Stereoselective and Stereospecific Triflate-Mediated Intramolecular Schmidt Reaction: Ready Access to Alkaloid Skeletons

L. Gnägi, R. Arnold, F. Giornal, H. Jangra, A. Kapat, E. Nyfeler, R. M. Schärer, H. Zipse, P. Renaud

Angew. Chem. Int. Ed. 2021, in press

Enantiomerically enriched azabicyclic compounds found in several important families of alkaloids can be prepared by a remarkably stereospecific and stereoselective intramolecular Schmidt reaction. The initial asymmetric alcohol center controls the whole process, leading to the formation of one out of up to four possible diastereoisomers with inversion of the configuration at the original asymmetric center.

Forskolin Editing via Radical Iodo- and Hydroalkylation

E. Pruteanu, N. D. C. Tappin, V. Gîrbu, O. Morarescu, F. Dénès, V. Kulciţki, P. Renaud

Synthesis 2021, 53, 1247-1261

The modification of highly oxygenated forskolin as well as manoyl and epi-manoyl oxide, two less functionalized model substrates sharing the same polycyclic skeleton, via intermolecular carbon-centered radical addition to the vinyl moiety has been investigated. Highly regio- and reasonably stereoselective iodine atom transfer radical addition (ATRA) reactions were developed. Unprotected forskolin afforded an unexpected cyclic ether derivative. Protection of the 1,3-diol as an acetonide led the formation of the iodine ATRA product. Interestingly, by changing the mode of initiation of the radical process, in situ protection of the forskolin 1,3-diol moiety as a cyclic boronic ester took place during the iodine ATRA process without disruption of the radical chain process. This very mild radical-mediated in situ protection of 1,3-diol is expected to be of interest for a broad range of radical and non-radical transformations. Finally, by using our recently developed tert-butyl­catechol-mediated hydroalkylation procedure, highly efficient preparation of forskolin derivatives bearing an extra ester or sulfone group was achieved.

A Giese reaction for electron-rich alkenes

Q. Huang, S. R. Suravarapu, P. Renaud

Chem. Sci. 2021, 12, 2225-2230

A general method for the hydroalkylation of electron-rich terminal and non-terminal alkenes such as enol esters, alkenyl sulfides, enol ethers, silyl enol ethers, enamides and enecarbamates has been developed. The reactions are carried out at room temperature under air initiation in the presence of triethylborane acting as a chain transfer reagent and 4-tert-butylcatechol (TBC) as a source of hydrogen atom. The efficacy of the reaction is best explained by very favorable polar effects supporting the chain process and minimizing undesired polar reactions. The stereoselective hydroalkylation of chiral N-(alk-1-en-1-yl)oxazolidin-2-ones takes place with good to excellent diastereocontrol.

Methyl Radical Initiated Kharasch and Related Reactions

N. D. C. Tappin, P. Renaud

Adv. Synth. Cat. 2021, 363, 275–282.

An improved procedure to run halogen atom and related chalcogen group transfer radical additions is reported. The procedure relies on the thermal decomposition of di-tert-butylhyponitrite (DTBHN), a safer alternative to the explosive diacetyl peroxide, to produce highly reactive methyl radicals that can initiate the chain process. This mode of initiation generates byproducts that are either gaseous (N2) or volatile (acetone and methyl halide) thereby facilitating greatly product purification by either flash column chromatography or distillation. In addition, remarkably simple and mild reaction conditions (refluxing EtOAc during 30 minutes under normal atmosphere) and a low excess of the radical precursor reagent (2 equivalents) make this protocol particularly attractive for preparative synthetic applications. This initiation procedure has been demonstrated with a broad scope since it works efficiently to add a range of electrophilic radicals generated from iodides, bromides, selenides and xanthates over a range of unactivated terminal alkenes. A diverse set of radical trap substrates exemplifies a broad functional group tolerance. Finally, di-tert-butyl peroxyoxalate (DTBPO) is also demonstrated as alternative source of tert-butoxyl radicals to initiate these reactions under identical conditions which gives gaseous by-products (CO2).

Desulfitative Thioalkylation of Alkenes

L. Cao, C. Jimeno, P. Renaud

Adv. Synth. Cat. 2020, 362, 3644–3648.

An efficient method for the thioalkylation of alkenes via radical desulfitative sulfur-group transfer is described. The reaction is based on the use of readily available thiosulfonates as starting materials and cheap radical initiators such as dilauroyl peroxide (DLP) and sun lamp irradiation. No transition metal catalyst is required, and the reaction takes place under mild conditions.

A General Approach to Deboronative Radical Chain Reactions with Pinacol Alkylboronic Esters

E. André‐Joyaux , A. Kuzovlev, N. D. C. Tappin, P. Renaud

Angew. Chem. Int. Ed. 2020, 59, 13859-13864

The generation of carbon‐centered radicals from air‐sensitive organoboron compounds through nucleohomolytic substitution at boron is a general method to generate non‐functionalized and functionalized radicals. Due to their reduced Lewis acidity, alkylboronic pinacol esters are not suitable substrates. We report their in situ conversion into alkylboronic catechol esters by boron‐transesterification with a substoichiometric amount of catechol methyl borate combined with an array of radical chain processes. This simple one‐pot radical‐chain deboronative method enables the conversion of pinacol boronic esters into iodides, bromides, chlorides, and thioethers. The process is also suitable the formation of nitriles and allylated compounds through C−C bond formation using sulfonyl radical traps. The power of combining radical and classical boron chemistry is illustrated with a modular 5‐membered ring formation using a combination of three‐component coupling and protodeboronative cyclization.

Radical Reactions of Boron-Ate Complexes Promoting a 1,2-Metallate Rearrangement

N. D. C. Tappin, P. Renaud

Chimia 2020, 74, 33-38

Recently there has been an explosion of interest in the synthetic community for the addition of radicals into unsaturated organoboron-ate complexes. This review will give a concise outline for radical processes involving boron-ate complexes which trigger a subsequent anionotropic rearrangement.

Two-Step Azidoalkenylation of Terminal Alkenes Using Iodomethyl Sulfones

N. Millius, G. Lapointe, P. Renaud

Molecules 2019, 24, 4184

The radical azidoalkylation of alkenes that was initially developed with α-iodoesters and α-iodoketones was extended to other activated iodomethyl derivatives. By using iodomethyl aryl sulfones, the preparation of γ-azidosulfones was easily achieved. Facile conversion of these azidosulfones to homoallylic azides using a Julia–Kocienski olefination reaction is reported, making the whole process equivalent to the azidoalkenylation of terminal alkenes.

Radical-mediated hydroalkylation of 2-vinylpyrrolidine derivatives: a versatile entry into indolizidine alkaloids

S. R. Suravarapu, B. Peter, P. Renaud,

Sci. China Chem. 2019, 62, 1504–1506

A concise route for the preparation of two simple optically pure indolizidin-5-ones has been developed. The key chain elongation process was achieved using a triethylborane/catechol mediated hydroalkylation of Boc-protected 2-vinylpyrrolidines. By using complementary strategies, these two bicyclic lactams can be alkylated with complete control of the stereochemistry at C(5) and their conversion to a variety of indolizidine alkaloids such as coniceine, indolizidine 209D and 167B, 5-epi-indolizidine 249A and monomorine has been reported in the literature.

A Short Synthesis of (+)-Brefeldin C through Enantioselective Radical Hydroalkynylation

L. Gnägi, S. V. Martz, D. Meyer, R. M. Schärer, P. Renaud

Eur. J. 2019, 25, 11646–11649.

A very concise total synthesis of (+)-brefeldin C starting from 2-furanylcyclopentene is described. This approach is based on an unprecedented enantioselective radical hydroalkynylation process to introduce the two cyclopentane stereocenters in a single step. The use of a furan substituent allows a high trans diastereoselectivity to be achieved during the radical process and it contains the four carbon atoms C1–C4 of the natural product in an oxidation state closely related to the one of the target molecule. The eight-step synthesis requires six product purifications and it provides (+)-brefeldin C in 18 % overall yield.

Cyclopropanation of Terminal Alkenes through Sequential Atom-Transfer Radical Addition/1,3-Elimination

N. D. C. Tappin, W. Michalska, S. Rohrbach, P. Renaud

Angew. Chem. Int. Ed. 2019, 58, 14240–14244.

An operationally simple method to affect an atom-transfer radical addition of commercially available ICH2Bpin to terminal alkenes has been developed. The intermediate iodide can be transformed in a one-pot process into the corresponding cyclopropane upon treatment with a fluoride source. This method is highly selective for the cyclopropanation of unactivated terminal alkenes over non-terminal alkenes and electron-deficient alkenes. Due to the mildness of the procedure, a wide range of functional groups such as esters, amides, alcohols, ketones, and vinylic cyclopropanes are well tolerated.