Enantioselective Desymmetrization of Cyclobutanones: A Speedway to Molecular Complexity

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.     

Pd‐Catalyzed Enantioselective Ring Opening/Cross‐Coupling and Cyclopropanation of Cyclobutanones

A palladium‐catalyzed enantioselective sequential ring‐opening/cross‐coupling of cyclobutanones is disclosed that provides chiral indanones bearing C3‐quaternary stereocenters. The reaction process involves palladium‐catalyzed nucleophilic addition of cyclobutanones and aryl halides, enantioselective β‐carbon elimination, and intermolecular trapping of a transient σ‐alkylpalladium complex with boronic acids. Alternatively, an intramolecular cyclopropanation is realized through C?H bond functionalization in the absence of external coupling reagents, affording chiral cyclopropane‐fused‐indanones in good yields and enantioselectivity.     

Fused‐Ring Formation by an Intramolecular “Cut‐and‐Sew” Reaction between Cyclobutanones and Alkynes

The development of a catalytic intramolecular “cut‐and‐sew” transformation between cyclobutanones and alkynes to construct cyclohexenone‐fused rings is described herein. The challenge arises from the need for selective coupling at the more sterically hindered proximal position, and can be addressed by using an electron‐rich, but less bulky, phosphine ligand. The control experiment and ¹³C‐labelling study suggest that the reaction may start with cleavage of the less hindered distal C?C bond of cyclobutanones, followed by decarbonylation and CO reinsertion to enable Rh insertion at the more hindered proximal position.     

Enantioselective Cross‐Exchange between C−I and C−C σ Bonds

A palladium‐catalyzed enantioselective intramolecular σ‐bond cross‐exchange between C?I and C?C bonds is realized, providing chiral indanones bearing an alkyl iodide group and an all‐carbon quaternary stereocenter. Pd/TADDOL‐derived phosphoramidite is found to be an efficient catalytic system for both C?C bond cleavage and alkyl iodide reductive elimination. In addition to aryl iodides, aryl bromides can also be used for this transformation in the presence of KI. Density‐functional theory (DFT) calculation studies support the ring‐opening of cyclobutanones occuring through an oxidative addition/reductive elimination process involving Pd^IV species.     

Highly Enantioselective Rhodium(I)‐Catalyzed Activation of Enantiotopic Cyclobutanone CC Bonds

The selective functionalization of carbon–carbon σ bonds is a synthetic strategy that offers uncommon retrosynthetic disconnections. Despite progress in C? C activation and its great importance, the development of asymmetric reactions lags behind. Rhodium(I)‐catalyzed selective oxidative additions into enantiotopic C? C bonds in cyclobutanones are reported. Even operating at a reaction temperature of 130 °C, the process is characterized by outstanding enantioselectivity with the e.r. generally greater than 99.5:0.5. The intermediate rhodacycle is shown to react with a wide variety of tethered olefins to deliver complex bicyclic ketones in high yields.     

Nickel‐Catalyzed Chemo‐ and Enantioselective Coupling between Cyclobutanones and Allenes: Rapid Synthesis of [3.2.2] Bicycles

Herein an intramolecular nickel‐catalyzed (4+2) coupling between cyclobutanones and allenes, by C?C cleavage, is reported. The reaction provides a distinct approach for accessing [3.2.2] bicyclic scaffolds which are challenging to prepare through conventional approaches. The reaction is efficient, chemoselective, and pH/redox neutral. Room temperature conditions and low catalyst loadings can be adopted. Excellent enantioselectivity is also achieved.     

Regiodivergent Cyclobutanone Cleavage: Switching Selectivity with Different Lewis Acids

The exploitation of strain release in small rings as driving force to enable complex transformations is a powerful synthetic tool. Among them, cyclobutanones are particularly versatile substrates that can be elaborated in a wide variety of structurally diverse building blocks. Herein, Lewis acid catalyzed rearrangement reactions are presented that provide selective access to two structurally distinct polycyclic scaffolds, that is, indenylacetic acid derivatives and benzoxabicyclo[3.2.1]octan‐3‐ones. The choice of the Lewis acid fully controls the reaction pathway and the regioselectivity of the cyclobutanone C?C bond cleavage site.     

Acids direct 2-styrylcyclobutanone into two distinctly different reaction pathways

Two structurally distinct carbocycles were selectively obtained by the reactions of 2-(o-styryl)cyclobutanones promoted by ytterbium salts. Treatment of the cyclobutanones with YbCl(3) in 1,4-dioxane at 100 degrees C afforded 2-(2-chloroethyl)naphthalenes. On the other hand, the reaction with Yb(OTf)(3) in chlorobenzene at 130 degrees C gave 9,10-dihydrobenzocycloocten-7(8H)-ones.     

Non-Diazo C−H Insertion Approach to Cyclobutanones through Oxidative Gold Catalysis

Cyclobutanones are synthetically versatile compounds that often require extensive effort to access. Herein, we report a facile synthesis of cyclobutanones based on the C(sp³)−H insertion chemistry of oxidatively generated gold carbenes. Various cyclobutanones were obtained in synthetically useful yields from substrates with minimal structural prefunctionalization. This discovery reveals new synthetic utilities of gold-catalyzed oxidative transformations of alkynones.     

Non‐Diazo C−H Insertion Approach to Cyclobutanones through Oxidative Gold Catalysis

Cyclobutanones are synthetically versatile compounds that often require extensive effort to access. Herein, we report a facile synthesis of cyclobutanones based on the C(sp³)?H insertion chemistry of oxidatively generated gold carbenes. Various cyclobutanones were obtained in synthetically useful yields from substrates with minimal structural prefunctionalization. This discovery reveals new synthetic utilities of gold‐catalyzed oxidative transformations of alkynones.     

Palladium-catalyzed, asymmetric Baeyer-Villiger oxidation of prochiral cyclobutanones with PHOX ligands

Described in this report is a general method for the conversion of prochiral 3-substituted cyclobutanones to enantioenriched γ-lactones through a palladium-catalyzed Baeyer-Villiger oxidation using phosphinooxazoline ligands in up to 99% yield and 81% ee. Lactones of enantiopurity ≥93% could be obtained through a single recrystallization step. Importantly, 3,3-disubtituted cyclobutanones produced enantioenriched lactones containing a β-quaternary center.     

Phenyl(trimethylsilyl)ketene. Some ketene reactions with diazomethane

Phenyl(trimethylsilyl)ketene was prepared by the zinc dehalogenation of phenyl(trimethylsilyl)bromoacetyl chloride. This ketene parallels tirmethylsilylketene in stabibility and lack of reactivity in cycloaddition reactions. The reaction of phenyl(ethyl)-, phenyl(trimethylsilyl)- and trimethylsilylketenes with diazomethane at ?78°C is described. Only the $\text{2}\text{1}$ cycloadducts, the cyclobutanones, could be isolated.     

Copper‐Catalyzed Intermolecular Heck‐Like Coupling of Cyclobutanone Oximes Initiated by Selective C−C Bond Cleavage

The first example of intermolecular olefination of cyclobutanone oximes with alkenes via selective C−C bond cleavage leading to the synthesis of nitriles in the presence of a cheap copper catalyst is reported. The procedure is distinguished by mild and safe reaction conditions that avoid ligand, oxidant, base, or toxic cyanide salt. A wide scope of cyclobutanones and olefin coupling components can be used without compromising efficiency and scalability. The alternative visible‐light‐driven photoredox process for this coupling reaction was also uncovered.     

Very high stereoselectivity in organocatalyzed desymmetrizing aldol reactions of 3-substituted cyclobutanones

N-Phenylsulfonyl (S)-proline catalyzes the direct aldol reaction of 3-substituted cyclobutanones and aryl aldehydes in good yield and with excellent diastereoselectivity and enantioselectivity. This desymmetrization process provides highly functionalized cyclobutanones with control over three contiguous stereogenic centers.     

Lewis acid-catalyzed intermolecular [4 + 2] cycloaddition of 3-alkoxycyclobutanones to aldehydes and ketones

Intermolecular [4 + 2] cycloaddition between 3-alkoxycyclobutanones and aldehydes or ketones by the activation with boron trifluoride etherate is reported. The carbonyl compounds are inserted into the less substituted C2-C3 bond of the cyclobutanone ring of 6-alkyl-2-oxabicyclo[4.2.0]octan-7-ones to afford 1-alkyl-5,7-dioxabicyclo[4.4.0]decan-2-one derivatives regioselectively (>99:1) and diastereoselectively. On the other hand, [4 + 2] cycloaddition of 3-ethoxy-2,2-dialkylcyclobutanones at low temperature proceeds at the more substituted C2-C3 bond to yield 3,3-dialkyl-6-ethoxy-2,3,5,6-tetrahydro-4H-pyran-4-one derivatives with high regioselectivities. This [4 + 2] cycloaddition is developed into a one-pot synthesis of tri- or tetrasubstituted dihydro-gamma-pyrones from 3-ethoxycyclobutanones which are readily prepared from acid chloride and ethyl vinyl ether. The two regioselectivities observed in ring-opening of cyclobutanones can ascribe to thermodynamic stabilities of zwitterionic intermediates generated from tetrahydropyran-fused cyclobutanones and 3-ethoxycyclobutanones.     

Palladium-catalyzed sequential carbon-carbon bond cleavage/formation producing arylated benzolactones

3-(2-Hydroxyphenyl)cyclobutanones react with aryl bromides in the presence of palladium catalysts to afford 4-arylmethyl-3,4-dihydrocoumarins in high yields through a sequence involving carbon-carbon bond cleavage and formation. In the case of the reaction with 2-(2-hydroxyphenyl)cyclobutanones, five- or seven-membered lactones were produced depending on the presence of an additional substituent at the 2-position.     

Regio and stereospecific ring expansion of optically active cyclopropylvinylcarbinols. Diastereoselective synthesis of cis Quercus- lactone b.

(-)-(S) dimethyl α-methylsuccinate, from enzymatic resolution, underwent acyloin cyclization followed by stereospecific C4→ C3 ring contraction to provide chiral cyclopropylvinylcarbinols. Then, BF₃-Et₂O induced regio- and stereospecific C3 → C4 ring expansion led to optically active cyclobutanones precursors of cis γ-lactones, with high enantiomeric excesses.     

Controllable Skeleton Rearrangement of 3‐Substituted Cyclobutanones under Basic Conditions†

Divergent skeleton rearrangements of cyclobutanones under simply basic conditions have been described. The reaction pathway is controlled by the nature of Z group on 3‐substituted cyclobutanones, leading to the formation of various lactones, lactams and acids. Preliminary results on enantioselective reaction were also reported.     

Asymmetric synthesis of cyclobutanones: synthesis of cyclobut-G

A simple, efficient, and stereoselective approach has been developed for obtaining chiral cis- and trans-disubstituted cyclobutanones from readily available alkyl- and functionalized alkyl-substituted enol ethers. The usefulness of these cyclobutanones is illustrated by an enantioselective synthesis of cyclobut-G (Lobucavir).     

The mass spectra of substituted cyclobutanones

The low resolution mass spectra of several di-, tri-and tetra-methylated cyclobutanones were determined at high and low ionizing voltages. The spectra are discussed in terms of the competition between loss of CO or loss of a ketene from the molecular ion of the cyclobutanone. The mass spectral results are correlated with the known photochemical behavior of the cyclobutanones and possible mechanistic implications are discussed.