Total Synthesis of (±)-Cephanolides B and C via a Palladium-Catalyzed Cascade Cyclization and Late-Stage sp 3 C H Bond Oxidation

Transcription

1 Total Synthesis of (±)-Cephanolides B and C via a Palladium-Catalyzed Cascade Cyclization and ate-stage sp 3 C Bond xidation un Xu, Chao Wang, Ziwei Gao, and Yu-Ming Zhao* Cameron McConnell Professor S.-Y. iu 05/23/2017 ntroduction The first total synthesis of Cephanolides B and C is reported. The Cephanolide norditerpenoids belong to a larger family of structurally diverse natural products produced by the plants of the Cephalotaxaceae family. Cephanolide diterpenoids have been shown to demonstrate potent antitumor activity. They feature a common pentacyclic core which includes a cis-fused tricarbocycle, a cyclohexane ring bearing 5 or 6 contiguous stereogenic centers, and a bridging lactone ring. These challenging yet intriguing structural features combined with the biological activity of the Cephanolide diterpenoids have led to the the total synthesis of several other natural products from this family. n this paper, the authors report the first total synthesis of Cephanolides B and C through a common pentacyclic core which was accessed via a ecktype/carbonylative C activation cascade. etrosynthetic Analysis cephanolide B (1) cephanolide C (2) ox. or red. common pentacyclic core (3) -catalyzed cascade cyclization X lactonization egishi Coupling Et obinson Annulation C 2 Et Xu,.; Wang, C.; Gao, Z.; Zhao, Y.-M. J. Am. Chem. Soc. 2018, 140, page 1

2 Synthesis of 5 6 Zn 7 C 2 Et (Ac) 2 SPhos TF 8 Et AgAc 2 Ac 88% 2 steps 5 Et egishi Coupling Electrophilic omatic Substitution Zn C 2 Et (Ac) 2 TM x 2 reductive elimination Et 2 0 reductive elimination oxidative addition Ag Ac Ag Ac Zn C 2 Et transmetalation Zn 2 Synthesis of Cyclohexenone 4 5 Et DA, C TF 9 C Et 3-penten-2-one Cu(Tf) 2, TF 78% 2 steps 4 C 2 Et d.r. = 4:1 page 2

3 Formyl Addition to Enolate and obinson Annulation i Et Et C Et taut. (Tf) 2 Cu CEt taut. x2 C CEt PT C Et Cu(Tf) 2 = PT (Tf) 2 Cu CEt 2 CEt Formation of actone 12 4 C 2 Et ab 4 Ce C 2 Et 1. aq. a 2. EDC C d.r. = 4:1 65%, single diastereomer 62%, two steps page 3

4 uche eduction C 2 Et Ce 3 B ab 4 ab (4 n) () n n 2 ydrolysis and actonization C 2 Et a aq. 11 Ce 3 Et PT C 2 Et Setting up the Key eaction 12 C DBA- PPTS C % 14 58% 15 (Ac) 2, PPh 3 C, Ag 2 C 3 K 2 C 3, Ph (Ac) 2, PPh 3 C, K 2 C 3, Ph %, incorrect stereochemistry 91%, single diastereomer page 4

5 Palladium-Catalyzed Cascade Annulation 0 oxidative addition (Ac) 2, PPh 3, C (1 atm), K 2 C 3, Ph, 90 o C, 18 h 91% n cis-migratory insertion K 2 C 3 K K path a K n C insertion n path b reductive elimination 0 product path c page 5

6 Preparation of Common Pentacyclic Core 16 BF 3 Et 2 m-cpba C 2 2 C % 70% 3 Tf Et 3 Si 17 e-oxidation to actone BF 3 eduction of Benzylic Ketone Tf Tf SiEt 3 Tf Tf 2 2 SiEt 3 Divergence from Common ntermediate 1 B 3 C % 17 DDQ 2 /C % 18 cephanolide B page 6

7 thoxy Deprotection B 3 B 2 B 2 B 2 B 2 + DDQ xidation 2 + Completing the Synthesis of Cephanolide C 18 PCC benzene 64% B 3, TBA 2. Tf 2, pyr 57%, two steps Tf 20 (Ac) 2 Et 3 Si dppp DMF 91% cephanolide C (2) PCC Benzylic xidation Cr V Cr V Cr V Cr Cr () 2 page 7

8 -Catalyzed De-oxygenation reductive elimination 0 Tf oxidative addition Tf Et 3 Si transmetalation Et 3 SiTf Conclusion The first syntheses of the cephalotaxus diterpenoids cephanolide B and cephanolide C were accomplished in a longest linear sequence of 13 and 17 steps, respectively. A novel -catalyzed cascade annulation reaction enabled the construction of a common pentacyclic core that can be elaborated into multiple cephalotane-type diterpenoids. The synthesis also featured two selective, late-stage, sp 3 C- oxidation reactions in order to prepare cephanolide C. page 8