Progress towards the total synthesis of azaspiracids

The azaspiracids, accumulated into the shellfish through the filter-feeding on the dinoflagellate Protoperidinium crassipes---their aetiology, are responsible for a new type of shellfish poisoning: azaspiracid shellfish poisoning (AZP). They bear an unique array of special frameworks including a trioxadispirokeal fused with a tetrahydrofuan ring (the ABCD domain) and a rare spiroaminal fused to a 2,9-dioxabicyclo[3.3.1]nonane ring (the FGHI domain).; Azaspiracid shellfish poisoning has been posing a great threat to the health of humans in many European countries. It is very urgent to develop some reliable methods for detecting these toxins in the production areas of shellfish. This thesis describes a convergent synthesis of a synthetic hapten based on the common structure of the FGHI domain in the azaspiracid analogs. This synthesis uses a novel strategy to install the spiroaminal moiety via the tandem Staudinger reduction/aza-Wittig reaction followed by the H ring closure. This hapten was conjugated with the proteins of Bovine serum albumin to generate the antibodies in sheep. These antibodies have a broadly specific recognition towards azaspiracids. They can potentially be used in the enzyme-linked immunosorbent assays (ELISAs) to monitor the shellfish samples quickly.; Azaspiracids show distinctly different modes of action in human lymphocytes. This phenomenon deserves further studies but it is almost impossible to obtain enough azaspiracids, especially the minor azaspiracid analogs such as azaspiracid-3, from shellfish for this purpose. Thus, we have been working to achieve a total synthesis of azaspiracid-3. This thesis describes an efficient synthesis of its EFGHI domain. This synthesis involves the coupling of three key building blocks: the E ring precursor, the FGH precursor and the I ring precursor, to set up the linear EFGHI precursor through NHK coupling and Mukaiyama aldol. Some manipulations of this linear precursor including DIHMA and spiroaminal formation produce the EFGHI domain. In addition, this thesis also presents some preliminary model studies of the coupling between the ABCD domain and the EFGHI domain.