Cyclic Precursors Research Articles

Combinatorial Synthesis of RGD Model Cyclic Peptides Utilizing a Palladium-Catalyzed Carbonylative Macrolactamization on a Polymer Support

A combinatorial synthesis of 24-member RGD models was accomplished on polymer-support. Ortho-, meta-, and para-iodobenzylamines loaded on an aldehyde linker by reductive amination were coupled with RGD sequences and various omega-amino acids by a split-and-pool method. Palladium-catalyzed carbonylative macrolactamization of the polymer-supported cyclization precursors, followed by acid cleavage, provided conformationally restricted RGD model cyclic peptides.

Novel Synthesis of Cinnolines and 1-Aminoindolines via Cu-Catalyzed Intramolecular N-Arylation of Hydrazines and Hydrazones Prepared from 3-Haloaryl-3-hydroxy-2-diazopropanoates

A new and facile access to cinnolines, dihydrocinnolines, and 1-aminoindolines was established by use of diazo functionalities. The hydrazines and hydrazones as cyclization precursors derived from 3-haloaryl-3-hydroxy-2-diazopropanoates, which are prepared by one-pot procedure utilizing phase-transfer catalysis, are successfully converted to the corresponding nitrogen heterocycle by Cu-catalyzed N-arylation. Furthermore, analysis of UV spectra proved that 4-oxo-3-carboxylates predominantly exist not as 4-hydroxycinnoline (enol form) but as cinnolone (keto form).

Temporary Silicon Connection Strategies in Intramolecular Allylation of Aldehydes with Allylsilanes

Three gamma-(amino)silyl-substituted allylsilanes 14a-c have been prepared in three steps from the corresponding dialkyldichlorosilane. The aminosilyl group has been used to link this allylsilane nucleophile to a series of beta-hydroxy aldehydes through a silyl ether temporary connection. The size of the alkyl substituents at the silyl ether tether governs the outcome of the reaction on exposure to acid. Thus, treatment of aldehyde (E)-9aa, which contains a dimethylsilyl ether connection between the aldehyde and allylsilane, with a range of Lewis and Brønsted acid activators provides an (E)-diene product. The mechanism of formation of this undesired product is discussed. Systems containing a sterically more bulky diethylsilyl ether connection react differently: thus in the presence of TMSOTf and a Brønsted acid scavenger, intramolecular allylation proceeds smoothly to provide two out of the possible four diastereoisomeric oxasilacycles, 23 (major) and 21 (minor). A diene product again accounts for the remaining mass balance in the reaction. This side product can be completely suppressed by using a sterically even more bulky diisopropylsilyl ether connection in the cyclization precursor, although this is now at the expense of a slight erosion in the 1,3-stereoinduction in the allylation products. The sense of 1,3-stereoinduction observed in these intramolecular allylations has been rationalized by using an electrostatic argument, which can also explain the stereochemical outcome of a number of related reactions. Levels of 1,4-stereoinduction in the intramolecular allylation are more modest but can be significantly improved in some cases by using a tethered (Z)-allylsilane in place of its (E)-stereoisomer. Oxidation of the major diastereoisomeric allylation product 23 under Tamao-Kumada conditions provides an entry into stereodefined 1,2-anti-2,4-syn triols 28.

Organocatalytic Enantioselective Diels−Alder Reaction of Dienes with α-(N,N-Diacylamino)acroleins

Catalytic and highly enantioselective Diels-Alder reaction of cyclic and acyclic dienes with alpha-phthalimidoacroleins provides cyclic alpha-quaternary alpha-amino acid precursors. The conformationally flexible chiral ammonium salt of H-L-Phe-L-Leu-N(CH(2)CH(2)) 2-reduced triamine with pentafluorobenzensulfonic acid is very effective as an asymmetric catalyst for the Diels-Alder reaction.

N-Substituted Tetronamides as Ambident Nucleophilic Building Blocks for the Synthesis of New 4-Aza-2,3-didehydropodophyllotoxins

Aza-analogues of podophyllotoxin were synthesized in two steps from N-substituted tetronamides. The acid-mediated benz-hydrylation of N-substituted tetronamides with a suitably functionalized benzhydrol quantitatively afforded the cyclization precursors. The target pentacyclic 4-aza-2,3-didehydropodo-phyllotoxins were next obtained via an intramolecular copper-mediated Ullmann-type N-arylation.

Cluster self-organization of germanate systems: Suprapolyhedral precursor clusters and self-assembly of K2Nd4Ge4O13(OH)4, K2YbGe4O10(OH), K2Sc2Ge2O7(OH)2, and KScGe2O6(PYR)

Geometric and topological analysis of all known types of K,TR germanates (TR = La-Lu, Y, Sc, In) is carried out with the use of computer techniques (the TOPOS 4.0 program package). Framework structures are represented as three-dimensional (3D) K,TR,Ge networks (graphs) with oxygen atoms removed. The following crystal-forming 2D TR,Ge networks are determined: for K2Nd4Ge4O13(OH)4, this is TR 4 3 3 4 3 3 + T 4 3 4 3; for K2YbGe4O10(OH), this is TR 6 6 3 6 + T 1 6 8 6 + T 2 3 6 8; for K2Sc2Ge2O7(OH)2, this is TR 6 4 6 4 + T 6 4 6; and for KScGe2O6, TR 6 6 3 6 3 4 + T 1 6 3 6 + T 2 6 4 3. The full 3D reconstruction of the self-assembly mechanism of crystal structures is performed as follows: precursor cluster—primary chain—microlayer-microframework (supraprecursor). In K2Nd4Ge4O13(OH)4, K2Sc2Ge2O7(OH)2, and KScGe2O6, an invariant type of cyclic six-polyhedral precursor cluster is identified; this precursor clusters is built of TR octahedra, which are stabilized by atoms K. For K2Nd4Ge4O13(OH)4, the type of cyclic four-polyhedral precursor cluster of tetrahedron-linked TR octatopes is identified. The cluster coordination number in a layer is six (the maximum possible value) only for anhydrous germanate KScGe2O6 (an analogue of pyroxene, PYR); in the other OH-containing germanates, this number is four. The mechanism of formation of Ge radicals in the form of groups Ge2O7 and Ge4O13, a chain GeO3, and a tubular assembly of linked cyclic groups Ge8O20 is considered.

Aryl Radical Cyclization: Regioselective Synthesis of 6a,7,8,12b‐Tetrahydro‐6H‐chromeno[3,4‐c]quinolin‐6‐one

Regioselective synthesis of 6a,7,8,12b‐tetrahydro‐6H‐chromeno[3,4‐c]quinolin‐6‐ones 4 in good to excellent yields from 3‐(2‐bromoanilinomethyl)coumarins 3 by aryl radical cyclization is described. The cyclization precursors 3 were prepared by the reaction of 3‐chloromethyl coumarin with different 2‐bromoaniline.

Cluster self-organization of silicate and germanate systems: Invariant suprapolyhedral cluster precursors and self-assembly of the crystal structures of Li,TR silicates (germanates)

The initial stages of formation of suprapolyhedral clusters (containing polyhedra of different types) in an evolving chemical system are considered. The suprapolyhedral clusters of the chain and cyclic types are used for modeling two-dimensional periodic structures. The developed model is used to search for cluster precursors in the structures of Li,TR silicates (germanates) of the known structure types. The complete threedimensional reconstruction of the self-assembly of Li,TR silicates (germanates) is performed using computer methods (with the TOPOS program package) according to the following scheme: cluster precursor → primary chain → microlayer → microframework (supraprecursor) → … framework. Two types of invariant cyclic cluster precursors composed of the TR polyhedra linked by tetrahedra and the TR polyhedra joined by diorthotetrahedra are identified in five and two structures, respectively. It is revealed that the lithium atoms are located at the centers of all clusters. New types of two-dimensional nets with a hierarchical structure formed as a result of the packing of cyclic four-, six-, and eight-node clusters are described.

ATRP-RCM Synthesis of 8-Shaped Poly(methyl acrylate) Using a 4-Armed Star Telechelics

Cyclic and multicyclic polymers have drawn increasing attention due to their unique architectures, i.e., free of chain ends. A number of protocols including, in particular, the ringexpansion polymerization and the end-to-end polymer cyclization, have now been developed for the selective and effective synthesis of single cyclic polymers to realize novel properties and functions unattainable by conventional linear or branched counterparts. We have also proposed a metathesis polymer cyclization (MPC) process, i.e., a ring-closing metathesis (RCM) reaction with a linear telechelic precursor having olefinic end groups under dilution. And the effective and selective synthesis of cyclic polyacrylate has been achieved through atom transfer radical polymerization (ATRP)-Keck allylation and the subsequent RCM reaction. In this process, the key telechelic prepolymer was produced by the ATRP using a difunctional initiator and the terminal bromide group was quantitatively converted to allyl group by the reaction with allyltributyltin. The subsequent intramolecular RCM reaction proceeded even under dilution in the presence of Grubbs catalyst to give a cyclic polymer in high efficiency. On the other hand, such a dicyclic as 8-shaped polymer has yet been an ongoing challenge in the synthetic polymer chemistry. We have shown that 8-shaped polymers are obtainable through an electrostatic self-assembly formed by two units of telechelic precursor having moderately strained cyclic ammonium salt end groups carrying one unit of tetracarboxylate counter anion. Alternatively, interand intramolecular metathesis condensation process have been applied between two units of a cyclic prepolymer having an allyloxy group (Scheme 1-a), and with a twin-tailed tadpole polymer precursor (Scheme 1-b), as well as with a cyclic polymer precursor having two allyloxy groups at the opposite positions (Scheme 1-c), respectively. The intramolecular metathesis condensation has also been applied with an H-shaped precursor having allyloxy end groups at each chain ends, to produce other types of dicyclic polymers having and manacle topologies (Scheme 1-d). As an extension of the preceding studies, we report in this paper on the synthesis of an 8-shaped polymer through the double ring-closing metathesis reaction using a 4-armed star polymer precursor, synthesized by means of the ATRP of methyl acrylate using a tetrafunctional initiator (Scheme 2). Since the ATRP has been recognized as a versatile means to give living star polymers upto hexafunctionalities by using multi-functional initiators, complex multicyclic polymers will be obtainable through the MPC process with end-functional star polymers.

Total synthesis of the indolizidine alkaloid tashiromine.

BackgroundTashiromine (1) is a naturally occurring indolizidine alkaloid. It has been the subject of thirteen successful total syntheses to date. Our own approach centres on the stereoselective construction of the indolizidine core by capture of an electrophilic acyliminium species by a pendant allylsilane. The key cyclisation precursor is constructed using olefin cross-metathesis chemistry, which has the potential to facilitate both racemic and asymmetric approaches, depending upon the choice of the allylsilane metathesis partner.ResultsThe use of the allyltrimethylsilane cross-metathesis approach enables the rapid construction of the key cyclisation precursor 3 (3 steps from commercial materials), which undergoes acid-induced cyclisation to give the desired bicyclic indolizidine skeleton as a 96:4 mixture of diastereomers. Simple functional group interconversions allowed the completion of the total synthesis of racemic tashiromine in six steps (19% overall yield). Three chiral α-alkoxyallylsilanes (12, 14 and 15) were prepared in enantioenriched form and their cross-metathesis reactions studied as part of a putative asymmetric approach to tashiromine. In the event, α-hydroxysilane 12 underwent isomerisation under the reaction conditions to acylsilane 17, while silanes 14 and 15 were unreactive towards metathesis.ConclusionA concise, stereoselective total synthesis of racemic tashiromine has been developed. Attempts to translate this into an asymmetric synthesis have thus far been unsuccessful.

Synthesis of Novel Enantiopure 4-Hydroxypipecolic Acid Derivatives with a Bicyclic β-Lactam Structure from a Common 3-Azido-4-oxoazetidine-2-carbaldehyde Precursor

Two different stereocontrolled accesses to new 4-hydroxypipecolic acid analogues with a bicyclic beta-lactam structure have been developed by using intramolecular reductive amination or allenic hydroamination reactions in 2-azetidinone-tethered azides. The access to the cyclization precursors was achieved from 3-azido-4-oxoazetidine-2-carbaldehyde via metal-mediated carbonyl-allenylation in aqueous environment or by organocatalytic direct aldol reaction. The tin hydride-promoted cyclization of the 2-azetidinone-tethered azidoallene is totally regioselective for the central allenic carbon providing a fused piperidine.

Cluster self-organization of silicate and germanate systems: Suprapolyhedral precursor clusters and self-assembly of orthotetrahedral structures in Na,TR-germanates (silicates)

The geometrical and topological analysis of all known types of the orthotetrahedral structures of Na,TR-germanates and their silicon analogues has been carried out using computer methods (TOPOS 4.0 program package). The full 3D reconstruction of the self-assembly mechanism of crystal structures has been performed as follows: precursor cluster-primary chain-microlayer-microframework (supraprecursor). For Na2HLaSiO5, NaHo4(GeO4)2O2OH, NaScGeO4, and NaSm3Ge2O8(OH)2, the same type of 2D TR, T-network has been recognized: 433334 + T 4433. For Na2HScGeO5, network TR 44444 + T 444 has been recognized. The coordination number (CN) of a precursor cluster in 2D networks is six. In all structures, the invariant type of cyclic four-polyhedral precursor clusters built of tetrahedron-linked TR-polyhedra has been identified with CNs being eight, seven, or six. In the Na5Y4Si4O16F structure, a tubular-type primary chain in which precursor clusters are tetrahedron-linked TR polyhedra with CN = 8 has been recognized. Their stacking in a layer is characterized by the network TR 8 8 4 + T 8 4 8, where 8 corresponds to the cross section of the primary chain. In a 3D network, the total number of neighboring tubular primary chains linked to the main chain is four. In the structures with TR: T = 1: 1 or 1.5: 1, the positions above and below the center of the precursor cluster are occupied by Na atoms; in NaHo4(GeO4)2O2(OH), where TR: T = 2: 1, these positions are occupied by an Na atom and a TR atom.

Synthesis of Caprazamycin Analogues and Their Structure−Activity Relationship for Antibacterial Activity

Synthesis of palmitoyl caprazol 7, which possesses a simple fatty acyl side chain at the 3' ''-position of the diazepanone moiety, was carried out and their antibacterial activity was evaluated. The key elements of our approach include the improved synthesis of the key 5'-beta-O-aminoribosyl-glycyluridine derivative, installation of the palmitoyl side chain to the cyclization precursor, and the construction of the diazepanone by an intramolecular reductive amination. The second generation synthesis of (+)-caprazol was also established. Palmitoyl caprazol 7 exhibited antibacterial activity against Mycobacterium smegmatis ATCC607 (MIC = 6.25 microg/mL) with potency similar to that of the caprazamycins (CPZs). Palmitoyl caprazol 7 and N6'-desmethyl palmitoyl caprazol 28 also exhibited antibacterial activity against drug-resistant bacteria including methyciline-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains (MIC = 3.13-12.5 microg/mL).

Synthesis of anhydride precursors of the environment-sensitive fluorophores 4-DMAP and 6-DMN

This protocol describes the synthesis of cyclic anhydride precursors of the environment-sensitive fluorophores 4-dimethylaminophthalimide (4-DMAP) and 6-dimethylaminonaphthalimide (6-DMN). The condensation of these anhydrides with a primary amino group confers on molecules of interest solvatochromic properties. In particular, two strategies for the insertion of the chromophores into peptides are presented in two companion protocols. The anhydride syntheses can be completed on the gram scale in 2 d for the 4-DMAP precursor and 10-15 d for the 6-DMN precursor.

Advances in Sesquiterpene Synthases (Cyclases) of Artemisia annua

Artemisinin, a novel and highly potent antimalarial drug, is produced from the plant Artemisia annua L. with very low yields ranging from 0.01% to 0.8% on a dry-weight basis. This makes artemisinin an expensive drug. Several studies reported the chemical synthesis of artemisinin, but none of them seems to be a viable economical alternative compared with the isolation of artemisinin from the plant. Hence, a higher concentration of artemisinin in the plant is necessary for the cheap production of antimalarial drug. Several types of cyclic sesquiterpenes in Artemisia annua have been characterized so far, and each was derived from the common cyclic precursor FDP in a reaction catalyzed by a sesquiterpene synthase. Sesquiterpene synthases are widely regarded as the rate-determining regulatory enzymes in the pathways they participate in, and several sesquiterpene synthases have been cloned from Artemisia annua till date. This report gives a brief review of the following sesquiterpene synthases: epi-cedrol synthase, amorpha-4,11-diene synthase, β-caryophyllene synthase, (E)-β-farnesene synthase, germacrene A synthase, as well as a novel sesquiterpene synthase whose function remains largely unknown. This study provides a better understanding of the metabolic engineering of Artemisia annua.

Oxygen Donor-Mediated Equilibration of Diastereomeric Alkene−Palladium(II) Intermediates in Enantioselective Desymmetrizing Heck Cyclizations

This investigation examines the origin of enantioselection in the desymmetrization of an acyclic prochiral Heck cyclization precursor. High asymmetric induction (97-98% ee) is attributed to a temporary interaction of a Lewis basic oxygen donor with weakly Lewis acidic palladium(II). A series of control experiments combined with quantum-chemical model calculations provided sound evidence for a mechanism involving oxygen donor-mediated, rapid equilibration of diastereomeric alkene-palladium(II) complexes prior to the selectivity-determining ring-closing event, a Curtin-Hammett scenario. Our study also highlights the importance of the cationic pathway (triflate counter anions versus halido ligand) and alkene stereochemistry (E versus Z) in asymmetric Heck reactions.

Structure of cyclic dihydroxyacetone phosphate dimethyl acetal, a cyclic DHAP precursor, in the crystalline state

The six-membered cyclic phosphate diester, 5,5-dimethoxy-2-oxo-1,3,2-dioxaphosphorinane-2-ol, the dimethyl acetal of cyclic dihydroxyacetone phosphate, (MeO) 2cDHAP, was obtained by the isolation of an intermediate in the basic hydrolysis of the cyclic triester derivative. The compound had been isolated in the form of the crystalline cyclohexylammonium (cha) salts: (cha)[(MeO) 2cDHAP]·3H 2O ( 5a) and (cha)[(MeO) 2cDHAP]·H 2O ( 5b), which were then converted into the free acid: (H 5O 2)[(MeO) 2cDHAP] ( 5c) and then into a series of different salts: Na[(MeO) 2cDHAP]·2H 2O ( 5d), K[(MeO) 2cDHAP]·1.5H 2O ( 5e), K[(MeO) 2cDHAP]·0.5H 2O ( 5e′), Ca[(MeO) 2cDHAP] 2·2H 2O ( 5f), CaK[(MeO) 2cDHAP] 3·2H 2O ( 5g) and NH 4[(MeO) 2cDHAP] ( 5h). The synthesis of the compounds, their crystallization and crystal structures determined by X-ray crystallography are described. The most interesting structural feature observed in 5a– g anions in the crystalline state is the chair conformation of the P/O/C/C/C/O 1,3,2-dioxaphosphorinane ring, which is generally not flattened, in contrast to the deformations often observed in the analogous aryl derivatives (also in (MeO) 2cDHAP(Ph); Ślepokura, K.; Lis, T. Acta Crystallogr. Sect. C 2004, 60, o315–o317). However, the anion in crystal 5h is disordered and exists in two conformations, 76% of which is the skew, S, conformation, not observed so far in the compounds of related structure.

Preparation of Potential Cell‐Permeant Nucleoside‐2′,3′‐cyclic Phosphate Precursors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Strategies for the Synthesis of 2-Substituted Indoles and Indolines Starting from Acyclic α-Phosphoryloxy Enecarbamates

Strategies have been developed for the synthesis of 2-substituted indoles and indolines starting from acyclic alpha-phosphoryloxy enecarbamates. A highly chemoselective cross-coupling of N-(o-bromophenyl)-alpha-phosphoryloxyenecarbamates with boron nucleophiles enabled the efficient preparation of various N-(o-bromophenyl)enecarbamates, which served as useful precursors for subsequent Heck-type cyclization or 5-endo-trig aryl radical cyclization to furnish 2-substituted indoles or indolines, respectively.

Synthesis and palladium-mediated cross-coupling reaction of cyclic ( kyklo-) and open-chain ( kentro-) telechelic precursors

A series of uniform-size, cyclic poly (THF)s having a bromophenyl ( 1a), a pentynoyl ( 1b) and a phenylboronate ( 1c) group, together with their open-chain, center-functional counterparts having the relevant functional group ( 2a and 2b), have been prepared in high yields through the esterification of a hydroxyl group of a cyclic ( kyklo-) and an open-chain ( kentro-) telechelic precursors. They were subsequently subjected to palladium-mediated, Sonogashira and Suzuki coupling reactions, i.e., 1a and 1b as well as 2a and 2b for the former, and 1a and 1c for the latter, respectively. SEC showed that the Sonogashira process could produce effectively the corresponding cross-coupling products, i.e, an 8-shaped and a 4-armed star polymer, respectively. The Suzuki process, on the other hand, failed to proceed under examined conditions.