Deconvoluting Nonlinear Catalyst-Substrate Effects in the Intramolecular Dirhodium-Catalyzed C-H Insertion of Donor/Donor Carbenes Using Data Science Tools.

Interactions between catalysts and substrates can be highly complex and dynamic, often complicating the development of models to either predict or understand such processes. A dirhodium(II)-catalyzed C-H insertion of donor/donor carbenes into 2-alkoxybenzophenone substrates to form benzodihydrofurans was selected as a model system to explore nonlinear methods to achieve a mechanistic understanding. We found that the application of traditional methods of multivariate linear regression (MLR) correlating DFT-derived descriptors of catalysts and substrates leads to poorly performing models. This inspired the introduction of nonlinear descriptor relationships into modeling by applying the sure independence screening and sparsifying operator (SISSO) algorithm. Based on SISSO-generated descriptors, a high-performing MLR model was identified that predicts external validation points well. Mechanistic interpretation was aided by the deconstruction of feature relationships using chemical space maps, decision trees, and linear descriptors. Substrates were found to have a strong dependence on steric effects for determining their innate cyclization selectivity preferences. Catalyst reactive site features can then be matched to product features to tune or override the resultant diastereoselectivity within the substrate-dictated ranges. This case study presents a method for understanding complex interactions often encountered in catalysis by using nonlinear modeling methods and linear deconvolution by pattern recognition.

One-Pot Assembly and Synthetic Applications of Geminal Acyl/Alkoxy Tetrasubstituted Allenes.

Polysubstituted allenes are useful synthetic intermediates in many applications, offering structural complexity, modularity, and their axial chirality in further transformations. While acyl and alkoxy-substituted allenes are known, there are currently few examples of allenes containing both functionalities and no reports of geminally substituted acyl/alkoxy allenes being isolated and characterized. Herein, we report the synthesis of tetrasubstituted allenes featuring a novel geminal acyl/alkoxy substitution. These unique "push-pull" allenes are bench-stable and exhibit interesting reactivity in several applications.

Divergent Asymmetric Synthesis of Panowamycins, TM-135, and Veramycin†F Using C-H Insertion with Donor/Donor Carbenes.

Panowamycins are a group of isochroman-based natural products first isolated from Streptomyces sp. K07-0010 in 2012 by Satoshi Omura and co-workers that exhibit modest anti-trypanosomal activity. Herein we demonstrate the first syntheses of these natural products and their epimers. Stereoselective dirhodium-catalyzed C-H insertion reactions with a donor/donor carbene construct the substituted isochroman core in the key bond-forming step. The syntheses are completed without the use of protecting groups and feature a late-stage Wacker oxidation. Incongruent NMR spectra between natural and synthetic samples revealed the structural misassignment of panowamycin A and veramycin F. Computational NMR studies suggested panowamycin A to be an alternate diastereomer, which was confirmed by synthesizing this isomer. Concurrent with this work, in 2021 Mahmud and co-workers came to the same conclusion with an updated NMR analysis of panowamycin A. In a divergent, asymmetric sequence, we report the synthesis of panowamycin A, panowamycin B, TM-135, and veramycin F.

Transition Metal Catalyzed Insertion Reactions with Donor/Donor Carbenes.

Donor/donor carbenes are relatively new in the field of carbene chemistry; although applications in C-H and X-H insertion reactions are few in number, they demonstrate exquisite chemo- and stereo-selectivity. Recent reports have shown that C-H, N-H, B-H, O-H, S-H, Si-H, Ge-H, Sn-H and P-H insertion reactions are feasible with a variety of transition metal catalysts, both inter- and intramolecularly. Furthermore, high degrees of diastereo- and enantioselectivity have been observed in several cases. Methods typically involve the formation of a diazo-based carbene precursor, but procedures using diazo-free metal carbenes have been developed with significant success. This Minireview covers transition-metal catalyzed insertion reactions with donor/donor and donor carbenes, providing context for future developments in this emerging field.

Enantioselective synthesis of isochromans and tetrahydroisoquinolines by C-H insertion of donor/donor carbenes.

Reports of C-H insertions forming six-membered rings containing heteroatoms are rare due to Stevens rearrangements occurring after nucleophilic attack on the carbene by a heteroatom. Using donor/donor carbenes and Rh2(R-PTAD)4 as a catalyst, we have synthesized a collection of isochroman substrates in good yield, with excellent diastereo- and enantioselectivity, and no rearrangement products were observed. Furthermore, we report the first synthesis of six-membered rings containing nitrogen by C-H insertion to form tetrahydroisoquinolines. In one case, a Stevens rearrangement product was isolated at elevated temperature from a carbamate-protected amine substrate and computational evidence suggests formation through a free ylide not bound to rhodium.

Correction: Enantioselective synthesis of isochromans and tetrahydroisoquinolines by C-H insertion of donor/donor carbenes.

[This corrects the article DOI: 10.1039/C9SC05111B.].

Antibacterial activity and safety of commercial veterinary cationic steroid antibiotics and neutral superoxidized water.

Antibiotic resistance of bacteria common to the ocular surface is an evolving problem. Thus, novel treatment options with new modes of action are required. We investigated the antibacterial activity and safety of three commercially available topical veterinary ophthalmic products (cationic steroid antibiotics, products A and B, and a neutral superoxidized water, product C) to determine their potential use as antimicrobial alternatives. The minimum inhibitory concentrations (MIC) of the three products were determined against 17 antibiotic resistant bacterial clinical isolates from the ocular surface. Using a standard cytotoxicity assay, the products at varying concentrations were evaluated with a corneal fibroblast cell line and a macrophage-like cell line to determine their potential toxic effect in vitro. The commercial ophthalmic solutions, ofloxacin 0.3%, tobramycin 0.3% and gentamicin 0.3% were used as positive controls for the MIC and tobramycin 0.3% was used as positive control for the cytotoxicity assays. For the MIC, Product C showed no inhibition of growth for any organisms, while Products A and B showed inhibition of growth similar to slightly less than the positive controls. For the cytotoxicity assays, Product C exhibited minimal toxicity while Products A and B exhibited toxicity similar to the controls. In conclusion, Product C had no antibacterial activity in these assays, while Products A and B had antibacterial profiles similar to slightly less than common topical ophthalmic antibiotics and cytotoxicity profiles similar to common topical ophthalmic antibiotics. To our knowledge, this is the first report on the antibacterial activity and safety of the cationic steroid antibiotics and superoxidized water.

The Use of Stroke Volume Variation to Guide Donor Management Is Associated With Increased Organs Transplanted per Donor.

BACKGROUND: There is a national shortage of organs available for transplantation, and utilization rates for thoracic organs are less than 40%. In addition, the optimal method of assessing cardiovascular status during donor management is uncertain. FloTrac is a noninvasive hemodynamic technique that measures cardiac output and fluid responsiveness. Our objective was to measure the impact of using this technique to guide management on fluid balance, vasopressor usage, thyroid hormone usage, and pulmonary function. We hypothesized that FloTrac guidance will increase thoracic organs transplanted per donor (OTPD). METHODS: Data were prospectively collected on a convenience sample of 38 donors after neurologic determination of death. Organs transplanted, net fluid balance, dosage of vasopressors, dosage of thyroid hormone, and Pao2:Fio2 were compared between treatment and control groups. RESULTS: The treatment group had greater thoracic OTPD (1.3 [1.0] vs 0.4 [0.6], P = .004) and overall OTPD (4.3 [1.5] vs 2.7 [1.5], P = .002). Donors in the treatment group maintained a neutral fluid balance, had more thyroid hormone used, and had an improvement in oxygenation. CONCLUSION: The implementation of this technology to aid providers may help ameliorate the shortage of thoracic and overall organs available for transplantation.

Canine panuveitis: a retrospective evaluation of 55 cases (2000-2015).

OBJECTIVE: To determine the most common etiologies of panuveitis in a group of dogs, patient response to therapy, and visual outcome. DESIGN: Retrospective study. MATERIALS AND METHODS: Medical records of 55 dogs diagnosed with panuveitis at the Purdue University Veterinary Teaching Hospital between December 2000 and December 2015 were reviewed. Data collected included signalment, season of diagnosis, descriptions of ocular lesions, diagnostic testing, treatment protocols, etiologic diagnoses (when determined), and visual outcome. RESULTS: The most common clinical sign in the anterior segment was aqueous flare and in the posterior segment was serous retinal detachment. The most common diagnosis was idiopathic/immune-mediated disease followed by systemic blastomycosis, lymphoma, and other causes (leptospirosis, aspergillosis, and histoplasmosis). Of the 43 dogs for which follow-up was available, 40% of dogs had resolution of visible inflammation and retinal reattachment, 32% of dogs had slight to moderate improvement, and 28% of dogs had no improvement or deterioration of lesions. Mean follow-up time was 11 months, and mean time to resolution of visible inflammation and retinal reattachment was 32 days. Sixty-five percent of dogs either retained or regained vision in one or both diseased eyes with initial medical therapy. CONCLUSIONS: Idiopathic/immune-mediated panuveitis was the most common diagnosis. Dogs with idiopathic/immune-mediated panuveitis tended to respond more favorably to medical therapy than dogs with infectious panuveitis. Visual outcome was favorable in those dogs that responded to initial medical therapy, but long-term therapy was required in many dogs to maintain vision and prevent recurrence of disease.