Efficient Synthesis of the C1‐C9 Fragment of 7,8‐O‐Isopropylidene Protected Iriomoteolide 3a Derivative

An efficient and stereoselective synthesis of the C1‐C9 moiety of the 7,8‐O‐isopropylidene protected iriomoteolide 3a derivative has been accomplished. In our strategy, we employed olefin cross‐metathesis of the L‐(+)‐tartaric acid derivative (((4S,5S)‐2,2‐dimethyl‐5‐vinyl‐1,3‐dioxolan‐4‐yl)methoxy)(tert‐butyl)diphenylsilane with a synthesized methyl (S)‐3‐methylhex‐5‐enate to successfully provide the correct olefin geometry of the desired fragment.     

Enantiospecific Formal Total Synthesis of Iriomoteolide 3a

A formal total synthesis of the marine macrolide iriomoteolide 3a is described. Salient features of the synthesis include the elaboration of a β‐keto phosphonate derived from D ‐(?)‐tartaric acid and the extension of a chiral butyrolactone derived from L ‐glutamic acid. Ring‐closing metathesis is employed to construct the macrolactone core of the natural product.     

Stereoselective synthesis of the C(1)-C(12) segment of iriomoteolide 1a: a very potent macrolide antitumor agent

A stereoselective synthesis of the C(1)-C(12) segment of the potent cytotoxic macrolide, iriomoteolide 1a, has been accomplished. The key steps involve an enzymatic kinetic resolution of a β-hydroxy amide, a Pd-catalyzed cross-coupling to a substituted allylsilane, a highly regio- and stereoselective conjugate addition of lithium dimethylcopper to an α, β-acetylenic esters and an elaboration of the C(6)-C(7) trans-olefin geometry by a Julia-Kocienski olefination.     

Synthesis of the C1-C12 fragment of iriomoteolide 1a by sequential catalytic asymmetric vinylogous aldol reactions

An efficient synthesis of the C1-C12 fragment of iriomoteolide 1a has been accomplished via sequential application of two catalytic, asymmetric, vinylogous aldol reactions: a catalytic vinylogous aldol reaction was used to enantioselectively introduce the C5-C8 segment, and a second catalytic vinylogous aldol reaction was used to install the remaining two stereocenters and a stereodefined alkene in the form of an alpha,beta-unsaturated delta-lactone in one step.     

Stereoselective synthesis of the C1-C12 segment of iriomoteolide-1a: a very potent macrolide antitumor agent

A stereoselective synthesis of the C₁-C₁₂ segment of the potent cytotoxic macrolide, iriomoteolide 1a, has been accomplished. The key steps involve an enzymatic kinetic resolution of a β-hydroxy amide, a Pd-catalyzed cross-coupling to construct a substituted allylsilane, a highly and stereoselective conjugate addition of lithium dimethylcopper to an α,β-acetylenic ester and an elaboration of the C₆-C₇ trans-olefin geometry by a Julia-Kocienski olefination.     

Enantioselective synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a

Synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a has been accomplished. Key steps include a cross metathesis to form the C15-C16 E olefin and a chelation controlled Grignard addition to form the tertiary alcohol at C14. Notably, 7 of the 9 stereocenters of the proposed structure have been set using various aldol reactions employing metallo enolates of thiazolidinethiones.     

Correct Modeling of Cisplatin: a Paradigmatic Case

Quantum chemistry is a useful tool in modern approaches to drug and material design, but only when the adopted model reflects a correct physical picture. Paradigmatic is the case of cis ‐diaminodichloroplatinum(II), cis ‐[Pt(NH₃)₂Cl₂], for which the correct simulation of the structural and vibrational properties measured experimentally still remains an open question. By using this molecule as a proof of concept, it is shown that state‐of‐the‐art quantum chemical calculations and a simple model, capturing the basic physical flavors, a cis ‐[Pt(NH₃)₂Cl₂] dimer, can provide the accuracy required for interpretative purposes. The present outcomes have fundamental implications for benchmark studies aiming at assessing the accuracy of a given computational protocol.     

A Cascade Strategy Enables a Total Synthesis of (±)‐Morphine

Morphine has been a target for synthetic chemists since Robinson proposed its correct structure in 1925, resulting in a large number of total syntheses of morphine alkaloids. Here we report a total synthesis of (±)‐morphine that employs two key strategic cyclizations: 1) a diastereoselective light‐mediated cyclization of an O‐arylated butyrolactone to form a tricyclic cis‐fused benzofuran and 2) a cascade ene–yne–ene ring closing metathesis to forge the tetracyclic morphine core. This approach enables a short and stereoselective synthesis of morphine in an overall yield of 6.6 %.     

1,3‐Dimethyl­isoguanine

The structure of 1,3‐dimethyl­isoguanine [or 6‐amino‐1,3‐dimethyl‐1H‐purin‐2(3H)‐one], C₇H₉N₅O, has been redetermined and the correct assignment of H atoms on the heterocycle is now reported. Inter­molecular hydrogen‐bonding inter­actions confirm that this form is the correct mol­ecular structure; this form is also in agreement with an earlier reported structure of the trihydrate form.     

Influence of the Delocalization Error and Applicability of Optimal Functional Tuning in Density Functional Calculations of Nonlinear Optical Properties of Organic Donor–Acceptor Chromophores

Nonempirically tuned hybrid density functionals with range‐separated exchange are applied to calculations of the first hyperpolarizability (β_∥) and charge‐transfer (CT) excitations of linear “push–pull” donor–acceptor‐substituted organic molecules with extended π‐conjugated bridges. An unphysical delocalization with increasing chain length in density functional calculations can be reduced significantly by enforcing an asymptotically correct exchange‐correlation potential adjusted to give frontier orbital energies representing ionization potentials. The delocalization error for a number of donor–acceptor systems is quantified by calculations with fractional electron numbers and from orbital localizations. Optimally tuned hybrid variants of the PBE functional incorporating range‐separated exchange can produce similar magnitudes for β_∥ as Møller–Plesset second‐order perturbation (MP2) correlated calculations. Improvements are also found for CT excitation energies, with results similar to an approximate coupled‐cluster model (CC2).     

Chemoselective Derivatization of Folded Synthetic Insulin Variants with Potassium Acyltrifluoroborates (KATs)

Synthetic folded insulin variants containing an ornithine‐hydroxylamine residue are readily modified in aqueous buffers by amide‐forming ligations with potassium acyltrifluoroborates (KATs). The synthetic insulin analogs were prepared by Fmoc‐SPPS, α‐ketoacid‐hydroxylamine (KAHA) ligation, and a prosthetic C‐peptide that delivers the correct disulfide pattern and allows facile incorporation at the B0 position of Glargine M2 of a new ornithine hydroxylamine protected with a photolabile group. The folded insulin is readily modified by photo‐deprotection followed by amide‐forming KAT ligation to give insulin variants labeled with dyes, lipids, and PEGs, as well as the formation of a covalent dimer.     

Dichlorobis(2‐methylquinoline N‐oxide‐κO)zinc(II) from powder data

The crystal structure of the title compound, [ZnCl₂(C₁₀H₉NO)₂], has been determined from laboratory powder diffraction data. Although the powder pattern was initially indexed with tetragonal unit‐cell dimensions, the correct solution was found in an orthorhombic space group using a combination of grid‐search and simulated‐annealing techniques. The subsequent bond‐restrained Rietveld refinement gave bond lengths and angles within expected ranges. The molecule has crystallographically imposed twofold symmetry.     

Total Syntheses of Cystobactamids and Structural Confirmation of Cystobactamid 919‐2

The cystobactamids are a family of antibacterial natural products with unprecedented chemical scaffolds that are active against both Gram‐positive and Gram‐negative pathogens. Herein, we describe the first total synthesis of cystobactamid 919‐2 from three fragments. Our convergent synthesis enabled both the confirmation of the correct structure and the determination of the absolute configuration of cystobactamid 919‐2.     

群柱虫内酯官能团化的C2-C10片段的立体选择性合成

本文以廉价的消旋甲基戊二酸酐为起始原料,完成了具有抗肿瘤活性的海洋天然产物群柱虫内酯（Clavulactone）官能团化的C2-C10片段的立体选择性合成。使用的关键方法包括不对称去对称化获得光学纯手性孤立甲基,和RCM方法构建顺式烯烃。该片段的获得为群柱虫内酯的全合成提供了基础。     

On the DFT Ground State of Crystalline Bromine and Iodine

We report on an erroneous ground state within common density functional theory (DFT) methods for the solid elements bromine and iodine. Phonon computations at the GGA level for both molecular crystals yield imaginary vibrational modes, erroneously indicating dynamic instability—that fact alone could easily pass as a computational artefact, but these imaginary modes lead to energetically more favorable and dynamically stable structures, made up of infinite monoatomic chains. In contrast, meta‐GGA and hybrid functionals yield the correct energetic order for bromine, while for iodine, most global hybrids do not improve the GGA result significantly. The qualitatively correct answer, in both cases, is given by the long‐range corrected hybrid LC‐ωPBE, the Minnesota functionals M06L and M06, and by periodic Hartree–Fock and MP2 theory. This poor performance of economic DFT functionals should be kept in mind, for example, during global structure optimizations of systems with significant contributions from halogen bonds.     

Trapped in Misbelief for Almost 40 Years: Selective Synthesis of the Four Stereoisomers of Mefloquine

Here we report the synthesis of all four stereoisomers of mefloquine. Mefloquine (Lariam) is an important anti‐malaria drug that is applied as a racemate of the erythro form. However, the (?)‐isomer induces psychosis, while the (+)‐enantiomer does not have this undesired side effect. There are six syntheses of which five lead to the wrong enantiomer without the authors of these syntheses noting that they had synthesized the wrong compound. At the same time physical chemistry investigations had assigned the absolute configuration correctly and the last enantioselective synthesis that took these results into account delivered the correct absolute configuration. Since various synthetic approaches failed to provide the correct stereoisomers in previous syntheses, we submit here a synthetic approach with a domino Sonogashira‐6π‐electrocyclisation as key step that confirmed synthetically the correct absolute configuration of all four isomers.     

Improving chip‐to‐chip precision in disposable microchip capillary electrophoresis devices with internal standards

To realize portable systems for routine measurements in point‐of‐care settings, MCE methods are required to be robust across many single‐use chips. While it is well‐known internal standards (ISTDs) improve run‐to‐run precision, a systematic investigation is necessary to determine the significance of chip‐to‐chip imprecision in MCE and how ISTDs account for it. This paper addresses this question by exploring the reproducibility of Na quantification across six basic, in‐house fabricated microchips. A dataset of 900 electrophoerograms was collected from analyzing five concentrations of NaCl with two ISTDs (CsCl and LiCl). While both improved the peak area reproducibility, the Na/Cs ratio was superior to the Na/Li ratio (improving the RSD by a factor of 2–4, depending on the Na concentration). We attribute this to the significant variation in microchannel surface properties, which was accounted for by cesium but not lithium. Microchip dimension and detector variations were only a few percent, and could be improved through commercial fabrication over in‐house made microchips. These results demonstrate that ISTDs not only correct for intrachip imprecision, but are also a viable means to correct for chip‐to‐chip imprecision inherent in disposable, point‐of‐care MCE devices. However, as expected, the internal standard must be carefully chosen.     

Synthesis of Two Metabolites of the Antiarrythmicum Amiodarone

The metabolism of the potent antiarrythmic drug amiodarone (AMI; 1 ) has yet not been fully investigated. Recently, in vitro experiments revealed that in rabbit‐liver microsomes, AMI ( 1 ) and its main metabolite MDEA ( 2 ) were biotransformed to the hydroxylated derivatives 3′‐OH‐AMI ( 3 ) and 3′‐OH‐MDEA ( 4 ), respectively. To establish the chemical structure of 3 and 4 , we developed a total synthesis of these two metabolites of AMI ( 1 ). ¹H‐ and ¹³C‐NMR Signal assignment from HSQC and HMBC 2D NMR data of synthesized 4 showed that the proposed structure of metabolite 4 is correct. Even the structure of 3 was found to be correct by comparing its HPLC/MS‐MS/MS with the data described earlier.     

Novel Dual Two‐Dimensional Liquid Chromatography Online Coupled to Ultraviolet Detector,Fluorescence Detector,Ion‐Trap Mass Spectrometer for Short Peptide Amino Acid Sequence Determination with Bottom‐Up Strategy

A novel dual two‐dimensional (2D) high‐performance liquid chromatography (LC) setup coupled online to an ultraviolet (UV) detector, fluorescence (FL) detector, and ion‐trap mass spectrometer (MS) has been developed for determining the amino acid sequence of short peptides using a novel bottom‐up strategy. Short peptides were electrothermally hydrolyzed to shorter peptides and amino acid enantiomers. The first 2D LC‐UV and FL system was used to separate and identify the produced parent and daughter short peptides and amino acid isomers and enantiomers in the hydrolysate; the second 2D LC‐MS was used to identify the presence of cysteine and obtain the molecular mass signals and N‐terminal peptide fragment ion signals for parent and daughter short peptides. The identified amino acid enantiomers are used to form any possible short peptides by permutation and combination in an order from dipeptide to a tripeptide, to a tetrapeptide, and to even higher short peptides. The correct short peptides are confirmed by comparing the molecular weights of the constituent amino acid enantiomers and the molecular weights of identified short peptides together, with the characteristic N‐terminal peptide fragment ion signals. The amino acid sequence of the dipeptide ester aspartame and the tripeptide glutathione was successfully determined by this method.     

Thermodynamic and Mechanistic Insights into Translesion DNA Synthesis Catalyzed by Y‐Family DNA Polymerase Across a Bulky Double‐Base Lesion of an Antitumor Platinum Drug

To determine how the Y‐family translesion DNA polymerase η (Polη) processes lesions remains fundamental to understanding the molecular origins of the mutagenic translesion bypass. We utilized model systems employing a DNA double‐base lesion derived from 1,2‐GG intrastrand cross‐links of a new antitumor Pt^II complex containing a bulky carrier ligand, namely [PtCl₂(cis‐1,4‐dach)] (DACH=diaminocyclohexane). The catalytic efficiency of Polη for the insertion of correct dCTP, with respect to the other incorrect nucleotides, opposite the 1,2‐GG cross‐link was markedly reduced by the DACH carrier ligand. This reduced efficiency of Polη to incorporate the correct dCTP could be due to a more extensive DNA unstacking and deformation of the minor groove induced in the DNA by the cross‐link of bulky [PtCl₂(cis‐1,4‐dach)]. The major products of the bypass of this double‐base lesion produced by [PtCl₂(cis‐1,4‐dach)] by Polη resulted from misincorporation of dATP opposite the platinated G residues. The results of the present work support the thesis that this misincorporation could be due to sterical effects of the bulkier 1,4‐DACH ligand hindering the formation of the Polη–DNA–incoming nucleotide complex. Calorimetric analysis suggested that thermodynamic factors may contribute to the forces that governed enhanced incorporation of the incorrect dATP by Polη as well.