodology to the syntheses of the related α-hydroxy amide natural products, phebestin, probestin and bestatin. The key step in the latter synthetic sequences involved diastereomeric selectivity in the reduction of the α-keto precursor to the corresponding α-hydroxy amide by the use of zinc borohydride.

Alpha-Keto amides as precursors to heterocycles--generation and cycloaddition reactions of piperazin-5-one nitrones.

alpha-Keto amides 10a,b, formed from reaction of pyruvic or benzoylformic acid with allyl amine are found to present as single rotameric forms whilst their tertiary amido analogues 10c, d present as two rotamers in solution at rt. The hydroxyimino derivatives 8 share the conformational characteristics of their parents. The geometrical make-up of the new alpha-amidooximes is seen to depend on the structure of the starting acid and on the degree of substitution of the amido group. The oxime 8a derived from pyruvic acid and allyl amine is formed solely as the (E)-isomer whilst its tertiary amido analogue 8c is formed as both (E)- and (Z)-isomers. Oximes derived from benzoylformic acid have the opposite selectivity with both geometrical isomers forming from the secondary amide 8b and only the (Z)-isomer from the tertiary amide 8d. With the exception of 8b all oximes were configurationally stable with (Z)-isomers reacting to form isoxazolopyrrolidinones 11--compounds with a relatively rare bicyclic nucleus and (E)-isomers cyclising to piperazin-5-one nitrones 1--ketopiperazine N-oxides have to date only appeared once in the literature. New nitrones were trapped with phenyl vinyl sulfone, dimethyl acetylenedicarboxylate and methyl propiolate yielding isoxazolidine and isoxazoline fused piperazinones 13, 15, 21 and 22. Cycloadducts from dimethyl acetylenedicarboxylate and 8a, b are thermally labile and their rearrangement provides a novel route to pyrrolopiperazinones 16. The structure of a representative isoxazolopyrrolidinone, 11c, and a 2,3-dihydroisoxazoline fused piperazinone, 21b, are unambiguously solved following x-ray structural analysis.

Application of Cyano Ylide Methodology to the Synthesis of Cyclotheonamides E2 and E3.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Photochemical cleavage and release of carboxylic acids from alpha-keto amides.

Carboxylate groups incorporated at the position alpha to the keto carbonyl of alpha-keto amides 1 were photochemically cleaved in aqueous media to give carboxylic acids in 70-90% yields with quantum yields of 0.3. The cleavage coproducts were diastereomeric hemiacetals 2. Prompt release of acetate and gamma-aminobutyrate (GABA) in buffer was observed by difference FT-IR spectroscopy upon 355 nm laser flash photolysis. The time-constant for release of GABA was <30 ms. [reaction--see text]

Application of cyano ylide methodology to the synthesis of cyclotheonamides E 2 and E 3

A total synthesis of cyclotheonamides E 2 and E 3 is reported. A key step in the synthesis involves the formation of the α-keto amide linkage by application of the cyano ylide activation of a carboxyl group as developed in our earlier syntheses of cyclic peptide protease inhibitors.

Total synthesis of cyclotheonamides E 2 and E 3: application of cyano ylide methodology

A total synthesis of cyclotheonamides E 2 and E 3 is reported. A key step in the synthesis involves the formation of the α-keto amide linkage by application of the cyano ylide activation of a carboxyl group as developed in our earlier syntheses of cyclic peptides in the family of protease inhibitors.

Hypervalent Iodine in Synthesis 68: Palladium-Catalysed Double Carbonylation of Diaryliodonium Salts to give α-keto-amides

In the presence of a palladium catalyst and the cocatalyst CuI, several diaryliodonium salts have been converted into α-keto amides on treatment with secondary amines and carbon monoxide in good yield and selectivity under mild reaction conditions.