A Sulfoxide Reagent for One-Pot, Three-Component Syntheses of Sulfoxides and Sulfinamides

Sulfoxides and sulfinamides represent versatile sulfur functional groups found in ligands, chiral auxiliaries, and bioactive molecules. Canonical two-component syntheses, however, rely on substrates with a preinstalled C-S bond and impede efficient and modular access to these sulfur motifs. Herein is presented the application of an easily prepared, bench-stable sulfoxide reagent for one-pot, three-component syntheses of sulfoxides and sulfinamides. The sulfoxide reagent donates the SO unit upon the reaction with a Grignard reagent (RMgX) as a sulfenate anion (RSO-). While subsequent trapping reactions of this key intermediate with carbon electrophiles provide sulfoxides, a range of tertiary, secondary, and primary sulfinamides can be prepared by substitution reactions with electrophilic amines. The syntheses of sulfinamide analogs of amide- and sulfonamide-containing drugs illustrate the utility of the method for the rapid preparation of medicinally relevant molecules

A Sulfur Monoxide Surrogate Designed for the Synthesis of Sulfoxides and Sulfinamides

Sulfur monoxide (SO) is a highly reactive species that cannot be isolated in bulk. However, SO can play a pivotal role as a fundamental building block in organic synthesis. Reported herein is the design and application of a sulfinylhydrazine reagent as an easily prepared sulfur monoxide surrogate. We show facile thermal SO transfer from this reagent to dienes where a reaction using a mechanistic probe suggests the generation of singlet SO. Combined with Grignard reagents and appropriate carbon or nitrogen electrophiles, the reagent serves as an effective “SO” donor to enable the one-pot, three-component synthesis of sulfoxides and sulfinamides

Trochanteric Claw Plate Fixation for Greater Trochanteric Fracture or Osteotomy in Total Hip Arthroplasty

This study retrospectively evaluated 41 consecutive open reductions and internal fixations following primary or revision total hip arthroplasty, which required trochanteric claw plate fixation for greater trochanteric fracture or osteotomy between January 2008 and December 2020. The mean duration of clinical follow-up was 4.2 years (range, 1-13 years). The patients included 13 men and 28 women, with a mean age of 68 years (range, 32-87 years). The indications for intervention included trochanteric osteotomy, intraoperative fracture, and non-union including postoperative fracture in 6, 9, and 26 cases, respectively. The mean Merle d’Aubigné Clinical Score improved from 9.4 points (range, 5-15 points) pre-operatively, to 14.3 points (range, 9-18 points) at the last follow-up. Bone union occurred in 35 cases (85%), while implant breakage occurred in four cases. At the last follow-up, the mean Merle d’Aubigné Clinical Scores of bone union and non-union were 15.3 and 14.1, respectively (p=0.48). The Kaplan-Meier survival rate, with the endpoint being revision surgery for pain, non-union, dislocation, or implant breakage, at 10 years was 80.0% (95% confidence interval: 62.6-97.4%). Greater trochanteric fixation using a trochanteric claw plate yielded successful results

A supramolecular helix that disregards chirality

The functions of complex crystalline systems derived from supramolecular biological and non-biological assemblies typically emerge from homochiral programmed primary structures via first principles involving secondary, tertiary and quaternary structures. In contrast, heterochiral and racemic compounds yield disordered crystals, amorphous solids or liquids. Here, we report the self-assembly of perylene bisimide derivatives in a supramolecular helix that in turn self-organizes in columnar hexagonal crystalline domains regardless of the enantiomeric purity of the perylene bisimide. We show that both homochiral and racemic perylene bisimide compounds, including a mixture of 21 diastereomers that cannot be deracemized at the molecular level, self-organize to form single-handed helical assemblies with identical single-crystal-like order. We propose that this high crystalline order is generated via a cogwheel mechanism that disregards the chirality of the self-assembling building blocks. We anticipate that this mechanism will facilitate access to previously inaccessible complex crystalline systems from racemic and homochiral building blocks

A Sulfoxide Reagent for One-Pot, Three-Component Syntheses of Sulfoxides and Sulfinamides

Sulfoxides and sulfinamides represent versatile sulfur functional groups found in ligands, chiral auxiliaries, and bioactive molecules. However, canonical two-component syntheses relying on substrates with a preinstalled C–S bond impede efficient and modular access to these sulfur motifs. Herein is presented the application of an easily prepared, bench stable sulfoxide reagent for one-pot, three-component syntheses of sulfoxides and sulfinamides. The sulfoxide reagent donates the SO unit upon the reaction with a Grignard reagent (RMgX) as a sulfenate anion (RSO–). While subsequent trapping reactions of this key intermediate with carbon electrophiles provide sulfoxides, a range of tertiary, secondary, and primary sulfinamides can be prepared by substitution reactions with electrophilic amines. The syntheses of sulfinamide analogs of amide- and sulfonamide-containing drugs illustrate the utility of the method for the rapid preparation of medicinally relevant molecules

Building Block Approaches to the Synthesis of Lasso Peptides and Polycyclic Saturated N-Heterocycles

The first part of this dissertation describes the synthesis of peptide-based [1]rotaxanes (lasso peptides). Lasso peptides are bacterially produced natural products with unique interlocked structure that endows them exceptional proteolytic stability. Therefore, lasso peptides have been employed as scaffolds to enhance the proteolytic stability of linear peptides. This approach – so-called molecular grafting– has been achieved by biosynthetic methods; however, there had been no example accomplished by the chemical synthesis. To achieve the synthesis of peptide-based [1]rotaxanes, we took a two-stage approach: the first is formation of [2]rotaxanes whose components are prefunctionalized with hydroxylamine and thioester for the subsequent steps; the second is two consecutive amide-forming ligation reactions, namely alpha-ketoacid-hydroxylamine ligation (KAHA ligation) and native chemical ligation (NCL) to attach linear peptide epitopes to the [2]rotaxane scaffold, ultimately providing peptide-based [1]rotaxanes. In this way, the incorporation of linear peptide epitopes with different lengths and amino acid residues onto a common rotaxane scaffold was achieved. The threaded structure in the synthesized molecules was confirmed by NMR, HPLC, and analysis of partial enzymatic degradation products. The synthetic lasso peptide mimetics were thermally stable and importantly, linear peptide epitopes gained significant proteolytic stability upon grafting onto the [1]rotaxane scaffold, as demonstrated by proteolytic stability assays using three different types of proteases. The stability of peptide-based [1]rotaxanes were comparable to the head-to-tail cyclic peptide bearing the same sequence. The second part of this dissertation deals with iterative, programmable synthesis of polycyclic saturated N-heterocycles with defined three-dimensional shapes. Shape is an important property of organic molecules and closely related to their properties and functions. This relationship is clearly observed in biomolecules such as proteins that adopt unique three-dimensional structures by folding. However, both de novo design of proteins and the synthesis of organic molecules with predictable shapes remain to be challenging. By executing iterative cyclizations with carefully designed SnAP reagents, we achieved the synthesis of polycyclic saturated N-heterocycles. The rigid backbones based on spirocyclic and/or fused bicyclic structures enabled reliable computational prediction of molecular shapes. A considerable number of X-ray crystal structures of dimers and trimers supported shape predictability of polycyclic molecules. The terminal ketone was further elaborated by the synthesis of fused N-heteroaromatics, amines, and carboxylic acids, demonstrating potential applications of the polycyclic compounds for catalysis, molecular recognition, and drug development

Distribution of wild mammal assemblages along an urban-rural-forest landscape gradient in warm-temperate East Asia.

Urbanization may alter mammal assemblages via habitat loss, food subsidies, and other factors related to human activities. The general distribution patterns of wild mammal assemblages along urban-rural-forest landscape gradients have not been studied, although many studies have focused on a single species or taxon, such as rodents. We quantitatively evaluated the effects of the urban-rural-forest gradient and spatial scale on the distributions of large and mid-sized mammals in the world's largest metropolitan area in warm-temperate Asia using nonspecific camera-trapping along two linear transects spanning from the urban zone in the Tokyo metropolitan area to surrounding rural and forest landscapes. Many large and mid-sized species generally decreased from forest landscapes to urban cores, although some species preferred anthropogenic landscapes. Sika deer (Cervus nippon), Reeves' muntjac (Muntiacus reevesi), Japanese macaque (Macaca fuscata), Japanese squirrel (Sciurus lis), Japanese marten (Martes melampus), Japanese badger (Meles anakuma), and wild boar (Sus scrofa) generally dominated the mammal assemblage of the forest landscape. Raccoon (Procyon lotor), raccoon dog (Nyctereutes procyonoides), and Japanese hare (Lepus brachyurus) dominated the mammal assemblage in the intermediate zone (i.e., rural and suburban landscape). Cats (feral and free-roaming housecats; Felis catus) were common in the urban assemblage. The key spatial scales for forest species were more than 4000-m radius, indicating that conservation and management plans for these mammal assemblages should be considered on large spatial scales. However, small green spaces will also be important for mammal conservation in the urban landscape, because an indigenous omnivore (raccoon dog) had a smaller key spatial scale (500-m radius) than those of forest mammals. Urbanization was generally the most important factor in the distributions of mammals, and it is necessary to consider the spatial scale of management according to the degree of urbanization

Enantioselective Synthesis of Sulfinamidines via Asymmetric Nitrogen Transfer from N-H Oxaziridines to Sulfenamides

Sulfinamidines are promising aza-SIV chiral building blocks in asymmetric synthesis and drug discovery. However, no report has documented their enantioselective synthesis. Here we present an enantioselective synthesis of sulfinamidines via electrophilic amination of sulfenamides using an enantiopure N-H oxaziridine. The resulting enantiomerically enriched primary sulfinamidines are configurationally stable at 90 oC in solution. We also demonstrate a one-pot, three-component, enantioselective synthesis of sulfinamides using N-H oxaziridine reagents