Cyclobutanones hold a privileged role in enantioselective desymmetrization because their inherent ring strain allows for a variety of unusual reactions to occur. Current strategies include ...α‐functionalization, rearrangement, and C−C bond activation to directly convert cyclobutanones into a wide range of enantiomerically enriched compounds, including many biologically significant scaffolds. This Minireview provides an overview of state‐of‐the‐art methods that generate complexity from prochiral cyclobutanones in a single operation.
Take the strain: The ring strain of cyclobutanones makes them ideal for enantioselective desymmetrization. α‐Functionalization, rearrangement, and C−C bond activation can be used to directly convert cyclobutanones into enantiomerically enriched compounds, including many biologically significant scaffolds. This Minireview provides an overview of state‐of‐the‐art methods that generate complexity from prochiral cyclobutanones in a single operation.
Identification of a novel catalyst-allenoate pair allows enantioselective 2+2 cycloaddition of α-methylstyrene. To understand the origin of selectivity, a detailed mechanistic investigation was ...conducted. Herein, two competing reaction pathways are proposed, which operate simultaneously and funnel the alkenes to the same axially chiral cyclobutanes. In agreement with the Woodward-Hoffmann rules, this mechanistic curiosity can be rationalized through a unique symmetry operation that was elucidated by deuteration experiments. In the case of 1,1-diarylalkenes, distal communication between the catalyst and alkene is achieved through subtle alteration of electronic properties and conformation. In this context, a Hammett study lends further credibility to a concerted mechanism. Thus, extended scope exploration, including β-substitution on the alkene to generate two adjacent stereocenters within the cyclobutane ring, is achieved in a highly stereospecific and enantioselective fashion (33 examples, up to >99:1 er).
Strain relief of oxetanes offers a plethora of opportunities for the synthesis of chiral alcohols and ethers. In this context, enantioselective desymmetrization has been identified as a powerful tool ...to construct molecular complexity and this has led to the development of elegant strategies on the basis of transition metal, Lewis acid, and Brønsted acid catalysis. This review highlights recent examples that harness the inherent reactivity of prochiral oxetanes and offers an outlook on the immense possibilities for synthetic application.
Prochiral oxetanes are excellent candidates for the synthesis of chiral alcohols and ethers via enantioselective desymmetrization. Recent methods relying on transition metal, Lewis acid, and Brønsted acid catalysis allow access to a remarkably diverse set of compounds, which are highlighted and put into context.
Asymmetric access to γ‐lactams is achieved via a cyclobutanone ring expansion using widely available (1S,2R)‐1‐amino‐2‐indanol for chiral induction. Mechanistic analysis of the key N,O‐ketal ...rearrangement reveals a Curtin–Hammett scenario, which enables a downstream stereoinduction (up to 88:12 dr) and is corroborated by spectroscopic, crystallographic, and computational studies. In combination with an easy deprotection protocol, this operationally simple sequence allows the synthesis of a range of optically pure γ‐lactams, including those bearing all‐carbon quaternary stereocenters. In addition, the formal synthesis of drug molecules baclofen, brivaracetam, and pregabalin further demonstrates the synthetic utility and highlights the general applicability of the presented method.
(1S,2R)‐2‐Amino‐1‐indanol was identified as a chiral nitrogen source in an oxidative rearrangement of prochiral cyclobutanones. Building on strain release as the driving force, this downstream stereoinduction enables a variety of γ‐lactams to be synthesized including those bearing quaternary stereocenters. In addition, drug molecules pregabalin, baclofen, and brivaracetam are accessible, which underlines the broad applicability of this method.
The synthetic utility of prochiral oxetanes, based on their inherent ring‐strain and Lewis‐basicity, is highlighted in the Minireview by A. Sandvoß and J. M. Wiest on page 5871. Elegant ...desymmetrization strategies have been established for 3‐substituted, 3,3 as well as 2,2‐disubstituted oxetanes, which give rise to a diversity of products. The enantioselectivity of these reactions can be controlled through sophisticated choice of Lewis acids or Brønsted acids.
Detailed insight into the internal structure of drug‐loaded polymeric micelles is scarce, but important for developing optimized delivery systems. We observed that an increase in the curcumin loading ...of triblock copolymers based on poly(2‐oxazolines) and poly(2‐oxazines) results in poorer dissolution properties. Using solid‐state NMR spectroscopy and complementary tools we propose a loading‐dependent structural model on the molecular level that provides an explanation for these pronounced differences. Changes in the chemical shifts and cross‐peaks in 2D NMR experiments give evidence for the involvement of the hydrophobic polymer block in the curcumin coordination at low loadings, while at higher loadings an increase in the interaction with the hydrophilic polymer blocks is observed. The involvement of the hydrophilic compartment may be critical for ultrahigh‐loaded polymer micelles and can help to rationalize specific polymer modifications to improve the performance of similar drug delivery systems.
From bulk properties to a molecular level understanding: Solid‐state NMR spectroscopy complemented by X‐ray diffraction data and calculations gives insights into the loading‐dependent structure of micelles formed by amphiphilic triblock copolymers. As coordination sites in the core become saturated, stabilization of higher loadings requires coordination by the hydrophilic corona, which compromises dissolution.
The first synthesis of hebelophyllene E is presented, along with assignment of its previously unknown relative configuration through synthesis of epi‐ent‐hebelophyllene E. Development of a catalytic ...enantioselective 2+2 cycloaddition of alkenes and allenoates provides access to the required chiral geminal dimethylcyclobutanes. Key to its success is the identification of a novel oxazaborolidine catalyst which promotes the cycloaddition in high enantioselectivities with good functional‐group tolerance (9 examples, up to 97:3 e.r.). Thus, a late‐stage cycloaddition using a fully functionalized alkene, followed by a diastereoselective reduction allows a concise entry to this class of natural products.
First design, then assign: The first synthesis of hebelophyllene E is presented, along with assignment of its previously unknown relative configuration through the synthesis of epi‐ent‐hebelophyllene E. Development of a catalytic enantioselective 2+2 cycloaddition of alkenes and allenoates, followed by diastereoselective conjugate reduction provides access to the required chiral geminal dimethylcyclobutane core.
The application of thioallenoates to catalytic enantioselective 2+2-cycloadditions with unactivated alkenes is reported. In many cases, the thioallenoates examined exhibit superior reactivity and ...selectivity compared to the allenic esters generally used in these cycloadditions.
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In inflammatory bowel disease, dysregulated T cells express pro-inflammatory cytokines. Using a chronic azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis model resembling ulcerative ...colitis, we evaluated whether and when treatment with the Janus kinase (JAK) inhibitor tofacitinib could be curative. Comparing the treatment with two and three cycles of tofacitinib medication in drinking water - intermittently with DSS induction - revealed that two cycles were not only sufficient but also superior over the 3-x regimen. The two cycles of the 2-x protocol paralleled the second and third cycles of the longer protocol. T cells were less able to express interferon gamma (IFN-γ) and the serum levels of IFN-γ, interleukin (IL)-2, IL-6, IL-17, and tumor necrosis factor (TNF) were significantly reduced in sera, while those of IL-10 and IL-22 increased under the 2-x protocol. Likewise, the frequency and effector phenotype of regulatory T cells (Tregs) increased. This was accompanied by normal weight gain, controlled clinical scores, and restored stool consistency. The general and histologic appearance of the colons revealed healing and tissue intactness. Importantly, two phases of tofacitinib medication completely prevented AOM-incited pseudopolyps and the hyper-proliferation of epithelia, which was in contrast to the 3-x regimen. This implies that the initial IBD-induced cytokine expression is not necessarily harmful as long as inflammatory signaling can later be suppressed and that time-restricted treatment allows for anti-inflammatory and tissue-healing cytokine activities.
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