Total Synthesis of (+)-Suaveolindole

Transcription

1 1 Total Synthesis of (+)-Suaveolindole 15 2 C Emile J. Velthuisen and Samuel J. Danishefsky J. Am. Chem. Soc. 2007, 9, Julia Vargas September 15, 2007

2 2 utline Isolation and Elucidation of (+)-Suaveolindole Biological activity verview of Indole Ring Syntheses Syntheses of Indolosesquiterpenes Total synthesis of (+)-Suaveolindole Summary

3 3 (+)-Suaveolindole Isolated from Greenwaydendron suaveolens - Annonaceae or custard apple family - flowering trees and shrubs - found in tropical, temperate regions of Africa - aromatic terpenoids and benzyl isoquinoline alkaloids ovel indolosesquiterpene structure Structure elucidation by 1D and 2D-MR, RESIMS, UV - IR and optical rotation not able to be determined 2 C J. at. Prod. 2005, 68, 2-4 Annona squamosa Brugmansia suaveolens

4 4 Biological Activity Potent activity against gram positive bacteria Bacillus subtilis (MIC) 4 µg/ml Staphylococcus aureus 8 µg/ml Staphylococcus aureus methicillin resistant 8 µg/ml ot active against gram negative bacteria Klebisella pneumoniae 8 µg/ml Pseudomonas aeruginosa 8 µg/ml White blood cell Bacillus anthracis (pictures of gram positive and negative bacteria taken from Wikipedia.org) J. at. Prod. 2005, 68, 2-4

5 5 Indole Ring Syntheses Gribble, G.W. J.Chem. Soc., Perkin. Trans. 1, 2000, 1045 tal diated Cyclizations egedus-mori-eck indole Synthesis Reductive Cyclizations o,!"dinitrostyrene reductive cyclization R 2 PdCl 2 (C) 2 R 1 benzoquinone LiCl, TF, ~74-86% R 2 R ZnS 4 as 2 4 p 4, 52% R 1 =,, Ac R 2 =, 5-, 5-C 2 Et, 6- R 3 + * I S 2 R 2 R Larock indole Synthesis PdCl 2 (PPh 3 ) 2 CuI, TMG, DMF 40 o C, 78-93% F rstner Indole Synthesis TiCl 3, Zn, TMSCl C, reflux, 70-90% 2 S R 3 * R 2 R 1 Radical Cyclizations Tin-diated Cyclizations I Boc Bu 3 Sn, TEMP, Ph, 70 o C, 83% Zn aq. Ac Boc R 1 TF, 70 o C, 90%

6 6 Indole Ring Syntheses Gribble, G.W. J.Chem. Soc., Perkin. Trans. 1, 2000, 1045 Sigmatropic Rearrangements Julia indole Synthesis S 1.) MgCl 2.) 2 S 110 o c, Ph ucleophilic Cyclizations Aza-Wittig Reaction R 3 S 2 R 1 PPh 3 R 2 CC, Ph 110 o C R 3 S 2 R 1 C R 2 a, DMS o C S 2 R 1 R 3 R 2 Electrophilic Cyclizations Sundberg indole Synthesis o C Ph, 3 3 sealed tube, 61%

7 7 Indolosesquiterpenes Anita Jocelyne Marsaioli, et al. (1989) Ac 1.) SCl 2 2.) o- toluidine, Ph, K 2 C 3 (70% over two steps) Ac a 2, PhEt 2, 150 o C, 25% SnCl 4, C 2 Cl 2, 0 o C, 70% Catherine Mirand, et al. (1987) S 2 Ph BF 3 Et 2, S 2 Ph 1 K/Et C 2 Cl 2 Polyveoline C. Mirand et. Al., Tet. Lett.,1987, 28(31), ; Marsaioli, A.J. et. Al, J.Chem.Soc. Perkin. Trans. 1, 1989, 559

8 8 Initial synthetic strategy X R Intramolecular eck R PdLn + M Cross Coupling X: I or PdLn M: SnR 3, BR 2 15 R R 2 C Suaveolindole I TIPS + SnBu 3 S 2 Ph Pd 2 dba 3 (2.5 mol %) Ph 3 As (5 mol %), Bu 4 Cl, DMF, 105 o C, (55%) TIPS (4:1 dr) S 2 Ph i. B 3 TF ii. ab (56%) TIPS S 2 Ph

9 9 The winning approach 1.) Br, Mg, TF 3,, 2.) PCC, C 2 Cl 2, (47% over two steps) 2 S, (88%) 1.) 2 I Pd(Ac) 2 (5 mol%) DABC, DMF, (68%) 2.) TsCl, TBAB, aq. a/benzene, (91%) Ts 15 i.) CuI, Li ii.) PhTf 2, Et 2 /TF Tf Ts C, Pd(PPh 3 ) 4, DIPEA /DMF (45% from 15) Ts

10 10 i.) Li, Et 2, (84%) LiMDS, TMSCl, 2 C Ts ii.) Ac 2, DIPEA, DMAP, C 2 Cl 2, (83%) Ts TF, -78 o C, (56%) Ts 1.) i.) Cl Cl, DMF (cat.), 2 C napthalene, a, DME 2 C C 2 Cl 2 ii.) C 2 2, DIPEA, TF, (62%) (94%) 2.) CF 3 C 2 Ag, Et 3, TF/ 2, (74%) Ts (+)-Suaveolindole

11 11 Summary 15 2 C Completed the first total synthesis of (+)-Suaveolindole 13 steps, 1.9% overall yield Determined optical rotation: Sequoia Sciences (isolated): [α] 22 D = +26o (c = 1.0, C 3 D) Synthetic Sample: [α] 22 D = +32o (c = 1.0, C 3 D) Determined Absolute Configuration (R,R,S) for C 11, C, C 16 respectively Synthetic sample exhibits comparable biological activity as reported for naturally occurring (+)-Suaveolindole