Ketone-imide versus ketone-oxime reductive cross-coupling promoted by samarium diiodide: new mechanistic insight gained from a failed aminocyclopentitol synthesis

[reaction: see text] The intramolecular 1,6-ketone/imide reductive coupling promoted by samarium diiodide competes favorably with an alternative 1,5-ketone/oxime ether coupling in a keto-oxime substrate derived from D-glucosamine N-protected with a phthalimido group. This pinacol coupling reaction affords new homochiral alpha-hydroxylactam scaffolds that could be useful in diversity-oriented synthesis. A mechanistic proposal for this reaction that explains the experimental results is supported by DFT quantum-mechanical calculations on model compounds.     

Samarium diiodide-catalyzed diastereoselective pinacol couplings

A complex of samarium diiodide (SmI(2)) with tetraglyme catalyzes the intermolecular pinacol coupling of aromatic or aliphatic aldehydes at loadings of 10 mol % in the presence of Me(2)SiCl(2) and Mg. Diastereoselectivity of up to 95/5 (+/-/meso) has been achieved for aliphatic aldehydes and up to 19/81 (+/-/meso) for aromatic aldehydes. De values of up to 99% have been achieved in intramolecular pinacol coupling reactions using the SmI(2)/tetraglyme/Mg/Me(2)SiCl(2) catalytic system.     

SmI(2)-mediated cyclizations of derivatized beta-lactams for the highly diastereoselective construction of functionalized prolines

A series of C4-keto-functionalized 1-[(benzoyloxy)(ethoxycarbonyl)methyl]-2-azetidinones were prepared and studied for their tendency to undergo a Reformatsky-type cyclization to fused bicyclic or tricyclic beta-lactams with the single-electron reducing agent samarium diiodide. Whereas the azetidinone 21a underwent reductive cyclization, affording the potent antibiotic sanfetrinem's tricyclic [4.5.6] core structure as the major component, all other examples tested resulted in cyclization followed by an N to O acyl migration involving cleavage of the beta-lactam ring as the favored pathway. Highly functionalized proline derivatives were therefore accessed as single diastereomers through the reductive cyclization of benzoates 21b, 22, 23a,b, 24b, and 25-28. Pertinent for the success of these cyclizations was the addition of 1 equiv of tert-butyl alcohol, allowing for the protonation of the basic amide derivative obtained after the acyl migration step. The diastereoselectivities of these reactions deviate from those of similar cyclizations involving the corresponding lithium enolate. This divergence could be rationalized by the coordination of the metal ion of the samarium(III) enolate intermediate to the beta-lactam amide functionality in the cyclization step, which may not be possible for lithium enolates.     

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.     

Can decarbonylation of acyl radicals be overcome in radical addition reactions? En route to a solution employing N-acyl oxazolidinones and SmI2/H2O

The application of acyl radicals in radical addition reactions in the absence of a CO atmosphere is generally limited to aryl or alpha-unsubstituted alkyl acyl radicals due to competing decarbonylations where the rate constant for this degradation process surpasses 104 s-1. In this work, a potential solution to avoid the problem of decarbonylations is presented employing N-acyl oxazolidinones which are reduced to acyl radical equivalents in the presence of samarium diiodide and water. In the company of an acrylamide, acrylate, or acrylonitrile, the product from a formal acyl radical addition is obtained in yields up to 87%. Examples are given where the decarbonylation rate constants even exceed 108 s-1. It is proposed that the reaction proceeds via a ketyl-like intermediate.     

Synthesis of

A series of 1,1'-dicinnamoylferrocenes were converted to the corresponding [3]ferrocenophane diols (4a-e) in a stereoselective manner by using samarium diiodide to effect the intramolecular coupling reaction, aldol reaction, and reduction in one-pot operation. The major reaction pathway might be derived from a samarium chelated transition state (I(A)()) having the moieties of s-cis enone and (Z)-enolate. A solid-state structure of such [3]ferrocenophane diol product showed that the cyclopentadienyl groups were in an eclipsed orientation and slightly tilted.     

Synthesis and desilylation of some bis(trimethylsilyl)alkenes and polymers bearing bis(silyl)alkenyl groups

The synthesis of various vinylbis(silanes) from some aryl and heteroaryl aldehydes and (Me₃Si)₃CLi in Et₂O is described. Friedel-Crafts reaction of 1,1-bis(trimethylsilyl)-2-(2-naphthyl)ethene with various acyl chlorides (RCOCl, R = Me, Et, i-Pr, i-Bu, n-pent) gave the corresponding α-silyl-α,β-unsaturated enones with high E steroselectivity. Moreover, poly(styrene)-co-[2,2-bis(trimethylsilyl)ethenyl(styrene)] obtained via the reaction of polymers bearing pendant enone functions and (Me₃Si)₃CLi, reacts with the same acyl chlorides in the presence of catalytic amount of AlCl₃ to give the new macromolecules bearing α-silyl-α,β-unsaturated enones and α,β-unsaturated enones.     

Rules for ring closure: application to intramolecular aldol condensations in polyketonic substrates

An extension of the nomenclature for classifying ring closures to include intramolecular reactions of enolate anions is described, and the rules governing such cyclizations are enumerated. The syntheses of the polyketonic substrates 4-acetyl-2,6-heptanedione (11), 4-acetyl-4-methyl-2,7-octanedione (24), and 3-acetyl-3-methyl-1,6-diphenyl-1,6-heptanedione (33) were carried out, and their base-induced intramolecular aldol condensations studied. With each substrate a favored 6-(enolendo)-exo-trig cyclization to produce cyclohexenone products was the only ring forming reaction observed, this process predominating in all instances over competing disfavored 5-(enolendo)-exo-trig closures, and also over other competing favored cyclizations. The identity of the cyclization product 12 derived from 11 was confirmed by aromatizing 12 to 17, and alternately synthesizing 17 from 3-bromo-5-methylphenol.     

SmI2 reduced thioesters as synthons of unstable acyl radicals: direct synthesis of potential protease inhibitors via intermolecular radical addition

Aromatic alpha-heterosubstituted thioesters were found to undergo radical 1,4-addition reactions to a series of alpha,beta-unsaturated amides and one ester when subjected to the single electron reducing agent, samarium diiodide, at -78 degrees C. These thioesters derived from alpha-amino acids represent a synthetically useful synthon of unstable acyl radicals. This reaction conveniently provides access to gamma-ketoamides and esters in yields up to 90%, structures that are common in various protease inhibitors derived from peptides. Examples with acryloyl and methacryloyl derivatives of alpha-amino acids and dipeptides lead directly to tri- and tetrapeptide mimetics possessing the gamma-ketoamide functionality. No epimerization was observed with the mild conditions used for these reactions.     

Phthalimides as exceptionally efficient single electron transfer acceptors in reductive coupling reactions promoted by samarium diiodide

Experimental and theoretical evidence shows that phthalimides are highly efficient single electron transfer acceptors in reactions promoted by samarium diiodide, affording ketyl radical anion intermediates, which participate in high-yielding inter- and intramolecular reductive coupling processes with different radicophiles including imides, oxime ethers, nitrones, and Michael acceptors.     

A concise approach for the total synthesis of pseudolaric acid A

A new strategy for the stereoselective total synthesis of natural product pseudolaric acid A (1) was accomplished in 16 steps from commercially available starting material, featuring a samarium diiodide (SmI(2))-mediated intramolecular alkene-ketyl radical cyclization and a ring-closing metathesis (RCM) reaction to stereoselectively cast the unusual trans-fused [5-7]-bicyclic core of pseudolaric acid A (1).     

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.     

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.     

Rate constants for 1,5- and 1,6-hydrogen atom transfer reactions of mono-, di-, and tri-aryl-substituted donors, models for hydrogen atom transfers in polyunsaturated fatty acid radicals

Rate constants for 1,5- and 1,6-hydrogen atom transfer reactions in models of polyunsaturated fatty acid radicals were measured via laser flash photolysis methods. Photolyses of PTOC (pyridine-2-thioneoxycarbonyl) ester derivatives of carboxylic acids gave primary alkyl radicals that reacted by 1,5-hydrogen transfer from mono-, di-, and tri-aryl-substituted positions or 1,6-hydrogen transfer from di- and tri-aryl-substituted positions to give UV-detectable products. Rate constants for reactions in acetonitrile at room temperature ranged from 1 x 10(4) to 4 x 10(6) s(-1). The activation energies for a matched pair of 1,5- and 1,6-hydrogen atom transfers giving tri-aryl-substituted radicals were approximately equal, as were the primary kinetic isotope effects, but the 1,5-hydrogen atom transfer reaction was 1 order of magnitude faster at room temperature than the 1,6-hydrogen atom transfer reaction due to a less favorable entropy of activation for the 1,6-transfer reaction. Solvent effects on the rate constants for the 1,5-hydrogen atom transfer reaction of the 2-[2-(diphenylmethyl)phenyl]ethyl radical at ambient temperature were as large as a factor of 2 with the reaction increasing in rate in lower polarity solvents. Hybrid density functional theory computations for the 1,5- and 1,6-hydrogen atom transfers of the tri-aryl-substituted donors were in qualitative agreement with the experimental results.     

Facile Syntheses of Substituted, Conformationally-Constrained Benzoxazocines and Benzazocines via Sequential Multicomponent Assembly and Cyclization

A multicomponent assembly process (MCAP) was utilized to prepare versatile intermediates that are suitably functionalized for subsequent cyclizations via Ullmann and Heck reactions to efficiently construct substituted 2,6-methanobenzo[b][1,5]oxazocines and 1,6-methanobenzo[c]azocines, respectively. The intramolecular Ullmann cyclization was conducted in tandem with an intermolecular arylation that enabled the rapid syntheses of a number of O-functionalized methanobenzoxazocines.     

Silylboranes as new sources of silyl radicals for chain-transfer reactions

Various silylboranes, which were outfitted with a catecholborane moiety at one end and a (Me(3)Si)(3)Si moiety at the other end of a carbon chain, were prepared through the hydroboration of the corresponding unsaturated silanes. The C-centered radical species generated from these silylboranes efficiently cyclized to provide, through a 5-exo intramolecular homolytic substitution at the silicon center, the corresponding silacycle and a Me(3)Si radical that was subsequently trapped by sulfonyl acceptors. These cyclizations proceeded at unprecedented rates, due, in part, to a strong gem-dialkyl effect that was attributable to the presence of bulky substituents on a quaternary center located on the chain. In parallel, we designed arylsilylboranes that produced silyl radicals through a 1,5-hydrogen transfer. Such silyl radicals may be valuable radical chain carriers, for instance, in oximation reactions of alkyl halides. Finally, computational studies allowed calculation of activation barriers of the homolytic substitution step and additionally illustrated that the overall reaction mechanism involved a transition state in which the attacking carbon center, the central silicon atom, and the Me(3)Si leaving group were collinear.     

Cross-aldol reactions of levoglucosenone and its derivatives with cyclohex-1-en-1-ol ethers

The reaction of levoglucosenone with cyclohex-1-en-1-yl trimethylsilyl ether under Mukaiyama reaction conditions gave [1 + 2]-Michael–aldol condensation product with participation of the acetal center. The reaction was accompanied by opening of the 1,6-anhydro bridge and intramolecular hemiketalization by the hydroxy group of the 2-oxocyclohex-1-enyl fragment. Under analogous conditions, dihydrolevoglucosenone gave rise to four diastereoisomeric 1,2-addition products. Internal cyclohex-1-en-1-ol ether obtained by treatment of the Michael adduct of levoglucosenone and cyclohexanone with Ac₂O–ZnCl₂ underwent intramolecular Mukaiyama reaction involving substituted α-carbon atom of the cyclohexanone fragment and acetal moiety to afford spiro derivative and product of subsequent AdE1 acetylation of intermediate α′-cyclohexenyl ether fragment.     

Enantiomerically Pure Cyclic trans-1,2-Diols,Diamines, and Amino Alcohols by Intramolecular Pinacol Coupling of Planar Chiral Mono-Cr(CO)3 Complexes of Biaryls

Without any formation of stereoisomers , the intramolecular pinacol cyclization of 1 —planar chiral mono-Cr(CO)₃ complexes of 1,1′-biphenyls with carbonyl functionalities at the 2- and 2′-positions—with samarium diiodide gives cyclic trans-1,2-diols 2 . Upon exposure to sunlight, the chromium-complexed diols 2 produce optically pure chromium-free trans-diols 3 . Similarly, the corresponding enantiomerically pure trans-1,2-diamines and amino alcohols are obtained from the planar chiral chromium complexes of biphenyls with diimino or keto-imino functionalities. R¹=H, OMe; R²=H, Me; R³=H, Me.     

Stereoselective Michael Addition and Michael-aldol Tandem Reaction of Diorganyl Diselenides or Disulfides with Conjugated Alkynones Mediated by Samarium Diiodide

Stereoselective Michael addition and Michael-aldol tandem reaction of diorganyl diselenides and disulfides with conjugated alkynones mediated by samarium diiodide were studied. The reaction temperature was critical for the stereoselectivity, β-Organylselenoalkenones or β-organylthioalkenones and γ-organylselenoallylic alcohols or γ-organylthioallylic alcohols were prepared in good yields.     

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.