Highly functionalized Bicyclo[2.2.2]octenone-fused [60]fullerenes from masked o-benzoquinones and C(60)

[reaction: see text] The Diels-Alder reactions of masked o-benzoquinones (MOBs) with [60]fullerene, affording novel and highly functionalized bicyclo[2.2. 2]octenone-fused [60]fullerene derivatives, are described.     

Cobalt(II)-Catalyzed [4+2] Annulation of Picolinamides with Alkynes via C−H Bond Activation

A cobalt(II)-catalyzed [4+2] annulation of picolinamides with alkynes via C−H bond activation has been developed. The operationally simple annulation reaction allows for the synthesis of acyl-substituted 1H-benzoquinoline bearing multiple aromatic rings (up to 96 % yield) without co-oxidant or other oxidation factors under mild conditions. Several control experiments were carried out. This practical [4+2] annulation provides an efficient route to access highly functionalized compounds.     

Stereoselective syntheses of highly functionalized bicyclo[3.1.0]hexanes: a general methodology for the synthesis of potent and selective mGluR2/3 agonists

[Chemical reaction: See text] A Et3Al mediated intramolecular epoxide opening, cyclopropanation reaction is described. The transformation provided highly functionalized bicyclo[3.1.0]hexane systems in high efficiency and with perfect H or F endo selectivity. Application of this reaction to the synthesis of mGluR2/3 agonist 1 (43% overall yield) and a few intermediates suitable for the synthesis of other bicyclo[3.1.0]hexane mGluR2/3 agonists is discussed.     

Highly diastereoselective desymmetrizations of cyclo(Pro,Pro): an enantioselective strategy toward phakellstatin and phakellin

[reaction: see text] Monoenolates of C(2)-symmetric, proline-derived piperazine-2,5-diones were generated and trapped with a variety of electrophiles to produce, in a highly diastereoselective fashion, functionalized diketopiperazines (DKPs). These reactions provide the basis for an asymmetric, desymmetrization strategy toward the marine alkaloids phakellstatin and phakellin. The relative stereochemistry of the functionalized DKPs was confirmed by single-crystal X-ray analysis and/or NOE experiments. Bis-functionalization of the DKPs was also found to proceed with high levels of diastereoselectivity.     

Enantiocontrolled synthesis of highly functionalized tropanes via [5 + 2] cycloaddition to eta(3)-pyridinylmolybdenum pi-complexes

[reaction: see text] A chiral, nonracemic eta(3)-pyridinyl scaffold participates in [5 + 2] cycloaddition with electron-deficient alkenes, an allene, and an alkyne to give eta(3)-allylmolybdenum bicyclic adducts. The adducts can be demetalated, providing a convergent route to highly functionalized tropanes. High enantiocontrol can be achieved throughout the cycloaddition and demetalation sequence.     

Efficient synthesis of highly functionalized dihydropyrido[2,3-d]pyrimidines by a double annulation strategy from alpha-alkenoyl-alpha-carbamoyl ketene-(S,S)-acetals

A convenient and efficient synthesis of highly functionalized dihydropyrido[2,3-d]pyrimidines via a double [5 + 1] annulation strategy starting from easily available alpha-alkenoyl-alpha-carbamoyl ketene-(S,S)-acetals 1 and cheap reagents (NH4OAc, DMF, and POCl3) has been developed. In the first step of the double annulation route, 2-amino-3-carbamoyl-5,6-dihydro-4-pyridones 2 were created in high to excellent yields by a formal [5C + 1N] annulation reaction of ketene-(S,S)-acetals 1 with ammonia (from ammonium acetate). In the second step of the double annulation strategy, the highly functionalized dihydropyrido[2,3-d]pyrimidine derivatives, 7,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-ones 3 (when R1 = aryl) and 7,8-dihydropyrido[2,3-d]pyrimidines 4 (when R1 = H), were constructed, respectively, in fair to good yields by reacting 2 with excessive Vilsmeier reagent (DMF/POCl3). A mechanism involved in the second [5 + 1] annulation step, including a formal [5 + 1] annulation and accompanied chlorovinylation, chloroformylation, amination, and aromatization reactions, is proposed.     

The fixation of bis(2-pyridylimino)isoindolato (BPI) ligands to dendritic carbosilanes

Bis(2-pyridylimino)isoindolato (BPI) ligands, containing an alkynyl linker unit which allows their fixation to carbosilane dendrimers and dendrons, were synthesized by reaction of 4-nitrophthalodinitrile with 4-butynol giving the phthalodinitrile derivative containing the linker. These were subsequently reacted with two molar equivalents of 2-amino-4-methylpyridine and 2-amino-4-(t)butylpyridine yielding the respective BPI protioligands 2a and 2b. Lithiation with LDA and reaction with Si-Cl or Si-OTf (OTf=triflate) end groups in core or peripheral positions of dendritic carbosilanes gave the endodendrally and expdendrally functionalized dendrimers. Among these the first and second generation dendrimers [G-1](8-exo)-4-[C[triple bond, length as m-dash]CCH2CH2O]-10-MeBPI (8), [G-1]12-exo-4-[C[triple bond, length as m-dash]CCH2CH2O]-10-MeBPI (9) and [G-2](16-exo)-4-[C[triple bond, length as m-dash]CCH2CH2O]-10-MeBPI (10) were synthesized and fully characterized. The functional dendrimers were metallated by reaction with [(PhCN)2PdCl2] in dichloromethane to give the corresponding pallada-dendrimers.     

Asymmetric intermolecular C-H activation,using immobilized dirhodium tetrakis((S)-N-(dodecylbenzenesulfonyl)- prolinate) as a recoverable catalyst

[reaction: see text] Heterogenization of dirhodium tetrakis((S)-N-dodecylbenzenesulfonyl)prolinate) (Rh(2)(S-DOSP)(4)) can be readily achieved on a pyridine functionalized highly cross-linked polystyrene resin. The immobilized complex is readily recycled and exhibits excellent catalytic activity for asymmetric intermolecular C-H activation by means of rhodium carbenoid induced C-H insertion.     

Synthesis of the C(1)-C(18) segment of lophotoxin and pukalide. Control of 2-alkenylfuran (E/Z)-configuration

[reaction: see text] The convergent synthesis of the fully functionalized C(1)-C(18) segment 24 of the furanocembranes lophotoxin and pukalide was accomplished in 11 steps and 10% overall yield. The key step was a stereoselective conversion of alkynoate 21 to trimethylsilyl 2-alkenylfuran 22.     

Copper-catalyzed highly efficient multicomponent reactions: synthesis of 2-(sulfonylimino)-4-(alkylimino)azetidine derivatives

[reaction: see text] Under very mild conditions, functionalized 2-(sulfonylimino)-4-(alkylimino)azetidine derivatives were prepared in good to excellent yields via a copper-catalyzed multicomponent reaction of readily available terminal alkynes, sulfonyl azides, and carbodiimides without the assistance of a base. The mechanism may be through a [2 + 2] cycloaddition.     

Synthesis of substituted chromenes through the DABCO-catalyzed reaction of but-3-yn-2-one and methyl propiolate with salicyl N-tosylimines (DABCO = 1,4-diazabicyclo[2.2.2]octane)

The DABCO-catalyzed (DABCO = 1,4-diazabicyclo[2.2.2]octane) reaction of but-3-yn-2-one and methyl propiolate with salicyl N-tosylimines yields highly functionalized chromenes and has been thoroughly investigated; the rational mechanism for the reaction has been demonstrated on the basis of 1H NMR spectroscopic investigation.     

Cobalt(II)-catalyzed cross-coupling between polyfunctional arylcopper reagents and aryl fluorides or tosylates

[reaction: see text] Organocopper compounds prepared by the transmetalation of functionalized arylmagnesium halides with CuCN.2LiCl undergo smooth cross-coupling reactions with aryl fluorides and tosylates bearing a carbonyl function in the ortho position in the presence of Co(acac)(2) (7.5 mol %), Bu(4)NI (1 equiv), and 4-fluorostyrene (20 mol %) as promoters in DME/THF/DMPU leading to polyfunctional aromatics or heterocycles.     

A cassette ligation strategy with thioether replacement of three Gly-Gly peptide bonds: total chemical synthesis of the 101 residue protein early pregnancy factor [psi(CH(2)S)28-29,56-57,76-77

The 101 residue protein "early pregnancy factor" (EPF), also known as human chaperonin 10, was synthesized from four functionalized, but unprotected, peptide segments by a sequential thioether ligation strategy. The approach exploits the differential reactivity of a peptide-NHCH(2)CH(2)SH thiolate with XCH(2)CO-peptides, where X = Cl or I/Br. Initial model studies with short functionalized (but unprotected) peptides showed a significantly faster reaction of a peptide-NHCH(2)CH(2)SH thiolate with a BrCH(2)CO-peptide than with a ClCH(2)CO-peptide, where thiolate displacement of the halide leads to chemoselective formation of a thioether surrogate for the Gly-Gly peptide bond. This rate difference was used as the basis of a novel sequential ligation approach to the synthesis of large polypeptide chains. Thus, ligation of a model bifunctional N(alpha)-chloroacetyl, C-terminal thiolated peptide with a second N(alpha)-bromoacetyl peptide demonstrated chemoselective bromide displacement by the thiol group. Further investigations showed that the relatively unreactive N(alpha)-chloroacetyl peptides could be "activated" by halide exchange using saturated KI solutions to yield the highly reactive N(alpha)-iodoacetyl peptides. These findings were used to formulate a sequential thioether ligation strategy for the synthesis of EPF, a 101 amino acid protein containing three Gly-Gly sites approximately equidistantly spaced within the peptide chain. Four peptide segments or "cassettes" comprising the EPF protein sequence (BrAc-[EPF 78-101] 12, ClAc-[EPF 58-75]-[NHCH(2)CH(2)SH] 13, ClAc-[EPF 30-55]-[NHCH(2)CH(2)SH] 14, and Ac-[EPF 1-27]-[NHCH(2)CH(2)SH] 15) of EPF were synthesized in high yield and purity using Boc SPPS chemistry. In the stepwise sequential ligation strategy, reaction of peptides 12 and 13 was followed by conversion of the N-terminal chloroacetyl functional group to an iodoacetyl, thus activating the product peptide for further ligation with peptide 14. The process of ligation followed by iodoacetyl activation was repeated to yield an analogue of EPF (EPF psi(CH(2)S)(28)(-)(29,56)(-)(57,76)(-)(77)) 19 in 19% overall yield.     

Bifunctional cinchona alkaloids-catalyzed asymmetric [4+2] cycloaddition reaction of β,γ-unsaturated α-keto esters with oxazolones

A highly enantioselective [4+2] cycloaddition reaction of β,γ-unsaturated α-keto esters with oxazolones was realized with readily available cinchona alkaloids as the catalysts. Using this reaction, a series of highly functionalized δ-lactones with adjacent α-quaternary-β-tertiary stereocenters were obtained in high yields (up to 97%) and with good-to-excellent enantioselectivities (up to 97% ee).     

C2-symmetric planar chiral ferrocene diamides by (-)-sparteine-mediated directed ortho-lithiation. Synthesis and catalytic activity

[reaction: see text] A variety of highly enantioenriched singly and doubly (4) functionalized derivatives of 1,1'-N,N,N',N'-tetraisopropylferrocenedicarboxamide 1 have been synthesized by (-)-sparteine (2)-mediated directed ortho-metalation and Pd-catalyzed cross coupling reactions. The synthetic applications of these chiral ligands in asymmetric alkylation of benzaldehyde and Pd(0)-catalyzed allylic substitution have been demonstrated.     

Oxidative demetalation of cyclohexadienyl ruthenium(II) complexes: a net Ru-mediated dearomatization

[reaction: see text] An experimentally simple method for the demetalation of spirocyclic cyclohexadienylruthenium(II) complexes has been developed. Treatment of an alkoxy-substituted cyclohexadienyl complex with CuCl(2) affords either azaspiro[4.5]decane derivatives or heavily functionalized tetrahydroisoquinolines. The former reaction manifold completes a net Ru-mediated dearomatization as the organometallic starting materials are prepared from (eta(6)-arene)Ru(II) precursors. Both of these heterocyclic products are well suited for further synthetic elaboration.     

4 + 1] cycloaddition of bis(alkylthio)carbenes with vinyl isocyanates. Total synthesis of (+/-)-mesembrine

[reaction: see text] The Sceletium alkaloid mesembrine has been synthesized in 13% overall yield by a sequence featuring a [4 + 1] cycloaddition of a bis(alkylthio)carbene with a functionalized vinyl isocyanate.     

Novel palladium(II) complex containing a chelating anionic N-O ligand: efficient carbonylation catalyst

[reaction: see text] A novel palladium(II) complex containing chelating anionic pyridine-2-carboxylato and labile tosylato ligands is a highly efficient catalyst for the carbonylation of organic alcohols and olefins to carboxylic acids/esters. Carbonylation of primary, secondary, and tertiary alcohols as well as linear and functionalized terminal olefins was studied. In all cases remarkable activity and selectivity were observed. The catalyst is stable under reaction conditions even in the absence of excess phosphine ligands.     

Palladium-catalyzed asymmetric [3 + 2] trimethylenemethane cycloaddition reactions

Transition-metal-catalyzed trimethylenemethane (TMM) [3 + 2] cycloadditions provide direct routes to functionalized cyclopentanes. This reaction has been shown to be a highly chemo-, regio-, and diastereoselective process. We report a palladium-catalyzed asymmetric [3 + 2] trimethylenemethane (TMM) cycloaddition between 3-acetoxy-2-trimethylsilylmethyl-1-propene and various di- and trisubstituted olefins. Yields of exo-methylenecyclopentane products range from 59 to 99%, and enantiomeric excesses range from 58 to 92% ee.     

Novel 1,3-dipolar cycloaddition reactions of calix[4]bis(spirodienones): synthesis of isoxazolidine derived macrocycles

Calix[4]bis(spirodienones) can perform as either 4π or 2π components in cycloaddition reactions with various carbo- and hetero-dienophiles and with 1,2-benzoquinones leading to the formation of highly functionalized macrocycles. In this Letter we report, highly regio- and stereoselective 1,3-dipolar cycloaddition reactions of a bis(spirodienone) derivative of calix[4]arene with nitrones that provide easy access to isoxazolidine derived macrocycles in excellent yields. These isoxazolidine derivatives can be considered as direct precursors of 1,3-amino alcohols.