Reaction Paradigms that Leverage Cycloaddition and Ring Strain to Construction Bicyclic Aryl Bioisosteres from Bicyclo[1.1.0]butanes

Abstract

Within a medicinal chemist’s toolbox, one of the most effective strategies to improve the overall properties of a biologically active compound is bioisosteric replacement. Ever since the first example of replacing benzene with a bicyclo[1.1.1]pentane (BCP) group was published in the late 1990s, the medicinal chemistry community has continually been expanding the scope of such phenyl bioisosteric replacements. Recent interest from academia has focused on novel synthetic strategies to access C(sp3)‐rich bicyclic hydrocarbons with expanded ring sizes. Herein, we summarize some of these transformations and reveal that most rely on strain releasing cycloadditions with bicyclo[1.1.0]butane (BCB) and bicyclo[2.1.0]pentane (housane). We have organized this review based on the mechanism of such strain release strategies, namely, carbene cycloadditions, energy transfer photocatalyzed cycloadditions, electron transfer catalyzed cycloadditions, and polar cycloadditions.

Theoretical investigation of a chiral Brønsted acid (CBA)-catalyzed isomerization reaction of BCB: mechanism and origin of stereoselectivity

“…As the smallest bridged hydrocarbon rings, bicyclo[1.1.0]butanes (BCBs) are highly strained, have exhibited excellent synthetic value and have attracted increasing attention in the field of organic synthesis through the strain release approach. 1 BCBs mono- or disubstituted at the bridgehead carbon have been extensively investigated through the rapid C–C bond cleavage, which provides a straightforward route for accessing various spirocycles or bridged cycles. 2…”

Lewis acid catalyzed [4+2] annulation of bicyclobutanes with dienol ethers for the synthesis of bicyclo[4.1.1]octanes

“… 5 Among cyclopropanes, the even more strained bicyclo[1.1.0]butanes (BCBs) have recently attracted interest, as strongly activating substituents are less needed and more rigid bicyclic carbocycles and their heterocyclic analogs can be obtained. 6 The synthesis of bicyclo[2.1.1]hexanes (BCHex's) through the formal [2 + 2] cycloaddition of BCBs has been extensively studied to access new bioisosteres of the benzene ring. 1 c Following the seminal reports by the groups of Glorius 7 a and Brown, 7 b several methods have appeared that rely on radical pathways, either under light-induced energy transfer ( Scheme 1 , (A.1): Glorius, 7 a , f Brown, 7 b Bach 7 g ) or electron-transfer conditions ( Scheme 1 , (A.2): Li, 7 c Procter, 7 d Wang 7 e ).…”

Catalytic Asymmetric Construction of Chiral Polysubstituted 3-Azabicyclo[3.1.1]heptanes by Copper-Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition

“…Over the past two years, BCBs have gained considerable momentum within the chemistry community, particularly as they have been extensively employed as privileged motifs in cycloadditions for the synthesis of bicyclic 3D scaffolds . However, achieving intermolecular enantioselective transformations of BCBs to generate chiral frameworks remains extremely challenging .…”