Creativity From the Chiral Pool Baran Group Meeting Part 1: Carvone Brandon Rosen A useful reference Some Basic (Obvious) Transformations of Carvone Enantioselective Synthesis: Natural Products From Chiral Terpenes by Tse-Lok Ho O H2O2, NaOH MeOH O O O 70 - 100% H OH LAH, Et2O (R)-(-)-carvone (S)-(+)-carvone 70 - 100% Spearmint oil Caraway seeds $0.29/g $2.58/g $43.56/mol $386.82/mol O H2, Wilkinson's cat. or H2, PtO2 Industrial preparation of (-)-Carvone: 82 - 100% See "Fragrances and Flavors", Ullman's Encyclopedia of Industrial Chemistry. O NO NOH O Zn, EtOH NOCl Base H O+ 3 O 50% Cl O (+)-limonene t-BuOCl (-)-carvone Cl 86% Fleming's Total Synthesis of (±)-Carvone Fleming, Synthesis, 1979, 736. O AcCl, MeOH BrMg O 96% O 1. LDA OTMS O Cl 2. TMSCl DDQ TMS 97% 73% CuCl O 85% TiCl4 TMS Et3N, TMSCl 82% "The beauty of this route is the 87% H simplicity with which functionality O has been introduced selectively on O to each side of the unsymmetrical OTMS KMnO4 HO O ketone 1". DDQ 52% CO2H Page 1 Creativity From the Chiral Pool Baran Group Meeting Part 1: Carvone Brandon Rosen An Overwhelming Sample of Carvone-Derived Syntheses Hapalindole Q Baran, JACS 2004, 126, 7450. O H O O O NCS HO O LHMDS, then [Cu] 4 steps O + O OH N N H 53% H Cyperolone Kirsch, 2012 O H H N Hapalindole Q Picrotoxinin HO H Baran 2004 Trost, 1999 O CO2H (N)-Methylwelwitindolinone C Isothiocyanate HO AcO OH Garg, JACS 2011, 133, 15797. H OH 7-deacetoxyalcyonin acetate N CO2H NCS H Overman, 1995 1. LAH O 2. PivCl OPiv Kainic Acid O H O 3. CrO3 3 steps N Fukuyama, 2011 AcO H CHO OH OMe Hapalindole Q H H 4. NaOMe HO Cyrneine A O Gademann, 2012 5. vinyl-MgBr, O CuBr•DMS Guanacastepene E OH Sorensen, 2006 OH OTBS Peribysin E O Cl TBSO Danishefsk, 2008 OAc H H Valerianonoid A O O 13 steps NaNH Srikrishna, 2004 2 SCN H O H O MOMO O O HO O 46% Br O O O O Cubitene OH N N Lindel, 2012 O H N BnO O H O (N)-Methylwelwitindolinone C HO OEt Salsolene Oxide Trilobolide Isothiocyanate HO CP-263,114 core OH Paquette, 1997 Ley, 2003 Yoshimitsu, 2000 HO Cyperolone HO HO H OH Kirsch, Org Lett 2012, 14, 1250. HO O H H O OTIPS HO O OTES OH O 6 steps PtCl , cod OH OH 4 O R O Ryanodol C7H15CO2 80% H H Deslongchamps, 1979 O OTES O O H H Briarellin F [M] Overman, 2003 Samaderine Y OH OH Shing, 2005 H O OH N CO2H OTIPS O O O H OH HO 8 steps H H Platensimycin O Lee, 2009 HO O O Omphadiol Chinensiolide B O Romo, 2011 Hall, 2010 Cyperolone Page 2 Creativity From the Chiral Pool Baran Group Meeting Part 1: Carvone Brandon Rosen Kainic Acid Fukuyama, Org Lett 2011,13, 2068. O I I MeO2C O O 1. H2O2, NaOH 1. NaClO2, 1. Me2NCH(OMe)2 O O HO 2. H2SO4 O NaH2PO4 O 11 steps Ac2O HO O H 3. NaIO 2. MeOH, ∆ O 2. LHMDS, TBHP 4 OH 4. I , KI O MeO2C 2 CHO NHCO2Me Br PhO P N O Hectogram Scale 3 OPh Name rxns? 3 steps 5 steps O O O "In view of the ease of the entire CO t-Bu operation and the use of the 2 HO O CO H readily available and inexpensive 2 4 steps O O reagents, we are convinced that O our synthetic route alone would O OH OH N CO2H N satisfy the global demand for (-)- H O O CO2Me Kainic Acid." Kainic Acid Corianin Picrotoxinin 7-Deacetoxyalcyonin Acetate Overman, JACS 1995, 117, 10391. Picrotoxinin and Corianin Trost, JACS 1996, 118, 233. OHC I Trost, JACS 1999, 121, 6131 and 6183. O 1. H2 O TMS 2. LDA, PhN(Tf)2 1. t-BuLi, OMe Br 3. Me Sn , [Pd] 2. PPTS O 1. LDA, CH2O CN 6 2 R3SiO NIS 2. TBDMSCl Br O 3 steps O 3. LiCH2CN H 4. C5H5NHBr3 OSiR3 OH H CHO OSIR3 OHC OTIPS CO2H 9 steps Pd(OAc) O OH TMS PPh2 P 2 Ligands BF3•OEt2 P 70 % OTIPS TMS Name rxn? Br MeO2C 7 steps O 1. NiCl2-CrCl2 R3SiO H H H H 2. Ac2O H H R SiO HO O O 3 O O MeO2C R SiO OSiR 3. TBAF Br 3 Br 3 I OSIR3 Name rxn? AcO OH O Name rxn? 7-deacetoxyalcyonin acetate Page 3 Creativity From the Chiral Pool Baran Group Meeting Part 1: Carvone Brandon Rosen Briarellin F Guanacastepene E Overman, JACS 2003, 125, 6650. Sorensen, JACS 2006, 128, 7025. O 1. 9-BBN, then 1. LDA, TMSCl, then O 1. H2, PtO2 O O OHC NaOH, H2O2 AcOH 2. LDA, MeI O 1. NaCN OH 2. TEMPO, NCS 2. LAH (> 20:1 d.r.) 3. O3, then H2, Pd/C 2. EDCI H OH H O O CN H H 1. NfF LHMDS O SnMe3 OH O O HO OH 2. [Pd], (Me3Sn)2 58% O C7H15CO2 O Briarellin F O PMP Cyrneine A [Pd] AcO O Gademann, ACIE 2012, 51, 4071 87% OTBS O TBSO 4 steps 3 steps O O PMP O O PMP O hv O 1. SmI2 O O CHO 82% 2. PhSeBr 3. mCPBA Name rxn? 175 °C 81% TBSO O O O PMP H O TBSO AcO 5 steps OH 1. PhNTf2 TBSO CHO O 2. CrO 8 steps H OTBS 3 TBSO 3) [Pd] O Guanacastepene E O Cladantholide 1. CH Br , LiTMP 2 2 Lee, JACS 1997, 119, 8391. 2. BuLi O 1. H2O2, NaOH O 2. LiCl, TFA Cl NaOMe MeO C OTHP TBSO HO 2 OTBS 3 steps OH 3) DHP, PPTS OTHP 95% Name rxn? O CHO Cyrneine A Page 4 Creativity From the Chiral Pool Baran Group Meeting Part 1: Carvone Brandon Rosen Upial Taschner, JACS 1985, 107, 5570. O O O OMe O MeO2C OTHP 3 steps THPO Bu3SnH 4 steps H 4 steps O 99% Br Name rxn? EtO HCl 70% HO H H 1. TsOH, MeOH 4 steps O 2. PCC THPO H H 1. MeMgBr 2. OsO , NaIO H 3. LDA, TMSCl H 4 4 O 4. DMDO O 3 steps 3. KOCl, MeOH O OMe OEt O OH Name rxn? OHC O 4. Swern MeO2C 5. SOCl2 O H O Upial Name rxn? H H Omphadiol O Romo, ACIE 2011, 50, 7537. O O [Mn(dpm)3] O - Cladantholide OH O PhSiH3, O2 1. H5IO6 O Thapsigargins PPY+ 63% 2. TsCl, 4-PPY Ley, ACIE 2003, 42, 5996 See "Steven Ley" group meeting OMOM H MeO C OTHP 12 steps 2 Grubbs O TBDPSO OH O 92% Grubbs 2 steps O 3 steps O H OEt OTES H 95% O Br OAc O H O OMOM H O HO O OH OH TBDPSO 1. tBuLi, DIBAL OH H O H OH H OEt 2. Et Zn, CH I OTES H 2 2 2 H O Name rxn? Omphadiol Thapsivillosin F Page 5 Creativity From the Chiral Pool Baran Group Meeting Part 1: Carvone Brandon Rosen TBSO HO O Salsolene Oxide TBSO O HO Paquette, JACS 1997, 119, 2767. AcO 5 steps OH See "Leo A. Paquette" group meeting O O H H H H O 1. H2, Pt Br O OMe O O 2. O 5 steps (COCl) H H H H 3 CO H 2 2 Samaderine Y CO2Et 3. NaBH4 Et3N, ∆ 4. HBr, EtOH 57% Platensimycin Lee, JACS 2009, 131, 8413. O O O 1. LAH 1. SeO2 Bu3SnH SPh O O 2. NBS Br 2. PCC Br CHO 81% Salsolene Oxide Samaderine Y Shing, ACIE 2005, 44, 7981. 3 steps TMSC(Li)N2 3 steps See "Traditional Chinese Medicine" group meeting O O O 65% CHO O O O O 1. LDA, CH2O 1. TBSOTf 2. (OMe) CMe 2. TBHP, NaOH 2 2 O 3. CrO 3 NaBH , CeCl 3 4 3 OH H 4. NaBH4, CeCl3 OH O O N CO2H O O O TBSO O MgBr TBSO O HO O TBSO TBSO TBSO 1. TFA 1. 2. TBSOTf Platensimycin O OH Peribysin E 2. NaH, crown ether O 3. NMO, TPAP Danishefsky, JACS 2008, 130, 13765 3. Ac O O O OAc 2 O O O PhMe, 180 °C OTMS 1. EtAlCl2 7 steps 62% 2. Pd(OAc)2 O O H H TBSO TBSO TBSO O O O O TBSO TBSO 1. MnOAc , TBSO 1. EtAlCl2 O 3 AcO 6 steps TBHP OTES 2. SiO2 O Adduct not available through O Robinson Annulation! H H H 2. MnOAc3, ∆ H H 3. Pd(OAc)2 O OAc O OMe O OMe H H H H H Page 6 Creativity From the Chiral Pool Baran Group Meeting Part 1: Carvone Brandon Rosen Carvone-Derived Diene Ligands Carreira, JACS 2004, 126, 1628. 1. OsO4, NaIO4 TMSN3 Carreira, Org Lett 2004, 6, 3873. O 2. mCPBA AcO O I2 ~ 1:1 d.r. H H O OMe OMe 1. NBS, MeOH 1. LDA, PhNTf2 2. KOtBu 2. ArZnCl, [Pd] O OTBS 3 steps OTBS Suzuki I O Ar TESO OTES AcO O 89% AcO O ~ 1:1 d.r. H H H 1. iBuLi 1. NBS, MeOH OMe TiCl4 2. PCC 2. KOtBu 50% O O H OTBS H OMe 1. LDA, allylBr HO HO 2. LiNEt , PhNTf HCl, MeOH O 2 2 CHO 3. [Pd], HCO2H 80% OH OH OMe ent-Peribysin E Ecklonialactones A and B Fürstner, JACS 2010, 132, 11042.