A variety of electrophiles (anhydrides, acid chlorides, carbonochloridates, sulfonyl chlorides, and alkyl bromides) react with 3-methoxy-2H-indazole (1a), benzoxazin[3,2-b]indazole (1d), and oxazolino[3,2-b]indazole (1e) – substrates available by the Davis-Beirut reaction – to yield a diverse set of N1,N2-disubstituted-1H-indazolones. With certain electrophiles, an AERORC (Addition of the Electrophile, Ring Opening, and Ring Closure) process on indazole 1d results in indazoloindazolone formation. An intriguing aspect of these N1,N2-disubstituted-1H-indazolones is that they are poised for diversification through, for example, azide-alkyne cycloaddition chemistry reported here.

In this study, we report the first total synthesis and complete stereostructure of gambieric acid A, a potent antifungal polycyclic ether metabolite, in detail. The A/B-ring exocyclic enol ether 32 was prepared through a Suzuki-Miyaura coupling of the B-ring vinyl iodide 18 and the alkylborate 33 and subsequent closure of the A-ring by using diastereoselective bromoetherification as the key transformation. Suzuki-Miyaura coupling of 32 with acetate-derived enol phosphate 49, followed by ring-closing metathesis of the derived diene, produced the D-ring. Subsequent closure of the C-ring through a mixed thioacetalization completed the synthesis of the A/BCD-ring fragment 8. The A/BCD- and F'GHIJ-ring fragments (i.e., 8 and 9) were assembled through Suzuki-Miyaura coupling. The C25 stereogenic center was elaborated by exploiting the intrinsic conformational property of the seven-membered F'-ring. After the oxidative cleavage of the F'-ring, the E-ring was formed as a cyclic mixed thioacetal (i.e., 70) and then stereoselectively allylated by using glycosylation chemistry. Ring-closing metathesis of the diene 3 thus obtained closed the F-ring and completed the polycyclic ether skeleton. Finally, the J-ring side chain was introduced by using a Julia-Kocienski olefination in the presence of CeCl3 to complete the total synthesis of gambieric acid A (1), thereby unambiguously establishing its complete stereostructure. The present total synthesis enabled us to evaluate the antifungal and antiproliferative activities of 1 and several synthetic analogues.

3-alkoxy-2H-indazoles. -A variety of indazole substrates undergoes electrophilic reactions leading to the small libraries of N,N'-disubstituted indazolones. Click diversification is carried out to prepare various triazolyl indazolones. Rearrangement of (VI) to (VIII) proceeds when a catalytic amount of (IIb) is applied. The reaction can be carried out under conventional or microwave-assisted conditions. -(CONRAD, W. E.; FUKAZAWA, R.; HADDADIN, M. J.; KURTH*, M. J.; Org. Lett. 13 (2011) 12, 3138-3141, http://dx.doi.org/10.1021/ol2010424 ; Dep. Chem., Univ. Calif., Davis, CA 95616, USA; Eng.) -R. Steudel

Gambieric acid A (GAA) and its congeners belong to the family of marine polycyclic ether natural products. Their highly complex molecular architecture and unique biological activities have been of intense interest within the synthetic community. We have previously reported the first total synthesis, stereochemical reassignment, and preliminary structure–activity relationships of GAA. Here we disclose a concise synthesis of the A/BCD-ring fragment of GAA. The synthesis started from our previously reported synthetic intermediate that represents the A/B-ring. The C-ring was synthesized via an oxiranyl anion coupling and a 6-endo cyclization, and the D-ring was forged by means of an oxidative lactonization and subsequent palladium-catalyzed functionalization of the lactone ring. In this manner, the number of linear synthetic steps required for the construction of the C- and D-rings was reduced from 22 to 11.

The first total synthesis of (+)‐gambieric acid A, a potent antifungal marine polycyclic ether, has been accomplished by H. Fuwa, M. Sasaki et al. in their Full Paper on in a convergent manner by relying on Suzuki–Miyaura reaction for the assembly of the A/BCD‐ and F′GHIJ‐ring fragments and a ring‐closing metathesis for formation of the nonacyclic backbone. The total synthesis unambiguously establishes the structure of this extraordinary complex molecule, thus demonstrating the important role of organic synthesis in the structural elucidation of natural products.