Total Synthesis and Biological Evaluation of (+)‐Gambieric Acid A and Its Analogues

Abstract

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.

Evolution of a Polyene Cyclization Cascade for the Total Synthesis of (−)‐Cyclosmenospongine

“…We chose to convert iodide 15 to its corresponding borinate using the “ B ‐OMe‐9‐BBN” variation . The borinate can be conveniently prepared by addition of tert ‐butyl lithium to a premixed solution of 15 and B ‐OMe‐9‐BBN (1 m in hexanes) in tetrahydrofuran at −78 °C . We found that the use of Buchwald ’s Pd SPhos precatalyst system (5 mol % SPhos Pd G2, 5 mol % SPhos, Cs 2 CO 3 , THF, DMF, H 2 O, 40 °C) was crucial to obtain high yields, short reaction times (typically around 1 h) and to efficiently suppress unwanted β‐hydride elimination .…”

“…[14] The borinate can be conveniently prepared by addition of tert-butyl lithium to ap remixed solution of 15 and B-OMe-9-BBN (1 m in hexanes) in tetrahydrofuran at À78 8C. [15] We found that the use of Buchwald 's Pd SPhos precatalysts ystem (5 mol %S Phos Pd G2, 5mol %S Phos, Cs 2 CO 3 , THF,D MF,H 2 O, 40 8C) was crucial to obtain high yields, short reaction times (typically around1h) and to efficiently suppress unwanted b-hydride elimination. [16] The generalityo ft hese optimizedc onditions was also demonstrated for as mall array of bromoenol ethers.…”

“…[3b-d] Meroterpenoids are hybrid naturalp roducts with am ixed biosynthetic pathway that incorporatesp olyketide and terpenoid building blocks (Scheme 1b). [4] The fusion of farnesyl pyrophosphate (C 15 ), which originates from the terpene pathway, and ap olyketide derived aromatic core gives linear polyene 5, which undergoes ac ationic cyclization cascade to initially produce the key biosynthetic intermediate, drimane 6. [5] Consecutive [1,2]-hydridea nd methyl shifts provide cation 7,w hich can be either trapped by the adjacentp henol to directly yield the cis-fused decalin ring system 9a (a-5-H) of aureol (1)a nd its congeners (2 and 3)o re liminate to give 8.T he latter is considered to be the direct biosynthetic precursor of the trans-fused decalin system 9b (b-5-H), which is presenti nc yclosmenospongine (4).…”

Recent applications in natural product synthesis of dihydrofuran and -pyran formation by ring-closing alkene metathesis

“…The strategy of convergent RCM substrate synthesis by Suzuki coupling with an unsaturated ester-derived enol phosphate, seen earlier in a 2,3-DHF approach towards okadaic acid (61) (Scheme 16), has also been applied in 3,4-DHP synthesis towards the attenol marine toxins (e.g., (−)-attenol A (156), Scheme 47), 59 and the D-ring of (+)-gambieric acid A (157) in the latter's first total synthesis (Scheme 48, NAP = 2-napthylmethyl), 60 and (+)-neopeltolide and analogues. 61 A popular route to 3,4-DHPs 151 from unsaturated esters 158 uses a reduced titanium alkylidene, derived from TiCl 4 and a 1,1-dibromoalkane (Takai-Utimoto reagent, Scheme 49).…”

Concise synthesis of the A/BCD-ring fragment of gambieric acid A

“…We have recently completed the first total synthesis of GAA to establish its absolute configuration as that shown by 1 (Fuwa et al, 2012 ; Ishigai et al, 2013 ; Sasaki and Fuwa, 2014 ). Our synthesis entailed convergent assembly of the A/BCD- and F′GHIJ-ring fragments, i.e., 2 and 3 , respectively, by means of Suzuki–Miyaura coupling (Miyaura and Suzuki, 1995 ; Sasaki and Fuwa, 2008 ; Suzuki, 2011 ) to give the endocyclic enol ether 4 , followed by closure of the E- and F-rings via a stereoselective allylation of a thioacetal (Suga et al, 2014 ) and a ring-closing metathesis (Hoveyda and Zhugralin, 2007 ), respectively, to construct the nonacyclic polyether core 5 (Figure 2 ).…”