Phosphorothioic Acids and Related Compounds as Surrogates for H₂S—Synthesis of Chiral Tetrahydrothiophenes

Abstract

The convenient preparation of chiral tetrahydrothiophenes (THTs) in high enantiopurity via phosphorothioic acids and related compounds is reported. We consider these to be safer alternatives to the use of H(2)S which is a highly toxic gas. Each of the THTs is derived from a common intermediate, thereby greatly enhancing the flexibility of the synthesis. The key transformation is a base-promoted, intramolecular, carbon-sulfur bond-forming event. These reactions are highly stereospecific as they operate through a double S(N)2 displacement mechanism. The methodology is amenable to a broad array of functional groups and heterocycles. The tetrahydrothiophene motif is important because it is present in a number of bioactive natural products. They have also been utilized to promote various asymmetric transformations including hydrogenation, epoxidation, cyclopropanation, and aziridination reactions.

Synthesis of Chiral Allylic Thioesters: Enantio‐ and Regioselective Iridium‐Catalyzed Allylations of KSAc

“…To test the feasibility of using different thiol precursors with this synthetic strategy, NaSCOPh,11c potassium O , O ‐diethyl phosphorothioate [KSPO(OEt) 2 ],22 and potassium ethyl xanthogenate (KSCSOEt)23,11c were examined under the optimum conditions. Unfortunately, both NaSCOPh and KSPO(OEt) 2 led to poor conversion (<10 %), and KSCSOEt afforded the linear allylation product as well.…”

Anionic Cascade Routes to Sulfur and Nitrogen Heterocycles Originating from Thio‐ and Aminophosphate Precursors

“…The second scenario employs an even more reactive Michael acceptor wherein the alkoxy anion needed for the phosphate cascade is generated by J. Wu has demonstrated that a chiral thietane can be synthesized using phosphate-mediated anionic hopping cascade (Scheme 18). [33] Finkelstein reaction on 3-chloro-1-phenylpropan-1-one affords an iodide, which can be carefully displaced with the sodium salt of diethyl thiophosphate in dimethylformamide. Chirality is installed using Corey-Bakshi-Shibata (CBS) carbonyl reduction protocol.…”

[1,4]‐S‐ to O‐Silyl Migration: Multicomponent Synthesis of α‐Thioketones through Chemoselective Transformation of Esters to Ketones with Organolithium Reagents

“…The sulfur in ester 1 would act not Keywords: multicomponent reactions · nucleophilic addition · organolithium reagents · silyl migration · thioketones Abstract: A [1,4]-S-to O-silyl migration has been exploited to chemoselectively transform esters into ketones by using organolithium reagents, allowing multicomponent synthesis of a-thioketones. Mechanistic studies reveal that this migration proceeds in an intramolecular manner and is more favorable than the corresponding [1,5]-S-to O-and [1,3]-C-to O-silyl migrations. The resulting a-thioketones are valuable building blocks for the synthesis of cyclic or multifunctionalized organosulfur compounds.…”

“…[2] In sharp contrast, intramolecular anionic silyl migration between two hetero atoms, especially the migration from a sulfur to an oxygen atom, has been studied to a much more limited extent (Scheme 1 b). [3] Because Si À O bonds are stronger than SiÀS bonds (ca. 110 vs. 70 kcal mol À1 ), [4] the migration from S to O should be thermodynamically favorable and, indeed, has been observed under some circumstances.…”

“…[9] This has been attributed to the premature release of ketone from the initially formed tetrahedral adduct, which is highly unstable at À78 8C. In fact, efforts to trap this intermediate even at À100 8C by using Me 3 SiCl have met with only limited success. [10] To avoid this problem, we used an alternative approach based on an intramolecular trapping process in which [1,4]-S-to O-silyl migration of 2 was expected to proceed faster than its collapse, generating the masked ketone 3 chemoselectively (Scheme 1).…”