- Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes
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Selective carbon-carbon (C-C) bond formation in chemical synthesis generally requires prefunctionalized building blocks. However, the requisite prefunctionalization steps undermine the overall efficiency of synthetic sequences that rely on such reactions, which is particularly problematic in large-scale applications, such as in the commercial production of pharmaceuticals. Herein, we describe a selective and catalytic method for synthesizing 1,3-enynes without prefunctionalized building blocks. In this transformation several classes of unactivated internal acceptor alkynes can be coupled with terminal donor alkynes to deliver 1,3-enynes in a highly regio- and stereoselective manner. The scope of compatible acceptor alkynes includes propargyl alcohols, (homo)propargyl amine derivatives, and (homo)propargyl carboxamides. This method is facilitated by a tailored P,N-ligand that enables regioselective addition and suppresses secondary E/Z-isomerization of the product. The reaction is scalable and can operate effectively with as low as 0.5 mol % catalyst loading. The products are versatile intermediates that can participate in various downstream transformations. We also present preliminary mechanistic experiments that are consistent with a redox-neutral Pd(II) catalytic cycle.
- Liu, Mingyu,Tang, Tianhua,Apolinar, Omar,Matsuura, Rei,Busacca, Carl A.,Qu, Bo,Fandrick, Daniel R.,Zatolochnaya, Olga V.,Senanayake, Chris H.,Song, Jinhua J.,Engle, Keary M.
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supporting information
p. 3881 - 3888
(2021/04/06)
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- Fluorohydration of alkynes via I(I)/I(III) catalysis
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Substrate specificity is ubiquitous in biological catalysis, but less pervasive in the realm of small-molecule catalysis. Herein, we disclose an intriguing example of substrate specificity that was observed whilst exploring catalysis-based routes to generate α-fluoroketones from terminal and internal alkynes under the auspices of I(I)/I(III) catalysis. Utilising p-TolI as an inexpensive organocatalyst with Selectfluor and amine/HF mixtures, the formation of protected α-fluoroketones from simple alkynes was realised. Whilst the transient p-TolIF2 species generated in situ productively engaged with pentynyl benzoate scaffolds to generate the desired α-fluoroketone motif, augmentation or contraction of the linker suppressed catalysis. The prerequisite for this substructure was established by molecular editing and was complemented with a physical organic investigation of possible determinants.
- Daniliuc, Constantin G.,Gilmour, Ryan,Neufeld, Jessica
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supporting information
p. 1627 - 1635
(2020/09/11)
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- S-Block cooperative catalysis: Alkali metal magnesiate-catalysed cyclisation of alkynols
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Mixed s-block metal organometallic reagents have been successfully utilised in the catalytic intramolecular hydroalkoxylation of alkynols. This success has been attributed to the unique manner in which these reagents can overcome the challenges of the reaction: namely OH activation and coordination to and then addition across a CC bond. In order to optimise the reaction conditions and to garner vital catalytic system requirements, a series of alkali metal magnesiates were enlisted for the catalytic intramolecular hydroalkoxylation of 4-pentynol. In a prelude to the main investigation, the homometallic magnesium dialkyl reagent MgR2 (where R = CH2SiMe3) was utilised. This reagent was unsuccessful in cyclising the alcohol into 2-methylenetetrahydrofuran 2a or 5-methyl-2,3-dihydrofuran 2b, even in the presence of multidentate Lewis donor molecules such as N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PMDETA). Alkali metal magnesiates MIMgR3 (when MI = Li, Na or K) performed the cyclisation unsatisfactorily both in the absence/presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA) or PMDETA. When higher-order magnesiates (i.e., MI2MgR4) were employed, in general a marked increase in yield was observed for MI = Na or K; however, the reactions were still sluggish with long reaction times (22-36 h). A major improvement in the catalytic activity of the magnesiates was observed when the crown ether molecule 15-crown-5 was combined with sodium magnesiate Na2MgR4(TMEDA)2 furnishing yields of 87% with 2a:2b ratios of 95:5 after 5 h. Similar high yields of 88% with 2a:2b ratios of 90:10 after 3 h were obtained combining 18-crown-6 with potassium magnesiate K2MgR4(PMDETA)2. Having optimised these systems, substrate scope was examined to probe the range and robustness of 18-crown-6/K2MgR4(PMDETA)2 as a catalyst. A wide series of alkynols, including terminal and internal alkynes which contain a variety of potentially reactive functional groups, were cyclised. In comparison to previously reported monometallic systems, bimetallic 18-crown-6/K2MgR4(PMDETA)2 displays enhanced reactivity towards internal alkynol-cyclisation. Kinetic studies revealed an inhibition effect of substrate on the catalysts via adduct formation and requiring dissociation prior to the rate limiting cyclisation step.
- Fairley, Michael,Davin, Laia,Hernán-Gómez, Alberto,García-álvarez, Joaquín,O'Hara, Charles T.,Hevia, Eva
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p. 5821 - 5831
(2019/06/18)
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- Mechanistic Studies on the Organocatalytic α-Chlorination of Aldehydes: The Role and Nature of Off-Cycle Intermediates
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Herein we report the isolation and characterization of aminal intermediates in the organocatalytic α-chlorination of aldehydes. These species are stable covalent ternary adducts of the substrate, the catalyst and the chlorinating reagent. NMR-assisted kinetic studies and isotopic labeling experiments with the isolated intermediate did not support its involvement in downstream stereoselective processes as proposed by Blackmond. By tuning the reactivity of the chlorinating reagent, we were able to suppress the accumulation of rate-limiting off-cycle intermediates. As a result, an efficient and highly enantioselective catalytic system with a broad functional group tolerance was developed.
- Ponath, Sebastian,Menger, Martina,Grothues, Lydia,Weber, Manuela,Lentz, Dieter,Strohmann, Carsten,Christmann, Mathias
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supporting information
p. 11683 - 11687
(2018/09/10)
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- Development of an Alkyne Analogue of the de Mayo Reaction: Synthesis of Medium-Sized Carbacycles and Cyclohepta[b]indoles
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Embedded medium-sized carbacycles and cyclohepta[b]indoles occur frequently as scaffold elements in natural products and bioactive compounds. Described herein is a conceptionally novel photochemically triggered cascade process to these scaffolds. Key to the cascading ring-expansion process is an unprecedented intramolecular alkyne analogue of the de Mayo reaction.
- Tymann, David,Tymann, Dina Christina,Bednarzick, Ulf,Iovkova-Berends, Ljuba,Rehbein, Julia,Hiersemann, Martin
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supporting information
p. 15553 - 15557
(2018/11/10)
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- STABILIZED POLYPEPTIDES AND USES THEREOF
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The present invention provides inventive stabilized STAT polypeptides, pharmaceutical compositions thereof, and methods of making and using inventive stabilized STAT polypeptides.
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- Identification and synthesis of macrolide pheromones of the grain beetle oryzaephilus surinamensis and the frog spinomantis aglavei
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Macrolide lactones, the so called cucujolides derived from unsaturated fatty acids, are aggregation pheromones of cucujid grain beetles. Thirty years ago, Oehlschlarger etaal. showed that (3Z,6Z)-dodeca-3,6-dien-11-olide (4) and the respective 12-olide (7) attract the sawtoothed grain beetle Oryzaephilus surinamensis, whereas (5Z,8Z,13R)-tetradeca-5,8-dien-13-olide (5) increases the response synergistically. The frass of this beetle is attractive for its parasitoid Cephalonomia tarsalis, which potentially can be used for pest control. A GC/MS analysis of attractive frass showed the presence of 5, together with an unknown isomer. CucujolideaV was tentatively identified also in the femoral glands, pheromone-releasing structures, of the Madagascan mantelline frog Spinomantis aglavei. Therefore, a new route to synthesize doubly unsaturated macrolides allowing the flexible attachment of the side chain was developed. A straightforward method to obtain Zaconfigured macrolides involves ring-closing alkyne metathesis (RCAM) followed by Lindlar-catalyzed hydrogenation. This methodology was extended to homoconjugated diene macrolides by using RCAM after introduction of one Zaconfigured double bond in the precursor by Wittig reaction. A tungsten benzylidyne complex was used as the catalyst in the RCAM reaction, which afforded the products in high yield at room temperature. With the synthetic material at hand, the unknown isomer was identified as the new natural product (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide, cucujolideaX (8). Furthermore, the route also allowed the synthesis of cucujolideaV in good yield. The natural products were identified by the synthesis of enantiomerically pure or enriched material and gas chromatography on chiral phases. The new macrolide (R)-8 proved to be biologically active, attracting female O.asurinamensis, but no males. The synthetic material allowed the identification of (R)-5 in both the beetle and the frog. Attractive synthesis: Females of the sawtoothed grain beetle Oryzaephilus surinamensis are attracted to the new macrolide (5Z,8Z,12R)-tetradeca-5,8-dien-12-olide, cucujolideaX, prepared by using a combination of Wittig reaction and ring-closing alkyne metathesis (RCAM; see scheme). The synthetic approach also allows the synthesis of the similar cucujolideaV, used by both the beetle and the mantellid frog Spinomantis aglavei.
- Hoetling, Susann,Haberlag, Birte,Tamm, Matthias,Collatz, Jana,Mack, Patrick,Steidle, Johannes L. M.,Vences, Miguel,Schulz, Stefan
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supporting information
p. 3183 - 3191
(2014/03/21)
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- Rh(III)-catalyzed intramolecular redox-neutral or oxidative cyclization of alkynes: Short, efficient synthesis of 3,4-fused indole skeletons
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A Rh(III)-catalyzed intramolecular redox-neutral or oxidative annulation of a tethered alkyne has been developed to efficiently construct 3,4-fused indoles via a C-H activation pathway. The advantages of this process are (1) ready availability of annulation precursors; (2) broad substrate scope; (3) complete regioselectivity; (4) simple and mild reaction conditions; and (5) no need for an external oxidant or to employ molecular oxygen as the stoichiometric terminal oxidant.
- Zhou, Bing,Yang, Yaxi,Tang, Huanyu,Du, Juanjuan,Feng, Huijin,Li, Yuanchao
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supporting information
p. 3900 - 3903
(2014/08/18)
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- Alkaline earth catalysis of alkynyl alcohol hydroalkoxylation/cyclization
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Heavier alkaline earth bis(trimethylsilyl)amides [Ae{N(SiMe 3)2}2]2 (Ae = Ca, Sr, Ba) are shown to act as effective precatalysts for the regioselective intramolecular hydroalkoxylation/cyclization of a wide range of alkynyl and allenyl alcohols. In the majority of cases, cyclization of alkynyl alcohols produces mixtures of the possible endo- and exocyclic enol ether products, rationalized as a consequence of alkynylalkoxide isomerization to the corresponding allene derivatives. Cyclization rates for terminal alkynyl alcohols were found to be significantly higher than for substrates bearing internal alkynyl substituents, while the efficacy of cyclization was in general found to be determined by a combination of stereoelectronic influences and the thermochemical viability of the specific alkaline earth metal catalysis, which we suggest is determined by the individual M-O bond strengths. Kinetic studies have provided a rate law pertaining to a pronounced catalyst inhibition with increasing [substrate], indicating that turnover-limiting insertion of C-C unsaturation into the M-O bond requires the dissociation of substrate molecules away from the Lewis acidic alkaline earth center.
- Brinkmann, Christine,Barrett, Anthony G. M.,Reid, Stephanie,Hill, Michael S.,Procopiou, Panayiotis A.
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p. 7287 - 7297,11
(2020/09/02)
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- Macrolides from the scent glands of the tropical butterflies Heliconius cydno and Heliconius pachinus
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The four major components present in scent gland extracts of the male Costa Rica longwing butterflies Heliconius cydno and Heliconius pachinus were identified as 12- and 14-membered macrolides containing a C18-carbon skeleton. By use of micro-reactions and spectrometric examinations, structural proposals were made and subsequently proven by synthesis, using ring-closing-metathesis as the key steps. These macrolides, (9Z,11E,13S)- octadeca-9,11-dien-13-olide (5, S-coriolide), (9Z,11E,13S,15Z)-octadeca-9,11,15- trien-13-olide (6), (9Z,13S)-octadec-9-en-13-olide (13), and (9Z,11S)-octadec-9-en-11-olide (25), are biosynthetically obviously derived from oleic, linoleic, and linolenic acids. Their absolute configurations were determined by gas chromatographic investigations on chiral phases, showing all to possess (S)-configuration. The Royal Society of Chemistry.
- Schulz, Stefan,Yildizhan, Selma,Stritzke, Katja,Estrada, Catalina,Gilbert, Lawrence E.
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p. 3434 - 3441
(2008/09/19)
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- Stereoselective synthesis of 5-(1-hydroxyalkyl)-2-pyrrolidinones utilizing oxidation of 5-alkylidene-2-pyrrolidinones to acyliminium ion precursors
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A general method was devised for the LiN(TMS)2/AgOTf (=2:1)-catalyzed intramolecular (5-exo-dig) cyclization of β-alkynylamides 1 possessing alkyl, aryl or no functional groups at the terminal alkynes, to 5-alkylidene-2-pyrrolidinones 2. These 5-alkylidene-2-pyrrolidinones were oxidized to the diol-type alkoxylactams 3 by dimethyldioxirane (DMD) or mCPBA in MeOH. These alkoxylactams are useful as tertiary N-acyliminium ion precursors for the synthesis of threo-5-(1-hydroxyalkyl)-2-pyrrolidinone derivatives 5. (C) 2000 Elsevier Science Ltd.
- Koseki, Yuji,Kusano, Shuichi,Ichi, Daisuke,Yoshida, Keiji,Nagasaka, Tatsuo
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p. 8855 - 8865
(2007/10/03)
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- Intramolecular cyclization of β-alkynylpropanamides to γ-alkylidene- γ-butyrolactams
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A general method for the base-catalized intramolecular cyclization of β-alkynylpropanamides 1 to γ-alkylidene-γ-butyrolactames 2 (and 3) was established. Reactions of β-alkynylamides 1c-h, possessing alkyl groups at the terminal acetylenes, in the presence of a catalytic amount of LiN(TMS)2/AgOTf (= 2:1) in toluene gave exclusively (Z)-alkylidenelactames 2c-h in good yields.
- Koseki,Kusano,Nagasaka
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p. 3517 - 3520
(2007/10/03)
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- Penicillin acylase-mediated synthesis of 2-acetyl-1-pyrroline and of 2-propionyl-1-pyrroline, key roast-smelling odorants in food. Inclusion complexes with i-cyclodextrin and their NMR and MS characterization
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The synthesis of the strong natural roast odorants 1 and 2 is achieved from the C-6 isomeric alcohols 16 and 21 via the acetylenic C-6 and C-7 amines 8 and 9. Key step in the process is the hydrolysis of the W-phenylacetamides 12 and 13 by means of immobilized penicillin acylase, which affords the l-amino-4,5-diketones 14 and 15, spontaneously ring closing to 1 and 2. These latter compounds form inclusion complexes with/?-cyclodextrin, as demonstrated by NMR measurements in deuterated water and FAB-MS spectra.
- Favino, Tito Fabrizio,Fronza, Giovanni,Fuganti, Claudio,Fuganti, Daniela,Grasselli, Piero,Mele, Andrea
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p. 8975 - 8979
(2007/10/03)
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- Preparation of E-alkenes using lithium and 1,3-diaminopropane
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A new selective reducing system, lithium in 1,3-diaminopropane, is described, which enables the preparation of E-olefins from acetylenes in high purity.
- Kovarova,Streinz
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p. 2397 - 2404
(2007/10/02)
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- Synthesis of Medium Ring Ethers. Part 3. Disproof of the Proposed 2,8-Disubstituted Oxocane Structure for Gloeosporone. Synthesis of pseudo-Gloeosporone
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Synthesis of the cis- and trans-2,8-disubstituted oxocane derivatives 2 and 3 (carrying the unusual γ,δ-diketohexanecarboxylic acid side chain) by ozonolysis of the alkynes 14 and 18 (prepared respectively from the alcohols 11 and 15) demonstrated unequivolally that neither of these compounds nor their hydroxy-γ-lactone ring (lactol) tautomeres 1 correspond to the naturally occurring fungal self germination inhibitor gloeosporone.A study of 4,5-dioxohexanoic itself 9 revealed a remarkably low tendency to exist as its hydroxy-γ-lactone (lactol) tautomer 10.
- Carling, Robert W.,Clark, J. Stephen,Holmes, Andrew B.,Sartor, Dirk
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- Regiochemistry and Stereochemistry of Intramolecular Photocycloaddition of Carbon-Carbon Double Bonds to Cyclohexenones
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The intramolecular photocycloaddition mechanism of alkenes tethered by a three-methylene chain to cyclohexenones has been studied.It was found that the reversion from a 1,4-diradical intermediate to starting material is slow relative to the rate of photoadduct formation.Only "straight" closure was observed in the systems studied.For compounds 1-3 and 5, the assumption that the first bond is formed between the β-carbon of the enone and C-4' leading to a 1,4-diradical is supported.For the formation of compounds 6-11, possible mechanisms are discussed.
- Becker, D.,Nagler, M.,Sahali, Y.,Haddad, N.
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p. 4537 - 4543
(2007/10/02)
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- Electron Impact Induced Fragmentation of β-Allenic and γ-Acetylenic Alcohols
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The main fragmentation pathway of ionized hydroxyallenes (1) consists of a methyl loss.Extensive deuterium-labelling experiments indicate that the terminal allenic carbon is implied in this fragmentation.Collisional activation spectra indicate a propenyl-acylium structure (a) for these (+) ions which can originate from a 1,4-hydroxyl migration followed by hydrogen rearrangements.Isomeric hydroxyacetylenes (2) behave similarly, also giving rise, by methyl loss, to acylium ions a.It is proposed that 2(+) radical is irreversibly isomerized into 1(+) radical by a 1,3-hydrogen transfer 'catalysed' by the hydroxy group.The proposed internal proton-bound complex justifies also the easier loss of water from 2(+) radical.Ethyl loss is also a prominent fragmentation for the hydroxyallene and hydroxyacetylene homologues.
- Arseniyadis, Simeon,Maquestiau, Andre,Flammang, Robert,Guenot, Pierre,Carrie, Robert
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p. 909 - 916
(2007/10/02)
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- STUDIES ON THE SYNTHESIS OF GLOEOSPORONE - SYNTHESIS OF THE PROPOSED 2,8-DISUBSTITUED OXOCANE STRUCTURE
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Gloeosporone is neither the cis- nor the trans-2,8-disubstituted oxocane (1) nor its tautomer (2) whose total syntheses are described in this Letter.
- Carling, Robert W.,Holmes, Andrew B.
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p. 6133 - 6136
(2007/10/02)
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- SYNTHESIS OF NAPHTHOQUINONE ANTIBIOTICS BY INTRAMOLECULAR ALKYNE CYCLOADDITION TO CARBENE-CHROMIUM COMPLEXES
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The reaction of carbene-chromium complexes with alkynes provides a direct route to naphthoquinone derivatives and is the key step in a new approach to the isochromanone antibiotics exemplified by deoxyfrenolicin (1) and nanaomycin A (2).While the regioselectivity of intermolecular addition of the appropriate unsymmetrical disubstituted alkyne is unfavourable, two successful approaches have been developed.Allylacetylene reacts with methoxy-(o-methoxyphenyl)methylidene-Cr(CO)5 with high regioselectivity.Bromination, lithiation, and reaction with acetaldehyde produced the desired precursor.Alkoxypalladation led to pyran ring formation and introduction of the acetate side chain.Following earlier procedures, nanaomycin A (2) was produced.A more convergent alternative involved intramolecular cycloaddition of an alkyne with the alkylidene-chromium unit.A series of model cyclizations established the tether to hold the alkyne in place for cyclization and allows easy removal at a later stage.Deoxyfrenolicin (1) was produced in a highly convergent and efficient process.
- Semmelhack, M. F.,Bozell, Joseph J.,Keller, Leonard,Sato, Tadahisa,Spiess, E.J.,et al.
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p. 5803 - 5812
(2007/10/02)
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- MECHANISM OF ACETYLENE AND OLEFIN INSERTION INTO PALLADIUM-CARBON sigma BONDS.
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The intramolecular acetylene insertion reactions of C1L//2PdCO//2(CH//2)//nC EQUVLNT CCH//3 (1a, L equals Ph//3P, n equals 2; 1b, L equals p-tol//3P, n equals 2; 2, L equals Ph//3P, n equals 3) and the intramolecular olefin insertion reaction of C1L//2PdCO//2CH//2CH//2CH equals CH//2 (3, L equals Ph//3P) have been investigated. The acetylene insertion reactions give stable vinyl complexes 5a, 5b, and 6; the olefin insertion reaction gives an unsaturated lactone by beta -hydrogen elimination from the initially formed insertion product. Kinetic and **3**1P NMR studies show that, as predicted by Thorn and Hoffmann, the reactions proceed by a four-coordinate mechanism, with the triple or double bond displacing a phosphine ligand in a rapidly maintained equilibrium prior to insertion. The triple bond in 2, with the longer carbon chain, is more easily coordinated than that in 1a but inserts less rapidly after coordination.
- Samsel,Norton
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p. 5505 - 5512
(2007/10/02)
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- VINYL CATIONS. 40. pi - AND sigma -ROUTES TO VINYL CATIONS. SOLVOLYSES OF 2-METHYLCYCLOHEXENYL, CYCLOPENTYLIDENEETHYL, HEX-5-YN-1-YL, AND RELATED TRIFLATES.
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Three triflates were solvolyzed at various temperatures in water-alcohol mixtures, in TFE-water mixtures, in TFA, in TFIP, in HFIP, and in 100% TFE in the presence of various buffers and the resulting products were determined. The three reactants were also solvolyzed in a standard mixture (1:100:100 equals triflate:TFE:Na//2CO//3) at various temperatures, and the yields of products were compared. The solvolysis products were shown to be under kinetic control.
- Hanack,Fuchs,Collins
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p. 4008 - 4017
(2007/10/12)
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