Influence of Appended Groups on the Formation of 16-Membered Macrolactone Core Related to the Plecomacrolides via Diene-Ene Ring-Closing Metathesis

Abstract

A 1,3-diene-ene ring-closing metathesis (RCM) strategy was investigated for assembling the 16-membered macrolactone core of the plecomacrolides. It was found that the desired (10E,12E)-diene unit could be constructed from the fully functionalized C13-C17 homoallyl alcohol fragment and the C1-C12 acid fragment possessing one E double bond at C2-C3 or C3-C4. The functional groups at C2 and C3 resulted in preferential formation of the undesired (12Z)-macrolactone, while additional appended groups at C6-C8 furnished the (12Z)-macrolactone as the sole RCM product.Bafilomycin A 1 (1, Figure 1) 1 is a representative member of the 16-membered plecomacrolide family, 2,3 which are best known for possessing a folding hemiacetal subunit on the side chain. The macrolactone core is connected to the hemiacetal via a three-carbon linker (C16-C18 for 1). Formation of an intramolecular hydrogen bonding network among the lactone/linker/hemiacetal motif was suggested to play an important role in the biological functions, 4 although non-supportive findings were obtained from a study on synthetic analogues. 5 Most of the plecomacrolides deliver antifungal and antibacterial activity. Moreover, bafilomycin A 1 is known to be a specific inhibitor of vacuolar H + -ATPase (V-ATPase) and it holds some promise for treating osteoporosis. 5-8 24-Demethylbafilomycin A 2 (2) 9a is produced together with 24-demethylbafilomycin C 1 (3) by a commensal microbe Streptomyces sp. CS associated with Maytenus hookeri. 9 It was reported that the macrolide 2 exerts strong cytotoxicity, with IC 50 values of 1.13 and 0.01 mM against P388 and A549 tumor cell lines, respectively. The complex structure of 1 has attracted much synthetic effort. After the first total synthesis of bafilomycin A 1 was accomplished by Evans and Calter in 1993, 10 several total syntheses of 1 were developed by Toshima, 11 Roush, 12 Hanessian, 13 and Carreira, 14 along with studies on the fragment syntheses by many other research groups. [15][16][17][18][19][20][21] In general, the 1,3-diene functionality between C10-C13 was constructed by formation of the C11-C12 bond via palladium-catalyzed cross-coupling reactions of vinyl tin 10,11,13,15,16,18 or boron 12 derivatives with vinyl iodides. Alternatively, a Sonogashira reaction has been used to form the enyne intermediate, which was subsequently reduced to the 1,3-diene. 14 We envisaged a different approach to the assembly of the 16-membered tetraene macrolactone core by employing 1,3-diene-ene ring-closing metathesis (RCM). [22][23][24] Here, we report on the construction of the 16-membered macrolactone core and on the finding that the appended groups influence the geometry of the forming C12-C13 double bond. Figure 1Structures of bafilomycin A 1 (1), 24-demethylbafilomycin A 2 (2), and 24-demethylbafilomycin C 1 (3) and the strategic bond disconnections between C11-C12 and C12-C13 According to the early findings by Yang and co-workers, 25 the non-functionalized 16-membered tetraene macrolactone could not be constructed directly vi...

Synthesis of the Macrolactone Cores of Maltepolides via a Diene–Ene Ring-Closing Metathesis Strategy

“…We envisioned that synthesis of maltepolide E ( 5 ) should be much more rewarding because it provides quick access to other maltepolide core structures, although it would be very challenging to concurrently handle two vinyl epoxide moieties during the synthesis. We envisioned use of a diene–ene ring-closing metathesis (RCM) strategy to build up the macrocyclic core of maltepolide E. According to the three key bond disconnections (see 5 in Figure a) at the macrolactone C­(O)–O bond, the C8/C9 double bond, and the C19/C20 single bond, building blocks 7 – 9 were required (Figure b). To quickly confirm the feasibility of the proposed diene–ene RCM reaction, we decided to focus on construction of the maltepolide E core without the C20–C24 vinyl epoxide side chain.…”