Intramolecular oxa-Michael Reaction Research Articles

An Organocatalytic Highly Enantioselective Stereospecific Synthesis of 1,1-Disubstituted-1,3-Dihydroisobenzofurans.

Herein, we disclosed the asymmetric construction of an oxa-quaternary stereocenter via an intramolecular oxa-Michael (IOM) reaction in β-substituted ortho-hydroxymethyl chalcone by the formation of 1,1-disubstituted-1,3-dihydroisobenzofuran using cinchona alkaloid-based chiral amino-squaramide catalyst. Both the (E- and Z)-β-substituted ortho-hydroxymethyl chalcone provide (S)- and (R)-enantiomers of the 1,1-disubstituted-1,3-dihydroisobenzofuran with excellent stereospecificity. In general, excellent yields (up to 95 %) and enantioselectivity (up to 98 % ee) were obtained. Furthermore, the resulting 1,1-disubstituted isobenzofuran or phthalan was converted to corresponding chiral 3,3-disubstituted phthalides without losing the enantioselectivity. This methodology provides the core moiety of the (S)-citalopram drug.

Catalytic role of the enol ether intermediate in the intramolecular Stetter reaction: a computational perspective.

The intramolecular Stetter reaction catalyzed by a carbene is investigated by density functional theory (DFT) calculations and kinetic simulations. Catalyst 1 first reacts with aldehyde 2 to give the primary adduct (PA). The PA undergoes the intramolecular oxa-Michael reaction to irreversibly generate enol ether intermediate 9. The conversion of the enol ether to the Breslow intermediate (BI) requires the assistance of a base such as the PA. The next step involves formation of a carbon-carbon bond through the Michael addition, and expulsion of the catalyst generates the Stetter product 7. Calculations show that the catalytic cycle is composed of two irreversible processes: the first one involves the exergonic formation of the enol ether intermediate, while the second one is the conversion of the enol ether to the final product. Kinetic simulations using initial concentrations of [1]0 = 0.005 M and [2]0 = 0.025 M demonstrate that under a steady-state condition, 35% of the catalyst rests on the state of the enol ether (0.0018 M). The catalyst resting state therefore consists of the unbound form (the free catalyst) and its bound form (the enol ether species). According to variable time normalization analysis, the reaction exhibits a second-order dependence (first order in catalyst and first order in substrate), which agrees with experiments. The oxa-Michael reaction to form the enol ether is identified to be turnover limiting in the intramolecular Stetter reaction, which rationalizes the observed electronic effect of the Michael acceptor on the reactivity, as well as the measured isotope effect with respect to the aldehydic proton/deuteron. The base that participates in the BI formation has a significant effect on the build-up of the resting state 9 and the active catalyst concentration. In addition, the thermodynamic stability of the enol ether is found to depend on the tether length between the aromatic aldehyde and the Michael acceptor, as well as the chemical nature of the carbene catalyst. The favorability for the oxa-Michael reaction is therefore suggested to govern the reactivity of the intramolecular Stetter transformation.

Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α,β-Unsaturated Esters and Amides.

A bifunctional iminophosphorane (BIMP)-catalyzed, enantioselective intramolecular oxa-Michael reaction of alcohols to tethered, low electrophilicity Michael acceptors is described. Improved reactivity over previous reports (1 day vs 7 days), excellent yields (up to 99%), and enantiomeric ratios (up to 99.5:0.5 er) are demonstrated. The broad reaction scope, enabled by catalyst modularity and tunability, includes substituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), oxaspirocycles, sugar and natural product derivatives, dihydro-(iso)-benzofurans, and iso-chromans. A state-of-the-art computational study revealed that the enantioselectivity originates from the presence of several favorable intermolecular hydrogen bonds between the BIMP catalyst and the substrate that induce stabilizing electrostatic and orbital interactions. The newly developed catalytic enantioselective approach was carried out on multigram scale, and multiple Michael adducts were further derivatized to an array of useful building blocks, providing access to enantioenriched biologically active molecules and natural products.

Squaramide-Catalyzed Asymmetric Intramolecular Oxa-Michael Reaction of α,β-Unsaturated Carbonyls Containing Benzyl Alcohol: Construction of Chiral 1-Substituted Phthalans.

Organocatalytic enantioselective intramolecular oxa-Michael reactions of benzyl alcohol bearing α,β-unsaturated carbonyls as Michael acceptors are presented herein. Using cinchona squaramide-based organocatalyst, enones as well as α,β-unsaturated esters containing benzyl alcohol provided their corresponding 1,3-dihydroisobenzofuranyl-1-methylene ketones and 1,3-dihydroisobenzofuranyl-1-methylene esters in excellent yields with high enantioselectivities. In addition, enantioenriched 1,3-dihydroisobenzofuranyl-1-methylene ketone could be obtained from the Wittig/oxa-Michael reaction cascade of 1,3-dihydro-2-benzofuran-1-ol.

A divergent chiron approach for the first total synthesis of (+)-pseudonocardide A, (+)-pseudonocardide C and an epimer of ent-pseudonocardide D.

A concise and divergent chiron approach for the first total synthesis of (+)-pseudonocardide A, (+)-pseudonocardide C and an epimer of ent-pseudonocardide D is reported starting from d-ribose. The salient features of this synthesis are a highly Z-selective Wittig olefination, one-pot formation of γ-butyrolactone and γ-butenolide through [1,4] O-to-O silyl migration followed by lactonization and an intramolecular oxa-Michael reaction.

Stereoselective synthesis towards (+)-trans-kumausyne employing vinylogous Mukaiyama type reaction on an α-chloro sulfide

A stereoselective synthesis towards (+)- trans- kumausyne is disclosed. The key steps of the synthesis include stereoselective C-C formation employing vinylogous Mukaiyama type reaction of an α-chloro sulfide with 2-trimethylsiloxy furan and base-catalyzed isomerization followed by intramolecular oxa-Michael reaction.

Total Synthesis and Structural Revision of Greensporone F and Dechlorogreensporone F.

The first asymmetric total syntheses of the real isolation product (2S,5R,8R)-greensporone F and (2S,5R,8R)-dechlorogreensporone F, 14-membered resorcylic acid lactones with a cis-2,5-disubstituted tetrahydrofuran ring system, was accomplished. The synthesis features a late-stage Lewis acid-catalyzed stereoselective intramolecular oxa-Michael reaction, E-selective ring-closing metathesis, De Brabander's esterification, and Jacobsen's hydrolytic kinetic resolution as the key steps. Synthesis of both real isolation and erroneously proposed structure necessitated the revision of the absolute configuration of greensporone F and dechlorogreensporone F. The erroneous representation of (2S,5S,8S)-configuration in greensporone F and dechlorogreensporone F was assigned to be (2S,5R,8R) by comparison with the NMR data and specific rotation of the synthetic compounds with that of the reported data.

Intramolecular Oxa-Michael Reactions of Aldols Generated from Enones and Isatins to Afford Spirooxindole Tetrahydropyrans

Intramolecular Oxa-Michael Reactions of Aldols Generated from Enones and Isatins to Afford Spirooxindole Tetrahydropyrans

Synthesis of C1–C11 eribulin fragment and its diastereomeric analogues

A practical stereoselective synthesis of the central C1–C10 fragment of eribulin and its two diastereomeric analogues is developed. Our approach relied on the use of l-ascorbic acid as the starting material which allowed accessing a key intermediate with a syn diol moiety (C9 and C10 of eribulin) and a carboxylic ester group. A functionalized six membered lactone having several required hydroxyl groups was then obtained. In a number of steps, the lactone was converted to an intermediate for our key oxa-Michael reaction. A regio- and stereocontrolled intramolecular oxa-Michael reaction completed the synthesis of the C1–11 fragment having a trans-fused tetrahydropyrans with the exact stereochemistry of various hydroxyl groups, as in eribulin.

Approach to the Core Structure of 15-epi-Exiguolide

The synthesis of seco acid 41 of the macrolactone part of 15-epi-exiguolide, containing a bis-pyran subunit and a trans double bond, is described. Key features of the synthetic strategy include a Feringa–Minnaard asymmetric organocuprate addition to unsaturated ester 17 to set the stereocenter at C15. The derived acid 8 (C9–C16 fragment) was ideally suited for combination with aldehyde 9 (C17–C21 fragment) via an aldol strategy leading to β-lactone 25 which upon thermal decarboxylation provided alkene 26. Chain extension led to propargylic alcohol 7. Treatment of 7 with a LAu+ catalyst promoted a Meyer–Schuster rearrangement to enone 30 that led to cis-tetrahydropyran 31 via intramolecular oxa-Michael reaction. The second pyran ring was prepared from alkoxy ketone 5 by reductive cyclization. The further steps toward macrolactone 43 were hampered by the epimeric mixture at C5.

An intramolecular oxa-Michael reaction on α,β-unsaturated α-amino-δ-hydroxycarboxylic acid esters. Synthesis of functionalized 1,3-dioxanes.

A highly diastereoselective intramolecular oxa-Michael reaction on α,β-unsaturated α-amino-δ-hydroxycarboxylic acid esters is presented; 1,3-dioxanes functionalized in positions 2,4 and 6 were obtained in good yields and with excellent selectivities; an experimental and computational study was carried out to understand the reaction course in terms of yields and selectivities. This reaction proceeds under mild reaction conditions using highly electrophilic aldehydes and ketones.

Synthesis of 6/6/6-Tricyclic Ether System via Achmatowicz and Intramolecular Oxa-Michael Reactions

Synthesis of 6/6/6-Tricyclic Ether System via Achmatowicz and Intramolecular Oxa-Michael Reactions

Diastereoselective synthesis of trifluoromethylated 1,3-dioxanes by intramolecular oxa-Michael reaction.

A highly diastereoselective synthesis of trifluoromethylated 1,3-dioxanes is described. The reaction proceeds by an addition/oxa-Michael sequence and works efficiently under mild reaction conditions, with a good substrate scope and acceptable to good yields.

Catalytic Asymmetric Conjugate Addition of Carboxylic Acids via Oxa-Michael Reaction of Peroxy Hemiacetals followed by Kornblum DeLaMare Fragmentation

Disclosed herein an overall methodology constitutes an equivalent to the long sought after enantioselective intramolecular oxa-Michael (IOM) reaction of carboxylic acids. An organocatalyzed IOM reaction of in situ formed peroxy hemiacetals followed by a Kornblum DeLaMare type rearrangement cascade provides a broad class of chiral lactones in good yields and with excellent enatioselectvities. Remarkably, the pure chiral lactones are obtained without any silica gel column chromatography, and in many cases, the enantioselectivity is further increased by a simple hexane wash of the isolated solid products.

Correction to "Organocatalytic Enantioselective Intramolecular Oxa-Michael Reaction of Enols: Synthesis of Chiral Isochromene".

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to “Organocatalytic Enantioselective Intramolecular Oxa-Michael Reaction of Enols: Synthesis of Chiral Isochromene”Biswajit Parhi, Jitendra Gurjar, Suman Pramanik, Abhisek Midya, and Prasanta Ghorai*Cite this: J. Org. Chem. 2016, 81, 19, 9520Publication Date (Web):September 22, 2016Publication History Published online22 September 2016Published inissue 7 October 2016https://doi.org/10.1021/acs.joc.6b02177Copyright © 2016 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views688Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (281 KB) Get e-Alerts Get e-Alerts

Organocatalytic Enantioselective Intramolecular Oxa-Michael Reaction of Enols: Synthesis of Chiral Isochromenes.

An unprecedented enantioselective intramolecular oxa-Michael reaction of enols has been described. A squaramide-containing tertiary amine based bifunctional organocatalyst efficiently activates the o-homoformyl chalcones to provide the chiral isochromenes in moderate yields and good to excellent enantioselectivities. Further, late-stage functionalizations of the vinyl ether moiety of the chiral isochromene products have also been exemplified.

Catalytic asymmetric formal synthesis of beraprost.

The first catalytic asymmetric synthesis of the key intermediate for beraprost has been achieved through an enantioselective intramolecular oxa-Michael reaction of an α,β-unsaturated amide mediated by a newly developed benzothiadiazine catalyst. The Weinreb amide moiety and bromo substituent of the Michael adduct were utilized for the C–C bond formations to construct the scaffold. All four contiguous stereocenters of the tricyclic core were controlled via Rh-catalyzed stereoselective C–H insertion and the subsequent reduction from the convex face.

Organocatalytic, Enantioselective Synthesis of 1- and 3-Substituted Isochromans via Intramolecular Oxa-Michael Reaction of Alkoxyboronate: Synthesis of (+)-Sonepiprazole.

The enantioselective oxa-Michael reaction of alkoxyboronate strategy was demonstrated to provide a new and practical route to enantioriched 1- and 3-substituted isochromans using a chiral bifunctional organocatalyst. Furthermore, this methodology was extended to the enantioselective synthesis of (+)-sonepiprazole, a dopamine receptor antagonist.

Stereoselective Total Synthesis of Decytospolides A and B Starting from D‐Mannitol

AbstractThe stereoselective total synthesis of decytospolides A and B, two naturally occurring pyran derivatives, has been achieved using D‐mannitol as the starting material. The intramolecular oxa‐Michael reaction has been employed to construct the tetrahydropyran ring of the molecules and Weinreb amide formation to generate their side chain with a keto function.

A New Stereoselective Total Synthesis of Phomonol

AbstractA stereoselective total synthesis of phomonol, following organocatalytic enantioselective epoxidation and intramolecular oxa‐Michael reaction as key steps, is described. The use of readily available D‐tartaric acid as a chiral source renders this approach quite simple and attractive.