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.     

A new, efficient and stereoselective synthesis of tricyclic and tetracyclic compounds by samarium diiodide induced cyclisations of naphthyl-substituted arylketones--an easy access to steroid-like skeletons

In this report, we present the application of samarium diiodide induced cyclisations of naphthyl-substituted ketones towards an easy and stereoselective access to tri- and tetracyclic-functionalised compounds. Typical naphthalene derivatives were studied to investigate the scope and limitations of this novel cyclisation process. The model substrates studied demonstrate that the samarium ketyl cyclisations are essentially restricted to the formation of six-membered rings. The diastereoselectivity of these reactions is strongly influenced by the connection of the alkyl side chain to the naphthalene core. Gamma-naphth-1-yl-substituted ketones furnished cyclisation products, such as 17 or 22-26, as single diastereomers, whereas gamma-naphth-2-yl-substituted precursors gave mixtures of diastereomers--as demonstrated by the conversion of model compound 10 into tricyclic products 18 a/18 b, or that of cyclohexanone derivative 33 into tetracyclic diastereomers 34 a/34 b. Cyclic ketones as ketyl precursors furnished steroid-like tetracyclic skeletons; however, due to the cis/cis fusion of rings B/C and C/D these products have an "unnatural" bowl-like shape. Several of the cyclisation products have been identified by X-ray analyses, which not only proved the constitutions, but also the relative configurations and the preferred conformations. Steroid analogue 23 was subjected to subsequent transformations, which demonstrate that the styrene-like double bond of such compounds can be used for further structural diversification. First attempts to synthesise related azasteroids by incorporating nitrogen atoms into the ketone moiety are also reported. Thus, pyrrolidine derivatives 44 and 47 as well as piperidine derivatives 50 and 52 were subjected to samarium diiodide induced cyclisations. The expected tetracyclic products 48, 49 a/49 b, 51 and 53 a/53 b were obtained in moderate to good yields. The stereoselectivities observed follow the rules already established for the all-carbon precursors. The resulting products, bearing a nitrogen atom in ring D, are interesting azasteroid analogues with "unnatural" configuration.     

钐试剂在有机合成中应用的若干新进展

综述了本课题组最近几年关于钐试剂在有机合成中应用的研究进展. 主要包括以下几部分内容: (1) 二碘化钐促进的有机反应研究; (2) 金属钐直接应用于有机合成的研究; (3) 其它钐试剂 (三碘化钐, 烯丙基溴化钐) 促进的有机反应研究.     

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.     

钐试剂在有机合成中的应用

钐试剂在有机合成中的应用是近年来有机合成方法学研究中的热点之一。综述了十余年来本课题组在钐试剂应用于有机合成方面所开展的有关工作：(1)二碘化钐作为偶联剂和还原剂在有机合成中的应用;(2)金属钐直接应用于有机合成;(3)三碘化钐作为路易斯酸应用于有机合成;(4)有机钐试剂在有机合成中的应用。     

Samarium Diiodide Acting on Acetone—Modeling Single Electron Transfer Energetics in Solution

Samarium diiodide is a versatile single electron transfer (SET) agent with various applications in organic chemistry. Lewis structures regularly insinuate the existence of a ketyl radical when samarium diiodide binds a carbonyl group. The study presented here investigates this electron transfer by the means of computational chemistry. All electron CASPT2 calculations with the inclusion of scalar relativistic effects predict an endotherm electron transfer from samarium diiodide to acetone. Energies calculated with the PBE0-D3(BJ) functional and a small core pseudopotential are in good agreement with CASPT2. The calculations confirm the experimentally measured increase of the samarium diiodide reduction potential through the addition of hexamethylphosphoramide also known as HMPA.     

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.     

Recent Developments in Samarium Diiodide Promoted Organic Reactions

In the early eighties, we introduced samarium diiodide for the transformation of various functional groups. Since then, this reducing agent has been extensively used for the reductive cleavage of single bonds, C‐C bond formations, C‐N bond formations, and β‐elimination reactions. In this Personal Account, we highlight our initial results, as well as some of the contributions from various research groups. Because of space limitations, we arbitrarily select some useful results that have recently been described in literature.     

二碘化钐在有机合成中的应用新进展

综述了2005年以来二碘化钐在有机合成中应用的新进展,主要涉及二碘化钐在还原偶联反应以及作为预催化剂方面的一些新的应用.     

Creating carbon-carbon bonds with samarium diiodide for the synthesis of modified amino acids and peptides

In this perspective, an overview of our experiences on the application of samarium diiodide in organic synthesis for the preparation of amino acid and peptide analogues is presented. Three different carbon-carbon bond forming reactions are discussed, including side chain introductions, gamma-amino acid synthesis and acyl-like radical additions for the construction of C-C mimics of the peptidic bonds.     

A Samarium "Soluble" Anode: A New Source of SmI(2) Reagent for Electrosynthetic Application

An electrochemical method to prepare solutions of samarium diiodide in THF is reported. The simple electrolysis of a samarium rod provides a rapid and straightforward in situ synthesis of SmI(2) . The electrogenerated complex catalyzes various C?C bond formations. The reagent is produced continuously and leads to efficient organic electrosynthesis with significantly smaller amounts of solvent than usually required.     

Synthesis of aromatic (E)- or (Z)-alpha,beta-unsaturated amides with total or very high selectivity from alpha,beta-epoxyamides and samarium diiodide

Highly stereoselective synthesis of aromatic alpha,beta-unsaturated amides was achieved by treatment of aromatic alpha,beta-epoxyamides with samarium diiodide. The starting compounds 1 and 3 are easily prepared by the reaction of enolates derived from alpha-chloroamides with carbonyl compounds at -78 degrees C. A mechanism to explain this transformation is proposed.     

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.     

Tripyrrolidinophosphoric acid triamide as an activator in samarium diiodide reductions

The electrochemical and spectrophotometric characterization of the complex formed from samarium diiodide and 4 equiv of tripyrrolidinophosphoric acid triamide (TPPA) is presented. Kinetic studies indicate that the SmI(2)/TPPA complex possesses reactivity greater than the complex formed between samarium diiodide and 4 equiv of HMPA. Examples of the use of SmI(2)/TPPA in synthesis are presented.     

Synthesis of a serine-based neuraminic acid C-glycoside

Cell-surface carbohydrates are classified by the nature of their linkages to the protein as either N-linked or O-linked. O- and N-glycans are involved in a number of important biological functions. These activities can be lost on glycoprotein catabolism when these glycan linkages are enzymatically hydrolyzed. The design and synthesis of novel C-linked glycans should provide catabolically stable glycoproteins useful for understanding and regulating important biological processes. Our efforts are currently directed toward the synthesis of C-glycosides of ulosonic acids. This paper describes the first synthesis of a serine-based neuraminic acid C-glycoside. The protecting group chemistry required for both carbohydrate and peptide syntheses complicates this approach. Different protecting group strategies were investigated for use in the samarium diiodide mediated C-glycosylation reaction. The key elements of our synthetic approach involve the following: (i) the substitution of homoserine for serine in the C-glycosylation reaction to introduce a carbon in place of the O-glycosidic oxygen, (ii) the use of benzyloxycarbonyl as a homoserine protecting group, compatible with samarium diiodide mediated C-glycosylation reaction, and (iii) the reduction of the carbonyl group in homoserine early in the synthesis to improve C-glycosylation yield and to avoid lactone formation. Using this combined approach, we prepared 4-O-acetyl-4-[2-C-(1-methyl 5-acetamido 4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-d-erythro-l-manno-nononate)]-2S-(benzyloxycarbonyl)amino-1-carboxylic acid (1), which will be used in peptide synthesis to prepare glycopeptides containing catabolically stable C-linked neuraminic acid.     

Spiranes synthesis based on samarium diiodide-mediated reductive cyclization

A general and efficient method for the preparation of spiro compounds is described. Enone–aldehydes were exposed to samarium diiodide under mild conditions and various spirocyclic γ-hydroxyketones were obtained in good yields.     

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.     

Beta-elimination reactions by using samarium diiodide

The development of methodologies for the formation of carbon-carbon double bonds could be considered one of the most important challenges in organic synthesis. To this end, beta-elimination reactions in 1,2-difunctionalised substrates have been one of the most important means of generating C=C bonds.This review is intended to highlight the use of SmI2 in beta-elimination procedures, such that the organization of this revision highlights conventional beta-elimination processes which are promoted by samarium diiodide. The synthetic applications of SmI2 will be covered, and 1,2-elimination reactions which are involved in sequential reactions promoted by samarium diiodide, will also be illustrated. These methodologies along with the more recent developments in the area are discussed in this tutorial review.     

SmI2-Promoted novel tandem elimination and coupling reactions of aliphatic imides with carbonyl compounds: application to the synthesis of dl-isoretronecanol

Treatment of α-hetero-substituted cyclic imides with carbonyl compounds mediated by samarium(II) diiodide in the presence of HMPA was found to undergo novel tandem elimination and reductive coupling reactions to generate α-hydroxyalkylated imides in good to high yields. Stereochemistry of the coupling products was researched and the result that increasing the steric bulkiness of the N-substituents leads to an increase of threo-selectivity was observed. The mechanistic origins of this stereoselectivity are also briefly documented and the reaction was further applied to the convenient synthesis of a simple pyrrolizidine alkaloid, isoretronecanol.     

Etude par RMN de composés organiques contenant des chalcogènes—IX.* RMN du 13C dans des dérivés aromatiques du tellurényle

In order to synthesize new tellurium heterocycles, we prepared o-halogenotellurobenzoyl chlorides. We present and discuss here the results of a ¹³C NMR study of these compounds, together with other intermediates that we have isolated during our synthesis and two new tellurium heterocycles.