Bridge Functionalisation of Bicyclo[1.1.1]pentane Derivatives

Abstract

"Escaping from flatland", by increasing the saturation level and three-dimensionality of drug-like compounds, can enhance their potency, selectivity and pharmacokinetic profile. One approach that has attracted considerable recent attention is the bioisosteric replacement of aromatic rings, internal alkynes and tert-butyl groups with bicyclo[1.1.1]pentane (BCP) units. While functionalisation of the tertiary bridgehead positions of BCP derivatives is well-documented, functionalisation of the three concyclic secondary bridge positions remains an emerging field. The unique properties of the BCP core present considerable synthetic challenges to the development of such transformations. However, the bridge positions provide novel vectors for drug discovery and applications in materials science, providing entry to novel chemical and intellectual property space. This Minireview aims to consolidate the major advances in the field, serving as a useful reference to guide further work that is expected in the coming years.

Keywords: bicyclopentanes; bioisosteres; propellanes; radical reactions; small-ring systems.

Scheme 1

A) Synthesis of the bicyclo[1.1.1]pentane framework through carbene insertion into the central bond of a bicyclo[1.1.0]butane. B) Synthesis of the bicyclo[1.1.1]pentane framework via radical or nucleophilic addition across a [1.1.1]propellane. LG=leaving group. EWG=electron‐withdrawing group. X=F, Cl, Br.

Scheme 2

A) Synthesis of bicyclo[1.1.1]pentan‐2‐ol (14 b) from acyl chloride 11 b. B) Synthesis of alcohols 16 a–f through NY cyclisation. mCPBA=meta‐chloroperoxybenzoic acid. 16 b–d; chemical yields not reported. [a] Obtained as a mixture with the corresponding bridgehead‐substituted compound.

Scheme 3

Deuterium‐labelling studies on alcohol 16 a, identifying two competitive mechanisms for ring opening. The structure of tricyclic alcohol 17.

Scheme 4

Solvolysis of aryl esters 20 and 21. PNB=para‐nitrobenzoyl. [a] Sole product; yield not reported.

Scheme 5

Synthesis of ketone 24 through ozonolysis of 16 a, and subsequent NaBH₄ reduction affording 14 b.

Scheme 6

Synthesis of 4,5‐dimethylenebicyclo[1.1.1]pentan‐2‐one (30). Boc=tert‐butoxycarbonyl; PPTS=pyridinium p‐toluenesulfonate; TFA=trifluoroacetic acid; t _1/2=half‐life.

Scheme 7

Direct chlorination of the parent BCP hydrocarbon.

Scheme 8

A, B): Direct chlorination of BCP derivatives. C): Protodechlorination of chlorinated BCP derivatives with TTMSS (tris(trimethylsilyl)silane). [a] Reaction mixture quenched with MeOH; yield refers to that of the obtained diester. [b] Hydrolytic workup then (COCl)₂/MeOH esterification; yield refers to that of the obtained diester. [c] Isolated as the methyl ester through (COCl)₂/MeOH esterification; yield refers to that of the obtained ester. AIBN=azobisisobutyronitrile; TFA=trifluoroacetic acid.

Scheme 9

Preparation and decomposition of the metastable 2,2‐dichloro[1.1.1]propellane (47).

Scheme 10

Preparation of 2,2‐difluorinated BCP derivatives through insertion of difluorocarbene into bicyclo[1.1.0]butanes.

Scheme 11

Preparation of acyl chlorides 11 a,b through photochemical chlorocarbonylation of the parent BCP hydrocarbon.

Scheme 12

NY cyclisation of cyclobutyl phenyl ketone and manipulation of resulting alcohol 16 a. The synthesis of compounds 14 b/24 and 60 (described in Sections 3.1 and 6, respectively) are also included for clarity. “quant”=quantitative; R*=enantiopure chiral fragment.

Scheme 13

Synthesis of bridge‐substituted BCP derivatives via substituted propellanes prepared from benzvalene. LDA=lithium diisopropylamide; TMS=trimethylsilyl; pTsOH=p‐toluenesulfonic acid; nonaflate=nonafluorobutanesulfonate.

Scheme 14

Synthesis of propellanes 88 and 90–93. Reagents and conditions: i) NaH, triethyl phosphonoacetate, 83 %; ii) LiAlH₄, AlCl₃, 90 %; iii) dimethoxymethane, P₂O₅, 90 % iv) CHBr₃, NaOH, PhMe₃N⁺Cl⁻, 30 %; v) MeLi, 57 %; vi) HCl, MeOH, 90 %; vii) TBSCl, imidazole, 95 %; viii) MeLi, 55 %; ix) TBAF; x) Ac₂O, Et₃N, DMAP; xi) BnNCO, Et₃N.

Scheme 15

Preparation of C2‐functionalised bicyclo[1.1.1]pent‐1‐ylamines. DB18‐c‐6=dibenzo‐18‐crown‐6.

Scheme 16

Preparation of compounds 101–106. DMM=dimethoxymethane; DPPA=diphenylphosphoryl azide.

Figure 1

Structures of lomitapide (107), sonidegib (109) and meclizine (111) and their BCP‐containing analogues (108, 110, and 112 a/b, respectively).

Scheme 17

General approach to arylation of the BCP core through decarboxylative Negishi arylation. DIC=diisopropylcarbodiimide; DMAP=4‐(dimethylamino)pyridine.

Scheme 18

A): Original preparation of the parent BCP hydrocarbon through intramolecular Wurtz coupling. DME=1,2‐dimethoxyethane. B): Synthesis of BCP derivatives 121. Reagents: i) MesSO₂NHNH₂, R′B(OH)₂, pinacol then aqueous H₂SO₄; ii) MesSO₂NHNH₂, Cs₂CO₃, 100 °C.

Scheme 19

Schmidt rearrangement of acid 59 to amine 130 and subsequent oxidation to 2‐nitrobicyclo[1.1.1]pentane (60).

Scheme 20

Synthesis of borylated BCP derivative 134 from [1.1.1]propellane 83.

Scheme 21

Synthesis of diborylated BCP 138 through the method of Qin and co‐workers.