Enantioselective Total Synthesis of (-)-Himalensine A via a Palladium and 4-Hydroxyproline Co-catalyzed Desymmetrization of Vinyl-bromide-tethered Cyclohexanones.

Herein, we describe the convergent enantioselective total synthesis of himalensine A in 18 steps, enabled by a highly enantio- and diastereoselective construction of the morphan core via a palladium/hydroxy proline co-catalyzed desymmetrization of vinyl-bromide-tethered cyclohexanones. The reaction pathway was illuminated by density functional theory calculations, which support an intramolecular Heck reaction of an in situ-generated enamine intermediate, where exquisite enantioselectivity arises from intramolecular carboxylate coordination to the vinyl palladium species in the rate- and enantio-determining carbopalladation steps. The reaction tolerates diverse N-derivatives, all-carbon quaternary centers, and trisubstituted olefins, providing access to molecular scaffolds found in a range of complex natural products. Following large-scale preparation of a key substrate and installation of a ß-substituted enone moiety, the rapid construction of himalensine A was achieved using a highly convergent strategy based on an amide coupling/Michael addition/allylation/ring-closing metathesis sequence which allowed the introduction of three of the five rings in only three synthetic steps (after telescoping). Moreover, our strategy provides a new enantioselective access to a known tetracyclic late-stage intermediate that has been used previously in the synthesis of many Daphniphyllum alkaloids.

Decompression alone versus decompression with instrumented fusion in the treatment of lumbar degenerative spondylolisthesis: a systematic review and meta-analysis of randomised trials.

OBJECTIVE: To determine the efficacy of adding instrumented spinal fusion to decompression to treat degenerative spondylolisthesis (DS). DESIGN: Systematic review with meta-analysis. DATA SOURCES: MEDLINE, Embase, Emcare, Cochrane Library, CINAHL, Scopus, ProQuest Dissertations & Theses Global, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform from inception to May 2022. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials (RCTs) comparing decompression with instrumented fusion to decompression alone in patients with DS. Two reviewers independently screened the studies, assessed the risk of bias and extracted data. We provide the Grading of Recommendations, Assessment, Development and Evaluation assessment of the certainty of evidence (COE). RESULTS: We identified 4514 records and included four trials with 523 participants. At a 2-year follow-up, adding fusion to decompression likely results in trivial difference in the Oswestry Disability Index (range 0-100, with higher values indicating greater impairment) with mean difference (MD) 0.86 (95% CI -4.53 to 6.26; moderate COE). Similar results were observed for back and leg pain measured on a scale of 0 to 100, with higher values indicating more severe pain. There was a slightly increased improvement in back pain (2-year follow-up) in the group without fusion shown by MD -5·92 points (95% CI -11.00 to -0.84; moderate COE). There was a trivial difference in leg pain between the groups, slightly favouring the one without fusion, with MD -1.25 points (95% CI -6.71 to 4.21; moderate COE). Our findings at 2-year follow-up suggest that omitting fusion may increase the reoperation rate slightly (OR 1.23; 0.70 to 2.17; low COE). CONCLUSIONS: Evidence suggests no benefits of adding instrumented fusion to decompression for treating DS. Isolated decompression seems sufficient for most patients. Further RCTs assessing spondylolisthesis stability are needed to determine which patients would benefit from fusion. PROSPERO REGISTRATION NUMBER: CRD42022308267.

Convergent Assembly of the Tricyclic Labdane Core Enables Synthesis of Diverse Forskolin-like Molecules.

We report a new synthetic strategy for the flexible preparation of forskolin-like molecules. The approach is different from the previously published works and employs a convergent assembly of the tricyclic labdane-type core from pre-functionalized cyclic building blocks. Stereoselective Michael addition enabled the fragment coupling with excellent control over three newly created contiguous stereocenters, all-carbon quaternary centers included. Silyl enol ether-promoted ring-opening metathesis paired with ring closure were the other key steps enabling concise assembly of the tricyclic core. Late-stage functionalization sequences transformed the tricyclic intermediates into a set of different forskolin-like molecules. The modular nature of the synthetic scheme described herein has the potential to become a general platform for the preparation of analogs of forskolin and other complex tricyclic labdanes.

An Asymmetric Suzuki-Miyaura Approach to Prostaglandins: Synthesis of Tafluprost.

We report the catalytic asymmetric synthesis of Tafluprost (1), a prostaglandin analogue. This synthesis demonstrates a new approach to prostaglandins involving symmetrization and desymmetrization of a racemic precursor to control the absolute and relative stereochemistry of the cyclopentyl core. Key steps include a diastereo- and enantioselective Rh-catalyzed Suzuki-Miyaura reaction of a racemic bicyclic allyl chloride and an alkenyl boronic acid and a regio- and diastereoselective Pd-catalyzed Tsuji-Trost reaction with an enolate surrogate.

Directed C-H Bond Oxidation of (+)-Pleuromutilin.

Antibiotics derived from the diterpene fungal metabolite (+)-pleuromutilin (1) are useful agents for the treatment Gram-positive infections in humans and farm animals. Pleuromutilins elicit slow rates of resistance development and minimal cross-resistance with existing antibiotics. Despite efforts aimed at producing new derivatives by semisynthesis, modification of the tricyclic core is underexplored, in part due to a limited number of functional group handles. Herein, we report methods to selectively functionalize the methyl groups of (+)-pleuromutilin (1) by hydroxyl-directed iridium-catalyzed C-H silylation, followed by Tamao-Fleming oxidation. These reactions provided access to C16, C17, and C18 monooxidized products, as well as C15/C16 and C17/C18 dioxidized products. Four new functionalized derivatives were prepared from the protected C17 oxidation product. C6 carboxylic acid, aldehyde, and normethyl derivatives were prepared from the C16 oxidation product. Many of these sequences were executed on gram scales. The efficiency and practicality of these routes provides an easy method to rapidly interrogate structure-activity relationships that were previously beyond reach. This study will inform the design of fully synthetic approaches to novel pleuromutilins and underscores the power of the hydroxyl-directed iridium-catalyzed C-H silylation reaction.

A Concise Synthesis of Forskolin.

A 24-step synthesis of (±)-forskolin is presented, which delivered hundred milligram quantities of this complex diterpene in one pass. Transformations key to our approach include: a) a strategic allylic transposition, b) stepwise assembly of a sterically encumbered isoxazole ring, and c) citric acid-modified Upjohn dihydroxylation of a resilient tetrasubstituted olefin. The developed route has exciting potential for the preparation of new forskolin analogues inaccessible by semisynthesis.

Implant complications, fusion, loss of lordosis, and outcome after anterior cervical plating with dynamic or rigid plates: two-year results of a multi-centric, randomized, controlled study.

STUDY DESIGN: Prospective, controlled, randomized, multicenter study. OBJECTIVE: To analyze implant complications and speed. SUMMARY OF BACKGROUND DATA: Rigid plate designs, in which the screws are locked to the plate, are in common use and thought to provide more fixation than dynamic designs, in which the screws may glide when the graft is settling. The aim of the study is to analyze (1) implant complications, (2) speed of fusion, (3) loss of lordosis, and (4) clinical outcome in both types of plates. METHODS: One hundred thirty-two patients were included and assigned by randomization to one of the groups in which they received a routine anterior cervical discectomy and autograft fusion with either a dynamic plate (ABC, study group) or a rigid plate (CSLP, control group). At discharge, after 3 and 6 months and finally after 2 years, implant complications, segmental mobility, absence of radiolucencies, absence of bone sclerosis, evidence of bridging trabecular bone, loss of lordosis, Visual Analog Scale (VAS) and Neck Disability Score were recorded. All radiographic measurements were performed by an independent radiologist. RESULTS: There have been 4 patients with implant complications within the control group and no implant complications within the study group, P = 0.045. Mean segmental mobility before discharge for the study group was 1.7 mm, 1.4 mm after 3 months, 0.8 mm after 6 months, and 0.4 mm after 2 years. For the control group, these values were 1.0, 1.8, 1.6, and 0.5 mm. The difference at 6 months between both groups was significant (P = 0.024). Neither absence of radiolucencies, nor absence of sclerosis, nor evidence of bridging bone showed significant differences between the 2 groups through the postoperative follow-up (P > 0.05). The loss of segmental lordosis for the study group with respect to intraoperative radiograph was 1.3 degrees at discharge and 4.3 degrees after 2 years. For the control group, these values were 0.9 degrees , 0.7 degrees . The difference at 2 years was significant (P = 0.003). Clinical postoperative outcome (VAS and ODI) was not different between the 2 groups through the postoperative follow-up (P > 0.05). CONCLUSION: Dynamic cervical plate designs provide less implant complications (no patient) compared with rigid plate designs (4 patients). Speed of fusion was faster in the presence of a dynamic plate. However, loss of segmental lordosis is significantly higher if dynamic plates are used, which did not result in differences regarding clinical outcome between dynamic and constrained plates after 2 years. Thus, dynamic plates should be considered to be the preferred treatment option because of the lower risk for implant failure-related revision surgery.