Total Synthesis of Cyanolide A in the Absence of Protecting Groups, - - PowerPoint PPT Presentation

Total Synthesis of Cyanolide A in the Absence of Protecting Groups, Chiral Auxiliaries, or Premetalated Carbon Nucleophiles

Wipf Group Current Literature Brandon Parks March 23rd, 2013

O O O O MeO MeO OMe O O O O O O OMe OMe OMe

Waldeck, ¡A.R.; ¡Krische, ¡M.J. ¡Angew. ¡Chem. ¡Soc., ¡2013, ¡52, ¡1. ¡

Cyanolide A

Ø Isolated cyanobacterium Lyungbya bouillonii in 2010 Ø Related to the clavoslide family of natural products Ø Possesses significant molluscicidal activity (LC50 = 1.2 µM) against

Biophalaria glabrata (water snail) involved in schistosomiasis

O O O O MeO MeO OMe O O O O O O OMe OMe OMe Pereira, A.R.; McCue, C.F.; Gerwick, W.H. J. Nat. Prod. 2010, 73, 217.

Schistosomiasis

Ø Caused by a parasitic worm often carried by Biophalaria glabrata

(water snail)

– ~200 million people are currently infected

Ø Leads to organ damage, impaired growth and cognitive

development in children, associated with increased risks of bladder cancer

Ø Several treatments are known but have several side-effects

N N O O praziquantel Cl OH N H O Cl NO2 niclosamide

Chitsulo, L.; Engels, D.A.; Montresor, S.L. Acta Trop. 2000, 77, 41.

Floreancig Retrosynthesis of Clavsolide A

Peh, G.; Floreancig, P.E. Org. Lett. 2012, 14, 5614.

O O O O MeO MeO OMe O O O O O O OMe OMe OMe O X OPG OH O X OPG OAc LG X + HO OPG H

• xidative cyclization

dimerization

Precursor Synthesis

TMS OMs + H O OTIPS Et2Zn, Pd(OAc)2 Ph3P CH2Cl2, -20 °C 82% 8:1 d.r., 85% ee HO OTIPS TMS H

• 1. NaH, 15-C-5, THF;

A, 0 °C, 63%

• 2. [(p-cymene)RuCl2]2

HOAc, Na2CO3, toluene 80 °C, 6 (B, 55%) or 12 h (C, 69%) O OTIPS H AcO OAc O OTIPS H + OAc B C A OMs [CpRu(NCCH3)3]PF6 PhMe2SiH acetone 71% O OTIPS H OAc PhMe2Si

Key Oxidative Cyclization

O OTIPS H OAc PhMe2Si O OTIPS PhMe2Si O DDQ, LiClO4 2,6-Cl2Py DCE, 40 °C, 6 h 51% O OTIPS H AcO OAc DDQ, LiClO4 2,6-Cl2Py DCE, 1.5 h 62% O OTIPS AcO O 6 steps clavosolide A 14 steps (LLS), 20 total steps

Rychnovsky Retrosynthesis of Cyanolide A

Gesinki, M.R.; Rychonovsky, S.D. J. Am. Chem. Soc. 2011, 133, 9727.

O O O O MeO MeO OMe O O O O O O OMe OMe OMe OH TMS O O CH(OMe)2 O O H O OH TMS O O H O OH TMS OH TMS HO O OH CH(OMe)2 Sakurai dimerization/ macrocyclization esterfication

Rychnovsky “Monomer” Synthesis

EtO OEt OEt O

• 1. LiCH2TMS

97%

• 2. KHMDS, PhNTf2

97% EtO OEt OTf

• 1. ClMgCH3TMS

Pd(PPh3)4 87%

• 2. pTSA · H2O

97% H O TMS S N S O +

• 1. (-)-sparteine

PhBCl2 70%

• 2. LiOH

91% OH TMS HO O O n-BuLi 100% (MeS)2CH2 OH CH(SMe)2 I2, MeOH 62% OH CH(OMe)2 OH TMS HO O + OH TMS O O CH(OMe)2 Cl3PhCOCl DMAP, Et3N 61%

Rychnovsky Formal Total Synthesis

OH TMS O O CH(OMe)2 TMSOTf CH2Cl2 76% O O O O H H O O O O O O O H H O O O OsO4, NMO; NaIO4 82% NaBH4 96% O HO O O O H H O O OH Ref. cyanolide A

Krische First Generation Synthesis

OH OH [{Ir(cod)Cl}2] (5 mol%) chiral ligand (10 mol%) 4-Cl-3-NO2-BzOH (20 mol%) Cs2CO3 (40 mol%) dioxane, 100 °C AcO (1000 mol%) OH OH (s)-Cl,MeO-biphep 48%, 20:1 d.r., >99% ee (S)-binap (gram scale) 40%, 20:1 d.r., >99% ee iPrO Ru Cl Cl NMes MesN (10 mol%) O (2000 mol%) DCE, 80 °C O OH EtOC COEt 75%, 10:1 d.r. iPrO Ru Cl Cl NMes MesN (10 mol%) ethylene (1 atm) toluene, 60 °C O OH EtOC 70% O PhS OMe OMe OMe (150 mol%) O O EtOC MeOTf (40 mol%) 4 Å M.S. (200 wt%) Et2O O OMe OMe OMe 69%, 2:1 d.r.

Waldeck, A.R.; Krische, M.J. Angew. Chem. Int. Ed. 2013, 52, 1. Iridium-Catalyzed Carbonyl Allylation: Kim. I.S.; Ngai, M.Y.; Krische, M.J. J. Am. Chem. Soc. 2008, 130, 14891.

Krische First Generation Synthesis

O O EtOC O OMe OMe OMe Li(sBu)3BH (100 mol%) THF, -78 to 25 °C O O O OMe OMe OMe HO 73%, 4:1 d.r. O O O OMe OMe OMe HO CO2H OsO4 (1 mol%)

• xone (400 mol)

DMF MNBA (300 mol%) DMAP (2000 mol%) toluene, 90 °C 18 % (over 2 steps) O O O O MeO MeO OMe O O O O O O OMe OMe OMe cyanolide A 7 steps (LLS), 11 total steps

Krische Second Generation Synthesis

O OH EtOC COEt O PhS OMe OMe OMe (150 mol%) MeOTf (40 mol%) 4 Å M.S. (200 wt%) Et2O O O EtOC O OMe OMe OMe COEt 68%, 2:1 d.r.

• zone

THF, -78 °C; Li(sBu)3BH (1000 %) THF, -78 to 25 °C O O HO O OMe OMe OMe HO TEMPO (30 mol%) NaOCl (225 mol%), NaHCO3(aq) CH2Cl2, 0 °C; iosbutylene (1400 mol%), NaClO2 (225 mol%), Na2HPO4(aq), NaBr(aq), tBuOH O O HO O OMe OMe OMe O HO 71%, 5:1 d.r. 62% 1,3,5,-Cl3-BzCl (120 mol%) Et3N (140 mol%) DMAP (500 mol%) toluene, 120 °C 47% cyanolide A 6 steps (LLS), 10 total steps

Conclusions

Ø Shortest route (6 steps LLS) to cyanolide A to date in 5.1% overall

yield

Ø Showcases an enantioselective Ir-catalyzed carbonyl allylation

methodology utilizing alcohols

Ø Demonstrates a Ru-catalyzed cross-metathesis/oxa-Michael

cyclization