Traceless Thioacid-Mediated Radical Cyclization of 1,6-Dienes.

Five-membered ring systems are ubiquitous throughout natural products and synthetic therapeutics, and thus, efficient methods to access this essential scaffold are required. Herein, we report the thioacid-mediated, 5--trig cyclization of various 1,6-dienes, with high yields of up to 98%. The labile thioester functionality can be exploited to generate a free thiol residue which can be used as a functional handle or removed entirely to provide the traceless cyclized product.

Fine Tuning of Quantum Dots Photocatalysts for the Synthesis of Tropane Alkaloid Skeletons.

Several types of Quantum Dots (QDs) (CdS, CdSe and InP, as well as core-shell QDs such as type I InP-ZnS, quasi type-II CdSe-CdS and inverted type-I CdS-CdSe) were considered for generating α-aminoalkyl free radicals. The feasibility of the oxidation of the N-aryl amines and the generation of the desired radical was evidenced experimentally by quenching of the photoluminescence of the QDs and by testing a vinylation reaction using an alkenylsulfone radical trap. The QDs were tested in a radical [3+3]-annulation reaction giving access to tropane skeletons and that requires the completion of two consecutive catalytic cycles.

Tropane and related alkaloid skeletons via a radical [3+3]-annulation process.

Tropanes and related bicyclic alkaloids are highly attractive compounds possessing a broad biological activity. Here we report a mild and simple protocol for the synthesis of N-arylated 8-azabicyclo[3.2.

Radical chain monoalkylation of pyridines.

The monoalkylation of -methoxypyridinium salts with alkyl radicals generated from alkenes ( hydroboration with catecholborane), alkyl iodides ( iodine atom transfer) and xanthates is reported. The reaction proceeds under neutral conditions since no acid is needed to activate the heterocycle and no external oxidant is required. A rate constant for the addition of a primary radical to -methoxylepidinium >10 M s was experimentally determined.

Intermolecular Radical C-H Bond Activation: A Powerful Tool for Late Stage Functionalization.

The synthesis of complex molecules radical reactions involving carbon-carbon and carbon-heteroatom bonds has become a very successful approach. Radical chemistry has long been dominated by the use of tin-based reagents. Those strongly contributed to the development of the field, allowing one to achieve spectacular transformations, most of which being difficult or impossible to achieve under ionic conditions, and giving access to invaluable kinetics data that paved the way for the development of improved protocols and the design of new synthetic strategies.

Rapid Access to Thiolactone Derivatives through Radical-Mediated Acyl Thiol-Ene and Acyl Thiol-Yne Cyclization.

A new synthetic approach to thiolactones that employs an efficient acyl thiol-ene (ATE) or acyl thiol-yne (ATY) cyclization to convert unsaturated thiocarboxylic acid derivatives into thiolactones under very mild conditions is described. The high overall yields, fast kinetics, high diastereoselectivity, excellent regiocontrol, and broad substrate scope of these reaction processes render this a very useful approach for diversity-oriented synthesis and drug discovery efforts. A detailed computational rationale is provided for the observed regiocontrol.

Radical-Mediated Reactions of α-Bromo Aluminium Thioacetals, α-Bromothioesters, and Xanthates for Thiolactone Synthesis.

Thiolactones have attracted considerable attention in recent years as bioactive natural products, lead compounds for drug discovery, molecular probes, and reagents for polymerisation. We have investigated radical-mediated C-C bond forming reactions as a strategy for thiolactone synthesis. Cyclisation of an α-bromo aluminium thioacetal was investigated under radical conditions.

Hemisynthesis of 2,3,4-C3-1,4-Androstadien-3,17-dione: A Key Precursor for the Synthesis of C3-Androstanes and C3-Estranes.

In this contribution, we describe two simple and efficient routes for the preparation of keto-aldehyde 1, a key intermediate for the synthesis of C3-androstanes and C3-estranes. In the first route, the targeted aldehyde 1 was obtained in 40% overall yield from 1,4-androstadien-3,17-dione (3 mmol scale) via a two-step sequence involving a one-pot, abnormal ozonolysis/sulfur oxidation/retro-Michael/ozonolysis process. Alternatively, a second route from 4-androsten-3,17-dione, using a six-step sequence, was optimized to produce 40 mmol batches of the key intermediate 1 in 42% overall yield.

Hydrosulfonylation Reaction with Arenesulfonyl Chlorides and Tetrahydrofuran: Conversion of Terminal Alkynes into Cyclopentylmethyl Sulfones.

An efficient and simple radical chain reaction to convert terminal alkynes into arenesulfonylmethylcyclopentanes is described. The reaction involves a radical addition-translocation-cyclization process and necessitates solely the use of readily available arenesulfonyl chlorides in tetrahydrofuran. Interestingly, this radical-mediated C-H activation process took place with a high level of retention of configuration when an enantiomerically pure starting material was used.

Synthesis of Ribonucleosidic Dimers with an Amide Linkage from d-Xylose.

An original and efficient stereocontrolled synthesis of ribonucleosidic homo- and heterodimers has been achieved from inexpensive d-xylose. This successful strategy involved the sequential introduction of nucleobases, using two stereocontrolled N-glycosidation reactions, from a common two-furanoside amide-linked scaffold offering the possibility of obtaining any given base sequence. The pertinence of this approach is illustrated through the preparation of the homodimers UU-34 and TT-35 in 18 steps with an excellent overall yield of more than 10% from d-xylose, while the heterodimer route led to UT-39 in 19 steps with around 10% overall yield.

Effect of Brønsted acids on the thiophenol-mediated radical addition-translocation-cyclization process for the preparation of pyrrolidine derivatives.

A thiophenol-mediated method for the conversion of propargylamines to pyrrolidines under acidic conditions is described. This cascade reaction involves addition of a thiyl radical to the terminal alkyne followed by a 1,5-hydrogen transfer (radical translocation) and a rapid cyclization affording the pyrrolidine ring. Our studies reveal that complete protonation of the tertiary amine with 10 equivalents of trifluoroacetic acid avoids undesired hydrogen atom abstractions by the thiyl radicals.

Memory of chirality in reactions involving monoradicals.

The effects of memory of chirality (MoC) in reactions involving monoradical species are reviewed here. Reactions involving a nonracemic chiral starting material bearing a single stereogenic element such as a chiral center or chiral axis directly involved in the new bond formation are discussed. These reactions lead to a nonracemic product via an intermediate susceptible to rapid racemization.

Radical Cyclisation of α-Halo Aluminium Acetals: A Mechanistic Study.

α-Bromo aluminium acetals are suitable substrates for Ueno-Stork-like radical cyclisations affording γ-lactols and acid-sensitive methylene-γ-lactols in high yields. The mechanistic study herein sets the scope and limitation of this reaction. The influence of the halide (or chalcogenide) atom X (X=Cl, Br, I, SPh, SePh) in the precursors α-haloesters, as well as influence of the solvent and temperature was studied.

Synthesis of Polysubstituted γ-Butenolides via a Radical Pathway: Cyclization of α-Bromo Aluminium Acetals and Comparison with the Cyclization of α-Bromoesters at High Temperature.

Polysubstituted butenolides were obtained in good to high yields from α-bromoesters derived from propargyl alcohols by a one-pot reaction involving the radical cyclization of α-bromo aluminium acetals, followed by the oxidation of the resulting cyclic aluminium acetals in an Oppenauer-type process and migration of the exocyclic C=C bond into the α,β-position. Comparison with the direct cyclization of α-bromoesters at high temperature and under high dilution conditions is described. Deuterium-labelling experiments allowed us to uncover "invisible" 1,5-hydrogen atom transfers (1,5-HATs) that occur during these cyclization processes, together with the consequences of the latter in the epimerization of stereogenic centres.

Thiols, thioethers, and related compounds as sources of C-centred radicals.

Due to their stability, availability and reactivity, sulfides are particularly attractive sources of carbon-centered radicals. However, their reactivity in homolytic substitution processes is strongly reduced when compared with the corresponding selenides or halides. Despite this, sulfur-containing compounds can be engineered so that they become effective agents in radical chain reactions.

A convenient access to γ-lactones from O-allyl-α-bromoesters using a one-pot ionic-radical-ionic sequence.

Cognac in the jar! An efficient one-pot sequence for the preparation of γ-lactones is described. Following reduction of α-bromo ester precursors with DIBAL-H and radical cyclization of the resulting O-aluminum acetals, a preparative in-situ Oppenauer-type oxidation of the cyclic O-aluminum acetal using simple aldehydes or ketones gives access to γ-lactones in high yields.

Tandem Payne/Meinwald versus Meinwald rearrangements on the α-hydroxy- or α-silyloxy-spiro epoxide skeleton.

Under Lewis acid activation, the new α-hydroxy-spiro epoxide scaffold 1a underwent an original tandem Payne/Meinwald rearrangement affording the cyclopentyl hydroxymethylketone 6 in a stereospecific manner, while a Meinwald-type epoxide rearrangement occurred when the derived α-trimethylsilyloxy-spiro epoxide 2a was treated with MABR, yielding stereoselectively the cyclohexane carbaldehyde 9.

Radical cyclization of α-bromo aluminum acetals onto alkenes and alkynes (radic[Al] process): a simple access to γ-lactols and 4-methylene-γ-lactols.

An efficient preparation of γ-lactols and methylene-γ-lactols is described. Highly acid-sensitive lactols are prepared in a concise manner by using a radical cyclization of aluminum acetals. The precursors for the radical reactions are readily prepared from allyl or propargyl alcohols and α-bromo acids.

Thiophenol-mediated 1,5-hydrogen transfer for the preparation of pyrrolizidines, indolizidines, and related compounds.

The efficient preparation of 1-azabicyclic alkanes is described. Highly functionalized skeletons are prepared in a concise manner using a radical tin-free 1,5-hydrogen transfer-cyclization process. The precursors for the radical reactions are readily assembled either from pyrrolidine/piperidine/hexahydro-1H-azepine or via condensation of a properly designed N-alkylimine with an allenylzinc species.

Diastereocontrolled synthesis of enantioenriched 3,4-disubstituted beta-prolines.

Enantioenriched 3,4-disubstituted beta-prolines have been prepared with a high diastereocontrol through a carbometalation reaction or through a domino Michael addition/carbometalation reaction.

Radical-polar crossover domino reactions involving organozinc and mixed organocopper/organozinc reagents.

A domino process involving Michael addition and carbocyclization has been developed starting from beta-N-allylamino enoates and various organometallic reagents (organozinc halides, diorganozinc reagents, and copper/zinc mixed species). In all cases the mechanism of this domino reaction has been evidenced to involve a radical-polar crossover mechanism.

Highly diastereoselective formation of spirocyclic compounds via 1,5-hydrogen transfer: a total synthesis of (-)-erythrodiene.

[reaction: see text] A highly stereoselective synthesis of (-)-erythrodiene starting from 4-isopropylcyclohexanone is described. The key reactions are an asymmetric methoxycarbonylation of the starting ketone and a highly diastereoselective radical cascade involving addition of a phenylthiyl radical to a terminal alkyne followed by a 1,5-hydrogen transfer and a 5-exo-cyclization.