Ring Junction Research Articles

Ring‐Closing Metathesis of C‐Terminal Allylglycine Residues with an N‐Terminal β‐Vinyl‐Substituted Phosphotyrosyl Mimetic as an Approach to Novel Grb2 SH2 Domain‐Binding Macrocycles

Ring-closing metathesis (RCM) of peptides often requires insertion of allylglycines at the intended sites of ring juncture, which can result in the displacement of residues that are needed for biological activity. This type of side-chain deletion can be avoided by appending beta-vinyl substituents onto the parent residues at the intended sites of ring juncture, thereby effectively converting them into functionalized allylglycine equivalents. Such an approach has been previously applied in modified form to growth-factor receptor bound 2 (Grb2) SH2 domain-binding peptides by using an N-terminal beta-vinyl-functionalized phosphotyrosyl mimetic and C-terminal 2-allyl-3-aryl-1-propanamides that lacked the alpha-carboxyl portion of allylglycine residues. These C-terminal moieties involved lengthy synthesis and once prepared, required an individual total synthesis of each final macrocycle. Work reported herein significantly enhances the versatility of the original approach through the use of C-terminal allylglycine amides that can be prepared from commercially available L- and D-allylglycines and suitable amines. This methodology could be generally useful where macrocylization is desired with maintenance of functionality at a site of ring juncture.

Imino Diels–Alder adducts. II. Two pyrano[3,2-c]quinolines

8-Chloro-9-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline and 10-chloro-9-fluoro-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline, both C18H17ClFNO, are diastereoisomers, formed as the result of the imino Diels-Alder reactions of N-benzylideneanilines with 3,4-dihydro-2H-pyran. The crystal structures reveal the stereochemistry of the pyran ring, which is endo/exo to the quinoline ring system formed in the cycloaddition step. In both structures, the pyran ring adopts a chair conformation, while the nitrogen-containing heterocyclic ring prefers a half-chair conformation. The structures differ essentially in the relative orientation of the ring junction H atoms.

Utilization of a Common Pathway for the Synthesis of High Affinity Macrocyclic Grb2 SH2 Domain-Binding Peptide Mimetics That Differ in the Configuration at One Ring Junction

As typified by 2-{(9S,10S,14R,18S)-18-(2-amino-2-oxoethyl)-14-[(5-methyl-1H-indol-1-yl)methyl]-8,17,20-trioxo-10-[4-(phosphonomethyl)phenyl]-7,16,19-triazaspiro[5.14]icos-11-en-9-yl}acetic acid ((14R)-1b), ring-closing methathesis-derived macrocyclic tetrapeptide mimetics have recently been reported that bind with high affinity to Grb2 SH2 domains in both extracellular and whole-cell assays. The synthetic complexity of this class of agents limits further therapeutic development. Although a significant component of this synthetic complexity arises from the presence of three stereogenic centers, C(9) (S), C(10) (S), and C(14) (R), it is unclear whether stereoselective introduction of defined configuration at C(14) is required for high-affinity binding. Reported herein is a synthetic route to these macrocycles lacking stereoselectivity in the formation of the C(14) ring junction, which is four synthetic steps shorter than the original stereoselective synthesis. Separation of C(14)-epimers obtained by this approach was achieved by preparative HPLC. Molecular-dynamics studies of ligands bound to the Grb2 SH2 domain protein indicated that the (14R)-configuration should display more-favorable interactions with the protein relative to the (14S)-epimer. Indeed, although surface-plasmon-resonance-derived binding constants to Grb2 SH2 domain protein indicated that the affinity of the (14R)-epimer (KD = 4.8 nM) is greater than that of the (14S)-epimer (KD = 11 nM), it is only marginally so. Therefore, little affinity would be lost through a non-stereoselective synthesis of the C(14)-center. Further studies are in progress to explore reduced structural complexity at the C(14)-center.

17-Oxo-5β-hydroxyandrostan-3β-yl acetate

The title compound, C21H32O4 crystallizes in a triclinic unit cell, which is very unusual for steroids. The asymmetric unit contains two independent mol­ecules with almost identical geometry, although they are slighly twisted in opposite directions. These mol­ecules form a dimer inter­connected via hydrogen bonds. Both mol­ecules have a cis A/B ring junction characteristic of a 5β-configuration, but differ in the orientation of their hydroxyl groups.

5-Methoxyspiro[1-benzofuran-2(3H),2′-chroman

The crystal structure of the title compound, C17H16O3, has been determined to establish the relative stereochemistry at the spiro ring junction. Both O atoms adjacent to the junction adopt axial positions because of anomeric effects.

Structures of pyrido[1,2a]pyrazinium and pyrido[1,2c][1,4]oxazinium bromides studied by 1H, 13C and 15N NMR, FTIR, X-ray and DFT methods

2-R-Pyridines (R CN, CH NOH and COMe) with phenacyl bromide gave the corresponding quaternary bicyclic ring system containing one ring junction nitrogen and one extra nitrogen or oxygen atom ( 1– 3). Their structures were confirmed by 1H, 13C and 15NMR spectra in DMSO-d 6 solution using 2D NMR techniques (COSY, NEOSY, HETCOR and HMBC). The structure of 1-oxo-3-phenyl-pyrido[1,2a]pyrazinium bromide monohydrate, 1, was unambiguously confirmed by X-ray crystallography. The crystals of 1 are monoclinic, space group P2 1/ n, with a=7.730(2) Å, b=14.094(3) Å, c=12.553(3) Å, β=106.18(3)°, V=1311.3(5) Å 3 and Z=4 (at 110 K). The isolated entities of 1– 3 were analyzed by the B3LYP/6-31G(d,p) level of theory in order to get information on the electrostatic interaction between the oppositely charged groups.

21-Acetoxy-17α-4-pregnene-3,20-dione

The synthetic steroid 21-acetoxy-17α-4-pregnene-3,20-dione, C 23H32O4, crystallizes with a single molecule in the asymmetric unit. The molecule contains four fused rings, typical of steroids. The cyclohexene ring A has nearly the conformation of a boat. One saturated six-membered ring, B, is intermediate between chair and half-chair conformations, while the other six-membered ring, C, is essentially a chair. The five-membered ring D tends towards a twist conformation. The ring junction A/B is quasi-trans, whereas the ring junctions B/C and C/D are both trans. The molecule is slightly convex towards the β side.

21-Deoxycortisone (17α-hydroxy-4-pregnene-3,11,20-trione)

The title compound, C21H28O4, a synthetic glucocorticoid, crystallizes with a single molecule in the asymmetric unit. Ring A is almost in a half-chair conformation, rings B and C are almost in chair conformations, and ring D is between a twist and a 13beta-envelope conformation. The A/B ring junction is quasi-trans, whereas the B/C and C/D ring junctions both approach trans characteristics. The molecule as a whole is slightly convex towards the beta side, with an angle of 9.60 (2) degrees between the C10-C19 and C13-C18 vectors. Molecular-packing and hydrogen-bonding (both intra- and intermolecular) interactions play a major role in the structural association of the compound.

Sterol stringency of proliferation and cell cycle progression in human cells

Cholesterol is a major component of the plasma membrane in mammalian cells, where it acts as a modulator of bulk physical state and integrity. In addition to its structural role, cholesterol is essential for proliferation and other cell processes. The present study was undertaken to explore the stringency of the requirement for cholesterol as a regulator of proliferation and cell cycle progression. Comparisons were made between cholesterol and other sterol analogs that differ from cholesterol in three specific elements: the presence of a Δ 5 double bond in ring B, the hydroxyl group at C-3, and the presence of an aliphatic side chain. The human leukemia cells HL-60 and MOLT-4 were cultured in cholesterol-free medium and treated with different sterols in the presence or absence of SKF 104976, a competitive inhibitor of lanosterol 14α-demethylase that allows the synthesis of isoprenoid derivatives but not cholesterol. Our results show that the β-hydroxyl group at C-3 and the unsaturated bond at Δ 5 are necessary for cell proliferation and cell cycle progression. The sterol analog 5α-cholestan-3β-ol (dihydrocholesterol), which is saturated at Δ 5 and has an A/B ring junction in the trans configuration, was also able to support cell growth. However, 5β-cholestan-3β-ol and 5β-cholestan-3α-ol, both of which have an A/B ring junction in the cis configuration, were totally ineffective in supporting cell growth. Indeed, they produced an inhibition of cell proliferation and arrested the cell cycle specifically in the G2/M phase. These effects of 5β-cholestanols were abrogated by cholesterol in a concentration-dependent manner. Moreover, 5β-cholestanols potently inhibited cholesterol biosynthesis and transcription driven by the sterol response element. In addition to providing a description of the structural features of sterols associated with their supporting action on cell proliferation in mammalian cells, the present results demonstrate that selected cholesterol analogs may act as cytostatic agents, interrupting cell cycle progression specifically in the G2/M phase.

A ring-closing metathesis route to 7-membered aza-heteroannulated sugars

Azepane rings have been constructed diastereoselectively upon a carbohydrate derivative utilising reductive amination and RCM. The stereochemistry of the ring junctions was confirmed by X-ray crystallography and NMR. Diastereoselective dihydroxylation has also been employed to afford a tetrahydroxylated azepane carbohydrate derivative with potential biological activity.

Total syntheses of the sesquiterpenoids (+)- trans-dracunculifoliol and (+)-4-hydroxyoppositan-7-one

Sesquiterpenoids (+)- trans-dracuncuflifoliol ( 1 ) and (+)-4-hydroxyoppositan-7-one ( 2 ) were prepared stereoselectively from enantiomerically pure (7a R)-7a-methyl-1,2,5,6,7,7a-hexahydro-4 H-inden-4-one ( (−)- 6 ), whose synthesis was described herein. Conjugate addition of the organocopper (I) reagent 10 to (−)- 6 , followed by epimerization of the ring junction, generated 3 of the 4 contiguous chiral centers of both natural products.

Synthesis and DNA binding properties of novel benzo[b]isoquino[2,3-h]-naphthyridines

Several benzo[b]isoquino[2,3-h]-naphthyridines have been prepared via formal hetero-Diels Alder reaction of N-aryl imines as a key step. These compounds have different side chains at C-11, and a cis or trans configuration at the C-8a,C-14a ring junction. Binding constants for the interaction with oligonucleotides and polynucleotides were determined by UV absorption and melting experiments. NMR experiments (NOE) revealed that the cis isomers, showing a slightly folded structure, preferentially bind to the minor groove of AT-rich oligomers. In contrast, the trans isomers prefer the CG-rich sequences, leading to cap-complexes with the isoquinoline moiety stacked at the top of the double helix, in agreement with the flatter shape, and with a preference for the 3'-terminals, as found for camptothecins. Models of the complexes were built up by molecular dynamics (MD) calculations, by using the inter-proton distances derived from the NOE values. Cytotoxicity assays against human Ewing sarcoma cell lines RD-ES and CAD-ES1 were performed.

An Asymmetric Formal Synthesis of Fasicularin

An asymmetric formal synthesis of fasicularin (1) is described. This natural product, isolated from the extracts of the marine invertebrate Nephteis fasicularis, has shown modest cytotoxicity towards Vero cells. Fasicularin is among only two members of the cylindricine family of natural products, along with lepadiformine (2), to possess a trans A-B ring junction. Key steps of this approach to 1 involve a siloxy-epoxide semipinacol rearrangement of 5 to 6, a B-alkyl Suzuki-Miyaura coupling reaction by using enol trifluoromethanesulfonate 19 and a substrate-directed hydrogenation reaction of 24. This formal synthesis also highlights the difficulty in the incorporation of the thiocyanate functionality present in 1.

Studies Toward the Total Synthesis of Wiedemannic Acid.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Antibacterial and resistance modifying activity of Rosmarinus officinalis

As part of a project to characterise plant-derived natural products that modulate bacterial multidrug resistance (MDR), bioassay-guided fractionation of a chloroform extract of the aerial parts of Rosmarinus officinalis led to the characterisation of the known abietane diterpenes carnosic acid ( 1), carnosol ( 2) and 12-methoxy- trans-carnosic acid. Additionally, a new diterpene, the cis A/B ring junction isomer of 12-methoxy- trans-carnosic acid, 12-methoxy- cis-carnosic acid ( 5), was isolated. The major components were assessed for their antibacterial activities against strains of Staphylococcus aureus possessing efflux mechanisms of resistance. Minimum inhibitory concentrations ranged from 16 to 64 μg/ml. Incorporation of 1 and 2 into the growth medium at 10 μg/ml caused a 32- and 16-fold potentiation of the activity of erythromycin against an erythromycin effluxing strain, respectively. Compound 1 was evaluated against a strain of S. aureus possessing the NorA multidrug efflux pump and was shown to inhibit ethidium bromide efflux with an IC 50 of 50 μM, but this activity is likely to be related to the inhibition of a pump(s) other than NorA. The antibacterial and efflux inhibitory activities of these natural products make them interesting potential targets for synthesis.

Stemmosides C and D, two novel unusual pregnane glycosides from Solenostemma argel: structural elucidation and configurational study by a combined NMR-quantum mechanical strategy

Stemmosides C and D, two novel pregnane glycosides characterized by an unusual C-17α side chain were isolated from the pericarps of Solenostemma argel. In addition, stemmoside D displays an uncommon 14β proton configuration, apparently being the first pregnane isolated from plants known to have a 15 keto, cis CD ring junction. Their structures have been established by ESIMS and NMR experiments. The relative configuration of the molecules was determined using a strategy based on the simulation of 1H, 13C, and J coupling NMR parameters. DFT calculations of 1H and 13C chemical shifts, and of the 1H homonuclear spin–spin coupling constants were performed with the mPW1PW91 functional using the 6-31G(d,p) basis set on the fully optimized geometries of all the possible stereoisomers.

Theoretical studies of structures and stabilities of a new odd-numbered fullerene dimer: C141.

The possible isomers of a newly synthesized C(141) molecule are calculated using MNDO, AM1, PM3, B3LYP/3-21G, and B3LYP/6-31G(d) methods. The geometry optimizations showed that the isomer 8-8 has the lowest total energy in all 64 possible structures of C(141). Unlike those of C(130), C(140), etc., the C(141) 8-8 shows a new structure: two C(70) side cages open [6.6] ring junctions located at the equator (instead of cap) area to create new chemical bonds for the bridge atom. Theoretical measurements of the average length of the long and short axes of C(70) side cages in the C(141) molecule reveal that when two C(70) cages are connected with each other at the equators, their geometric shapes become more spherical compared with the pristine C(70); this leads to a reduction of the molecular polarizability. Analysis of the local and global strain indicates that the global strain of C(70) monomer in the C(141) 8-8 is greatly reduced compared to the pristine C(70). The stable C(70) derivatives that are formed with reacted C-C bonds in the equator area may put new insights into fullerene chemistry, in particular, for C(70) to react with a large molecule. The results are discussed together with the experimental data.

Formal Total Synthesis of Hemibrevetoxin B by a Convergent Strategy.

Concise construction of the trans-fused 7/7/6/6 tetracyclic ether part of hemibrevetoxin B (1) was achieved by a convergent strategy based on coupling reaction of an acyl anion equivalent, reductive cyclization of an α,e-dihydroxyketone, and introduction of a methyl group at the central ring junction by the Nicolaou method. The resultant tetracyclic ether was transformed into the known intermediate, which was already converted to 1 by the Yamamoto group, thereby completing the formal total synthesis of 1.

Studies toward the total synthesis of Wiedemannic acid.

[reaction: see text] We report a novel and efficient diastereoselective synthesis of wiedemannic acid analogue 30 in 16 steps from 7 using a tandem oxy-Cope/Claisen/ene reaction as the key step. Comparison of NMR data between wiedemannic acid (1) and analogue 30 leads us to believe that the reported stereochemistry at the ring junction of 1 is incorrect.

Synthesis and structure determination of 3 -hydroxyandrost-5-en-17-one (C19H28O2·CH3OH)

3β-Hydroxyandrost-5-en-17-one (C19H28O2.CH3OH) has been prepared for undertaking its crystallographic analysis and to investigate the role of intra- and intermolecular interactions in steroids. The title compound crystallizes in the orthorhombic space group C2221 with unit cell parameters a = 6.7892(17), b = 12.624(2), and c = 41.136(5) A; V = 3525.7(12) A3 and Z = 8. The three-dimensional structure has been solved by direct methods. The final reliability index for the computed structure is 0.050 for 1088 observed reflections. Ring A exist in chair conformation, Ring B in half-chair conformation, and the Ring C assumes a distorted chair conformation. The five-membered Ring D adopts half-chair conformation. The A/B ring junction is quasi-trans while as B/C and C/D are trans-fused. The oxygen atom of the solvent molecule (CH3OH) is involved in O–H···O intermolecular interaction.