High Regioand Research Articles

TANDEM REACTIONS OF THERMOLYSIS AND [3+2] CYCLOADDITION IN THE SYNTHESIS OF 3-HETARYL-4-NITROFUROXANS FROM 4-NITROFUROXANNITROLIC ACID

A tandem method of synthesis of 3-hetaryl-4-nitrofuroxans was developed based on the one-pot sequence of thermolysis of 4-nitrofuroxannitrolic acid to the corresponding 4-nitro-3-furoxancarbonitrile oxide and [3+2] cycloaddition of the latter to acetylenes and olefins. It was established that the synthesized 3-(isoxazol-3-yl)- and 3-(isoxazolin-3-yl)-4-nitrofuroxans are formed with high regioand diastereoselectivity.

Tandem Reactions of Thermolysis and [3+2] Cycloaddition in the Synthesis of 3-Hetaryl-4-Nitrofuroxans from 4-Nitrofuroxannitrolic Acid

A tandem method of synthesis of 3-hetaryl-4-nitrofuroxans was developed based on the one-pot sequence of thermolysis of 4-nitrofuroxannitrolic acid to the corresponding 4-nitro-3-furoxancarbonitrile oxide and [3+2] cycloaddition of the latter to acetylenes and olefins. It was established that the synthesized 3-(isoxazol-3-yl)- and 3-(isoxazolin-3-yl)-4-nitrofuroxans are formed with high regioand diastereoselectivity.

Chloropalladation Triggering the Cascade Annulation to Construct Functionalized Saturatedγ-Lactones in Ionic Liquids

A highly efficient and mild palladium-catalyzed cascade annulation has been developed to afford functionalized γ-lactones in moderate to good yields with high regioand diastereo-selectivities in ionic liquids. Their structures were confirmed by H NMR, C NMR and HRMS. Moreover, this reaction provided a novel and convenient methodology for the construction of naturally occurring biologically active γ-lactones.

Rearrangement of bornyl phenyl ether

We previously studied rearrangement of isobornyl phenyl ether under catalysis by acids and aluminum phenoxide [1]. Comparison of the experimental data obtained in the reaction catalyzed by acids and in the presence of aluminum phenoxide led us to presume that in the first case the rearrangement follows mainly intermolecular mechanism, and in the second, intramolecular. As a result, high regioand stereoselectivity of the process were rationalized by tandem Claisen and Wagner–Meerwein rearrangements occurring intramolecularly in the initially formed aluminum complex with isobornyl phenyl ether [1].

An Investigation on the Transition Metal Catalyzed Selective Additions of Styrenes with Diacetoxyiodobenzene (DIB)- Tetrabutylamidebromide (TBAB) System

The transition metal catalyzed addition of diacetoxyiodobenzene (DIB)-tetrabutylamidebromide (TBAB) system with styrenes could introduce bromo and oxide groups to olefins. This reaction provides a high regioand stereo-selective synthetic strategy and is much useful in organic synthesis.

Rotation of the Allylselenic Intermediate in Moderating the Stereochemical Course of the Selenium Dioxide-Mediated Allylic Oxidation

Allylic oxidation adjacent to C = C bonds to produce allylic alcohols remains a reaction of considerable interest in organic chemistry and various methods for this purpose have been developed. Among those the selenium dioxide-mediated oxidation is regarded as the most reliable and predictable method to introduce a hydroxy group into the allylic position for substituted alkenes regioand stereo-selectively. The key mechanistic basis to induce a high regioand stereo-selectivity in the allylic oxidation is the concerted and pericyclic process through two consecutive steps (an electrophilic ‘ene’ reaction followed by the [2,3]-sigmatropic rearrangement) (Scheme 1) as in a theoretical mechanism proposed by Sharpless and a recent account concerning theoretical and experimental data. We reported the overall stereochemical pathways by elucidating both an ‘ene’ reaction and the [2,3]-sigmatropic rearrangement of the selenium dioxide-mediated oxidation of 2methyl-2-butene. Those efforts seem successful to explain regioand stereo-selective aspects experimentally observed in the selenium dioxide-mediated allylic oxidation of several trisubstituted olefin compounds, particularly those where the concerted nature can be maintained during the whole process. However, modes of selectivity in the allylic oxidation of substituted olefin compounds are found to depend strongly on the geometric features of the alkene substrates. In the case of the allylic oxidation of more general cyclic systems such as 1-tert-butyl-4-alkylidene cyclohexanes, where the system can avoid the concerted mode throughout two steps, an unexpected isomeric compound, cis-5-tert-butyl-2-ethylidenecyclohexanol was obtained. There should be involved a rotation of the allylselenic intermediate between two pericyclic steps. The purpose of this note is to provide a clearer explanation for the mechanism of the selenium dioxide-mediated oxidation in the substituted alkenes how the rotation of the allylselenic intermediate affects the stereochemical mechanism. The Rotation of the Allylselenic Intermediate in the Allylic Oxidation of 1-tert-Butyl-4-alkylidene Cyclohexanes. In the allylic oxidation of 1-tert-butyl-4-alkylidene cyclohexanes, we observed a different stereo-selectivity mode compared to 2-methyl-2-butene. Two important approaches of selenium dioxide toward the olefin function in the pericyclic ‘ene’ step of the allylic oxidation of 1-tert-butyl-4-ethylidene cyclohexane (1) are trans-anti approach (A) and trans-syn (B) approach (Figure 1). Thus, theoretical calculations show significant products obtained from the allylic oxidation of 1-tertbutyl-4-ethylidene cyclohexane should be ones via two approaches (A and B). The relative transition state energy of as shown in Figure 1, the trans-anti approach (A) is predicted moderately preferred than trans-syn approach (B), The TS energy of A has been calculated to be more stable than B by 0.633 and 0.577 kcal/mol in HF/3-21G and B3LYP/6-31G*, respectively. According to the theoretical study of the reaction using HF/3-21G method, the trans-isomer 2a is predicted as a major product (73%). The trans-isomer can be provided from the initial trans-anti approach (A) in the ‘ene’ step and in situ [2,3]-rearrangement. The allylselenic intermediate generated after trans-anti approach proceeds with a concerted mode, i.e., without C3-C4 bond rotation into a [2,3]-sigmatropic rearrangement. In this case, the position where the ‘anti’ hydrogen (Hanti in Scheme 2) originally located is substituted by the OSeOH group after two concerted steps. The dominant option after trans-syn ‘ene’ approach is to

ChemInform Abstract: Effects of Lithium Salts on the Stereochemistry of Ketone Enolization by Lithium 2,2,6,6-Tetramethylpiperidide (LiTMP). A Convenient Method for Highly E-Selective Enolate Formation.

Studies of the reactivity of lithium 2,2,6,6-tetramethylpiperidide (LiTMP) with added lithium salts are described. The E/Z selectivity of 3-pentanone enolization by LiTMP displays a marked decrease as a function of added ketone (percent conversion). The enolization also shows a notable maximum of 501 selectivity at 0.3-0.4 equiv of added LiCl and an approximate asymptotic approach to 50-6O:l selectivity when >1.0 equiv of LiBr are added. The LiTMP-LiBr complex generated from 2,2,6,6-tetramethylpiperidinium bromide affords enolates with generally high regioand stereoselectivity as shown by several representative enolizations. The selectivities appear to have exclusively kinetic origins and are suggested to stem from the intervention of LiTMP-LiX mixed aggregates characterized in the following paper.

Enzymatic preparation of neomycin C from ribostamycin

The high regioand stereospecificities of enzymes and their ability to catalyze reactions in the absence of organic solvents make enzymatic synthesis of antibiotics an attractive way to prepare complex natural products. Enzymatic total syntheses of several complex natural products have been recently achieved, which illustrates the power of this synthetic methodology.1,2 Combinations of biosynthetic enzymes and substrates, including unnatural types, can afford structurally diverse natural product-like compounds.3 In this study, we report the enzymatic synthesis of the aminoglycoside antibiotic neomycin C from ribostamycin by the use of four neomycin biosynthetic enzymes. So far, all nine enzymes for ribostamycin biosynthesis from D-glucose 6-phosphate have been characterized using the enzymes derived from the butirosin producer Bacillus circulans and the neomycin producer Streptomyces fradiae.4 Furthermore, two neomycin biosynthetic enzymes NeoF and NeoD were recently found to catalyze the glycosylation of ribostamycin using

Inorganic Molecular Capsules: From Structure to Function

The assembly of nanoscale capsules or cages using metal coordination represents one of the most interesting and challenging areas of chemical nanoscience. These high-symmetry capsules are invariably comprised of many metal–ligand components, which often selfassemble rapidly and in high yield into a single gigantic species—sometimes even protein-sized. However, the interest in these systems goes far beyond aesthetics. An understanding of the mechanisms of the assembly process that leads to their formation will allow systems with unmatched physical properties and functionalities to be designed from first principles. As the emphasis changes from structure to function, cages have been constructed that can serve as supramolecular containers, reaction vessels, and ion channel models for biological cells. In this Highlight, the very recent advances in the formation of cages and capsules through metal ion coordination is explored. The self-assembly process of coordination cages mediated by metal–ligand coordination depends critically upon the building blocks chosen and their respective reactivities. One very important route to the formation of metallosupramolecular architectures involves the selection of building blocks that are preorganized, kinetically stable, that incorporate labile coordination sites, and are complementary. For instance, the [Pd(en)] unit (en= ethylenediamine) has emerged as a versatile building block in molecular self-assembly. Importantly, the 908 coordination angle present between one of the blocking groups and one of the labile ligands at the Pd metal ion has been judiciously used in the design of new discrete twoand three-dimensional structures ranging from cages, bowls, boxes, tubes, catenanes, and spheres. An example of an octahedral cage is [{Pd(en)}6L4] 12+ (1; Figure 1), which is based on the coordination of six Pd centers with [Pd(en)] corners and four 2,4,6-tris(4-pyridyl)1,3,5-triazine units. The cage has a large hydrophobic cavity, yet the outer part is hydrophilic. The tricoordinated ligand in 1 is relatively electron-deficient, therefore the cavity binds preferentially electron-rich aromatic guests. The cavity of 1 is well-defined stereochemically and is able to control chemical reactions. For example, Diels–Alder reactions are dramatically accelerated by a factor of over 100, and [2+2] photodimerizations of olefins proceed faster and with high regioand stereoselectivity. The formation of “molecular ice” within variants of 1, whereby ten water molecules are complexed within the cavity, may help further the understanding of the reactivity and host–guest binding properties of such capsules. Indeed, the sequencespecific binding of tripeptides was observed with capsule 1, wherein the encapsulation of Trp-Trp-Ala was favored over other sequences and singly mutated tripeptides. The encapsulation of paramagnetic moieties has also revealed interesting results, and the pHresponsive switching of spin–spin interactions of stable organic radicals has been possible in 1. The design of a similar cage, 2, comprising two 2,4,6-tris(4-pyridyl)1,3,5-triazine units and three 4,4’-bipyridine ligands with six [Pd(en)] corner units yielded a pillared cylinder. The organic-pillared nature of the cylinder resulted in interesting guest-binding properties through a combination of interactions. The complexation of tetrathiafulvalene (TTF) allowed the generation of a mixed-valence radical dimer cation within the self-assembled cage 2. This result is significant because this noncovalently bound species can only be generated in such a cage or by covalent linking. A similar effect is observed in the complexation of 2 with large planar aromatic organic moleFigure 1. Molecular structure of [{Pd(en)}6L4] 12+ (1; L=2,4,6-tris(4-pyridyl)1,3,5-triazine), in which the Pd ions occupy the corners of an octahedron (the en ligands and guest molecule are omitted for clarity). The cavity is illustrated by the large orange– brown sphere; Pd ions blue spheres; stick representation: C gray, N blue, H white. [*] Prof. L. Cronin WestCHEM, Department of Chemistry The University of Glasgow Glasgow, G128QQ (UK) Fax: (+44)141-330-4888 E-mail: l.cronin@chem.gla.ac.uk Highlights

Discovery of superior enzymes by directed molecular evolution.

Natural selection has created optimal catalysts that exhibit their convincing performance even with a number of sometimes counteracting constraints. Optimal performance of enzyme catalysis does not refer necessarily to maximum reaction rate. Rather, it may involve a compromise between specificity, rate, stability, and other chemical constraints ; in some cases, it may involve aintelligento control of rate and specificity. Because enzymes are capable of catalyzing reactions under mild conditions and with high substrate specificity that often is accompanied by high regioand enantioselectivity, it is not surprising that a continually increasing number of industrial and academic reports concern the use of enzyme catalysts in chemical synthesis as well as in biochemical and biomedical applications. However, the demands of modern synthesis and their commercial application were obviously not targeted during the natural evolution of enzymes. Considering a specific, nonnatural application, any property (or combination of properties) of an enzyme may therefore need to be improved. Of course, scientists desired to mimick nature's powerful concepts for tailoring specific enzymatic properties: Following pioneering experiments for evolving molecules in the test tube, evolutionary engineering of biomolecules was successfully realized with first selections of functional nucleic acids (ribozymes) by using the SELEX (systematic evolution of ligands by exponential enrichment with integrated optimization by non-linear analysis) procedure, 8] and with the development of high-affinity ligands (aptamers) by using similar techniques. Meanwhile, evolutionary engineering, also termed adirected evolutiono, has emerged as a key technology for biomolecular engineering and generated impressive results in the functional adaptation of enzymes to artificial environments. Certainly, evolution in the laboratory does not come to a halt at the optimization of single genes and proteins. Recent results excitingly demonstrate the success of amolecular breedingo of metabolic pathways, and even of complete genomes, and the end is not in sight yet. Directed evolution in the laboratory is highly attractive because its principles are simple and do not require detailed knowledge of structure, function, or mechanism. Essentially like natural evolution, directed evolution comprises the iterative implementation of (1) the generation of a alibraryo of mutated genes, (2) its functional expression, and (3) a sensitive assay to identify individuals showing the desired properties, either by selection or by screening (Figure 1). After each round, the genes of improved variants are deciphered and subsequently serve as parents for another round of optimization. This review covers the most important aspects of directed evolution and summarizes key solutions to problems of optimizing and understanding enzyme function.

SYNTHESIS AND HYDROLYTIC STABILITY OF TERT-BUTOXYDIMETHYLSILYL ENOL ETHERS

tert-Butoxydimethylsilyl enol ethers derived from aldehydes and ketones were synthesized in good yields with high regioand stereoselectivities, under thermodynamically and kinetically controlled conditions. The hydrolytic stability of tert-butoxydimethylsilyl enol ether of cyclohexanone was studied under acidic and basic conditions and compared to that of trimethylsilyl, tert-butyldimethylsilyl and (2,4,6-tri-tert-butylphenoxy) dimethylsilyl enol ethers.

Synthesis and transformations of metallocycles

* For Part 18, see Ref. I. High regioand stereoselectivities of the preparat ion of compounds 2 based 4,5 on the use o f accessible fireand explosion-safe reagents (RAICI2) made this method promising in synthetic practice. However , no formation of monoalkyl-substituted ACPs (1) is observed in experiments with EtAICI 2 or RA1CI 2. For the purpose of developing an efficient catalytic method for the synthesis of 3-substi tuted ACPs with different structures on the basis o f the aforement ioned approach to ACPs from RAICI 2 and ct-olefins, we studied the Cp2ZrCl2-catalyzed react ions of RAICI 2 (R = Alk, OR, NR2) with a-olef ins and ethylene, assuming that the reaction can thus be di rected toward the formation of compounds 1 (Scheme 2). However, the reaction of EtAICI 2 with l -hexene and ethylene gives a mixture of cyclic organoaluminum compounds (OACs) (1--3), whose ratio depends on the concentration of gaseous ethylene in the reaction mixture.

Dioxirane oxidations: Taming the reactivity-selectivity principle

Abstract

Syntheses of nitrogen heterocycles by means of amine-directed carbonylation and hydrocarbonylation

Amine-directed carbonylation of 2-allylpiperidine (5) gives 8-methyl-1-azabicyclo[4.3.0]nonan-9-one (7) with extremely high regio-and stereosel

Effects of lithium salts on the stereochemistry of ketone enolization by lithium 2,2,6,6-tetramethylpiperidide (LiTMP). A convenient method for highly E-selective enolate formation

Studies of the reactivity of lithium 2,2,6,6-tetramethylpiperidide (LiTMP) with added lithium salts are described. The E/Z selectivity of 3-pentanone enolization by LiTMP displays a marked decrease as a function of added ketone (percent conversion). The enolization also shows a notable maximum of 501 selectivity at 0.3-0.4 equiv of added LiCl and an approximate asymptotic approach to 50-6O:l selectivity when >1.0 equiv of LiBr are added. The LiTMP-LiBr complex generated from 2,2,6,6-tetramethylpiperidinium bromide affords enolates with generally high regioand stereoselectivity as shown by several representative enolizations. The selectivities appear to have exclusively kinetic origins and are suggested to stem from the intervention of LiTMP-LiX mixed aggregates characterized in the following paper.

A search for peptide ligase: cosolvent-mediated conversion of proteases to esterases for irreversible synthesis of peptides

Serine and cysteine proteases (trypsin, chymotrypsin, papain, subtilisin) in the presence of certain concentrations of water-miscible organic solvents express no amidase activities. The esterase activities, however, remain significant. These modified enzymes can be used as peptide ligases in a kinetically controlled approach (aminolysis) for the stepwise synthesis and fragment coupling of peptides, the products of which are free from secondary hydrolysis. Preparative syntheses of peptides containing both Dand L-amino acids and penicillin precursors containing 0-methyl-D-allothreonine and a-aminoadipic acid under such conditions are demonstrated. A comparative study of the enzymatic synthesis of Z-Phe-Leu-NH, in anhydrous DMF and in aqueous DMF (50% water, v/v) indicates that the rate in aqueous DMF is >10000 times faster. Chymotrypsin, subtilisin, and Streptomyces griseus protease are inactive toward Z-Phe-OMe + Leu-NH2 in anhydrous DMF. The utilization of proteases as catalysts in peptide synthesis began early this century2 and is still an area of active r e ~ e a r c h . ~ Some of the processes have been commercialized; of particular importance is the production of aspartame4 and human i n s u h 5 The advantages of enzymatic peptide synthesis are freedom from racemization, minimal activation and side-chain protection, mild reaction conditions, high regioand stereoselectivity, and enzyme immobilization allowing for catalyst recovery in large-scale processes. Further, the reactions can be carried out in a mixture of organic solvent and water, devoid of the problem of low solubility of protected peptides in the organic solvents employed in chemical synthesis. With these advantages, however, come the disadvantages that the amidase activity of proteases causes a secondary hydrolysis of the growing peptides and that the substrates of proteases are generally limited to natural L-amino acid derivat i v e ~ . ~ ~ ~ Two strategies are generally used in enzymatic peptide synthesis: One is a thermodynamically controlled synthesis (Le., a direct reversal of the catalytic hydrolysis of peptides; eq I) , and the other RCO2H + H2NR' RCONHR' + H20 (1 ) a