Tosvinyl and Besvinyl as Protecting Groups of Imides, Azinones, Nucleosides, Sultams, and Lactams. Catalytic Conjugate Additions to Tosylacetylene

Abstract

ABSTRACT:The use of the 2-(4-methylphenylsulfonyl)ethenyl (Tosvinyl, Tsv) group for the protection of the NH group of a series of imides, azinones (including AZT), inosines, and cyclic sulfonamides has been examined. The Tsv-protected derivatives are obtained in excellent yields by conjugate addition to tosylacetylene (ethynyl p-tolyl sulfone). The stereochemistry of the double bond can be controlled at will: with only 1 mol % of Et 3 N or with catalytic amounts of NaH the Z stereoisomers are generated almost exclusively, while the E isomers are obtained using a stoichiometric amount of DMAP. Analogous phenylsulfonylvinyl-protected groups (with the Besvinyl or Bsv group instead of Tsv) are obtained stereospecifically by reaction with (Z)-or (E)-bis(phenylsulfonyl)ethene. For lactams and oxazolidinones, this last method is much better. The Tsv and Bsv groups are stable in the presence of non-nucleophilic bases and to acids. They can be removed highly effectively via a conjugate addition-elimination mechanism using pyrrolidine or sodium dodecanethiolate as nucleophiles.

Computational Study of the Addition of Methanethiol to 40+ Michael Acceptors as a Model for the Bioconjugation of Cysteines

“…However, in aqueous media this is not the case, as Z adducts largely predominate. 5 , 6 Calculations of the corresponding intermediates would allow us to gain more insight into this issue.…”

“…As mentioned in the Introduction, mixtures of Z and E adducts are expected when thiols add to activated triple bonds (calculations indicate that E adducts are usually around 1 kcal/mol more stable than their Z counterparts). However, in aqueous media this is not the case, as Z adducts largely predominate. , Calculations of the corresponding intermediates would allow us to gain more insight into this issue.…”

“…Equilibration of the anions must therefore be very rapid. If it is not produced in aqueous media, it must be due to the even more rapid protonation of the initially formed Z -like anion, as it is generally accepted …”

“…Bernardes and coworkers 5d used quaternized 2-vinylpyridines and 2-ethynylpyridines, which exhibit a reactivity comparable to that of N -alkylmaleimides and much higher than that of 2-vinylpyridine or 2-ethynylpyridine, with the Cys residues of five different protein scaffolds (including Thiomab). 5d Winne et al 5e published work on reversible dynamic exchanges of thioacetal linkages, that is, the double addition of thiols to several ynones, one propynamide, one ethynesulfonamide, and tosylacetylene (ethynyl 4-methylphenyl sulfone) 6 in connection with the formation of cross-linked polymers. 5e Even more recently, Cameron et al 5f investigated the reaction of Cys with allenamides, following the work of Loh et al., 5g but preparing modified cyclic peptides by intramolecular addition.…”

“…The true percentages of the thiolate anions will obviously depend on the p K a of each sulfanyl/sulfhydryl/mercapto group . Since it is known that in aqueous media, activated triple bonds are mainly converted into Z adducts, , for the sake of simplicity, the E adducts (which are predominantly formed in organic solvents, in the presence of tertiary amines) are not included in Scheme and in many of the following schemes and figures.…”