Copper-mediated synthesis of drug-like bicyclopentanes

Abstract

Multicomponent reactions (MCRs) have become a mainstay in both academic and industrial synthetic organic chemistry due to their step- and atom-economy advantages over traditional synthetic sequences 1 . Recently, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable pharmaceutical bioisosteres of benzene rings, and, in particular, 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para -phenyl ring replacements 2 . Often these structures are generated from [1.1.1]propellane via opening of the internal C─C bond, either through the addition of radicals or metal-based nucleophiles 3 - 13 . The resulting propellane-addition adducts are subsequently transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. While this approach has been effective to date, it is clear that a multicomponent reaction that enables single-step access to complex and diverse polysubstituted BCP products would be synthetically advantageous over the current stepwise approaches. Herein we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicycles using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. The reaction operates on short time scales (five minutes to one hour) across multiple (>10) nucleophile classes and can accommodate a diverse array of radical precursors, including those which generate alkyl, α-acyl, trifluoromethyl, and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which has substantially different pharmacokinetic properties to those of its commercial progenitor.

Rationalizing the diverse reactivity of [1.1.1]propellane through σ–π-delocalization

“…26 The reaction of 1 with amide anions was computed using NH Our attention next turned to the reactivity of 1 with radicals, chemistry that is of much utility in the synthesis of highlyfunctionalized BCPs. [15][16][17][18][19][20][21]23,24 Such reactions proceed through addition of a radical to the C1-C3 bond to give a bridgehead BCP radical that subsequently reacts either via atom transfer, or addition to a radical trap (such as an azodicarboxylate, a further molecule of 1, or an organometallic species). Alkoxycarbonyl, alkyl and aryl radical additions have been studied using DFT (B3LYP, M06-2X, uB97X-D, B2PLYP) 66,67,73,74 by the Uchiyama group 17 and ourselves, 18,20 where the focus has lain on the fate of the bicyclo[1.1.1]pentyl radical.…”

“…BCPs are also useful motifs for organic materials, including rodlike one-dimensional polymers, 11 supramolecular spacer units, 12 liquid crystals 13 and FRET sensors. 14 Such applications have stimulated the development of a number of methods to access BCPs in a single step from 1 via radical [15][16][17][18][19][20][21][22][23][24] and anionic [25][26][27][28][29] intermediates (Fig. 1b).…”

Triphenylphosphine-Catalyzed Alkylative Iododecarboxylation with Lithium Iodide under Visible Light

“…Decarboxylative transformations [1][2][3][4] that convert a carboxylate group into a functionality that is a versatile handle for various further transformations, such as the recent development of alkylative decarboxylative borylation 5,6 , are of great signi cance in organic synthesis. Alternatively, a low-cost alkylative decarboxylative iodination reaction has similarly high merits for use with aliphatic carboxylic acids in organic synthesis.…”

“…A broad range of alkyl carboxylates with various functionalities was readily converted into the corresponding primary, secondary, and bridgehead tertiary alkyl iodides. Functional groups, such as ether (4,14), imide (5), aryl bromide (6), aryl aldehyde (7), aryl pinacol boronate (8), alkene (9), ester (10,26,27), amide (15,16), tri uoromethyl (12), aryl chloride (13), aryl iodide (20), ketone (24), and hydroxy (25) were compatible. Iodination of the electron-rich arene moiety (4, 6, 10) was not observed.…”

Triphenylphosphine-catalyzed Alkylative Iododecarboxylation with Lithium Iodide under Visible Light

“…A broad range of alkyl carboxylates with various functionalities was readily converted into the corresponding primary, secondary, and bridgehead tertiary alkyl iodides. Functional groups, such as ether (4,14), imide (5), aryl bromide (6), aryl aldehyde (7), aryl pinacol boronate (8), alkene (9), ester (10,26,27), amide (15,16), tri uoromethyl (12), aryl chloride (13), aryl iodide (20), ketone (24), and hydroxy (25) were compatible. Iodination of the electron-rich arene moiety (4, 6, 10) was not observed.…”