Multistep synthetic routes to eight structurally diverse and medicinally relevant targets were planned autonomously by the Chematica computer program, which combines expert chemical knowledge with network-search and artificialintelligence algorithms. All of the proposed syntheses were successfully executed in the laboratory and offer substantial yield improvements and cost savings over previous approaches or provide the first documented route to a given target. These results provide the long-awaited validation of a computer program in practically relevant synthetic design.
Convenient methods for the direct conversion of imidazolium salts to the corresponding 2-imidazolone or 2-imino imidazole derivatives have been developed. Treatment of the salt with commercial bleach leads to effective oxidation at C2 and the formation of the corresponding imidazolone. Alternatively, treatment of the salt with an N-chloro amide affords the corresponding protected 2-amino derivative in good yield.
The total synthesis of an analog of the marine alkaloid kealiiquinone has been completed through application of an intramolecular Diels-Alder reaction of an imidazole-containing enyne. Oxidative aromatization of the lactone adduct and N-methylation facilitates C2-oxidation via the imidazolium salt. Conversion of the lactone to the phthalaldehyde derivative and then to the dihydroxybenzoquinone was achieved via a reaction with glyoxal in the presence of KCN. Esterification of the vinylogous diacid and deprotection provided 7′-desmethylkealiiquinone.
Synthetic
approaches to the imidazonaphthoquinone core
of kealiiquinone and related Leucetta-derived alkaloids
are described. The polysubstituted benzimidazole framework can be
constructed through intramolecular Diels–Alder reactions of
propiolate-derived enynes followed by oxidation. Adjustment of the
oxidation state of the thus formed lactone allows introduction of
the 2,3-dihydroxybenzoquinone moiety through a presumed
benzoin-like condensation between a phthaldehyde derivative and a
masked glyoxal equivalent catalyzed by a cyanide ion. Oxidation of
the C2-position can be accomplished through application of an operationally
simple treatment of an imidazolium salt with bleach, thus producing
the corresponding 2-imidazolone. Debenzylation of a late stage intermediate
en route to kealiiquinone was compromised by concomitant O-demethylation upon treatment with triflic acid resulting in the
formation of non-natural 7′-desmethylkealiiquinone.
Other endgame strategies were evaluated; however, these efforts did
not lead to completion of a synthesis of kealiiquinone but did provide
access to other closely related analogues.
An investigation of 4-vinylimidazoles as diene components in the intramolecular Diels-Alder reaction is described. In the course of these studies several parameters affecting the cycloaddition were evaluated including the nature of the imidazole protecting group, the type of dienophile and the linking group. These investigations established that amino linkers were generally more effective than either ethers or esters. In most cases, the cycloadditions were highly stereoselective, resulting in the formation of products derived from an anti transition state. The polysubstituted tetrahydrobenzimidazole core of the pyrrole-imidazole alkaloid ageliferin can be constructed through the use of pseudo dimeric 4-vinylimidazoles.
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