Asymmetric Radical Cyclization of Alkenes by Stereospecific Homolytic Substitution of Sulfinamides

We report a novel asymmetric radical cyclization of alkenes via stereospecific homolytic substitution of sulfinamides. This reaction produces a variety of cyclic sulfinamides with excellent stereocontrol. The protocol features broad functional group tolerance, high product diversity, and easy accessibility to feedstocks, and outlines a new pathway for the synthesis of chiral cyclic sulfinamides.

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We have developed a new method for asymmetric phenylseleno group transfer radical cyclization of unsaturated beta-hydroxy esters. Various unsaturated alpha-phenylseleno beta-hydroxy esters underwent radical cyclization in the presence of Et(2)AlCl in benzene with sunlamp irradiation at 25-30 degrees C to give mono- and bicyclic group-transferred products in an efficient and highly regioselective and diastereoselective manner. To rationalize the high diastereoselectivities observed in this reaction, we propose a model based on chelation control of the aluminum alkoxides that are formed in situ. We devised a general method to prepare chiral radical precursors from which we obtained highly optically pure mono- and bicyclic group transfer products. The synthetic advantages of this method are demonstrated by our formal total synthesis of (-)-wilforonide. This paper presents the first examples of stereoselective group transfer radical cyclizations that occur via 1,2-asymmetric induction.

Due to the innate highly reactive properties and short life‐time, organic free radicals can often serve as promoters or intermediates to engage in various radical transformations, which are often otherwise difficult to access by ionic pathway‐based mechanisms. With the evolvement of radical chemistry, chiral radical catalyzed‐transformations have recently emerged as an attractive and robust platform for synthesis of chiral molecules of interest. Herein, we highlight several creative and strategic advances in chiral radical catalyst design, cyclization reaction achievements, and future challenges. Key ScientistsIn the 1980s, some pioneering studies by Feldman and Oshima revealed that the thiyl radical could catalyze cyclization of vinylcyclopropane with alkenes, providing access to racemic cyclopentanes. In 1996, Brian P. Roberts reported an interesting enantioselective hydrosilylation of prochiral alkenes by using thioglucose‐derived chiral thiyl radical catalysts. Since then, chiral radical catalysis has become an emerging and promising catalytic strategy in organic synthesis. However, this field has not been extensively explored further until the Maruoka group in 2014 achieved the asymmetric C—C bond formation by employing a newly designed indanol core‐based chiral thiyl radical catalyst. In this protocol, an enantioselective radical cyclization of vinylcyclopropanes with electron‐rich alkenes was developed. In 2020, Chen and Xiao disclosed a nitrogen radical‐catalyzed version of this reaction. Later, this strategy was further expanded to metalloradical catalyzed asymmetric radical cascade cyclization reactions by Zhang in 2021. Later on, Wang, Fu and Zhang et al. described a novel class of boryl radical‐catalyzed asymmetric radical cycloisomerization reactions, further showcasing enormous synthetic potential of chiral radical catalysis. This Emerging Topic has focused on asymmetric radical cyclization reactions involving diverse chiral radical catalysts.

How Does Plant Diversity Affect Soil Aggregate Stability and Erosion Processes in Disturbed Alpine Ecosystems

Comprehensive Summary The pentafluorosulfanyl (SF 5 ) moiety has garnered significant attention as a fluorinated functional group in the fields of medicinal chemistry, agrochemistry, and materials science, attributable to its distinctive physicochemical properties. In comparison to its structural analogue, trifluoromethyl, the SF 5 group demonstrates notably increased lipophilicity and pronounced electron‐withdrawing capacity. However, the direct pentafluorosulfanylation of unactivated alkenes remains challenging due to the intrinsic propensity of SF 5 Cl to undergo spontaneous chloropentafluorosulfanylation. Herein, we report a photoinduced radical pentafluorosulfanylation‐cyclization of alkenes enabled by an in situ substrate‐derived radical moderator strategy. Upon irradiation with LEDs, homolytic cleavage of the S–Cl bond in SF 5 Cl affords an electrophilic SF 5 radical, which undergoes addition to the alkene unit of the sulfinamide substrate, thereby generating a carbon‐centered radical intermediate. Subsequent intramolecular S H i cyclization yields the cyclic sulfinamide product, while a tert ‐butyl radical partakes in an XAT process with SF 5 Cl to regenerate the SF 5 radical and perpetuate the radical chain mechanism. Intriguingly, intramolecular hydrogen‐bonding interactions between the sulfinyl group and the CH 2 SF 5 moiety are posited to be responsible for the exceptional stereocontrol observed. Furthermore, the resulting SF 5 ‐containing motifs are readily amenable to further functionalization, thereby highlighting the broad synthetic utility and potential applications of these cyclic sulfinamides in pharmaceutical and materials science research.

Asymmetric radical cyclizations: the synthesis of 6-Alkyl Pyrrolizidin-2-ones

Key words allylic amidation - auto-tandem catalysis - radical cyclization - γ-lactams - ruthenium

The rhodium(III)-catalyzed kinetic resolution of racemic nonactivated terminal alkene-tethered cyclohexadienones (1,6-dienes) has been developed with high to excellent selectivities (s up to 458) via asymmetric borylative cyclization, providing recovered cyclohexadienones and cis-hydrobenzofuranones with good to excellent yields and enantioselectivities (up to 99% ee). This reaction shows broad functional group tolerance and allows the further conversions of these two-type products to many optically active derivatives bearing multiple functionalities via Rh, Cu, Pd, and Ag catalysis.

N,3,4-Trisubstituted pyrrolidines by electron transfer-induced oxidative cyclizations of N-allylic β-amino ester enolates

Flavin-dependent ‘ene’-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. While these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyze reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here we demonstrate that these enzymes can catalyze redox-neutral radical cyclizations to produce enantioenriched oxindoles from a-haloamides. This transformation is a C–C bond forming reaction currently unknown in nature and one for which there are no catalytic asymmetric examples. Mechanistic studies indicate the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground state flavin semiquinone provides the electron for substrate reduction and flavin quinone oxidizes the vinylogous a-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.

Flavin-dependent ‘ene’-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. While these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyze reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here we demonstrate that these enzymes can catalyze redox-neutral radical cyclizations to produce enantioenriched oxindoles from α-haloamides. This transformation is a C–C bond forming reaction currently unknown in nature and one for which there are no catalytic asymmetric examples. Mechanistic studies indicate the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground state flavin semiquinone provides the electron for substrate reduction and flavin quinone oxidizes the vinylogous α-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.

Key words radical cyclization - flavoenzymes - ene-reductases - asymmetric catalysis - photocatalysis - indolones

Highly stereocontrolled total synthesis of dart frog indolizidine alkaloids (–)‐167B, (–)‐209I, and (–)‐223A was accomplished, with a common tricyclic lactone intermediate as the starting compound, in overall yields of 17 %, 14 %, and 17 %, respectively. The C7–C8 bond of the 167B, without a C8 chiral substituent, was formed through ring closure metathesis followed by hydrogenation. In 209I and 223A, which have a C8 chiral substituent, highly substrate‐controlled asymmetric radical cyclization was used to form the C7–C8 bond, and the correct stereochemistry of the C8 substituents was obtained in both molecules. Ethyl substituent at the C6 position of 223A was obtained with correct stereochemistry through asymmetric alkylation/epimerization sequences of the tricyclic lactone. Cleavage of the excess carbon on the C5 position of all three indolizidines was performed by using a Barton decarboxylation protocol. Reduction of the corresponding indolizidin‐3‐ones by LAH completed the total synthesis of (–)‐167B, (–)‐209I and (–)‐223A.

Chiral, non-racemic N-(2-iodoethyl)-5-vinylpyrrolidin-2-ones have been synthesized and then cyclized with tributyltin hydride and azoisobutyronitrile (AIBN) to produce chiral, non-racemic pyrrolizidin-2-ones, with high diastereoselectivity. Reduction of the lactam moiety provides a facile route to naturally occurring pyrrolizidine alkaloids.