Total synthesisof marinenatural productswithout using protecting groups

The field of organic synthesis has made phenomenal advances in the past fifty years, yet chemists still struggle to design synthetic routes that will enable them to obtain sufficient quantities of complex molecules for biological and medical studies. Total synthesis is therefore increasingly focused on preparing natural products in the most efficient manner possible. Here we describe the preparative-scale, enantioselective, total syntheses of members of the hapalindole, fischerindole, welwitindolinone and ambiguine families, each constructed without the need for protecting groups—the use of such groups adds considerably to the cost and complexity of syntheses. As a consequence, molecules that have previously required twenty or more steps to synthesize racemically in milligram amounts can now be obtained as single enantiomers in significant quantities in ten steps or less.

Through the extension of the general principles demonstrated here, it should be possible to access other complex molecular architectures without using protecting groups. Total synthesis, which involves the construction of complex organic molecules from simpler starting materials, has made remarkable progress in the past fifty years. Despite this, the demand for new synthetic routes capable of generating large natural products for further biological studies remains high. A team of chemists has now identified the abandonment of the routine use of 'protecting' groups in synthesis as a way of satisfying this demand.

Protecting groups are often used to mask reactive parts of a molecule while chemical transformations take place elsewhere in that molecule. The potential of the 'unprotected' approach was demonstrated by the synthesis of several members of a large class of marine alkaloids without using a single protecting group. The procedure yields significant quantities of molecules that previously required 20 or more distinct chemical operations in 10 steps or fewer. Members of the hapalindole, fischerindole, welwitindolinone and ambiguine families were synthesized, each constructed without the use of a single protecting group.

As a consequence, molecules that have previously required 20 or more steps to synthesize racemically in milligram amounts can now be procured as single enantiomers in significant quantities in 10 steps or less.