Control of competing N-H insertion and Wolff rearrangement in dirhodium(II)-catalyzed reactions of 3-indolyl diazoketoesters. synthesis of a potential precursor to the marine 5-(3-indolyl)oxazole martefragin A

Dirhodium(II)-catalyzed reaction of 3-indolyl alpha-diazo-beta-ketoester 25 in the presence of hexanamide results in competing metal carbene N-H insertion and Wolff rearrangement. The corresponding phenyl diazoketoester 32, on the other hand, gives only the product of N-H insertion, suggesting that the indole moiety is more prone to 1,2-rearrangement. The competing processes were investigated in a range of 3-indolyl alpha-diazo-beta-ketoesters (36, 38, 40, 44); these studies established that the Wolff rearrangement could be effectively suppressed by the presence of a strong electron-withdrawing group on the indole nitrogen. Dirhodium(II) catalysts were also more effective than copper or Lewis acid catalysts in favoring the insertion process. The products of N-H insertion, the ketoamides (26, 47, 49, 51, 53), were readily cyclodehydrated to the corresponding 5-(3-indolyl)oxazoles. The N-H insertion/cyclodehydration methodology was used in a formal synthesis of the marine natural product martefragin A. Thus the N-Boc homoisoleucine amide 23, prepared by asymmetric hydrogenation of a dehydro amino acid, underwent N-H insertion with the rhodium carbene derived from the N-nosyl indolyl diazoester 40, followed by cyclodehydration and deprotection to give the 5-(3-indolyl)oxazole martefragin A precursor 75.     

Rhodium carbenoid N-H insertion reactions of primary ureas: solution and solid-phase synthesis of imidazolones

[reaction: see text] The solution and solid-phase synthesis of imidazolones is reported. The key step for the preparation of these compounds is the N-H insertion reaction of primary ureas into highly reactive rhodium carbenoid intermediates. Typically, a soluble or support-bound alpha-diazo-beta-ketoester is treated with a rhodium carboxylate catalyst in the presence of a primary urea to give the corresponding N-H insertion product. Subsequent acid-catalyzed cyclodehydration of these insertion products affords the desired imidazolone products.     

The diazo route to diazonamide A: studies on the tyrosine-derived fragment

Various approaches to the tyrosine-derived fragment of the marine secondary metabolite diazonamide A are described. Initial efforts were focused on the originally proposed structure of the natural product, and a feasibility study established that a model 4-aryltryptamine could be readily prepared. Protected 4-bromotryptamine underwent Pd0-catalyzed coupling with the boronic acid derived from 2-bromophenyl allyl ether by Claisen rearrangement, O-methylation and lithiation-boration. The resulting biaryl was elaborated into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Z-valinamide gave the desired tryptamine-oxazole following cyclodehydration of the intermediate ketoamide. A potential precursor to the benzofuran ring of the original structure of diazonamide A was prepared in eight steps from N-Z-tyrosine tert-butyl ester. Iodination, O-protection and Stille coupling gave the cinnamyl alcohol 25, converted via the bromide into the allyl aryl ether 27. Subsequent Claisen rearrangement and oxidative cleavage of the alkene gave the lactol 29, converted into the desired benzofuranone 31. The revision in the structure of diazonamide A to 2 resulted in the targeting of an alternative tyrosine-derived model benzofuranone 41 synthesized in four steps from N-Z-tyrosine methyl ester 36 by a route involving Claisen rearrangement of cinnamyl ether 37. Poor yields in this sequence prompted an investigation into the intramolecular Heck reaction as a route to benzofuranone 50. Coupling of 3-iodotyrosine 44 with 2-phenylbutenoic acid 48 gave ester 49 that readily underwent intramolecular Heck reaction to give benzofuranone 50, albeit with poor stereocontrol.     

Total synthesis of siphonazole and its O-methyl derivative, structurally unusual bis-oxazole natural products

The details of the first syntheses of the unusual bis-oxazole natural products siphonazole and its O-methyl derivative are reported. The cinnamyl substituted oxazole was constructed using diazocarbonyl chemistry, whereby the cinnamamide was reacted with the rhodium carbene derived from methyl 2-diazo-3-oxobutanoate to give a beta-ketoamide that was cyclodehydrated to the corresponding oxazole-4-ester. Reduction to the corresponding aldehyde was followed by coupling with a zinc reagent derived from methyl 2-iodomethyl-5-methyloxazole-4-carboxylate, also prepared using rhodium carbene chemistry, to give, after oxidation of the resulting secondary alcohol, the desired bis-oxazole ketone. The syntheses were completed by hydrolysis of the ester and coupling of the 2,4-pentadienylamine side chain.     

Total synthesis of stephanotic acid methyl ester

[structure: see text]The methyl ester of the naturally occurring macrocyclic pentapeptide stephanotic acid, containing an unusual beta-substituted alpha-amino acid with a tryptophan C-6 to leucine beta-carbon link, has been synthesized. The key steps include the formation of this amino acid through a thioxo-oxazolidine intermediate and a Horner-Wadsworth-Emmons reaction using a phosphonoglycine, derived by a dirhodium(II)-catalyzed N-H insertion reaction, to give a dehydroamino acid and subsequent rhodium(I)-catalyzed asymmetric hydrogenation to introduce the modified tryptophan residue.     

Telomestatin: formal total synthesis and cation-mediated interaction of its seco-derivatives with G-quadruplexes

The structurally unique natural product telomestatin incorporates seven oxazole rings and one sulfur-containing thiazoline in a macrocyclic arrangement. The compound is a potent inhibitor of the enzyme telomerase and therefore provides a structural framework for developing new potential therapeutic agents for cancer. An efficient formal total synthesis of telomestatin is reported in which the key steps are the use of dirhodium(II)-catalyzed reactions of diazocarbonyl compounds to generate six oxazole rings, demonstrating the power of rhodium carbene methodology in organic chemical synthesis. CD spectroscopy establishes that seco-derivatives of telomestatin are potent stabilizers of G-quadruplex structures derived from the human telomeric repeat sequence. Mass spectrometry studies, confirmed by molecular dynamics simulations, provide the first evidence that high affinity binding to terminal G-tetrads in both 1:1 and 2:1 ligand complexes is mediated through the macrocycle coordinating a monovalent cation, with selectivity for the antiparallel structure.     

Total synthesis of the thiopeptide antibiotic amythiamicin D

The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels-Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels-Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N-H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels-Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.     

Solid-phase rhodium carbenoid N-H insertion reactions: the synthesis of a diverse array of indoles

A solid-phase synthesis of an array of indoles is reported. The key step in our approach involves a N-H insertion reaction of N-alkylanilines into a highly reactive polymer-bound rhodium carbenoid intermediate to yield the corresponding alpha-arylamino-beta-ketoester. These insertion products were then treated under acid-catalyzed cyclodehydration conditions to yield a series of polymer-bound indole esters, which were subsequently cleaved from the resin under Lewis acid-promoted amidation conditions to yield the desired indoles in good yields and with excellent purities.     

Mechanism of C[bond]H bond activation/C[bond]C bond formation reaction between diazo compound and alkane catalyzed by dirhodium tetracarboxylate

The B3LYP density functional studies on the dirhodium tetracarboxylate-catalyzed C-H bond activation/C-C bond formation reaction of a diazo compound with an alkane revealed the energetics and the geometry of important intermediates and transition states in the catalytic cycle. The reaction is initiated by complexation between the rhodium catalyst and the diazo compound. Driven by the back-donation from the Rh 4d(xz) orbital to the C[bond]N sigma*-orbital, nitrogen extrusion takes place to afford a rhodium[bond]carbene complex. The carbene carbon of the complex is strongly electrophilic because of its vacant 2p orbital. The C[bond]H activation/C[bond]C formation proceeds in a single step through a three-centered hydride transfer-like transition state with a small activation energy. Only one of the two rhodium atoms works as a carbene binding site throughout the reaction, and the other rhodium atom assists the C[bond]H insertion reaction. The second Rh atom acts as a mobile ligand for the first one to enhance the electrophilicity of the carbene moiety and to facilitate the cleavage of the rhodium[bond]carbon bond. The calculations reproduce experimental data including the activation enthalpy of the nitrogen extrusion, the kinetic isotope effect of the C[bond]H insertion, and the reactivity order of the C[bond]H bond.     

Convenient synthesis of polyfunctionalized beta-fluoropyrroles from rhodium(II)-catalyzed intramolecular N-H insertion reactions

Polyfunctionalized beta-fluoropyrrole can be readily prepared from rhodium(II) acetate-catalyzed intramolecular N-H insertion reaction of delta-amino-gamma,gamma-difluoro-alpha-diazo-beta-ketoesters. A cyanomethylene group can be introduced at C-3 of the pyrrole ring through the Wittig reaction of the diazo compounds followed by rhodium(II)-catalyzed intramolecular N-H insertion reactions.     

Cycloaddition chemistry of 2-vinyl-substituted indoles and related heteroaromatic systems

[reaction: see text] The intramolecular Diels-Alder cycloaddition reaction (IMDAF) of several N-phenylsulfonylindolyl-substituted furanyl carbamates containing a tethered pi-bond on the indole ring were examined as an approach to the iboga alkaloid catharanthine. Only in the case where the tethered pi-bond contained two carbomethoxy groups did the [4 + 2]-cycloaddition occur. Push-pull dipoles generated from the Rh(II)-catalyzed reaction of diazo imides, on the other hand, undergo successful intramolecular 1,3-dipolar cycloaddition across both alkenyl and heteroaromatic pi-bonds to provide novel pentacyclic compounds in good yield and in a stereocontrolled fashion. The facility of the cycloaddition was found to be critically dependent on conformational factors in the transition state. Ligand substitution in the rhodium(II) catalyst markedly altered the product ratio between [3 + 2]-cycloaddition and intramolecular C-H insertion. The variation in reactivity reflects the difference in electrophilicity between the various rhodium carbenoid intermediates. Intramolecular C-H insertion is enhanced with the more electrophilic carbene generated using Rh(II) perfluorobutyrate.     

Convenient preparation of indolyl Malonates via Carbenoid insertion

Indoles, when treated with methyldiazomalonate under catalysis by rhodium(II)acetate, undergo C-H and N-H insertion reactions regioselectively depending on the substitution pattern on the indole moiety. In indoles where the 3-position is unsubstituted, high yields of the C3-H insertion product were observed. In 3-alkylindoles, 2-substitution predominated, while N-methyltetrahydrocarbazole yielded the product resulting from insertion into the C6-H bond. Indoles in which the nitrogen is unprotected yield varying degrees of N-H insertion.     

N-H Insertion reactions of rhodium carbenoids. Part 5: A convenient route to 1,3-azoles

Dirhodium(II) carboxylate catalysed reaction of diazocarbonyl compounds 2 in the presence of primary amides 1 results in the formation of α-acylaminoketones 3 (12 examples) by N-H insertion reaction of the intermediate rhodium carbene. The 1,4-dicarbonyl compounds 3 are readily converted into structurally diverse oxazoles 4 (11 examples) by cyclodehydration, thiazoles 5 (10 examples) by treatment with Lawesson's reagent, or imidazoles 6 (2 examples) by reaction with ammonia or methylamine.     

Cu(I)-carbenoid- and Ag(I)-Lewis acid-catalyzed asymmetric intermolecular insertion of alpha-diazo compounds into N-H bonds

Chiral Cu(I)-bisoxazoline- and Cu(I)-PN-complexes were found to catalyze the intermolecular insertion of alpha-diazo compounds into N-H bonds. The insertion reactions proceed with enantioselectivities of up to 28% ee for the different alpha-diazo acetates into one of the N-H bonds of different amines. Analogous chiral Ag(I) complexes were found to give higher enantioselectivities of up to 48% ee, however, lower yields were obtained. There are indications, that the Ag(I)-mediated reactions follow a different reaction mechanism compared to the Cu(I)-catalyzed insertions. It is demonstrated that different alpha-amino acid derivatives can be obtained via this approach in good yields and with low to moderate enantioselectivities. However, the results obtained are the highest asymmetric inductions obtained for an intermolecular N-H insertion via chiral carbene complexes or chiral Lewis acid catalysis.     

Rh(Ⅱ)催化吲哚衍生物[3+3]环化机理及产物性质分析

采用密度泛函理论研究了双铑催化3-重氮吲哚啉-2-亚胺与2H-吖丙因[3+3]内环化反应过程. 该过程主要包含铑金属卡宾体形成、 C―N键活化裂解和吲哚啉[3+3]内环化反应. 研究结果表明, 双铑催化剂发生偶联作用, 促进C-N偶联及2H-吖丙因C―N键裂解; 反应控速步骤为吲哚[3+3]环化反应过程, 铑催化剂在[3+3]环化前脱出. 对产物吡嗪并吲哚类化合物光电性质的分析表明产物具有较低空穴重组能, 吸收与荧光发射光谱存在较大斯托克斯位移. 因此该产物可作为潜在的空穴传输材料和荧光发射材料.     

Highly chemo-, regio-, and stereoselective [3+2]-cyclization of activated and deactivated allenes with alkenyl Fischer carbene complexes: a straightforward access to alkylidenecyclopentanone derivatives

A broad range of functionalized 5-alkylidenecyclopentene derivatives are synthesized by the rhodium(I)-catalyzed [3+2]-cyclization reaction of chromium alkenyl(methoxy)carbene complexes 1 and activated allenes. Thus, amidocyclopentenes 4a-n are readily available from N-allenylamides 2a-c, while phenoxyallene 2e gives access to phenoxycyclopentenes 6. In turn, the cyclization reaction with (alkoxycarbonyl)allenes 3 leads to (alkoxycarbonyl)methylidenecyclopentenes 7-10. In terms of selectivity, most cyclization reactions take place with complete chemo-, regio-, and diastereoselectivity. Representative cycloadducts are efficiently hydrolyzed to the corresponding 2-alkylidenecyclopentanones 11a-e without tautomerization or isomerization. Finally, a tentative reaction pathway is proposed that involves the rhodium(I) carbene complexes as the species responsible for the [3+2]-cyclization.     

One-pot synthesis of N-methylindoles from N-methylanilines and of benzofurans from phenols using transition-metal carbene X-H insertion reactions

Transition-metal carbene X-H insertion reactions (X=N or O) have been employed in the simple conversion of anilines and phenols into indoles and benzofurans, respectively. Thus copper(II) catalyzed N-H insertion reactions of α-diazo-β-ketoesters with N-methylanilines followed by treatment with acidic ion-exchange resin gives indoles. In a similar manner, dirhodium(II) catalyzed O-H insertion reactions of α-diazo-β-ketoesters with phenols followed by treatment with PPA gives benzofurans.     

Asymmetric synthesis of the central tryptophan residue of stephanotic acid

The C-6 substituted tryptophan di- and tri-peptides and , representing the tryptophan core of stephanotic acid, have been synthesized, the key steps being the formation of the phosphono-di- and tri-peptides and by a highly chemoselective rhodium(II) catalyzed carbene N-H insertion reaction, their subsequent Horner-Wadsworth-Emmons reactions with N-Boc-6-bromoindole-3-carboxaldehyde, and the rhodium(I) catalyzed asymmetric hydrogenation of the resulting dehydro di- and tri-peptides.     

Immobilized alpha-diazophosphonoacetate as a versatile key precursor for palladium catalyzed indole synthesis on a polymer support

Rh(II)-catalyzed N-H insertion reaction of immobilized alpha-diazophosphonoacetate with 2-haloanilines followed by Horner-Emmons reaction gave immobilized enaminoesters, which were efficiently cyclized to indoles via intramolecular palladium catalyzed reaction on a polymer support.     

Catalytic asymmetric reactions for organic synthesis: the combined C-H activation/siloxy-cope rearrangement

Tetrakis(N-[4-dodecylbenzenesulfonyl]-(L)-prolinate) dirhodium [Rh(2)(S-DOSP)(4)]-catalyzed decomposition of vinyldiazoacetates in the presence of allyl silyl ethers results in the formation of the direct C-H insertion product and the product derived from a combined C-H activation/siloxy-Cope rearrangement. Both products are formed with very high diastereoselectivity (>94% de) and high enantioselectvity (78-93% ee). Under thermal or microwave conditions, the direct C-H insertion product undergoes a siloxy-Cope rearrangement in a stereoselective manner.