Total Synthesis of (±)-Phomactin A. Lessons Learned from Respecting a Challenging Structural Topology

Abstract

Our struggles and ultimate success in achieving a total synthesis of phomactin A are described. Our strategy features an intramolecular oxa-[3 + 3] annulation to construct its unique ABD-tricyclic manifold. Although the synthesis would constitute a distinctly new approach with the 12-membered D-ring of phomactin A being assembled simultaneously with the 1-oxadecalin at an early stage, the ABD-tricycle represents a unique structural topology that would pose a number of unprecedented challenges. One challenge concerned elaborating this tricycle to have oxygenation at the proper carbon atoms. To overcome this, we would utilize a Kornblum-DeLaMare ring-opening of a peroxide bridge as well as a challenging late-stage 1,3-allylic alcohol transposition. Further, the structural intricacies of the ABD-tricycle were uncovered by a conformational analysis that would be critical for the C5a-homologation.

Natural Products with Anti‐Bredt and Bridgehead Double Bonds

“…[82] Not too surprisingly, synthetic chemists and pharmaceutical companies, such as Sankyo (Japan) and Schering-Plough (USA), have shown considerable interest in these natural products. [83,84] The Goldring, [85] Hsung, [86] and Wulff [87] groups are amongst those who have been successful in the total synthesis of these compounds. The structures of Sch 47918 (116) [80c] and phomactins E (123), [80e] I (125), [80g] and J (127) [80g] were all solved by X-ray crystallography (Figure 22).…”

Naturstoffe mit Anti‐Bredt‐ und Brückenkopf‐Doppelbindung

“…Natürlich ist daher das Interesse an diesen Naturstoffen sowohl von Synthesechemikern als auch von pharmazeutischen Unternehmen wie Sankyo (Japan) und Schering‐Plough (USA) hoch 83. 84 Erfolgreiche Totalsynthesen verzeichneten die Gruppen von Goldring,85 Hsung86 und Wulff 87. Die Strukturen von Sch 47918 ( 116 )80c und Phomactin E ( 123 ),80e I ( 125 )80g und J ( 127 )80g wurden jeweils durch Röntgenkristallographie gelöst (Abbildung 22).…”

Self-Sensitized Photooxygenation of 2H-Pyrans: Characterization of Unexpected Products Assisted by Computed Structural Elucidation and Residual Dipolar Couplings

“…1 Generally, singlet oxygen is the reagent of choice in these processes, requiring the use of an external sensitizer for the energy transfer process to occur. [2][3][4][5] During our studies on the photochemical behavior of dienones in the presence of molecular oxygen, we established an easy one-pot approach for the preparation of bridged 1,2,4-trioxanes (Scheme 1). [6][7][8] The process involves a singlet 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 oxygen Diels-Alder type oxygenation of 2H-pyran in situ generated intermediates, revealing the ability of dienones bearing an ionone-type skeleton to act as singlet oxygen sensitizers.…”