The total synthesis of natural products and biologically active compounds, such as pharmaceuticals and agrochemicals, has reached an extraordinary level of sophistication. We are, however, still far away from the 'ideal synthesis' and the state of the art is still frequently hampered by lengthy protecting-group strategies and costly purification procedures derived from the step-by-step protocols. In recent years several new criteria have been brought forward to solve these problems and to improve total synthesis: atom, step and redox economy or protecting-group-free synthesis. Over the past decade the research area of organocatalysis has rapidly grown to become a third pillar of asymmetric catalysis standing next to metal and biocatalysis, thus paving the way for a new and powerful strategy that can help to address these issues - organocatalytic cascade reactions. In this Review we present the first applications of such asymmetric organocascade reactions to the total synthesis of natural products.

Contrary to the common idea that Fischer indole cyclization often cannot be effectively applied to the synthesis of the corresponding azaindoles, we show that this approach can be actually very efficient for the formation of 4- and 6-azaindoles bearing an electron-donating group on the starting pyridylhydrazines. Two 4-azaindole natural product analogues were synthesized in a few steps and very good overall yields.

The synthesis of 37 1-(1H-indol-3-yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti-staphylococcal activity. By contrast, several of the compounds restored, in a concentration-dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure-activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)-N-benzylidene-2-(tert-butoxycarbonylamino)-1-(5-iodo-1H-indol-3-yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA-1199B strain when used at a concentration of 0.5 mg L(-1) . To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert-butyl (2-(3-hydroxyureido)-2-(1H-indol-3-yl)ethyl)carbamate, which is not toxic for human cells, was also found.

We have synthesized and characterized novel bis-indole derivatives as promising candidates for the development of new antistaphylococcal treatments, with preserved activity against MDR S. aureus strains.

An organocatalytic asymmetric multicomponent domino reaction employing the bulk chemical nitromethane and a,b-unsaturated aldehydes as substrates is described. The new triple cascade reaction based on two subsequent Michael additions and an intramolecular aldol condensation provides an atom-economic entry to diastereo-and enantiomerically pure 5-nitrocyclohexene carbaldehydes after flash chromatography.

C3-Substituted-4-azaindoles were synthesized from pyridylacetonitriles in a two-step sequence allowing the easy introduction of a range of substituents. This strategy permits the rapid synthesis of 4-azamelatonin and a protected 4-azatryptophan.

No abstract

Fischer indole cyclization has recently been described as an efficient approach to the synthesis of azaindoles bearing electron‐donating groups. We now show that this cascade reaction can be very efficient for the formation of a wider range of 4‐ and 6‐azaindoles by using microwave irradiation.