A novel and efficient method for the synthesis of α-ketoamides, employing a dimethyl sulfoxide (DMSO)-promoted oxidative amidation reaction between 2-oxoaldehydes and amines under metal-free conditions is presented. Furthermore, mechanistic studies supported an iminium ion-based intermediate as a central feature of reaction wherein C1-oxygen atom of α-ketoamides is finally derived from DMSO.

Marine natural products offer an abundant source of pharmacologically active agents with great diversity and complexity, and the potential to produce valuable therapeutic entities. Indole alkaloids is one of the important class of marine-derived secondary metabolites, with wide occurrence amongst variety of marine sources such as sponges, tunicates, algae, worms and microorganisms and have been extensively studied for their biological activities. Among this chemical family, a sponge-derived bis-indole alkaloid fascaplysin (1) exhibited broad range of bioactivities including antibacterial, antifungal, antiviral, anti-HIV-1-RTase, p56 tyrosine kinase inhibition, antimalarial, anti-angiogenic, antiproliferative activity against numerous cancer cell lines, specific inhibition of cyclin-dependent kinase-4 (IC(50) 350 nM) and action as a DNA intercalator. In the present review, the chemical diversity of natural as well as synthetic analogues of fascaplysin has been reviewed with a detailed account on synthetic reports and pharmacological studies. Our analysis of the structure-activity relationships of this family of compounds highlights the existence of various potential leads for the development of novel anticancer agents.

Daptomycin(DAP) is ac alcium (Ca 2 +)-dependent FDA-approved antibiotic drug for the treatment of Grampositivei nfections. It possesses ac omplex pharmacophore hampering derivatizationa nd/or synthesis of analogues.T o mimic the Ca 2 +-bindinge ffect, we used ac hemoenzymatic approach to modify the tryptophan (Trp) residue of DAP and synthesize kinetically characterized and structurally elucidated regiospecific Trp-modifiedDAP analogues. We demonstratedt hat the modified DAPs are severalt imes more active than the parentm olecule against antibiotic-susceptible and antibiotic-resistant Gram-positive bacteria. Strikingly,a nd in contrastt ot he parentm olecule, the DAP derivatives do not rely on calciumo ra ny additional elements for activity.

The late-stage functionalization of indole-and tryptophan-containing compounds with reactive moieties facilitates downstream diversification and leads to changes in their biological properties. Here, the synthesis of two hydroxy-bearing allyl pyrophosphates is described. A chemo-enzymatic method is demonstrated which uses a promiscuous indole prenyltransferase enzyme to install a dual reactive hydroxy-bearing allyl moiety directly on the indole ring of tryptophan-containing peptides. This is the first report of latestage indole modifications with this reactive group.

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Given the attractive ability of iminium ions to functionalize molecules directly at ostensibly unreactive positions, the reactivity of iminium ions, in which an α CH2 group is replaced by CO was explored. Background studies on the ability of such iminium cations to promote reactions via an iminium-catalyzed or iminium-equivalent pathway are apparently unavailable. Previously, tandem cross-coupling reactions were reported, in which an iminium ion undergoes nucleophilic 1,2-addition to give a putative three-component intermediate that abstracts a proton in situ and undergoes self-deamination followed by unprecedented DMSO/aerobic oxidation to generate α-ketoamides. However, later it was observed that iminium ions can generate valuable α-ketoamides through simple aerobic oxidation. In all reactions, iminium ions were generated in situ by reaction of 2-oxoaldehydes with secondary amines.

Novel reactions under Pictet-Spengler conditions between tryptophan methyl ester/tryptamine and 2-oxoaldehydes have been developed and successfully utilized for the total synthesis of Merinacarboline (A and B), Eudistomin Y1, Pityriacitrin B, Pityriacitrin, Fascaplysin and analogues.2-Oxoaldehydes (OA) are among a few precursors that have been used extensively to synthesize a large variety of heterocyclic compounds. 1 Pictet-Spengler is one of the various reactions reported on OA leading to the synthesis of b-carbolines. 2-11 A large number of naturally occurring b-carbolines with acyl substitution at the C-1 position have shown promising antiinammatory, 2 anti-malarial, 12 anti-cancer, 3,13 anti-phospholipase A2, 14 anti-microbial, 15 and anti-bacterial activities. 16 In view of these biochemical observations, convenient synthetic methods for the synthesis of such constructs are desirable. Even though the Pictet-Spengler reaction of tryptamine/tryptophan/ tryptophan methyl ester with OA for generation of 1-substituted b-carbolines has been explored, 2,6 a few areas are still untouched. As we know in contemporary organic synthesis, coupled domino reactions, wherein two or more domino processes occur sequentially in the same reaction, are considered to be most effective for the synthesis of complex organic compounds using simple and readily available building blocks. 17,18 In this context, we developed a few unexplored reactions between tryptophan methyl ester/tryptamine and 2-oxoaldehydes with a focus on establishing a multicoupled domino strategy for the synthesis of various marine based natural products and their analogues.We initiated the present study with a reaction of 2,4-dimethoxy acetophenone 1 with tryptophan methyl ester 2 in the presence of iodine in DMSO. The reaction of 1 (1 equiv.) and 2 (1 equiv.) with I 2 (1 equiv.) in DMSO at 90 C for 1.5 h afford the desired product in low yield (38%, Table 1, entry 15). To improve upon the yields of desired product, a preliminary set of reactions between tryptophan methyl ester (1 equiv.) and acetophenone (1 equiv.) under different condition were carried out (Table 1). Table 1 Optimization studies for synthesis of 3a employing 2,4-dimethoxy acetophenone as building block a Entry (Equiv.) Temp. Time Yield b (%)