Nalanthalide synthesis

Initial attempts to realize the direct conversion of 1 to 2 under conventional basic conditions (1 M NaOH, MeOH, it reflux) were unsuccessful (Scheme 9). The expected hydrolysis of the y-pyrone moiety in 1 followed by the tautomerization of y-pyrone to a-pyrone proceeded smoothly and cleanly at reflux temperature however, the unfavorable deprotection of the acetyl group occurred during the reaction, producing de-O-acetylsesquicillin (37) in good yield (83%). Therefore, we decided to pursue the synthesis of 2 in a step-by-step manner from de-O-acetylnalanthalide (36), which is the most advanced intermediate of the nalanthalide synthesis (cf. Scheme 7, but... 

Intermediate 40 would be produced through a coupling reaction between the appropriately functionalized decalin aldehyde 41 (available from alcohol 42) and 3-lithio-y-pyrone 23. Intermediate 42 would be formed through the strategic [2,3]-Wittig rearrangement of stannylmethyl ether 43. On the basis of the results accumulated from the nalanthalide synthesis (cf. Section Total Synthesis of (—)-Nalanthalide and Scheme 6), we expected that the C9 stereogenic center and the C8 exo-methylene function in the product 42 would be simultaneously formed. Intermediate 43, in turn, would be derived from 14 [17]. 

In the total synthesis of nalanthalide, the crucial coupling of the 7-pyrone moiety with the diterpenoid core was achieved by lithium halogen exchange of 3-bromo-2-methoxy-5,6-dimethyl-4/7-pyran-4-one 353 and addition of the resulting 3-lithio-7-pyrone 354 to aldehyde 355 to produce 356 in an impressive 87% yield (Scheme 53) <2005OL3745, 2006TL3251>. 

Total Synthesis of Diterpenoid Pyrones, Nalanthalide, Sesquicillin, Candelalides A-C, and Subglutinols A, B... 

In this chapter, the total synthesis of biologically attractive diterpenoid pyrones— nalanthalide (1), sesquicillin (2), candelalides A-C (3-5), and sub-glutinols A (6), B (7)—has been summarized with particular focus on then-synthetic strategies. It is of interest to look at each respective method for approaching the target molecules. 

---