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Totally Synthetic by Paul H. Docherty, 15 December 2008

Total Synthesis of Norzoanthamine


Y. Murata, D. Yamashita, K. Kitahara, Y. Minasako, A. Nakazaki, S. Kobayashi, Angew. Chem. Int. Ed. 2009, 48, 1400-1403.

DOI: 10.1002/anie.200804544

D. Yamashita, Y. Murata, K.-i. Takao, A. Nakazaki, S. Kobayashi, Angew. Chem. Int. Ed. 2009, 48, 1404-1406.

DOI: 10.1002/anie.200804546

The total synthesis of Norzoanthamine is spaced over two papers, which shows that the construction of the natural product needs many steps. The synthesis was first completed by Miyashita back in 2004. Offering interesting biological activity such as the prevention of decrease in bone weight in osteoporotic mice, medicinal chemist already synthesise analogues.

Kobayashi’s approach is surprisingly linear, starting with the now rather familiar Hajos-Parrish ketone (discussed here a few months back); the easily installed asymmetry in this starting material is used to control the bulk of the synthesis. However, it has to be said that elaboration of the 6,5-fused system took quite a bit of effort; eighteen steps took them to a tightly functionalised, but still small core. In a few more steps, though, this was to change, as a rather nice alkylation constructed a diene, which allowed a powerful intramolecular Diels-Ader reaction (IMDA) reaction to occur, creating a further pair of stereocenters, and completing the A,B,C fragment.

Next up was the fragmentation of the original penanone moiety found in the starting materials, which was intended to become the D ring, a lactone, and thus an oxidative fragmentation was intended. However, things didn’t go as planned (which I’m sure involved a Baeyer Villiger oxidation), but the job was done using a pretty interesting series of reactions. Formation of a silyl enol ether using base and silyl chloride went as expected, but treatment of the enol ether with ozone didn’t result in cleavage as expected, but in a single diastereomer of the α-hydroxy ketone. When this was treated with lead acetate, cleavage of the carbon-carbon bond was this time evident, but again the result was not quite as expected - rather than delivering homolytic oxidation, it appears that the hydroxy center is the focus of the oxidation action. The group postulate a mechanism for this chemistry, including a 1,2-hydride shift of the intermediate lead complex…

Formation of the desired D ring was very simple: treatment of the starting material with unbuffered TBAF resulted in selective deprotection of the C-ring TBS ether and cyclisation in the basic environment. The last of the carbon skeleton was appended using a Horner-Wadsworth-Emmons olefination, and the group were soon ready to build the distictive bicyclic N,O-acetal. The reaction proceeded in reasonable yield, generating the desired stereocenter; which was predicted in model studies.

The D-ring, which had only been in place for a few steps, was then broken apart to allow oxidation of the C-ring centre. Then a final cyclisation, building two rings, completed the synthesis by formation of the second N,O-acetal. This is certainly tidier than the end-game employed by Miyashita, but a similar strategy.

There are certainly some nice reactions used in this total synthesis, but I don’t think I learned a lot along the way...