Berkelic acid

Yaodong Huang, while pursuing the synthesis of ( + )-berkelic acid (69), reported a diastereoselective cycloaddition using method H that leads to another type of 5,6-aryloxy spiroketals (Fig. 4.36).32 For example, addition of three equivalents of t-butyl magnesium bromide to alcohol 70 in the presence of the exocyclic enol ether 71 proceeds in a 72% yield to the spiroketal 72 with a 4.5 1 selectivity favoring the endo approach (Fig. 4.36). Additional experiments suggest the bromine atom decreases the HOMO-LUMO band gap and improves diastereoselectivity. 

FIGURE 4.36 A diastereoselective cycloaddition strategy for (+ )-berkelic acid 69. 

Huang, Y. Pettus, T. R. R. A cycloaddition strategy for use toward berkelic acid, a MMP inhibitor and potent anticancer agent displaying a unique chroman spiroketal motif. Synlett 2008, 1353-1356. 

Scheme 13.24 Total synthesis of (-)-berkelic acid (165) using a silver-catalyzed cascade reaction.

In 2011, a practical and scalable route to (-)-berkelic acid was developed by the group of Fafiands (Scheme 13.24) [29]. The synthesis was accomplished in only seven steps by using a silver-catalyzed cascade reaction, which allowed the construction of the central core containing four rings and five stereogenic centers in just one step. 

Fanands, R, Mendoza, A., Arto, T., Temelli, B., Rodriguez, R (2012). Scalable total synthesis of (—)-berkelic acid by using a protecting-group-free strategy. Angewandte Chemie International Edition, 51, 4930-4933. 

Berkelic Acid Lessons Learned From Our Investigations on a Scalable Total Synthesis... 

Structural Assignation and Previous Total Syntheses of (-)-Berkelic Acid... 

FIGURE 1 Berkeley Pit Lake in Butte (Montana, US) and structure of (—)-berkelic acid. 

STRUCTURAL ASSIGNATION AND PREVIOUS TOTAL SYNTHESES OF (-)-BERKELIC ACID... 

Following their initial studies on the real structure of ( )-berkelic acid previously mentioned, Fiirstner and coworkers published in 2010 a total synthesis of this natural product. The successful route was based on an aldol reaction between methyl ketone 13 and benzaldehyde derivative 14 to give enone derivative 12 (Scheme 3). A subsequent deprotection/1,4-addition/ spiroacetalization cascade reaction delivered the tetracyclic core 11. Installation of the lateral chain was achieved by oxidative rupture, reduction, and... 

While the three reported total syntheses of ( )-berkelic acid allowed access to synthetic samples of the natural product, achieving a scalable and modular synthesis of this target remained, for various reasons, an unmet challenge. It should also be noted that Pettus and Brimble s groups have also reported formal total syntheses of (—)-berkelic acid. 

OUR APPROACH TO BERKELIC ACID FROM RESEARCH ON NEW METHODOLOGY MODEL STUDIES... 

All these results seemed to indicate that this reaction was ideal for the con-stmction of the (—)-berkelic acid skeleton. However, a serious problem was still unresolved at this point how to constmct the additional pyran ring contained in the natural product. Nevertheless, our experience on cycloisomerization reactions led us to speculate on the possibility that a unique metal complex could promote the cycloisomerization of alkynol 15 to give the exo-cyclic enol ether 19 and also that the cycloisomerization of an alkynyl-substituted salicylaldehyde 23 would give 25. Thus, activation of the alkyne of 15 should promote a hydroalkoxylation reaction to give the exocyclic enol ether 19. On the other hand, activation of the alkyne in 23 should promote a cascade cyclization process to finally give the 8//-isochromen-8-one derivative 25. The formal [4-F 2]-cycloaddition reaction between intermediates 19 and 25 would result in the formation of the core structure of (—)-berkehc acid 24 in a very simple way (Scheme 7). 

Before facing the total synthesis of (—)-berkelic acid, we still needed to know about the diastereoselectivity of the reaction when a chiral alkynol derivative such as 15b was reacted with the simple alkynyl-substituted salicy-laldehyde derivative 23a (Scheme 11). This study would serve to teU us if the stereocenter of 15b could direct the formation of the other two in the desired way. 

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