Unsymmetrical Organotrisulfide Formation via Low-Temperature Disulfanyl Anion Transfer to an Organothiosulfonate

Abstract

New methodology is presented for the formation of unsymmetrical organotrisulfides in a high yield and purity, relatively free of polysulfide byproducts. The highlight of the method is the low-temperature (−78 °C) deprotection of a disulfanyl acetate with sodium methoxide in THF to form a disulfanyl anion, which reacts rapidly in situ with an organothiosulfonate (S-aryl or S-alkyl) within 30 seconds followed by quenching. The discovery of these new reaction conditions together with the relative greenness of the chemistry overall makes for an efficient protocol, from which a range of organotrisulfides covering aliphatic, aromatic, as well as cysteine and sugar groups can be accessed in a high yield and purity.

A Review of Heterolytic Synthesis Methodologies for Organotri- and Organotetrasulfane Synthesis

“…The targeted nature of these two recent methods ensures that homotrisulfanes do not overly interfere as by-products. Similarly, we have utilised 74 Witt's conditions for disulfanyl acetate deprotection, but at -78 °C, demonstrating that a very fast reaction (within 30-60 s) occurs between a disulfanyl acetate and a thiotosylate (RSTs; R = alkyl or aryl) in the presence of sodium methoxide in a mixture of THF/methanol to afford unsymmetrical trisulfanes in high yield and purity (Scheme 6, entry 26). 74 Finally, two groups have cleverly exploited certain disulfanyl reagents of the type RSSX that can generate in situ both the electrophilic (RSLg) and nucleophilic reagent (RSS -) for methodology D. The reaction constitutes a homo-coupling with two prerequisites.…”

Synthesis of (Furyl)Methyl Disulfides via Tandem Reaction of Conjugated Ene-Yne-Ketones with Acetyl-Masked Disulfide Nucleophiles

“…In the past few years, a variety of cross-coupling reactions using these acetyl-masked disulfide nucleophile reagents have been developed to synthesize disulfides and polysulfides (Scheme A). For instance, Witt’s group and Rees-Jones’s group reported successively a novel strategy for the construction of asymmetric trisulfide compounds by using RSSAc as nucleophiles to react with disulfide thiophosphate or thiosulfonates . In 2016, Jiang’s group developed a Cu-catalyzed oxidative cross-coupling reaction between RSSAc and phenylboronic acid or silicate esters, affording a wide range of unsymmetrical disulfanes .…”

Neogrisemycin, a Trisulfide-Bridged Angucycline, Produced upon Expressing the Thioangucycline Biosynthetic Gene Cluster in Streptomyces albus J1074

“…Natural products bearing a trisulfide bridge have been attractive and challenging targets for synthetic campaigns, exemplified by the total synthesis of calicheamicin γ 1 ( 2 ) by Nicolaou and co-workers in 1992 and of luteoalbusins by Movassaghi and co-workers in 2015 . Trisulfide bridge-containing natural products, such as luteoalbusin B ( 3 ), (2 E ,4′ R ,5′ S ,6′ S ,7′ R )-3-{7′-hydroxy-4′,6′-dimethyl-4′-(3″-methylenepent-4″-enyl)­[1′,2′,3′]­trithiocan-5′-yl} acrylic acid ( 4 ), cis -5-hydroxy-4-(4′-hydroxy-3′-methoxyphenyl)-4-(2″-imidazolyl)-1,2,3-trithiane ( 5 ), and a psammaplin congener ( 6 ) (Figure ), therefore continue to inspire innovations in synthetic organic chemistry. − , …”