Mechanism of triplet photosensitized Diels-Alder Reaction between indoles and cyclohexadienes: theoretical support for an adiabatic pathway

Diels-Alder reactions between indoles (InHs) and 1,3-cyclohexadienes (CHDs) were achieved by using aromatic ketones as photosensitizers. For instance, irradiation of deaerated dichloromethane solutions containing benzoylthiophene (BT, 1 mM), indole (20 mM), and phellandrene (40 mM), in the presence of an acylating agent, led to the N-acetylated Diels-Alder cycloadduct in 46% yield (endo:exo ratio of 1.8:1). Energy transfer from the BT triplet to the CHD gave rise to diene dimers as byproducts. Several combinations of CHDs, InHs, and aromatic ketones were tested; the Diels-Alder reaction was found to be a general process, except when the indole nucleus was substituted at position 2 or 7 and when aromatization of the CHD was favored. Theoretical calculations support a stepwise mechanism involving a triplet ternary complex TC(T1), arising from a nearly barrierless reaction between CHD and the 3(BT...HIn) exciplex. All subsequent steps proceed downhill in the triplet excited state, leading to a triplet cycloadduct-sensitizer CA-BT(T1) radical pair. Attempts to detect this species, which is basically an aminyl/BT ketyl radical pair, were performed by laser excitation of a solution containing BT, phellandrene, and indole. The observed transient absorption spectra could be compatible with the added spectra of the expected components of the radical pair.     

Ring expansion of functionalized octahydroindoles to enantiopure cis-decahydroquinolines

A new synthetic entry to enantiopure cis-decahydroquinolines is reported. Endo and exo derivatives of cis-1-benzyl-2-(hydroxymethyl)octahydroindol-6-one ethylene acetal undergo ring enlargement upon treatment with TFAA and then Et3N (thermodynamic conditions) to give enantiopure 1-benzyl-3-hydroxydecahydroquinolin-7-one derivatives in 77 and 82% yield, respectively. For 2-(1-hydroxyethyl) analogues, the best synthetic result is obtained from the (2S,1'R) endo isomer, which under kinetic reaction conditions (MsCl, THF, -20 degrees C, then AgOAc at rt ) gives the expanded product in 54% yield.     

Better understanding of the ring-cleavage process of cyanocyclopropyl anionic derivatives. A theoretical study based on the electron localization function

[reaction: see text] Theoretical calculations at the B3LYP/6-31+G(d), MP2/6-31+G(d), and G3(MP2) levels have been carried out to understand the alternative reaction pathways (the cyclopropyl ring cleavage (RC) and the retrocycloaddition reaction (rCA)) of a constrained tricyanocyclopropyl anionic derivative. The more energetically favorable path is found to be the RC process, a formally "forbidden" rearrangement (Leiviers, M.; Tam, I.; Groves, K.; Leung, D.; Xie, Y.; Breslow, R. Org. Lett. 2003, 5, 19, 3407) yielding an allylic anion system via a concerted transition structure, in agreement with experimental outcomes. rCA is more energetically favorable along a two-stage mechanism, via an intermediate, than a synchronous concerted process. By using isodesmic reactions, we have found that B3LYP presents limitations when it calculates carbon-carbon bond-breaking processes along the present rCA reaction. A detailed analysis of the nature of the topology of the reactive potential energy surface for the RC process points out the presence of a valley-ridge inflection point in the uphill part. An explanation for the low-energy barrier associated with RC is furnished on the analysis of the evolution of the twisting (dis-/conrotatory) motions of cyano substituents in the cyclopropyl ring as well as on the number and type of electron pairs provided by the electron localization function (ELF).     

Multivariate statistics for the differentiation of erythropoietin preparations based on intact glycoforms determined by CE-MS

Owing to the increasing number of erythropoietin biosimilars being approved, the comparison of different erythropoietin preparations in the pharmaceutical area is gaining in importance. Erythropoietin has a distinct natural heterogeneity arising from its glycosylation, which shows strong composition variations. This heterogeneity increases the complexity of the analysis of erythropoietin considerably, but may also be used to distinguish different preparations. Here, a method is presented for the differentiation of various erythropoietin preparations by capillary electrophoresis–mass spectrometry and the subsequent application of multivariate statistics. Relative peak areas of selected intact erythropoietin isoforms were used as variables in principal component analysis and hierarchical agglomerative clustering. Both of these strategies were suited for the clear differentiation of all erythropoietin preparations, including marketed products and preproduction preparations, which differ in the manufacturer, the production cell line, and the batch number. By this means, even closely related preparations were distinguished on the basis of the combined information on the antennarity, the sialoform, and the acetylation of the observed isoforms.     

Controlled Positioning of Nanoparticles on Graphene by Noninvasive AFM Lithography

Atomic force microscopy is shown to be an excellent lithographic technique to directly deposit nanoparticles on graphene by capillary transport without any previous functionalization of neither the nanoparticles nor the graphene surface while preserving its integrity and conductivity properties. Moreover this technique allows for (sub)micrometric control on the positioning thanks to a new three-step protocol that has been designed with this aim. With this methodology the exact target coordinates are registered by scanning the tip over the predetermined area previous to its coating with the ink and deposition. As a proof-of-concept, this strategy has successfully allowed the controlled deposition of few nanoparticles on 1 μm(2) preselected sites of a graphene surface with high accuracy.     

A systematic study of two complementary protocols allowing the general,mild and efficient deprotection of N-pivaloylindoles

Two mild and general protocols for the high-yielding deprotection of indoles and related fused heterocyclic systems are described, involving either hydride transfer from LDA or hydrolysis by the DBU–water system. Both methods were shown to tolerate a wide variety of substituents and functional groups, but the hydrolytic one proved to be particularly general, being compatible with 2-alkyl substituents, aldehydes, ketones, carboxylic acids, halogens, ethers, amides and esters. Yields were normally excellent in both cases, but were usually slightly higher for the reductive method. Taken together, these two protocols provide a general solution to the problem of pivaloyindole deprotection.     

Two-stage least squares and indirect least squares algorithms for simultaneous equations models

This paper analyzes the solution of simultaneous equations models. Efficient algorithms for the two-stage least squares method using QR-decomposition are developed and studied. The reduction of the execution time when the structure of the matrices in each equation is exploited is analyzed theoretically and experimentally. An efficient algorithm for the indirect least squares method is developed. Some techniques are used to accelerate the solution of the problem: parallel versions for multicore systems, and extensive use of the MKL library, thus obtaining efficient, portable versions of the algorithms.     

Nature of the ring-closure process along the rearrangement of octa-1,3,5,7-tetraene to cycloocta-1,3,5-triene from the perspective of the electron localization function and catastrophe theory

We analyze the behavior of the energy profile of the ring‐closure process for the transformation of (3Z,5Z)‐octa‐1,3,5,7‐tetraene 5 to (1Z,3Z,5Z)‐cycloocta‐1,3,5‐triene 6 through a combination of electron localization function (ELF) and catastrophe theory (CT). From this analysis, concepts such as bond breaking/forming processes, formation/annihilation of lone pairs, and other electron pair rearrangements arise naturally through the reaction progress simply in terms of the different ways of pairing up the electrons. A relationship between the topology and the nature of the bond breaking/forming processes along this rearrangement is reported. The different domains of structural stability of the ELF occurring along the intrinsic reaction path have been identified. The reaction mechanism consists of six steps separated by fold and cusp catastrophes. The transition structure is observed in the third step, d(C1? C8) = 2.342 Å, where all bonds have topological signature of single bonds (C? C). The “new” C1? C8 single bond is not formed in transition state and respective catastrophe of the ELF field (cusp) is localized in the last step, d(C1? C8) ≈ 1.97 Å, where the two monosynaptic nonbonding basins V(C1) and V(C8) are joined into single disynaptic bonding basin V(C1,C8). The V(C1,C8) basin corresponds to classical picture of the C1? C8 bond in the Lewis formula. In cycloocta‐1,3,5‐triene 6 the single C1? C8 bond is characterized by relatively small basin population 1.72e, which is much smaller than other single bonds with 2.03 and 2.26e. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011