Enone Precursors Research Articles

Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction.

A practical and high-yielding Schmidt reaction for the synthesis of fused tetrazoles from bile acid precursors was developed. Mild reaction conditions using TMSN3 instead of hydrazoic acid as an azide source produced good yields of the desired tetrazoles. These conditions could be applied to other steroidal precursors. Additionally, an improved methodology for the synthesis of different ketone and enone precursors from cholic acid, deoxycholic acid, and chenodeoxycholic acid was established. Newly obtained tetrazole derivatives were characterized by NMR and X-ray diffraction spectroscopy. In a number of cases, preliminary antiproliferative tests of new compounds showed strong and selective activity towards certain tumor cell lines.

Bioinspired manganese complexes catalyzed epoxidation for the synthesis of the epoxyketone fragment of carfilzomib

We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone (tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermediate of carfilzomib. A series of bioinspired manganese complexes bearing N4 ligands are carefully investigated in the epoxidation of enone precursor with H2O2 as oxidant in the presence of carboxylic acid (e.g., acetic acid).

Synthesis of 2,4,5-Trisubstituted Oxazoles with Complementary Regioselectivity from α-Oxoketene Dithioacetals and β-(Methylthio)-β-(het)aryl-2-propenones.

An efficient protocol for the synthesis of 2,5-substituted 4-acyloxazoles and the related 2,4-substituted 5-acyloxazoles with complementary regioselectivity from the corresponding α-oxoketene dithioacetals or β-(het)aryl/(methylthio)enone precursors has been reported. In the first protocol, the α-oxoketene dithioacetals or β-(methylthio)enones were converted to the corresponding α-bromo-β-(methylthio)enones followed by copper catalyzed inter/intramolecular annulation of these intermediates with various primary amides affording 2-(het)aryl/alkyl-4-(het)aroyl-5-(methylthio)/(het)aryloxazoles via concomitant formation of the C4-N and C5-O bond via enamide intermediates. In the second approach, the starting α-oxoketene dithioacetals or β-(methylthio)-β-(het)arylenones were subjected to base induced conjugate addition-elimination with various primary amides to furnish β-aroylenamides, which, on subsequent iodine catalyzed intramolecular oxidative C-H functionalization/C-O bond formation, afforded the corresponding regioisomeric 2-(het)aryl/alkyl-4-(methylthio)/(het)aryl-5-(het)aroyloxazoles in excellent yields. The methodology has also been extended for the synthesis of regioisomeric 4- or 5-aminooxazoles and 4- or 5-( n-butyl)oxazoles from the corresponding 4- or 5-(methylthio)oxazoles.

Enantioselective Synthesis of Caprolactam and Enone Precursors to the Heterocyclic DEFG Ring System of Zoanthenol.

The enantioselective synthesis of both caprolactam and enone synthons for the DEFG ring system of zoanthenol are described. The evolution of this synthetic approach proceeds first through a synthesis using the chiral pool as a starting point. Challenges in protecting group strategy led to the modification of this approach beginning with (±)-glycidol. Ultimately, an efficient approach was developed by employing an asymmetric hetero-Diels-Alder reaction. The caprolactam building block can be converted by an interesting selective Grignard addition to the corresponding enone synthon. Addition of a model alkyne provides support for the late-stage addition of a hindered alkyne into the caprolactam building block.

Mannich Bases as Enone Precursors for Water-Mediated Efficient Synthesis of 2,3,6-Trisubstituted Pyridines and 5,6,7,8-Tetrahydroquinolines

A highly efficient, regioselective, and environmentally friendly method has been developed for water-mediated synthesis of 2,3,6-trisubstituted pyridines and 5,6,7,8-tetrahydroquinolines. The introduced method allows easy preparation of various polysubstituted pyridines and 5,6,7,8-tetrahydroquinolines via domino reaction of an enolizable ketone, ammonia and enones derived from different Mannich bases in mild reaction conditions. Montmorillonite K-10 promoted this one-pot three-component reaction and gave both new and known 2,3,6-trisubstituted pyridines and 5,6,7,8-tetrahydroquinolines in good yields. The reaction protocol provides a wide array of functionality in construction of polysubstituted pyridines and 5,6,7,8-tetrahydroquinolines from commercially available starting materials in easily applicable and environmentally friendly conditions.

Basis Set Dependence of Vibrational Raman and Raman Optical Activity Intensities.

We present a systematic study of the basis set dependence of the backscattering vibrational Raman intensities and Raman Optical Activity (ROA) intensity differences. The accuracies of computed Raman intensities and ROA intensity differences for a series of commonly used basis sets are reported, relative to large reference basis sets, using the B3LYP density functional. This study attempts to separately quantify the relative accuracies obtained from particular basis set combinations: one for the geometry optimization and force field computation and the other for the computation of Raman and ROA tensors. We demonstrate here that the basis set requirements for the geometry and force fields are not similar to those of the Raman and ROA tensors. The Raman and ROA tensors require basis sets with diffuse functions, while geometry optimizations and force field computations typically do not. Eleven molecules were examined: (S)-methyloxirane, (S)-methylthirane, (R)-epichlorhydrin, (S)-CHFClBr, (1S,5S)-α-pinene, (1S,5S)-β-pinene, (1S,4S)-norborneneone, (M)-σ-[4]-helicene, an enone precursor to a cytotoxic sesquiterpene, the gauche-gauche conformer of the monosaccharide methyl-β-d-glucopyranose, and the dipeptide Ac-(alanine)2-NH2. For the molecules examined here, intensities and intensity differences obtained from Raman and ROA tensors computed using the aug-cc-pVDZ basis set are nearly equivalent to those computed with the larger aug-cc-pVTZ basis set. We find that modifying the aug-cc-pVDZ basis set by removing the set of diffuse d functions on all atoms (while keeping the diffuse s and p sets), denoted as aug(sp)-cc-pVDZ, results in a basis set which is significantly faster without much reduction in the overall accuracy. In addition, the popular rDPS basis set introduced by Zuber and Hug offers a good compromise between accuracy and efficiency. The combination of either the aug(sp)-pVDZ or rDPS basis for the computation of the Raman and ROA tensors with the 6-31G* basis set for the geometry optimization and force field calculation is a reliable and cost-effective method for obtaining Raman intensities and ROA intensity differences.

ChemInform Abstract: A New Heck Reaction Modification Using Ketone Mannich Bases as Enone Precursors: Parallel Synthesis of anti‐Leishmanial Chalcones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Total synthesis of pteridic acids A and B

A convergent synthesis of pteridic acids A and B, epimeric spiroacetal polyketides with potent plant growth promoter properties, is described. The use of boron aldol methodology efficiently achieved the stereocontrolled construction of advanced C1–C11 and C12–C16 subunits, which were coupled to generate a linear ( Z)-enone precursor that underwent spiroacetalization with HF·pyridine, providing pteridic acids A and B after saponification.

A new Heck reaction modification using ketone Mannich bases as enone precursors: Parallel synthesis of anti-leishmanial chalcones

A new Heck-type reaction for the synthesis of chalcones has been established using Mannich bases as enone precursors. The novel reaction proceeds rapidly in air atmosphere under ligandless conditions and can be adapted for library synthesis in a parallel reactor station. Screening of the synthesized chalcones revealed N-{4-[(1E)-3-oxo-3-(3-pyridinyl)-1-propenyl]phenyl}benzamide (3f) to be a potent anti-leishmanial agent.

The Mizoroki-Heck reaction in organic and aqueous solvents promoted by a polymer-supported Kaiser oxime-derived palladacycle

A polystyrene-supported palladacycle derived from Kaiser oxime resin 3 is examined in organic and aqueous media used for the Mizoroki-Heck reactions. The couplings are efficiently performed in the presence of polymeric palladacycles in DMF, aqueous DMA, or water at relatively moderate temperature (110-130 oC) similarly to that in the presence of dimeric 4- hydroxyacetophenone 6 and 4-nitrobenzophenone oxime 2 palladacycles. Different acrylic, crotonic, and cinnamic acid derivatives as well as styrenes are arylated with aryl iodides, bromides, and chlorides with high efficiency. Enone precursors of 4-(p-hydroxyphenyl) and 4- (p-methoxy)phenylbutan-2-one, which are natural odorous products extracted from Aloe wood with raspberry scent, have been prepared by arylation of methyl vinyl ketone. Methylated resveratrol and the anti-cancer agent DMU-212 ((E)-3,4,5,4'-tetramethoxystilbene) have been prepared in high yields. Related Mizoroki-Heck reactions of o-halobenzaldehydes and o- iodoaniline with tolane afforded indenone and indol derivatives, respectively. XPS analysis of the starting and recycled polymer indicated that contains exclusively Pd(II). In addition, poisoning studies with Hg(0) of the reaction mixture stop the process indicating that the palladacycle acts as source of Pd(0) species. Recycling experiments are performed in organic and aqueous solvents with relatively low palladium leaching from the polymer (0.4-5% in DMF and 2-2.7% in H2O). ICP-OES analyses also indicate very low levels of Pd in the isolated crude products (2.9-37.2 ppm).

Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A1

Studies dealing with the diastereoselective installation of nine stereogenic centers of the C-12-C-25 subunit of bafilomycin A1 1 are described. A spiroketal precursor has been chosen as a rigid scaffold owing to the central spiro center, the configuration of which is dictated by predictable anomeric effects. A strategy using a previously described anti-Danishefsky condensation of chiral anti-aldehyde 6( O TES) with pentan-2,4-dione bis(trimethylsilyl)ether 7 (M = TMS), followed by an oxalate condensation to the other end of the pentanedione unit, afforded the required spiroketalic enone precursor 24. After generating the C-18 and C-17 centers through an enolate methylation reaction-Luche reduction sequence followed by a Mitsunobu inversion to give 27, the remaining C-16 methyl group was achieved via a hydroxy-directed cyclopropanation-reductive opening sequence to give the fully functionalized C-15-C-25 spiroketal 35. Further elongation at the C-14 center involved a Felkin-Ahn stereocontrolled addition of trimethylsilyl­acetylene followed by a one-pot O-methylation-desilylation, affording the acetylenic subunit 44, ready to be transformed into the vinylstannne required for the subsequent Stille coupling reaction with a C-1-C-11 subunit of bafilomycin A1. A 15-epi spiroketal intermediate has also been synthesized, as well as various 18-des­methyl analogues for comparative studies.

Efficient and general approach to eremophilanes using siloxyalkyne-alkene metathesis.

An efficient skeletal reorganization of a terminal alkene armed with an appropriate siloxy alkyne fragment is a pivotal step in our novel and general strategy for the construction of a bicyclic core of eremophilanes with complete diastereocontrol and high synthetic efficiency. Our approach features three significant strategic elements. First, the enyne metathesis precursor is assembled via a highly endo-selective Diels-Alder reaction. Second, installation of the siloxy group at the alkyne terminus enables the regioselective assembly of the ensuing enone fragment via intramolecular enyne cyclization. Third, the common enone precursor offers the necessary flexibility of accessing several natural products of the eremophilane family.

Mesoporous Zr and Hf catalysts for chemoselective MPV reductions of unsaturated ketones

Zr and Hf catalysts were immobilized in mesoporous materials such as MCM-41 or MCM-48; in comparison with the homogeneous catalysts, the resulting materials display strongly increased activity in the Meerwein–Ponndorf–Verley (MPV) reduction of ketones with alcohols as reductants. In the reduction of unsaturated ketones, a very high selectivity for the allylic alcohol is obtained. For efficient reduction, an excess of the reducing alcohol with respect to the enone is required. For the model reduction of benzalacetone with cyclopentanol, the adsorption of reagents and products on the catalytic material is studied. Even complex substrates such as prostaglandin enone precursors can be reduced; in certain cases a substantial diastereomeric excess is observed.

Peptido-organic Diels–Alder reactions on hydrophilic resin: scope for combinatorial chemistry

A simple route to activated dienes generated from enone precursors at the N-terminal of immobilised dipeptides is described. The dienes are subjected to reaction with a maleimide dieneophile containing a protected amino functionality for continued peptide synthesis. The reactions are pure and quantitative with dienes generated at the N-terminal of a variety of different dipeptides, including substrates containing amino acids with protected sidechain functionalities. In the work presented, hydrophilic POEPOP resin is used as a solid support. Also described in this paper is a high-yielding method for functional-group exchange of resin hydroxylic functionalities into azido groups via a Mitsunobu reaction, followed by reduction to yield amino-functionalised POEPOP.

Ready Access to 6-Alkyl, 6-Phenyl, 5,6-Dialkyl, and 5-Alkyl-6-phenyl Substituted 1,2,3,4-Tetrahydroisoquinolines

Readily available bicyclic enone precursors were used in a novel strategy for the synthesis of 6-mono- and 5,6-disubstituted tetrahydroisoquinolines (alkyl and phenyl in position 6, hydrogen and methyl in position 5). After 1,2-addition of the respective organometallic reagents to the enones, the crude intermediate alcohols were subjected to a dehydratization/aromatization procedure using the in situ generated triphenylmethyl cation. Overall yields obtained by this procedure were between 27 and 86%. Whereas the synthesis of N-benzyl protected 6-t-butyl-tetrahydroisoquinoline was successful, partial dealkylation occurred in the 5-methyl-6-t-butyl analogue. Some of the new N-benzyl tetrahydroisoquinolines were transformed into the corresponding unprotected heterocycles.

Auxiliary-controlled stereoselective enolate protonation: Enantioselective synthesis of cis and trans annulated decahydroquinoline alkaloids

The diastereoselective synthesis of the octahydroquinoline enone precursor of pumiliotoxin C is achieved via tandem Mannich-Michael reaction on N-galactosyl imines. Conjugate cuprate addition to the bicyclic enone stereoselectively forms the trans annulated 4a- epi-pumiliotoxin C skeleton in the presence of the carbohydrate auxiliary, and the cis annulated pumiliotoxin C skeleton in its absence.

Nickel-Catalysed Conjugate Addition of Trimethylaluminum to Sterically Hindered α,β-Unsaturated Ketones

Nickel acetylacetonate is an efficient catalyst for the 1,4-addition of trimethylaluminum to α,β-unsaturated ketones. The reaction is strongly solvent dependent and gives best results in tetrahydrofuran or ethyl acetate. The reaction is especially useful for the nucleophilic 1,4-methyl transfer to sterically hindered enones. A β-cuparenone synthesis via conjugate methyl group addition to an enone precursor is described.

Four isomeric 7-isopropyloctahydro-4H-inden-4-ones

The four isomeric 7-isopropyl-4-hydrindanones (2)–(5) have been prepared and their configurations assigned, using arguments based on the results of equilibration of the two pairs of ketones and on the products formed on hydrogenation of enone precursors. Base-catalysed equilibration at ca. 22 °C indicates that for (3)⇄(2), –ΔG 4.5 kcal mol–1 and for (5)⇄(4), –ΔG ca. 0.1 kcal mol–1. Possible diagnostic features in the 1H n.m.r. spectra of (2)–(5) are discussed briefly.

Acyl anion equivalents: synthesis of ketones and enones from α-phenylthioalkylphosphine oxides

The sulphenylated phosphine oxides Ph2P(O)·CH(SR2)R1, easily prepared from triphenylphosphine, diphenyl or dimethyl disulphide, and an alkyl halide, form anions which act as acyl anion equivalents. Reaction with aldehydes and ketones gives vinyl sulphides, which can be hydrolysed to carbonyl compounds. Reaction with α-phenylthio- and α-methoxy-aldehydes and ketones gives enone precursors. The scope and limitations of the method are described.

Synthesis of prostaglandins by conjugate addition and alkylation of a directed enolate ion. 11-Deoxy prostaglandins

Over the previous two decades many elegant syntheses of prostaglandins, which in more sophisticated forms, allow the stereospecific introduction of the various asymmetric carbons have been accomplished. However, among these approaches the cuprate addition/enolate alkylation of suitable cyclopentenone {sup 2} stands out because of brevity and convergence. The recent reports by Noyori{sup 3} and Corey{sup 4} and their colleagues have reduced to practice the conversion of 4-alkoxycyclopentenones to prostaglandin E{sub 2} (PGE{sub 2}) by conjugate addition of an organocopper derivative of the lower side chain followed by alkylation of the resulting carbanion with methyl 7-halohept-2-enoate. The subject of this paper is application of the Tardella tin enolate alkylation developed by Noyori to the synthesis of 4, 5-allenic prostaglandins, a pharmacologically important class of compounds. The authors results demonstrate that the tandem alkylation of an enone precursor with a cuprate reagent followed by alkylation of the corresponding tin enolate with bromide reagent is a viable synthetic method for 4,5-didehydro-PGE{sub 2}. Because the optically active forms of 1 and the vinyl iodide precursor of the PGE{sub 2} lower side chain have been employed to produce a single enantiomer of PGE{sub 2}, the extension of the methodology described here to the synthesis ofmore » single enantiomers of 4a awaits only the preparation of the separate enantiomers of allene 14.« less