Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes

Abstract

Cyclic products can be obtained through the intramolecular version of the Nicholas reaction, which requires having the nucleophile connected to the alkyne unit. Here, we report the synthesis of 1-oxa-3-cyclooctynes starting from commercially available (1R,3S)-camphoric acid. The strategy is based on the initial preparation of propargylic alcohols, complexation of the triple bond with Co2(CO)8, and treatment with BF3·Et2O to induce an intramolecular Nicholas reaction with the free hydroxyl group as nucleophile. Finally, oxidative deprotection of the alkyne afforded the cyclooctynes in good yields. Notably, large-sized R substituents at the chiral center connected to the O atom were oriented in such a way that steric interactions were minimized in the cyclization, allowing the formation of cyclooctynes exclusively with (R) configuration, in good agreement with theoretical predictions. Moreover, preliminary studies demonstrated that these cyclooctynes were reactive in the presence of azides yielding substituted triazoles.

Heterocycloalkynes Fused to a Heterocyclic Core: Searching for an Island with Optimal Stability-Reactivity Balance

“…As a result, a variety of SPAAC reagents have been synthesized. [8][9][10]24 Currently, there are two general strategies to facilitate SPAAC reactions: 10 the first is the destabilization of a cyclooctyne reagent by applying extra strain through the annulation of a cyclooctyne core with additional rings, which was first demonstrated for dibenzocyclooctyne (DIBO) by Boons' group. 25 The second strategy is the stabilization of the cyclooctyne−azide interaction transition state (TS) and bending assistance by stereoelectronic effects (Figure 1), which was developed by Alabugin's group 26,27 and extended recently.…”

“…Since then, SPAAC has attracted biologists’ attention, resulting in the broad application of this reaction. − Different research groups have been involved in the structural design of cyclooctynes aimed at improving the kinetics of SPAAC without the loss of cycloalkyne stability and synthetic accessibility. As a result, a variety of SPAAC reagents have been synthesized. − , …”

Development of Fluorescent Isocoumarin‐Fused Oxacyclononyne – 1,2,3‐Triazole Pairs

“…The crucial role of SPAAC is determined by the unique properties of the azido group, [16] fast SPAAC kinetics, and a wide range of available cycloalkyne‐based reagents [17–27] …”

“…[12][13][14][15] The crucial role of SPAAC is determined by the unique properties of the azido group, [16] fast SPAAC kinetics, and a wide range of available cycloalkyne-based reagents. [17][18][19][20][21][22][23][24][25][26][27] Nevertheless, to use SPAAC to visualize modified biomolecules, a cycloalkyne reagent should be preconjugated with a fluorescent dye which introduces an additional synthetic, structural, and functional load. [28] In this regard, the design and synthesis of cycloalkynes which give fluorescent triazoles, would enable the avoidance of additional synthetic steps and undesirable structural complexity.…”

Síntesis de éteres cíclicos naturales

“…Recordemos que el número de moléculas que podemos preparar antes de desaparecer está comprendido entre 10 20 y 10 42 , números gigantescos si se comparan con las conocidas (10 8 ) y con las del conjunto de Reymond (10 11 ).…”