A concise and stereoselective synthesis of the A-ring fragment of the gambieric acids

The A-ring fragment of the gambieric acids has been prepared by a short and efficient route. The key 3(2H)-furanone intermediate has been obtained by [2,3] rearrangement of an allylic oxonium ylide generated from intramolecular reaction of a crotyl ether with a copper carbenoid. A single stereogenic center has been set by using a chiral pool starting material and the other three have been established by using highly diastereoselective substrate-controlled transformations. [reaction--see text]     

A synthesis of bicyclo[n.1.0]alkanes having tert-butyl carboxylate or acetamide moiety via the intramolecular 1,3-CH insertion of magnesium carbenoids

Treatment of 1-chlorovinyl p-tolyl sulfoxides, derived from various cyclic ketones and chloromethyl p-tolyl sulfoxide, with lithium enolate of carboxylic acid tert-butyl esters or N,N-dimethylacetamide gave adducts in high yields. The adducts were treated with ether solution of isopropylmagnesium chloride in dry toluene to give bicyclo[n.1.0]alkane derivatives having tert-butyl carboxylate or acetamide moiety on the bridgehead carbon in high to quantitative yields via magnesium carbenoid 1,3-CH insertion reaction. The 1,3-CH insertion reaction proved to be regioselective and stereospecific. The reaction mechanism and origin of the selectivity and specificity are discussed.     

A versatile synthesis, including asymmetric synthesis, of bicyclo[n.1.0]alkanes from cyclic ketones via the magnesium carbenoid 1,3-CH insertion as a key reaction

Treatment of 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from various cyclic ketones and chloromethyl p-tolyl sulfoxide in three steps, in high yields, with lithium enolate of tert-butyl acetate or its homologues gave the adducts in quantitative yields. The adducts were treated with isopropylmagnesium chloride in ether in dry toluene as the reaction solvent to afford bicyclo[n.1.0]alkanes in high to quantitative yields via magnesium carbenoid 1,3-CH insertion. When this method was carried out starting from unsymmetrical cyclic ketones and (R)-chloromethyl p-tolyl sulfoxide, an asymmetric synthesis of bicyclo[n.1.0]alkane was realized.     

Electronic control of the Bergman cycloaromatization: synthesis and chemistry of chloroenediynes

[reaction: see text] A series of cyclic mono- and dichloroenediynes have been prepared using an intramolecular carbenoid coupling reaction. The halogen atom had a retardative effect on Bergman cycloaromatization in every case examined, and atom transfer chemistry was demonstrated, resulting in formation of adducts.     

A new approach to the synthesis of 1-oxaspiro[4.n]alkanes and tetrahydrofurans by the 1,5-CH insertion reaction of magnesium carbenoids

1-Alkoxy-1-[2-chloro-2-(p-tolylsulfinyl)ethyl]cycloalkanes were prepared from various cyclic ketones in good overall yields. Treatment of these cycloalkanes bearing a sulfinyl group with i-PrMgCl resulted in the formation of 1-oxaspiro[4.n]alkanes in high to quantitative yields via the 1,5-CH insertion reaction of generated magnesium carbenoid intermediates. When this procedure was commenced with acyclic ketones, multi-substituted tetrahydrofurans were obtained in up to a 96% yield. This procedure provides a new and good way for the synthesis of 1-oxaspiro[4.n]alkanes and tetrahydrofurans with the formation of a carbon–carbon bond between a carbenoid carbon and a non-activated carbon in high yields. The oxygen atom in the magnesium carbenoid intermediates was proved to act very important roles in the 1,5-CH insertion reaction.     

Rhodium(II) mediated cyclizations of diazo alkynyl ketones

The rhodium(II)-catalyzed reaction of -diazo ketones bearing tethered alkyne units represents a new and useful method for the construction of a variety of substituted cyclopentenones. The process proceeds by addition of the rhodium-stabilized carbenoid onto the acetylenic π-bond to give a vinyl carbenoid intermediate. The resulting rhodium complex undergoes a wide assortment of reactions including cyclopropanation, 1,2-hydrogen migration, CH-insertion, addition to tethered alkynes and ylide formation. The exact pathway followed is dependent on the specific metal/ligand employed and is also influenced by the nature of the solvent. Sulfonium ylide formation occurred both intra and intermolecularly when the reaction was carried out in the presence of a sulfide. In the case where an ether oxygen was present on the backbone of the vinyl carbenoid, cyclization afforded an oxonium ylide which underwent a [1,2] or [2,3]-sigmatropic shift to give a rearranged product. These cyclic metallocarbenoids were also found to interact with a neighboring carbonyl π-bond to produce carbonyl ylide dipoles that could be trapped with added dipolarophiles. The domino transformation was also performed intramolecularly by attaching an alkene directly to the carbonyl group. When 2-alkynyl-2-diazo-3-oxobutanoates were treated with a Rh(II)-catalyst, furo[3,4-c]furans were formed in excellent yield. The 1,5-electrocyclization process involved in furan formation has also been utilized to produce indeno[1,2-c]furans. Rotamer population was found to play a significant role in the cyclization of -diazo amide systems containing tethered alkynes. In this account, an overview of our work in this area is presented.     

Rhodium(II)-catalyzed carbocyclization reaction of alpha-diazo carbonyls with tethered unsaturation

o-Alkynyl-substituted alpha-diazoketones undergo internal cyclization to produce indenone derivatives upon treatment with catalytic quantities of Rh(II)-carboxylates. A variety of structural influences were encountered by varying the nature of the substituent group attached to the diazo center. The cyclization reaction involves addition of a rhodium-stabilized carbenoid onto the acetylenic pi-bond to generate a cycloalkenone carbenoid. The cyclized carbenoid was found to undergo both aromatic and aliphatic C-H insertion as well as cyclopropanation across a tethered pi-bond. Subjection of diazo phenyl acetic acid 3-phenylprop-2-ynyl ester to Rh(II) catalysis furnished 8-phenyl-1, 8-dihydro-2-oxacyclopenta[a]indenone in high yield. The formation of this compound involves cyclization of the initially formed carbenoid onto the alkyne to produce a butenolide which then undergoes C-H insertion into the neighboring aromatic system. When a vinyl ether is added, the initially formed rhodium carbenoid intermediate can be intercepted by the electron-rich pi-bond prior to cyclization. Different rhodium catalysts were shown to result in significant variation in the product ratios. The competition between bimolecular cyclopropanation, 1,2-hydrogen migration, and internal cyclization was probed using several enol ethers as well as diazoesters which possess different substituent groups on the ester backbone. The specific path followed was found to depend on electronic, steric, and conformational factors.     

2-Ene-1,4-diols by dimerization of terminal epoxides using hindered lithium amides

[reaction: see text] Reaction of hindered lithium amides with readily available (enantiopure) terminal epoxides gives 2-ene-1,4-diols via carbenoid dimerization of the corresponding alpha-lithiated epoxides. D-Mannitol and D-iditol were synthesized using this method in three steps from (S)-tritylglycidyl ether.     

Rhodium(II) catalysed three-component coupling: a novel reaction of in situ generated iodonium ylides

Cyclic ethers are cleaved in the presence of nitromethane, a base, a hypervalent iodine compound and a Rh(II) catalyst to give nitromethoxy acetates in up to 71% isolated yields. The reaction is a three-component coupling of an ether with a nitromethane derived carbenoid and a carboxylate group originating from the hypervalent iodine compound.     

Density functional theory study of the platinum-catalyzed cyclopropanation reaction with olefin

A computational study of the platinum-catalyzed cyclopropanation reaction with olefin is presented. The model system is formed by an ethylene molecule and the active catalytic species, which forms from a CH2 fragment and the Cl2Pt(PH3)2 complex. The results show that the active catalytic species is not a metal-carbene of the type (PH3)2Cl2Pt=CH2 but two carbenoid complexes which can exist in almost two degenerate forms, namely (PH3)2Pt(CH2Cl)Cl (carbenoid A) and (PH3)Pt(CH2PH3)Cl2 (carbenoid B). The reaction proceeds through three pathways: methylene transfer, carbometalation for carbenoid A, and the reaction of a monophosphinic species for carbenoids (A and B). The most favored reaction channel is methylene transfer pathway for (PH3)Pt(CH2PH3)Cl2 (carbenoid B) species with a barrier of 31.32 kcal/mol in gas phase. The effects of dichloromethane, THF, and benzene solvent are investigated with PCM method. For carbenoid A, both methylene transfer and carbometalation pathway barriers to reaction become remarkably lower with the increasing polarity of solvent (from 43.25 and 52.50 kcal/mol for no solvent to 25.36 and 38.53 kcal/mol in the presence of the dichloromethane). In contrast, the reaction barriers for carbenoid B via the methylene transfer path hoist 6.30 kcal/mol, whereas the barriers do not change significantly for the reaction path of a monophosphinic species for carbenoids (A and B).     

Concise synthesis of the C-1-C-12 fragment of amphidinolides T1-T5

The C-1-C-12 segment of the amphidinolides T1-T5 has been synthesised in an efficient manner. The key transformations are highly diastereoselective rearrangement of an oxonium ylide, or metal-bound ylide equivalent, produced by intramolecular reaction of a copper carbenoid with an allylic ether, and macrocyclic fragment coupling by one-pot ring-closing metathesis and hydrogenation.     

Synthesis of novel alpha-substituted and alpha,alpha-disubstituted amino acids by rearrangement of ammonium ylides generated from metal carbenoids

[reaction: see text] A new and general four-step synthesis of protected alpha-substituted and alpha,alpha-disubstituted amino acids has been developed. The key step involves intramolecular ammonium ylide generation from a copper carbenoid with concomitant [2,3] rearrangement. The aromatic template serves as a tether, protecting group, and activating group for peptide coupling. The ylide rearrangement products can be converted into protected cyclic amino acids by ring-closing metathesis.     

Anomalous intramolecular C-H insertion reactions of rhodium carbenoids: factors influencing the reaction course and mechanistic implications

The intramolecular insertion of rhodium carbenoids into the alpha-C-H bonds of allylic ethers to give 3(2H)-furanones has been explored. Cyclopropanation is favored irrespective of the complex used for carbenoid generation or the substitution pattern of the allylic ether, unless a substituent is placed on the tether connecting the ether to the alpha-diazo ketone. Unusual acetal products resulting from an anomalous C-H insertion process are obtained in addition to the expected 3(2H)-furanones formed by conventional carbenoid C-H insertion. These acetals are the favored C-H insertion products in certain circumstances and particularly in cases where carbenoid generation is effected using an electron-deficient rhodium complex. Experiments with simple deuterium labeled substrates reveal that anomalous C-H insertion products arise by a mechanism that is distinct from that leading to the formation of conventional C-H insertion products. The formation of acetal products and the outcome of reactions performed using deuterium-labeled substrates suggest that a mechanism involving hydride migration to the rhodium center of the carbenoid is operative.     

Rhodium-catalyzed cyclopropanation using ene-yne-imino ether compounds as precursors of (2-pyrrolyl)carbenoids

[reaction: see text] The reaction of alkenes with conjugated ene-yne-imino ether or ene-yne-aldimine in the presence of a catalytic amount of [Rh(OAc)(2)](2) gives (2-pyrrolyl)cyclopropanes in good yields. The key intermediate of this cyclopropanation is a (2-pyrrolyl)carbenoid generated by the nucleophilic attack of imine nitrogen atom at an internal alkyne carbon activated by rhodium complex. The intramolecular reaction also proceeds to afford a polycyclic pyrrole.     

Halo-enediynes: probing the electronic and stereoelectronic contributions to the Bergman cycloaromatization

A series of halogen-substituted cyclic enediynes were prepared with use of carbenoid coupling strategy. DFT analysis, initially used to identify synthesis candidates, was also employed to rationalize the propensity for cycloaromatization of the compounds. In all cases studied the halogen atom had a strongly retardative effect on the thermal Bergman cycloaromatization reaction. The isolation of the first C-9 monochloroenediyne is noteworthy, and may find application in prodrug design.     

Synthesis and properties of gem-(difluorocyclopropyl)amine derivatives of bicyclo[n.1.0]alkanes

[reaction: see text] Generation of difluorocarbene(carbenoid) in the presence of enamines derived from cyclic ketones results in overall insertion of CF2 to produce bicyclic difluorocyclopropylamines. These adducts are very weakly basic, and their thermal stabilities vary markedly with their structures.     

Addition reaction of spiro orthoesters with electrophiles: A model reaction for the development of novel polyaddition accompanying ring-opening isomerization

The addition reaction of spiro orthoesters (SOEs) with electrophiles accompanying ring-opening isomerization was investigated as a model reaction for polyaddition of bifunctional SOEs with bifunctional electrophiles. Among several electrophiles such as carboxylic acids and carboxylic anhydrides, acid halides showed particularly high reactivities to SOEs. An equimolar reaction of SOEs with acid chlorides took place selectively, leading to the corresponding 1 : 1 adducts. SOEs with seven-membered cyclic ether rings—1,4,6-trioxaspiro[5.6]undecane derivatives—showed higher reactivities than SOEs with six- and five-membered cyclic ether rings. The reaction accompanied zero shrinkage in volume. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 4502–4509, 1999     

Asymmetric synthesis of cis-5-tert-butylproline with metal carbenoid NH insertion

The highly stereoselective intramolecular metal carbenoid insertion reaction of sulfinimine-derived delta-amino alpha-diazoesters is used to prepare cis-5-tert-butylproline. A concerted or nearly concerted metal carbenoid N-H insertion reaction mechanism is proposed.     

Metalated epoxides as carbenoids. Competing C-H and CC insertion in α-alkoxy epoxide systems

In a reinvestigation of the reactivity of carbenoids derived from epoxides, we studied the factors that could influence the chemoselectivity of the carbenoid insertion into vicinal C-H or CC bond in cyclic α-alkoxy epoxides bearing an alkenyl side chain. This reaction gives access to bi- or tricyclic systems, respectively.     

Synthesis of Highly Substituted N‐(Furan‐3‐ylmethylene)benzenesulfonamides by a Gold(I)‐Catalyzed Oxidation/1,2‐Alkynyl Migration/Cyclization Cascade

A variety of N‐(furan‐3‐ylmethylene)benzenesulfonamides were obtained by a gold(I)‐catalyzed cascade reaction from easily accessible starting materials. The reaction pathway involves a rarely observed 1,2‐alkynyl migration onto a gold carbenoid. This observation further enriches gold carbenoid chemistry with regard to group migration.