Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3H-spiro[benzofuran-2,4'-piperidine] Building Block.

An efficient and scalable route to tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate, a central prochiral intermediate in the synthesis of SHP2 inhibitor GDC-1971 (migoprotafib), was achieved. Preparation of the title compound from readily available 2-fluorobenzaldehyde included formation of a modified Katritzky benzotriazole hemiaminal, which, upon deprotonation by n-butyllithium, participated in umpolung reactivity via 1,2-addition to tert-butyl 4-oxopiperidine-1-carboxylate (N-Boc-4-piperidone). Most notably, this reaction was developed as a robust plug-flow process that could be executed on multiple kilograms without the need for pilot-scale reaction vessels operating at low cryogenic temperatures. Treatment of the resulting tetrahedral intermediate with oxalic acid resulted in collapse to the corresponding 4-(2-fluorobenzoyl)-4-hydroxypiperidine, which was isolated as a solid via crystallization. The synthesis concluded with an optimized intramolecular SNAr reaction and final crystallization to generate tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate as a stable, high-quality intermediate suitable for further functionalization toward GDC-1971.

Catalytic asymmetric and stereodivergent oligonucleotide synthesis.

We report the catalytic stereocontrolled synthesis of dinucleotides. We have demonstrated, for the first time to our knowledge, that chiral phosphoric acid (CPA) catalysts control the formation of stereogenic phosphorous centers during phosphoramidite transfer. Unprecedented levels of diastereodivergence have also been demonstrated, enabling access to either phosphite diastereomer. Two different CPA scaffolds have proven to be essential for achieving stereodivergence: peptide-embedded phosphothreonine-derived CPAs, which reinforce and amplify the inherent substrate preference, and C2-symmetric BINOL-derived CPAs, which completely overturn this stereochemical preference. The presently reported catalytic method does not require stoichiometric activators or chiral auxiliaries and enables asymmetric catalysis with readily available phosphoramidites. The method was applied to the stereocontrolled synthesis of diastereomeric dinucleotides as well as cyclic dinucleotides, which are of broad interest in immuno-oncology as agonists of the stimulator of interferon genes (STING) pathway.

Total Synthesis and Anti-Cancer Activity of All Known Communesin Alkaloids and Related Derivatives.

A unified enantioselective total synthesis and anticancer evaluation of all known epoxide-containing communesin alkaloids and related derivatives is described. Our synthesis is predicated on the convergent and modular diazene-directed assembly of two complex fragments to secure the critical C3a-C3a' linkage followed by a guided biomimetic aminal reorganization to deliver the heptacyclic core of these alkaloids. Concise enantioselective syntheses of the fragments were devised, with highlights including the application of a rationally designed sulfinamide chiral auxiliary, an efficient calcium trifluoromethanesulfonate promoted intramolecular amination, and a diastereoselective epoxidation that simultaneously converts the new chiral auxiliary to a versatile amine protective group. The modularity of our convergent approach enabled the rapid synthesis of all epoxide-containing members of the communesin family from a single heterodimeric intermediate, including the first total synthesis of communesins C-E, and G-I, and facilitated our stereochemical revision of (-)-communesin I, the most recently isolated communesin alkaloid. Furthermore, the generality of our biogenetically inspired heterodimer rearrangement was demonstrated in a guided synthesis of a communesin derivative with an unnatural topology. Finally, we report the first comparative analysis of the anticancer activities of all naturally occurring communesin alkaloids A-I and eight complex derivatives against five human cancer cell lines. From these data, we have identified (-)-communesin B as the most potent natural communesin and discovered that derivatives with N8'-sulfonamide substitution exhibit up to a 10-fold increase in potency over the natural alkaloids.

Healing Rate of Chronic and Subacute Lower Extremity Ulcers Treated With Contact Ultrasound Followed by Noncontact Ultrasound Therapy: The VIP Ultrasound Protocol.

BACKGROUND: Contact and noncontact ultrasounds are types of low-frequency ultrasonic treatments for wound care. OBJECTIVE: The purpose of this research was to collect data in order to see if healing rates are accelerated when both forms of ultrasound therapies are utilized. MATERIALS AND METHODS: The Viana-Pompeo (VIP) Ultrasound Protocol consists of high-intensity, low-frequency, contact ultrasound therapy followed by low-intensity, low-frequency, noncontact ultrasound therapy. A total of 11 subjects with a total of 24 chronic or subacute lower extremity wounds were enrolled in the study. Of the 11 subjects, 6 finished the protocol (12 wounds). All subjects started with contact ultrasound for debridement at a frequency of 25 kHz and at the maximum intensity the subject could tolerate (equipment range, 20%-100% of 1.0 W/cm²). Once the wound was sufficiently clean with ≤ 20% of necrotic tissue or adherent slough, therapy was switched to noncontact, low-frequency ultrasound (NLFU) for cellular stimulation at 40 kHz and intensities of 0.1 W/cm² to 0.5 W/cm². Subjects received ultrasound treatment 3 times weekly for the 12-week study. Progress was analyzed based on reductions in wound area, volume, and slough and increases in granulation and epithelialization. Wounds were divided into 2 groups: group A, wound duration between 4 and 21 weeks; and group B, wound duration ≥ 47 weeks. There were no wounds between 21 and 47 weeks. RESULTS: In group A (4 wounds), all wounds improved in wound area and epithelialization; 75% achieved an improvement of > 99% before or at 12 weeks of treatment. In addition, all wounds saw a wound volume reduction of 93% to 100%. Granulation in group A was 100%, and by visit 10 of 36, all wounds had 0% slough or eschar. In group B (8 wounds), 50% of wounds improved with a wound volume reduction of 50%; all wounds increased in granulation, with 50% achieving 75% to 100% granulation. Sixty-two percent of wounds in group B saw an increase in epithelialization, and 75% of wounds had 85% to 100% reduction in slough and eschar by the last visit (end of week 12). There was a strong positive correlation between wound age and healing time (r = 0.94). CONCLUSIONS: Both groups benefited from the VIP Protocol, which promoted wound closure or wound bed preparation for graft. The results seem to favor an earlier start of the protocol for best outcomes and indicate that contact and noncontact ultrasound therapies are not exclusionary but rather complementary.

Designing Pd-N-Heterocyclic Carbene Complexes for High Reactivity and Selectivity for Cross-Coupling Applications.

Over the past decade, the use of Pd-NHC complexes in cross-coupling applications has blossomed, and reactions that were either not previously possible or possible only under very forcing conditions (e.g., > 100 °C, strong base) are now feasible under mild conditions (e.g., room temperature, weak base). Access to tools such as computational chemistry has facilitated a much greater mechanistic understanding of catalytic cycles, which has enabled the design of new NHC ligands and accelerated advances in cross-coupling. With these elements of rational design, highly reactive Pd-NHC complexes have been invented to catalyze the selective formation of single products in a variety of transformations that have the potential to afford multiple compounds (e.g., isomers). Pd-NHC catalysts may be prepared as stable Pd(II) precatalysts that are readily reduced to the active Pd(0) species in the presence of an organometallic cross-coupling partner or nucleophile possessing ß-hydrogens. It has been found from computational and experimental results that Pd-NHC complexes bearing a single bulky NHC ligand are well-suited to tackle challenging cross-coupling reactions. N-Aryl-substituted imidazole-2-ylidenes with branched alkyl chains at the ortho positions of the aryl group are effective for the challenging couplings of hindered biaryls, secondary alkyl organozincs, electron-deficient anilines, α-amino esters, primary alkylamines, and ammonia. The bulk of the NHC has been tuned by increasing the size of the alkyl groups at the ortho positions and substituting the NHC core with chlorine substituents. All of the cross-coupling transformations studied benefit from the increased bulk when the ortho groups are changed from methyl to 2-propyl to 3-pentyl. However, there is a limit to the positive effect of steric bulk, as some reactions do not benefit from the increased size of the 4-heptyl group compared with 3-pentyl. Thus, there is an optimum size for the NHC ligand that depends upon whether reactivity (turnover frequency and turnover number), selectivity, or both are needed to obtain the desired reaction outcome. In the cases that we have studied, reactivity and selectivity increase together (i.e., the fastest catalyst is also the most selective), allowing cross-couplings to be carried out under mild conditions to obtain one product with high selectivity. This Account focuses on seminal literature reports that have disclosed new Pd-NHC complexes that have led to significant breakthroughs in efficacy for challenging couplings while demonstrating high selectivity for the desired target. These catalysts have been used widely in materials science, pharmaceutical, and agrochemical applications.

Convergent and Biomimetic Enantioselective Total Synthesis of (-)-Communesin F.

The first biomimetic enantioselective total synthesis of (-)-communesin F based on a late-stage heterodimerization and aminal exchange is described. Our synthesis features the expedient diazene-directed assembly of two advanced fragments to secure the congested C3a-C3a' linkage in three steps, followed by a highly efficient biogenetically inspired aminal reorganization to access the heptacyclic communesin core in only two additional steps. Enantioselective syntheses of the two fragments were developed, with highlights including the catalytic asymmetric halocyclization and diastereoselective oxyamination reactions of tryptamine derivatives, a stereoselective sulfinimine allylation, and an efficient cyclotryptamine-C3a-sulfamate synthesis by either a new silver-promoted nucleophilic amination or a rhodium-catalyzed C-H amination protocol. The versatile syntheses of the fragments, their stereocontrolled assembly, and the efficient aminal exchange as supported by in situ monitoring experiments, in addition to the final stage N1'-acylation of the communesin core, provide a highly convergent synthesis of (-)-communesin F.

Pyoderma Gangrenosum:Recognition and Management.

Pyoderma gangrenosum is an unusual cause of skin ulcerations that wound specialists must be prepared to recognize. There is no diagnostic test since it is a diagnosis of exclusion, and if the disease is not recognized it can quickly become much worse. Pathergy, whereby a lesion begins or worsens due to trauma, such as a scrape, bite, debridement, surgery, or biopsy, is seen with pyoderma and requires special consideration. This case series and review will summarize the salient features of pyoderma and its treatment with an emphasis on the controversial role of surgery with pyoderma.

The Selective Cross-Coupling of Secondary Alkyl Zinc Reagents to Five-Membered-Ring Heterocycles Using Pd-PEPPSI-IHept(Cl).

The ability to cross-couple secondary alkyl centers is fraught with a number of problems, including difficult reductive elimination, which often leads to ß-hydride elimination. Whereas catalysts have been reported that provide decent selectivity for the expected (non-rearranged) cross-coupled product with aryl or heteroaryl oxidative-addition partners, none have shown reliable selectivity with five-membered-ring heterocycles. In this report, a new, rationally designed catalyst, Pd-PEPPSI-IHept(Cl), is demonstrated to be effective in selective cross-coupling reactions with secondary alkyl reagents across an impressive variety of furans, thiophenes, and benzo-fused derivatives (e.g., indoles, benzofurans), in most instances producing clean products with minimal, if any, migratory insertion for the first time.

[(IPent)PdCl2(morpholine)]: a readily activated precatalyst for room-temperature, additive-free carbon-sulfur coupling.

A series of new, easily activated NHC-Pd(II) precatalysts featuring a trans-oriented morpholine ligand were prepared and evaluated for activity in carbon-sulfur cross-coupling chemistry. [(IPent)PdCl2(morpholine)] (IPent=1,3-bis(2,6-di(3-pentyl)phenyl)imidazol-2-ylidene) was identified as the most active precatalyst and was shown to effectively couple a wide variety of deactivated aryl halides with both aryl and alkyl thiols at or near ambient temperature, without the need for additives, external activators, or pre-activation steps. Mechanistic studies revealed that, in contrast to other common NHC-Pd(II) precatalysts, these complexes are rapidly reduced to the active NHC-Pd(0) species at ambient temperature in the presence of KOtBu, thus avoiding the formation of deleterious off-cycle Pd(II)-thiolate resting states.

A knowledge-based modeling for plantar pressure image reconstruction.

It is known that prolonged pressure on the plantar area is one of the main factors in developing foot ulcers. With current technology, electronic pressure monitoring systems can be placed as an insole into regular shoes to continuously monitor the plantar area and provide evidence on ulcer formation process as well as insight for proper orthotic footwear design. The reliability of these systems heavily depends on the spatial resolution of their sensor platforms. However, due to the cost and energy constraints, practical wireless in-shoe pressure monitoring systems have a limited number of sensors, i.e., typically K < 10. In this paper, we present a knowledge-based regression model (SCPM) to reconstruct a spatially continuous plantar pressure image from a small number of pressure sensors. This model makes use of high-resolution pressure data collected clinically to train a per-subject regression function. SCPM is shown to outperform all other tested interpolation methods for K < 60 sensors, with less than one-third of the error for K = 10 sensors. SCPM bridges the gap between the technological capability and medical need and can play an important role in the adoption of sensing insole for a wide range of medical applications.

Room-temperature amination of deactivated aniline and aryl halide partners with carbonate base using a Pd-PEPPSI-IPentCl-o-picoline catalyst.

Current state-of-the-art protocols for the coupling of unreactive amines (e.g., electron-poor anilines) with deactivated oxidative-addition partners (e.g., electron-rich and/or hindered aryl chlorides) involve strong heating (usually >100°C) and/or tert-butoxide base, and even then not all couplings are successful. The aggressive base tert-butoxide reacts with and in many instances destroys the typical functional groups that are necessary for the function of most organic molecules, such as carbonyl groups, esters, nitriles, amides, alcohols, and amines. The new catalyst described herein, Pd-PEPPSI-IPentCl-o-picoline, is able to aminate profoundly deactivated coupling partners when using only carbonate base at room temperature.

Pressure map technology for pressure ulcer patients: can we handle the truth?

UNLABELLED: Objective. The purpose of this study was to trial new pressure mapping technology for patients with pressure ulcers. METHODS: Pressure mapping data was recorded during 3 phases of technology implementation, as nurses became increasingly familiar with pressuremapping technology in a 55-bed, long-term acute care (LTAC) facility in North Texas. Forty-three patients with pressure ulcers were selected for the study. Patients with pressure ulcers, or who were considered at high risk for developing pressure ulcers based on a Braden score of ≤ 12, were selected to utilize a pressure-sensing device system. RESULTS: Turning timeliness improved greatly from the baseline phase to the last phase. The average turning after the 2-hour alarm decreased from 120 minutes to 44 minutes, and the median time to turning decreased from 39 minutes to 17 minutes. If time past 2 hours is considered the most damaging time to tissue, these reductions (average and median) represented 63% and 56% less potential tissue damage. CONCLUSION: Pressure mapping technology is in its infancy and this paper discusses implications for the future, including barriers to implementation and potential advanced applications. While only changes in nursing practice were measured in this study, the changes observed suggest the technology can be instrumental in reducing hospital-acquired pressure ulcers and improving the healing of pressure wounds in the future. .

Pd-PEPPSI-IPent(Cl): a highly effective catalyst for the selective cross-coupling of secondary organozinc reagents.

No migration? No problem! A series of new N-heterocyclic carbene based Pd complexes has been created and evaluated in the Negishi cross-coupling of aryl and heteroaryl chlorides, bromides, and triflates with a variety of secondary alkylzinc reagents. The direct elimination product is nearly exclusively formed; in most examples there is no migratory insertion at all.

A resource-efficient planning for pressure ulcer prevention.

Pressure ulcer is a critical problem for bed-ridden and wheelchair-bound patients, diabetics, and the elderly. Patients need to be regularly repositioned to prevent excessive pressure on a single area of body, which can lead to ulcers. Pressure ulcers are extremely costly to treat and may lead to several other health problems, including death. The current standard for prevention is to reposition at-risk patients every two hours. Even if it is done properly, a fixed schedule is not sufficient to prevent all ulcers. Moreover, it may result in nurses being overworked by turning some patients too frequently. In this paper, we present an algorithm for finding a nurse-effort optimal repositioning schedule that prevents pressure ulcer formation for a finite planning horizon. Our proposed algorithm uses data from a commercial pressure mat assembled on the beds surface and provides a sequence of next positions and the time of repositioning for each patient.

Sensor architectural tradeoff for diabetic foot ulcer monitoring.

The diabetic foot complications constitute a tremendous challenge for patients, caregivers, and the healthcare system. Studies show up to 25% of diabetic individuals will develop a foot ulcer during their lifetime and many of these patients eventually must undergo amputation as a result of infection due to untreated foot ulcers. With current technology, in-shoe monitoring systems can be implemented to continuously monitor at-risk ulceration sites based on known indicators such as peak pressure. The important parameters in designing a pressure-sensing insole include the number, location and size of sensors. In this paper, we aim at showing the criticality of sensor architectural tradeoff in developing the in-shoe plantar pressure monitoring systems. We evaluate this tradeoff by using our custom-made platform for data collection during normal walking.

Misconceptions about protein requirements for wound healing: results of a prospective study.

The successful treatment of protein malnutrition is critical for patient healing but traditional estimates of the amount of calories and protein needed for wound patients have been empiric. In particular, only the presence of a wound, not its severity or extent, is currently included as a stratifying "stress factor." To 1) ascertain reasons for feeding failure, 2) evaluate a hypothesis that patients with wounds require more protein than is generally recommended in the literature, and 3) affirm that wound burden effects protein requirements, a 1-year, descriptive, prospective study was conducted involving 150 tube-fed patients with (n = 93) and without (n = 57) wounds admitted to a long-term, acute care facility. On admission, 11% of wound and 21% of non-wound patients had normal pre-albumin levels. Using an aggressive protein provision regimen, pre-albumin levels improved in 42% of wound patients (mean 36.9 days) and in 46% of non-wound patients (mean 29.7 days). The most common cause of feeding failure was inadequate provision or assimilation of protein. Signs and symptoms of overfeeding were not observed. The average maximum amount of protein provided to patients whose pre-albumin improved was significantly higher in the wound (1.85 g/Kg/day) than in the non-wound (1.47 g/Kg/day) group (P = .0002). Among wound patients whose pre-albumin improved, a trend between higher wound burden (defined by total Pressure Ulcer Scale for Healing score) and maximum amounts of protein provided was seen. In addition to the need for more research in this area, study findings suggest that commonly estimated protein requirements for wound patients are too low and that better tools and procedures for protein assessment and maintenance need to be implemented.

Guidelines for managing pressure ulcers with negative pressure wound therapy.

Pressure ulcers are a serious health issue, leading to clinical, financial, and emotional challenges. Numerous treatment modalities are available to promote wound healing, yet clinicians may be unsure how to incorporate these treatment options into an overall plan of care for the patient with a pressure ulcer. A consensus panel of experienced wound care clinicians convened in July 2004 to review the mechanisms of action and research basis for one such treatment modality: negative pressure wound therapy. After answering key questions about this modality, they developed an algorithm to assist the clinician in making decisions about using negative pressure wound therapy appropriately in patients with Stage III and Stage IV pressure ulcers.

Implementing the push tool in clinical practice: revisions and results.

The ability to measure outcomes is increasingly important in the practice of medicine. For wound care, the Pressure Ulcer Scale for Healing tool was developed to assess and standardize wound healing progress. However, for a variety of reasons, use of the tool to monitor an individual patient's wounds is not widespread. Following revisions to the tool for the purpose of capturing system-wide wound outcomes data, a prospective study in two long-term, acute care hospitals was conducted. Admission and discharge wound scores from 374 patients (989 wounds), representing 13,737 patient-days of care were obtained and recorded to document overall progress of healing and to calculate healing as a function of time. The results obtained are now used as a benchmark in the participating facilities and can be used by others to gauge the effectiveness of care. Although these tools cannot provide information about the effectiveness of specific interventions, and the data will always require careful interpretation by thoughtful wound providers, results of this study show that, at this time, the revised Pressure Ulcer Scale for Healing may be the best tool available for comparing healing outcomes.