Facial Diastereoselectivity Research Articles

An Access to Chiral Phthalides: Enantioselective Synthesis of Escitalopram

AbstractA method for the asymmetric synthesis of phthalides containing a stereogenic γ‐carbon has been described. The protocol, based on the arylogous Michael addition to chiral alkenoyl oxazolidinones catalyzed by a crown ether under phase‐transfer conditions does not require anhydrous conditions and uses commercially available materials. A complete syn‐stereocontrol is achieved and facial diastereoselectivities are moderate to excellent (62:38 to 99:1 dr). Purification of the major diastereomer by chromatography and selective cleavage of the chiral auxiliary affords enantiopure Michael products. The protocol has been applied to the formal synthesis of escitalopram.

Unveiling the Mg(ii) promoted [3+2] cycloaddition reaction of mesitonitrile oxide to Baylis–Hilman adduct from the molecular electron density theory perspective

The presence of Mg(ii) cation does not substantially accelerate this low polarzw-type[3+2] cycloaddition reaction, but changes the facial diastereoselectivity. These low polar reactions are completelyorthoregioselective.

Synthesis of Tetrahydroisoquinolines by Visible-Light-Mediated 6-exo-trig Cyclization of α-Aminoalkyl Radicals

Starting from the respective tertiary α-silylmethyl amines, the intramolecular cyclization of α-aminoalkyl radicals to Michael acceptors produced tetrahydroisoquinolines. The reaction conditions included the use of 5 mol% of an iridium photoredox catalyst, dimethylformamide as the solvent, and equimolar amounts of water and cesium carbonate as the additives. 13 substrates were synthesized from ortho-alkylbenzaldehydes in a three-step procedure involving a carbonyl condensation, a radical bromination, and a substitution by a secondary α-silylmethyl amine. After optimization of the photocyclization, the reaction delivered tetrahydroisoquinolines in moderate to high yields (41–83%). A facial diastereoselectivity (dr ≅ 80:20) was observed with chiral substrates and a crystal structure provided evidence for the relative configuration of the major diastereoisomer. A catalytic cycle with direct electron transfer to the photoexcited metal catalyst is proposed.

Photochemical Reaction Cascade from O-Pent-4-enyl-Substituted Salicylates to Complex Multifunctional Scaffolds.

The arene ring of the title compounds is cleaved by a reaction cascade which is initiated by an intramolecular ortho photocycloaddition reaction. Tricyclic products were obtained in a highly regio- and diastereoselective fashion via a cyclooctatriene intermediate. The facial diastereoselectivity exerted by a stereogenic center in the tether is moderate to good (dr = 65/35 to 82/18). Yields were acceptable (44-87%) except for a single substrate which had a geminal dimethyl substitution in the tether and which gave the respective product in only 14% yield. The reaction is stereoconvergent with regard to the olefin configuration ( E or Z) in agreement with a triplet mechanism of the ortho photocycloaddition step.

Diels–Alder Reactions of 1,3-Dienes Incorporated into 8-Oxa- and 8-Thiabicyclo[3.2.1]octane Skeletons: A Convenient Access to Complex Tri- and Tetracyclic Compounds

The Diels–Alder reactions of eight different 1,3-dienes incorporated into an 8-oxa- or 8-thiabicyclo[3.2.1]octane backbone were studied employing N -phenylmaleimide as standard dienophile. The facial diastereoselectivity was very high, in all cases furnishing only products resulting from a top-face attack. The [4+2] cycloadditions proceeded often with high exo / endo selectivity depending on the substitution degree of the 1,3-diene system. For one of the 1,3-dienes it could be demonstrated that the scope of the Diels–Alder reaction is fairly broad. The approach described here allows an efficient and fast access to complex tri- and tetracyclic compounds ready for further functionalization.

SN1‐Type Substitution Reactions of N‐Protected β‐Hydroxytyrosine Esters: Stereoselective Synthesis of β‐Aryl and β‐Alkyltyrosines

The title compounds were prepared by aldol reaction of anisaldehyde and the respective N,N-dibenzyl glycinates. Deprotection of the nitrogen atom with Pearlman's catalyst delivered the unprotected β-hydroxytyrosine esters, which were further N-protected as N,N-phthaloyl (Phth) and N-fluorenylmethylcarbonyloxy (Fmoc) derivatives. The Friedel-Crafts reaction with various arenes was studied employing these alcohols as electrophiles. It turned out that the facial diastereoselectivitiy depends on the nitrogen protecting group and on the ester group. The unprotected substrates (NH(2)) gave preferentially syn-products but the anti-selectivity increased when going from NHFmoc over NPhth to NBn(2). If the ester substituent was varied the syn-preference increased in the order Me < Et < iPr. The reactions were shown to be fully stereoconvergent and proceeded under kinetic product control. A model is suggested to explain the facial diastereoselectivity based on a conformationally locked benzylic cation intermediate. The reactions are preparatively useful for the N-unprotected isopropyl ester, which gave Friedel-Crafts alkylation products with good syn-selectivity (anti/syn=21:79 to 7:93), and for the N,N-dibenzyl-protected methyl ester, which led preferentially to anti-products (anti/syn=80:20 to >95:5). Upon acetylation of the latter compound to the respective acetate, Bi(OTf)(3) -catalyzed alkylation reactions became possible, in which silyl enol ethers served as nucleophiles. The respective alkylation products were obtained in high yield and with excellent anti-selectivitiy (anti/syn≥95:5).

Synthesis of Purine Nucleosides Built on a 3-Oxabicyclo[3.2.0]heptane Scaffold

The photochemical [2 + 2] cycloaddition of chiral 3-chloro and 3-fluoro-5-hydroxymethyl-2(5H)-furanone to ethylene and acetylene has been studied. The effect of the halogen atom on the chemical yield and facial diastereoselectivity of the cycloaddition process has been evaluated. From the major anti cycloadducts, practical syntheses of several purine cyclobutane and cyclobutene-fused nucleosides containing a halogen atom have been developed. The anti-HIV activity of the new nucleoside analogues has been evaluated.

Per(poly)fluoroalkanesulfinamides assisted diastereoselective three-component inverse-electron-demand aza Diels–Alder reaction

A highly diastereoselective three-component inverse-electron-demand aza Diels-Alder reaction assisted by per(poly)fluoro-alkanesulfinamides is presented, providing a broad spectrum of highly functionalized piperidine derivatives with excellent endo/exo and facial diastereoselectivities. The electron-withdrawing perfluoroalkyl groups are crucial for the success of this reaction under mild conditions and facilitate monitoring the process and stereoselectivities of the reaction. The synthetic potential of these cycloadducts is also highlighted.

ChemInform Abstract: Hetero-Diels-Alder Reactions of Homochiral 1,2-Diaza-1,3-butadienes with Diethyl Azodicarboxylate under Microwave Irradiation. Theoretical Rationale of the Stereochemical Outcome.

The stereoselective normal electron demand Diels−Alder reactions of chiral 1,2-diaza-1,3-butadienes, derived from acyclic carbohydrates having different configurations (1−6), with diethyl azodicarboxylate (DEAD) are disclosed. Reactions proceed slowly in benzene solution at room temperature, but are greatly accelerated by microwave irradiation to form the corresponding functionalized 1,2,3,6-tetrahydro-1,2,3,4-tetrazines (7−18) in good yields. The observed stereoselectivity is markedly dependent on the relative stereochemistry at C-1‘,2‘. Thus, 1,2-diazoalkenes derived from per-O-acylated sugars having threo configuration at C-1‘,2‘ give tetrazines with a high facial selectivity, whereas those having erythro configuration at C-1‘,2‘ afford products in lower diastereomeric ratios. The facial diastereoselection has been rationalized by a PM3 computational study. These results prove that in the transition structures (TSs) the reacting azoalkene exhibits formal negative charges at C-3 and N-2, the former bein...

Reação da cânfora com boroidreto de sódio: uma estratégia para o estudo da estereoquímica da reação de redução

Reduction of camphor to a mixture of borneol and isoborneol was performed using NaBH4 as the reducing agent under suitable conditions. Although more effective reduction was accomplished using toxic methanol, an alternative non-toxic ethanolic system is described. This experiment is important to introduce undergraduate students in reductive procedures, and can be used to show details on stereoselective procedures on carbonyl moieties (facial diastereoselectivity, Burgi-Dunitz trajectory, diastereomeric excess).

Paternò-Büchi Reactions of Silyl Enol Ethers and Enamides

3-(Silyloxy)oxetanes are obtained by irradiating mixtures of aromatic aldehydes and silyl enol ethers in benzene as the solvent. The reactions occur with high simple diastereosciectivity and, when R' is chiral, with high facial diastereoselectivity. Under similar conditions, but in acetonitrile rather than benzene as the preferred solvent, the Paternoo-Buchi reaction of N-acyl enamines (enamides) gives the corresponding protected 3-aminooxetanes. The cis-products are obtained with significant simple diastereoselectivity.

Gas-Phase Facial Diastereoselectivity of Equatorial and Axial 4-Chloro-adamant-2-yl Cations

The acid-catalyzed addition of CH3(18)OH to 2-methylene-adamantanes bearing a chlorine atom in the 4-equatorial (1e) or 4-axial (1a) position has been investigated in the gas phase, at 760 Torr, in the 40-120 degrees C temperature range. Two different experimental approaches were employed: (1) by adding neutral CH3(18)OH to the 2-methyl-4-Cl-adamant-2-yl cation, generated by protonation of the corresponding 2-methylene-4-Cl-adamantane (the extracomplex reaction) and (2) by reaction of 2-methylene-4-Cl-adamantane with CH3(18)OH2+, generated by methylation of H2(18)O (the intracomplex reaction). The crucial role of the nature of the noncovalent intermediates involved along the reaction coordinates emerges from the difference between the results obtained in the extracomplex and intracomplex reactions for both substrates investigated. The kinetic and stereochemical results indicate that the 4-Cl substituent plays a different role depending on its equatorial or axial orientation. Examination of the experimental results in the light of MP2/6-31G* theoretical calculations provides important information about the intrinsic factors governing the facial diastereoselectivity of trigonal carbocations. The effects due to differential face solvation phenomena emerge from the comparison of the present gas-phase results with those obtained from strictly related studies in solution.

Stereoselective Control of Planar α-Dimethylsulfonium Benzyl Carbanions. Synthesis of Optically Pure trans-Aziridines

(R)-N-sulfinylimine and (S)-N-sulfinylimine react with the ylide derived from (S)-dimethyl-[2-(p-toluenesulfinyl)phenyl]sulfonium salt, affording trans-2,3-disubstituted aziridines. A complete trans selectivity in low facial diastereoselectivity is observed when the configuration at the sulfur atoms of the reagents is the same. Otherwise, when their configurations are different, the reaction evolved with total facial diastereoselectivity and the cis/trans ratio ranged between 1/4.2 and 1/9. Theoretical calculations indicate the reaction proceeds mainly by evolution of a planar free carbanion. The relative stability of the transition states predicts a trans/cis ratio that is in excellent agreement with the experimental results.

Regio- and diastereoselectivity studies on the photocycloaddition of ketene diethyl acetal to chiral 2(5 H)-furanones

The photochemical [2+2] cycloaddition of 1,1-diethoxyethylene to chiral 2(5 H)-furanones is investigated. The effect of the substituents of the lactone and the polarity of the solvents on the chemical yield, regioselectivity, and facial diastereoselectivity is evaluated. The reactions in ether proceed with excellent regioselectivity and good yields. Hydrolysis of the ketal group of the major cycloadducts afforded enantiopure cyclobutanones fused to γ-lactones.

Diastereoselective Friedel−Crafts Alkylation of Indoles with Chiral α-Phenyl Benzylic Cations. Asymmetric Synthesis of Anti-1,1,2-Triarylalkanes

The reactions of chiral benzyl carbocations bearing alpha-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with anti-selectivities. This outcome is a reversal of facial diastereoselectivity relative to Bach's alpha-alkyl-bearing benzyl cations. The reactions are promoted by either a Brønsted acid (TFA) or Lewis acid (BF3.OEt2), offering differential diastereoselectivities and reactivities. The electronic properties of both reacting partners strongly influence the reaction rates and the product diastereoselectivities and appear to operate under kinetic control. This chemistry provides an efficient access to sterically congested tetrasubstituted ethanes.

Dye-sensitized photooxygenation of sugar furans: novel bis-epoxide and spirocyclic C-nucleosides

Dye-sensitized photooxygenation of 2-methyl 5-(2,3,5-tri- O-acetyl-β- d-ribofuranosyl)furoate leads to (1 S,4 R)- endo-peroxide, highlighting a high facial diastereoselectivity. This endo-peroxide rearranges into syn-(1 R,2 R:3 S,4 R)-diepoxide C-nucleoside, while by Et 2S-reduction followed by NEt 3 catalysis affords a spirocyclic C-nucleoside.

Highly Diastereoselective Friedel–Crafts Alkylation Reactions via Chiral α‐Functionalized Benzylic Carbocations

A series of chiral 1-aryl-1-alkanols, which carry different functional groups (FGs) at the 2-position, were subjected to an acid (HBF4)-catalyzed reaction with various arenes. An S(N)1 substitution reaction was observed, in the course of which 1,1-diarylalkanes were formed. In most cases (40 out of 51 reactions), yields were very good to excellent (75-99 %). The diastereoselectivity of the reaction was heavily dependent on the FG at the 2-position. If the FG was methoxycarbonyl, nitro, hydroxy, cyano, trimethylsilylethynyl, or chloro, the corresponding anti products were favored and with a decreasing preference in this order. The methoxycarbonyl-substituted substrates gave the anti products with diastereomer ratios (d.r.) that exceeded 92:8 (16 examples). Nitro- and hydroxy-substituted products were obtained in most instances with d.r. > or = 90:10, whereas cyano-, trimethylsilylalkynyl-, or chloro-substituted substrates delivered only with certain arenes products with high selectivity (d.r. > or = 90:10). The sterically more demanding FGs ethylsulfonyl, ethoxysulfonyl, and diethoxyphosphonyl induced diastereofacial selectivity in favor of the corresponding syn products, with diethoxyphosphonyl being the most effective. The substrate with FG = PO(OEt)2 delivered, with eight different arenes, the corresponding syn substitution products (d.r. = 80:20 - >95:5). The relative configuration of the products was elucidated by spectroscopic and synthetic methods. On selected examples, the reactions were shown to proceed stereoconvergently, under kinetic control, and without racemization. Depending on the functional group, the onset of the reactions between 2-methylthiophene and some representative alcohols was found to occur at a temperature Theta between -78 and -40 degrees C. There was no correlation between the selectivity and theta. A model is suggested to explain the facial diastereoselectivity based on a preferred conformation of the putative intermediate carbocation.

Ionic liquids in methyltrioxorhenium catalyzed epoxidation–methanolysis of glycals under homogeneous and heterogeneous conditions

The efficient and high yielding domino epoxidation–methanolysis of glycals has been achieved under environment friendly conditions by oxidation with urea hydrogen peroxide adduct (UHP) and H 2O 2 in ionic liquids (ILs) catalyzed by methyltrioxorhenium and different heterogeneous methyltrioxorhenium derivatives. The facial diastereoselectivity of the oxidation ranged from satisfactory to excellent ones depending on the substrate and could be optimized by ample screening of catalysts. The oxidations performed with UHP proceeded with a higher degree of diastereoselectivity than those performed with H 2O 2. High yields of products and conversions of substrates were obtained under mild experimental conditions and by the use of simple work-up procedures.

Chemo- and diastereoselective Bi(OTf) 3-catalyzed benzylation of silyl nucleophiles

The direct alkylation of silyl enol ethers with para-methoxybenzylic alcohols or their corresponding acetates was efficiently catalyzed by Bi(OTf) 3 in CH 3NO 2 as the solvent. The reaction provided the α-benzylated carbonyl compounds in high yields after short reaction times using 1–2.5 mol % of the catalyst. Benzylic acetates other than para-methoxybenzylic acetates also underwent the reaction. High facial diastereoselectivities were observed with acetates derived from chiral α-branched para-methoxybenzylic alcohols. In addition, a catalytic reduction with Et 3SiH as the reducing agent is reported.

Chiral tetrahydroquinoline derivatives as potent anti-hyperalgesic agents in animal models of sustained inflammation and chronic neuropathic pain

Chiral tetrahydroquinoline derivatives have been prepared by an asymmetric Mannich-type condensation reaction using commercially available vinyloxyethylsilane and a N-arylimino R-(+)- t-butyl lactate ester, in the presence of a catalytic amount of metal triflates as Lewis acids. This synthetic approach gave rise to the target aldehyde intermediate in moderate facial diastereoselectivity and in high chemical yield. This efficient route enabled to scale up the synthesis of an orally bioavailable glycine antagonist showing outstanding in vivo anti-hyperalgesic activity in different animal models of sustained inflammation and chronic neuropathic pain.