Exocyclic Derivatives Research Articles

Nickel-Catalyzed Anionic Cross-Coupling Reaction of Lithium Sulfonimidoyl Alkylidene Carbenoids With Organolithiums.

The mechanistic platform for a novel nickel0‐catalyzed anionic cross‐coupling reaction (ACCR) of lithium sulfonimidoyl alkylidene carbenoids (metalloalkenyl sulfoximines) with organometallic reagents is reported herein, affording substituted alkenylmetals and lithium sulfinamides. The Ni0‐catalyzed ACCR of three different types of metalloalkenyl sulfoximines, including acyclic, axially chiral and exocyclic derivatives, with sp2 organolithiums and sp2 and sp3 Grignard reagents has been studied. The ACCR of metalloalkenyl sulfoximines with PhLi in the presence of the Ni0‐catalyst and precatalyst Ni(PPh3)2Cl2 afforded alkenyllithiums, under inversion of configuration at the C atom and complete retention at the S atom. In a combination of experimental and DFT studies, we propose a catalytic cycle of the Ni0‐catalyzed ACCR of lithioalkenyl sulfoximines. Computational studies reveal two distinctive pathways of the ACCR, depending on whether a phosphine or 1,5‐cyclooctadiene (COD) is the ligand of the Ni atom. They rectify the underlying importance of forming the key Ni0‐vinylidene intermediate through an indispensable electron‐rich Ni0‐center coordinated by phosphine ligands. Fundamentally, we present a mechanistic study in controlling the diastereoselectivity of the alkenyllithium formation via the key lithium sulfinamide coordinated Ni0‐vinylidene complex, which consequently avoids an unselective formation of an alkylidene carbene Ni‐complex and ultimately racemic alkenyllithium.

ChemInform Abstract: The Energetics of Cyclopropene, 1,4-Cyclohexadiene, and Some of Their Hetero- and/or Exocyclic Derivatives.

The recently defined concept of “ultradiagonal” strain energy is applied to cyclopropene, cyclopropenone, and methylenecyclopropene and their respective diaza and diphospha derivatives using ab initio (DFT) calculations. In the relatively few cases where comparisons could be made between theory and either experiment or earlier calculational studies, very good agreement for both energies and structures were found. This gives us confidence for the remaining species. The results were also qualitatively explained, and the concept of ultradiagonal strain gibbs energy is briefly discussed.

Studies in sigmatropic rearrangement: synthesis of 3,11a-dimethyl-6a,11a-dihydro-1H,6H-pyrano[3',4':5,6]thiopyrano[4,3-b][1]benzofuran-1-one

Abstract Thermal rearrangement of 4-aryloxymethyl-7-methylthiopyrano-[3,2-c]pyran-5-ones 6a-f afforded a number of hitherto unreported benzofuro[3,2-c]-6a,11a-dihydro-3,11adimethylthiopyranopyran-1-one 15a-e in good yields (60-67%) along with the exocyclic derivatives 16d,e,f as minor products (10-15%). Compounds 6a-f were in turn synthesized in 7285% yields by the thermal rearrangement of 4-(4'-aryloxybut-2'-ynylthio)-6-methylpyran-2-ones 5a-f. Compounds 5a-f were obtained in (50-55%) yields by the phase-transfer catalyzed alkylation of 4-mercapto-6-methyl-2-pyrone 3 with 1-aryloxy-4-chlorobut-2-yne 4a-f.

Solution structure of an 11-mer duplex containing the 3, N4-ethenocytosine adduct opposite 2′-deoxycytidine: implications for the recognition of exocyclic lesions by DNA glycosylases

Lipid peroxidation products, as well as the metabolic products of vinyl chloride, react with cellular DNA producing the mutagenic adduct 3, N 4-etheno-2′-deoxycytidine (ϵdC), along with several other exocyclic derivatives. High-resolution NMR spectroscopy and restrained molecular dynamics simulations were used to establish the solution structure of an 11-mer duplex containing an ϵdC·dC base-pair at its center. The NMR data suggested a regular right-handed helical structure having all residues in the anti orientation around the glycosydic torsion angle and Watson-Crick alignments for all canonical base-pairs of the duplex. Restrained molecular dynamics generated a three-dimensional model in excellent agreement with the spectroscopic data. The (ϵdC·dC)-duplex structure is a regular right-handed helix with a slight bend at the lesion site and no severe distortions of the sugar-phosphate backbone. The ϵdC adduct and its partner dC were displaced towards opposite grooves of the helix, resulting in a lesion-containing base-pair that was highly sheared but stabilized to some degree by the formation of a single hydrogen bond. Such a sheared base-pair alignment at the lesion site was previously observed for ϵdC·dG and ϵdC·T duplexes, and was also present in the crystal structures of duplexes containing dG·T and dG·U mismatches. These observations suggest the existence of a substrate structural motif that may be recognized by specific DNA glycosylases during the process of base excision repair.

The Energetics of Cyclopropene, 1,4-Cyclohexadiene, and Some of Their Hetero- and/or Exocyclic Derivatives

The recently defined concept of “ultradiagonal” strain energy is applied to cyclopropene, cyclopropenone, and methylenecyclopropene and their respective diaza and diphospha derivatives using ab initio (DFT) calculations. In the relatively few cases where comparisons could be made between theory and either experiment or earlier calculational studies, very good agreement for both energies and structures were found. This gives us confidence for the remaining species. The results were also qualitatively explained, and the concept of ultradiagonal strain gibbs energy is briefly discussed.

What structural features determine repair enzyme specificity and mechanism in chemically modified DNA?

A crucial question in repair is how do enzymes recognize substrates. In surveying the relevant literature, it becomes evident that there are no rules which can be clearly applied. At this time it appears that uracil glycosylase is the only repair enzyme for which all the known substrates can be rationalized on the basis of chemical structure. When surveying the multiplicity of substrates for m3A-DNA glycosylase, it is difficult, on the basis of present knowledge, to explain why 1,N6-etheno-A (epsilon A) is as good a substrate, if not better, than m3A for which the enzyme is named. There is no apparent unifying chemical structure which is required for recognition. It should also be noted that many studies of the mechanism of m3A-DNA glycosylase only utilized-N-3- and N-7-alkylpurines. On this basis, an electron-deficient purine, and later pyrimidine, was considered to be the recognition signal. Since epsilon A and Hx do not fall in this class, this is one illustration of why exploring new substrates becomes important in elucidating enzyme mechanisms. Ubiquitous enzymes, such as 5'-AP endonucleases, are present in both prokaryotes and eukaryotes. The primary function is the same, i.e., repair of an AP site which occurs through natural processes or from the action of DNA glycosylases. There are, however, completely unrelated substrates such as the exocyclic adducts pBQ-dC and pBQ-dG. pBQ-dC is repaired by both the human HAP1 and E. coli Exo III and Endo IV, while pBQ-dG is only repaired by the E. coli enzymes. Yet, when repair of these adducts occurs, it is by the same unusual pathway which differs from the usual base excision repair mechanism. This finding may ultimately not be as unusual as it now seems. The understanding of substrate recognition by repair enzymes, which can have different repair pathways, is complex. For example, three exocyclic derivatives which each have either the same modification (1,N4-epsilon dA and 3,N4-epsilon dC) or the same base with different modifying groups (3,N4-epsilon dC and 3,N4-pBQ-dC) are repaired by three separate enzymes and two mechanism (Figure 9). Investigators have also reported that two separate enzymes and pathways can be found for simple adducts such as m6G and O4T. It is not clear why, for these adducts, both MGMT and excision repair can be utilized. This could be visualized as a "backup" system and may be more common than now known. We cannot think like an enzyme or vice versa. In the absence of enough necessary information, we can only be descriptive. What information is necessary for further understanding? (1) More detailed structural studies of adducts in defined oligonucleotides would be useful. (2) New substrates should be explored. For example, is the mechanism for PBQ-dC (and pBQ-dG) repair unique? This involves guesswork and intuition. (3) For the adducts mentioned in this Perspective and others, understanding enzyme/substrate recognition will be facilitated by cocrystallography and site-directed mutagenesis. (4) Genetic approaches, such as knockouts or targeted mutations in repair genes, should be expanded in order to focus on the physiological role of a specific enzyme. Above all: structure, structure, structure! Enzymologists, organic chemists, physical chemiste, X-ray crystallographers, and others must combine forces if the fundamental problems addressed here are to be understood.

A New Series of Organoboranes. VI. The Synthesis and Reactions of Some Silyl Neocarboranes

Abstract : The preparation and some reactions of silyl neocarboranes are reported. These derivatives contrast the isomeric silyl carboranes since they do not tend to form exocyclic derivatives. Some differences in reactivity of chlorosilyl neocarboranes when compared with the similar carboranes are noted. (Author)