Baran lab Group Meeting Shigenobu Umemiya Keisuke Suzuki 6/11/16 Akira Suzuki 1978 Ph.D., Teruaki Mukaiyama, University of Tokyo 1983 Assistant Professor, Keio University Pd0 (cat.), ligand, base 1987 Lecturer, Keio University R1 X R2 BY R1 R2 1989 Assocate Professor, Keio University 2 1990 Visiting Professor, ETH Takanori Suzuki (Hokkaido University) 1994 Full Professor, Keio University 1996 Full Professor, Tokyo Institute of Technology Award (Selected) 1986 The Chemical Society of Japan Award (for young chemist) 1999 Nagoya Silver Medal Award 2003 The Society of Synthetic Organic Chemisty, Japan Award 2008 Humboldt Award (Germany) 2008 The Chemical Society of Japan Award 2010 Medal with Purple Ribbon 2014 Japan Academy Prize ACIE, 2014, 53, 780.
Eiichi Nakamura Shu Kobayashi Isamu Shiina Nobuharu Iwasawa (University of Tokyo) (University of Tokyo) (Tokyo University of Science) (Tokyo Institute of Technology) ligand NO2 O O NO2 OH O O OTMS Pr(OTf) 3 N CO2 N Me O R R' R R' aq. EtOH ligand Me Me Me H [Rh], [Al] CO2H Science, 2001, 291, 1944. JACS, 2003, 125, 2989. CL, 2002, 286. JACS, 2011, 133, 1251. Kouichi Narasaka Yujiro Hayashi Masahiko Yamaguchi (Tohoku University) NaBH4 (Tohoku University) Et B(OMe) Ph Ar OH O 2 OH OH Takahiko Akiyama Ph Ar (Gakushuin University) R R' R R' N N H OTMS H OH R Tetrahedron, 1984, 40, 2233. ACIE, 2005, 44, 4212. Masahiro Murakami ACIE, 2008, 47, 2082. O O (Kyoto University) O P O Ouyou Mitsunobu O O OH PPh [Rh] 3 cat. [Rh] OH O O R3 DEAD R 1 2 3 ACIE, 2004, 43, 1566. Ph Ph R R HO R R1 R2 Nature, 1994, 370, 540. BCSJ, 1967, 40, 935. Shigenobu Umemiya Baran lab Group Meeting Keisuke Suzuki 6/11/16 ·Asymmetric pinacol-type rearrangement O OR TMS R=BOM OH 1 MsCl, Et N Et Al R 3 3 Me Me R2 Br O R2 o o O O n DCM, 0 C DCM, -78 C H R1 BuLi HO H Me Me Me R1=aryl, vinyl OEt NMe >99% ee R1 2 then H SO Me 2 4 OR' TMS OR R2 OH OEE O O 92% R'=H O quant. Me Me Me O H O R'=Ms Ph Ph Ph OH O S AlEt2 Et Al TMS OH H Ph H Ph H O DIBAL-H 3 Me Me 83%, >99% ee 77%, >99% ee 75%, >99% ee DCM RO DCM OMs TMS OBOM o o Tetrahedron Lett. 1983, 24, 4997. -78 oC -78 C to -20 C 85% (3 steps) TMS O O 3 steps HO MsCl, Et3N Me3Al 1) (COCl)2, DMSO OR TMS OH Me Me o OEE O NMe Et3N, -78 C 2 DCM, 0 oC DCM, -78 oC EEO H HO H 88% 2) MeCH=CHCH2Br o O CrCl2, 0 C TMS O TMS OH 72% Me LiBEt3H R2 O HO Et TMS O Et3Al H o Me OR Me H THF, -78 C Me H Me NMe RO Et TMS 95% 2 DCM O OEE OMs TMS -78 oC Me OPh 80% O O H OEE HO O
Me H (+)-eldanolide A Tetrahedron Lett. 1985, 26, 861. ·Total synthesis of protomycinolide IV O OH OH O O 9 O 8 A 5 O 8 6 OH n-BuLi O 1 OEE O 9 4 4 6 O RO 5 Et Et Me hexane OEE O OEt o Et 0 C OEE O 1 OH OH O 91% 14 14 15 O RO 15 protomycinolide IV J. Am. Chem. Soc. 1986, 108, 5221. Baran lab Group Meeting Shigenobu Umemiya Keisuke Suzuki 6/11/16
·Epoxy silyl ether rearrangement ·Cp2ZrCl2-AgClO4 -an efficient activator of glycosyl fluorides 3 R OH O Me Me O Cp2MCl2 1 TiCl4 1 Me O O R OTMS R AgClO4 AcO AcO R5 AcO O OR o R2 F ROH 2 4 5 DCM, -78 C 3 4 MeO MeO R R R R R MeO DCM MeO OR MeO MeO α β O Me OH Me ROH = cyclohexamethanol O O OTMS Me OTMS OTMS O substrate Entry Metallocene Conditions Yield α : β Ph Me Et TMS OBn TMS o 1 Cp2TiCl2 0 C, 2 h 90% 1 : 1.8 2 Cp ZrCl o 90% 1.2 : 1 OH O OH O OH O OH O 2 2 -20 C, 5 min Me o 3 Cp2HfCl2 -20 C, 30 min 86% 1.7 : 1 product Me Me Me Et OBn Ph H Cp ZrCl Me Me TMS TMS Me 2 2 AgClO AcO O AcO O AcO O 4 OtBu 95% 85% 86% 79% F tBuOH MeO MeO J. Am. Chem. Soc. 1986, 108, 3827. MeO solvent MeO OtBu MeO MeO ·Co-complexed alkynyl group -an excellent migrator- α β
MsO Ph O Solvent Conditions Yield α : β OH Me3Al n n Bu Bu DCM -20 oC, 40 min 93% 1.4 : 1 DCM Ph (OC)3Co Co(CO)3 -78 to -50 oC (OC)3Co Co(CO)3 PhH 20 oC, 30 min 59% 0 : 1 75% Co-complex >> Ph Caution : AgClO4 is potentially explosive. Tetrahedron Lett. 1988, 29, 3567. n Bu Modified condition : Cp2HfCl2, AgOTf (less reactive but much safer) 1) Co(CO)3 Angew. Chem. Int. Ed. 2005, 44, 3871. 2) TMSOTf, DCM Me nBu Me O 3) CAN, MeOH ·Total synthesis of mycinamicin IV Me Ph Me O OR Ph AcO O OTMS 90%, 3 steps OH O F OMe J. Am. Chem. Soc. 1996, 118 , 8949. OR O OMe ·Glycosylation -one of the oldest but unresolved problems- NO2 Cp2ZrCl2 Et X X = F, Cl, Br, I, AgClO4 O SPh, SO Ph, NH O 2 S Et O P(O)(OPh) , PhH, rt Me 2 O O 21 OAc, OMs, O CCl3 N AcO O glycosyl O O 86% SePh, etc. donors O 21 OMe O OMe mycinamicin IV Review, see; HO R=sugar O :Chem. Rev. 1993, 93, 1503. Schmidt Mukaiyama C :Tetrahedron 1998, 54, 9913. ACIE, 1980, 19, 731 CL, 2003, 32, 442. Tetrahedron Lett. 1988, 29, 3575. Baran lab Group Meeting Shigenobu Umemiya Keisuke Suzuki 6/11/16
·Rearrangement of O-Glycoside to C-Glycoside ·[2+2] cycloaddition of benzyne and ketene silyl acetal OBn OBn OBn OH n OSiR3 O O I RO OSiR3 BuLi Step 1 Step 2 OR O O F o R' R' O OTf R' R' THF, -78 C HO R' R' 64-90% OH 50 mol% TMSO OMe Synlett 1995, 177. MeO MeO OAr MeO Ar R=Me, Et, alkyl activaor O O R'=alkyl, OEt O F DCM, -20 oC OTBS inductive MeO OMe MeO OMe MeO OMe effect OBn OMe BF ·OEt 71% 14% 1) aq. HF OBn 3 2 OBn - SnCl 67% 11% OMe 2) (MeO)3CH OMe δ 4 PTSA CpHfCl2-AgClO4 - 76% OTMS OMe δ+ Tetrahedron Lett. 1988, 29, 6935. 3) SO ·Py, Et N ·[2+4] cycloaddition -an efficient generation of aryne- 3 3 OTBS DMSO O OR OR OMe MeO OR OMe Helv. Chim. Acta 2002, 85, 3589. I nBuLi O O ·SmI2-mediated pinacol cyclization THF, -78 oC OTf R 10 min Conditions R R=Me, MOM, Bn 74~82% OH Tetrahedron Lett. 1991, 32, 6735. 0 oC ·Total synthesis of (+)-gilvocarcin M CHO OH CHO OBn CHO CHO OH Cp2HfCl2 I Chiral BnO H OBn AgClO4 Entry Reductant Yield trans/cis Transmission Me I BnO H O 4ÅMS OAc Me OH R BnO O R 1 SmI2 99% >99 : 1 DCM BnO OTf OH o o BnO -78 C to -20 C 2 SmI2, HMPA 93% >99 : 1 BnO 87%, = 8:1 3 TiCl , Zn 96% 20 : 1 α:β 4 OH MeO OBn OMe OH OMe 4 TiCl4, Mg(Hg) 94% 16 : 1 OH
CO2Me O OMe CO2Me MeO Me BnO H HO H MeO Me MOMO Me 3 steps Me nBuLi O O MOMO SmI2 OH O BnO HO Me THF o >99% ee O THF, 0 C OH -78 oC HO CHO BnO (+)-gilvocarcin M CHO 85% OH J. Am. Chem. Soc. 1992, 114 , 3568. >99% ee Angew. Chem. Int. Ed. 1999, 38, 1226. Baran lab Group Meeting Shigenobu Umemiya Keisuke Suzuki 6/11/16
·Total synthesis of TAN-1085 achiral chiral OAc HO O O OH BnO OMOM BnO CO2Me Me RO R' MeO MeO RO RO R' RO OBz BF3·OEt 2 OH OBz OBz OH O O OH O DCM BnO MeO OH BnO MeO OH 95% Me O OR OR OH OR OR O BnO CO2Me BnO CO2Me MeO MeO OH TAN-1085 OMOM OMOM including separation OBz OBz tBuLi O OR BnO MeO OR BnO MeO OR OR Et2O BnO BnO R=sugar MeO 1:1 mixture HO OMe then O OH I MeOTf BnO OMe MeO OH OBn OMe OR OR 85% from OMe 1) CAN, aq. MeCN [2+2] cycloaddition R=TBDPS OBn OH 2) H , Pd/C, MeOH OMOM OH 2 OH O O BnO MeO O 53% (2 steps) Me O (COCl) BnO OR 2 MeO Me O OH DMSO OH BnO TAN-1085 Et3N MeO OH Angew. Chem. Int. Ed. 2004, 43, 3167. DCM O ·Amine-promoted cyclocondensation -synthesis of isoxazoles- -78 to 25 oC OMe OH BnO MeO O 1 1 O N O MeO R NOH NCS R O R1 OMe N Et N Et3N C 3 OBn 6π cyclization H EtOH R2 DCM O R2 R2 O rt BnO OR rt BnO OR MeO stable 71~87% MeO MeO NCS 95~99% 1 pyridine R =OMe, OMOM, Me Tetrahedron Lett. 2003, 44, 3555. SmI2 2 1 R =OMe,Br, etc. 5 R NOH then 6 O ·previous work R NOH O OBz fast 3 BzCl MeO O SmIII Cl R3=OMe,Br, Me MeO O BnO MeO OH decomp. Cl 86% III Sm 2 62~83% yields R=MOM pinacol cyclization R unstable Org. Lett. 2003, 5, 391. Org. Lett. 2003, 5, 391. Baran lab Group Meeting Shigenobu Umemiya Keisuke Suzuki 6/11/16
·Intramolecular aldehyde-ketone benzoin reaction ·Total synthesis of BE-43472B 20 mol% Me Et OH O OH OH N O N Br MOMO N O OH N O HO MOMO S Me Me DBU H H O O O O t o O Me O Me O BuOH, 40 C 95% HO O O HO HO MeO N O MeO N O MeO N O
Me O O Me Me Me Me Me BE-43472B HO HO HO OR N O O O CO2Et O N O OR N O 90%, dr=>20:1 79%, dr=>20:1 96% OR J. Am. Chem. Soc. 2003, 125, 8432. Me ·Isoxazole-directed pinacol rearrangement O OH O O Me CO2R OBn N O OBn N O OBn N O O 20 mol% HO CO2R BF ·OEt MeO Li 3 2 OMe OR OR NOH Cl Br THF DCM, 0 oC Cl OH OH O OH O H OMe 98% ee 99%, 98% ee 96%, 98% ee OMe 3M H2SO4 no racemization THF, 40 oC OBn N O OBn N O OMe OMOM TMS Cl Br OMe N O BF3·OEt 2
OH O O OMe N O OMe Me 94%, 60% ee 92%, 0% ee t HO OH n BuLi MOMO CO Et OBn N O Bu 2 o R = Co Co Me THF, -78 C MeO nBu OH Me (CO)3 (CO)3 O CO2Et quant. 92% 95% 86% 82% Cl OMe R 98% ee 98% ee 71% ee 96% ee O single isomer Angew. Chem. Int. Ed. 2007, 46, 3252. Baran lab Group Meeting Shigenobu Umemiya Keisuke Suzuki 6/11/16
OMe N O OMe N O OMe N O OMe N O OMe N O nBuLi THF/DMPU -100 oC; TfOH Me Me CSA Me Me PhSeBr Me HO OH H H H MOMO CO Et HO O CO Et O O O O O O 2 DCM 2 MeO PhMe MeO O MeO Me then MeO Me rt reflux MeO aq. H2O2 96% Cl 98% Cl Cl Cl Cl OMe pinacol 70% (2 steps) rearrangement OMe OMe OMe OMe 88% CAN-SiO2 O OBoc N O OMe N O OMe N O N O OTMS OCHO N Br Me S OMe O Me Me Br O Me O H O H Me H H HCOOH O O O O O Me O Me PhH/DCM O Me BocO HO N O DCM, 0 oC 0 oC to rt Cl Br 94% OCHO O O O Me Me Me H ·Regioselective C-glycosylation
OH OH O Me OAc Lewis acid (30 mol%) Drierite OBoc N O OH O OH Me O 10 NCOCF3 DCM Na CO BnO o o 2 3 O OH H (1 eq.) -30 C to -10 C MeOH, rt Me Me 8 (2 eq.) 77~82% H H O O O O Me 83% (2 steps) BnO O O Me O Me OH OH O OH OH O N3 BocO HO sugar OAc sugar 10 Sc(OTf)3 (50 mol%) Drierite, DCM O O 8 -30 oC to -10 oC Me Me C10: C8 : both sugar BE-43472B 98% TMSOTf 52 : 27 : 21 Angew. Chem. Int. Ed. 2013, 52, 6658. Sc(OTf)3 >95 : nd : nd Angew. Chem. Int. Ed. 2014, 53, 1258. Baran lab Group Meeting Shigenobu Umemiya Keisuke Suzuki 6/11/16
·Total synthesis of saptomycin B ·Catalytic generation of arynes Me I Li Me OAc fast Me nBuLi (1) Me O OTf OTf N3 OH nBuI LiOTf OH O O BnO Me 10 sp3 sp2 : favorable Li O O Me I slow NMe OAc (2) 2 8 R Li HO Me O OTf O OTf 2 O Me sp sp : unfavorable LiOTf saptomycin B R I Me N3 OAc BnO ·Proposed mechanism NMe Me R Li BnO 2 O I I Me (catalytic) N3 BnO OTf R I Nu OH OH O OH OH O Sc(OTf)3 (30 mol%) Me Drierite 10 Me O Li Li o N DCE, -30 to 10 C BnO 3 Me Me Me OH OH O 82% OTf Nu BnO O Me N3 10 Me O OAc N3 BnO Me LiOTf Sc(OTf)3 (50 mol%) 8 Nu (stoichiometric) Drierite O OBn o OBn 30 mol% DCE, -30 to 28 C Me I I 96% TMS Li N3 t BnO BuO2C Li Me THF OTf Me o CO tBu OH OH O OH -78 to -60 C 82% 2 Me 10 10 mol% OBn pKa (H2O) Me O O TMS Li 5 Me K2CO3 I H H 24 N3 BnO Me O 8 Li H MeOH 5 O 96% Me 20 77% Me Me saptomycin B N BnO 3 Angew. Chem. Int. Ed. 2014, 53, 1262. Angew. Chem. Int. Ed. 2012, 51, 3368. Baran lab Group Meeting Shigenobu Umemiya Keisuke Suzuki 6/11/16
·Total synthesis of (+)-Cinnamtannin B1 OBn Br OBn OH Br BnO O OBn BnO O HO O O Ar OBn OH OH O OR O OH OTBS OH OH OH OBn OBn O OH O R=TBS BnO OBn not detected O OH OH (less stabilized than A) O 93%
Ar OBn OH Br OBn HO Br HO OH putative BnO O OH OBn BnO O biogenesis O OBn (+)-cinnamtannin B2 O O OTBS O Ar OR O Ar OBn BF ·OEt 3 2 OBn O OH OR OH OH OH DCM O Ar O OBn 91% their SXy O OBn OH strategy O OR O OR BnO Ar SXy R=TBS a possible precursor OBn Ar OTBS Xy=2,6-xylyl BnO OR1 ·Model study OR OR Br OBn (1.2 eq.) DDQ R1O O RO O RO O NBS OR1 OR1 OR (CH2OH)2 OR O O OR1 DCM OR2 OTBS DCM -10 oC I2, Ag2O, 4Å MS, DCM O OTBS o OR1 OR reflux OR -78 to -40 C 69-81% 95% O OH OH R=Bn OH O 96% OBn unreactive OR Br BnO O Br O OBn OR2 BnO O Ar R1O RO O BnO OBn R1O OR1 OR OH OR1 O R1=Bn BF3·OEt 2 OTBS OBn DCM R2=TBS OBn (+)-cinnamtannin B2 O OTBS -78 to -20 oC OR intermediate A Angew. Chem. Int. Ed. 2014, 53, 10129.