Photo-oxygenation of Styrenic Estrogens: Structural Analysis of 8,9-Didehydro-, 6,7-Didehydro-, and 9,11-Didehydroestrone Derivatives and Their Reactivity towards Singlet Oxygen

A series of didehydro-3-O-methyl-estrones having a styrenic framework, with the ring-A-conjugated double bond in all three possible positions (8,9-didehydro- ( 6 ),9,11-didehydro- ( 1b ), 6,7-didehydro- ( 9 ), and the 12,18-di-nor-8,9-didehydroestrone analog 11 ), were compared for their reactivity towards singlet oxygen. Under dye-sensitized photo-oxygenation conditions, both, products derived from ene-type reactions with the isolation of a stable hydroperoxide and a fragmentation product, were obtained from 6 (see Scheme 3), while only fragmentation took place for 1b (Scheme 1), Kinetic studies indicated that 6 is more reactive towards ¹O₂ than 1b (β = 9.2·10^?3 mol·1^?1 vs 3.3·10^?2 mol·1^?1, resp.). The observed reactivity, apparently, does not match with ene-type reaction and [2 + 2]cycloaddition being in competition, since the most activated substrate 6 preferentially yields ene-type products and their derivatives. Conformational analysis on the structure of 6 and 1b , both calculated by molecular-mechanic techniques (MMPMI) and determined by X-ray diffraction, show that the allylic H-atoms satisfy the orthogonality rule for ene-type reactions. The product distribution is best rationalized by applying Fukui's rule which takes into account a combination of electronic and geometric factors. Substrates 9 and 11 yielded photo-products arising from ene-type reaction with no stable primary products isolated (Scheme 4). Geometric considerations based on the calculated structures by molecular mechanics are consistent with the observed results.     

High-Throughput Diversification of Complex Bioactive Molecules by Accelerated Synthesis in Microdroplets

Late-stage diversification of drug molecules is an important strategy in drug discovery that can be facilitated by reaction screening using high-throughput experimentation. Here we present a rapid method for functionalizing bioactive molecules based on accelerated reactions in microdroplets. Reaction mixtures are nebulized at throughputs better than 1 reaction/second and the accelerated reactions occurring in the microdroplets are followed by desorption electrospray ionization mass spectrometry (DESI-MS). Because the accelerated reactions occur on the millisecond timescale, they allow an overall screening throughput of 1 Hz working at the low nanogram scale. Using this approach, an opioid agonist (PZM21) and an antagonist (naloxone) were diversified using three reactions important in medicinal chemistry: sulfur fluoride exchange (SuFEx) click reactions, imine formation reactions, and ene-type click reactions. Some 269 functionalized analogs of naloxone and PZM21 were generated and characterized by tandem mass spectrometry (MS/MS) after screening over 500 reactions.     

The Reaction of Silyl Enol Ethers With Ethyl Azodicarboxylate and 4-Phenyl-1,2,4-Triazoline-3,5-Dione

The ene-type reaction between silyl enol ethers and azodiesters yields α-keto 4-phenyl 1,2,4 triazolidine-3,5-dione in the case of 1,2,4-triazoline-3,5-dione. and α-keto dicarbo-ethoxyhydrazides in the case of diethyl azodicarboxylate. These reactions proceed in qcod yield and offer potential routes to α-nitrogen substituted ketones.     

Revealing carbocations in highly asynchronous concerted reactions: The ene-type reaction between dithiocarboxylic acids and alkenes

The ene-type reaction between (dithio)carboxylic acids and alkenes has been studied computationally by DFT and topological (analysis of the electron localization function, ELF) methods. The reaction proceeds under kinetic control and the observed differences in regioselectivity are well-explained by the relative stability of the different transition structures. In agreement with experimental observations, electron-rich alkenes lead to Markownikoff adducts while electron-poor alkenes lead to Michael adducts. In all cases the reaction proceeds through an only transition structure (one kinetic step) although a different synchronicity was observed depending on the alkene electronics. The ELF analysis of the reactions corroborates the existence of a transient carbocation (hidden intermediate) in the reactions with electron-rich alkenes. On the other hand, electron-poor alkenes proceed through a more synchronous concerted mechanism. It can be predicted that with electron-rich alkenes bearing highly donating the transient carbocations might be captured by a nucleophile.     

Regio- and Stereoselective Oxidation of Ene-Type Chlorinated Olefins

Regio- and stereoselective oxidation of ene-type chlorinated olefins has been achieved by using potassium 2-propanenitronate as an oxidant and tetrakis(triphenylphosphine)palladium as a catalyst.     

Highly enantioselective alkaloid synthesis via ene-type cyclizations catalyzed by cationic chiral palladium(II) complexes of PN-ligands with an achiral oxazoline unit

A highly efficient asymmetric alkaloid synthesis via ene-type cyclizations catalyzed by cationic chiral palladium(II) complexes of PN-ligands with an achiral gem-dimethyl oxazoline unit is shown to give 5-membered products with a quaternary carbon center, including a spiro-amide, almost quantitatively with extremely high enantiomeric excesses.     

A Convenient Preparative Route to 1,2-Epoxy-3-Methyl-3-Butene Via Ene-Type Chlorination

1,2-Epoxy-3-methyl-3-butene has been synthesized from prenyl acetate by using ene-type chlo-rination.     

Imino ene-type reaction of enamines with N-sulfonylimines and application to diastereoselective synthesis of N-sulfonyl-1,3-diamines

Enamines react rapidly with N-sulfonylimines to afford imino ene-type adducts. The reaction proceeds even at −78 °C in the presence of acetic acid and shows high diastereoselectivity. Acid hydrolysis of imino ene-type products affords β-amino ketones, and reduction with NaBH₃CN furnishes N-sulfonyl-1,3-diamines with high diastereoselectivities. The stereochemistry of these transformations is considered based on transition state models.     

Enantioselective spiro ene-carbocyclization of 1,6-enynes catalyzed by tropos rhodium(I) complex with skewphos ligand

A tropos rhodium(I) complex having skewphos ligand is shown to be a highly enantioselective catalyst for asymmetric ene-type carbocyclization of 1,6-enynes with tri-substituted olefins to control quaternary stereogenic centers or spiro-rings.     

Synthesis of Unsaturated Nitriles from Trisubstituted Olefins Via Ene-Type Chlorination

Unsaturated nitriles have been synthesized from trisubstituted olefins via ene-type chlorination and regioselective substitution with cyanide ion followed by double bond migration.     

Density functional theory study on a missing piece in understanding of heme chemistry: the reaction mechanism for indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are heme-containing dioxygenases and catalyze oxidative cleavage of the pyrrole ring of L-tryptophan. On the basis of three recent crystal structures of these heme-containing dioxygenases, two new mechanistic pathways were proposed by several groups. Both pathways start with electrophilic addition of the Fe(II)-bound dioxygen concerted with proton transfer (oxygen ene-type reaction), followed by either formation of a dioxetane intermediate or Criegee-type rearrangement. However, density functional theory (DFT) calculations do not support the proposed concerted oxygen ene-type and Criegee-type rearrangement pathways. On the basis of DFT calculations, we propose a new mechanism for dioxygen activation in these heme systems. The mechanism involves (a) direct electrophilic addition of the Fe(II)-bound oxygen to the C2 or C3 position of the indole in a closed-shell singlet state or (b) direct radical addition of the Fe(III)-superoxide to the C2 position of the indole in a triplet (or open-shell singlet) state. Then, a radical-recombination or nearly barrierless charge-recombination step from the resultant diradical or zwitterionic intermediates, respectively, proceeds to afford metastable dioxetane intermediates, followed by ring-opening of the dioxetanes. Alternatively, homolytic O-O bond cleavage from the diradical intermediate followed by oxo attack and facile C2-C3 bond cleavage could compete with the dioxetane formation pathway. Effects of ionization of the imidazole and negatively charged oxyporphyrin complex on the key dioxygen activation process are also studied.     

Synthesis of tert-alkyl amino hydroxy carboxylic esters via an intermolecular ene-type reaction of oxazolones and enol ethers

tert-Alkyl amino hydroxy carboxylic acids are abundantly present within the structure of many biologically active natural products. We describe herein the synthesis of these substrates using an oxazolone-mediated ene-type reaction with enol ethers followed by NaBH4 reduction of the intermediate oxazolone.     

The first method for protection-deprotection of the indole 2,3-pi bond

[reaction: see text] The scope and generality of a new reaction of indoles with MTAD is discussed. In most cases the ene-type reaction proceeds within seconds or minutes at 0 degrees C to provide the urazole adducts in high yield. This reaction provides the first method for protecting the indole 2,3-double bond since the urazole adducts can be reconverted to the starting indole (retro-ene) simply by heating.     

Iron-catalyzed ene-type propargylation of diarylethylenes with propargyl alcohols

The diarylalkenyl propargylic complex framework has been found in many natural products and medicinal regents. Herein, we have disclosed an unprecedented FeCl(3) catalyzed ene-type reaction of propargylic alcohols with 1,1-diaryl alkenes which enabled us to furnish a diarylalkenyl propargylic complex framework in moderate to high chemical yields (up to 98%).     

A synthetic pathway to diquinane and angular triquinane systems via an iron carbonyl promoted tandem [6+2] ene type reaction

A model study is described on a new approach to the synthesis of diquinane and angular triquinane systems, via iron-promoted tandem [6+2] ene-type double cyclization followed by ozonolysis and intramolecular aldol reaction.     

Ene-type reaction of trisubstituted monoterpene alkenes with methyl sulfite and thionyl chloride

Trisubstituted methylalkenes react with methyl sulfite at 25°C in the presence of BF₃ · Et₂O in the ene-type fashion to give the corresponding methallyl sulfinates. Such compounds can also be prepared under considerably milder conditions by the Et₂AlCl-catalyzed reaction of thionyl chloride with mono- and dienes followed by methanolysis of intermediate alkyl sulfinyl chlorides. These reactions represent a new method for terminal functionalization of linear isoprenoids.Deceased Nov.1, 1992.Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 1, pp. 105–107, January, 1993.     

Nucleus- and side-chain fluorinated 3-substituted indoles by a suitable combination of organometallic and radical chemistry

Regioselectively fluoro-, trifluoromethyl- and trifluoromethoxy-substituted 3-methyleneindolines have been prepared using a four-step procedure involving metalation/bromination of fluorinated Boc-protected anilines, N-propargylation of the resulting o-bromoarylcarbamate and reductive radical cyclization of the product with tributyltin hydride/AIBN. 3-Methyleneindolines, as valuable, versatile intermediates, can be transformed into highly functionalized 3-substituted indoles by ene-type reactions using different enophiles. Thus, fluoro-, trifluoromethyl- and trifluoromethoxy-substituted diethyl 2-hydroxy-2-[(1H-indol-3-yl)methyl]malonates, ethyl 2-hydroxy-3-(1H-indol-3-yl)propionates and ethyl 2-hydroxy-3-(1H-indol-3-yl)-2-trifluormethylpropionates were obtained in 77-86% yield by simply heating the corresponding tert-butyl 3-methyleneindoline-1-carboxylate with an equimolar amount of diethyl ketomalonate, ethyl glyoxalate and ethyl 3,3,3-trifluoropyruvate, respectively, at 100 °C, without solvent, for 0.5-4 h.     

Chiral aminoalcohol NOBIN for instantaneous chirality control of racemic but tropos BIPHEP-Rh(I)-complexes: highly enantioselective ene-type cyclization of 1,6-enynes catalyzed by the Rh(I)-complexes without use of acid

The tropos (chirally flexible) or atropos (chirally rigid) nature of BIPHEP-Rh complexes critically depends on amines and alcohols complexed. The BIPHEP-Rh complex with aminoalcohol NOBIN is significantly tropos and can be chirally controlled by aminoalcohol NOBIN instantaneously even at room temperature. The BIPHEP-Rh/NOBIN complex thus controlled can be used as an asymmetric catalyst to give higher enantioselectivity (up to 98% ee) and yield in ene-type cyclization of 1,6-enynes without use of acid.     

New Synthetic Method for Bicyclic Compounds Through a Sequence of Ene-Type Chlorination,Palladium Catalyzed Dehydrochlorination,and Intramolecular Diels-Alder Reaction

A sequence of ene-type chlorination, palladium catalyzed dehydrochlorination, and the intramolecular Diels-Alder reaction afforded a new method for conversion of prenyl derivatives into bicyclic compounds.     

Theoretical investigation of linalool oxidation

This study concerns the autoxidation of one of the most used fragrances in daily life, linalool (3,7-dimethyl-1,6-octadien-3-ol). It reacts with O2 to form hydroperoxides, which are known to be important contact allergens. Pathways for hydroperoxide formation are investigated by means of quantum mechanical electronic structure calculations. Optimized molecular geometries and harmonic vibrational frequencies are determined using density functional theory (DFT). Insight into how the addition of O2 to linalool occurs is obtained by establishing a theoretical framework and systematically investigating three smaller systems: propene, 2-methyl-2-butene, and 2-methyl-2-pentene. 2-Methyl-2-pentene was chosen as a model system and used to compare with linalool. This theoretical study characterizes the linalool-O2 biradical intermediate state, which constitutes a branching point for the further oxidation reactions pathways. Thus, the observed linalool oxidation product spectrum is discussed in terms of a direct reaction path, the ene-type mechanism, and the radical mechanism. The major hydroperoxide found in experiments is 7-hydroperoxy-3,7-dimethyl-octa-1,5-diene-3-ol, and the calculated results support this finding.