Short Enantioselective Total Syntheses of trans-Clerodane Diterpenoids: Convergent Fragment Coupling Using a trans-Decalin Tertiary Radical Generated from a Tertiary Alcohol Precursor

Abstract

The evolution of a convergent fragment-coupling strategy for the enantioselective total synthesis of trans-clerodane diterpenoids is described. The key bond construction is accomplished by 1,6-addition of a trans-decalin tertiary radical with 4-vinylfuran-2-one. The tertiary radical is optimally generated from the hemioxalate salt of the corresponding tertiary alcohol upon activation by visible light and an Ir(III) photoredox catalyst. The enantioselective total synthesis of trans-clerodane diterpenoid 1 reported here was accomplished in seven steps from 3-methyl-2-cyclohexenone. The synthetic strategy described in this report allows a number of trans-clerodane diterpenoids to be synthesized in enantioselective fashion by synthetic sequences of 10 steps or less. This study illustrates a powerful tactic in organic synthesis in which a structurally complex target structure is disconnected at a quaternary carbon stereocenter to fragments of comparable complexity, which are united in the synthetic pathway by conjugate addition of a nucleophilic tertiary radical to a fragment harboring an electron-deficient C-C double bond.

Catalytic diastereo- and enantioselective additions of versatile allyl groups to N–H ketimines

“…These investigations provide the first step towards development of a series of catalytic enantioselective reactions involving N-H ketimines and other types of readily available and versatile carbon-based nucleophiles, protocols that render a range of chiral drug candidates with one or more α-tertiary amine moieties much more accessible. Finally, this study further expands the utility of sulfonate-containing chiral NHC ligands, previously utilized in catalytic enantioselective conjugate additions 48 , allylic substitutions 49 as well as copper-boryl additions to alkenes 50 and allenes 51 and copper–hydride additions to alkenes 52 , to include allyl additions to ketimines.…”

Decarboxylative alkenylation

“…Prior approaches 39,40 to the clerodane diterpene natural products target each through a different strategy with, for example, the syntheses of 76a–c ranging from 8–21 steps (Figure 3B). …”

Versatile Homoallylic Boronates by Chemo‐, SN2′‐, Diastereo‐ and Enantioselective Catalytic Sequence of Cu−H Addition to Vinyl‐B(pin)/Allylic Substitution

“…By providing an efficient, chemo-, S N 2’-, diastereo- and enantioselective method for accessing otherwise difficult-to-prepare and readily alterable homoallylic boronate compounds, we provide further evidence regarding the importance of sulfonate-containing chiral NHC ligands. These Cu-based complexes have formerly proven optimal in catalyzing enantioselective allylic substitution reactions [24] and conjugate addition processes [15,25] with C-based nucleophiles as well as Cu–B(pin) additions to alkenes [26] and allenes; [27] this is however the first time that a member of this catalyst class has emerged as the most effective for enantioselective Cu–H additions to an alkene.…”