Biomimetic Intramolecular Cyclization of 1-Trimethylacetyl-3-(3-Methanesulfonoxybutyl) Indole at the 4-Position of Indole Nucleus

Abstract

1-Trime thy lace tyl indole derivative 4c was regioselectively cyclized in 54% yield at the 4-position of indole nucleus to afford dihydrobenz [c,d]indole 3h.In the biosynthsis of ergot alkaloids 1, a prenyl group is first introduced at 4-position of L-tryptophan (1). However, introduction of such substituent on the benzen ring part of indole Brought to you by | Purdue University Libraries Authenticated Download Date | 5/31/15 2:09 PMIn our studies on synthesis of indole alkaloids, we have succeeded inter-, intramolecular cyclizations and direct introduction of a substituent at benzen ring part of simple indole derivatives (2). Now, we report much more efficient method of intramolecular cyclization for the synthesis of ergot alkaloids.In the previous paper (2j), we reported novel AlCl3-catalyzed cycliztion of the trisubstituted olefin 2a to afford 5,5-dimethyl-dihydrobenz [c,d]indole derivative 3a in 70% yield.But cyclization yield of di-substituted 212 was only 15% to afford 5-methyl derivative 3b which contains the same carbon subsitiuents with ergot alkaloids (Schemel). Here we report an efficient cyclization starting from methanesulfonate 4c (3) toward our desired 3b (4).An alcohol 4a was acetylated with Ac 2 0/Pyr. to afford the corresponding acetate 4b in quantitative yield. Although 4a or 4h was treated with AICI3 in CH2CI2 etc. in various conditions, each maximum yield of 3b was less than 30%. Therefore an methanesulfonate 4c was synthesized from 4a with MsCl/Pyr. in quantitative yield. A1C1 3 treatment of 4c in various reaction conditions were carried out and the results of typical case are shown in Table 1. When 2 equiv. A1C1 3 was used, no cyclization product 3b could be observed in the reaction mixture and the corresponding chloride 5 was obtained in 86% yield (entry 1).Maximum yield of 3b, 54% was obtained when large excess (19 equiv.) A1C1 3 was used in highly diluted CH 2 C1 2 solution at r.t. for 10 min (entry 4).The cyclization of 4fi was carried out as follows: powdered A1C1 3 was added to a CH 2 C1 2 solution (104 mg 4fi in 40 ml CH2CI2) at r.t. and stirred for 10 min. The reaction mixture was washed with sat. potassium sodium tartrate solution and extracted with CH 2 C1 2 (3 times) .After evapolation of the combined and dried extract with Na 2 S0 4 , the mixture was purified with PTLC (10% EtOAc in Hexane) to give cyclized product 3h (41mg, 54%).When the chloride £ was treated with large excess AICI3 under the same condition with entry 4, 3b was obtained in 55% yield. Therefore, cyclization of 4c may proceed through the chloride 5· No cyclization products at the 2-position of indole nucleus were obserbed in the reaction mixture. Reaction mechanism producing 3b was realised that nucleophilic pyrrole part (1, 2 and 3-positions) of 4fi was deactivated by formation of A1C1 3 -complex such as I or II, and relatively electron rich 4-position was attacked by Friedel-Crafts type cationic site on the side chain at 3-position of indole nucleus to afford 5-methyl-3,4dihydro(l//)benz [c,d]indole 3b. Hydro...