Total Synthesis of Platencin

Transcription

1 Total Synthesis of Platencin 2 C N Platencin K. C. Nicolaou,* G. Scott Tria, David J. Edmonds Angew. Chem. Int. Ed. 2008, 47, Shuli Mao Current Literature Presentation Shuli Wipf Group 1 2/16/2008

2 Background Emergence of bacterial resistance to all known classes of antibiotics made discovery of new antibiotics critical New discovery should emphasize on novel mode of action Fatty acids are required for bacterial survival and their biosynthesis is catalyzed by condensing enzyme FabF Two poor inhibitors (cerulenin and thiolactomycin) were reported toward FabF (IC50= µg/ml) with poor antibacterial activity (Staphylococcus aureus MIC 64 µg/ml) 2 N S Cerulenin Thiolactomycin Shuli Wipf Group 2 2/16/2008

3 Platensimycin and Platencin rck scientists discovered 1 inhibits FabF (IC50=0.29µM) [Fab (IC50=247µM)] while 2 inhibits both FabF (IC50=4.6µM) and Fab (IC50=9.2µM) through a target-based, whole-cell, high throughput screening assay of 250,000 compounds Both were isolated from strains of Streptomyces platensis Both has an amide linker, but 1 has a pentacyclic core with a cyclic ether ring while 2 has a tetracyclic core Both exhibits broad-spectrum antibacterial activity but 2 is more potent Nature 2006, 441, PNAS 2007, 104, Shuli Wipf Group 3 2/16/2008

4 in vitro Gram-positive Activity Linezolid: synthetically derived agent in clinical use since 2000 PNAS 2007, 104, N N NAc F linezolid (Zyvox TM ) Shuli Wipf Group 4 2/16/2008

5 Plausible Biogenesis from Isoprenoid Precursors DMAPP: dimethylallyl pyrophosphate IPPP: isopentenyl pyrophosphate GGPP: geranyl geranyl phrophosphate Precursor feeding experiment is in progress. Shuli Wipf Group 5 2/16/2008

6 Docking Experiment E. Coli condensing enzyme active site of Fab with docked platensimycin (green) and platencin (cyan). ACIE 2007, 46, Shuli Wipf Group 6 2/16/2008

7 Docking Experiment E. Coli condensing enzyme active site of FabF with docked platensimycin (green) and platencin (cyan). ACIE 2007, 46, Shuli Wipf Group 7 2/16/2008

8 Synthesis of Platensimycin K.C.Nicolaou: 1 st racemic; 1 st asymmetric; chiral pool based synthesis Et 4steps 4steps SmI 2,FIP TFA 46%, dr=2:1 87% TBS Nicolaou intermediate ACIE 2006, 45, ; ACIE 2007, 46, 3942.; ACIE 2008, 47, Barry B. Snider: formal synthesis to core 2 L 2007, 9, Shuli Wipf Group 8 2/16/2008

9 Synthesis of Platensimycin isashi Yamamoto: enantioselective synthesis to core 9 JACS 2007, 129, Arun K. Ghosh: enantioselective synthesis to core 2 L 2007, 9, thers: E.J.Corey: L 2007, 9, Johann Mulzer: ACIE 2007, 46, Krishna P. kaliappan: L 2007, 9, Shuli Wipf Group 9 2/16/2008

10 Two Isosteres of Platensimycin: Synthesized by Nicolaou Group ACIE 2007, 46, ; JACS 2007, 129, Shuli Wipf Group 10 2/16/2008

11 Retrosynthetic Analysis of Platencin 2 C N amidation alkylation to construct quaternary center aldol condensation N 2 TMSE N 2 + homoallyl radical rearrangement SEM S S SEM Michael addition SEM SEM TIPS Au-catalyzed cyclization Shuli Wipf Group 11 2/16/2008

12 Synthesis of Aniline Derivative Previous synthesis: 5 steps, 36% from commercially available compound MM MM N 2 a) Na, MMCl, 82% b) 2, Pd/C, 99% c) Boc 2, 99% N 2 d) nbuli,c()cn,54% MM e) 205 o C, MW, 83% 2 C N 2 MM $ ACIE 2006, 45, Present synthesis: 2 steps, 61% from known compound N 2 a) nbu 2 Sn TMS 61% b) 2,10%Pd/C,100% TMSE N 2 Known P. eretsch, A. Giannis Synthesis 2007, 17, Shuli Wipf Group 12 2/16/2008

13 Synthesis of Tetracyclic Core Bn N C 2 a) BnNC 2, 89% b) TBSTf, 87% c) S 3. Py, DMS N Cl 53% TBS Known d) 5mol% Cr III -salen catalyst 92% TBS Bn e) LA, then aq Cl, 63%, 93%ee f) SEMCl, 94% N C 2 C SEM g) TIPSTf, 97% SEM TIPS K. C. Nicolaou, G. Scott Tria, David J. Edmonds Angew. Chem. Int. Ed. 2008, 47, Shuli Wipf Group 13 2/16/2008

14 Synthesis of Tetracyclic Core (Cont d) SEM h) 2mol% [AuCl(PPh 3 )] 2mol% AgBF 4,94% SEM i) allylmgcl, CuBr. 2 S SEM TIPS 74% j) NaB 4,97% k) KMDS, CS 2,I,100% SEM SEM SEM l) nbu 3 Sn, cat AIBN SEM m) cat PdCl 2, CuCl, 2 50% (2 steps) C 2 S S SEM n) TASF 80% (BRSM) o) TPAP, NM 54% p) Na, 99% Shuli Wipf Group 14 2/16/2008

15 X-ray of emiacetal Intermediate Shuli Wipf Group 15 2/16/2008

16 Completion of the Synthesis q) KMDS, I, 68% r) KMDS, allyl iodide, 86% s) oveyda-grubbs II cat. B B t) 3 N N 2 TMSE v) ATU, 61% C u) NaCl 2 39% (3 steps) C TMSE N w) TASF, 93% N Platencin Shuli Wipf Group 16 2/16/2008

17 Summary First enantioselective synthesis of platencin was achieved in 22 steps (longest linear sequence) with a yield of 0.76% Key transformations are: homoallyl radical rearrangement and Au-catalyzed cyclization Platencin is a potent and dual inhibitor of Fab and FabF; it exhibits broad-spectrum antibacterial activity against many Gram-positive pathogens that show resistance to current antibiotics Future work will involve the synthesis of platencin analogs and the exploration of other synthetic routes toward platencin Shuli Wipf Group 17 2/16/2008