Small Rings
Our group has developed novel methodologies for the synthesis and functionalisation of bicyclo[1.1.1]pentanes (BCPs). BCPs are molecules of increasing importance to medicinal chemistry and agrochemical industries as surrogates for metabolically-susceptible para-substituted benzene rings.
BCPs are synthetically accessible through opening [1.1.1]propellane bridgheaded C-C bond. Since its initial synthesis by Wiberg et al. in 1982, [1.1.1]propellane itself remains a mystery of theoretical chemistry with an unusual “inverted hydrocarbon” geometry. Our group challenges the current dogma of strain release reactivity of [1.1.1]propellane, working closely with Prof. Fernanda Duarte to show computationally how electronic delocalisation can explain the omniphilic reactivity of [1.1.1]propellane. We hope through deeper mechanistic understanding we can develop more precise synthetic methodologies with [1.1.1]propellane being harnessed efficiently to produce valuable BCP compounds.
Chem. Sci., 2020, 11, 4895-4903.
We have reported the insertion of C–I bonds across [1.1.1]propellane through both BEt3 and photoredox catalysed initiation ➌. Further, we showed how the iodoBCPs can be functionalized via Fe-catalyzed Kumada-coupling with Grignard reagents ➎. A direct organocatalytic asymmetric synthesis of α-chiral BCPs was also established by our group ➋. Additionally, we have developed a radical-based synthesis of N,C-difunctionalized BCPs using sulfonamidyl radicals, generated through fragmentation of α-iodoaziridines ➍, and a subsequent silyl-mediated Giese reaction ➏. Most recently, a synergistic organophotoredox and hydrogen atom transfer catalysis approach enabled access to highly congested α-quaternary BCPs ➊.
➊ Org. Lett. 2021, 23, 21, 8628–8633. ➋ Nat Commun. 2021, 12, 1644. ➌ ACS Catal. 2019, 9, 10, 9568–9574. and Chem. Sci., 2018,9, 5295-5300. ➍ + ➏ J. Am. Chem. Soc. 2021, 143, 26, 9729–9736. ➎ Angew. Chem. Int. Ed. 2020, 59, 11866.
Similarly, we explored bicyclo[3.1.1]heptanes (BCHeps) as a novel bioisostere for meta-substituted arenes finding accurate mapping behaviour of the exit vectors and enhanced ADME-profiles for two synthesised drug examples BCHep-Sonidegib and BCHep-URB597. We recognised that BCHeps can be easily synthesised through ring-opening of [3.1.1]propellane for which we disclosed a scalable, convenient synthesis.
Nature 2022, 611, 721–726
To accompany the diverse portfolio of [1.1.1]propellane based methodology, our group has developed a divergent approach to access BCP precursors through bridgehead-directed metalation of bicyclo[1.1.0]butanes (BCBs).
Chem. Sci., 2021, 12, 7480-7485.