Gramine derivatives

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

The preferred substrates of acetyltransferases are amino-groups of antibiotics, like chloramphenicol, strepto-gramin derivatives, and the various aminoglycosides. The modification is believed to block a functional group involved in the drug-target-interaction. All acetyltransferases use acetyl-coenzyme A as cofactor. 

Somei-Kamatani coupling of 116 [Fig. (32)] with the gramine derivative 94 in the presence of tri(n-butyl)phosphine gave the tryptophan derivative 117 as a 3 1 mixture of diastereomers in 70% yield. 

The aminoalkylation of indole 473 via treatment with Eschenmoser s salt (A,A-dimethylmethyleneiminium iodide) gives Gramine derivative 474 (Equation 114) <1996JOC1916, 1997JOC3597>. When the 2-acyl analog of indole 473 was treated with Eschenmoser s salt no reaction was observed. 

Perez-CasteUs found that treatment of lV-(triisopropylsilyl)-3-methoxymethyIindole also gave 4-(substituted)indoles although the yields tended to be lower than the correspcaiding gramine derivatives [340]. 

Fluorinated 3-indolyl carbaldehyde 175 was obtained in yields up to 89 % by Vilsmeier-Haack reaction [58c, 63]. Aminomethylation afforded the corresponding fluorinated gramine derivatives 176 in good yields [58c, 63]. 

Sato, A., and W. Fenical Gramine-Derived Bromo-Alkaloids from the Marine Bryozoan Zoobotryon verticillatum. Tetrahedron Lett. 24, 481 (1983). 

Sato, A. and Fenical, W. (1983) Gramine-derived bromoalkaloids from the marine bryozoan Zoobotryon verticillatum. Tetrahedron Lett., 24, 481-484. 

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