Generation of Dithianyl and Dioxolanyl Radicals Using Photoredox Catalysis: Application in the Total Synthesis of the Danshenspiroketallactones via Radical Relay Chemistry

Abstract

Visible-light-induced generation of dithianyl and dioxolanyl radicals via selective hydrogen atom transfer (HAT) has been achieved. This radical relay tactic enables remote C(sp 3)-H functionalization to permit rapid access to polyol and spiroketal segments, and in turn has been exploited as a key synthetic construct in the total synthesis of the danshenspiroketallactones. The conformational stability of the danshenspiroketallactones has also been defined via experiments and DFT calculations.

Site-Tunable Csp3–H Bonds Functionalization by Visible-Light-Induced Radical Translocation of N-Alkoxyphthalimides

“…Then the N -alkoxyphthalimide radical anion A fragments to form a carbon-centered radical in two pathways depending on the acid or base additive: (1) In the presence of acid BNDHP, the intermediate A is subsequently protonated and then undergoes a homolytic N–O cleavage under formation of an alkoxy radical B and phthalimide. This intermediate B engages in an intramolecular 1,5-HAT to yield a remote carbon-centered radical C . (2) In the presence of DABCO as a base, intramolecular proton transfer of intermediate A followed by N–O bond homolytic cleavage generates radical anion intermediate D which could exist in its more stable resonance structure α-oxy carbon-centered radical anion D′ .…”

Visible-Light-Induced Alkoxyl Radicals Enable α-C(sp3)-H Bond Allylation

“…Our investigation was initiated by the serendipitous discovery with N-alkoxylphthalimide 1 as the alkoxyl radical precursor, which can be readily prepared from alcohols and are bench-stable (Scheme 2) (Zhu et al., 2009, Kim et al., 1998, Zhang et al., 2016, Zhang et al., 2017, Wang et al., 2016, Ito et al., 2018, Han et al., 2019, Deng et al., 2019, Shi et al., 2019). Under the reaction conditions of fac -Ir(ppy) 3 and Hantzsch ester known to generate alkoxyl radicals (Zhang et al., 2016, Zhang et al., 2017, Wang et al., 2016, Ito et al., 2018, Han et al., 2019, Deng et al., 2019, Shi et al., 2019), the ester-derived N-alkoxylphthalimide 1 gave no δ-C(sp 3 )-H allylation adduct 3 with allyl sulfone 2 under blue LED irradiation. Instead, the α-C(sp 3 )-H allylation adduct 4 was observed in 41% yield, together with the hydrogenation adduct alcohol 5 in 52% yield (entry 1 in Table 1) (Zhang et al., 2016).…”

Factors Controlling Reactivity in the Hydrogen Atom Transfer and Radical Addition Steps of a Radical Relay Cascade

“…Upon HAT, the resulting carbon radical (vii), stabilized by either a dioxanyl or a dithianyl group, further engages in radical additions to electrophiles. 5 This radical “relay” reaction permits remote C–H functionalization and was employed in the total synthesis of (±)-danshenspiroketallactone (x). The originally generated oxy radical reacts in an energetic cascade with a series of electrophiles to generate multiple bonds in a single-flask operation.…”

“…This proved to be the case as it was possible to introduce multiple relay steps after the initial HAT, as demonstrated in the original report. 5…”

“…An elimination then occurs that leads to a double addition adduct 20 in 56% overall yield after oxidation. 5 We have now investigated this relay process computationally. Upon generation of benzylalkoxy radical 16 , a facile 1,5-HAT ( TS5 , 5.9 kcal/mol, Scheme 5) generates benzylic radical 17 .…”