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.
Methylenecyclobutanes are found to undergo Wacker oxidation via a semi‐pinacol‐type rearrangement. Key to a successful process is the use of tert‐butyl nitrite as oxidant, which not only enables ...efficient catalyst turn‐over but also ensures high Markovnikov‐selectivity under mild conditions. Thus, cyclopentanones (26 examples) can be accessed in an overall good yield and excellent selectivity (up to 97 % yield, generally >99 : 1 ketone:aldehyde ratio). Stereochemical analysis of the reaction sequence reveals migration aptitudes in line with related 1,2‐shifts. By introducing a pyox ligand to palladium, prochiral methylenecyclobutanes can be desymmetrized, thus realizing the first enantioselective Wacker oxidation.
Methylenecyclobutanes undergo Wacker oxidation towards cyclopentanones under mild reaction conditions. A semi‐pinacol‐type rearrangement is proposed to be responsible for the intermediary 1,2‐shift, which not only explains the formation of the products, but also rationalizes the reaction outcomes in terms of site‐, regio‐ and enantioselectivity.
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.
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).
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.
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.
α-Aminoacetophenones are identified as promising building blocks for the synthesis of highly substituted dioxolanes. The presented strategy is founded on the build and release of molecular strain and ...achieves a formal transposition of a methyl group. During light irradiation, 3-phenylazetidinols are forged as reaction intermediates, which readily undergo ring opening upon the addition of electron-deficient ketones or boronic acids. Key to the successful development of this two-step process is the identification of a benzhydryl-protecting group, which orchestrates the photochemical Norrish–Yang cyclization and facilitates the subsequent ring opening.
Identification of an electron poor trifluoroacetophenone allows the formation of uniquely stable hemiketals from prochiral oxetanols. When exposed to a cobalt(
ii
) catalyst, efficient ring-opening ...to densely functionalized dioxolanes is observed. Mechanistic studies suggest an unprecedented redox process between the cobalt(
ii
) catalyst and the hemiketal that initiates the oxetane-opening. Based on this observation, a dynamic kinetic resolution of the transient hemiketals is explored that uses a Katsuki-type ligand for stereoinduction (up to 99 : 1 dr and 96 : 4 er) and allows a variety of 1,3-dioxolanes to be accessed (20 examples up to 98% yield).
Desymmetrization of prochiral oxetanols
via
an electron-deficient hemiketal intermediate is achieved. Key to this process is the catalyst's chiral recognition of one of the two hemiketal enantiomers enabling an efficient dynamic kinetic resolution.
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