We have developed two different types of tandem reactions for the synthesis of highly functionalized cyclohexenones from cyclopropyl substituted propargyl esters. Both reactions were initiated by rhodium-catalyzed Saucy-Marbet 1,3-acyloxy migration. The resulting cyclopropyl substituted allenes derived from acyloxy migration then underwent [5+1] cycloaddition with CO. The acyloxy group not only eased the access to allene intermediates but also provided a handle for further selective functionalizations.
The title compound, C8H13NO2Se, crystallizes as a non-merohedral twin with an approximate 9:1 component ratio with two symmetry-independent molecules in the asymmetric unit. Our density-functional theory (DFT) computations indicate that the carboxy C atom is expected to be slightly pyramidal due to an n→ π* interaction, wherein the lone pair (n) of the Se atom overlap with the antibonding orbital (π*) of the carbonyl group. Such pyramidalization is observed in one molecule of the title compound but not the other.
An efficient asymmetric synthesis of the 22nd amino acid L-pyrrolysine has been accomplished. The key stereogenic centers were installed by an asymmetric conjugate addition reaction. A Staudinger/aza-Wittig cyclization was used to form the acid-sensitive pyrroline ring. Pyrrolysine was synthesized in thirteen steps in 20% overall yield.
A Rh-catalyzed 1,3-acyloxy migration of propargyl ester followed by intramolecular [4 + 2] cycloaddition of vinylallene and unactivated alkyne was developed. This tandem reaction provides access to bicyclic compounds containing a highly functionalized isotoluene or cyclohexenone structural motif, while only aromatic compounds were observed in related transition metal-catalyzed cycloadditions.
Quasiracemic crystallization has been used to obtain high-resolution structures of two variants of the villin headpiece subdomain (VHP) that contain a pentafluorophenylalanine (F5Phe) residue in the hydrophobic core. In each case, the crystal contained the variant constructed from L-amino acids and the native sequence constructed from D-amino acids. We were motivated to undertake these studies by reports that racemic proteins crystallize more readily than homochiral forms, and the prospect that quasiracemic crystallization would enable us to determine whether a polypeptide containing a non-canonical residue can closely mimic the tertiary structure of the native sequence. The results suggest that quasiracemic crystallization may prove to be generally useful for assessing mimicry of naturally evolved protein folding patterns by polypeptides that contain unnatural side chain or backbone subunits.
Racemic Protein Crystallization; Quasiracemic Proteins; Unnatural Amino Acids; Pentafluorophenylalanine; Villin Headpiece Subdomain
alkenynes; cycloaddition; cycloisomerization; polycycles; rhodium
Peptoids, or oligomers of N-substituted glycines, are a class of foldamers that have shown extraordinary functional potential since their inception nearly two decades ago. However, the generation of well-defined peptoid secondary structures remains a difficult task. This challenge is due, in part, to the lack of a thorough understanding of peptoid sequence-structure relationships and consequently, an incomplete understanding of the peptoid folding process. We seek to delineate sequence-structure relationships through the systematic study of noncovalent interactions in peptoids and the design of novel amide side chains capable of such interactions. Herein, we report the synthesis and detailed structural analysis of a series of (S)-N-(1-naphthylethyl)glycine (Ns1npe) peptoid homooligomers by X-ray crystallography, NMR and circular dichroism (CD) spectroscopy. Four of these peptoids were found to adopt well-defined structures in the solid state, with dihedral angles similar to those observed in polyproline type I (PPI) peptide helices and in peptoids with α-chiral side chains. The X-ray crystal structure of a representative Ns1npe tetramer revealed an all cis-amide helix, with approximately three residues per turn, and a helical pitch of approximately 6.0 Å. 2D-NMR analysis of the length-dependent Ns1npe series showed that these peptoids have very high overall backbone amide Kcis/trans values in acetonitrile, indicative of conformationally homogeneous structures in solution. Additionally, CD spectroscopy studies of the Ns1npe homooligomers in acetonitrile and methanol revealed a striking length-dependent increase in ellipticity per amide. These Ns1npe helices represent the most robust peptoid helices to be reported, and the incorporation of (S)-N-(1-naphthylethyl)glycines provides a new approach for the generation of stable helical structure in this important class of foldamers.
N-hydroxy amides can be found in many naturally occurring and synthetic compounds and are known to act as both strong proton donors and chelators of metal cations. We have initiated studies of peptoids, or N-substituted glycines, that contain N-hydroxy amide side chains to investigate the potential effects of these functional groups on peptoid backbone amide rotamer equilibria and local conformations. We reasoned that the propensity of these functional groups to participate in hydrogen bonding could be exploited to enforce intramolecular or intermolecular interactions that yield new peptoid structures. Here, we report the design, synthesis, and detailed conformational analysis of a series of model N-hydroxy peptoids. These peptoids were readily synthesized, and their structures were analyzed in solution by 1D and 2D NMR and in the solid-state by X-ray crystallography. The N-hydroxy amides were found to strongly favor trans conformations with respect to the peptoid backbone in chloroform. More notably, unique sheet-like structures held together via intermolecular hydrogen bonds were observed in the X-ray crystal structures of an N-hydroxy amide peptoid dimer, which to our knowledge represent the first structure of this type reported for peptoids. These results suggest that the N-hydroxy amide can be utilized to control both local backbone geometries and longer-range intermolecular interactions in peptoids, and represents a new functional group in the peptoid design toolbox.
We report crystallographic data for a set of homologous γ-peptides that contain a Boc-protected residue derived from the flexible gabapentin monomer at the N-terminus and cyclically constrained γ-residues at all other positions. The crystallized γ-peptides range in length from 3 to 7 residues. Previously only one atomic-resolution structure had been available for a short γ-peptide 14-helix. The new data provided here allow derivation of characteristic parameters for the γ-peptide 14-helix, and establish guidelines for characterizing 14-helical folding in solution via 2D NMR. In addition, the results suggest that the substitution pattern of a γ-residue has a profound effect on the propensity for 14-helical folding.
γ-peptides; 14-helix; H-bond; backbone; NOE
The title compound, C38H30N4, a potentially mono- and bidentate ligand, does not seem to form palladium complexes similar to other poly(pyrazol-1-ylmethyl)benzenes due to the large steric size of the phenyl substituents on the pyrazole rings. The pyrazole rings have a 21.09 (5)° angle between their mean planes and exhibit a trans-like geometry in which the in-plane lone pairs of electrons on the 2-N nitrogen atoms point in opposite directions.
The angles within the benzene ring in the title compound, C30H49N3O, ranging from 116.34 (16) to 124.18 (16)°, reflect the presence of electron-donating and electron-withdrawing substituents. The angles at the two electron-donating tert-butyl substituents are smaller than 120°, at the electron-withdrawing ethoxy substituent larger than 120°, and at the imine substituent equal to 119.59 (16)°. The latter does not reflect the electron-donating nature of the imine group due to the presence of other substituents.
The title compound, C21H17N3, crystallizes with the phenyl ring in the 3-position coplanar with the pyrazole ring within 4.04 (5)°, whereas the phenyl ring in the 5-position forms a dihedral angle of 50.22 (3)° with the pyrazole ring. There is no ambiguity regarding the position of pyridine N atom, which could have exhibited disorder between the ortho positions of the ring.
Photocatalytic reactions of enones using metal polypyridyl complexes proceed by very different reaction manifolds in the presence of either Lewis or Brønsted acid additives. Previous work from our lab demonstrated that photocatalytic [2+2] cycloadditions of enones required the presence of a Lewis acidic co-catalyst, presumably to activate the enone and stabilize the key radical anion intermediate. On the other hand, Brønsted acid activators alter this reactivity and instead promote reductive cyclization reactions of a variety of aryl and aliphatic enones via a neutral radical intermediate. These two distinct reactive intermediates give rise to transformations differing in the connectivity, stereochemistry, and oxidation state of their products. In addition, this reductive coupling method introduces a novel approach to the tin-free generation of β-ketoradicals that react with high diastereoselectivity and with the high functional group compatibility typical of radical cyclization reactions.
The title compound, [Fe(C5H5)(C17H16N3O2)], crystallizes with an essentially eclipsed conformation of the cyclopentadienyl (Cp) rings. The unsubstituted ring is disordered over two positions with the major component being present 90 (1)% of the time. The substituted Cp ring, the pyrazole ring and three atoms of the ethoxycarbonyl group form a conjugated π-system. These 13 atoms are coplanar within 0.09 Å.
The title compound, C28H30N2, is a symmetrical 2:2 product from the condensation of indole and cyclohexanone. It is the only reported 5,11-dihydroindolo[3,2-b]carbazole compound in which the spiro atoms are quaternary C atoms. Crystals were grown by vapor diffusion in a three-zone electric furnace. The molecule resides on a crystallographic inversion center. The cyclohexyl rings are in a slightly distorted chair conformation, whereas the indole units and the spiro-carbons are coplanar within 0.014 Å.
aminohydroxylation; chiral auxiliaries; copper; indoles; oxaziridines
EuS nanocrystals (NCs) were doped with Gd resulting in an enhancement of their magnetic properties. New EuS and GdS single source precursors (SSPs) were synthesized, characterized, and employed to synthesize Eu1-xGdxS NCs by decomposition in oleylamine and trioctylphosphine at 290 °C. The doped NCs were characterized using X-ray diffraction, transmission electron miscroscopy and scanning transmission electron microscopy, which supports the uniform distribution of Gd dopants through electron energy loss spectroscopy (EELS) mapping. X-ray absorption spectroscopy (XAS) revealed the dopant ions in Eu1-xGdxS NCs to be predominantly Gd3+. NCs with a variety of doping ratios of Gd (0 ≤ x < 1) were systematically studied using vibrating sample magnetometry and the observed magnetic properties were correlated with the Gd doping levels (x) as quantified with ICP-AES. Enhancement of the Curie temperature (TC) was observed for samples with low Gd concentrations (x ≤ 10 %) with a maximum TC of 29.4 K observed for NCs containing 5.3 % Gd. Overall, the observed TC, Weiss temperature (θ), and hysteretic behavior correspond directly to the doping level in Eu1-xGdxS NCs and the trends qualitatively follow those previously reported for bulk and thin film samples.
EuS; nanocrystals; magnetism; magnetic semiconductor; spintronics; doping
The title zinc complex, [ZnCl2(C18H22N4)], contains a bidentate 1,2-bis(3,5-dimethyl-1H-pyrazol-1-ylmethyl)benzene ligand that binds to the zinc atom, forming a nine-membered metallocyclic ring. The geometry about the Zn atom is distorted tetrahedral, with the largest deviation observed in the magnitude of the Cl—Zn—Cl angle. Similar distortions are observed in the cobalt analogue and related zinc compounds containing metallocyclic rings with more than six members. The copper analogue exhibits a more severe distortion of the metal coordination sphere than is observed in the title compound.
Pd-catalyzed C–H oxidation reactions often require the use of oxidants other than O2. Here, we demonstrate a ligand-based strategy to replace benzoquinone with O2 as the stoichiometric oxidant in Pd-catalyzed allylic C–H acetoxylation. Use of 4,5-diazafluorenone (1) as an ancillary ligand for Pd(OAc)2 enables terminal alkenes to be converted to linear allylic acetoxylation products in good yields and selectivity under 1 atm O2. Mechanistic studies reveal that 1 facilitates C–O reductive elimination from a π-allyl-PdII intermediate, thereby eliminating the requirement for benzoquinone in this key catalytic step.
In the title compound, [Au2(C6H8N2S4)(C18H15P)4]·2CHCl3, the digold complex resides on a crystallographic inversion center and co-crystallizes with two molecules of chloroform solvent. The piperazine-1,4-dicarbodithioate linker has an almost ideal chair conformation. The geometry about the gold atoms is severely distorted tetrahedral punctuated by a very acute S—Au—S bite angle.
The amine title complex, [ZnCl2(C7H13N3)], resulted from imine hydrolysis in a Schiff base compound. The Zn metal atom has a distorted tetrahedral geometry with the most significant deviation identified in the magnitude of the N—Zn—N angle. This deviation stems from the participation of the Zn and N atoms in a six-membered metallocyclic ring. The latter is in an approximate screw-boat conformation. Two strong N—H⋯Cl hydrogen bonds link the molecules into ribbons propagating along the b-axis direction. The ribbons contain two second-order hydrogen-bonded motifs: a chain and a ring. The chain described by the graph set notation C
2(6) is formed by one hydrogen bond going in the forward direction (donor to acceptor) and the other in the backward direction (acceptor to donor). In the ring motif R
2(8), both hydrogen bonds propagate in the forward direction.
Helices are the most extensively studied secondary structures formed by β-peptide foldamers. Among the five known β-peptide helices, the 12-helix is particularly interesting because the internal hydrogen bond orientation and macrodipole are analogous to those of α-peptide helices (α-helix and 310-helix). The β-peptide 12-helix is defined by i, i+3 C=O…H-N backbone hydrogen bonds and promoted by β-residues with a five-membered ring constraint. The 12-helical scaffold has been used to generate β-peptides with specific biological functions, for which diverse side chains must be properly placed along the backbone and, upon folding, properly arranged in space. Only two crystal structures of 12-helical β-peptides have previously been reported, both for homooligomers of trans-2-aminocyclopentanecarboxylic acid (ACPC). Here we report five additional crystal structures of 12-helical β-peptides, all containing residues that bear side chains. Four of the crystallized β-peptides include trans-4,4-dimethyl-2-aminocyclopentanecarboxylic acid (dm-ACPC) residues, and the fifth contains a β3-hPhe residue. These five β-peptides adopt fully folded 12-helical conformations in the solid state. The new crystal structures, along with previously reported data, allow a detailed characterization of the 12-helical conformation; average backbone torsion angles of β-residues and helical parameters are derived. These structural parameters are found to be similar to those for i, i+3 C=O…H-N hydrogen-bonded helices formed by other peptide backbones generated from α- and/or βamino acids. The similarity between the conformational behavior of dm-ACPC and ACPC is consistent with previous NMR-based conclusions that 4,4-disubstituted ACPC derivatives are compatible with 12-helical folding. In addition, our data show how a β3-residue is accommodated in the 12-helix, thus enhancing understanding of the diverse conformational behavior of this flexible class of β-amino acids.
The ability to design foldamers that mimic the defined structural motifs of natural biopolymers is critical for the continued development of functional biomimetic molecules. Peptoids, or oligomers of N-substituted glycine, represent a versatile class of foldamers capable of folding into defined secondary and tertiary structures. However, the rational design of discretely folded polypeptoids remains a challenging task, due in part to an incomplete understanding of the covalent and noncovalent interactions that direct local peptoid folding. We have found that simple, peptoid monomer model systems allow for the effective isolation of individual interactions within the peptoid backbone and side chains, and can facilitate the study of the role of these interactions in restricting local peptoid conformation. Herein, we present an analysis of a set of peptoid monomers and an oligomer containing N-aryl side chains capable of hydrogen bonding with the peptoid backbone. These model peptoids were found to exhibit well-defined local conformational preferences, allowing for control of the ω, φ, and ψ dihedral angles adopted by the systems. Fundamental studies of the peptoid monomers enabled the design and synthesis of an acyclic peptoid reverse-turn structure, in which N-aryl side chains outfitted with ortho-hydrogen bond donors were hypothesized to play a critical role in the stabilization of the turn. This trimeric peptoid was characterized by X-ray crystallography and 2D NMR spectroscopy, and was shown to adopt a unique acyclic peptoid reverse-turn conformation. Further analysis of this turn revealed an n→π*C=O interaction within the peptoid backbone, which represents the first reported example of this type of stereoelectronic interaction occurring exclusively within a polypeptoid backbone. The installation of N-aryl side chains capable of hydrogen bonding into peptoids is straightforward and entirely compatible with current solid-phase peptoid synthesis methodologies. As such, we anticipate that the strategic incorporation of these N-aryl side chains should facilitate the construction of peptoids capable of adopting discrete structural motifs, both turn-like and beyond, and will facilitate the continued development of well-folded peptoids.
Prolyl 4-hydroxylases install a hydroxyl group in the 4R configuration on the γ-carbon atom of certain (2S)-proline (Pro) residues in tropocollagen, elastin, and other proteins and other proteins to form (2S,4R)-4-hydroxyproline (Hyp). The gauche effect arising from this prevalent post-translational modification enforces a Cγ-exo ring pucker and stabilizes the collagen triple helix. The Hyp diastereomer (2S,4S)-4-hydroxyproline (hyp) has not been observed in a protein, despite the ability of electronegative 4S substituents to enforce the more common Cγ-endo ring pucker of Pro. Here, we use density functional theory, spectroscopy, crystallography, and calorimetry to explore the consequences of hyp incorporation on protein stability using a collagen model system. We find that the 4S-hydroxylation of Pro to form hyp does indeed enforce a Cγ-endo ring pucker, but a transannular hydrogen bond between the hydroxyl moiety and the carbonyl of hyp distorts the main-chain torsion angles that typically accompany a Cγ-endo ring pucker. This same transannular hydrogen bond enhances an n→π* interaction that stabilizes the trans conformation of the peptide bond preceding hyp, endowing hyp with the unusual combination of a Cγ-endo ring pucker and high trans:cis ratio. O-Methylation of hyp to form (2S,4S)-4-methoxyproline (mop) eliminates the transannular hydrogen bond and restores a prototypical Cγ-endo pucker. mop residues endow the collagen triple helix with much more conformational stability than do hyp residues. These findings highlight the critical importance of the configuration of the hydroxyl group installed on Cγ of proline residues.
We report the first high-resolution structural data for the
C=O···H-N H-bonds), a secondary structure that
is formed by oligomers with a 1:1 alternation of β- and γ-amino
acid residues. Our characterization includes both crystallophaphic and 2D NMR
data. Previous studies suggested that β/γ-peptides constructed
from conformationally flexible residues adopt a different helical secondary
structure in solution. Our design features preorganized β- and
γ-residues, which strongly promote 13-helical folding by the