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Scope of the photocatalytic crossed [2 + 2] cycloaddition. Reactions were performed on 0.20 mmol scale. Yields refer to isolated material after flash column chromatography. S = substituent position. a Yield estimated from the ¹H NMR spectrum of the reaction mixture relative to 1,3,5-trimethoxybenzene as internal standard. b Isolated together with unreacted diene 1l. c 66 h reaction time. Displacement ellipsoids are drawn at 50% probability level
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![Bioisosteres of benzene and intramolecular crossed [2 + 2]...](publication/373541412/figure/fig2/AS:11431281190176195@1695222879632/Bioisosteres-of-benzene-and-intramolecular-crossed-2-2-cycloaddition-as-a-strategy-to_Q320.jpg)
![Scope of the photocatalytic crossed [2 + 2] cycloaddition. Reactions...](publication/373541412/figure/fig3/AS:11431281190166348@1695222880775/Scope-of-the-photocatalytic-crossed-2-2-cycloaddition-Reactions-were-performed-on_Q320.jpg)
Saturated bridged-bicyclic compounds are currently under intense investigation as building blocks for pharmaceutical drug design. However, the most common methods for their preparation only provide access to bridgehead-substituted structures. The synthesis of bridge-functionalised species is highly challenging but would open up many new opportuniti...
Citations
... D: Lebold, Sarpong and co-workers' synthesis of 1,2-disubstituted BCPs [32]. DB = Dibenzo, TTMSS = tris(trimethylsilyl)silane, NHPI = N-hydroxyphthalimide, DPPA = diphenylphosphoryl azide, Levin's reagent = N-(benzyloxy)-1-[4-(trifluoromethyl)phenyl]formamido 2,2-dimethylpropanoate. [14,34,35]. Comparison of exit vector parameters of 1,2-BCH (+)-23 and ortho-benzene telmisartan has been reported by Walker and co-workers ( Figure 4) [34]. ...
... DB = Dibenzo, TTMSS = tris(trimethylsilyl)silane, NHPI = N-hydroxyphthalimide, DPPA = diphenylphosphoryl azide, Levin's reagent = N-(benzyloxy)-1-[4-(trifluoromethyl)phenyl]formamido 2,2-dimethylpropanoate. [14,34,35]. Comparison of exit vector parameters of 1,2-BCH (+)-23 and ortho-benzene telmisartan has been reported by Walker and co-workers ( Figure 4) [34]. They found that both the substituent distance d and scaffold carbon distance r of 1,2-BCH (+)-23 closely resemble the ones found in telmisartan. ...
... The related 1,3-disubstituted bicyclo[2.1.1]hexane (1,3-BCH) scaffolds have been suggested as isosteres for meta-benzenes ( Figure 16) [14,34]. Exit vector analysis of 1,3-BCH 96a shows that substituent distance d, scaffold carbon distance r, and substituent angle φ 1 are remarkably similar to the aromatic counterpart. ...
Saturated bioisosteres of substituted benzenes offer opportunities to fine-tune the properties of drug candidates in development. Bioisosteres of para -benzenes, such as those based on bicyclo[1.1.1]pentane, are now very common and can be used to increase aqueous solubility and improve metabolic stability, among other benefits. Bioisosteres of ortho - and meta -benzenes were for a long time severely underdeveloped by comparison. This has begun to change in recent years, with a number of potential systems being reported that can act as bioisosteres for these important fragments. In this review, we will discuss these recent developments, summarizing the synthetic approaches to the different bioisosteres as well as the impact they have on the physiochemical and biological properties of pharmaceuticals and agrochemicals.
... [33] Similar methods to construct 1,4-disubsituded and polysubstituted BCHs were independently developed by Bach [34] and Walker. [35] Both methods use visible light with an iridium photocatalyst and the authors demonstrated broad substrate scopes bearing a wide varieties of functional groups, including boronic esters 85, alcohols (not shown), carboxylic acids (not shown), and polyfluorinated substrates 87. Even an aza-Paternò-Büchi reaction [36] with a methoxyimine to give a 5-aza-BCH derivative 86 was effective in this system. ...
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,[1] 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.
... 129 in moderate to excellent yields (19 examples, 61-97 % yield). Recently, a similar work by Walker and co-workers [66] further extended the scope of this transformation to the use of polysubstituted dienes, thus giving a rapid access to densely functionalized [2.1.1]-BCHs. ...
Bicycloalkanes, cubanes and their structural analogues have emerged as bioisosteres of (hetero)arenes. To meet increasing demand, the chemical community has developed a plethora of novel synthetic methods. In this review, we assess the progress made in the field of light‐driven construction and functionalization of such relevant molecules. We have focused on diverse structural targets, as well as on reaction processes giving access to: (i) [1.1.1]‐bicyclopentanes (BCPs); (ii) [2.2.1]‐bicyclohexanes (BCHs); (iii) [3.1.1]‐bicycloheptanes (BCHeps); and (iv) cubanes; as well as other structurally related scaffolds. Finally, future perspectives dealing with the identification of novel reaction manifolds to access new functionalized bioisosteric units are discussed.
The absence of catalytic asymmetric methods for synthesizing chiral (hetero)bicyclo[n.1.1]alkanes has hindered their application in new drug discovery. Here we demonstrate the achievability of an asymmetric polar cycloaddition of BCB using a chiral Lewis acid catalyst and a bidentate chelating BCB substrate, as exemplified by the current enantioselective formal [4π+2σ] cycloaddition of BCBs with nitrones. In addition to the diverse BCB incorporating an acyl imidazole group or an acyl pyrazole moiety, a wide array of nitrones are compatible with this Lewis acid catalysis, successfully assembling two congested quaternary carbon centers and a chiral aza-trisubstituted carbon center in the pharmaceutically important hetero-bicyclo[3.1.1]heptane product with up to 99% yield and >99% ee .
The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S‐BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid‐catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3‐benzylideneindoline‐2‐thione derivatives have been established. The first hetero‐(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf) 2 , was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf) 3 ‐catalyzed [2π+2σ] reaction with 1,1,2‐trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E ‐1,1,2‐trisubstituted alkenes. Additionally, the hetero‐(4+3) cycloaddition may involve a concerted nucleophilic ring‐opening mechanism.
The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S‐BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid‐catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3‐benzylideneindoline‐2‐thione derivatives have been established. The first hetero‐(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3‐catalyzed [2π+2σ] reaction with 1,1,2‐trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E‐1,1,2‐trisubstituted alkenes. Additionally, the hetero‐(4+3) cycloaddition may involve a concerted nucleophilic ring‐opening mechanism.
Bicycloalkanes, cubanes and their structural analogues have emerged as bioisosteres of (hetero)arenes. To meet increasing demand, the chemical community has developed a plethora of novel synthetic methods. In this review, we assess the progress made in the field of light‐driven construction and functionalization of such relevant molecules. We have focused on diverse structural targets, as well as on reaction processes giving access to: (i) [1.1.1]‐bicyclopentanes (BCPs); (ii) [2.2.1]‐bicyclohexanes (BCHs); (iii) [3.1.1]‐bicycloheptanes (BCHeps); and (iv) cubanes; as well as other structurally related scaffolds. Finally, future perspectives dealing with the identification of novel reaction manifolds to access new functionalized bioisosteric units are discussed.
