Copper-mediated synthesis of drug-like bicyclopentanes

Abstract

Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences¹. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements². These structures are often generated from [1.1.1]propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles^3-13. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.

Figure 1 ∣. Direct three-component coupling of [1.1.1]propellane.

a, Examples of the BCP core appearing in bioactive compounds. b, Typical approaches to BCP structures require stepwise synthetic sequences. In contrast, a multicomponent approach might enable single-step access to complex BCP molecules. c, A three-component coupling enabled by a sequence of radical addition and BCP radical capture could be synthetically powerful if selectivity over two-component coupling and oligomerization could be achieved. d, A photoredox-copper platform enables single-step access to an array of diverse products. Ph, phenyl; Et, ethyl; (pin), pinacolato; Boc, tert-butoxycarbonyl; Ac, acetyl; L, ligand; Me, methyl.

Figure 2 ∣. Plausible mechanism and catalyst evaluation for three-component coupling.

a, Reductive radical generation gives an alkyl radical (4) which can be intercepted by [1.1.1]propellane (5) to give BCP radical 6. Trapping by an appropriate copper species, such as 7, followed by reductive elimination would give the desired three-component BCP product 9. b, Evaluation of copper salts and ligands to achieve the desired reactivity revealed that copper (II) acetoacetonate (acac) is the optimal catalyst. c, Studies on the effect of radical s-character reveal that selectivity trends with this characteristic. ^a30 mol% of each copper salt and ligand was used unless otherwise specified. ^{b 1}H-NMR yields. ^c60 mol% Cu(acac)₂ used. SET, single-electron transfer; Nu, N-nucleophile; TC, thiophene-2-carboxylate; BPhen, bathophenanthroline.

Figure 3 ∣. Radical precursor scope for three-component coupling.

Numerous radical precursors can be utilized in this transformation. All yields are isolated unless otherwise noted. Experiments typically run with 1 eq. of nucleophile, 1.5 eq. of [1.1.1]propellane, and 2 eq. of iodonium dicarboxylate; however, alternative stoichiometry is optimal in some cases. See Supplementary Information for exact experimental conditions. ^aConditions vary slightly for each class of radical precursor. See Supplementary Information for exact reaction conditions. ^{b 1}H-NMR yield. ^c30 mol% Cu(acac)₂, no light (see SI). ^dTHF as solvent. NR₂, 6-bromo-4-azaindole; Mes, mesityl; BTMG, 2-tert-butyl-1,1,3,3- tetramethylguanidine; ^tBu, tert-butyl.

Figure 4 ∣. Nucleophile scope of three-component coupling.

All yields are isolated, and conditions are similar to those in Figure 3 unless otherwise noted. ^{a 1}H-NMR yields. Isolated yields for these compounds typically 10–15% lower, see Supplementary Information for details. ^bCu(TMHD)₂ used instead of Cu(acac)₂. ^cCu(II) bis-(2-isobutyrylcyclohexanone) complex used instead of Cu(acac)₂. ^dBTTP used as base instead of BTMG.^eUPLC yields. THP, 4-tetrahydropyranyl; Trt, trityl; TMHD, 2,2,6,6-tetramethyl-3,5-heptanedionate; BTTP, tert-butylimino-tri(pyrrolidino)phosphorane.

Figure 5 ∣. Rapid functionalization of drugs and natural products and preparation of pharmaceutical analogues.

a, Drug and natural product carboxylic acids can be leveraged in this three-component coupling for rapid diversification. b, This protocol can also be applied to the rapid preparation of pharmaceutical analogues, such as compounds 67 and 69. All yields are isolated, see Supplementary Information for exact conditions.