Natural product synthesis Agelastatin

Applications to natural product synthesis probe the limits of any synthetic method, as situations arise that would never have been considered in the course of first developing the method. Recent syntheses of valienamine 6, agelastatin 9 and tonantzitlolone 15 pressed the limits of ring-closing metathesis. 

This interesting chemistry has been apphed in natural product synthesis, especially in the context of the marine alkaloid agelastatin A. In 1999 the first total synthesis of racemic agelastatin A was achieved by Weinreb [70] (Scheme 24). Key intermediate 95 was synthesized via the already mentioned allylic amination sequence, this time using the new sulfodiimide 91. As an-... 

The numerous excellent synthetic procedures published by A.C. Richardson also continue to be relied upon by contemporary organic chemists because of their great practicality and reproducibility. Indeed, a recent highly cited enantiospecific total synthesis of the antitumor agent, (—)-agelastatin A, justly testifies to this fact it exploits the remarkably useful Hough-Richardson aziridine as a key synthetic intermediate in the eventual published route to this complex natural product. 

At last, we had achieved our goal of completing a full enantiospecific total synthesis of (-)-agelastatin A, and with our new route we then went on to prepare 223 mg of the pure natural product to allow us to commence the biological studies we will now describe. 

The intramolecular variant of the alkylidene carbene cyclization is achieved by treating functionalized alkynyliodonium salts with a suitable nucleophile. These cyclizations are exemplified by the following works the preparation of various functionalized 2,5-dihydrofurans by treatment of 3-alkoxy-l-alkynyl-(phenyl)iodonium triflates with sodium benzenesulfinate [1002], employment of the alkylidene carbene cyclization in the total syntheses of natural products agelastatin A and agelastatin B [1003] and preparation of the tricyclic core of ( )-halichlorine through the use of an alkynyliodonium salt/alkylidenecarbene/1,5 C—H insertion sequence [1004]. In particular, Wardrop and Fritz have employed the sodium benzenesulfinate-induced cyclization of alkynyliodonium triflate 751 for the preparation of dihydrofuran 752 (Scheme 3.295), which is a key intermediate product in the total synthesis of ( )-magnofargesin [1002]. 

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