Nucleophilic cyclizations of enediynes as a method for polynuclear heterocycle synthesis

Abstract

In this review, data on the heterocyclization of enediynes, initiated by attack of an external anionic nucleophile or a nucleophilic group present in the molecule at the C≡C bond of the enediyne, are summarized.Today, the chemistry of acetylenes is experiencing its new birth. Effective methods for the synthesis of acetylenes based on the transition metal catalyzed cross-coupling of organic halides and triflates with 1-alkynes [1], alkynylboronic acids [2], alkynylstannanes [3] have been developed. The acetylenes that became accessible are used successfully for the synthesis of various carbo-and heterocyclic compounds [4][5][6][7][8][9]. In the general case addition of a nucleophilic group to a carbon-carbon triple bond leads to a hetero-ring closure according to Scheme 1, and here the formation both of endo-dig cyclization products and of heterocycles with an exocyclic C=C bond (exo-dig cyclization) is possible: exo-digR Nu X R Nu = NH, O, S, etc.; X = H or other leaving groupThe interest of researchers in the chemistry of acetylenes is also due to the discovery of a whole family of antibiotics containing a cis-3-hexene-1,5-diyne fragment in their structures and therefore called enediyne antibiotics [10][11][12][13][14]. When heated or irradiated the enediynes undergo a Bergman cyclization; they close to 1,4-arynes, which are converted in the presence of suitable donors of hydrogen atoms or other free radicals into the corresponding arenes (Scheme 2) [15]. It is supposed that the mechanism of biological action of enediyne antibiotics is based on this rather exotic transformation. At the biological level the role of hydrogen atom donor is played by a DNA molecule that leads to its destruction. This determines not only the antibacterial, but also the antiviral and anticancer activity of the enediyne antibiotics.

Recent advances of the Bergman cyclization in polymer science

“…With 2,3-substituted thiophene derived enediyne systems, the 6-endo cyclization initially led to a 1,3-diaurated species, which underwent a gold shift by an aryne-gold transition state to form a 1,4-diaurated species bearing a carbene moiety, followed by C-H insertion (Scheme 17). Other ionic cycloaromatization reactions of enediynes initiated by the attack of an external anionic nucleophile or a nucleophilic group present in the molecule at the C≡C bond were also discovered in the last decade [70], which often obtained derivatives of polynuclear heterocyclic molecules that are important from a biochemical point of view. All these studies lay a mechanistic foundation for the further development of this emerging field.…”

Enediynes, enyne‐allenes, their reactions, and beyond

“…The naturally occurring enediynes have inspired chemists to make strategical use of the Bergman cyclization in synthesis where these applications ranged from the natural product synthesis of target enediynes with antibiotic, antitumor activity to the use of designer enediynes in heterocyclic synthesis, polymer chemistry, and materials science . For these purposes, the understanding of the kinetics of the Bergman cyclization and the electronic factors, which determine its barrier and the endothermicity of the reaction, is of fundamental importance.…”

“…Enediynes had an important impact on organic chemistry. Today, one makes strategical use of the Bergman cyclization in organic synthesis . To some extent, this holds also for the Meyers–Saito, Schmittel, or the Garatt–Braveman reaction .…”

“…The Bergman cyclization had also its impact on the closely related Cope rearrangement . The work on heteroenediynes and their nucleophilic cyclization has turned out to be a promising method in heterocyclic synthesis …”

“…Maretina summarized design strategies of enediynes and enyne‐allenes stretching from organic to metallorganic chemistry . Guleskaya and Tyaglivy reviewed the use of enediynes in heterocyclic synthesis Biosynthesis : Liang highlighted the progress in the understanding of how natural enediynes are synthesized by nature .…”