Total Synthesis of Brevetoxin A: Part 2: Second Generation Strategy and Construction of EFGH Model System

✍ Scribed by K. C. Nicolaou; Paul A. Wallace; Shuhao Shi; Michael A. Ouellette; Mark E. Bunnage; Janet L. Gunzner; Konstantinos A. Agrios; Guo-qiang Shi; Peter Gärtner; Zhen Yang

• Publisher: John Wiley and Sons
• Year: 1999
• Tongue: English
• Weight: 252 KB
• Volume: 5
• Category: Article
• ISSN: 0947-6539
• DOI: 10.1002/(sici)1521-3765(19990201)5:2<618::aid-chem618>3.0.co;2-i

✦ Synopsis

Our second generation strategy for the total synthesis of brevetoxin A involved dissection of the molecule at the ring F oxocene. Synthetically, the F ring formation was expected to occur through Wittig coupling of requisite polycyclic fragments 2 and 3, followed by a hydroxy dithioketal cyclization. In order to test this synthetic plan, model phosphonium salt 9 and aldehyde 10 were successfully synthesized and coupled. The deprotected product ( 46) was shown to undergo an efficient hydroxy dithioketal cyclization and the product (47) was selectively reduced to the EFGH ring system of brevetoxin A (8).

The synthesis of phosphonium salt 9 utilized our cyclic ketene acetal phosphate methodology and a [4 2] addition of singlet oxygen to generate intermediate endoperoxide 11. The success of this model study facilitated a synthetic plan to form and functionalize ring E nonacene and ring F oxocene for the total synthesis of brevetoxin A.