Diastereoisomeric Ratio Research Articles

Ficini Reaction with Acrylates for the Stereoselective Synthesis of Aminocyclobutanes.

The first Ficini reaction between ynamides and acrylates is reported herein. The reaction is catalyzed by B(C6F5)3 acting as a Lewis acid and is giving access to stable tri-substituted aminocyclobutenes in high yield. The resulting products can be hydrogenated and epimerized under basic conditions or in presence of a Lewis acid, providing two distinct trans- aminocyclobutane monoester stereoisomers in high yield and diastereoisomeric ratio (up to quantitative yield and >99 : 1 dr).

Organophotoredox-Catalyzed Synthesis of Unnatural α/β Amino Acids and Peptides via Deaminative Three-Component Coupling.

Herein, we disclose an expedient visible-light-mediated, organophotoredox-catalyzed multicomponent synthesis of unnatural amino acids using a Katritzky salt, glyoxal derivatives, and substituted anilines. Mechanistically, an alkyl radical is generated from the Katritzky salt via a deaminative process that undergoes addition to the in situ-generated imine to furnish α-amino acids in a moderate diastereoisomeric ratio. For the first time, we have demonstrated this deaminative protocol to access substituted β-amino acids from α-amino acid-derived Katritzky salts. Furthermore, α-amino amides are also generated from the corresponding 2-oxoacetamide derivatives.

Electro‐Organic Stereoselective Dehydrogenative Homo‐Coupling of β‐Naphthylamines Derivatives

AbstractThe electrochemical stereoselective dehydrogenative homocoupling of β‐naphthylamine derivatives was investigated and successfully accomplished, the chiral diaryl amines being obtained in up to 60 % yield. The use of an enantiopure β‐naphthylamine featuring an aminoalcohol as chiral auxiliary led to the expected 2,2’‐binaphthyl diamine derivative in up to 96/4 diastereoisomeric ratio. The application of the methodology to the intramolecular cross coupling of the enantiopure bis‐N‐β‐naphthylamine 1,2‐trans‐diamino cyclohexane led to the formation of a single enantiopure diastereoisomer in 37 % yield.

Rhodium(I)-Catalyzed O-H Insertions on O-Protected α-Diazo-β-Hydroxyesters.

The X-H insertion reaction constitutes a powerful tool to create diversity through the diazo decomposition of diazocarbonyl compounds. However, until now, X-H insertion on α-diazo-β-aryl-β-hydroxyester scaffolds, readily prepared by aldol-type addition, remained a challenge for the organic chemist. We report herein the first O-H insertions on O-protected α-diazo-β-aryl-β-hydroxyesters, providing straightforward access to a wide range of α,β-dioxygenated esters through modulation of the alcohol and of the aryl substituent. The key feature to achieving this transformation is the use of Rh(I) catalysts, which proved to be crucial to favor the targeted O-H insertion product over the competing 1,2-H and 1,2-Ar migration products. Overall, 32 O-H insertion products have been prepared, in moderate to good yields, with a diastereoisomeric ratio up to 7.5:1 in favor of the syn diastereoisomer.

Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions.

An original total synthesis of the antiepileptic drug brivaracetam (BRV) is reported. The key step in the synthesis consists of an enantioselective photochemical Giese addition, promoted by visible-light and the chiral bifunctional photocatalyst Δ-RhS. Continuous flow conditions were employed to improve the efficiency and allow an easy scale-up of the enantioselective photochemical reaction step. The intermediate obtained from the photochemical step was converted into BRV by two different pathways, followed by one alkylation and amidation, thus giving the desired active pharmaceutical ingredients (API) in 44% overall yield, 9:1 diastereoisomeric ratio (dr) and >99:1 enantiomeric ratio (er).

Epoxidation of Electron‐Deficient Alkenes Triggered by Visible‐Light‐Driven Phenol Photooxidation for the Synthesis of Epoxy Dienone Products

AbstractThis article describes a synthesis of epoxy dienone products starting from para‐substituted phenols bearing an electron‐deficient alkene at the meta position. This one‐pot photooxygenation/epoxidation transformation takes place at room temperature using catalytic amounts of Rose Bengal and cesium carbonate upon green light irradiation. This reaction provides access to a range of functionalized epoxy dienone products with diastereoisomeric ratios ranging from 4:1 to >12:1. DFT calculations and mechanistic experiments revealed that this reaction would proceed through singlet oxygen‐mediated photooxidation of phenols followed by an intramolecular oxygen atom transfer on the alkene side arm.magnified image

Diastereoselective C-alkylation of aldimines, derived from chiral α-carbon heteroatom-substituted aldehydes, with triethylborane. Application to the synthesis of benzylisoquinolines.

The one-pot reaction of a chiral aldehyde, p-methoxyaniline or p-fluoroaniline, and triethylborane produces the corresponding alkylated chiral amine with high yields and diastereoisomeric ratios. Stereocontrol is induced by the presence of a heteroatom in the α-position to the aldehyde. In the case of alkylation of imines derived from chiral aliphatic amines, good yields and moderate to high diastereoselectivity are obtained: yields are significantly better when the preformed imine is used in the reaction with triethyl borane, and diastereoselectivity of the reactions largely depends on the structure of the chiral aliphatic amine. The methodology is successfully applied to the synthesis of romneine, a natural benzylisoquinoline.

Synthesis of 7-Arylthiomethyl Dibenzo[b,d]azepines through Imidoylative Heck Cyclization and CPA-Catalyzed Thio-Michael Addition/Enantioselective Protonation.

A chiral phosphoric acid-catalyzed thio-Michael addition/enantioselective protonation has been developed for the first time. The reaction applies 7-methylene-6-aryl-7H-dibenzo[b,d]azepines, products of Pd-catalyzed imidoylative Heck cyclization, as Michael acceptors in reactions with a wide range of aryl thiols. Diversified 7-[(arylthio)methyl]-7H-dibenzo[b,d]azepines bearing a benzylic stereocenter and a thermodynamically regulated biaryl axis were produced with good to excellent enantioselectivity and 14-25:1 diastereoisomeric ratios.

Chemical, Analytical and Pharmacokinetic Characterisation of RO7304898, an API Consisting of Two Rapidly Interconverting Diastereoisomers.

Exploration of the chemical, analytical and pharmacokinetic properties of the API, RO7304898, an allosteric EGFR inhibitor, intended to be developed as a mixture of two rapidly interconverting diastereoisomers with composition ratio of approximately 1:1. Assessment of diastereoisomer stereochemistry, interconversion rates, binding to EGFR protein, metabolic stability and in vivo PK in Wistar-Han rats was conducted. The two diastereoisomers of the API undergo fast interconversion at physiologically relevant pH and direct EGFR binding studies revealed diastereoisomer B to be the active moiety. Pharmacokinetic studies in rat revealed a low-moderate total plasma clearance of the API along with similar plasma concentration-time profiles for diastereoisomers A and B, and the diastereoisomeric ratio reached stable equilibrium favoring formation of the potent diastereoisomer B. In in vitro incubations, the API was metabolically stable in plasma and hepatocyte suspension incubations in all species tested except that of rat hepatocytes. Additionally, only small species differences in the A:B composition were observed in vitro with the potent diastereoisomer B being the predominant form. We demonstrated that the API, a mixture of two diastereoisomers; A (impotent) and B (potent), undergoes rapid interconversion which is faster than the apparent distribution and elimination rates of the individual diastereoisomers in vivo in rat, serving to diminish concerns that separate diastereoisomer effects may occur in subsequent pharmacologic and pivotal toxicological studies. Whilst vigilant monitoring of the diastereoisomeric ratio will need to be continued, this data adds confidence on the development pathway for this API to the clinic.

α-Amino-iso-Butyric Acid Foldamers Terminated with Rhodium(I) N-Heterocyclic Carbene Catalysts.

To investigate how remotely induced changes in ligand folding might affect catalysis by organometallic complexes, dynamic α‐amino‐iso‐butyric acid (Aib) peptide foldamers bearing rhodium(I) N‐heterocyclic carbene (NHC) complexes have been synthesized and studied. X‐ray crystallography of a foldamer with an N‐terminal azide and a C‐terminal Rh(NHC)(Cl)(diene) complex showed a racemate with a chiral axis in the Rh(NHC) complex and a distorted 310 helical body. Replacing the azide with either one or two chiral L‐α‐methylvaline (L‐αMeVal) residues gave diastereoisomeric foldamers that each possessed point, helical and axial chirality. NMR spectroscopy revealed an unequal ratio of diastereoisomers for some foldamers, indicating that the chiral conformational preference of the N‐terminal residue(s) was relayed down the 1 nm helical body to the axially chiral Rh(NHC) complex. Although the remote chiral residue(s) did not affect the stereoselectivity of hydrosilylation reactions catalysed by these foldamers, these studies suggest a potential pathway towards remote conformational control of organometallic catalysts.

Synthesis of drynaran and analogues

In a previous work, the natural compound drynaran, namely E-3-(5-hydroxymethyl)furan-2-yl)-2-phenylacrylaldehyde, was isolated from the Asian medicinal plant Drynaria bonii. Although this plant is used for several therapeutic purposes, drynaran was isolated in small quantities and, therefore, evaluated only for a few biological activities. Here, we propose a simple, fast, diastereoselective, and green synthesis of drynaran, using ethanol as solvent and 5-hydroxymethylfurfural as starting material. Drynaran was obtained in 66% yield and 98:2 E:Z diastereoisomeric ratio. The method was also used to produce a series of drynaran analogues, some of them as pure E-isomer and others in E:Z ratio of at least 90:10. Besides, five drynaran analogues formed crystals with suitable qualities for single-crystal X-ray diffraction data collection, and their crystal structures are described for the first time.

Stereoselective reduction of flavanones by marine-derived fungi

Biotransformation is an alternative with great potential to modify the structures of natural and synthetic flavonoids. Therefore, the bioreduction of synthetic halogenated flavanones employing marine-derived fungi was described, aiming the synthesis of flavan-4-ols 3a-g with high enantiomeric excesses ( ee ) of both cis- and trans -diastereoisomers (up to >99% ee ). Ten strains were screened for reduction of flavanone 2a in liquid medium and in phosphate buffer solution. The most selective strains Cladosporium sp. CBMAI 1237 and Acremonium sp. CBMAI1676 were employed for reduction of flavanones 2a-g . The fungus Cladosporium sp. CBMAI 1237 presented yields of 72–87% with 0–64% ee cis and 0–30% ee trans with diastereoisomeric ratio ( dr ) from 52:48 to 64:36 ( cis:trans ). Whereas Acremonium sp. CBMAI 1676 resulted in 31% yield with 77–99% ee of the cis and 95–99% ee of the trans- diastereoisomers 3a-g with a dr from 54:46 to 96:4 ( cis:trans ). To our knowledge, this is the first report of the brominated flavon-4-ols 3e and 3f . The use of fungi, with emphasis for these marine-derived strains, is an interesting approach for enantioselective reduction of halogenated flavanones. Therefore, this strategy can be explored to obtain enantioenriched compounds with biological activities.

Synthesis of α‐Heterocycle Anchored Spirocyclic Azetidin‐2‐ones in a Minute by p‐TSA Catalyzed Cyclocondensation of Azetidin‐2,3‐diones with Difunctionalized Substrates

AbstractMonocyclic azetidin‐2,3‐diones provide easy extensions to spiro‐fused azetidin‐2‐ones upon p‐toluenesulfonic acid (p‐TSA) catalyzed cyclocondensation reaction with difunctionalized substrates [mercaptoacids (mercaptoacetic acid, 2‐mercaptopropionic acid, 3‐mercaptopropionic acid), ethan‐1,2‐dithiol, ortho‐difunctionalized benzenes (ortho‐phenylenediamine, ortho‐aminothiophenol)]. 1,3‐Oxathiolan‐5‐one/6‐one, 1,3‐dithiolane, 2,3‐dihydrobenzo[d]imidazole and 2,3‐dihydrobenzo[d]thiazole tethered spirocyclic azetidin‐2‐ones were obtained in good overall isolated yields (69–89 %) in a very short‐time duration (max 1 min) using toluene Dean‐Stark reflux/dichloromethane rt stirring conditions. The stereochemical and spectral studies, stabilities and diastereoisomeric ratio for trans and cis spiro‐fused products are reported. The trans and cis configuration has been assigned to spiro‐β‐lactams wrt the stereochemical relationship between sulfur atom (at spiro centre) and the vicinal methine hydrogen atom at C3/C2. The absolute configuration of one trans 1,3‐oxathiolan‐5‐one fused spirocyclic azetidin‐2‐one was clearly identified by X‐ray single crystal structure analysis.

Evaluation of In-Batch and In-Flow Synthetic Strategies towards the Stereoselective Synthesis of a Fluorinated Analogue of Retro-Thiorphan.

A stereoselective synthetic strategy for the preparation of trifluoromethylamine mimics of retro-thiorphan, involving a diastereoselective, metal-free catalytic step, has been studied in batch and afforded the target molecule in good yields and high diastereoselectivity. A crucial point of the synthetic sequence was the catalytic reduction of a fluorinated enamine with trichlorosilane as reducing agent in the presence of a chiral Lewis base. The absolute configuration of the key intermediate was unambiguously assigned by X-ray analysis. The synthesis was also investigated exploiting continuous flow reactions; that is, an advanced intermediate of the target molecule was synthesized in only two in-flow synthetic modules, avoiding isolation and purifications of intermediates, leading to the isolation of the target chiral fluorinated amine in up to an 87:13 diastereoisomeric ratio.

Convergent and flexible approach to stereodefined polyhydroxylated fragments

Stereodefined acyclic polyhydroxylated fragments characteristic to polyketide natural products could be easily prepared in good yields and excellent diastereoisomeric ratios from common and simple enol carbamates. The reaction provides these fragments through a combined, one-pot sequence of metalation, carbamoyl transfer, aldol reaction, and finally Tishchenko reduction. This strategy assembles up to five consecutive stereogenic centers with exceptional stereocontrol. 2009 Elsevier Ltd. All rights reserved.

Palladium-catalyzed synthesis of 3-trifluoromethylated 1,3-dienes from acrylate derivatives and BTP

Here we reported a Pd-catalyzed coupling reaction between acrylate derivatives and BTP (2-bromo-3,3,3-trifluoropropene) to access 3-trifluoromethylated 1,3-dienes. The reaction allows the formation of the corresponding products in good to excellent yields and moderate Z/E diastereoisomeric ratios. This method broadens the current toolbox to access 3-trifluoromethylated 1,3-dienes.

Assessing Biodegradation Susceptibilities of Selected Petroleum Hydrocarbons at Contaminated Soils

Assessing Biodegradation Susceptibilities of Selected Petroleum Hydrocarbons at Contaminated Soils (M.H. Langsa): The susceptibility to biodegradation of selected saturated hydrocarbons (SHCs), polycyclic aromatic hydrocarbons (PAHs) and asphaltenes in a Barrow crude oil and extracts isolated from soils contaminated with the Barrow crude oil at day 0 and 39 was determined. Soil samples were contaminated with a Barrow crude oil across the surface (5% w/w) as part of a mesocosm experiment in order to mimic similar conditions in the environment. The extent of biodegradation of the Barrow oil extracted from the contaminated soils at day 0 and day 39 was assessed by GC-MS analyses of SHCs and PAHs fractions. Changes in the relative abundances of n-alkanes (loss of low-molecular-weight hydrocarbons) and pristane relative to phytane (Pr/Ph) and their diastereoisomers were determined. Changes in the diastereo-isomer ratios of Pr and Ph relate to the decrease in abundance of the phytol-derived 6(R),10(S) isoprenoids with increasing biodegradation. The percentage change in abundances of each of selected alkylnaphathalenes with time (day 0 to 39) was determined, enabling an order of susceptibility of their isomers to biodegradation. It was established that the 2-methylnaphthalene isomers (2-MN) is more susceptible to microbial attack than 1-MN isomer indicated by decreasing in percent abundance from day 0 to 39 for the 2-MN isomer. The GC-MS analyses of the original Barrow oil indicated the oil had not undergone biodegradation. When this oil was used in the soil mesocosm experiments the oil was shown to biodegrade to about a level 2 -3 based on the biodegradation susceptibility of the various SHCs and PAHs described above.

3-Phenylphosphaprolines – Synthesis, structure and properties of heterocyclic α-phosphanyl amino acids

“Phenylphosphaprolines”, containing trivalent phosphorus within the five-membered ring of proline, were synthesized by cyclocondensation of 2-phenylphosphanyl ethylamines 1a,b with equimolar amounts of glyoxylic acid hydrate (GAH) or pyruvic acid in diethyl ether or 1,4-dioxane. Reaction monitoring revealed primary formation of acyclic intermediates that then converted more (1a) or less (1b) rapidly to the phosphanyl amino acids cis/trans-2a,b or cis/trans-4a,b. Ammonium-ethylphosphonium-bis(glycolate) impurities, e.g. 3b, were formed when an excess of GAH was applied. The conversion of 1a with phenylformic acid via the acyclic precursors 5a and 6a to the heterocyclic product cis/trans-7a was very slow, whereas heating of the mixture in 1,4-dioxane proceeded with decarboxylation to cis/trans-8a. The structures and diastereoisomer ratios of all new compounds were determined by 1H, 31P and 13C solution NMR spectra. The cis/trans-ratio of 2a depends on the synthetic route, i.e. addition of the phosphanylethyl amine 1a to GAH (acidic medium) or of GAH to 1a (basic medium). Furthermore, this ratio changed slowly during storage of the solution of 2a in CD3OD or methanol, indicating ring-opening ring-closure reactions and lower kinetic stability than for proline. XRD analyses established the structures of trans-2a and likewise of trans-4a and trans-8a, which from concentrated solutions crystallized in pure form.

Scientific Opinion on Flavouring Group Evaluation 302 (FGE.302): N-(2-methylcyclohexyl)-2,3,4,5,6-pentafluoro-benzamide from Chemical Group 30.

The EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids was requested to evaluate N‐(2‐methylcyclohexyl)‐2,3,4,5,6‐pentafluoro‐benzamide [FL‐no: 16.119] in the Flavouring Group Evaluation 302, using the Procedure in Commission Regulation (EC) No 1565/2000. The substance is intended to be used as a flavour modifier and the current evaluation is only applicable to this use. Information on the ratios of diastereoisomers of the substance has been provided (cis 20–40% and trans 60–80%). Information on the ratio of enantiomers is lacking. The available data on genotoxicity do not preclude the evaluation of the candidate substance [FL‐no: 16.119] through the Procedure. The substance was evaluated through the B‐side of the Procedure. A ‘No Observed Adverse Effect Level’ (NOAEL) of 55 mg/kg body weight (bw) per day could be derived for [FL‐no: 16.119] from a 90‐day subchronic toxicity study in rats. This NOAEL provides an adequate margin of safety of 1.4 × 106, based on the ‘Maximised Survey‐Derived Daily Intake’ (MSDI) of 2.4 μg/capita per day. Based on the ‘modified Theoretical Added Maximum Daily Intake’ (mTAMDI) approach, the Panel concluded that more information is needed on use and use levels. Besides the safety assessment of this flavouring substance, the specifications for the material of commerce have also been considered. Additional information on the stereoisomeric composition of the flavouring substance is required.

A divergent McMurry coupling of the bis-salisaldehyde with methylene linker: The characterization of a key by-product with the possible pathway formation

ABSTRACTThe McMurry coupling of a bis-salisaldehyde 3a with methyl linker as the smallest member of its alkyl series is known to give the remarkably lower yield of the corresponding stilbenophanes. The half part of this molecule, unlike bigger analogues, is a good leaving group which affordsthreo isomer of 4H, 4′H–4,4′-bibenzo[d][1,3]dioxine 4 in high diastereoisomeric ratio (99>). A further study showed that the formation of this key by-product is the reason for formation of other by-products, namely, 5a,10b-dihydrobenzofuro[2,3-b]benzofuran 9 and 2-(2,3-dihydrobenzofuran-2-yl)phenol 10. Two reaction pathways for the formation of by-products have been proposed which are responsible for the unusual activity of dialdehyde 3a.