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AlCl3 catalyzed oxa-Diels-Alder reaction of aromatic aldehydes with simple dienes
Abstract
Highly regioselective and diastereoselective oxa-Diels-Alder reaction catalyzed by AlCl3 has been developed. This reaction is efficient and characterized by good functional group compatibility, F, Cl, CN, NO2, OMe and thiophenyl group are tolerated. A Lewis acid catalyzed concerted cycloaddition mechanism is proposed based on the results.
The data on the use of carbocationic catalysis in the synthesis of heterocyclic compounds presented in the literature over the last 5–10 years are summarized and analyzed. Particular attention is paid to the discussion of reaction mechanisms and the problem of selectivity.
Zirconium-based metal-organic frameworks (Zr-MOFs) have aroused enormous interest owing to their superior stability, flexible structures, and intriguing functions. Precise control over their crystalline structures, including topological structures, porosity, composition, and conformation, constitutes an important challenge to realize the tailor-made functionalization. In this work, we developed a new Zr-MOF (PCN-625) with a csq topological net, which is similar to that of the well-known PCN-222 and NU-1000. However, the significant difference lies in the conformation of porphyrin rings, which are vertical to the pore surfaces rather than in parallel. The resulting PCN-625 exhibits two types of one-dimensional channels with concrete diameters of 2.03 and 0.43 nm. Furthermore, the vertical porphyrins together with shrunken pore sizes could limit the accessibility of substrates to active centers in the framework. On the basis of the structural characteristics, PCN-625(Fe) can be utilized as an efficient heterogeneous catalyst for the size-selective [4 + 2] hetero-Diels-Alder cycloaddition reaction. Due to its high chemical stability, this catalyst can be repeatedly used over six times. This work demonstrates that Zr-MOFs can serve as tailor-made scaffolds with enhanced flexibility for target-oriented functions.
The selectivity and the mechanism of the uncatalyzed and AlCl3 catalyzed hetero-Diels-Alder reaction (HDR) between ([E]-4-methylpenta-2,4-dienyloxy)(tert-butyl)dimethylsilane 1 and benzaldehyde 2 have been studied using density functional theory at the MPWB1K/6-31G(d) level of theory. The uncatalyzed HDR between diene 1 and alkene 2 is characterized by a polar character and proceeds via an asynchronous one-step mechanism for the meta paths and synchronous for the ortho ones. In the presence of AlCl3 catalyst, the mechanism changes to be stepwise, while the first step is the rate-determining step. The activation energies widely decrease, and the polar character increases dramatically. A large analysis of the mechanism is performed using the activation strain model/energy decomposition analysis (ASM/EDA) model, the natural bond orbital (NBO) and state specific dual descriptors (SSDDs). The obtained results indicate that the combined interaction energy associated with the distortion of the reactants in these HDR are at the origin of the observed kinetics. NBO analyses were applied to estimate the Lewis-acid catalyst donor-acceptor interaction with the molecular system. The SSDD analysis shed light into the orientation effects on the reaction kinetics by providing important information about charge transfer interactions during the chemical reaction. It indicates that the more favorable HDR pathway have the lowest excitation energies, facilitating the interaction between diene 1 and benzaldehyde 2 moieties. Non-covalent interaction (NCI) and QTAIM analyses of the meta-endo structure indicate that the presence of several weak NCIs formed at this approach is at the origin of the meta-endo selectivity.
1,3-dienes are versatile synthons and important monomers. Herein we report a carbon dioxide promoted dehydration reaction of primary allylic alcohols to produce substituted 1,3-dienes in good yields. Taking advantage of...
This Chapter Contains Sections titled: Pericyclic Reactions Reviews Cycloaddition–Cycloreversion Ene Reaction Sigmatropic Shifts Electrocyclic Reactions Molecular Rearrangements Acid Catalysed Base Catalysed Small Ring Rearrangements 1,2‐Rearrangement Alkyl Shifts Ring Expansion Ring Opening and Ring Closure Oxidation Reduction Phosphorus Photochemical Reactions Radical and Biradical Thermal Named Reactions Achmatowicz Reaction Balysis–Hillman Beckmann Bergmnan Brook Cloke–Wilson Rearrangement Curtius Dimroth Rearrangement Fischer Indole Friedel–Crafts Heyns Rearrangement Lossen Rearrangement Meyer–Schuster Mislow–Evans Morita–Baylis–Hillman Nazarov Phospho‐Fries Ritter Reaction Smiles Stevens Trost–Rychnovsky Reaction Wittig Wolff Rearrangement Metal Catalysed Aluminium Cobalt Copper Gold Iridium Iron Nickel Ruthenium Rhodium Silver Palladium Platinum Vanadium Miscellaneous References This chapter provides a review on the applicability of the frontier orbital theory to transition‐metal and lanthanide‐mediated intramolecular and metathesis reactions. It reviews of Bronsted acid catalysts for asymmetric induction in pericyclic reactions which has reported promising examples that rely on multiple non‐covalent interactions in the transition state. The chapter gives the pericyclic reactions of enediynes, enyne‐cumulenes, and yne‐diynes. It reports the Claisen rearrangements of 3‐oxa‐1,5‐hexadienes in which one or more carbon atoms were replaced with atoms different than carbon. The regioselectivity of the 2+2‐photocycloaddition of 2‐pyridone and methylacrylate has been studied using ab initio molecular orbital methods and the results explained from the conformation of parallel‐type conical intersections. Computational studies show that the Diels–Alder pathway is favoured in the enzyme environment.
The effects of the Lewis acid (LA) AlCl3 catalyst on the oxa-Diels-Alder (ODA) reaction of 2-
aryl-butadiene 1 toward benzaldehyde 2 have been studied within the molecular electron density
theory at the M06-2X/6-311G(d,p) computational level. Coordination of the LA AlCl3 to the
carbonyl oxygen of benzaldehyde 2 not only considerably accelerates the reaction, but also
facilitates the ODA reaction along a high polar two-step mechanism. The complete regioselectivity
and endo-stereoselectivity experimentally observed are explained through Parr functions,
respectively, non-covalent interactions analyses. Electron localization function topological
analysis along the most favorable meta/endo reaction path permits characterizing the CC and
CO single bond formation along this two-step mechanism.
The selective synthesis of 2,6-trans-tetrahydropyran derivatives employing the rhodium catalysed addition of organoboron reagents to dihydropyranone templates, derived from a zinc-catalysed hetero-Diels-Alder reaction, is reported. The addition of both arylboronic acids and potassium alkenyltrifluoroborates have been accomplished in high yields using commercially-available [Rh(cod)(OH)]2 catalyst. The selective formation of the 2,6-trans-tetrahydropyran stereoisomer is consistent with a mechanism involving alkene association and carbometalation on the less hindered face of the dihydropyranone.
Ionic liquid (IL) tagged organocatalysts based on TADDOL (α,α,α',α'-tetraaryl-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol) comprising various aryl substituents tethered with triazolium and imidazolium based ionic liquids are synthesised in good yields. Investigation of these IL-tagged catalysts on hydrogen-bonding catalyzed hetero-Diels-Alder (HDA) reactions between activated dienes (such as Rawal's diene and Brassard's diene) and benzaldehyde indicated their potential and limitations for applications in organocatalysis.
The aza-Diels Alder reaction has become one of the most widely used synthetic tools for the preparation of N-containing 6-membered heterocycles. Numerous important developments have been reported to render this reaction catalytic and enantioselective. This tutorial review highlights strategies and recent advances to achieve high efficiency and selectivity through the use of organocatalysts and transition metal complexes, allowing also the extension of this transformation substrate scope.
The first catalytic asymmetric hetero-Diels-Alder reaction of Brassard's dienes with isatins was realized using Mg(ii)/N,N'-dioxide complexes as catalysts, affording the corresponding chiral spirolactones bearing tetrasubstituted centers in up to 99% yield with up to 99% ee and >99 : 1 dr within 3 hours. In the mechanism, based on the operando IR experiments, a predominant Diels-Alder pathway was found in the reaction. A possible transition state model was also proposed.
Irrespective of the presence of cytotoxic acetogenins and styryl-lactones in the genus Goniothalamus, only 22 species in the genus Goniothalamus, out of 160 species (13.7%) have so far been investigated. In an effort to promote further research on the genus Goniothalamus which could represent a source of drugs for the treatment of cancers and bacterial infections, this work offers a broad analysis of current knowledge on Goniothalamus species. Therefore, it includes (i) taxonomy (ii) botanical description (iii) traditional medicinal uses and (iv) phytochemical and pharmacological studies. We discuss the molecular mechanisms of actions of acetogenins and styryl-lactones, with some emphasis on the possible involvement of protein kinase, Bax and TRAIL receptors in the cytotoxic effects of styryl-lactones. We also report (v) the growth inhibition of several nosocomial bacteria by Goniothalamus. scortechinii. The crude methanol extract of G. scortechinii showed a good and broad spectrum of antibacterial activity against both Gram-negative and Gram-positive bacteria.
The versatility of the trityl cation (TrBF4) as a highly efficient Lewis acid organocatalyst is demonstrated in the oxa-Diels–Alder reaction of various unactivated aromatic and aliphatic aldehydes and simple unactivated dienes, such as isoprene and 2,3-dimethylbutadiene. The transformation proceeds smoothly to give 3,6-dihydropyrane adducts in high to moderate yields with catalyst loadings down to 1.0 mol-% under mild reaction conditions. In contrast to most previously reported strategies, this protocol does not require substrate functional group activation, neither by electron-deficient aldehydes (2-oxo aldehydes) or electron-rich dienes (methoxy or amino-butadiene).
Chemoselective oxa‐Diels–Alder reactions between electrically neutral 1,3‐dienes and various aldehydes were achieved using the commercially available silver tetrafluoroborate (AgBF 4 ) as catalyst. This catalytic process has high functional group tolerance. Heteroatoms at the β‐position of the aryl aldehydes can greatly promote the reactivity of the substrates even with heterocyclic aldehydes that were previously believed to be unreactive for the oxa‐Diels–Alder reaction. In addition, acroleins with β‐heteroatom substitution are also good substrates. High chemoselectivity and regioselectivity were achieved at room temperature for the oxa‐Diels–Alder reaction between acroleins and stoichiometric simple 1,3‐dienes.
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We have developed cationic iron(IV) corrole-catalyzed formal hetero-Diels-Alder reaction of aldehydes with dienes, which opens the way for divergent synthesis of pyrans. The potential utility of the catalyst was also demonstrated by carrying out cycloaddition of alpha,beta-unsaturated aldehyde with a diene to give pyran selectively. Furthermore, the catalytic reactivity of iron corrole complex on the cycloaddition was determined by comparing that of iron porphyrin complex.
A new strategy for the synthesis of di- and trisaccharides based on the de novo synthesis of the linking saccharide unit is presented. In this strategy, functionalized monosaccharide building blocks already incorporating the glycosidic linkages are welded together using a metal-catalyzed hetero-Diels–Alder (HDA) reaction to generate a new monosaccharide unit between them. The highest yields and selectivities in the HDA reaction were obtained by using chiral Schiff base chromium complexes. Disaccharide products were accessible by reaction of Danishefsky's diene with acetyl- and benzyl-protected galactoside aldehydes. For the synthesis of trisaccharide products, acetyl-protected glucose or galactose-derived dienes were fused with monosaccharide-derived aldehydes using chromium catalysts for the HDA reaction. The desired trisaccharide products were obtained in moderate to good yields with excellent stereoselectivity. The central pyranulose-ring generated in the process possessed an L-cis-enulose configuration according to NMR spectroscopy and modeling studies.
The successful development of planar-chiral bis-silanols 3a–d and their application as asymmetric organocatalysts in hetero-Diels–Alder (HDA) reactions is described. All precursors were easily prepared by addition of commerically available silyl electrophiles to a dilithiated [2.2]paracyclophane derivative followed by silane oxidations. The analogous bis-carbinols 7a–c have been prepared by addition of suitable Grignard reagents to bis-methoxycarbonyl derivative 6. Both racemic as well as enantiopure planar-chiral bis-silanols and bis-carbinols were obtained in good yields. The catalytic activities of the bis-silanols were analyzed by monitoring HDA reactions between Rawal's diene and aldehydes by in situ IR spectroscopy and comparing the resulting data with those obtained in catalyses with the corresponding bis-carbinol derivatives. The results show for the first time that planar-chiral bis-silanols with hydrogen-bonding capabilities can be applied as asymmetric organocatalysts leading to enantiomerically enriched products.
Computational calculations of the hetero-Diels–Alder (HDA) reactions of benzaldehyde with 2,3-dimethyl-1,3-butadiene (DMB) catalyzed by BF3, EtAlCl2 or TiCl4 at the density functional theory (DFT) (B3LYP/6-31G(d,p)) level reveal that the reactions involve activation energy barriers of 14.59, 14.34, and 17.44 kcal mol−1, respectively. In the first two cases, reaction occurs through a concerted mechanism, whereas in the presence of TiCl4, stepwise mechanism involving zwitterionic intermediate is followed. The reaction with isoprene proceeds with complete regioselectivity leading to the expected regioisomer having O/Me in 1:4 positions. The computational results have been verified experimentally when aromatic aldehydes react with 1,3-dienes in the presence of a catalyst to give 3,6-dihydro-2H-pyran derivatives in high yields.
A general method of annellating quinones in high yield has been devised using mixed vinylketene acetals obtained directly from the enolate ions of unsaturated esters.
Eu(hfc)3 catalyzes the title reaction with substantial asymmetric induction.
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Scandium(III) perfluorooctanesulfonate [scandium(III) perflate, Sc(OPf)3] was prepared from either scandium(III) chloride or oxide and perfluorooctanesulfonic acid. The perflate thus obtained acts as a novel Lewis acid catalyst for the intermolecular hetero Diels–Alder reaction of aldehydes with non-activated dienes under mild conditions. The characteristic features of the catalyst include (i) low hygroscopicity, (ii) ease of handling, and (iii) robustness for the recycling use.
A concise and efficient synthesis of the macrolactone core of migrastatin, a new natural product with potent anticancer properties, has been achieved. The key features of our synthetic strategy encompass a Lewis acid catalyzed diene aldehyde condensation (LACDAC) to install the three contiguous stereocenters and the trisubstituted (Z)-double bond of migrastatin, and a (E)-selective ring-closing metathesis (RCM) to construct the macrocycle.
Trifluoromethanesulfonic (triflic) acid (1 mol%) has been found to be an efficient catalyst for the hetero Diels-Alder reaction between aromatic aldehydes and unactivated dienes. © 1997 Elsevier Science Ltd.
Cationic palladium(II) complexes, [PdL2(RCN)2](BF4)2, have been found to catalyze the hetero Diels-Alder reaction of nonactivated simple dienes with aldehydes, affording the corresponding 5,6-dihydro-2H-pyrans in good yields under mild conditions.
This review is intended to update the most recent developments in asymmetric hetero-Diels–Alder (HDA) reactions of carbonyl compounds, covering the literature from 2000 to 2008. The reactions of unactivated aldehydes, activated aldehydes, activated ketones and the inverse HDA reactions of α,β-unsaturated ketones and α,β-unsaturated aldehydes are successively investigated. This review clearly demonstrates the power of asymmetric HDA reactions of carbonyl compounds for the construction of chiral six-membered oxygen-containing heterocycles, with extensive synthetic applications in natural or unnatural products with a wide range of biological activity.Figure optionsView in workspaceDownload full-size imageDownload as PowerPoint slide
Eu(fod)3 and Eu(hfc)3 catalyze the cycloaddition of a variety of aldehydes with oxygenated highly substituted butadienes. With achiral dienes, (+)-Eu(hfc)3 shows only modest enantiofacial selectivities. Similarly, modest selectivities were observed in the reactions of several chiral dienes with aldehydes in the presence of the achiral Eu(fod)3. However, the combination of chiral dienes with chiral (+)-Eu(hfc)3 catalyst exhibited striking interactivities, resulting in some instances in diastereofacial excesses of 95%. Of the systems examined, only those dienes whose intrinsic facial selectivities are small and opposite in direction to that of the (+)-Eu(hfc)3 catalyst exhibit useful interactivity of the two chiral components. Thus, the diastereomeric excesses observed here do not arise from strictly numerical factoring of componental preferences (simple double diastereoselectivity) but are a consequence of a "specific interactivity", inherent in the process itself. Application of these findings to the synthesis of optically pure substituted pyrans, L-glycolipids, and L-glucose is described.
The stereoselective total synthesis of several members of the styryllactone family was achieved efficiently from common intermediate 8, prepared by a catalytic asymmetric inverse-electron-demand hetero-Diels–Alder/allylboration sequence. The transformation of 8 into α,β-unsaturated lactone led to the preparation of (+)-goniodiol (1) in a reduced number of steps. The epoxidation reaction was used to generate the remaining stereogenic centers on the lactone moiety of 8, and these intermediates were then elaborated into (+)-goniotriol (2), (–)-goniofupyrone (3), and (+)-altholactone (4) by an isomerization or cyclization step.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
The evolution of a strategy to synthesize the title compounds is described. Three principal developments allowed realization of this goal: (1) the attainment of high margins of diastereofacial selectivity and regioselectivity in the construction of pyranoid systems via the Lewis acid-catalyzed cyclocondensation reaction of activated dienes and aldehydes; (2) the exploitation of stereoselective reactions for functionalization of the pyranoid matrix; and (3) the discovery of stereoselective reactions for extending the chiral biases of pyranoid systems to newly emerging stereogenic centers on side chains. The coordination of these components in the synthesis of target systems of high biological interest is described.
This paper describes the successful development of the hetero-Diels–Alder (HDA) reaction of the Brassard diene with aldehydes in the presence of a series of titanium(IV) tridentate Schiff-base complexes under mild conditions. The influence of the substituent of the chiral Schiff-base ligands on the enantioselectivities of the reaction was studied. It was found that ligand L13 is a highly enantioselective ligand for the Ti-catalyzed HDA reaction, affording 6-substituted 4-ethoxy-5,6-dihydropyran-2-one in up to 99 % ee. The mechanism of the HDA reaction between the Brassard diene and benzaldehyde in the presence of the (Schiff base)TiIV complex was investigated. The results indicate that the reaction pathway is influenced by reaction temperature: at higher temperature (0 °C), the reaction is mostly a Diels–Alder process, whereas at lower temperature (–78 °C) it is a Mukaiyama aldol process. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Addition reactions between Rawal’s diene and different carbonyl compounds are rapidly and efficiently promoted by water. No catalyst or any other additive, water as an eco-friendly medium, clean reaction conditions, a simple work-up, and short reaction times are the salient features in this procedure. The protocol is general, proceeding well with moderate to good yields for various aldehydes and activated ketones. Based on the experimental 1H NMR results, a Mukaiyama aldol mechanism was proposed as the reaction pathway, affording open chain products.
The hetero Diels-Alder reaction is one of the most important methods for the synthesis of heterocycles. In this article an overview is given for the period since 1989 describing the reaction of heterobutadienes such as oxabutadienes, thiabutadienes, azabutadienes, diaazabutadienes, nitroso-alkenes and nitroalkenes as well as of heterodienophiles such as carbonyls, thiocarbonyls, imines, iminium salts, azo- and nitroso compounds. In addition, several other less common hetero Diels-Alder reactions such as cycloadditions of thiaazabutadienes, oxaazabutadienes, dioxabutadienes, dithiabutadienes, oxathiabutadienes, diazaoxabutadienes as well as the use of N-sulfinyl-phosphaalkynes and other dienophiles are mentioned. A main point of discussion is the stereoselectivity of the reactions and the preparation of enantiopure compounds either using dienes and dienophiles carrying a chiral auxiliary or employing chiral Lewis acids. A point stressed is the synthesis of natural products using hetero Diels-Alder reactions leading to carbohydrates, alkaloids, terpenes, antibiotics, mycotoxins, cytochalasans, antitumor agents and several other classes of natural products.
Another topic is the use of high pressure in hetero Diels-Alder reactions discussing the influence on the rate constants and the stereoselectivity. Finally, modern developments such as reactions on solid phase, the use of catalytic monoclonal antibodies, transformations in aqueous solution and the microwave activation are described.
Cationic iron(III) porphyrin was found to be an efficient catalyst for the highly chemoselective hetero-Diels-Alder-type reaction of aldehydes with 1,3-dienes. The catalyzed process did not require the use of electron-deficient aldehydes such as glyoxylic acid derivatives or activated electron-rich 1,3-dienes such as Danishefsky's diene and Rawal's diene. The high functional group tolerance and robustness of the catalyst were demonstrated. Further, the potential utility of the catalyst was demonstrated by performing the cycloaddition in the presence of water and by carrying out cycloaddition of an unactivated ketone such as cyclohexanone with a diene.
A highly diastereo- and enantioselective hetero-Diels-Alder (HDA) reaction of a Brassard-type diene with aliphatic aldehydes has been developed. The chiral N,N'-dioxide L2/In(OTf)(3) complex was efficient toward the obtention of the corresponding beta-methoxy-gamma-methyl alpha,beta- unsaturated delta-lactones in good yields (up to 86%) as well as dr and ee values (up to 97:3 cis/trans and 94% ee). In addition, the product 4a could be easily transformed into the methyl-protected epi-prelactone B by hydrogenation.
Boron complexes that contain new tridentate ligands, tris(o-oxyaryl)methanes and -silanes, were prepared. These complexes had a cage-shaped structure around a boron center and showed higher Lewis acidity and catalytic activity than open-shaped boron compounds. The cage-shaped ligands determined the properties of the borates by altering the geometry and were consistently bound to the metal center by chelation. The synthesized compounds were L⋅B(OC(6)H(4))(3)CH, L⋅B(OC(6)H(4))(3)SiMe, and its derivatives (L=THF or pyridine as an external ligand). Theoretical calculations suggested that the cage-shaped borates had a large dihedral angle (C(ipso)-O-B-O) compared with open-shaped borates. The geometric effect due to the dihedral angle means that compared with open-shaped, the cage-shaped borates have a greater Lewis acidity. The introduction of electron-withdrawing groups on the aryl moieties in the cage-shaped framework increased the Lewis acidity. Substitution of a bridgehead Si for a bridgehead C decreased the Lewis acidity of the boron complexes because the large silicon atom reduces the dihedral angle of C(ipso)-O-B-O. The ligand-exchange rates of the para-fluoro-substituted compound B(OC(6)H(3)F)(3)CH and the ortho-phenyl-substituted compound B(OC(6)H(3)Ph)(3)CH were less than that of the unsubstituted borate B(OC(6)H(4))(3)CH. The ligand-exchange rate of B(OC(6)H(4))(3)SiMe was much faster than that of B(OC(6)H(4))(3)CH. A hetero Diels-Alder reaction and Mukaiyama-type aldol reactions were more effectively catalyzed by cage-shaped borates than by the open-shaped borate B(OPh)(3) or by the strong Lewis acid BF(3) ⋅OEt(2). The cage-shaped borates with the bulky substituents at the ortho-positions selectively catalyzed the reaction with less sterically hindered substrates, while the unsubstituted borate showed no selectivity.
A modular catalyst structure was applied to evaluate the effects of catalyst acidity in a hydrogen bond-catalyzed hetero Diels-Alder reaction. Linear free energy relationships between catalyst acidity and both rate and enantioselectivity were observed, where greater catalyst acidity leads to increased activity and enantioselectivity. A relationship between reactant electronic nature and rate was also observed, although there is no such correlation to enantioselectivity, indicating the system is under catalyst control.
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The mechanism of the hetero-Diels-Alder reactions of Brassard's diene and 1,3-butadiene catalyzed by a titanium(IV) complex of a tridentate Schiff base was investigated by DFT and ONIOM methods. The calculations indicate that the mechanism of the reaction is closely related to the nucleophilicity-electrophilicity between diene and carbonyl substrates. A stepwise pathway is adopted for Brassard's diene, and the step corresponding to the formation of the C--C bond is predicted to be the rate-determining step with a free-energy barrier of 8.4 kcal mol(-1). For 1,3-butadiene, the reaction takes place along a one-step, two-stage pathway with a free-energy barrier of 14.9 kcal mol(-1). For Brassard's diene as substrate, the OCH(3) and OSi(CH(3))(3) substituents may play a key role in the formation of the transition state and zwitterionic intermediate by participating in charge transfer from Brassard's diene to formaldehyde. The combination of the phenyl groups at the amino alcohol moiety and the ortho-tert-butyl group of the salicylaldehyde moiety in the chiral tridentate Schiff base ligand plays an important role in the control of the stereoselectivity, which is in agreement with experimental observations.
The preparation of the polyketide natural products anguinomycin C and D is reported based on key steps such as Negishi stereoinversion cross coupling, Jacobsen Cr(III)-catalyzed Hetero Diels-Alder reaction, Evans B-mediated syn-aldol chemistry, and B-alkyl Suzuki-Miyaura cross coupling. The configuration of both natural products was established as (5R,10R,16R,18S,19R,20S). Biological evaluation demonstrated that these natural products are inhibitors of the nuclear export receptor CRM1, leading to shutdown of CRM1-mediated nuclear protein export at concentrations above 10 nM. Analogues of anguinomycin and leptomycin B (LMB) have been prepared, and the simple alpha,beta-unsaturated lactone analogue 4 with a truncated polyketide chain retains most of the biological activity (inhibition above 25 nM). The structural basis for this inhibition has been demonstrated by modeling the transport inhibitors into X-ray crystal structures, thus highlighting key points for successful and strong biological action of anguinomycin and LMB.
The first example of a chiral Lewis acid-catalyzed enantioselective hetero-Diels-Alder (HDA) reaction between 1-dimethylamino-3-silyloxy-1,3-butadiene (Rawal's diene) and aldehydes is described. The cycloaddition reaction under the influence of 1 mol% of dirhodium(II) tetrakis[N-benzene-fused-phthaloyl-(S)-piperidinonate], Rh(2)(S-BPTPI)(4), proceeded cleanly and gave, after treatment with acetyl chloride, the corresponding dihydropyranones in up to 99% ee.
With sequential use of catalytic asymmetric Cr-mediated coupling reactions, E7389 C14-C35 and halichondrin C14-C38 building blocks have been stereoselectively synthesized. The C19-C20 bond is first formed via the catalytic asymmetric Ni/Cr-mediated coupling, i.e., 8 + 9 --> 10 (90%; dr = 22:1), in which vinyl iodide 8 is used as the limiting substrate. The C23-C24 bond is then formed via the catalytic asymmetric Co/Cr-mediated coupling, i.e., 13 + 14 --> 4 (82%; dr = 22:1), in which the alkyl-iodide bond in 14 is selectively activated over the vinyl-iodide bond. The catalytic asymmetric Ni/Cr-mediated reaction is employed to couple C14-C26 segment 19 with E7389 C27-C35 segment 20 (91%; dr = >55:1). In this synthesis, the C23-O bond is stereoselectively constructed via a double-inversion process, i.e., 21 --> 22, to furnish E7389 C14-C35 building block 22 in 84% yield. The same synthetic sequence has been employed to synthesize halichondrin C14-C38 building block 18b, i.e., 16a + 19 --> 18b.
Even moderately nucleophilic dienes react with simple aldehydes in the presence of a new Cr(III) catalyst in a hetero-Diels-Alder reaction [Eq. (1)]. Tetrahydropyranyl products with up to three stereogenic centers are generated in near-perfect diastereoselectivities and with greater than 90 % ee (99 % ee for the example shown). TBAF=tetrabutylammonium fluoride; TBS=tert-butyldimethylsilyl; TES=triethylsilyl.
The hetero Diels-Alder reaction of 1-amino-3-siloxy-1,3-butadiene (1a) with a range of unactivated aldehydes proceeds readily under remarkably mild conditions: at room temperature and in the absence of Lewis acid catalysts. The cycloadducts are formed in good yields and can be converted directly to the corresponding dihydro-4-pyrones using acetyl chloride. Ketones and imines are also reactive in hetero Diels-Alder reactions with this diene.
Macrocycle 1 is a new highly potent analogue of bryostatin 1, a promising anti-cancer agent currently in human clinical trials. In vitro, 1 displays picomolar affinity for PKC and exhibits over 100-fold greater potency than bryostatin 1 when tested against various human cancer cell lines. Macrocycle 1 can be generated in clinically required amounts by chemical synthesis in only 19 steps (LLS) and represents a new clinical lead for the treatment of cancer.
The first total synthesis of (+)-migrastatin, a macrolide natural product with interesting antimetastatic properties, has been accomplished. Our concise and flexible approach utilizes a Lewis acid-catalyzed diene aldehyde condensation to install the three contiguous stereocenters and the trisubstituted (Z)-alkene of migrastatin. Construction of the two remaining stereocenters and incorporation of the glutarimide-containing side chain have been achieved via an anti-selective aldol reaction, followed by a Horner-Wadsworth-Emmons olefination. Finally, the assembly of the macrocycle has been realized by a highly (E)-selective ring-closing metathesis.
Hydrogen bonding acts as a ubiquitous glue to sustain the intricate architecture and functionality of proteins, nucleic acids and many supramolecular assemblies, but this weak interaction is seldom used as a force for promoting chemical reactions. Here we show that a simple chiral alcohol uses hydrogen bonding to catalyse an important family of cycloaddition reactions of a diene with various aldehydes - moreover, this reaction is highly enantioselective, generating only one of the mirror-image forms of each dihydropyran product. This type of catalysis mimics the action of enzymes and antibodies, and is unlike traditional, metal-based catalysts used in organic chemistry.
Like molecules of life (e.g., proteins and DNA), many pharmaceutical drugs are also asymmetric (chiral); they are not superimposable on their mirror images. One mirror image form (enantiomer) of a drug can have desirable activity, the other not. Consequently, the development of methods for the selective synthesis of one enantiomer is of great scientific and economic importance. We report here that a simple, commercially available chiral alcohol, alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL), catalyzes the all-carbon Diels-Alder reactions of aminosiloxydienes and substituted acroleins to afford the products in good yields and high enantioselectivities (up to 92% enantiomeric excess). It is remarkable that the reactions are promoted by hydrogen bonding, the ubiquitous "glue" that helps to keep water molecules together and holds up the 3D structures of proteins. Hydrogen bond catalysis is little used in chemical synthesis, wherein most reactions are promoted by complexes of Lewis acidic metal salts coordinated to chiral ligands. As it does for enzymes, hydrogen bonding not only organizes TADDOL into a well defined conformation, but, functioning as a Brønsted acid catalyst, it also activates the dienophile toward reaction with the diene. The gross structure of the TADDOL has been found to have a profound influence on both the rate and the enantioselectivity of the cycloadditions. These structure-function effects are rationalized by evaluating the conformation adopted by the TADDOLs in the crystal state. It is suggested that pi,pi-stacking plays an central role in the overall catalytic cycle, in particular, the enantioselective step.
[reaction: see text] Hetero-Diels-Alder reactions of Brassard diene with aromatic aldehydes were carried out smoothly in the presence of titanium(IV) tridentate Schiff base complexes to give the corresponding chiral delta-lactones in high enantioselectivities (up to 99% ee) under mild conditions.
The first catalytic enantioselective hetero-Diels-Alder reaction between Brassard's diene and aldehydes has been achieved through hydrogen-bonding activation using TADDOL derivatives as catalysts to afford the corresponding delta-lactone derivatives in moderate-to-good yields and with high enantioselectivities (up to 91 % ee). The reactions can be carried out either under solvent-free conditions or in toluene. On the basis of the absolute configurations of the products and the hydrogen-bonding interaction pattern between TADDOL (alpha,alpha,alpha',alpha'-tetraaryl-1,3-dioxolan-4,5-dimethanol) and the carbonyl group disclosed by X-ray diffraction analysis, a possible mechanism for the catalytic reaction has been proposed. To demonstrate the usefulness of the methodology, a natural product, (S)-(+)-dihydrokawain, has also been prepared in 50 % isolated yield and with 69 % enantioselectivity in one step starting from 3-phenylpropionaldehyde by using this methodology. Therefore, this catalytic system is one of the most direct approaches to the construction of delta-lactone units, which will make the methodology very attractive for the synthesis of a variety of biologically important compounds and natural products.
(Chemical Equation Presented) Defining the relationship: The effect of catalyst acidity has been systematically probed by using a modular oxazoline catalyst in a hetero-Diels-Alder reaction catalyzed by hydrogen bonding. Linear free energy relationships were observed between the catalyst acidity and both the reaction rate and enantioselectivity (see picture).
Clear oil, 77.4 mg, 48%, dr > 10:1, determined by 1 H NMR. 1 H NMR (400 MHz
- V Eschenbrenner-Lux
- K Kumar
- H Waldmann
(m, 5H), 5.50 (s, 1H), 5.12 (s, 1H), 4.53 (d, J ¼ 12.0 Hz, 1H), 4.34 (s,
2H), 2.34e2.28 (m, 1H), 2.14e2.05 (m, 5H), 1.69 (s, 3H), 1.61 (s,
3H). 13 C NMR (100 MHz, CDCl 3 ) d 142.71, 135.80, 131.83, 128.39,
127.46, 125.89, 123.89,119.44, 75.89, 66.55, 36.99, 36.34, 25.95,
25.73, 17.75. IR (thin film): 2964, 2930, 1717, 1452, 1378, 1267,1120,
1062, 1027, 700 cm À1. HRMS (ESI) calcd for [C 17 H 22 Na] þ ([MþNa] þ ):
265.1568, found: 256.1576.
10. Clear oil, 77.4 mg, 48%, dr > 10:1, determined by 1 H NMR. 1 H
NMR (400 MHz, CDCl 3 ) d 7.32e7.17 (m, 5H), 5.50 (s, 1H), 4.52 (dd,
J 1 ¼ 4.0 Hz, J 2 ¼ 12.0 Hz, 1H), 4.24 (m, 1H), 3.74 (m, 1H), 3.51 (m, 1H),
2.16 (m, 1H), 2.02 (d, J ¼ 16.0 Hz, 1H), 1.68 (s, 3H),0.84 (s, 9H), 0.01
(d, J ¼ 8.0 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) d 141.74, 132.12,
127.23, 126.25, 124.80, 120.37, 75.28, 74.88, 65.36, 37.19, 24.91,
21.93, 17.35, À6.19, À6.27. HRMS (ESI) calcd for [C 19 H 34 NO 2 Si] þ
([MþNH 4 ] þ ): 336.2353, found: 336.2355.
References
1. a) Eschenbrenner-Lux V, Kumar K, Waldmann H. Angew Chem Int Ed. 2014;53:
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Fujiwara K, Kurahashi T, Matsubara S. J Am Chem Soc. 2012;134:5512. and
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