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All-carbon N-heterocyclic Carbene-catalyzed (3+2) Annulation using Donor-Acceptor Cyclopropanes
Abstract
Donor-acceptor cyclopropanes are known to serve as dipole precursors capable of engaging in (3+2) annulations with electron-deficient π-systems. In 2013, the reaction of donor-acceptor cyclopropanes with α,β-unsaturated acyl fluorides in an all-carbon (3+2) annulation was discovered. The reaction proceeds in good yields using the IMes NHC to provide diastereomerically pure β-lactone-fused cyclopentanes bearing four contiguous stereocentres. Subsequent studies demonstrated that N-t-butyl substituted homochiral morpholinone NHCs allowed the reaction to be achieved in up to 98 % ee. In this account, a background to this reaction is introduced, along with a complete account of the strengths, limitations and challenges encountered while developing this chemistry.
... Òàê, íóêëåîôèëüíûå NHC êàòàëèçèðóþò ðàñêðûòèå òðåõ÷ëåííîãî öèêëà ÄÀÖ, êîòîðûå ñîäåðaeàò ñèëüíûå ýëåêòðîíîäîíîðíûå ãðóïïû. Óêàçàííûå ðåàêöèè ìîãóò ïðîòåêàòü â ìÿãêèõ óñëîâèÿõ ýíàíòèîñåëåêòèâíîãî êàòàëèçà ñ îáðàçîâàíèåì îïòè÷åñêè àêòèâíûõ ïðîäóêòîâ öèêëîïðèñîåäèíåíèÿ [106,[124][125][126][127], îäíàêî ïðèìåðû òàêèõ ðåàêöèé ïîêà ìàëî÷èñëåííû. ...
This is the second book in the Donor-Acceptor Cyclopropanes series. It summarizes and analyzes for the first time the main intermediates formed from D-A cyclopropanes, and also systematizes the main ways of their further transformations. The main attention is paid to the cycloaddition and annulation reactions of D-A cyclopropanes with various substrates under the action of Lewis acids, which are of the greatest practical importance in organic synthesis. The monograph is addressed to a wide range of specialists in the field of small cycle chemistry and organic synthesis, including the synthesis of natural compounds and biologically active substances.
... Many bioactive compounds and secondary metabolites are known as cyclopropane derivatives existing in nature [13][14][15][16][17][18][19], and some drug explorations showed that the presence of a cyclopropane moiety could enhance drug potency [20][21][22][23][24][25]. Many synthetic methods have been reported for stereoselective construction of three-membered carbocyclic rings [26][27][28][29][30][31][32][33][34][35][36][37][38][39]. A beneficial synthetic method is nucleophilic addition-ring closure sequence which was developed and refined by Corey et al. [40,41], Hanessian et al. [42], Dai et al. [43], and Aggarwal et al. [44][45][46][47]. ...
The present work explores the highly trans-stereoselective reaction of a pyridinum ylide (PY1) with 2-(4-chlorobenzylidene)malononitrile (4-CBM) in acetonitrile at 50°C, leading to a cyclopropane-1,1-dicarbo-nitrile derivative (trans-CP2). The energy transformation, selectivities, and mechanistic aspects of the reaction were figured out by molecular electron density theory (MEDT) at the B3LYP/6-31G(d) computational level. All possible reaction paths were explored, and assessment of the relative Gibbs free energies showed that the ring closure process is the rate-determining step. According to the conceptual density functional theory (CDFT) reactivity indices, PY1 and 4-CBM are classified as a strong nucleophilic and a strong electrophilic species, respectively, which rationalizes the highly polar character of the addition of PY1 to 4-CBM. The preferential C 1-C 2 bond formation over C 1-C 3 bonding (regioselectivity) could be explained through an analysis of the calculated electrophilic and nucleophilic Parr functions at the reactive sites of the reactants.
Herein, we report the metal-free synthesis of methylenecyclobutane containing tetrasubstituted alkenyl nitriles via a strain-release driven addition reaction of [1.1.1]propellane under mild conditions. Using this strategy, TMSN3 was shown to interact with various hypervalent iodine(iii) alkyne species to generate cyanocarbene upon N2 evolution. The resulting cyanocarbene intermediate was then trapped by [1.1.1]propellane to produce tetrasubstituted alkenyl nitriles. This protocol could be scaled up to gram quantities and the resulting alkenyl nitriles were shown to be able to undergo various derivatization reactions, offering a plethora of possible transformation reactions.
Acylcyclopropanes are employed as useful donor-acceptor cyclopropanes that undergo formal (4 + 2) cyclocondensation with N-unprotected 3-substituted indoles in the presence of a Brønsted acid catalyst. The reaction involves the simultaneous alkylation of both the N and C-2 positions of the indole and provides access to the 8,9-dihydropyrido[1,2-a]indole scaffold that is the central core of several biologically relevant indole alkaloids in excellent yields and good selectivities.
N-heterocyclic carbene/copper-cocatalyzed [4 + 3] annulation of salicylaldehydes with aziridines was developed, giving the corresponding 1,4-benzoxazepinones in good yields with exclusive regioselectivity. Copper serves as a Lewis acid to activate the small strained aziridines, and the formation of NHC-salicylaldehyde adduct plays an important role in improving the regioselectivity.
Organocatalysis represents a powerful and reliable tool in modern organic chemistry. Cyclopropanes are a versatile compound class whose reactivity exceeds that of other cyclic hydrocarbons. The organocatalytic synthesis of cyclopropanes has become an established and well-studied transformation. However, the implementation of the cyclopropyl motif into the scaffolds of organocatalysts and the activation of cyclopropanes offers potential to further combine these two areas. Here, we discuss organocatalytic cyclopropanations together with organocatalytic reactions where the cyclopropane motif is implemented either in the catalyst or the substrate to demonstrate how organocatalysis can benefit from the unique reactivity of cyclopropanes.
In recent years, acyl fluorides have received a great deal of attention in organic chemistry. Among carboxylic acid derivatives, acyl fluorides display a good balance between stability and reactivity due to their moderate electrophilicity. They are easily prepared from the corresponding carboxylic acids and can be used without any special precautions against moisture. In this review, we describe the recent progress of transformation with acyl fluorides: Lewis base-assisted reactions and transition-metal-catalyzed reactions. The reactions with Lewis base proceeded well to provide a variety of acyl compounds such as lactones, and ketones, etc. In addition, transition-metal-catalyzed transformation gave the corresponding acyl compounds or decarbonylative compounds such as ketones and biaryls, etc.
[1.1.1]Propellane is a highly strained tricyclic hydrocarbon whose reactivity is dominated by addition reactions across the central inverted bond to provide bicyclo[1.1.1]pentane derivatives. These reactions proceed under both radical and two-electron pathways, hence providing access to a diverse array of products. Conversely, transition metal-catalyzed reactions of [1.1.1]propellane are underdeveloped and lack synthetic utility, with reported examples generally yielding mixtures of ring-opened structural isomers, dimers, and trimers, often with poor selectivity. Herein, we report that nickel(0) catalysis enables the use of [1.1.1]propellane as a carbene precursor in cyclopropanations of a range of functionalized alkenes to give methylenespiro[2.3]hexane products. Computational studies provide support for initial formation of a Ni(0)-[1.1.1]propellane complex followed by concerted double C–C bond activation to give the key 3-methylenecyclobutylidene-nickel intermediate.
Donor‐acceptor cyclopropanes not only participate in a broad range of ring openings with nucleophiles, electrophiles, radical and red‐ox agents, but also are excellent substrates for various (3+n)‐cycloaddition and (3+n)‐annulation processes. Moreover, under treatment with Lewis acid donor‐acceptor cyclopropanes can produce new ring systems via isomerization or cyclodimerization. Authors’ contribution to the synthesis of diverse carbocycles from donor‐acceptor cyclopropanes is summarized in this account. In this account we describe investigations of our research group devoted to the transformations of donor‐acceptor cyclopropanes into diverse carbocycles, from polysubstituted cycloalkanes to complex polycyclic structures including molecules wherein a newly formed ring is annulated to heterocyclic moiety.
Cyclopropanes, one of the most important strained rings, have drawn much attention for more than a century on account of the charming and unique reactivity. They not only exist in many natural products, but also have been widely used in the fields of organic synthesis, medicinal chemistry and materials science as versatile building blocks. Based on sustainable development in this area, this review mainly focus on the recent advances in the synthesis of cyclopropanes classified by the types of catalytic systems, and the related applications of cyclopropanes are also mentioned.
The interest in cyclopropane derivatives is caused by the facts that, first, the three-carbon ring is present in quite a few natural and biologically active compounds and, second, compounds with this ring are convenient building blocks for the synthesis of diverse molecules (acyclic, alicyclic and heterocyclic). The carbon–carbon bonds in cyclopropane are kinetically rather inert; hence, they need to be activated to be involved in reactions. An efficient way of activation is to introduce vicinal electron-donating and electron-withdrawing substituents into the ring; these substrates are usually referred to as donor-acceptor cyclopropanes. This review gives a systematic account of the key methods for the synthesis of donor-acceptor cyclopropanes. The most important among them are reactions of nucleophilic alkenes with diazo compounds and iodonium ylides and approaches based on reactions of electrophilic alkenes with sulfur ylides (the Corey – Chaykovsky reaction). Among other methods used for this purpose, noteworthy are cycloalkylation of CH-acids, addition of α-halocarbonyl compounds to alkenes, cyclization via 1,3-elimination, reactions of alkenes with halocarbenes followed by reduction, the Simmons – Smith reaction and some other. The scope of applicability and prospects of various methods for the synthesis of donor-acceptor cyclopropanes are discussed.
The bibliography includes 530 references.
4+1 annulation based reaction offers a versatile tool for the synthesis of 5-membered carbo/heterocycles. Recent advances of 4+1 annulation through transition-metal-catalyzed C–H bond activation have provided straightforward and widely applicable alternatives to the traditional methods. In particular, the redox-neutral strategies emerged in the past 5 years overcome the inherent disadvantages caused by the external oxidant which are generally required in the early protocols to regenerate the active catalyst, such as limited substrate scope, harsh reaction conditions and generation of stoichiometric by-products. Progress in oxidant-free 4+1 annulations through transition-metal-catalyzed C–H bond activation are discussed in this review until September 2017.
N-Heterocyclic carbene catalysed redox isomerisation with reduction about the carbonyl has been developed in the transformation of trienyl esters to tetrasubstituted benzaldehydes. The reaction proceeds in good to excellent yield, and in cases that provide 2,2′-biaryls, enantioselectivity is observed. Mechanistic studies demonstrate the intermediacy of a cyclohexenyl β-lactone, while implicating formation of the homoenolate as turnover limiting.
With the intention of improving synthetic efficiency, organic chemists have turned to bioinspired organocascade or domino processes that generate multiple bonds and stereocentres in a single operation. However, despite the great importance of substituted cyclopentanes, given their prevalence in complex natural products and pharmaceutical agents, the rapid, enantioselective assembly of these carbocycles lags behind cyclohexanes. Here, we describe a Michael-aldol-β-lactonization organocascade process for the synthesis of complex cyclopentanes utilizing chiral α,β-unsaturated acylammonium intermediates, readily generated by activation of commodity unsaturated acid chlorides with chiral isothiourea catalysts. This efficient methodology enables the construction of two C-C bonds, one C-O bond, two rings and up to three contiguous stereogenic centres delivering complex cyclopentanes with high levels of relative and absolute stereocontrol. Our results suggest that α,β-unsaturated acylammonium intermediates have broad utility for the design of organocascade and multicomponent processes, with the latter demonstrated by a Michael-Michael-aldol-β-lactonization.
NHC-Katalysator: Eine Reihe von N-tert-Butyl-substituierten N-heterocyclischen Triazolylidencarbenen wurde hergestellt. Darunter erwies sich der von Morpholinon abgeleitete Katalysator 1 als am besten geeignet für enantioselektive Synthesen von Cyclopropanen ausgehend von Donor-Akzeptor-Cyclopropanen und α,β-ungesättigten Acylfluoriden. Die Aktivität dieses Katalysators wurde durch eine 13C-NMR-Analyse mit den elektronischen Eigenschaften korreliert. M.S.=Molekülsieb, TMS=Trimethylsilyl.
An enantioselective N-heterocyclic carbene (NHC)-catalyzed diene regenerative (4 + 2) annulation has been achieved through the use of highly nucleophilic morpholinone-derived catalysts. The reaction proceeds with good to excellent yields, high enantioselectivity (most >92% ee), and good diastereoselectivity (most >7:1). The generality of the reaction is high, with 19 examples reported. The utility of the products has been examined with subsequent derivatization in Diels-Alder reactions using electron-poor dienophiles. Furthermore, interception of the proposed β-lactone intermediate has been achieved, allowing the synthesis of compounds bearing four contiguous stereocenters with high levels of enantio- and diastereoselectivity.
Efficient construction of complex cylcopentane- or cyclohexane-fused δ-lactones employing redox activation of enals using a chiral N-heterocyclic carbene and LiCl as cooperative catalysts is described. The organocascade proceeds with excellent diastereo- (>99:1) and enantioselectivity (up to >99% ee) and comprises the formation of three bonds with three contiguous stereocenters.
The N-heterocyclic carbene-catalyzed cascade reaction of enals with malonates to give bicyclic δ-lactones was developed. The cyclopentane- and cyclohexane-fused δ-lactones with three continued stereocenters were obtained in high yields with excellent diastereo- and high enantioselectivities.
N-heterocyclic carbenes (NHC) have had a broad impact on the field of organic chemistry, often allowing for the mild construction of complex molecules from simple starting materials. The most widely used approach for the synthesis of imidazolium and imidazolinium salts is the introduction of the precarbenic carbon in the cyclization step. Using this strategy, imidazoliums have been generated from a variety of 1,1-biselectrophiles, including diiodomethane, Weiss' reagent, chloromethyl ethers, and chloromethyl pivalates. Knight and Leeper first introduced chiral bicyclic triazolium salts in 1998, using a three-step sequence from the chiral morpholinone or γlactam. Since many NHC-catalyzed reactions generate the active carbene in situ by deprotonation of the corresponding azolium a discussion of the acidity of these precatalysts is important. Suzuki and colleagues reported the intramolecular heterocoupling of aldehydes and ketones in 2003, synthesizing preanthraquinones in high yields. A Michael addition-intramolecular benzoin cascade reaction strategy was developed by Rovis and co-workers to synthesize highly functionalized cyclopentanones with high enantioselectivity.
This review summarizes research directed towards the formation of carbocyclic adducts from donor-acceptor cyclopropanes. The focus of the review is on annulation and cycloaddition reactions both inter- and intramolecularly mediated by Lewis or protic acid, bases, or thermal conditions. Rearrangements resulting in carbocycles and those reactions mediated by transitions metal catalysis have been excluded.
The enantioselective vinylogous Michael/aldol cascade is an underdeveloped approach to cyclohexenes. Herein we describe a highly enantio- (most ≥98:2 er) and diastereoselective (all ≥15:1 dr) N heterocyclic carbene catalyzed cycloisomerization of acyclic ester dienolates to cyclohexyl β-lactones. Derivatizations avail various cyclohexenes bearing 4-contiguous stereogenic centers while mechanistic studies support olefin isomerization prior to cyclization.
Katalytische Umwandlungen mit N-heterocyclischen Carbenen (NHCs) haben sich als effiziente Ansätze zum Aufbau komplexer Moleküle erwiesen. Seit der Veröffentlichung von Stetter 1975 zur Totalsynthese von cis-Jasmon und Dihydrojasmon durch Carbenkatalyse hat sich die Anwendung von NHCs in der Totalsynthese, insbesondere in den letzten zehn Jahren, schnell verbreitet. Dieser Aufschwung ist zweifellos die Folge neuerer Entwicklungen bei NHC-katalysierten Reaktionen, einschließlich der neuen Benzoin-, Stetter-, Homoenolat- und Aroylierungsprozesse. Die Umwandlungen ermöglichen ebenso typische wie auf Umpolung beruhende Bindungsbildungen und sind bereits als Schlüsselschritte in mehreren neuen Totalsynthesen aufgetreten. Dieser Kurzaufsatz beschreibt diese neuen Arbeiten und zeigt die verstärkten Einsatzmöglichkeiten der Carbenkatalyse in der Totalsynthese auf.
Oxidative Carbenkatalyse kehrt über zwei aufeinanderfolgende Umpolungsreaktionen die Reaktivität der β-Position in α,β-ungesättigten Aldehyden um: von der typischen elektrophilen zur nukleophilen und wieder zur elektrophilen. Die redoxaktivierten Michael-Akzeptoren sind in β-Position reaktiver als die Aldehyde. Mit β-Dicarbonylverbindungen entstehen unter milden Bedingungen Dihydropyranone in guten bis exzellenten Ausbeuten.
Während sich die organokatalytischen Dominoreaktionen (auch Organokaskadenkatalysen genannt) im letzten Jahrzehnt zu einem wichtigen Hilfsmittel in der Synthesechemie entwickelt haben, fand die Anwendung von N-heterocyclischen Carbenen (NHCs) als Katalysatoren in Dominoreaktionen erst in den letzten drei Jahren zunehmend Beachtung. Unter Berücksichtigung der besonderen Aktivierungsmodi der Substrate durch die NHC-Katalysatoren ist eine Unterscheidung zwischen einer einzelnen chemischen Transformation und einer sequenziellen Eintopfreaktion schwierig. Das Ziel dieses Kurzaufsatzes besteht darin, die Domino-, Kaskaden- und Tandemkatalyse in Gegenwart von NHC-Katalysatoren kritisch zu betrachten und jüngste Publikationen auf diesem Gebiet vorzustellen.
The reaction of enals with β-diketones, β-ketoesters, and malonates bearing a β-oxyalkyl substituent at the α-position by oxidative NHC catalysis to provide highly substituted β-lactones is described. Reactions occur with excellent diastereo- and enantioselectivity. The organo cascade comprises two CC bond formations and one CO bond formation. Up to four contiguous stereogenic centers including two fully substituted stereocenters are formed in the cascade.
The reaction of enals with β-diketones, β-ketoesters, and malonates bearing a β-oxyalkyl substituent at the α-position by oxidative NHC catalysis to provide highly substituted β-lactones is described. Reactions occur with excellent diastereo- and enantioselectivity. The organo cascade comprises two C-C bond formations and one C-O bond formation. Up to four contiguous stereogenic centers including two fully substituted stereocenters are formed in the cascade. Highly substituted β-lactones are generated by NHC catalysis of enals with β-diketones, β-ketoesters, and malonates bearing a β-oxyalkyl substituent at the α-position. LiCl acts as cooperative Lewis acid. The organocascade comprises two C-C bond formations and one C-O bond formation. Up to four contiguous stereogenic centers including two fully substituted stereocenters are formed with high diastereo- and enantioselectivity.
The successful isolation and characterization of an N-heterocyclic carbene in 1991 opened up a new class of organic compounds for investigation. From these beginnings as academic curiosities, N-heterocyclic carbenes today rank among the most powerful tools in organic chemistry, with numerous applications in commercially important processes. Here we provide a concise overview of N-heterocyclic carbenes in modern chemistry, summarizing their general properties and uses and highlighting how these features are being exploited in a selection of pioneering recent studies.
Ester – was sonst! Eine neue Strategie in der NHC‐Organokatalyse (NHC=N‐heterocyclisches Carben) ermöglicht die α‐, β‐ und γ‐Aktivierung gesättigter und ungesättigter Ester (siehe Schema). Die entstehenden Acylazolium‐Intermediate gehen effizient Dominoreaktionen mit geeigneten Substraten ein, wodurch Carbo‐ und Heterocyclen mit sehr guten Diastereo‐ und Enantioselektivitäten gebildet werden.
Ringspannung gewinnbringend zu nutzen, ist seit jeher für den Aufbau komplexer Systeme von großem Vorteil. Schnell richtet sich somit der Blick auf Cyclopropane als Bausteine für die organische Synthese. Auch wenn die Thermodynamik dabei auf der Seite des Synthesechemikers steht, ermöglicht erst ein spezielles Substitutionsmuster am Cyclopropan besonders milde, effiziente und selektive Umsetzungen. Die erforderliche Absenkung der Aktivierungsbarriere wird durch die Kombination von zueinander vicinal stehendem Elektronendonor und ‐akzeptor erreicht. Dieser Aufsatz beleuchtet die richtigen Hilfsmittel, um mit Donor‐Akzeptor‐substituierten Cyclopropanen Ringöffnungen, Cycloadditionen und Umlagerungen durchzuführen. GermanTauziehen am Cyclopropan: In den letzten Jahren haben die schon vor über 30 Jahren intensiv untersuchten Donor‐Akzeptor‐substituierten Cyclopropane eine Renaissance erlebt. Dieser Aufsatz zeichnet die wichtigsten aktuellen Entwicklungen im Zusammenhang mit Ringöffnungen, Cycloadditionen und Ringerweiterungen nach.
The effective use of ring strain has been applied to considerable advantage for the construction of complex systems. The focus here is directed towards cyclopropanes as building blocks for organic synthesis. Although thermodynamics should take the side of synthetic chemists, only a specific substitution pattern at the cyclopropane ring allows for particularly mild, efficient, and selective transformations. The required decrease in the activation barrier is achieved by the combined effects of vicinal electron-donating and electron-accepting moieties. This Review highlights the appropriate tools for successfully employing donor–acceptor cyclopropanes in ring-opening reactions, cycloadditions, and rearrangements.
Esters-what else! A new strategy in NHC organocatalysis allows the α-, β- and γ-activation of saturated and unsaturated esters. The resulting acyl azolium intermediates efficiently participate in domino reactions with suitable substrates to generate synthetically valuable carbo- and heterocycles with very good diastereo- and excellent enantioselectivities.
Catalytic reactions promoted by N-heterocyclic carbenes (NHCs) have exploded in popularity since 2004 when several reports described new fundamental reactions that extended beyond the long-studied generation of acyl anion equivalents. These new NHC-catalyzed reactions allow chemists to generate unique reactive species from otherwise inert starting materials, all under simple, mild reaction conditions and with exceptional selectivities. In analogy to transition metal catalysis, the use of NHCs has introduced a new set of elementary steps that operate via discrete reactive species, including acyl anion, homoenolate, and enolate equivalents, usually generated by oxidation state reorganization (“redox neutral” reactions). Nearly all NHC-catalyzed reactions offer operationally simple reactions, proceed at room temperature without the need for stringent exclusion of air, and do not generate reaction byproducts. Variation of the catalyst or reaction conditions can profoundly influence reaction outcomes, and researchers can tune the desired selectivities through careful choice of NHC precursor and base.
Cyclization reactions of donor-acceptor (D-A) cyclopropanes are recognized as versatile methods for construction of carbocyclic and heterocyclic scaffolds. In the literature, many examples of these polarized cyclopropanes' reactivity with nucleophiles, electrophiles, and radicals are prevalent. Although intermolecular reactivity of donor-acceptor cyclopropanes is widely reported, reviews that center on their intramolecular chemistry are rare. Thereupon, this tutorial review focalizes on new intramolecular transformations of donor-acceptor cyclopropanes for cycloisomerizations, formal cycloadditions, umpolung reactions, rearrangements and ring-opening lactonizations/lactamizations from 2009 to 2013. Furthermore, the role of D-A acceptor cyclopropanes as reactive subunits in natural product synthesis is underscored.
Ming Yu was born and grew up in Centre China, Hubei Province. In 1991, after finishing Middle school at his hometown, he went to Shanghai and attended East China University of Science and Technology, where he earned his BS in Pharmaceutical Technology in 1995 and MS in Medicinal Chemistry in 1998. He then joined the graduate school at The University of Texas at Austin in the Department of Chemistry and Biochemistry and received his chemistry PhD in 2004. During his PhD research, he made several significant discoveries in the area of donor–acceptor cyclopropanes. Dr. Yu is currently employed in California in the pharmaceutical industry.
But(yl) not futile: A range of N-tert-butyl-substituted triazolylidene N-heterocyclic carbenes have been prepared. Of these, the morpholinone-derived catalyst (1) proved best suited to the enantioselective synthesis of cyclopentanes from donor-acceptor cyclopropanes and α,β-unsaturated acyl fluorides. The performance of this catalyst has been correlated to the electronic nature of the catalyst by (13) C NMR analysis. M.S.=molecular sieves, TMS=trimethylsilyl.
Chiral bicyclic 1,2,4-triazolium salts having a defined face of the heterocyclic ring hindered have been synthesised and they catalyse the benzoin condensation in good yield; the enantiomeric excesses obtained (up to 80%) are much better than with closely related thiazolium salts and the opposite enantiomer of benzoin predominates.
A mild and efficient transprotection of alcohols from silyl ethers 1a-f to benzoates 2a-f is reported in fair to good yields (50-98%). This silyl-acyl exchange reaction proceeds readily in acetonitrile at room temperature in the presence of benzoyl fluoride and DMAP as an acyl transfer catalyst. A two-step 'one-pot' DMAP-catalyzed silylcyanation-transprotection sequence which gives the corresponding O-benzoyl cyanohydrines 2g-l in high yields (72-98%) from various benzaldehyde and ketone derivatives is also reported. This original organocatalytic acyl transfer process was also found to be effective in the O-benzoylation of trimethysilyl enolates 1m-o, providing enol esters 2m-o. Lastly, the potential of this strategy is also illustrated by a DMAP-mediated Claisen condensation between ketene silyl acetals 1p-r and benzoyl fluoride.
Die in großer Vielfalt zur Verfügung stehenden 2-(Trialkylsiloxy)cyclopropancarbonsäuremethylester C1–C31 werden unter sehr milden Bedingungen und in hohen Ausbeuten in die 4-Oxoalkansäure-methylester D1–D31 übergeführt, die als Synthesebausteine von Bedeutung sind. Es können auch empfindliche Ester mit Formyl-, Vinylketon- oder Trimethylsiloxyfunktion dargestellt werden. Der regioselektiven Synthese von C entsprechend kann man gezielt isomere 4-Oxoalkansäureester D aufbauen. Die alkylierende Ringöffnung in Gegenwart eines Elektrophils führt zu 2-substituierten 4-Oxoalkansäureestern, deren Alkylierungsgrad allerdings 60% nicht übersteigt. Weitere Spaltungsvarianten, die im Eintopfverfahren andere 4-Oxoalkansäurederivate liefern, werden mitgeteilt.Ring Opening Reactions of Methyl 2-Siloxycyclopropanecarboxylates to 4-Oxoalkanoic Acid DerivativesA great variety of methyl 2-(trialkylsiloxy)cyclopropanecarboxylates C1–C31 are cleaved under very mild condition and with excellent yields providing 4-oxoalkanoic esters D1–D31 Which are important synthetic building blocks. Even sensible esters with formyl, vinyl ketone, or trimethylsiloxy functions can be prepared. Corresponding to the regioselective synthesis of C isomeric pairs of D Can deliberately be constructed. In the presence of an electrophile alkylating ring opening delivers 4-oxoalkanoates substituted in position 2, however, the degree of alkylation does not exceed 60%. Several other cleavage variations allow syntheses of other 4-oxoalkanoic acid derivatives in effective one-pot procedures.
N-heterocyclic carbenes are well known for their role in catalyzing benzoin and Stetter reactions: the generation of acyl anion equivalents from simple aldehydes to react with a variety of electrophiles. However, when an aldehyde bearing a leaving group or unsaturation adjacent to the acyl anion equivalent is subjected to an NHC, a new avenue of reactivity is unlocked, leading to a number of novel transformations which can generate highly complex products from simple starting materials, many of which are assembled through unconventional bond disconnections. The field of these new reactions - those utilizing α-reducible aldehydes to access previously unexplored catalytic intermediates - has expanded rapidly in the past eight years. This review aims to provide the reader with a historical perspective on the underlying discoveries that led to the current state of the art, a mechanistic description of these reactions, and a summary of the recent advances in this area.
This Concept article discusses the potential of oxidative carbene catalysis in synthesis and comprehensively covers pioneering studies as well as recent developments. Oxidative carbene catalysis can be conducted by using inorganic and organic oxidants. Applications in cascade processes, in enantioselective catalysis, and also in natural product synthesis are discussed. Cascading down: Reaction of an aldehyde with an NHC provides the corresponding Breslow intermediate A, which can be readily oxidized with various organic and inorganic oxidants to give the acylazolium ion B (see scheme). Intermediate B can react with various nucleophiles either at the 2 or 4-position. With enals as starting aldehydes, elegant cascade processes have been developed using oxidative carbene catalysis.
Reaction discovery using N-heterocyclic carbene organocatalysis has been dominated by the chemistry of acyl anion equivalents. Recent studies demonstrate that NHCs are far more diverse catalysts, with a variety of reactions discovered that proceed without acyl anion equivalent formation. In this tutorial review selected examples of acyl anion free NHC catalysis using carbonyl compounds are presented.
The NHC-catalyzed Claisen rearrangement of hybrid Ireland Coates structures has been achieved allowing (3 + 2) annulation between donor-acceptor cyclopropanes and α,β-unsaturated acyl fluorides. The reaction proceeds with high diastereoselectivity (>20:1) affording a diverse range of β-lactone fused cyclopentanes. Mechanistic studies are detailed.
N-Heterocyclic carbene (NHC) catalyzed transformations have emerged as powerful tactics for the construction of complex molecules. Since Stetter's report in 1975 of the total synthesis of cis-jasmon and dihydrojasmon by using carbene catalysis, the use of NHCs in total synthesis has grown rapidly, particularly over the last decade. This renaissance is undoubtedly due to the recent developments in NHC-catalyzed reactions, including new benzoin, Stetter, homoenolate, and aroylation processes. These transformations employ typical as well as Umpolung types of bond disconnections and have served as the key step in several new total syntheses. This Minireview highlights these reports and captures the excitement and emerging synthetic utility of carbene catalysis in total synthesis.
The N-heterocyclic carbene-catalyzed reaction of alkynyl aldehydes with 1,3-keto esters or 1,3-diketones has been studied. This protocol offers an entirely new, mild and atom-economical access to highly functionalized 3,4-dihydropyranones.
A combination of a chiral N-heterocyclic carbene catalyst and α,β-unsaturated aldehyde leads to a catalytically generated α,β-unsaturated acyl azolium, which participates in a highly enantioselective annulation to give dihydropyranone products. This full account of our investigations into the scope and mechanism of this reaction reveals the critical role of both the type and substitution pattern of the chiral triazolium precatalyst in inducing and controlling the stereochemistry. In an effort to explain why stable enols such as naphthol, kojic acid, and dicarbonyl are uniquely efficient, we have postulated that this annulation occurs via a Coates-Claisen rearrangement that invokes the formation of a hemiacetal prior to a sigmatropic rearrangement. Detailed kinetic investigations of the catalytic annulation are consistent with this mechanistic postulate.
The umpolung strategy encompasses all the methods that make organic molecules react in an inverse manner compared to their innate polarity-driven reactivity. This concept entered the field of organocatalysis when it was recognized that N-heterocyclic carbenes (NHCs) can provide catalytic access to acyl anion equivalents. Since then, tremendous efforts have followed to develop a broad variety of NHC-catalyzed reactions. In addition to this, more recent research developments have shown that other families of organocatalysts are also able to mediate transformations in which inversion of polarity is involved. This tutorial review aims at offering a didactic overview of organocatalytic umpolung and should serve as an inspiration for further progress in this field.
The N-heterocyclic carbene catalyzed (4 + 2) cycloaddition between α,β-unsaturated acid fluorides and TMS dienol ethers provides cyclohexene fused β-lactone intermediates stable below -20 °C. These can be intercepted reductively or with organolithium reagents to produce diastereomerically pure cyclohexenes (>20:1 dr) with up to four contiguous stereocenters. The mechanism has been investigated using theoretical calculations and by examining secondary kinetic isotope effects. Together these studies implicate the formation of a diastereomerically pure β-lactone intermediate by a stepwise (4 + 2) cycloaddition involving Michael addition, aldol cyclization, and lactonization.
While organocatalyzed domino reactions or "organocascade catalysis" developed into an important tool in synthetic chemistry during the past decade, the utility of N-heterocyclic carbenes (NHCs) as catalysts in domino reactions has only received growing attention in the past three years. Taking into account the unique activation modes of the substrates by NHC catalysts, it is often difficult to distinguish between a single chemical transformation and a sequential one-pot transformation. Therefore, herein we present a critical consideration of domino, cascade, and tandem catalysis in the case of NHC catalysts and highlight recent publications in this area.
NHC catalysed rearrangement of α,β-unsaturated enol esters derived from formyl acetates and cyclopentyl annulated α,β-unsaturated acids provides the cyclopentapyranone core of (-)-7-deoxyloganin (1) with diastereo- and chemoselectivity in 6 steps starting from (-)-citronellal. The elaboration to the natural product has been investigated using two new approaches. The most successful intercepts our previous work on (-)-7-deoxyloganin (1) allowing completion of a formal total synthesis in 10-steps.
Three stereocenters are formed in the carbene catalyzed cascade reaction of enals with various β-diketones to give the corresponding indane derivatives with excellent stereoselectivities. The products are readily transformed to the corresponding 1,2,3-trisubstituted indane derivatives, which represent privileged substructures in medicinal chemistry.
Homoenolate is a reactive intermediate that possesses an anionic or nucleophilic carbon β to a carbonyl group or its synthetic equivalent. The recent discovery that homoenolates can be generated from α,β-unsaturated aldehydes via N-Heterocyclic Carbene (NHC) catalysis has led to the development of a number of new reactions. A majority of such reactions include the use of carbon-based electrophiles, such as aldehydes, imines, enones, dienones etc. resulting in the formation of a variety of annulated as well as acyclic products. The easy availability of chiral NHCs has allowed the development of very efficient enantioselective variants of these reactions also. The tolerance showed by NHCs towards magnesium and titanium based Lewis acids has been exploited in the invention of cooperative catalytic processes. This tutorial review focuses on these and other types of homoenolate reactions reported recently, and in the process, updates the previous account published in 2008 in this journal.
Herein we report the first all-carbon N-heterocyclic carbene-catalyzed (4 + 2) cycloaddition. The reaction proceeds with α,β-unsaturated acid fluorides and silyl dienol ethers and produces 1,3-cyclohexadienes with complete diastereocontrol (dr >20:1) while demonstrating a new type of reaction cascade exploiting α,β-unsaturated acyl azoliums.
Enals react with various 1,3-dicarbonyl compounds as redox-activated Michael acceptors in the presence of TAZ as NHC precursor and a bisphenol derived quinone TBQ as the organic oxidant to produce dihydropyranones.
The diastereoselective N-heterocyclic carbene (NHC) catalyzed rearrangement of α,β-unsaturated enol ester (S)-2b has been used to assemble dihydropyranone (S)-3b, a material embodying the bicyclic core of the iridoid family of natural products. Elaboration of this intermediate, by chemoselective reduction followed by stereoselective β-glycosylation, has allowed the total synthesis of (-)-7-deoxyloganin (1) to be achieved in four subsequent steps.
In the presence of a chiral azolium salt (10 mol %), enols and ynals undergo a highly enantioselective annulation reaction to form enantiomerically enriched dihydropyranones via an N-heterocyclic carbene catalyzed variant of the Claisen rearrangement. Unlike other azolium-catalyzed reactions, this process requires no added base to generate the putative NHC-catalyst, and our investigations demonstrate that the counterion of the azolium salt plays a key role in the formation of the catalytically active species. Detailed kinetic studies eliminate a potential 1,4-addition as the mechanistic pathway; the observed rate law and activation parameters are consistent with a Claisen rearrangement as the rate-limiting step. This catalytic system was applied to the synthesis of enantioenriched kojic acid derivatives, a reaction of demonstrated synthetic utility for which other methods for catalytic enantioselective Claisen rearrangements have not provided a satisfactory solution.
The construction of heterocyclic compounds from activated cyclopropane derivatives offers an alternative strategy for the preparation of molecules that may be of interest from a structural or biological standpoint. Several newly developed methods provide access to densely functionalized heterocycles in a manner that can be considered useful for both diversity- and target-oriented synthetic approaches. This tutorial review focuses on the latter, describing recent developments and applications of cyclopropane ring-expansion reactions in natural product synthesis.
(Chemical Equation Presented) Catalytic generation of α,β- unsaturated acyl imidazolium cations and enolates has been achieved, and their involvement in a Michael addition acylation sequence exploited, to provide a range of dihydropyranones. α,β-Unsaturated enol esters, or α,β-unsaturated acid fluorides in association with TMS enol ethers, serve as appropriate substrates for this reaction. The transformation can also be achieved enantioselectively using catalysts derived from chiral triazolium salts.
In this article we have described the different types of reactions that have been investigated by means of optically active
compounds. It remains to determine the scope of the different mechanisms suggested, and to formulate stereochemical rules
for use in further synthetic work.
The manifold synthetic methods and their applications demonstrate considerable growth of the chemistry of D-A cyclopropanes during the last 5 years. Although most of the principles employed have long been known, quite a number of new modifications and variations have been developed that characterize D-A cyclopropanes as extremely versatile and valuable tools for organic synthesis. Their ring opening for the preparation of substituted and functionalized 1,4-dicarbonyl compounds and derivatives thereof is remarkably successful.
[reaction: see text] Stereoselective, carbene-mediated redox esterification of alkynyl aldehydes provides mild and atom economical access to (E)-configurated, alpha,beta-unsaturated carboxylic esters. The organocatalytic method relies on the generation of activated carboxylates via extended/conjugated umpolung in the presence of catalytic amounts of carbene precursor and base.