Enantioselective Synthesis of α-Aryl Ketones by a Cobalt-Catalyzed Semipinacol Rearrangement.

A highly enantioselective cobalt-catalyzed semipinacol rearrangement of symmetric α,α-diarylallylic alcohols is disclosed. A chiral cobalt-salen catalyst generates a highly electrophilic carbocation surrogate following hydrogen atom transfer and radical-polar crossover steps. This methodology provides access to enantioenriched α-aryl ketones through invertive displacement of a cobalt(IV) complex during 1,2-aryl migration. A combination of readily available reagents, silane and N-fluoropyridinium oxidant, are used to confer this type of reactivity. An exploration into the effect of aryl substitution revealed the reaction tolerates para- and meta-halogenated, mildly electron-rich and electron-poor aromatic rings with excellent enantioselectivities and yields. The yield of the rearrangement diminished with highly electron-rich aryl rings whereas very electron-deficient and ortho-substituted arenes led to poor enantiocontrol. A Hammett analysis demonstrated the migratory preference for electron-rich aromatic rings, which is consistent with the intermediacy of a phenonium cation.

Unique Reactivity of the 1,4-Bis(silyloxy)-1,3-cyclopentadiene Moiety: Application to the Synthesis of 7-Norbornanone Derivatives.

We describe a method for the synthesis of various 2-silyloxy-2-norbornen-7-ones by exploiting the specific reactivity of the 1,4-bis(silyloxy)-1,3-cyclopentadiene framework, which is generated by the silylation of a 2,2-disubstituted-1,3-cyclopentanedione bearing a picolinoyloxy group at the 2' position of its C-2 side chain. The release of the acyloxy group during the reaction generates carbocations that are then attacked by silyloxy-substituted carbons in the 1,4-bis(silyloxy)-1,3-cyclopentadiene moiety skeleton, forming a 4,5-cis-fused ring skeleton. Skeletal rearrangement of the bicyclic core results in the formation of the corresponding 2-silyloxy-2-norbornen-7-one. This novel transformation of 1,3-cyclopentanedione moieties can be used to synthesise other cyclopentenone-fused bicyclic frameworks.

A Domino Radical Amidation/Semipinacol Approach to All-Carbon Quaternary Centers Bearing an Aminomethyl Group.

A photoredox-mediated radical amidation ring-expansion sequence that enables the generation of all-carbon quaternary centers bearing a protected aminomethyl substituent is described. The methodology can be applied to both styrene and unactivated alkene substrates generating structurally diverse sp3 -rich amine derivatives in a concise manner.

Expedient synthesis of spiro[3.3]heptan-1-ones via strain-relocating semipinacol rearrangements.

A novel approach for the formation of the highly strained spiro[3.3]heptan-1-one motif was developed through the reaction of 1-sulfonylcyclopropanols and lithiated 1-sulfonylbicyclo[1.1.0]butanes. Following initial nucleophilic addition to the cyclopropanone formed in situ, the resulting 1-bicyclobutylcyclopropanol intermediate is prone to a 'strain-relocating' semipinacol rearrangement in the presence of acid, directly affording the substituted spiro[3.3]heptan-1-one. The process is shown to be fully regio- and stereospecific when starting from a substituted cyclopropanone equivalent, leading to optically active 3-substituted spiro[3.3]heptan-1-ones. The reaction likely proceeds via initial protonation of the bicyclobutyl moiety followed by [1,2]-rearrangement of the resulting cyclopropylcarbinyl cation.

Catalytic Asymmetric Halogenation/Semipinacol Rearrangement of 3-Hydroxyl-3-vinyl Oxindoles: A Stereodivergent Kinetic Resolution Process.

A highly enantioselective halogenation/semipinacol rearrangement of isatin-derived allylic alcohols has been developed with a chiral N,N'-dioxide/ScIII complex as catalyst. This strategy involved a pivotal stereodivergent kinetic resolution process and provided a facile and efficient entry to optically active halo-substituted quinolone derivatives and quinoline alkaloids with a quaternary stereocenter simultaneously under mild reaction conditions. Based on the control experiments together with kinetic studies and DFT calculations, a possible catalytic cycle was proposed to illustrate the reaction process and enantiocontrol.

Semipinacol rearrangement of a bicyclo[7.2.0]undecane framework into a bicyclo[6.3.0]undecane skeleton: a model study on the biosynthesis of seiridiasteriscane A.

Seiridiasteriscane A is an asteriscane-type sesquiterpenoid bearing a trans-fused bicyclo[6.3.0]undecane skeleton. Although its biosynthesis has been proposed to involve a semipinacol rearrangement of a putative intermediary acetate bearing a bicyclo[7.2.0]undecane ring system (presumably derived from coisolated pestalotiopsin M) followed by epimerization of the resulting cis-fused seiridiasteriscane B, such a type of semipinacol rearrangement has never been reported so far. Our model study revealed that a 1-hydroxybicyclo[7.2.0]undecan-2-yl acetate underwent a smooth and stereospecific semipinacol rearrangement with the assistance of Et2AlCl to give the corresponding bicyclo[6.3.0]undecane-9-one. In addition, the resulting cis-fused 5,8-bicyclic ketone was partially epimerized to the corresponding trans-fused ketone by prolonged adsorption onto a silica gel plate. These results may support a recently proposed biosynthetic pathway of seiridiasteriscane A.

Total Synthesis of Kopsinitarine†E.

Kopsinitarines A-E are complex octacyclic caged Kopsia alkaloids with strained cage skeletons and a unique cyclic hemiaminal bridge that makes total synthesis challenging. Herein, we disclose the first total synthesis of kopsinitarine E. The key synthetic features include a SmI2 -mediated radical cascade cyclization and a subsequent semi-pinacol rearrangement to install the key carbocyclic skeleton, a chemoselective hydrosilyl amide reduction to construct the hemiaminal ether bridge, and an intramolecular Mannich reaction to establish the highly strained cage system.

Collective Total Synthesis of Aspidofractinine Alkaloids through the Development of a Bischler-Napieralski/Semipinacol Rearrangement Reaction.

A tandem Bischler-Napieralski/semipinacol rearrangement reaction has been developed for the purpose of assembling a bis(spirocyclic) indole framework, a privileged structural unit of aspidofractinine-type monoterpenoid indole alkaloids, and was used in combination with a subsequent Mannich reaction to expeditiously construct the central bridged bicyclo[2.2.1]heptane ring system of these molecules with contiguous quaternary centers. The development of this novel strategy culminated in the collective total synthesis of four aspidofractinine alkaloids.

Enantioselective Catalytic Aldehyde α-Alkylation/Semipinacol Rearrangement: Construction of α-Quaternary-δ-Carbonyl Cycloketones and Total Synthesis of (+)-Cerapicol.

An enantioselective aldehyde α-alkylation/semipinacol rearrangement was achieved through organo-SOMO catalysis. The catalytically generated enamine radical cation serves as a carbon radical electrophile that can stereoselectively add to the alkene of an allylic alcohol and initiate ensuing ring-expansion of cyclopropanol or cyclobutanol. This tandem reaction enables the production of a wide range of nonracemic functionalizable α-quaternary-δ-carbonyl cycloketones in high yields and excellent enantioselectivity from simple aldehydes and allylic alcohols. As a key step, the intramolecular reaction was also successfully applied in the asymmetric total synthesis of (+)-cerapicol.

Lewis Base/Brønsted Acid Co-catalyzed Enantioselective Sulfenylation/Semipinacol Rearrangement of Di- and Trisubstituted Allylic Alcohols.

An enantioselective sulfenylation/semipinacol rearrangement of 1,1-disubstituted and trisubstituted allylic alcohols was accomplished with a chiral Lewis base and a chiral Brønsted acid as cocatalysts, generating various ß-arylthio ketones bearing an all-carbon quaternary center in moderate to excellent yields and excellent enantioselectivities. These chiral arylthio ketone products are common intermediates with many applications, for example, in the design of new chiral catalysts/ligands and the total synthesis of natural products. Computational studies (DFT calculations) were carried out to explain the enantioselectivity and the role of the chiral Brønsted acid. Additionally, the synthetic utility of this method was exemplified by an enantioselective total synthesis of (-)-herbertene and a one-pot synthesis of a chiral sulfoxide and sulfone.

Cis/Trans Energetics in Epoxide, Thiirane, Aziridine and Phosphirane Containing Cyclopentanols: Effects of Intramolecular OH⋯O, S, N and P Contacts.

A recent computational analysis of the stabilizing intramolecular OH⋯O contact in 1,2-dialkyl-2,3-epoxycyclopentanol diastereomers has been extended to thiiriane, aziridine and phosphirane analogues. Density functional theory (DFT), second-order Møller-Plesset perturbation theory (MP2) and CCSD(T) coupled-cluster computations with simple methyl and ethyl substituents indicate that electronic energies of the c i s isomers are lowered by roughly 3 to 4 kcal mol-1 when the OH group of these cyclopentanol systems forms an intramolecular contact with the O, S, N or P atom on the adjacent carbon. The results also suggest that S and P can participate in these stabilizing intramolecular interactions as effectively as O and N in constrained molecular environments. The stabilizing intramolecular OH⋯O, OH⋯S, OH⋯N and OH⋯P contacts also increase the covalent OH bond length and significantly decrease the OH stretching vibrational frequency in every system with shifts typically on the order of -41 cm-1.

Sonochemically assisted 2,3-dideoxygenation and skeletal rearrangement of ecdysteroid derivatives.

Sonochemical 2,3-dideoxygenation of ecdysteroids with the Δ 2(3)-bond generation and activation of the C-C bonds of the steroid core in the poststerone derivatives, that causes the skeletal rearrangement have been carried out for the first time. Thus, the ultrasonically assisted reaction of 2,3-dimesyloxy derivatives of ecdysteroids with the NaI-Zn-DMF system gives rise to their 2,3-dideoxy-Δ2(3)-analogues with yields 70-92%. In the case of 2,3-dimesyloxypoststerone as the initial ecdysteroid substrate the reaction is accompanied by the activation of the allyl moiety and semipinacol rearrangement, resulting in the C13-C14 bond migration with C/D rings contraction/expansion and providing novel short chain (8R)-13(14 → 8)-abeo-isomer.

A Facile Approach to Oximes and Ethers by a Tandem NO+ -Initiated Semipinacol Rearrangement and H-Elimination.

An efficient oximation method has been developed on the basis of NO+ -initiated semipinacol rearrangement and subsequent proton elimination. The procedure enabled the rapid construction of a series of oximes and oxime ethers with spiro quaternary stereocenters from allylic silyl ethers. Additional features of this reaction include wide substrate tolerance as well as the commercial availability of the safe nitrosation reagent NOBF4 . The key N-heterotricyclic cores of three natural alkaloids, tuberostemoninol B, (+)-quebrachidine, and an insecticide, were also constructed efficiently by this method.

Organocatalytic Asymmetric Cascade Aerobic Oxidation and Semipinacol Rearrangement Reaction: A Visible Light-Induced Approach to Access Chiral 2,2-Disubstituted Indolin-3-ones.

An enantioselective cascade aerobic oxidation and semipinacol rearrangement reaction of 2-aryl-3-alkyl-substituted indoles via visible-light-driven cooperative organophotoredox and H-bonding catalysis is reported. The current method provides an expedient and sustainable approach to furnish a variety of valuable chiral 2-aryl-2-alkyl-substituted indolin-3-ones in 64-90 % yield with 58-94 % ee. Preliminary control experiments present important insights into the stereochemistry.

Recent Advances in the Synthesis of ß-Functionalized Ketones by Radical-Mediated 1,2-Rearrangement of Allylic Alcohols.

ß-Functionalized ketones are a highly important and valuable class of compounds that have gained increasing attention from organic chemists due to their intensive uses as versatile synthetic intermediates and building blocks in complex molecule assembly and natural product synthesis. Accordingly, there is continuing interest in the development of new approaches for the synthesis of ß-functionalized ketones. In recent years, radical-mediated 1,2-rearrangement reactions of allylic alcohols, which proceed through cationic (semipinacol) rearrangements or radical (neophyl) rearrangements, have presented an attractive and powerful strategy to access various diversely ß-functionalized ketones. Interestingly, this strategy allows for the direct installation of a variety of valuable functional groups at the ß-position of cyclic and acyclic ketones by employing different radical precursors. However, a review focusing on the preparation of ß-functionalized ketones by radical-mediated 1,2-rearrangement reactions of allylic alcohols has not been summarized to date. This Minireview highlights recent progress made in this highly active and interesting research area, and the corresponding mechanisms will also be discussed.

Copper-Catalyzed Enantioselective Domino Arylation/Semipinacol Rearrangement of Allylic Alcohols with Diaryliodonium Salts.

A copper-catalyzed enantioselective arylative semipinacol rearrangement of allylic alcohols was developed. In the presence of a catalytic amount of an in situ generated chiral copper-bisoxazoline complex, reaction of allylic alcohols with diaryliodonium salts afforded spirocycloalkanones in high yields with high diastereo- and enantioselectivities. A two-point binding model engaging the carbon-carbon double bond and the proximal hydroxyl group was proposed to be responsible for the highly efficient chirality transfer.

Total Syntheses of the Tetracyclic Cyclopiane Diterpenes Conidiogenone, Conidiogenol, and Conidiogenone†B.

Total syntheses of the biologically important and structurally unique tetracyclic diterpenes conidiogenone, conidiogenol, and conidiogenone B of the cyclopiane class are reported. The absolute configuration of naturally occurring conidiogenone B was also corrected. The key step of our strategy involved the highly efficient construction of both ring C and the quaternary carbon center shared by rings A and C through a one-step regioselective and diastereoselective cycloenlargement in the form of a semipinacol-type rearrangement. In particular, the desired regioselectivity was made possible by properly adjusting the migratory aptitude of the migrating carbon atom through the introduction of an electron-donating phenylthio group at this position.

Asymmetric Total Synthesis of (-)-Maoecrystal†V.

The asymmetric total synthesis of (-)-maoecrystal V, a novel cytotoxic pentacyclic ent-kaurane diterpene, has been accomplished. Key steps of the current strategy involve an early-stage semipinacol rearrangement reaction for the construction of the C10 quaternary stereocenter, a rhodium-catalyzed intramolecular O-H insertion reaction, and a sequential Wessely oxidative dearomatization/intramolecular Diels-Alder reaction to forge the pentacyclic framework of maoecrystal V.

Enantioselective halogenative semi-pinacol rearrangement: extension of substrate scope and mechanistic investigations.

The present Full Paper article discloses a survey of our recent results obtained in the context of the enantioselective halogenation-initiated semi-pinacol rearrangement. Commencing with the fluorination/semi-pinacol reaction first and moving to the heavier halogens (bromine and iodine) second, the scope and limitations of the halogenative phase-transfer methodology will be discussed and compared. An extension of the fluorination/semi-pinacol reaction to the ring-expansion of five-membered allylic cyclopentanols will be also described, as well as some preliminary results on substrates prone to desymmetrization will be given. Finally, the present manuscript will culminate with a detailed mechanistic investigation of the canonical fluorination/semi-pinacol reaction. Our mechanistic discussion will be based on in situ reaction progress monitoring, complemented with substituent effect, kinetic isotopic effect and non-linear behaviour studies.

A synthetic approach for constructing the 3/6/6/5-fused tetracyclic skeleton of tenuipesine A.

An efficient approach toward the 3/6/6/5-fused tetracyclic skeleton of tenuipesine A has been accomplished. The strategy featured 1) a tandem Mitsunobu and 3,3-rearrangement reaction yielding the key intermediate 7 with two adjacent all-carbon quaternary centers with high d.r.; and 2) a tandem DBDMH-mediated semipinacol rearrangement via a 1,2-oxygen migration of an allylic hemiketal to construct the highly substituted tetrahydropyran ring.