Indolines solid-phase synthesis

Fig. 17.6 Solution and solid phase synthesis from the racemic first-generation indoline scaffold to obtain a 100-membered library using an intramolecular Mitsunobu approach.

Other approaches to indoles based on transition metal-mediated couplings have been outlined in Sections 4.2.2 and 4.2.4. Nicolaou et al. recently described a novel solid-phase synthesis of substituted indolines and indoles [414]. 

Nicolaou KC, Roecker AJ, Pfefferkom JA, Cao G-Q (2000) A novel strategy for the solid-phase synthesis of substituted indolines. J Am Chem Soc 122 2966-2967... 

SCHEME 1.6 Solid-phase synthesis of indoline-like alkaloids. 

In 2005, Ary a and co-workers reported on the stereocon-trolled solid-phase synthesis of a 90-membered library of indoline-alkaloid-like polycycles 41 and 42." These compounds are structurally related to a number of alkaloids such as vindoline, tabersonine, and yohimbine, and they could lead to compounds with similar or improved biological properties. Thus, chiral aminoindoline 36 was loaded via a silyl linker unit 37, deprotected, and reacted with an acid chloride to introduce the first point of diversity and to give 38. Treatment with piperidine removed the Fmoc group, and concomitant cyclization provided tricyclic... 

Gan Z, Reddy PT, Quevillon S, Couve-Bonnaire S, Arya P. Stereocontrolled solid-phase synthesis of a 90-membered library of indoline-alkaloid-like polycycles from an enan-tioenriched aminoindoline scaffold. Angew. Chem. Int. Ed. 2005 44 1366-1368. 

Scheme 31 Solid-phase synthesis of indolines via Pd-catalyzed intramolecular C-d l bond formatimi...

Using the same strategy, Houghten et al. developed a solid-phase synthesis for indolines (Scheme 31) [64]. When enantiopure amines were used, cyclization conditions did not lead to the racemization of the products. 

Larock extended this Pd-catalyzed diene heteroannulation to other dienes and anilines [399], including functionalized dienes leading to, for example, ketotetrahydrocarbazoles [400]. Back has employed 1-sulfonyl-l,3-dienes in this 2-vinylindoline synthesis [401], and the use of 1,3-dienes in constructing indolines has been adapted to the solid phase by Wang [402]. Interestingly, Larock has shown that the electronically-related vinylcyclopropanes undergo a similar cyclization with o-iodoanilines to form 2-vinylindolines, e.g., 310 [403, 404]. Vinylcyclobutane also reacts in a comparable manner. 

FIGURE 11.63 Library synthesis of indoline-derived tricyclic derivatives using a Mitsunobu approach. (From Arya, P. et al., A solid-phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsunobu approach, J. Am. Chem. Soc., 6, 65, 2004.)... 

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