Flow Photochemical Syntheses of trans‐Cyclooctenes and trans‐Cycloheptenes Driven by Metal Complexation

Abstract

trans-Cyclooctenes and trans-cycloheptenes have long been the subject of physical organic study, but the broader application had been limited by synthetic accessibility. This account describes the development of a general, flow photochemical method for the preparative synthesis of trans-cycloalkene derivatives. Here, photoisomerization takes place in a closed-loop flow reactor where the reaction mixture is continuously cycled through Ag(I) on silicagel. Selective complexation of the trans-isomer by Ag(I) during flow drives an otherwise unfavorable isomeric ratio toward the transisomer. Analogous photoreactions under batch-conditions are low yielding, and flow chemistry is necessary in order to obtain trans-cycloalkenes in preparatively useful yields. The applications of the method to bioorthogonal chemistry and stereospecific transannulation chemistry are described.The unusual reactivity and well-defined chiral structure of trans-cycloalkenes has made them attractive targets for synthesis for nearly 70 years. [1][2][3] For example, trans-cyclooctene possesses planar chirality and displays a high barrier to racemization (E a = 35.6 kcal/mol), [4] and the most stable "crown" conformer has an alternating sequence of equatorial and axial hydrogens that is akin to chair cyclohexane. [5][6] The double bond of trans-cyclooctene is twisted severely in the crown conformation, [7] and as a consequence the HOMO of trans-cyclooctene is relatively high in energy. [8] trans-Cycloheptene also has a rigid structure with a distorted alkene. [7] The double bonds of medium-ring trans-alkenes are twisted. [7] trans-Cycloalkenes display unusual reactivity in HOMOalkene controlled cycloaddition reactions with dienes, [9] 1,3dipoles [8] and ketenes. [10] Strained trans-cycloalkenes also serve as ligands for transition metals. [11][12][13][14][15][16] This reactivity profile has made trans-cycloalkanes interesting targets for applications in synthesis and biology.The broadest applications of trans-cycloalkenes are in the field of bioorthogonal chemistry. The inverse-electron demand Diels-Alder reaction between tetrazines and strained alkenes has a rich history in physical organic and synthetic chemistry (Figure 1). [17][18][19] In 2008, three groups described the bioorthogonal reactions of tetrazines with strained alkenes. [20][21][22] The variant introduced by our group that used trans-cyclooctene is marked by exceptionally rapid kinetics, with rate constants that can exceed 10 6 M À 1 s À 1 in the fastest cases. [23][24] With the advances including the development of fluorogenic tetrazines [25] and reactions in live cells [26] and animals, [27] the tetrazine ligation has become a widely used tool for applications that span chemical biology, biomedical imaging, and materials science. [28][29][30][31][32][33][34][35][36][37] This account describes the development of general, flow photochemical methods for the preparative synthesis of transcycloalkene derivatives and enabled applications in synthesis and bioorthogonal chemistry. Selectiv...

General, Divergent Platform for Diastereoselective Synthesis of trans‐Cyclooctenes with High Reactivity and Favorable Physiochemical Properties**

“…[20] Photochemical isomerization of 1 was conducted using the general photochemical flow method. [6,9] Using a small cartridge and bed of capture silica, ketone 2 was prepared in 62% yield and at a rate of ~150 mg/h, and in a typical workflow, ketone 2 was prepared in 2.5 g batches. Computation was used to predict if nucleophilic addition to TCO 2 would be diastereoselective ( Figure 2B).…”

Highly Strained Unsaturated Carbocycles

“…The enantiocontrolled photoisomerization of cis to trans-cycloalkenes was pioneered by Inoue et al [71,72] Stereospecific transannulation of stereo-defined transcyclooctenes was elegantly exploited by Fox et al for the synthesis of stereodefined pirrolizidine alkaloids. [73] Further examples of the stereocontrolled generation of trans-cycloalkenes have been recently reported (see Scheme 34, Ref. [96] ).…”

“…Fox and co-workers synthesised trans-cycloheptene photochemically from cis-cycloheptene (82) using a closed loop photochemical flow reactor via metal complexation of the trans-isomer (Scheme 28). [73,94] This involved the trans-isomer being selectively retained by the silver nitrate (83), while the cis-isomer 82 runs off with silica within the flow reactor. The proclivity of trans-cycloalkenes to form stable Ag(I) salts -whereas cis-isomers generally do notis a general property of this class of compounds and appears to be due to a strain release of the severely twisted trans C=C bond.…”

“…[96] There have been several reviews published on bioorthogonal labelling and copper-free click chemistry with transcyclooctene. [60,73,96] As such, this mini-review will briefly discuss the synthesis and conformation of this highly strained isomer, followed by a couple of recent examples of its use.…”

General, Divergent Platform for Diastereoselective Synthesis of trans-Cyclooctenes with High Reactivity and Favorable Physiochemical Properties

“…[6] Flow photoisomerization has been carried out on scales as large as 20 grams, [7] and protocols have been developed where flow is mimicked by periodically stopping irradiation and capturing TCO product by filtering through AgNO3-silica and resubjecting the filtrate to photoisomerization (254 nm). [8] While this method has been used to synthesize a large number of different TCO derivatives, [9] the production of diastereomers due to the planar chirality of the alkene presents a bottleneck for the majority of TCO syntheses. For example, the most frequently utilized TCO derivatives are the axial and equatorial diastereomers of 5-hydroxy-trans-cyclooctene, which are produced through photoisomerization of 5-hydroxy-cis-cyclooctene in 72%.…”