Alkynylation‐Desilylation‐Alkynylation‐Cycloisomerization (ADAC) Three‐Component Synthesis of 2,2′‐Biindolyls – Concise Synthesis of Tjipanazole I

A sequentially Pd/Cu‐catalyzed alkynylation‐desilylation‐alkynylation‐cycloisomerization (ADAC) process in the sense of a consecutive three‐component reaction using TIPS‐butadiyne as a four carbon building block gives a rapid and efficient access to 2,2′‐biindolyls in a one‐pot fashion. This facile entry to unsymmetrically substituted title compounds has been employed in a concise two‐step synthesis of the alga alkaloid tjipanazole I.

Multicomponent Reactions (MCR) [1] are characterized by the formation of more than two bonds from more than two compounds in a one-pot reaction. Consequently, this multifaceted reactivity based concept [2] has opened many avenues from reaction design [3] over natural product syntheses [4] and diversity-oriented syntheses [5] to sustainable organic syntheses [6] and application in medicinal chemistry. [7] MCR syntheses of heterocycles [8] are particularly attractive, because they provide many scaffolds for the development of lead structures in active pharmaceutical ingredients [9] and functional molecules for advanced photonic and electronic technologies. [10] MCR syntheses of heterocycles catalyzed or initiated by transition metal catalysis even more enhance the versatility of this highly efficient and efficacious concept. [11] The 2,2'-biindolyl ligation ( Figure 1) is present in indigoids, indolocarbazole and indolotryptoline alkaloids. [12] Most prominently, staurosporine, an indolo[2,3-a]carbazole alkaloid, and related compounds reveal potent protein kinase inhibition, [13] which is particularly interesting for developing anticancer therapeutics. [14] Tjipanazole I, isolated from bluegreen alga Tolypothrix tjipanasensis, turned out to show antifungal activity. [15] Interestingly, tjipanazole I is accessible in a straightforward cyclocondensation with 2,2-diethoxy-N,Ndimethylethylamine starting from an unsymmetrically substituted 2,2'-biindolyl. [16] Finally, unsymmetrically halogen substituted 2,2'-biindolyls have been shown to efficiently inhibit MRSA-pyruvate kinase with high antibacterial activity against Staphylococcus aureus ATCC 29213, however, without significant cytotoxicity in mammals. [17] While symmetrically substituted 2,2'-biindolyls are accessible by Madelung cyclization of N-aryloxamides, [18] cycloisomerization of 1,4-bis(ortho-aminoaryl)-1,3-butadiynes, [19] Ir-catalyzed cyclization of 2-ethynyl anilines, [20] or protecting group directed metal catalyzed homocoupling of indoles, [21] concise syntheses of unsymmetrically substituted 2,2'-biindolyl derivatives still remain a major challenge. Although 2-iodo indoles can be coupled to the title compounds by Pd-catalyzed coupling with stannanes (Stille coupling) [22] or boronic acids (Suzuki coupling), [23] often the starting materials have to be prepared in multistep reactions. In 2003 for the total syntheses of tjipanazoles B, D, E, and I, Davies and coworkers reported a robust multistep approach to 2,2'-biindolyls using an ortho-nitro toluene aldol-type condensation followed by Cadogan-Sundberg cyclization or Pd-catalyzed reductive cyclization. [16] In recent years, starting with catalytic generation of alkynoyl intermediates as an entry to consecutive multicomponent syntheses of many classes of functional heterocycles [24] we became increasingly interested in sequentially Pd-catalyzed processes, [25] in particular for developing them for one-pot syntheses of heterocycles.
[25e] Inspired by our one-pot couplingcyclization synthesis of (aza)indoles [26] and the implementation of TIPS-butadiyne as an ideal C4-building block in sequentially catalyzed MCR-formations of triazole derivatives [27] we reasoned that unsymmetrically substituted 2,2'-biindolyls might be accessible in a one-pot fashion by sequential Sonogashira alkynylation with TIPS-butadiyne followed by base-catalyzed cycloisomerization in the sense of a MCR. Here, we communicate our first findings on a consecutive three-component alkynylationdesilylation-alkynylation-cycloisomerization (ADAC) synthesis of unsymmetrically substituted 2,2'-biindolyls.
With optimized conditions for the one-pot synthesis of 2,2'biindolyl 3 a in hand we set out to check the scope of this novel consecutive three-component synthesis by varying the substitution pattern on the 2-iodo aniline derivatives 1. The versatility of this process was illustrated by the synthesis of 17 examples in yields from 35 to 88 % (Scheme 2). [28] Taking into account that four new bonds and two rings are being formed in this one-pot process the average bond forming yield amounts to 77-97 %. Interestingly, the electronic nature of substituents on the aniline aryl ring of substrate 1 and 1' can be electron-rich, electron-poor and even chloro and bromo substituents can be carried through the sequence uneventfully. N-Methyl and benzyl substituted anilines 1' are also tolerated (see products 3 p and 3 q), which are perfectly suited for desymmetrizing applications in complex molecules synthesis. In this study, we primarily employed commercially available substituted anilines 1 and 1', yet, 2-iodo-5-methylaniline (1 e) and 2-benzyloxy-6-iodoaniline (1 j) were successfully employed to demonstrate the accessibility of substitution patterns at 7and 6-positions in title molecules 3 (see products 3 d and 3 i).
Most favorably, the three components are efficiently reacted in an almost equistoichiometric ratio to give the desired target compounds in good yield. It is noteworthy mentioning that an N-tosyl substituent is not tolerated, because it is cleaved under the strongly basic conditions of the terminal twofold-cycloisomerization.
The straightforward one-pot synthesis of the unsymmetrically substituted 2,2'-biindolyl 3 a encouraged us to apply it in the total synthesis of tjipanazole I applying Davies' final cyclization step. [16] Starting from 2-iodo aniline (1 a), TIPSbutadiyne (2), and 4-chloro-2-iodoaniline (1 b) 2,2'-biindolyl 3 a was obtained in 82 % yield by three-component alkynylationdesilylation-alkynylation-cycloisomerization (ADAC) synthesis (Scheme 3). Then, compound 3 a was heated in acetic acid to 135°C under argon atmosphere and over a period of 6 h every hour an equivalent of (dimethylamino)acetaldehyde diethylacetal (in total 4 equivalents) was added to the hot reaction mixture. After workup tjipanazole I (6) was isolated after flash chromatography in 67 % yield. This concise synthesis furnishes tjipanazole I in 56 % yield over two steps the highest reported yield, which is also more than twice of the combined yield of 27 % of Davies' synthesis.
In conclusion we have developed a concise one-pot synthesis of unsymmetrically substituted 2,2'-biindolyls in the sense of a consecutive three-component alkynylation-desilylationalkynylation-cycloisomerization (ADAC) process taking advantage of TIPS-butadiyne as a four carbon building block, which can be unsymmetrically coupled by a sequentially Pd/Cucatalyzed sequence. The scope of the substitution pattern of 2,2'-biindolyls is broad and allows exploration of potential therapeutics for the treatment of MRSA infections. Furthermore, this novel ADAC synthesis has successfully applied to a twostep synthesis of tjipanazole I in higher yield than the published three-step synthesis. Studies directed to expand the diversity oriented scope to complex functionalization of 2,2'-biindolyls, their use in alkaloid syntheses and evaluation of MRSA inhibition are currently underway.