Enantioselective Synthesis of Piperidines through the Formation of Chiral Mixed Phosphoric Acid Acetals: Experimental and Theoretical Studies

An enantioselective intramolecular chiral phosphoric acid‐catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two‐step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous S_N2′‐like displacement to yield the product with stereoselectivity in agreement with experimental observations.     

Mn(III)-based oxidative free-radical cyclizations of substituted allyl alpha-methyl-beta-ketoesters: syntheses,DFT calculations,and mechanistic studies

The cyclizations of the substituted allyl alpha-methyl-beta-ketoester radicals 11, 14, and 18 were studied by the DFT method at the UB3LYP/6-31G level; the results show that the cis cyclization is easier than the corresponding trans cyclization, but the generated cis radicals are not necessarily more stable than the corresponding generated trans radicals after the cyclizations. The free-radical cyclizations of 11, 14, and 18 in the presence of Mn(OAc)(3) in acetic acid or acetonitrile are all reversible and operate under thermodynamic control, and stereoselectivity of the cyclizations depends on relative stability of the cyclization-generated radicals. Therefore, the oxidative free-radical cyclization of allyl alpha-methyl-beta-ketoester 5a with Mn(OAc)(3) gives a cis product as a major product, while the same oxidative free-radical cyclizations of substituted allyl alpha-methyl-beta-ketoesters 5b and 5c with Mn(OAc)(3) produce trans products as major products.     

Radical 4‐exo Cyclizations via Template Catalysis

The mechanism of catalytic 4‐exo cyclizations without gem‐dialkyl substitution was investigated by a comparison of cyclic voltammetry, EPR, and computational studies with previously published synthetic results. The most active catalyst is a super‐unsaturated 13‐electron titanocene(III) complex that is formed by supramolecular activation through hydrogen bonding. The template catalyst binds radicals via a two‐point binding that is mandatory for the success of the 4‐exo cyclization. The computational investigations revealed that formation of the observed trans‐cyclobutane product is not possible from the most stable substrate radical. Instead, the most stable product is formed with the lowest energy of activation from a disfavored substrate in a Curtin–Hammett related scenario.     

Synthesis of (-)-centrolobine by Prins cyclizations that avoid racemization

[formula: see text] The segment-coupling Prins cyclization avoids two of the problems common to other Prins cyclization protocols: side-chain exchange and partial racemization by reversible 2-oxonia Cope rearrangement. Model studies demonstrate the stereochemical fidelity of Prins cyclizations using alpha-acetoxy ethers compared with direct aldehyde-alcohol Prins reactions. Furthermore, we propose a mechanism for the racemization observed in some intermolecular Prins cyclizations. Two straightforward syntheses of optically pure (-)-centrolobine highlight the utility of Prins cyclizations.     

7-endo selective aryl radical cyclization onto enamides leading to 3-benzazepines: concise construction of a cephalotaxine skeleton

Bu3SnH-mediated radical cyclizations of 2-(2-bromophenyl)-N-ethenylacetamide gave 6-exo cyclization product 15 as the major product, whereas N-[2-(2-bromophenyl)ethyl]-N-ethenylamides gave almost exclusively 7-endo cyclization products. These results indicated that the position of the carbonyl group on enamide played an important role in deciding the course of the cyclization. The 7-endo selective cyclization was applied to concise construction of a cephalotaxine skeleton.     

Synthesis of 3,4-disubstituted piperidines by carbonyl ene and prins cyclizations: switching between kinetic and thermodynamic control with Brønsted and Lewis acid catalysts

A novel approach to cis and trans 3,4-disubstituted piperidines is described. Carbonyl ene cyclization of aldehydes 4a-e catalyzed by MeAlCl(2) in refluxing chloroform afforded the trans piperidines 7a-e with diastereomeric ratios of up to 93:7, while aldehyde 4f afforded solely the cis product 6f, which was resistant to isomerization to the trans isomer. It was demonstrated for 4a that the cyclization catalyzed by a variety of Lewis acids at low temperature proceeded under kinetic control to afford predominantly the cis piperidine 6a, and this isomerized to the thermodynamically more stable trans piperidine 7a on warming. In contrast, Prins cyclization of 4a-e catalyzed by concentrated hydrochloric acid in CH2Cl2 at low temperature afforded cis piperidines 6a-e with diastereomeric ratios of up to >98:2. The yield and diastereoselectivity of these cyclizations could be improved by using HCl-saturated CH2Cl2 to form the corresponding chloride, followed by elimination of HCl effected by ammonia. Aldehydes 4f and 4galso cyclized in good yield under the latter conditions. Mechanistic studies supported by DFT calculations (B3LYP/6-31G(d)) suggest that the cyclizations proceed via a mechanism with significant carbocationic character, with the cis carbocation being more stable than the trans carbocation. DFT calculations (B3LYP/6-31G(d)) of the transition state energies for concerted cyclization show that the cis piperidine is also the favored product from cyclization through a more concerted mechanism.     

A Transannular Polyene Tetracyclization for Rapid Construction of the Pimarane Framework

Polyene cyclizations are one of the most powerful and fascinating chemical transformations to rapidly generate molecular complexity. However, cyclizations employing heteroatom‐substituted polyenes are rare. Described here is the tetracyclization of a dual nucleophilic aryl enol ether involving an unprecedented transannular endo‐termination step. In this transformation, five stereocenters, two of which are quaternary, four carbon–carbon bonds, and four six‐membered rings are formed from a readily available cyclization precursor. The realization of this cyclization enabled short synthetic access to the tricyclic diterpenoid pimara‐15‐en‐3α‐8α‐diol.     

On the regioselectivity of the cyclization of enyne-ketenes: a computational investigation and comparison with the Myers-Saito and Schmittel reaction

The Moore (C(2)-C(7)) cyclization and the alternative C(2)-C(6) cyclization of enyne-ketenes belong to the family of biradical cyclization reactions such as the Bergman reaction of ene-diynes, both the cyclizations of enyne-allenes and enyne-cumulenes. The latter garnered substantial interest due to their antitumor efficacy. The mechanisms of both cyclization modes of enyne-ketenes are still unclear, but as the enyne-ketenes can formally be regarded as heteroanalogues of enyne-allenes, both cyclizations are expected to react via biradical routes. Nevertheless, as shown recently for cyclic allenes, the substitution of a methylene group by oxygen can lead to different energetic ordering of the electronic states of the key intermediates. To elucidate the mechanism, the present work investigates the course of both cyclization modes for various model compounds. To reveal general motifs for the large family of biradical cyclizations, a comparison with enyne-allenes is performed.     

Functionalized Contorted Polycyclic Aromatic Hydrocarbons by a One‐Step Cyclopentannulation and Regioselective Triflyloxylation

The oxidative cyclodehydrogenation (often named the Scholl reaction) is still a powerful synthetic tool to construct even larger polycyclic aromatic hydrocarbons (PAHs) by multiple biaryl bond formations without the necessity of prior installation of reacting functional groups. Scholl‐type reactions are usually very selective although the resulting products bear sometimes some surprises, such as the formation of five‐membered instead of six‐membered rings or the unexpected migration of aryl moieties. There are a few examples, where chlorinated byproducts were found when FeCl₃ was used as reagent. To our knowledge, the direct functionalization of PAHs during Scholl‐type cyclization by triflyloxylation has not been observed. Herein we describe the synthesis of functionalized PAHs by the formation of five‐membered rings and a regioselective triflyloxylation in one step. The triflyloxylated PAHs can be used as reactants for further transformation to even larger contorted PAHs.     

Recent Progress on Nazarov Cyclizations: The Use of Iron Salts as Catalysts in Ionic Liquid Solvent Systems

Nazarov cyclization is an important and versatile method for the synthesis of five‐membered carbocycles, and extensive studies have been conducted to optimize the reaction. Among recent studies, several trends are recognized. One is the combination of different reactions with Nazarov cyclization in a one‐pot reaction system which enables the preparation of unique cyclization products. The second is the use of a transition‐metal catalyst, though Lewis or Brønsted acids have generally been used for the reaction. The third is the realization of the asymmetric Nazarov cyclization. The fourth is the base‐catalyzed Nazarov cyclization. Furthermore, several useful protocols for realizing Nazarov cyclization have also been developed. The recent progress on Nazarov cyclizations is summarized in Section 2. Section 3 is our chronicle in this field. We focused on the use of iron as the catalyst in Nazarov cyclizations and ionic liquids as solvents: Nazarov cyclization of thiophene derivatives using FeCl₃ as the catalyst was accomplished and we succeeded in demonstrating the first example of an iron‐catalyzed asymmetric Nazarov reaction. We next established Nazarov cyclization of pyrrole or indole derivatives using Fe(ClO₄)₃·Al₂O₃ as the catalyst with high trans selectivities in excellent yields. Since the cyclized product was reacted with a vinyl ketone in the presence of the same iron salt, the system allowed realization of the sequential type of Nazarov/Michael reaction of pyrrole derivatives. Furthermore, we demonstrated the recyclable use of the iron catalyst and obtained the desired Nazarov/Michael reaction products in good yields for five repetitions of the reactions without any addition of the catalyst using an ionic liquid, [bmim][NTf₂], as the solvent. We expect that the iron‐catalyzed Nazarov cyclization, in particular, in an ionic liquid solvent might become a useful method to synthesize functional molecules that include cycloalkene moieties.     

Highly enantioselective reductive cyclization of acetylenic aldehydes via rhodium catalyzed asymmetric hydrogenation

Catalytic hydrogenation of acetylenic aldehydes 1a-12a using chirally modified cationic rhodium catalysts enables highly enantioselective reductive cyclization to afford cyclic allylic alcohols 1b-12b. Using an achiral hydrogenation catalyst, the chiral racemic acetylenic aldehydes 13a-15a engage in highly syn-diastereoselective reductive cyclizations to afford cyclic allylic alcohols 13b-15b. Ozonolysis of cyclization products 7b and 9b allows access to optically enriched alpha-hydroxy ketones 7c and 9c. Reductive cyclization of enyne 7a under a deuterium atmosphere provides the monodeuterated product deuterio-7b, consistent with a catalytic mechanism involving alkyne-carbonyl oxidative coupling followed by hydrogenolytic cleavage of the resulting oxametallacycle. These hydrogen-mediated transformations represent the first examples of the enantioselective reductive cyclization of acetylenic aldehydes.     

A Twisted Nanographene Consisting of 96 Carbon Atoms

Herein we report synthesis, structure and properties of a new type of twisted nanographene, which contains an [8]circulene moiety in a polycyclic framework of 96 sp² carbon atoms. The key steps in this synthesis are the Diels–Alder reaction of a macrocyclic diyne and the subsequent Scholl reaction forming the [8]circulene moiety. Two incompletely cyclized products were isolated from the Scholl reaction, providing insight into the cyclization of the strained octagon. This nanographene is twisted along two directions with end‐to‐end twists of 142.4° and 140.2° as revealed by X‐ray crystallography, and is flexible at room temperature as found from the computational and experimental studies.     

Theoretical elucidation of kinetic and thermodynamic control of radical addition regioselectivity

The cyclizations of two structurally similar 2-oxo-5-hexenyl-type radicals have been investigated by ab initio and density functional (UB3LYP/6-31+G**//UHF/6-31G* and UB3LYP/6-31G*//UB3LYP/6-31G*) calculations. The origin of apparently contradictory reports of 6-endo and 5-exo cyclizations is determined. Kinetic control favors 6-endo cyclization, while thermodynamic control gives 5-exo cyclization, and the observation of different products from different research groups arises from the difference in experimental conditions used by the two groups. The outcome of a new cyclization reaction was predicted by using these theoretical techniques. Kinetic control is predicted to yield exclusively the products of 6-endo cyclization, while thermodynamic control would lead to an approximately equal mixture of one 6-endo and one 5-exo cyclized product. Experimental studies revealed that the reaction yields only the products of 6-endo cyclization through kinetic control.     

Hydrazide‐Catalyzed Polyene Cyclization: Asymmetric Organocatalytic Synthesis of cis‐Decalins

Polyene cyclizations offer rapid entry into terpenoid ring systems. Although enantioselective cyclizations of (E)‐polyenes to form trans‐decalin ring systems are well precedented, highly enantioselective cyclizations of (Z)‐polyenes to form the corresponding cis‐decalins have not been reported. Here, we describe the first application of iminium catalysis to the initiation of polyene cyclizations. Ethyl 1,2‐diazepane‐1‐carboxylate catalyzes the cyclization of polyenes bearing enal initiators. Moreover, chiral bicyclic hydrazides catalyze the cyclizations of (Z)‐polyene substrates to form cis‐decalins with enantioselectivities of up to 97:3 er. DFT calculations suggest the catalysts promote the reaction by stabilizing positive charge as it develops during the bicyclization.     

5-endo-dig radical cyclizations: "the poor cousins" of the radical cyclizations family

Kinetics and thermodynamics of 5-endo-dig radical cyclizations were studied using a combination of DFT computations and Marcus theory. When the reactant is stabilized by conjugation of the radical center with the bridge pi-system, the cyclization starts with reorientation of the radical orbital needed to reach the in-plane acetylene pi-orbital in the bond-forming step. This reorientation leads to loss of the above conjugative stabilization, increases the activation energy, and renders such cyclizations less exothermic. As a result, even when the radical needed for the 5-endo cyclization is formed efficiently, it undergoes either H-abstraction or equilibration with an isomeric radical. Only when the bridging moiety is saturated or when intramolecular constraints prevent the overlap of the bridge pi-orbital and the radical center, 5-endo cyclizations may be able to proceed with moderate efficiency under conditions when H-abstraction is slow. The main remaining caveat in designing such geometrically constrained 5-endo-dig cyclizations is their sensitivity to strain effects, especially when polycyclic systems are formed. The strain effects can be counterbalanced by increasing the stabilization of the product (e.g., by introducing heteroatoms into the bridging moiety). Electronic effects of such substitutions can be manifested in various ways, ranging from aromatic stabilization to a hyperconjugative beta-Si effect. The 4-exo-dig cyclization is kinetically competitive with the 5-endo-dig process but less favorable thermodynamically. As a result, by proper design of reaction conditions, 5-endo-dig radical cyclizations should be experimentally feasible.     

From Fenestrindane towards Saddle‐Shaped Nanographenes Bearing a Tetracoordinate Carbon Atom

Two saddle‐shaped polycyclic aromatic compounds ( 8 a and 8 b ) bearing an all‐cis‐[5.5.5.5]fenestrane core surrounded by an o,p,o,p,o,p,o,p‐cyclooctaphenylene belt were synthesized and characterized by NMR spectroscopy and mass spectrometry. The key step of this synthesis involves the formation of four cycloheptatriene rings from the corresponding electron‐rich 1,4,9,12‐tetraarylfenestrindane derivatives 7 a and 7 b in Scholl‐type cyclizations. The structural details of the D_2d‐symmetric saddle compound 8 a were determined by X‐ray crystallography, and the properties of 8 a and 8 b were studied by UV/Vis and fluorescence spectroscopy and cyclic voltammetry.     

Mechanistic Understanding of the Divergent Cyclizations of o‐Alkynylbenzaldehyde Acetals and Thioacetals Catalyzed by Metal Halides

The mechanisms of regiodivergent cyclizations of o‐alkynylbenzaldehyde acetals and thioacetals catalyzed by Pd and Pt halides are studied. DFT calculations found that both reactions are initiated by electrophilic activation of the acetylenic moiety instead of the previously proposed metal‐triggered C?X (X=O, S) cleavage. Both the regioselective cyclization of the π‐alkyne complex and the chemoselective [1,2]‐migration in the carbenoid intermediate were determined as key steps to achieving the observed divergence. For acetal derivatives containing an internal alkyne, the 6‐endo‐dig cyclization is more favorable and leads to the carbenoid intermediate easily through further steps of C?X fragmentation and carbocation cyclization. Then, from the carbenoid intermediate, the [1,2]‐migration of sulfur is easier than that of H, Me, and Ph; whereas, a reversed aptitude was predicted for the oxygen analogue, which is consistent with the greater ability of sulfur atoms to stabilize β‐carbocations. However, for precursors containing a terminal alkyne, the 5‐exo‐dig pathway is preferred and only the 1,2‐disubstituted indene product is seen, irrespective of the nature of the acetal; thus, a different product from that reported in the literature is predicted for benzaldehyde acetal with a terminal alkyne at the ortho position. This prediction led us to reconsider some of the reported results and hidden realities were uncovered with solid new experimental evidence.     

Palladium‐Catalyzed Cascade Cyclization/Alkynylation Reactions

Palladium‐catalyzed cascade cyclization reactions have witnessed significant improvements in recent years. Among them, palladium‐catalyzed cascade cyclization/alkynylation are especially attractive, which can assemble structurally diverse monocyclic, bicyclic, fused polycyclic, and spirocyclic skeletons with excellent chemoselectivities. In this Minireview, palladium‐catalyzed cascade cyclization/alkynylation have been summarized and discussed in detail with focus on oxypalladation and aminopalladation‐initiated cascade cyclization, intramolecular Heck‐type cascade cyclization, carbocyclizations, cascade cyclizations, and other types of cascade cyclization reactions. Some significant and representative synthetic methodologies and their synthetic applications and reaction mechanisms have also been described.     

Cyclic nitriles: stereodivergent addition-alkylation-cyclization to cis- and trans-abietanes

Diverse cyclic hydroxy nitriles are readily synthesized through sequential 1,2-1,4-Grignard addition-methylations to 3-oxo-1-cyclohexene-1-carbonitrile. Acid-catalyzed intramolecular cyclizations of the cyclic hydroxy nitriles reveal fundamental stereoselectivity trends in Friedel-Crafts cyclizations to cis- and trans-abietanes. In contrast to previous assumptions, comparative cationic cyclizations with electron-rich and electron-poor aromatic nucleophiles exhibit similar preferences for cyclization to cis-abietanes. Optimizing the cyclizations for trans-abietanes has identified ZrCl 4 as an exceptional Lewis acid which, for cyclizations of iminolactones, favors trans-abietanes as the only observable diastereomer. The sequential oxonitrile addition-Friedel-Crafts cyclization strategy provides a rapid, stereodivergent synthesis of cis- or trans-abietanes, demonstrates the dramatic influence of ZrCl 4 in promoting cationic cyclizations, and in contrast to previous assumptions suggests that the cyclization stereoselectivity is not correlated with the electronic nature of the aromatic nucleus.     

Highly Chemoselective Synthesis of Indolizidine Lactams by SmI2‐Induced Umpolung of the Amide Bond via Aminoketyl Radicals: Efficient Entry to Alkaloid Scaffolds

Samarium(II) iodide enables a wide range of highly chemoselective umpolung radical transformations proceeding by electron transfer to carbonyl groups; however, cyclizations of important nitrogen‐containing precursors have proven limited due to their prohibitive redox potential. Herein, we report the first reductive cyclizations of unactivated cyclic imides onto N‐tethered olefins using SmI₂/H₂O. This new umpolung protocol leads to the rapid synthesis of nitrogen‐containing heterocycles that are of particular significance as precursors to pharmaceutical pharmacophores and numerous classes of alkaloids. The reaction conditions tolerate a wide range of functional groups. Excellent chemoselectivity is observed in the cyclization over amide and ester functional groups. Such unconventional reactivity has important implications for the design and optimization of new bond‐forming reactions by umpolung radical processes. The reaction advances the SmI₂ cyclization platform to the challenging unactivated N‐tethered acyl‐type radical precursors to access nitrogen‐containing architectures.