Literature Report 2 Total Synthesis of Caribenol A and Caribenol B Reporter : Xiao-Yong Zhai Checker : Shubo Hu Date : 2017-04-24 Hao, H.-D.; Trauner, D. J. Am. Chem. Soc. 2017, 139, 4117. CV of Dirk Trauner Education: 1986–1991 B.S., University of Vienna 1992–1995 M.S., Free University of Berlin 1996–1997 Ph.D., University of Vienna 1998–2000 Postdoc., Memorial Sloan Kettering Cancer Center 2001–2008 Associate Professor, University of California, Berkeley 2009-2017 Professor, University of Munich and New York University Dirk Trauner Research: chemical synthesis, natural product chemistry, neuroscience, cell biology and photopharmacology. 2 Contents 1 Introduction 2 Total Synthesis of Caribenol A 3 Total Synthesis of Caribenol B 4 Summary 3 Introduction Me H H B C A HO Me Me O O Caribenol A Pseudopterogorgia Isolated from the Pseudopterogorgia elisabethae in 2007; Exhibiting biological activity against Mycobacterium tuberculosis H37Rv and plasmodium; A caged structure and tricarbocyclic ring system with six stereocenters. Wei, X.; Rodríguez, I. I.; Rodríguez, A. D.; Barnes, C. L. J. Org. Chem. 2007, 72, 7386. 4 Introduction Natural products isolated from Pseudopterogorgia elisabethae Me H Me H Me H H Me H O Me O O H Me Me O H O O O OH O Aberrarone Elisabethin A Amphilectolide Me Me Me H H H H OH HO HO Me Me Me Me HO Me O OH O Me O O O Caribenol B Caribenol A Sandresolide B Wei, X.; Rodríguez, I. I.; Rodríguez, A. D.; Barnes, C. L. J. Org. Chem. 2007, 72, 7386. 5 Retrosynthetic analysis of Caribenol A O O CO Me O O O 2 Me Me Me Me Me Me TBSO Me Me A C A OH C A H C B B B H H H H H Me Me Me Caribenol A (1) 2 3 O H Me CO2Me Me CO2Me Me + + Me O I TBSO CO Me Me Me 2 4 7 6 5 Liu, L-Z.; Han, J-C.; Yue, G-Z.; Li, C-C.; Yang, Z. J. Am. Chem. Soc. 2010, 132, 13608. 6 Total synthesis of Caribenol A I PCC-mediated oxidative Me CO2Et rearrangement Me CO2Et o t-BuLi, Et2O, -78 C PCC, CH2Cl2, rt Me Me CO Et O then 2 (89%) (87%) Me Me Me OH Me Me O 5 8 9 o o (1) LiBEt3H, THF, -78 C (1) DIBAL-H, CH2Cl2, -78 C o Me CO2Et o (2) TBSOTf, Et3N, CH2Cl2, -78 C (2) DMP, NaHCO3, CH2Cl2, -78 C o (88%) TBSO (3) n-BuLi, THF, -78 C H CO Et Me Me 2 (72% over 3 steps) 10 HO CO2Me O CO2Me Me Me DMP, NaHCO3, CH2Cl2, rt TBSO (90%) TBSO Me Me Me Me 11 4 CO Me Intramolecular Diels-Alder O 2 Me Me reaction O 120 o 24 h TBSO BHT, toluene, C, O Me Me (92%) Me H OH 3 Me H H Me 7 PCC mediated oxidative rearrangement Me CO2Et Me CO2Et O Me Me Me Me OH OH O R R -Pyridine PCC -Hydrochloride -H2CrO3 O O Cr OH O O O Cr [3,3]-sigmatropic reaction OH R O R 8 Total synthesis of Caribenol A I PCC-mediated oxidative Me CO2Et rearrangement Me CO2Et o t-BuLi, Et2O, -78 C PCC, CH2Cl2, rt Me Me CO Et O then 2 (89%) (87%) Me Me Me OH Me Me O 5 8 9 o o (1) LiBEt3H, THF, -78 C (1) DIBAL-H, CH2Cl2, -78 C o Me CO2Et o (2) TBSOTf, Et3N, CH2Cl2, -78 C (2) DMP, NaHCO3, CH2Cl2, -78 C o (88%) TBSO (3) n-BuLi, THF, -78 C H CO Et Me Me 2 (72% over 3 steps) 10 HO CO2Me O CO2Me Me Me DMP, NaHCO3, CH2Cl2, rt TBSO (90%) TBSO Me Me Me Me 11 4 CO Me Intramolecular Diels-Alder O 2 Me Me reaction O 120 o 24 h TBSO BHT, toluene, C, O Me Me (92%) Me H OH 3 Me H H Me 9 Total synthesis of Caribenol A O CO Me o O 2 (1) Rh(PPh3)3Cl, H2, PhH, 66 C Me Me O (2) HF/Pry,THF, rt Me Me o TBSO (3) NaBH4, CeCl3•7H2O, EtOH, 0 C HO (80% over 3 steps) H H Me H 3 12 Me O O (1) KHMDS, THF (1) TPAP, NMO, 4 Å MS O O Comins -78 oC CH2Cl2, rt Me Me reagent, Me Me Pd/C, H , THF , Me Zn, THF, rt (2) 2 O (2) Pd(PPh3)4 2 Me (86 % over 2 steps) H (77 % over 2 steps) H H H H H 13 Me 14 Me O O O O O2, DMF, K2CO3 Me Me Me Me , 60 o 80 h P(OEt)3 C, Me P(OEt)3 Me O (66 %) O OH H H H H H Me Me 15 Caribenol A (1) 10 Retrosynthetic analysis of Caribenol A Me Me Me H H H H H H cross B C B C C coupling A HO Me A A Me Me Me O O Me O furan O O O oxidation Friedel-Crafts Caribenol A (1) 2 3 Me H 14 steps OH Me gram scale HO Me O 4 (-)-β-citronellol Hao, H-D.; Trauner, D. J. Am. Chem. Soc. 2017, 139, 4117. 11 Total synthesis of Caribenol A Me Me Me H H H (1) (COCl)2, DMSO then NEt3 DIBAL-H OH (92%) HO CO Me Me (2) 2 MeO2C Me Me Ph3P O (86% over two steps) O O 4 5 6 Me Me reductive Myers' allylic H Hoveyda-Grubbs || H transposition method CO2Me Ph3P, DEAD (1) TMSOK IPNBSH (63% over two steps) NEt O Me Me (2) Piv-Cl, 3 then HFIP, H2O (76% over two O NLi O CO2Me O steps) 7 8 Ph O O Me O O Me H H N CuCN, TMSCl, HMPA N O O Ph Me (86%) Ph Me Me MgBr H O H 9 10 O HO Me Me O O 12 Myers' allylic reductive transposition method Me Me H H Me Me OH O O Ph3P, DEAD IPNBSH -N2 Me Me H H HFIP, H2O Me -acetone Me N O -ArSO2H O N O N S O HN Ar O2N O O O S N N N OEt IPNBSH = H DEAD = EtO N O 13 Total synthesis of Caribenol A Me Me Me H H H (1) (COCl)2, DMSO then NEt3 DIBAL-H OH (92%) HO CO Me Me (2) 2 MeO2C Me Me Ph3P O (86% over two steps) O O 4 5 6 Me Me reductive Myers' allylic H Hoveyda-Grubbs || H transposition method CO2Me Ph3P, DEAD (1) TMSOK IPNBSH (63% over two steps) NEt O Me Me (2) Piv-Cl, 3 then HFIP, H2O (76% over two O NLi O CO2Me O steps) 7 8 Ph O O Me O O Me H H N CuCN, TMSCl, HMPA N O O Ph Me (86%) Ph Me Me MgBr H O H 9 10 O HO Me Me O O 14 Total synthesis of Caribenol A O O Me , MeOH O Me H (1) Sm(OTf)3 H (2) HNMe(OMe)•HCl MeO N Me2AlCl N (1) MgBr (94 %) O (76% over two steps) (2) H-G || (77 %) Ph Me Me O 10 O 11 Me Me Me H H H H H H tBu N tBu TMSOK Tf2O (53 % over two steps) Me Me Me O TfO O O Me O Me O 3 12 2 Me Me Barton's protocol iodide H H for vinyl formation H CH3CO3H H (1) N2H4•H2O, Et3N NaOAc then I , TMG 2 (56 %) HO HO (72 %) (2) Me4Sn, AsPh3 Me Me Pd(PPh3)4 (33 %) O Me O Me O O O 13 Caribenol A (1) 15 Barton’s protocol for vinyl iodide formation Me Me H H H H HO HO (1) N2H4•H2O, Et3N, then I2, TMG Me Me (2) Me4Sn, AsPh3, Pd(PPh3)4 O Me O Me O O Caribenol A (5) N2H4•H2O I2 I C O C N C N C N N I C N N NEt NH2 3 NHI I C I I -N2 I C Stille coupling H Me Sn, AsPh I 4 3 Me -H C Pd(PPh3)4 C C C 16 Retrosynthetic analysis of Caribenol B Me Me H H A OH B OH C Me Me HO Me O Oxidation and R O aldol-type ring closure Grignard Caribenol B (14) 15 Me H Me H Me O Me O Vilsmeler-Haack H O CHO α olefination -arylation 16 17 Me Me H H O Me MeO2C Me H O O 18 5 17 Total synthesis of Caribenol B Me Me Me H H H Rh(PPh3)3Cl, H2 DIBAL-H (98 %) O MeO2C Me MeO2C Me Me O O H O 5 19 18 Ph O N O N N Me S Me H N H Bn N tBu N O (40 mol%) H •TFA LiHMDS over CAN, H2O O (26% three steps) α Me Me -Arylation of aldehyde Julia-Kocienski H O Olefination O 17 20 Me Me H H Tos-MIC, t-BuOK POCl3, DMF then MeOH (79%) Me (57%) Me Vilsmeier-Haack O Van Leusen Reaction Reaction O O CN 21 16 H 18 α-Arylation of aldehyde Me Me H H O O Me Me H O H O O O O Me H O N H O H2O t Bn N Bu H2O R1 R2 H N O R1 R2 N O CAN R1 R2 N O CAN R1 R2 N O R1 R2 N O -H H 19 Total synthesis of Caribenol B Me Me Me H H H Rh(PPh3)3Cl, H2 DIBAL-H (98 %) O MeO2C Me MeO2C Me Me O O H O 5 19 18 Ph O N O N N Me S Me H N H Bn N tBu N O (40 mol%) H •TFA LiHMDS over CAN, H2O O (26% three steps) α Me Me -Arylation of aldehyde Julia-Kocienski H O Olefination O 17 20 Me Me H H Tos-MIC, t-BuOK POCl3, DMF then MeOH (79%) Me (57%) Me Vilsmeier-Haack O Van Leusen Reaction Reaction O O CN 21 16 H 20 Julia−Kocienski olefination The Julia Olefination enables the preparation of alkenes from 1- phenyl-1H-tetrazol-5-yl sulfone and aldehydes in a single step.