Synthesis of unsymmetrical benzil licoagrodione

A synthesis of unsymmetrical 1,2-diarylethane-1,2-dione is reported involving the intramolecular cyclization of anionic benzylic ester of the aryl benzyl ether followed by oxidation employing dioxirane. With the use of microwave irradiation, licoagrodione was prepared from Claisen rearrangement of the corresponding allyl phenyl ether 1,2-diketone readily available from the Lindlar's reduction of the corresponding alkyne derivative. Subsequent removal of protecting groups then furnished the desired product.     

Approaches to the quaternary stereocentre and to the heterocyclic core in diazonamide A using the Heck reaction and related coupling reactions

In model studies towards the quaternary centre at the heart of diazonamide A (early structure 2; revised structure 1), cyclisations of the alkene-substituted iodoaryls 4, 13, 18 and 23, under Heck reaction conditions, were shown to lead to the corresponding benzodihydrofuran 5, benzofuranone 14 and the oxindoles 19 and 24 respectively, in 50-80% yield. Further manipulation of the benzodihydrofuran 5 then led to the intermediates 30, 33 and 39, which make up parts of the oxazole-indole heterocyclic core in diazonamide A. Attempts to perform a corresponding 13-exo-trig Heck cyclisation from the precursor 46a, prepared from 44 and 45, leading to 47 were not successful. A similar outcome was obtained during attempts to effect Heck cyclisations from the ester 57 and the related ether 59. Treatment of the chromene-substituted iodoaryl 62 with Pd(OAc)2, PPh3 and Ag2CO3 led to the spirocycle 64 as a crystalline solid. X-Ray crystal structure analysis established that the quaternary centre in 64 had the same configuration as that present in diazonamide A (1).     

The diazo route to diazonamide A. Studies on the indole bis-oxazole fragment

[structure: see text] Various approaches to the indole bis-oxazole fragment of the marine secondary metabolite diazonamide A are described, all of which feature dirhodium(II)-catalyzed reactions of diazocarbonyl compounds in key steps. Thus, 3-bromophenylacetaldehyde is converted into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Boc-valinamide resulted in N-H insertion of the intermediate rhodium carbene to give a ketoamide that readily underwent cyclodehydration to give (S)-2-(1-tert-butoxycarbonylamino)-2-methylpropyl]-5-(3-bromobenzyl)oxazole-4-carboxamide, after ammonolysis of the initially formed ester. This aryl bromide was then coupled to a 3-formyl-indole-4-boronate under Pd catalysis to give the expected biaryl. Subsequent conversion of the aldehyde group into a second alpha-diazo-beta-ketoester gave a substrate for an intramolecular carbene N-H insertion, although attempts to effect this cyclization were unsuccessful. A second approach to an indole bis-oxazole involved an intermolecular rhodium carbene N-H insertion, followed by oxazole formation to give (S)-2-[1-tert-(butoxycarbonylamino)-2-methylpropyl]-5-methyloxazole-4-carboxamide. A further N-H insertion of this carboxmide with the rhodium carbene derived from ethyl 2-diazo-3-[1-(2-nitrobenzenesulfonyl)indol-3-yl]-3-oxopropanoate gave a ketoamide, cyclodehydration of which gave the desired indole bis-oxazole. Finally, the boronate formed from 4-bromotryptamine was coupled to another diazocarbonyl-derived oxazole to give the corresponding biaryl, deprotection and cyclization of which produced a macrocyclic indole-oxazole derivative. Subsequent oxidation and cyclodehydration incorporated the second oxazole and gave the macrocyclic indole bis-oxazole.     

Pd(II)-catalyzed aliphatic Claisen rearrangements of acyclic allyl vinyl ethers

Palladium (II)-catalyzed [3,3] sigmatropic rearrangement of acyclic allyl vinyl ethers delivers 2,3-anti disubstituted pentenal Claisen adducts with high diastereoselectivity. Reaction conditions for circumventing allyl vinyl ether cleavage that had previously plagued catalyzed rearrangement of α-unsubstituted vinyl ether substrates are described. Merging Pd(II) catalysis with the facile access to the Claisen substrates afforded by Ir(I)-catalyzed olefin isomerization provides an expedient procedure for realizing asymmetric anti-selective Claisen rearrangements.     

Strategies for expanding structural diversity available from olefin isomerization-claisen rearrangement reactions

Boron-substituted di(allyl) ethers provide an efficient conduit for expanding the structural diversity available from olefin isomerization-Claisen rearrangement (ICR) reactions. Easily prepared allyl propargyl ethers undergo chemoselective Zr(IV)-catalyzed hydroboration to afford the boron-substituted ICR substrates. The boron-substituted allyl residue undergoes chemoselective Ir(I)-catalyzed olefin isomerization and in situ Claisen rearrangement to afford stereodefined beta-boryl aldehyde products. Functionalization of the C-B linkage by oxidation or Suzuki cross-coupling provides a route to Claisen adducts previously inaccessible from the ICR methodology.     

A novel, expeditious synthesis of racemic camptothecin

[reaction: see text] A novel and efficient synthesis of racemic camptothecin, starting from a readily accessible hydroxy pyridone, is presented. Key steps include a Claisen rearrangement of a functionalized allylic ether, a hindered Heck coupling, and a Friedl?nder condensation.     

Tandem Sakurai-aldol addition reactions as a route to structurally complex carbocycles

Tandem intramolecular Sakurai-aldol reactions provide a concise and highly diastereoselective route to substituted cyclohexenone derivatives. The cyclization substrates are readily obtained using olefin isomerization-Claisen rearrangement (ICR) reactions to prepare the key chiral allyl silane precursors. The Claisen reaction products are elaborated to the chiral Sakurai-aldol substrates by an efficient two-step sequence involving vinyl organometallic-aldehyde addition and oxidation of the resulting alcohol. The reaction of the resulting enones with TiCl(4) elicits a highly stereoselective allyl silane conjugate addition to produce a trichlorotitanium enolate as the reaction intermediate; intermolecular trapping of the enolate with an aldehyde provides pentasubstituted cyclohexanone derivatives in which the annulation reaction establishes four stereocenters and two new C-C bonds. A fully intramolecular variant of the Sakurai-aldol reaction that creates four stereocenters, two new C-C bonds, and establishes two new carbocyclic rings is also described.     

1,3-dipolar cycloaddition chemistry for the preparation of novel indolizinone-based compounds

[Chemical reaction: See text] Starting from methyl 5-oxo-6-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydroindolizine-8-carboxylate, obtained by a Rh(II)-catalyzed 1,3-dipolar cycloaddition reaction of 1-(2-benzenesulfonyl-2-diazoacetyl)pyrrolidin-2-one and methyl acrylate, several indolo- and furano-fused indolizinones were efficiently prepared. In the first case, a palladium-mediated C-N coupling of the triflate with a variety of substituted anilines provided the desired methyl 5-oxo-6-(arylamino)-1,2,3,5-tetrahydroindolizine-8-carboxylates in high yield. Methyl 6-(2-bromophenylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate as well as its decarboxylated analogue, 6-(2-bromophenylamino)-2,3-dihydro-1H-indolizin-5-one, were synthesized in excellent yield and were found to undergo an intramolecular Heck cyclization to give 1,2,3,6-tetrahydroindolizino[6,7-b]indol-5-ones. To prepare furano-fused indolizinones, methyl 6-hydroxy-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate was etherified with different allyl halides, and the resultant allyl ethers were subjected to a thermal Claisen rearrangement to give the corresponding methyl 7-allyl-6-hydroxy-5-oxo-1,2,3,4-tetrahydroindolizine-8-carboxylates. Cyclization under Wacker oxidation conditions afforded methyl 2-methyl-8-oxo-5,6,7,8-tetrahydro-1-oxa-7a-aza-s-indacene-4-carboxylates in near-quantitative yield.     

A mercury mediated route to the mitosenes

A Mitsunobu type of coupling is used to prepare a complex phenyl allyl ether which undergoes a Claisen rearrangement. A synthetic route to a mitosene is achieved.     

Asymmetric claisen rearrangements enabled by catalytic asymmetric Di(allyl) ether synthesis

Merging the catalytic asymmetric synthesis of di(allyl) ethers with ensuing olefin isomerization-Claisen rearrangement (ICR) reactions provides a convenient, two-step route to asymmetric aliphatic Claisen rearrangements from easily obtained starting materials. These reactions deliver the 2,3-disubstituted 4-pentenal derivatives characteristic of aliphatic Claisen rearrangements with excellent relative and absolute stereocontrol. A catalytic enantioselective synthesis of the (+)-calopin dimethyl ether demonstrates the utility of this reaction technology in asymmetric synthesis enterprises.     

Synthesis of the ABC ring system of manzamine A

A synthesis of the core ABC ring system of the manzamine alkaloids is described, starting from arecoline. The key steps involve a Claisen rearrangement to set up a 4-substituted-3-methylenepiperidine and a stereoselective azomethine ylide dipolar cycloaddition reaction. Condensation of the aldehyde 6 and sarcosine ethyl ester hydrochloride salt gives an intermediate azomethine ylide, which undergoes an intramolecular cycloaddition reaction to set up two new rings and three new chiral centers stereoselectively. The aldehyde 6 was not a suitable substrate for related azomethine ylide cycloaddition reactions with other amines. However, the related dimethyl acetal 26 could be condensed with a variety of amines to give the desired tricyclic products. The cycloaddition reaction with N-methyl or N-allyl glycine ethyl ester gave almost exclusively the exo adduct, whereas cycloaddition with glycine ethyl ester gave the endo adduct.     

An isomerization—claisen rearrangement route to olefinic dicarbonyl starting materials for conjugate cyclization

Unsaturated dicarbonyl compounds which are useful in conjugate cyclization processes are synthesized by a route which makes use of a sequential isomerization and Claisen rearrangement of the allyl ether of a substituted allyl alcohol.     

Transition-metal-mediated cascade reactions: the water-accelerated carboalumination-Claisen rearrangement-carbonyl addition reaction

[Chemical reaction: See text] A three-step cascade reaction involving a water-accelerated catalytic carboalumination, a Claisen rearrangement, and a nucleophilic carbonyl addition converts terminal alkynes and allyl vinyl ethers into allylic alcohols containing up to three contiguous asymmetric carbon centers. Stoichiometric quantities of water as an additive increase the rate of the [3,3] sigmatropic rearrangement as well as the diastereoselectivity of the carbonyl addition process. Reaction products contain 1,6-diene functionalities that are readily cyclized to substituted cyclopentenes. An extension of this methodology to a sequence involving a [1,3] sigmatropic shift was feasible with a cyclopropylmethyl vinyl ether substrate.     

Synthesis of the fully functionalized core structure of the antibiotic abyssomicin C

[reaction: see text] The fully functionalized core structure 23 of abyssomicin C (6) containing an oxabicyclooctane ring and a tetronate was prepared via a Diels-Alder approach. After hydroxylation of lactone 10 to the alpha-hydroxylactone 12, lactone opening led to the hydroxy ester 16. A directed epoxidation furnished the desired syn-epoxide 20. Acetylation of the tertiary hydroxyl group, followed by intramolecular Claisen condensation, gave directly the core structure 23.     

Catalyzed olefin isomerization leading to highly stereoselective Claisen rearrangements of aliphatic allyl vinyl ethers

Iridium(I)-catalyzed olefin isomerization in bis(allyl) ethers is integrated into a generally applicable strategy for affecting highly stereoselective Claisen rearrangements. Catalyzed alkene isomerization affords allyl vinyl ethers from easily prepared di(allyl) ethers; direct thermolysis of these reaction mixtures leads to highly diastereoselective [3,3] sigmatropic rearrangements affording syn-2,3-dialkyl-4-pentenal derivatives. An easily executed strategy for realizing asymmetric variants of the isomerization-Claisen rearrangement (ICR) reactions is also described.     

Synthetic studies on perophoramidine and the communesins: construction of the vicinal quaternary stereocenters

An efficient synthetic strategy for installation of the two vicinal quaternary carbon centers of the communesins is reported. Key steps include the O-allylation/Claisen rearrangement of spirolactone systems, which are formed by tandem intramolecular Heck cyclization/carbonylation. Substituent and solvent effects on the stereochemical outcome of the Claisen rearrangements have been examined. The stereochemical assignment of the allyl spirolactone previously reported as 17 has now been revised to 31, which has the communesin relative configuration at the quaternary carbons. Key C-allyl spirolactone 59 bearing functional handles required for the communesin core has been constructed with a 9.8:1 diastereomer ratio.     

Double decarboxylative Claisen rearrangement reactions: microwave-assisted de novo synthesis of pyridines

Microwave-assisted double decarboxylative Claisen rearrangement of bis(allyl) 2-tosylmalonates provides substituted 1,6-heptadienes, which may be alkylated, and then converted into pyridines by ozonolysis followed by reaction with ammonia generated in situ under microwave conditions.     

Synthesis of Sporochnol A,a Marine Fish Deterrent

Abstract

A synthesis of the methyl ether of the fish‐deterrent sporochnol A is described. The route involves the application of Claisen ortho‐ester rearrangement to generate the key quaternary carbon.     

Towards a total synthesis of the new anticancer agent mensacarcin: synthesis of the carbocyclic core

A synthesis of the carbocyclic core associated with the new anticancer agent mensacarcin (1) is reported. The strategy involves the synthesis of several novel highly substituted aromatic compounds, such as 12 and 23. The lithium derivative of 12 readily engages in a nucleophilic addition to benzaldehyde 4 to provide the diphenylcarbinol rac-15. The analogous benzyl ether rac-16 undergoes an intramolecular Heck reaction to provide the required tetrahydroanthracene rac-17, which can be transformed into the key tricyclic methyl ether rac-20. In a second approach, the lithium derivative of 21 is added to the hexasubstituted benzaldehyde 23 to give the diphenylcarbinol rac-35. Subsequent methylation to rac-36 followed by an intramolecular Heck reaction provides tricycle rac-37. Similarly, the oxidised compound 40 provides an electronically more suitable intramolecular Heck partner to afford compound 41. Further transformations of these substrates leads to rac-43, which incorporates the core structure of mensacarcin (1).     

Rearrangement of Aryl Geranyl Ethers

This article describes the thermal rearrangement reactions of aryl geranyl ethers. These reactions depend on the structure of the aryl moiety of the substrate and the reaction conditions used. The naphthyl ethers underwent a [1,3]-alkyl shift, followed by acid-catalyzed intramolecular cyclization. The microwave-assisted rearrangement of isoquinolinyl ether showed a pattern of an abnormal Claisen rearrangement. The multi step rearrangement of the quinolyl ether afforded a spiro compound. These new reactions were used to synthesize novel heterocyclic compounds.