Cascade Reactions. A Simple One‐pot Synthesis of the Mitomycin Skeleton

Abstract

~ ~Nitroso-arene dienophiles 1 react regiospecifically with the conjugated dienals 2 and 3a/3b, and lead thereby to the unstable Dzels-Alder cycloadducts 4 and 5 These undergo two types of cascade reactions which give pyridmium betaines 6 and pyrrolo-indoles 8 as the major reaction products The one-pot syntheses of pyrroloindoles 8 represent a new and easy access to the basic skeleton of mitomycins 10 The scope and limitations of the cascade reactions were investigated Diels-Alder Cycloadditions of Nitroso-arene Dienophiles with Conjugated Dienals and their Cascade Reactions'). -We shall describe herein some cascade-reaction sequences which we observed, when conjugated dienals were treated with nitrosoarene dienophiles 1. To our knowledge, no cycloaddition reactions have been described so far between nitroso dienophiles and linear conjugated dienals. Nevertheless, some oximeand dimethylacetal derivatives of these dienals are known to undergo Diels-Alder reactions with nitroso dienophiles [2-71.The reaction of nitrosobenzene with pentadienal2 or with the commercially available mixture of hexadienals 3a (80 YO) and 3b (20 YO) occurred rapidly leading, in each instance, to four heterocyclic products, none of which being the expected primary Diels-Alder adduct. For example, the reaction of pentadienal 2 with PhNO gave the betaine 6a, trace amounts of the pyrrole-2-carbaldehyde 7a, the tricyclic alcohol 8a, and the corresponding ketone 9a (Scheme I). It should be noted that the preparation of the tricyclic products 8a and 9a, via a different multistep approach, had already been described as part of a synthetic plan for the mitomycins [8-lo].Mitomycins 10 represent a class of well-known natural products [l 11 which exhibit antibiotic and antitumor properties [12].Since our procedure for the synthesis of pyrrolo-indoles 8a/8b and 9a/9b represents a new one-pot process, using easily available starting materials, we decided to investigate the scope and limitations as well as the mechanism of these obviously complex cascade reactions (see below), our ultimate goal being the synthesis of some mitomycin derivatives.

Copper-Mediated Nitrosation: 2-Nitrosophenolato Complexes and Their Use in the Synthesis of Heterocycles

“…4-Nitroso-2-methylphenol (2-methyl-1,4-benzoquinone, E and Z isomers (9:4)) (3l) [32] : Eluent: hexane-ethyl acetate (9:1) to yield a brown solid. Yield: 48%, 147 mg. LC-MS m / z 154.7 ([M + H] + , 100%), 152.4 ([M − H] − , 100).…”

Synthesis of Aryl Nitroso Derivatives by tert-Butyl Hypochlorite Oxidation in Homogeneous Media. Intermediates for the Preparation of High-Hyperpolarizability Chromophore Skeletons

“…4-Nitronitrosobenzene (4a). Using method B and 3a in diethyl ether, the crude product was obtained in 97% yield and was used without further purification after spectral and chromatographic comparison with an authentic sample …”

Synthesis and Applications of 9H‐Pyrrolo[1,2‐a]indole and 9H‐Pyrrolo[1,2‐a]indol‐9‐one Derivatives

“…In 1986, Streith reported an elegant synthetic strategy for the synthesis of 9 H ‐pyrrolo[1,2‐ a ]indol‐9‐ol 139 and the related fluorazone 140 (Scheme ) . The key transformations involved first a regioselective hetero Diels‐Alder cycloaddition between (2 E ,4 E )‐hexa‐2,4‐dienal (or pentadienal) 134 and nitrosobenzene 135 , followed by a hetero‐Cope rearrangement.…”