Allylic Hydroxy Group Research Articles

Die Totalsynthese von Isoxeniolid A**

AbstractIsoxeniolid A ist ein hochgespanntes marines Diterpenoid aus der Familie der Xenicane. Es steht repräsentativ für eine Unterfamilie von Xenicanen, deren 9‐gliedriger Ring eine allylische Hydroxygruppe aufweist; derartige Xenicane wurden bisher nicht als Zielmoleküle von Totalsynthesen verfolgt. Wir beschreiben hier die erste asymmetrische Totalsynthese eines derartigen Xenicans, nämlich des Isoxeniolid A. Dabei lag der Schlüssel zum Aufbau des besonders herausfordernden E‐konfigurierten Cyclononenrings in einer diastereoselektiven intramolekularen Nozaki–Hiyama—Kishi‐Reaktion. Andere wichtige Transformationen waren eine enzymatische Desymmetrisierung zur Kontrolle der absoluten Stereochemie, eine diastereoselektive Cuprat‐Addition und die Verwendung eines bifunktionalen Vinylsilan‐Bausteins. Unsere Synthesestrategie ermöglicht auch den Zugang zur enantiomeren Form des Naturstoffs sowie prinzipiell zu einer Vielzahl anderer natürlicher Xenicane und synthetischer Analoga für Struktur‐Aktivitäts‐Untersuchungen.

Total Synthesis of Isoxeniolide A.

Isoxeniolide A is a highly strained xenicane diterpenoid of marine origin. This natural product is representative for a subfamily of xenicanes incorporating an allylic hydroxy group in the nine-membered ring; members of this xenicane subfamily so far have not been targeted by total synthesis. Herein, we describe the first asymmetric total synthesis of isoxeniolide A. Key to forming the challenging E-configured cyclononene ring was a diastereoselective intramolecular Nozaki-Hiyama-Kishi reaction. Other important transformations include an enzymatic desymmetrization for absolute stereocontrol, a diastereoselective cuprate addition and the use of a bifunctional vinyl silane building block. Our strategy also permits access to the enantiomer of the natural product and holds potential to access a multitude of xenicane natural products and analogs for structure-activity relationship studies.

Concise Total Syntheses of (+)‐Brefeldin A, Diastereomers and Analogs and Their Biological Activity

AbstractBrefeldin A is an important natural product and biochemical tool with cell‐modulating and other diverse biological activities. To explore its chemical space, a generally applicable strategy for total syntheses of naturally occurring (+)‐brefeldin A (BFA), 2‐epi‐BFA, their diastereomers and analogs with varying macrocyclic ring size is reported. The five‐membered ring fragment was constructed by a short three‐step sequence consisting of tandem nucleophilic epoxide opening/Brook rearrangement/radical oxygenation and subsequent thermal radical cyclization based on the persistent radical effect. Further key steps are asymmetric aldehyde vinylation, which enables control of the absolute configuration at the allylic hydroxy group of BFA, cross‐metatheses reactions for attachment of the northern and southern side chains to the cyclopentane unit and final Shiina macrolactonization. The cytotoxic activity of all compounds was determined, and several analogs proved to be similarly active as BFA, providing insight about regions of the skeleton that can be varied or have to be conserved with respect to their biological activities. Fluorescence microscopy revealed that BFA and some non‐natural analogs disassemble the Golgi apparatus in cells with large variation of the disassembly and subsequent reassembly times.

Unified synthesis and assessment of tumor cell migration inhibitory activity of optically active UTKO1, originally designed moverastin analog.

UTKO1 is a synthetic analog of a natural tumor cell migration inhibitor, moverastin, isolated from microbial extracts of Aspergillus sp. 7720. UTKO1 was initially developed as a mixture of the stereoisomers. In this study, a concise and unified synthesis of the 4 optically active stereoisomers of UTKO1 was achieved from a known optically pure dihydro-α-ionone through a 5-step sequence. The key transformation in the synthesis was a Nozaki-Hiyama-Kishi (NHK) reaction between an optically active enoltriflate and a known aldehyde to install the chiral allylic hydroxy group at C2'. Simple chromatographic separation of the 2 diastereomers with regard to the allylic hydroxy group was possible by the derivatization into the corresponding acetals with Nemoto's optical resolution reagent, (S)- or (R)-5-allyl-2-oxabicyclo[3.3.0]octene (ALBO). All 4 synthetic stereoisomers of UTKO1 exhibited comparable tumor cell migration inhibitory activity.

2,3-cis-Cyclization of 4-pentenoxyl radicals

4-Pentenoxyl radicals cyclize 2,3-cis-selectively, when substituted by an allylic hydroxy, acetyloxy, or benzoyloxy group. Additional substituents increase or decrease the fraction of 2,3-cis-cyclized product, depending on relative configuration, positioning, and their chemical nature. The preference for 3-acceptor-subsituted pentenoxyl radicals to furnish products of 2,3-cis-ring closure arises from a secondary orbital interaction between the allylic oxygen substituent and the alkene entity, kinetically disfavoring the 2,3-trans-mode of 5-exo-cyclization. Aligning the β-C,O-bond in anticline orientation to the plane of the alkene, which is the preferred conformation for transition structures for 2,3-trans-cyclization, stabilizes the double bond by delocalizing π-electrons into the σ*(C,O)-orbital. Along with energy decreases the affinity of π-electrons for forming a σ (C,O)-bond with the oxygen radical. In 2,3-cis-cyclization, a similar stabilizing effect cannot occur, because the allylic oxygen substituent and the alkene align synperiplanar. The kinetic effect of an allylic oxygen substituent becomes furthermore apparent in cyclization of the 3-hydroxynona-1,8-dien-5-oxyl radical, favoring intramolecular addition to the unsubstituted allylic double bond by a factor three.

Epoxidation of trans-4-Aminocyclohex-2-en-1-ol Derivatives: Competition of Hydroxy-Directed and Ammonium-Directed Pathways

N-Substituted trans-4-aminocyclohex-2-en-1-ols undergo epoxidation upon treatment with Cl3CCO2H followed by meta-chloroperbenzoic acid (m-CPBA) via competitive pathways resulting from hydrogen-bonding delivery by both the hydroxy group and the in situ formed ammonium ion. The absence of epoxide ring-opening in these reactions renders these substrates a unique platform for analysing the effect of the two competing directing groups on the rate of the epoxidation reaction: the diastereoisomeric ratio of the epoxide products is also the ratio of the rate constants describing the competing epoxidation processes (the group with the higher directing ability dominating the stereochemical course of the reaction). Analysis of the diastereoisomeric epoxide mixtures obtained from these reactions allowed the following order of directing group ability to be defined: NHBn >> NMeBn > OH > NBn2. The large difference in rate between the secondary and tertiary amino groups is consistent with superior directing ability of the former due to the presence of two hydrogen-bond donor sites on the secondary ammonium ion and/or an increased conformational flexibility to adopt an optimum geometry. The rate of an ammonium-directed epoxidation proceeds ~10 times slower in the presence of an allylic hydroxy group than in its absence, consistent with the presence of the additional, inductively electron-withdrawing heteroatom abating the nucleophilicity of the olefin. The relative rate of the hydroxy-directed epoxidation process in the presence of a more sterically demanding ammonium substituent is greater than that in the presence of a less sterically demanding one: this effect is attributed to an increased bias for the half-chair conformer in which the bulky ammonium substituent and, hence, the hydroxy group occupy pseudo-equatorial sites, thus allowing the latter to direct the reaction more efficiently.

Asymmetric Synthesis of 2-Propylisofagomine Using Allylic Hydroxy Group Accelerated Ring-Closing Enyne Metathesis

Asymmetric Synthesis of 2-Propylisofagomine Using Allylic Hydroxy Group Accelerated Ring-Closing Enyne Metathesis

ChemInform Abstract: The Allylic Chalcogen Effect in Olefin Metathesis

AbstractReview: 45 refs.

The allylic chalcogen effect in olefin metathesis

Olefin metathesis has emerged as a powerful tool in organic synthesis. The activating effect of an allylic hydroxy group in metathesis has been known for more than 10 years, and many organic chemists have taken advantage of this positive influence for efficient synthesis of natural products. Recently, the discovery of the rate enhancement by allyl sulfides in aqueous cross-metathesis has allowed the first examples of such a reaction on proteins. This led to a new benchmark in substrate complexity for cross-metathesis and expanded the potential of olefin metathesis for other applications in chemical biology. The enhanced reactivity of allyl sulfide, along with earlier reports of a similar effect by allylic hydroxy groups, suggests that allyl chalcogens generally play an important role in modulating the rate of olefin metathesis. In this review, we discuss the effect of allylic chalcogens in olefin metathesis and highlight its most recent applications in synthetic chemistry and protein modifications.

ChemInform Abstract: Asymmetric Synthesis of N-Methyl-α-amino Esters from a Glyoxal Derived Chiral Heterocycle.

Abstract The reaction between a chiral template derived from glyoxal with organometallic reagents leads ultimately to the optically active title compounds. The stereochemical outcome of the key-step which involves substitution of a thiophenol group depends on the organometallic: predominantly inversion with alkyl copper or complete retention with alkyl zinc halides. The stereodirecting effect of an allylic hydroxy group in an iminium intermediate is evidenced in the case of the organozinc reagent.

ChemInform Abstract: Further Study on the Regioselectivity of (Dimethylvinylidene)carbene upon the Cycloaddition to the α,β-Unsaturated Double Bond of an Allylic Alcohol and the Normal Olefinic Group.

Abstract Further study on the regioselective addition of vinylidenecarbene 1 to the α,β-unsaturated double bond of allylic alcohol and the normal olefinic group is described. This selectivity was found to be influenced by both of the allylic hydroxy group and the degree of alkyl substitution of the double bonds.

Effect of the allylic substituents on ring closing metathesis: the total synthesis of stagonolide B and 4-epi-stagonolide B

The total syntheses of stagonolide B and its 4-epimer were carried out to probe into how the relative stereochemistry of allylic hydroxy groups and their protecting groups influence the efficiency of the ring closing metathesis.

Stereoselective synthesis of 2-C-methylene glycosides and disaccharides via direct allylic substitution of hydroxy group in benzylated glycals

InCl3 efficiently catalyzes allylic substitution of the hydroxy group of 2-C-hydroxymethyl glycals to afford a diversity of 2-C-methylene alkyl and aryl glycosides as well as disaccharides in high yields. This protocol surpasses the existing methods for the synthesis of 2-C-methylene glycosides as it obviates the need for functionalizing the allylic hydroxy group of glycals. The interest of this methodology relies on the extremely mild conditions required even with a free hydroxyl group at the allylic position of the glycals and that too only with a catalytic amount of InCl3. The reaction is fast (30min.), stereoselective and is compatible with a variety of oxygenated nucleophiles including those possessing acid-labile groups. A mechanistic investigation on the direct formation of an α,α-(1→1)linked disaccharide derivative from 2-C-hydroxymethyl galactal reveals that the reaction proceeds through a domino Ferrier rearrangement followed by a facile 1,3-alkoxy migration.

ChemInform Abstract: Acceleration Effect of an Allylic Hydroxy Group on Ring‐Closing Enyne Metathesis of Terminal Alkynes: Scope, Application, and Mechanistic Insights.

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.

Acceleration Effect of an Allylic Hydroxy Group on Ring‐Closing Enyne Metathesis of Terminal Alkynes: Scope, Application, and Mechanistic Insights

An interesting acceleration effect of an allylic hydroxy group on ring-closing enyne metathesis has been found. Ring-closing enyne metathesis of terminal alkynes possessing an allylic hydroxy group proceeded smoothly without the ethylene atmosphere generally necessary to promote the reaction. The synthesis of (+)-isofagomine with the aid of this efficient reaction has been demonstrated. Mechanistic studies of the acceleration effect were also carried out. Results of NMR studies suggested that the reaction proceeded via an "ene-then-yne" pathway. Kinetic studies indicated switching of the rate-determining step as a consequence of the presence of an allylic hydroxy group. These results suggest acceleration of the reentry step of Ru-carbene species by the allylic hydroxy group.

ChemInform Abstract: Acceleration Effect of Allylic Hydroxy Group on Ring‐Closing Enyne Metathesis of Terminal Alkynes: Scope and Application to the Synthesis of Isofagomine.

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.

Acceleration effect of allylic hydroxy group on ring-closing enyne metathesis of terminal alkynes: scope and application to the synthesis of isofagomine

An interesting allylic substituent effect on ring-closing enyne metathesis has been found. An allylic hydroxy group on enyne substrates accelerates ring-closing enyne metathesis of terminal alkynes. The reaction proceeds smoothly without ethylene atmosphere and/or more reactive newer generation Ru-carbene catalysts, which are generally necessary to promote the reaction. This efficient reaction was applied to the synthesis of isofagomine.

Synthesis of Dihydrofurans and Dihydropyrans with Unsaturated Side Chains Based on Ring Size‐Selective Ring‐Closing Metathesis

AbstractEnantiomerically pure 1,5‐hexadiene‐3,4‐diol, derived from D‐mannitol in a few steps, may serve as a starting material for enantiopure dihydropyrans and dihydrofurans bearing an unsaturated side chain which is amenable for further synthetic transformations. The synthesis relies on a ring size‐selective ring‐closing metathesis reaction of a triene. Most likely, a catalyst‐directing effect of an allylic hydroxy group is responsible for the selectivity.

N-Acyl migration in ceramides

Upon exposure of truncated ceramides, such as N-acetyl-sphingenine, and long-chain ceramides to moderate acidic conditions, three derivatives are formed. Two of them turned out to be O-acylated sphingenine, 1-O- and 3-O-acyl-sphingenine, and the other was identified as sphingenine. Truncated dihydroceramides (e.g., N-acetyl- and N-hexanoyl-sphinganine) also show this type of rearrangement, which is therefore not related to the presence of the allylic hydroxy group or to the length of the N-acyl chain. Of particular concern is the fact that the O-acylated compounds, which can be considered sphingoid base analogs, can be formed in chloroform or chloroform-methanol mixtures upon storage. For long-term storage, methanol or dichloromethane is the preferred solvent. A procedure to document the presence/formation of such O-acylated sphingoid bases in ceramide solutions in the picomole range, based on reversed-phase chromatography after derivatization of their amino group with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate, is presented.

Absolute Configuration, Conformation, and Circular Dichroism of Monocyclic Arene Dihydrodiol Metabolites: It is All Due to the Heteroatom Substituents

Absolute configurations and conformations of selected cis-1,2-dihydrodiols, isolated from bacterial enzyme-catalyzed arene dihydroxylation, have been examined by comparison of experimental and DFT-calculated CD spectra and confrontation with the results of X-ray diffraction studies in the crystalline phase. The equilibrium between the diene P and M conformers in cis-dihydrodiols is strongly dependent on the intramolecular OH-OH, OH-pi, and OH-F hydrogen bonding pattern and is crucial in determining the sign and magnitude of the long-wavelength diene pi-pi transition Cotton effect. The differences originate from a dominant contribution of either P-helical (1b, X=Me) or M-helical conformers (1d, X=F), or are due to M and P low-energy conformers, both contributing a positive rotational strength (1c, X=Br). Computations show that cis-dihydrodiol 1e (X=CF3) has only one M conformer stabilized by an intramolecular O-H...F hydrogen bond. cis-Dihydrodiol 1f (X=CN) shows a Cotton effect of the sign opposite to the sense of helicity of the dominating conformer. The results of the computations highlight the inadequacy of the Diene Helicity Rule and the Allylic Chirality Rule to correlate observed Cotton effects with dihydrodiol absolute configuration. A reliable model is presented to predict the absolute configuration of substituted benzene dihydrodiol derivatives from CD spectra, based on the confrontation of DFT-computed and experimental CD spectra. For 3-alkyl derivatives, a simple noncomputational model is offered, which is based on the contributions of the allylic hydroxy groups and the diene core in P and M conformers.