Abstract
The structural motif that results from the fusion of a benzene ring to a heterocyclic pyran ring, known as chromene, is broadly found in nature and it has been reported to be associated with a wide range of biological activity. Moreover, asymmetric organocatalysis is a discipline in expansion that is already recognized as a well-established tool for obtaining enantiomerically enriched compounds. This review covers the particular case of the asymmetric synthesis of 2-amino-3-cyano-4H-chromenes using organocatalysis. Herein, we show the most illustrative examples of the methods developed by diverse research groups, following a classification based on these five different approaches: (1) addition of naphthol compounds to substituted α,α-dicyanoolefins; (2) addition of malononitrile to substituted o-vinylphenols; (3) addition of malononitrile to N-protected o-iminophenols; (4) Michael addition of nucleophiles to 2-iminochromene derivatives; and (5) organocatalyzed formal [4+2] cycloaddition reaction. In most cases, chiral thioureas have been found to be effective catalysts to promote the synthetic processes, and generally a bifunctional mode of action has been envisioned for them. In addition, squaramides and cinchona derivatives have been occasionally used as suitable catalysts for the substrates activation.
Highlights
Chromene analogues can be frequently found as structural core motif in a great number of natural and synthetic compounds exhibiting interesting medicinal and pharmacological properties [1,2]
Among the different types of chromenes, we want to focus on 2-amino-3-cyano-4H-chromene scaffolds
It is noteworthy that distinct enantiomers often show different biological activity, such as one enantiomer of the anticancer agent 1, which is about 50 times more active than the other enantiomer [16]
Summary
Chromene analogues can be frequently found as structural core motif in a great number of natural and synthetic compounds exhibiting interesting medicinal and pharmacological properties [1,2]. In 2012, a new enantioselective synthesis of 4-aryl derivatives 13 was reported by Wang’s group [36] In this case, bencylidenemalonitrile derivatives 6 reacted with α-naphthols 11 to afford the corresponding product 13 with moderate to high yields and high selectivities after short reaction times (up to 84% yield and up to 83% ee) (Scheme 4). Bencylidenemalonitrile derivatives 6 reacted with α-naphthols 11 to afford the corresponding product 13 with moderate to high yields and high selectivities after short reaction times (up to 84% yield and up to 83% ee) (Scheme 4) This process works through a catalyzed tandem Michael addition/intramolecular cyclization reaction in the presence of a catalytic amount of abietic acid-cinchona-thiourea compound 12 in diethyl ether and at room temperature.
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