Stereodivergent synthesis of vicinal quaternary-quaternary stereocenters and bioactive hyperolactones

Abstract

Although great success has been achieved in asymmetric Claisen rearrangement for the synthesis of chiral γ,δ-unsaturated carbonyl compounds bearing vicinal tertiary-quaternary stereocenters, the development of asymmetric versions for stereodivergent construction of adjacent quaternary-quaternary stereocenters remains a formidable challenge because of the high steric hindrance. Here we report a catalytic enantioselective dearomatization Claisen rearrangement of allyl furyl ethers catalyzed by chiral N,N′-dioxide-NiII complex catalysts. A variety of chiral γ,δ-unsaturated carbonyl compounds bearing vicinal quaternary-quaternary stereocenters were obtained with excellent outcomes under mild conditions. Furthermore, we disclosed that by matching the configuration of the catalysts and the alkene unit of the substrates, four stereoisomers of the products could be prepared in excellent yields and stereoselectivities. Finally, the fascination of this strategy was demonstrated by stereodivergent synthesis of bioactive natural products hyperolactones B, C, and their epimers. A possible catalytic model was proposed to explain the origin of the asymmetric induction.

Pentanidium-Catalyzed Direct Assembly of Vicinal All-Carbon Quaternary Stereocenters through C(sp 3 )–C(sp 3 ) Bond Formation

“…Separately, the use of multi-substituted alkenes in [3+2] annulation, 11,12 Diels-Alder [13][14][15] and other cycloadditions 16,17 is another common approach (Figure 1a). Recent advances include dearomatization addition of -naphthols on 3-bromooxindoles, 18 Claisen rearrangement of -unsaturated carbonyl compounds, 19 dialkylation of bisoxindoles, 20 phosphine-catalyzed cyclization of allenes 21 and a nucleophilic substitution at a quaternary carbon center with concomitant opening of a cyclopropane ring. 22,23 On the other hand, direct radical coupling of two C(sp 3 ) centers is a promising possibility as it can overcome steric hindrance; but currently it is limited to a narrow substrates scope such as bisoxindoles and chiral auxiliaries need to be deployed if enantioenriched compounds are required (Figure 1b).…”

Recent Advances in Catalytic [3,3]-Sigmatropic Rearrangements

“…With different alkyl substituents containing allene 3 (R3 ≠ R4), both E-and Z-isomers were obtained with 99% ee, but the E/Z ratio was only 2:3. In 2018, the catalytic asymmetric Claisen rearrangement of allyl furyl ethers 5 was developed to produce the chiral γ,δ-unsaturated carbonyl compounds 6 (Scheme 1c) [18]. By controlling the chirality of the ligand and olefin geometry, all possible stereochemistries could be generated at the adjacent two quaternary carbon centers.…”

Synthetic Access to Aromatic α-Haloketones

“…The existence of two adjacent electrophilic centres, namely the α-halocarbon and the carbonyl group, transforms these reactive carbonyl compounds into highly valuable building blocks for the construction of more complex structures. In that context, a wide variety of N , S , and O -heterocycles have been accessed using protocols involving α-haloketones [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. These compounds have also proven to be important intermediates in the synthesis of various organometallic species.…”