Abstract
Palau'amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and significant immunosuppressive activity. Here we report the total synthesis of palau'amine characterized by the construction of an ABDE tetracyclic ring core including a trans-bicylo[3.3.0]octane skeleton at a middle stage of total synthesis. The ABDE tetracyclic ring core is constructed by a cascade reaction of a cleavage of the N–N bond, including simultaneous formation of imine, the addition of amide anion to the resulting imine (D-ring formation) and the condensation of pyrrole with methyl ester (B-ring formation) in a single step. The synthetic palau'amine is confirmed to exhibit excellent immunosuppressive activity. The present synthetic route has the potential to help elucidate a pharmacophore as well as the mechanistic details of immunosuppressive activity.
Highlights
Palau’amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and significant immunosuppressive activity
There has been only one report of a total synthesis, by Baran and colleagues[44] in 2010, which was followed by the development of an asymmetric version in 2011
The most difficult challenge in the total synthesis of 1 would be the construction of a transbicyclo[3.3.0]octane system that corresponds to a D/E ring junction and Baran and colleagues[44] has addressed this by adopting the transannular reaction of nine-membered lactam 2, named macro-palau’amine, leading to 1 at the final step (Fig. 1)
Summary
Palau’amine has received a great deal of attention in the past two decades as an attractive synthetic target by virtue of its intriguing molecular architecture and significant immunosuppressive activity. The most difficult challenge in the total synthesis of 1 would be the construction of a transbicyclo[3.3.0]octane system that corresponds to a D/E ring junction and Baran and colleagues[44] has addressed this by adopting the transannular reaction of nine-membered lactam 2, named macro-palau’amine, leading to 1 at the final step (Fig. 1). As the basic structure of 1 remains to be established, there is need of an efficient method for constructing an ABDE tetracyclic ring system that includes a trans-bicyclo[3.3.0]octane skeleton and, the development of such a system will be extremely difficult, it is absolutely critical for the field of synthetic organic chemistry and the elucidation of pharmacophores and the development of palau’amine probes. We report the successful establishment of an alternative synthetic route to 1 based on the efficient construction of an ABDE tetracyclic ring core at the middle stage of total synthesis, in which many analogues of 1 possessing various ring core systems are first obtained
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