C-methyl Groups Research Articles

Total syntheses of (-)-kopsifoline D and (-)-deoxoapodine: divergent total synthesis via late-stage key strategic bond formation.

Divergent total syntheses of (−)-kopsifoline D and (−)-deoxoapodine are detailed from a common pentacyclic intermediate 15, enlisting the late-stage formation of two different key strategic bonds (C21–C3 and C21–O–C6) unique to their hexacyclic ring systems that are complementary to its prior use in the total syntheses of kopsinine (C21–C2 bond formation) and (+)-fendleridine (C21–O–C19 bond formation). The combined efforts represent the total syntheses of members of four classes of natural products from a common intermediate functionalized for late-stage formation of four different key strategic bonds uniquely embedded in each natural product core structure. Key to the first reported total synthesis of a kopsifoline that is detailed herein was the development of a transannular enamide alkylation for late-stage formation of the C21–C3 bond with direct introduction of the reactive indolenine C2 oxidation state from a penultimate C21 functionalized Aspidosperma-like pentacyclic intermediate. Central to the assemblage of the underlying Apidosperma skeleton is a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole that provided the functionalized pentacyclic ring system 15 in a single step in which the C3 methyl ester found in the natural products served as a key 1,3,4-oxadiazole substituent, activating it for participation in the initiating Diels–Alder reaction and stabilizing the intermediate 1,3-dipole.

Reactions of 5-methylcytosine cation radicals in DNA and model systems: Thermal deprotonation from the 5-methyl group vs. excited state deprotonation from sugar

Purpose: To study the formation and subsequent reactions of the 5-methyl-2′-deoxycytidine cation radical (5-Me-2′-dC•+) in nucleosides and DNA-oligomers and compare to one-electron oxidized thymidine.Materials and methods: Employing electron spin resonance (ESR), cation radical formation and its reactions were investigated in 5-Me-2′-dC, thymidine (Thd) and their derivatives, in fully double-stranded (ds) d[GC*GC*GC*GC*]2 and in the 5-Me-C/A mismatched, d[GGAC*AAGC:CCTAATCG], where C* = 5-Me-C.Results: We report 5-Me-2′-dC•+ production by one-electron oxidation of 5-Me-2′-dC by Cl2•− via annealing in the dark at 155 K. Progressive annealing of 5-Me-2′-dC•+ at 155 K produces the allylic radical (C-CH2•). However, photoexcitation of 5-Me-2′-dC•+ by 405 nm laser or by photoflood lamp leads to only C3′• formation. Photoexcitation of N3-deprotonated thyminyl radical in Thd and its 5′-nucleotides leads to C3′• formation but not in 3′-TMP which resulted in the allylic radical (U-CH2•) and C5′• production. For excited 5-Me-2′,3′-ddC•+, absence of the 3′-OH group does not prevent C3′• formation. For d[GC*GC*GC*GC*]2 and d[GGAC*AAGC:CCTAATCG], intra-base paired proton transferred form of G cation radical (G(N1-H)•: C(+ H+)) is found with no observable 5-Me-2′-dC•+ formation. Photoexcitation of (G(N1-H)•:C(+ H+)) in d[GC*GC*GC*GC*]2 produced only C1′• and not the expected photoproducts from 5-Me-2′-dC•+. However, photoexcitation of (G(N1-H)•:C(+ H+)) in d[GGAC*AAGC:CCTAATCG] led to C5′• and C1′• formation.Conclusions: C-CH2• formation from 5-Me-2′-dC•+ occurs via ground state deprotonation from C5-methyl group on the base. In the excited 5-Me-2′-dC•+ and 5-Me-2′,3′-ddC•+, spin and charge localization at C3′ followed by deprotonation leads to C3′• formation. Thus, deprotonation from C3′ in the excited cation radical is kinetically controlled and sugar C-H bond energies are not the only controlling factors in these deprotonations.

Expanding the structural footprint of xenoestrogens

Many synthetic chemicals with structural similarity to estradiol bind to the estrogen receptor and disrupt the normal estrogen physiology in humans and other vertebrates. Most of these xenoestrogens contain a structure that mimics the phenolic A ring on E2. This phenolic A ring is a defining property of E2 that distinguishes it from aldosterone, cortisol, progesterone and testosterone. However, Δ5-androstenediol, 5α-androstanediol and 27-hydroxy-cholesterol also have estrogenic activity, despite having important structural differences in their A rings compared to E2. Unlike E2, these steroids have a saturated A ring with a 3β-hydroxyl and a C19 methyl group. An implication of their estrogenic activity is that synthetic chemicals containing a saturated A ring with a 3β-hydroxyl and a C19 methyl group are potential xenoestrogens.

‘At’ Content as a Determinant of the Chromosome Structure

We propose the variation of AT content along the genome as a determinant of the chromosome structure. Genome-wide map of chromosomal contacts has recently been revealed and it strongly correlates with the local AT content of the sequence. AT-rich domains attract each other while GC-rich domains, which contain most of the actively transcribed regions, show weaker aggregation. Using single molecule imaging and vesicle encapsulation to detect transient binding events between short double-stranded DNAs in the presence of spermine, one of the linear polycations essential in regulating cellular functions, we show that the inherent properties of DNAs lead to such correlation even without mediating proteins. Molecular dynamics simulations reveal how polycations specifically bridge AT-rich domains. C5 methyl group of thymine restricts polycations at the bridge site by steric hindrance. CpG methylation converts the major groove structure of cytosine to that of thymine, thus mimicking AT-rich DNAs with stronger attraction. This effect suggests an epigenetic implication of the polycation-driven DNA interaction.

A new NMR technique to probe protein–ligand interaction

Non covalent grafting of proteins on affinity phases is a very common approach for isolation, purification and re-concentration of tagged proteins. Many biophysical studies are conducted on these grafted proteins (surface plasmon resonance, quartz crystal microbalance, etc.) showing that the integrity and function of the protein is usually maintained. However, NMR studies of such samples were not undertaken so far, due to the broadening observed on this kind of heterogeneous samples.We present here the use of the HR-MAS technology to obtain 2D NMR spectra of the MAGI-1 PDZ2/6 protein domain, C13-labeled, tagged with a His-tag and grafted on a Nickel affinity resin. We optimized the C13 Methyl SOFAST HMQC experiment allowing important gains in terms of signal-to-noise. The gain comes from the gathering of proton magnetization from the resin material to the protein under study.Several methyl signals from the unstructured C-terminal tail, which is involved in the binding of the PDZ domain to C-terminal peptides of its partners, were observed and measured. The interaction of the bound PDZ domain with cognate peptides was monitored using <500μg of protein sample. A response proportional to the peptide Kd is obtained, indicating that the method can be used to rapidly and efficiently monitor protein–ligand interactions.

Diffusion coefficients of C18 unsaturated fatty acid methyl esters in supercritical carbon dioxide containing 10% mole fraction ethanol as modifier

To determine the molecular diffusion coefficients of C18 unsaturated fatty acid methyl esters in supercritical carbon dioxide (scCO2) containing 10mol% ethanol as a modifier, four methyl esters of C18 fatty acids, i.e., methyl oleate, methyl ricinoleate, methyl linoleate and methyl linolenate were selected as the typical solutes. The diffusion coefficients were measured at temperatures from 313.15 to 333.15K and pressures from 15 to 27MPa using the Taylor–Aris chromatographic peak broadening (CPB) technique. The influences of temperature, pressure, density and viscosity of the solvent mixture on the diffusion coefficients were examined. The results show that methyl oleate always diffuses faster than methyl ricinoleate at the same operating condition. Moreover, the D12 values in ethanol-modified scCO2 decrease with the increase of the number of C-C double bonds in C18-methyl ester, which is consistent with the trend reported in pure scCO2. The diffusivity data are compared with the estimation of eleven predictive models. The modified Wilke–Chang equation is the best purely predictive model and the free volume model of Dymond with two adjustable parameter gives the least errors with average absolute deviations lower than 2.5%.

Synthesis of ent‐Kaurane and Beyerane Diterpenoids by Controlled Fragmentations of Overbred Intermediates

Efficient access to minimally oxidized members of the ent-kaurane and beyerane class of terpenes has been achieved by using a polyene cyclization precursor designed to directly yield oxidation at the axial C19-methyl group. Construction of the [3.2.1]bicyclic system found in the ent-kaurane skeleton was realized with two overbred intermediates. Wagner–Meerwein rearrangement of the [3.2.1]bicyclic system yields the beyerane skeleton of isosteviol.

Amphidynamic crystals of a steroidal bicyclo[2.2.2]octane rotor: a high symmetry group that rotates faster than smaller methyl and methoxy groups.

The synthesis, crystallization, single crystal X-ray structure, and solid state dynamics of molecular rotor 3 provided with a high symmetry order and relatively cylindrical bicyclo[2.2.2]octane (BCO) rotator linked to mestranol fragments were investigated in this work. By use of solid state (13)C NMR, three rotating fragments were identified within the molecule: the BCO, the C19 methoxy and the C18 methyl groups. To determine the dynamics of the BCO group in crystals of 3 by variable temperature (1)H spin-lattice relaxation (VT (1)H T1), we determined the (1)H T1 contributions from the methoxy group C19 by carrying out measurements with the methoxy-deuterated isotopologue rotor 3-d6. The contributions from the quaternary methyl group C18 were estimated by considering the differences between the VT (1)H T1 of mestranol 8 and methoxy-deuterated mestranol 8-d3. From these studies it was determined that the BCO rotator in 3 has an activation energy of only 1.15 kcal mol(-1), with a barrier for site exchange that is smaller than those of methyl (E(a) = 1.35 kcal mol(-1)) and methoxy groups (E(a) = 1.92 kcal mol(-1)), despite their smaller moments of inertia and surface areas.

A Direct Stereoselective Preparation of a Fish Pheromone and Application of the Zinc Porphyrin Tweezer Chiroptical Protocol in Its Stereochemical Assignment

A two-step stereoselective preparation of a goldfish pheromone, 17α,20β-dihydroxy-4-pregnen-3-one, is reported from the readily available cortexolone in 64% overall yield. The (20S)-epimer was also synthesized in three steps from cortexolone with an overall yield of 47%. A microscale chiroptical technique based on a host/guest complexation mechanism between the substrate and a dimeric metalloporphyrin host (tweezer) was used to confirm the stereochemical assignment, while Density Functional Theory (DFT) calculations were employed to explain the high stereoselectivity induced by the 17α-hydroxyl and C18-methyl groups.

N-[3-(Dimethylamino)propyl]-N,N′,N′,N′′,N′′-pentamethylguanidinium tetraphenylborate

In the title salt, C11H27N4 +·C24H20B−, the C—N bond lengths in the central CN3 unit of the guanidinium ion are 1.333 (4), 1.334 (4) and 1.351 (4) Å, indicating partial double-bond character. The C atom of this unit is bonded to the three N atoms in a nearly ideal trigonal-planar geometry [N—C—N angles = 118.8 (3), 120.0 (3) and 121.2 (3)°] and the positive charge is delocalized in the CN3 plane. The bonds between the N atoms and the terminal C-methyl groups of the guanidinium moiety have values in the range 1.459 (4)–1.478 (4) Å, close to a typical single bond. In the crystal, there are C—H⋯π inter­actions between the guanidinium H atoms and the phenyl rings of the tetra­phenyl­borate ion. These inter­actions combine to form a ladder of linked chains of ions which runs parallel to the c axis.

Sterol metabolism disorders and neurodevelopment—an update

Cholesterol has numerous quintessential functions in normal cell physiology, as well as in embryonic and postnatal development. It is a major component of cell membranes and myelin, and is a precursor of steroid hormones and bile acids. The development of the blood brain barrier likely around 12-18 weeks of human gestation makes the developing embryonic/fetal brain dependent on endogenous cholesterol synthesis. Known enzyme defects along the cholesterol biosynthetic pathway result in a host of neurodevelopmental and behavioral findings along with CNS structural anomalies. In this article, we review sterol synthesis disorders in the pre- and post-squalene pathway highlighting neurodevelopmental aspects that underlie the clinical presentations and course of Smith-Lemli-Opitz Syndrome (SLOS), mevalonic aciduria (MVA) or the milder version hyper-immunoglobulinemia D and periodic fever syndrome (HIDS), Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1), congenital hemidysplasia with icthyosiform nevus and limb defects (CHILD) syndrome, CK syndrome, sterol C4 methyl oxidase (SC4MOL) deficiency, X-linked dominant chondrodysplasia punctata 2(CDPX2)/ Conradi Hunermann syndrome, lathosterolosis and desmosterolosis, We also discuss current controversies and share thoughts on future directions in the field.

N-[3-(Benzyldimethylazaniumyl)propyl]-N′,N′,N′′,N′′-tetramethylguanidinium bis(tetraphenylborate)

In the crystal structure of the title salt, C17H32N4 2+·2C24H20B−, the C—N bond lengths in the CN3 unit of the guanidinium ion are 1.323 (4), 1.336 (5) and 1.337 (5) Å, indicating partial double-bond character in each. The C atom of this unit is bonded to the three N atoms in a nearly ideal trigonal–planar geometry [N—C—N angles = 117.7 (4), 120.9 (3) and 121.4 (3)°] and the positive charge is delocalized in the CN3 plane. The bonds between the N atoms and the terminal C-methyl groups of the guanidinium moiety all have values close to a typical single bond [1.452 (5)–1.484 (6) Å]. In the crystal, C—H⋯π inter­actions are present between guanidinium H atoms and the phenyl rings of both tetra­phenyl­borate ions. This leads to the formation of a two-dimensional supramolecular pattern along the ab plane.

Synthesis of a highly functionalized core of verrillin.

An efficient stereoselective synthesis of furanoverrillin (5), a highly functionalized core of verrillin (1), is reported. The synthetic strategy is based on constructing bicyclic lactone 17 prior to the 10-membered ring macrocyclization. The effect of the C4 methyl group on the furan reactivity is also discussed.

Corrigendum: A Bioreducible Polymer for Efficient Delivery of Fas-Silencing siRNA into Stem Cell Spheroids and Enhanced Therapeutic Angiogenesis

The authors of this Communication unintentionally provided the incorrect recommended name “9β-presilphiperfolan-1α-ol” for the natural product isolated by König and Leitão. The correct name should instead be “9β-presilphiperfolan-1β-ol” to reflect the syn orientation of the hydroxy group relative to the C9-methyl group of the natural product. This error appears in the table-of-contents graphic, a portion of the article text, and a portion of the Supporting Information.

N,N,N′,N′-Tetramethyl-N′′-[3-(trimethylazaniumyl)propyl]guanidinium bis(tetraphenylborate) acetone disolvate

In the title solvated salt, C11H28N4 2+·2C24H20B−·2C3H6O, the C—N bond lengths in the central CN3 unit of the guanidinium ion are 1.3331 (16), 1.3407 (16) and 1.3454 (16) Å, indicating partial double-bond character in each. The central C atom is bonded to the three N atoms in a nearly ideal trigonal–planar geometry [N—C—N angles = 118.96 (11), 120.51 (12) and 120.53 (11)°] and the positive charge is delocalized in the CN3 plane. The bonds between the N atoms and the terminal C-methyl groups of the guanidinium moiety all have values close to a typical single bond [1.4601 (16)–1.4649 (16) Å]. In the crystal, the guanidinium ion is connected by N—H⋯O and C—H⋯O hydrogen bonds with the acetone mol­ecules. C—H⋯π inter­actions are present between the guanidinium H atoms and the phenyl rings of both tetra­phenyl­borate ions. The phenyl rings form aromatic pockets, in which the guanidinium ions are embedded.

Synthesis and Reactivity of Cationic Triruthenium Clusters Derived from 2‐Methyl‐ and 4‐Methylpyrimidines: From Conventional Cyclometalated Ligands to Novel Types of N‐Heterocyclic Carbenes

The methylation of the uncoordinated nitrogen atom of the cyclometalated triruthenium cluster complexes [Ru(3)(μ-H)(μ-κ(2)N(1),C(6)-2-Mepyr)(CO)(10)] (1; 2-MepyrH = 2-methylpyrimidine) and [Ru(3)(μ-H)(μ-κ(2)N(1),C(6)-4-Mepyr)(CO)(10)] (9; 4-MepyrH = 4-methylpyrimidine) gives two similar cationic complexes, [Ru(3)(μ-H)(μ-κ(2)N(1),C(6)-2,3-Me(2)pyr)(CO)(10)](+) (2(+)) and [Ru(3)(μ-H)(μ-κ(2)N(1),C(6)-3,4-Me(2) pyr)(CO)(10)](+) (9(+)), respectively, whose heterocyclic ligands belong to a novel type of N-heterocyclic carbenes (NHCs) that have the C(carbene) atom in 6-position of a pyrimidine framework. The position of the C-methyl group in the ligands of complexes 2(+) (on C(2)) and 9(+) (on C(4)) is of key importance for the outcome of their reactions with K[N(SiMe(3))(2)], K-selectride, and cobaltocene. Although these reagents react with 2(+) to give [Ru(3)(μ-H)(μ-κ(2)N(1),C(6)-2-CH(2)-3-Mepyr)(CO)(10)] (3; deprotonation of the C(2)-Me group), [Ru(3)(μ-H)(μ(3)-κ(3)N(1),C(5),C(6)-4-H-2,3-Me(2)pyr)(CO)(9)] (4; hydride addition at C(4)), and [Ru(6)(μ-H)(2){μ(6)-κ(6) N(1),N(1'),C(5),C(5'),C(6),C(6')-4,4'-bis(2,3-Me(2)pyr)}(CO)(18)] (5; reductive dimerization at C(4)), respectively, similar reactions with 9(+) have only allowed the isolation of [Ru(3)(μ-H)(μ(3)-κ(2)N(1),C(6)-2-H-3,4-Me(2)pyr)(CO)(9)] (11; hydride addition at C(2)). Compounds 3 and 11 also contain novel six-membered ring NHC ligands. Theoretical studies have established that the deprotonation of 2(+) and 9(+) (that have ligand-based LUMOs) are charge-controlled processes and that both the composition of the LUMOs of these cationic complexes and the steric protection of their ligand ring atoms govern the regioselectivity of their nucleophilic addition and reduction reactions.

What are the physiological estrogens?

Estradiol (E2) is the principal physiological estrogen in mammals. E2 and its active metabolites, estrone and estriol have a characteristic phenolic A ring, unlike progesterone, testosterone, cortisol and aldosterone, which have an A ring containing a C3-ketone, a Δ4 bond and a C19 methyl group. Crystal structures of E2 in the estrogen receptor (ER) confirm the importance of the A ring in stabilizing E2 in the ER. However, other steroids, including Δ5-androstenediol, 5α-androstanediol and 27-hydroxycholesterol, which have a saturated A ring containing a 3β-hydroxyl and a C19 methyl group, also mediate physiological responses through binding to estrogen receptor-α (ERα) and ERβ. Moreover, selective estrogen response modulators (SERMs) with diverse structures also regulate transcription of ERα and ERβ. Our understanding of the physiological responses mediated by these “alternative” estrogens is in its infancy. Further studies of the role of these steroids and SERMs in regulating responses mediated by ERα and ERβ a variety of tissues, during different stages of development, are likely to uncover additional estrogenic activities.

Dual Structure–Activity Relationship of Osteoclastogenesis Inhibitor Methyl Gerfelin Based on TEG Scanning

Methyl gerfelin derivatives, each having an amine-terminated tri(ethylene glycol) linker at the peripheral position, were designed and systematically synthesized. These "TEGylated" derivatives were then subjected to a structure-activity relationship (SAR) study to examine their glyoxalase 1-inhibition activity and binding affinity toward the three binding proteins identified. Among the derivatives synthesized, that with a NH(2)-TEG linker at the C6-methyl group showed the most potent glyoxalase 1-inhibiting activity and glyoxalase 1 selectivity. These results indicated that derivatization at the C6-methyl group would be suitable for the further development of selective glyoxalase 1 inhibitors.

Total synthesis and biological evaluation of (−)-exiguolide analogues: importance of the macrocyclic backbone

(-)-Exiguolide (1), isolated from the marine sponge Geodia exigua, has been shown to inhibit the growth of the A549 human lung adenocarcinoma and NCI-H460 human lung large cell carcinoma cells in vitro. In this study, we synthesized structural analogues of 1 to explore its skeletal structure-activity relationships and found that the C18 methyl group and the configuration of the C16-C17 double bond of 1 are important for the potent antiproliferative activity. Furthermore, we prepared a series of side-chain analogues of 1 by diversification of a late-stage intermediate of our total synthesis, and found that the triene side chain of 1 could be modified to some extent without significant loss of activity, provided a Lewis basic heteroatom is placed at the terminus.

3-[Bis(dimethylamino)methylene]-1,1-diphenylurea

In the title compound, C18H22N4O, the C=N and C—N bond lengths in the CN3 unit are 1.3179 (11), 1.3551 (11) and 1.3737 (11) Å, indicating double- and single-bond character, respectively. The N—C—N angles are 115.91 (8), 118.20 (8) and 125.69 (8), showing a deviation of the CN3 plane from an ideal trigonal–planar geometry. The bonds between the N atoms and the terminal C-methyl groups all have values close to a typical single bond [1.4529 (12)–1.4624 (12) Å]. The dihedral angle between the phenyl rings is 79.63 (4)°. In the crystal, the mol­ecules are connected via weak C—H⋯O hydrogen bonds, generating chains along [100].