A Mild and General Larock Indolization Protocol for the Preparation of Unnatural Tryptophans

Abstract

A mild and general protocol for the Pd(0)-catalyzed heteroannulation of o-bromoanilines and alkynes is described. Application of a Pd(0)/P( t Bu) 3 catalyst system enables the efficient coupling of o-bromoanilines at 60 °C, mitigating deleterious side reactions and enabling access to a broad range of useful unnatural tryptophans. The utility of this new protocol is demonstrated in the highly convergent total synthesis of the bisindole natural product (−)-aspergilazine A. Graphical abstractThe development of new methods to prepare unnatural tryptophan derivatives is an important endeavor with interdisciplinary applications. In the context of natural product synthesis, a large number of alkaloids contain tryptophan subunits embedded explicitly or implicitly within their structures; 1 in chemical biology, functionalized tryptophan derivatives have emerged as important molecules for studying protein function and dynamics. 2 Although subtle perturbations to this core amino acid may seem trivial, the preparation of the requisite tryptophan building block often constitutes a substantial synthetic undertaking. The Pd-catalyzed heteroannulation reaction between o-bromoanilines and serine-derived alkynes represents a convergent approach to unnatural tryptophan derivatives; yet, its versatility has thus far been limited due to challenges of reactivity and functional group tolerance. Herein, we describe the development and application of a Pd-catalyzed synthesis of structurally complex and synthetically useful tryptophan derivatives from widely-* Corresponding Author: reisman@caltech.edu. Supporting Information: The Supporting Information is available free of charge on the ACS Publications website. Experimental data, characterization information, and spectra (PDF) commonly known as the Larock indole synthesis, is a powerful method for the preparation of 2,3-disubstituted indoles. 4,5,6 Larock's original conditions, which employ a "ligand-less" Pd-catalyst in conjunction with an inorganic base and chloride salt additive, were developed for o-iodoanilines and remain the most widely utilized ( Figure 1A). 7 In 2004, Senanayake and co-workers expanded the scope of this transformation to include o-chloro-and obromoanilines by employing a bidentate phosphine ligand, 1,1′-bis-di-tertbutylphosphinoferrocene (dtbpf), at elevated temperatures (110-130 °C), providing simple indoles in good yield and high regioselectivity (not shown). 8 HHS Public AccessDespite these advances, efforts to employ the Larock indole synthesis in complex settings, particularly using alkynyl substrates containing peptide functionality and o-bromoanilines, reveal significant limitations in the state of the art. For example, Baran's elegant synthesis of (+)-kapakahine B necessitated prolonged reaction times (24 h) and increased catalyst loadings (20 mol %) under Larock's standard conditions (Scheme 1A). 5c Similarly, Boger's landmark synthesis of the chloropeptins, which employed an intramolecular Larock macrocyclization of an aryl bromide, required e...

Enantioselective Synthesis of Pyrroloindolines via Noncovalent Stabilization of Indole Radical Cations and Applications to the Synthesis of Alkaloid Natural Products

“…Adopting a strategy originally developed by Baran in his synthesis of psychotriasine, the iodoaniline was subjected to a Larock annulation with alkyne 30 to furnish the core of the natural product. 38 Subsequent reduction of the carbamate protecting groups with Red-Al resulted in the synthesis of (−)-psychotriasine 31 in 93% ee in four chemical steps and 38% overall yield from tryptamine 1 (Figure 5). Taken together, these syntheses highlight the versatility of this method and suggest that its use in even more complex contexts might prove feasible.…”

Activation of 6-bromoquinoline by nitration: synthesis of morpholinyl and piperazinyl quinolines

“…Both AcOH/H2O2 and m-CPBA reacted smoothly with (13) and afforded the N-oxide derivative (20) in good yield (60% and 87%, respectively). Several attempts to effect the same results for the N-oxidation of (19) to yield (21) failed, however, under the same or similar conditions. These attempts resulted in polymeric materials instead of the expected product.…”

“…To afford the 2-and 4-nitro-substituted-bromoquinoline derivatives (22) and (23), it was first attempted to convert bromoquinolines (13) and (19) into the quinoline N-oxides (20) and (21), respectively (Scheme 4). which facilitated the nitration at the pyridine ring of the quinoline moiety due to +R effect of the N-oxide form.…”

“…which facilitated the nitration at the pyridine ring of the quinoline moiety due to +R effect of the N-oxide form. The Noxidations of 6-bromo (13) and 6,8-dibromoquinoline (19) were carried out in the presence of AcOH/H2O2 or m-CPBA (Scheme 5). Both AcOH/H2O2 and m-CPBA reacted smoothly with (13) and afforded the N-oxide derivative (20) in good yield (60% and 87%, respectively).…”

“…It is thought that the unsuccessful formation of the N-oxide (21) may have been the result of steric-hindrance effects of the bulky bromine group at C-8 (Scheme5). (13) and (19). Therefore, we focused on the nitration of 6-bromoquinoline-1-oxide (20).…”