Yanxing Jia

Direct Olefination at the C-4 Position of Tryptophan via C—H Activation: Application to Biomimetic Synthesis of Clavicipitic Acid.

The first Pd-catalyzed method for direct olefination at the C4 position of tryptophan derivatives has been developed via C-H activation to prepare 4-substituted tryptophans, which could be used for the synthesis of many hemiterpenoid indole alkaloids. This reaction proceeds under mild reaction conditions and with exceptional tolerance to a variety of functional groups. Furthermore, the efficiency of this method is demonstrated by the rapid and biomimetic synthesis of clavicipitic acid.

Intramolecular Larock Indole Synthesis: Preparation of 3,4‐Fused Tricyclic Indoles and Total Synthesis of Fargesine

The indole nucleus is arguably one of the most significant heterocycles since they are found in numerous natural products and bioactive molecules. Among the naturally occurring indole alkaloids, 3,4-fused indoles (those in which the 3-position of the indole is bridged to the 4-position) have been considered attractive synthetic targets because of their biological activities and synthetic challenges. Examples include the well-known dehydrobufotenine, lysergic acid, welwistatin, communesin F, dragmacidin E, decursivine, penitrem D, indolactam V, and diazonamide A, where the indole is bridged with different ring sizes (6-, 7-, 8-, 9-, and 12-membered rings) and various tethers linked by carbon, nitrogen, and oxygen atoms at different positions (Figure 1). Accordingly, various strategies have been developed for the construction of 3,4-fused tricyclic indoles, including Witkop photocyclizations, 6p-electrocyclizations, intramolecular Fischer indole syntheses, transition metal catalyzed reactions, Diels–Alder reactions, Friedel–Crafts reactions, and Pictet–Spengler reactions. However, most of these methods are based on the introduction of functional groups to the 3or 4-positions of existing indoles with subsequent cyclization. As a further complication, the direct functionalization of the indole 4-position is extremely difficult since most electrophiles prefer reaction at either the 5or 7position. The preparation of 4-substituted indole derivatives, the precursor of 3,4-fused tricyclic indoles, normally requires multistep synthesis. 15b] The development of general synthetic methods for the rapid synthesis of these skeletons in a single operation remains an important challenge facing organic chemists. In connection with some of our work on the total synthesis of indole alkaloids, 7b,c,9a, 18] we have endeavored to identify a general approach for the rapid access to 3,4-fused tricyclic indoles. It was envisaged that this approach would not only expedite the total synthesis of 3,4-fused indole alkaloids but also enable the modular construction of a library of their analogues for additional medicinal chemistry studies. Palladium-catalyzed transformations generally require only a catalytic amount of a metal complex and tolerate a large number of functional groups, and have thus made a major impact on the synthesis of indoles. We were curious whether a palladium-catalyzed intramolecular Larock indolization process (Scheme 1a) could be applied for the preparation of such polycyclic indoles. To the best of our knowledge, although Figure 1. Selected examples of 3,4-fused indole alkaloids.

One-Pot AgOAc-Mediated Synthesis of Polysubstituted Pyrroles from Primary Amines and Aldehydes: Application to the Total Synthesis of Purpurone

A simple and efficient method for the synthesis of 1,3,4-trisubstituted or 3,4-disubstituted pyrroles has been developed. The reaction represents the first time that pyrroles are synthesized directly from readily available aldehydes and amines (anilines) as starting materials. This method has been successfully applied to the rapid synthesis of purpurone.

Water-Controlled Regioselectivity of Pd-Catalyzed Domino Reaction Involving a C−H Activation Process: Rapid Synthesis of Diverse Carbo- and Heterocyclic Skeletons

A palladium-catalyzed domino reaction involving a C-H activation process to synthesize diverse carbo- and heterocyclic skeletons was developed. H(2)O (as cosolvent) is used to control the regioselectivity.

Total Synthesis of (±)‐Decursivine and (±)‐Serotobenine: A Witkop Photocyclization/Elimination/O‐Michael Addition Cascade Approach

The ’ideal’ synthesis is pursued actively by organic chemists since it encompasses the ideas of atom, step, and redox economy. Cascade reactions offer an attractive strategy for the synthesis of complicated natural products, especially when the cyclization is a biomimetic process. Additionally, the avoidance of protecting groups is a major aspect of streamlining a synthesis. With our ongoing interest in the study of indole alkaloids and the pursuit of the ideal synthesis, we describe herein short and efficient total syntheses of the indole alkaloids ( )-decursivine (1) and ( )-serotobenine (2) that are facilitated by a cascade Witkop photocyclization/ elimination/O-Michael addition sequence (Figure 1).

Total synthesis of clavicipitic acid and aurantioclavine: stereochemistry of clavicipitic acid revisited.

The stereocontrolled total synthesis of clavicipitic acid and aurantioclavine from a common azepino[5,4,3-cd]-indole intermediate is reported. This key azepinoindole nucleus was constructed via a one-pot Heck/Boc-deprotection/aminocyclization process from the 4-iodotryptophan derivative, which was assembled by a Pd-catalyzed indole synthesis procedure. After two or three additional deprotection steps from the azepinoindole intermediates, (-)-trans- and (-)-cis-clavicipitic acid were prepared. The syntheses of both (-)- and (+)-aurantioclavine were achieved with the same azepinoindole intermediates utilizing the Barton decarboxylation reaction as the key step to remove the stereohindered carboxylic acid. During the course of our synthesis, mis-assigned configurations of the synthesized clavicipitic acids and their derivatives in the literature were identified. Extensive studies including 2D-NMR study, X-ray diffraction analysis, titration experiment, and Rf value comparison unambiguously confirmed the new configuration assignment. The trans and cis configuration assignments of the synthesized clavicipitic acids and their derivatives in the past literature should be switched.

Synthesis of diastereomers of complestatin and chloropeptin I: substrate-dependent atropstereoselectivity of the intramolecular Suzuki-Miyaura reaction

Atropisomers as well as CC2 epimers of complestatin and chloropeptin I are readily synthesized through an intramol. SNAr reaction and the Suzuki-Miyaura reaction. The abs. configuration of amino acid N-methyl-2-(3,5-dichloro-4-hydroxyphenyl)glycine was found to det. the atropselectivity of the aryl-aryl bond-forming reaction. [on SciFinder (R)]

Efficient Total Synthesis of (−)-cis-Clavicipitic Acid

An efficient total synthesis of (-)-cis-clavicipitic acid has been achieved in seven linear steps (42% overall yield) from the known compound 6. The present synthesis features a palladium-catalyzed indole synthesis to provide the optically pure 4-chlorotryptophan derivative and a Heck reaction using aryl chloride as partner. It has also been discovered that the key azepinoindole nucleus could be stereoselectively constructed via a Mg(ClO(4))(2)-mediated intramolecular aminocyclization.

Total synthesis of dictyodendrins B and E.

The concise synthesis of the novel telomerase inhibitors dictyodendrins B and E was completed in only 9 and 11 steps (longest linear sequence). The highly convergent strategy employed a palladium-catalyzed Larock indole synthesis and a palladium-mediated one-pot consecutive Buchwald-Hartwig amination/C-H activation reaction as key steps. The present synthesis exhibits respectable levels of atom-, redox-, and step-economy.

Stereocontrolled and efficient total synthesis of (-)-stephanotic acid methyl ester and (-)-celogentin C.

A highly stereocontrolled and efficient total synthesis of (-)-stephanotic acid methyl ester and (-)-celogentin C was accomplished in longest linear 14 steps (4.6% overall yield) and in 20 steps (1.6% overall yield) from l-tryptophan, respectively. Highlights of the synthesis include a tandem asymmetric Michael addition/bromination/azidation strategy for a ready access to the leucine-tryptophan moiety (Leu-Trp linkage) and an oxidative coupling reaction to form the indole-imidazole linkage.