Concise Total Synthesis of (+)-Brefeldin A:  A Combined β-Lactone/Cross-Metathesis-Based Strategy

Wang, Yingcai; Romo, Daniel

doi:10.1021/ol026438g

Cited by 41 publications

(28 citation statements)

References 34 publications

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“…[8] Two stereogenic centers at the future C4 and C7 positions in 5 would be created by taking advantage of the convex nature of 7. [8] Two stereogenic centers at the future C4 and C7 positions in 5 would be created by taking advantage of the convex nature of 7.…”

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Total Synthesis of Aspergillide A and B Based on the Transannular Oxy‐Michael Reaction

2011

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The aspergillides A, B, and C (1, 2, and 3) comprise a novel class of 14-membered macrolides that were isolated by Kusumi and co-workers from the marine-derived fungus Aspergillus ostianus strain 01F313 that was cultured in a medium composed of bromine-modified artificial sea water. [1] Their structures were determined by extensive spectroscopic studies, and their absolute configurations were established by X-ray crystallography (for 1 and 2) and the modified Mosher method (for 3).[2] These compounds contain tri-substituted tetrahydro and dihydropyran units and exhibit cytotoxicity against mouse lymphocytic leukemia cells (L1210) with LD 50 values of 2.1, 71.0, and 2.0 mg mL À1 , respectively. Because of their intriguing structural features and biological profile, these polyketides have attracted much attention in the synthetic community as targets for total synthesis. To date, four total syntheses of 1, [3] six of 2, [3c, 4] and two of 3 [5] have been reported. Herein, we describe our total synthesis of the aspergillides A (1) and B (2) from a common macrolide intermediate by employing an interesting transannular oxyMichael reaction [6] as the key step. Our strategy for the synthesis of the aspergillides A and B, illustrated in Scheme 1, proposes the formation of the trisubstituted pyran moiety through a base-mediated transannular oxy-Michael reaction from the 14-membered macrolactone 4. It was thought that stereochemical control at the newly generated stereogenic center at C3 could be achieved by the choice of reaction conditions. The macrolactone 4 could be assembled by using a sequential cross-metathesis and intramolecular Horner-Wadsworth-Emmons reaction of the acyclic precursors 5, which could be accessed from the chiral building block 7 [7] and compound 6, which was known in the literature.[8] Two stereogenic centers at the future C4 and C7 positions in 5 would be created by taking advantage of the convex nature of 7.The optically pure enone 7 with a bicyclo[3.2.1]octane framework, prepared from 2-furfural by a six-step sequence, served as the starting material for the synthesis of the alkenyl alcohol 14 (Scheme 2). Attempted transformation of 7 into 10 using the Wharton transposition [7,9] gave unsatisfactory results ( % 20 % yield), prompting us to find another route. Reduction with NaBH 4 followed by the Hata reaction [10] of Scheme 1. Retrosynthetic analysis. Bn = benzyl, HWE = Horner-Wadsworth-Emmons, TBS = tert-butyldimethylsilyl. then TESCl, DMAP, CH 2 Cl 2 , RT, 1 h; k) LiBH 4 , THF, 0 8C, 3 h, 96 % (over 2 steps, based on recovered diol 13). DMAP = 4-dimethylaminopyridine, mCPBA = m-chloroperoxybenzoic acid, Ms = methanesulfonyl, Piv = pivaloyl, TES = triethylsilyl, THF = tetrahydrofuran.

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“…and intramolecular Horner-Wadsworth-Emmons reaction of the acyclic precursors 5, which could be accessed from the chiral building block 7 [7] and compound 6, which was known in the literature. [8] Two stereogenic centers at the future C4 and C7 positions in 5 would be created by taking advantage of the convex nature of 7.…”

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confidence: 99%

Total Synthesis of Aspergillide A and B Based on the Transannular Oxy‐Michael Reaction

2011

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“…The macrolactone 41 would be assembled by using a sequential cross metathesis and intramolecular Horner Wadsworth Emmons (HWE) reaction of the hemiacetal 17, prepared from the chiral building block 12 (see Scheme 3), and the phosphonate 42, which is known in the literature. 34 Cross metathesis of the hemiacetal 17 with the phosphonate 42, 34 prepared from (R) ( ) propylene oxide through a two step sequence, 35 in the presence of a mixture of Grubbs rst and second generation catalysts (5 mol % each) in re uxing CH 2 Cl 2 provided the coupled product 43 as the E alkene ( 20:1) in 61% yield (Scheme 9). It was found that a combined use of the two types of Grubbs catalysts was essential for obtaining a higher yield.…”

Section: Synthesis Of Aspergillides a And B 4fmentioning

confidence: 99%

Total Synthesis of Aspergillides Using a Transannular Oxy-Michael Strategy

Kanematsu¹,

Shishido

2012

J. Synth. Org. Chem. Jpn.

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“…Recently, three different groups have used CM reactions to prepare highly functionalized allylsilanes which were then transformed into bioactive natural products. Wang and Romo reported the synthesis of (+)-brefeldin A, which exhibits antitumor, antifungal, antimitotic, and immunosuppressive activities (Scheme 23) [46]. Cross-metathesis of compound 82 with allyltrimethylsilane in the presence of complex [Ru]-II furnished allylsilane 83 in good yield as a 3:1 mixture of E/Z-isomers.…”

Section: (-)-Tuberos Temoninementioning

confidence: 99%

Application of Olefin Cross-Metathesis to the Synthesis of Biologically Active Natural Products

Prunet¹

2005

CTMC

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Concise Total Synthesis of (+)-Brefeldin A: A Combined β-Lactone/Cross-Metathesis-Based Strategy

Cited by 41 publications

References 34 publications

Total Synthesis of Aspergillide A and B Based on the Transannular Oxy‐Michael Reaction

Total Synthesis of Aspergillide A and B Based on the Transannular Oxy‐Michael Reaction

Total Synthesis of Aspergillides Using a Transannular Oxy-Michael Strategy

Application of Olefin Cross-Metathesis to the Synthesis of Biologically Active Natural Products

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