Synthesis of new steroid analogues by samarium diiodide induced cyclisations of γ-naphthyl 1,3-diones

We present the synthesis of new steroid analogues via samarium diiodide mediated intramolecular ketyl–aryl coupling reactions of γ-naphthyl-substituted 1,3-diones. From previous experiments with γ-naphthyl monoketones high stereoselectivities with the ‘unnatural’ cis/cis annulation of rings B/C/D were expected. Surprisingly, we observed the formation of two diastereomers with cis- and trans-fused rings B and C of the tetracyclic skeleton. The diastereoselectivity proved to be strongly dependent on the amount of the proton source employed in the reaction. A rationale for this unexpected behaviour is discussed. In addition, we observed a smooth aluminium chloride induced cyclisation of one of the γ-naphthyl-substituted 1,3-diones to furnish an equilenine precursor. Another cyclisation product was converted by Grob-fragmentation into a naphthannulated cyclononane derivative.     

Samarium diiodide mediated 6-exo cyclisations of methylenecyclopropyl ketones

6-exo Cyclisations of methylenecyclopropyl ketones, mediated by samarium diiodide, have been investigated with a series of substrates. The efficiency of the cyclisations are highly dependent on the stereochemistry of the cyclisation precursor.     

Stereoselective formation of tri- and tetracycles by samarium diiodide-induced cyclizations of naphthyl-substituted ketones

[reaction: see text] Samarium diiodide promotes smooth reductive cyclizations of gamma-naphthyl-substituted ketones to afford tri- and tetracyclic compounds in high yields and with excellent stereoselectivities. Cyclic ketones furnish steroid-like compounds with "unnatural" cis/cis annulation of rings B/C/D. The remaining styrene-type double bond of ring B allows further stereoselective reactions. Cases with matched and mismatched relative configuration could be identified leading to dramatic differences in the ring closure ability.     

Towards the Core Structure of Strychnos Alkaloids Using Samarium Diiodide‐Induced Reactions of Indole Derivatives

This report describes the development of a first and second generation approach towards the synthesis of the ABCEG pentacyclic core structure of Strychnos alkaloids. First, we discuss a sequential approach applying a series of functional group transformations to prepare suitable precursors for cyclization reactions. These include attempts of samarium diiodide‐induced cyclizations or a Barbier‐type reaction of a transient lithium organyl, which successfully led to a tetracyclic key building block earlier used for the synthesis of strychnine. Secondly, we account our first steps towards the development of an atom‐economical samarium diiodide‐induced cascade reaction using “dimeric” indolyl ketones as cyclization precursors. In this context, we discuss plausible mechanisms for the samarium diiodide‐induced cascade reaction as well as transformations of the obtained tetracyclic dihydroindoline derivatives.     

Samarium diiodide induced ketyl-(het)arene cyclisations towards novel N-heterocycles

In this tutorial review we discuss recent advances in the field of ketyl-(het)arene cyclisations promoted by samarium diiodide and related processes. Couplings of samarium ketyls with carbon-carbon multiple bonds are perhaps the most useful reactions to create carbocycles and heterocycles of various ring sizes. They have also successfully been exploited for the synthesis of biologically active compounds or natural products. In this article we intend to summarise our diversity orientated approaches towards nitrogen heterocycles and emphasize other approaches with SmI(2) as well as electrochemical cyclisation methods providing similar N-heterocycles. We also briefly discuss our recently published formal total synthesis of strychnine employing a new samarium diiodide induced cascade reaction as key step. All these examples demonstrate the high synthetic potential of samarium ketyl-(het)arene cyclisations for the preparation of various types of important heterocyclic compounds.     

Samarium diiodide induced cyclizations of γ-, δ- and ε-indolyl ketones: reductive coupling, intermolecular trapping, and subsequent transformations of indolines

This comprehensive study describes our results of samarium diiodide induced 5-exo-trig to 8-exo-trig cyclization/alkylation sequences of 3'-acceptor-substituted indolyl ketones. All cyclization precursors were easily prepared by simple N-alkylation or N-acylation of indole derivatives with the corresponding iodo alkanones, acid chlorides, or lactones. After treatment of indolyl ketones with two equivalents of SmI(2), the generated stabilized carbanionic intermediates were trapped with different electrophiles leading to a variety of highly substituted indoline derivatives in good to very good yields. In general, the cyclization products were obtained as single diastereomers bearing a newly generated quaternary center, a common structural motif in various indole alkaloids. The relative configurations of the products were established by NOE experiments and by single-crystal analysis and follow the rules already established. Furthermore, the obtained products were subjected to a series of chemical transformations, such as oxidation, reduction, and metathesis reactions resulting in a range of interesting synthetic building blocks valuable for further applications.     

Samarium diiodide mediated cascade radical cyclisations—synthesis of the eudesmane tricyclic framework

Radical cascade cyclisation of methylenecyclopropyl cyclohexanone adducts, using samarium diiodide to generate an initial ketyl radical, provide a short route to tricyclic ethers, and the stereochemical outcome can be influenced by the solvent used for the reaction.     

The first example of samarium diiodide-promoted intramolecular ketone-ester coupling of ketones tethering acyloxyalkyl side chains producing 2-hydroxy cyclic hemiacetals

The reaction of samarium diiodide with some cyclic and acyclic ketones tethering acyloxyalkyl side chains produced 2-hydroxy cyclic hemiacetals in moderate to good yields, in which an intramolecular addition of samarium ketyl radicals to distant ester carbonyls would be involved.     

Enantiopure Aminopyrans by a Lewis Acid Promoted Rearrangement of 1,2‐Oxazines: Versatile Building Blocks for Oligosaccharide and Sugar Amino Acid Mimetics

1,3‐Dioxolanyl‐substituted 1,2‐oxazines, such as syn‐ 1 and anti‐ 1 , rearrange under Lewis acidic conditions to provide bicyclic products 2 – 5 . Subsequent reductive transformations afforded enantiopure 3‐aminopyran derivatives such as 7 and 9 or their protected diastereomers 16 and 18 , which can be regarded as carbohydrate mimetics. An alternative sequence of transformations including selective oxidation of the primary hydroxyl groups in 21 and 24 led to two protected β‐amino acid derivatives with carbohydrate‐like backbone (sugar amino acids). Treatment of bicyclic ester 23 with samarium diiodide cleaved the N? O bond and furnished the unusual β‐lactam 27 in excellent yield. Alternatively, γ‐amino acid derivative 29 was efficiently prepared in a few steps. Fairly simple transformations gave azides 32 and 35 or alkyne 30 which are suitable substrates for the construction of oligosaccharide mimetics such as 34 by copper iodide catalyzed cycloadditions. With this report we demonstrate that enantiopure rearrangement products 2 – 5 are protected precursors of a variety of polyfunctionalized pyran derivatives with great potential for chemical biology.     

Stereoselective Cascade Cyclizations with Samarium Diiodide to Tetracyclic Indolines: Precursors of Fluorostrychnines and Brucine

A series of γ-indolylketones with fluorine, cyano or alkoxy substituents at the benzene moiety was prepared and subjected to samarium diiodide-promoted cyclization reactions. The desired dearomatizing ketyl cascade reaction forming two new rings proceeded in all cases with high diastereoselectivity, but with differing product distribution. In most cases, the desired annulated tetracyclic compounds were obtained in moderate to good yields, but as second product tetracyclic spirolactones were isolated in up to 29 % yield. The reaction rate was influenced by the substituents at the benzene moiety of the substrate as expected, with electron-accepting groups accelerating and electron-donating groups decelerating the cyclization process. In case of a difluoro-substituted γ-indolylketone a partial defluorination was observed. The intermediate samarium enolate of the tetracyclic products could be trapped by adding reactive alkylating agents as electrophiles delivering products with quarternary carbons. In the case of a dimethoxy-substituted tetracyclic cyclization product a subsequent reductive amination stereoselectively provided a pentacyclic compound that was subsequently N-protected and subjected to a regioselective elimination. The obtained functionalized pentacyclic product should be convertible into the alkaloid brucine by four well-established steps. Overall, the presented report shows that functionalized tetracyclic compounds with different substituents are rapidly available with the samarium diiodide cascade cyclization as crucial step. Hence, analogues of the landmark alkaloid strychnine, for example, with specific fluorine substitutions, should be easily accessible.     

Regioselective samarium diiodide induced couplings of carbonyl compounds with 1,3-diphenylallene and alkoxyallenes: a new route to 4-hydroxy-1-enol ethers

Since its introduction into synthetic organic chemistry, samarium diiodide has found broad application in a variety of synthetically important transformations. Herein, we describe the first successful intermolecular additions of samarium ketyls to typical allenes such as 1,3-diphenylallene (7), methoxyallene (12) and benzyloxyallene (25). Reaction of different samarium ketyls with 1,3-diphenylallene (7) occurred exclusively at the central carbon atom of the allene to afford products 9 in moderate to good yields. In contrast, reductive coupling of cyclic ketones to methoxyallene (12) regioselectively provided 4-hydroxy-1-enol ethers 13, which derive from addition to the terminal allene carbon atom of 12, in moderate to good yields. Whereas the E/Z selectivity with respect to the enol ether double bond is low, excellent diastereoselectivity has been observed in certain cases with regard to the ring configuration (e.g. compound 13 b). Studies with deuterated tetrahydrofuran and alcohol were performed to gain information about the reaction mechanism of this coupling process, which involves alkenyl radicals. The couplings of samarium ketyls derived from acyclic ketones and aldehydes gave lower yields, and in several cases cyclopentanols 20 are formed as byproducts. Branched acyclic ketones and conformationally more flexible cyclic ketones such as cycloheptanone led to a relatively high amount of cyclopentanol derivatives 20, whose formation involves an intramolecular hydrogen atom transfer through a geometrically favoured six-membered transition state followed by a cyclization step. The samarium diiodide mediated addition of 8 b to benzyloxyallene (25) afforded the expected enol ethers 26, albeit in only low yield. Additionally, spirocyclic compounds 27 and 28 were obtained, which are formed by a cascade reaction involving an addition/cyclization sequence. In the novel coupling process described here methoxyallene (12) serves as an equivalent of acrolein. The 1,4-dioxygenated products obtained contain a masked aldehyde functionality and are therefore valuable building blocks in organic synthesis.     

A New Samarium Diiodide Induced Reaction: Intramolecular Attack of Ketyl Radical Anions on Aryl Substituents with Formation of 1,4-Cyclohexadiene Derivatives

Beware of samarium diiodide and aryl ketones! If the ketyl radical anion which is formed by electron transfer finds a properly placed aryl group, a highly diastereoselective cyclization may occur. After the transfer of a second electron and protonation bi- and polycyclic products with a common 1,4-cyclohexadiene moiety may be isolated [Eq. (a)]. X=CHCO₂R, NCH₂Ph; HMPA=(Me₂N)₃PO.     

Lithium Bromide/Water as Additives in Dearomatizing Samarium‐Ketyl (Hetero)Arene Cyclizations

New conditions for dearomatizing samarium‐ketyl (hetero)arene cyclizations are reported. In many examples of these samarium diiodide‐mediated reactions, lithium bromide and water can be used as additives instead of the carcinogenic and mutagenic hexamethylphosphoramide (HMPA). The best results were obtained for the cyclizations of N‐acylated indole derivatives delivering the expected indolines in good yields and excellent diastereoselectivities. A new type of cyclization delivering indolyl‐substituted allene derivatives is also described. The scope and limitations of the lithium bromide/water system are discussed.     

Application of samarium diiodide (SmI2)-induced reduction of gamma-acetoxy-alpha,beta-enoates with alpha-specific kinetic electrophilic trapping for the synthesis of amino acid derivatives

Gamma-acetoxy-alpha,beta-enoates were easily reduced by samarium diiodide (SmI2) in THF to generate samarium dienolates which were kinetically trapped with ease at their alpha-positions by electrophiles (proton, aldehydes or ketones) to yield (E)-alkene dipeptide isosteres or gamma-amino acid derivatives in high chemical yields.     

Facile synthesis of substituted phenanthroline ligands by samarium-promoted coupling of phenanthroline with ketones

[formula: see text] 1,10-Phenanthroline undergoes coupling with ketones promoted by samarium diiodide to produce 2-(1-hydroxyalkyl)-1,10-phenanthrolines. O-Methylation of these derivatives provides the corresponding 2-(1-methoxyalkyl)phenanthrolines. Demethoxylation with samarium diiodide then affords 2-alkylphenanthrolines. This process may be repeated to obtain 2,9-disubstituted phenanthrolines. A variety of new, substituted phenanthrolines are thus obtained. These compounds have numerous potential applications as ligands in metal-promoted reactions, including asymmetric catalysis.     

A borylative cyclisation towards indole boronic esters

2-Alkynylaniline borylative cyclisations provide a direct means to access indole 3-boronic esters from simple precursors. The Pd-catalysed cyclisation can be merged with cross-coupling processes in the same reaction vessel, moreover, the products can be exploited in C-N bond forming reactions.     

SmI(2)-promoted radical addition of nitrones to alpha,beta-unsaturated amides and esters: synthesis of gamma-amino acids via a nitrogen equivalent to the ketyl radical

[reaction: see text] Alkyl nitrones undergo radical addition reactions to a series of alpha,beta-unsaturated amides and esters when subjected to samarium diiodide via a nitrogen equivalent to a ketyl radical anion. This reaction conveniently provides access to a variety of functionalized gamma-amino acids. The methodology was extended to the asymmetric synthesis of 4-substituted gamma-amino acids, via the nitrone radical addition reaction to acrylates/amides possessing a chiral auxiliary.     

Synthesis of (E)-α,β-unsaturated ketones with total or high diastereoselectivity by using samarium diiodide or triiodide

(E)-α,β-Unsaturated ketones are obtained by reaction of α-chloro-β-hydroxy ketones with samarium diiodide or with samarium triiodide with total or high diastereoselectivity and in good yield.     

Friedel-crafts cyclisation—VI: Polyphosphoric acid-catalysed reactions of crotonophenones and chalcones

Polyphosphoric acid-catalysed cyclisation of derivatives of crotonophenone and chalcone is shown to be a general reaction which occurs without migration of aryl substituents evident with other Friedel-Crafts catalysts. Two other reactions, however, may intervene: hydrogenation and α-carbonyl cleavage. Thus 4-bromochalcone gives 3 - (p - bromophenyl) -1 - phenylpropan -1 - one, 3 - (p - bromophenyl)indan -1 - one and some benzole acid. A mechanism for the cyclisation is discussed in comparison with those reported for cyclisations of α,β-unsaturated esters and divinyl ketones. The formation of intermediate Wheland complexes is predicted to be conrotatory.     

A novel photoinduced reduction system of low-valent samarium species: reduction of organic halides and chalcogenides, and its application to carbonylation with carbon monoxide

Visible light irradiation is found to enhance the reducing ability of samarium diiodide (SmI₂) dramatically. Organic halides (RCl, RBr, RI) and chalcogenides (RSPh, RSePh, RTePh) are smoothly reduced to the corresponding hydrocarbons by using this SmI₂–hv system. The photoactivation can be also applied to ytterbium diiodide (YbI₂) successfully. When the reduction of alkyl chlorides (RCl) by using the SmI₂–hv system is conducted under the pressure of carbon monoxide, unsymmetric ketones (RC(O)CH₂R) are obtained as carbonylating products. A mechanistic pathway may involve the formation of acylsamarium species (RC(O)SmI₂), which undergo dimerization, followed by reduction with SmI₂, leading to the unsymmetric ketones.