Baran Group Meeting Yang Gao Total Syntheses of 7/11/2020

genus Gelsemium

Gelsemium elegans Gelsemium rankinii nickname "heartbreak grass" yellow jasmine

♦highly toxic species ♦used as traditional Asian medicine over 1000 years ♦exihibits analgesic, anti-inflammatory, potent antitumor activities...

Native to and Southeast Asia Native to North America Six subclasses of the Gelsemium alkaloids

Sarpagine type Koumine type OH Yohimbane type O For total synthesis of Sarpagine alkaloids H see: Ajmaline and Sarpagine alkaloids H NMe N (Baran GM, Newhouse, 2006) H Me N H N N For total synthesis of koumine N H N N H H see: Philip D. Magnus H O semperivirine (Baran GM, Yan, 2012) koumidine taberpsychine koumine

Humantenine type Gelsemine type Gelsedine type

H O O H O O N N O N OMe N OMe O H H N H H O OMe N OMe O O H H NMe NH N N H H O O O O Me Me N H NH rankinidine humantenine gelsemine 21-oxogelsemine gelsecine gelsedine No total synthesis reported to date

For reviews on syntheses of Gelsemium alkaloids see: Danishefsky et al. Angew. Chem. Int. Ed. 2003, 42, 36. Semi-synthesis, formal synthesis and synthetic efforts Carter et al. Angew. Chem. Int. Ed. 2019, 58, 681. are not covered in this GM. Baran Group Meeting Yang Gao Total Syntheses of Gelsemium Alkaloids 7/11/2020

Structural features and synthetic challenges H H H H H N N N N N O O O O O 20 6 7 8 21 14 3 N 5 N N N N O O O O O Me 16 4 Me Me Me 17 Me gelsemine [3.2.1] bicyclic ring system spirooxindole motif THP moiety N-heterocycle with a quaternary center

♦First isolated in the extracts of G. Sempervirens in 1870 by Wormley ♦The correct molecular formula, C20H22N2O2, was established in 1910 by Moore ♦Structure determined independently by the groups of Conroy and Wilson in 1959 via NMR and X-ray crystallography

Chronology of the total syntheses of gelsemine 1994 1996 1999 2002 Johnson Fukuyama Overman Danishefsky racemic racemic racemic racemic 29 steps 32 steps 26 steps 36 steps

1994 1997 2000 2012 2015 Hart Speckamp Fukuyama Qin Zhai & Qiu racemic asymmetric asymmetric asymmetric racemic 23 steps 19 steps 31 steps 25 steps 12 steps Baran Group Meeting Yang Gao Total Syntheses of Gelsemium Alkaloids 7/11/2020 Johnson 1994 H CO Me 2 O H O H O H MeO2C CO2Me hv CO2Me CO Me 53% 5 steps 2 PhSeTMS CO2Me 3 steps CO2Me ZnI O [2+2] TBSO 2 TBSO TBSO O O 94% OTMS O

N MeNH2 N PhSe N N MeOH 86% N MeO O N OMe OMe N OTIPS O H Br TFA CO2Me + N N OMe O H TMS O 74% 7 steps O O O n N O N H LDA; BuLi; N N N O N O Me O TIPSO Me 65% R Me TIPSO Me Me Me Br O n R = Br O oxindole Bu3SnH intramolecular synthesis hv, -N2 70% R = H Mannich cyclization MeO N MeO N 1. HCl gelsemine O 2. DIBAL-H O N O 29 steps N 0.58% overall yield O Me Johnson J. Chem. Soc., Chem. Commun. 1994, 763. Me 12% desired + 24% epimer Johnson J. Chem. Soc., Chem. Commun. 1994, 765. Speckamp 1994 TIPSO O

6 steps BF3•Et2O 5 steps + N Me O H 70% O N N 5 Me O O N OEt Me 16 CHO intramolecular OH Me OTIPS Mannich cyclization Br SEM SEM O NH N N O O 1. SEMCl 1. TBAF O 2. Pd2(dba)3 2. Hg(OTf)2 1. TBAF, 90% O O gelsemine N 60% 3. NaBH4 2. AlH , 50% N N 3 Me OTDS +30% epimer OTDS 80% O Me Me intramolecular 19 steps oxymercuration-reduction 0.83% overall yield TDS= Si Heck cyclization Speckamp J. Chem. Soc., Chem. Commun. 1994, 767. Baran Group Meeting Yang Gao Total Syntheses of Gelsemium Alkaloids 7/11/2020

Fukuyama 1996 O OAc NH O O O OAc 4-iodooxindole DCC, DMSO; Cu(acac)2 piperidine (cat.) Et N, 91% OEt 4 steps O 3 OEt 68% 89% CO2Me N2 EtO CO Me CO2Me 2 HO I O O HO oxindole 4:1 E:Z, photochemical isomerization 1:1 E:Z 4-bromooxindole exlusively Z, but debromination failed MOM NHCO Et 2 O O EtO2CHN MOM O NH N O PhMe/MeCN HO O Cl N NH 2 steps AgOTf O 12 steps 90 oC O 52% N 98% CO2Me N Me MeO2C O I CO Me CO2Me I a Me 2 divinylcyclopropane-cycloheptadiene MOM MOM rearrangement N O N O O O O O 1. Hg(OTf)2 2 steps gelsemine NH b NH 2. NaBH4 O 63% O 32 steps N Oxymercuration N O 0.67% overall yield OH MeO C MeO2C Me Me 2 I I Fukuyama J. Am. Chem. Soc. 1996, 118 , 7426

Hart 1997 BnO BnO SPh O H AIBN O TMSO n 8 steps Bu3SnH O O O N Me O O N Me + 61% N O N O O Me Me CH2CH2OTHP H O OBn CO Et 2 CO2Et CO Et 2 Ac Ac Ac BnO N BnO O N BnO O N n 4 steps Br Bu3SnH, hv 3 steps 5 steps O gelsemine 40% desired O O O 23 steps N OAc N OAc N O 0.25% overall yield Me Me Me Ph (MeO)C OH 2 Ph2(MeO)C Hart J. Am. Chem. Soc. 1994, 116, 6943. Baran Group Meeting Yang Gao Total Syntheses of Gelsemium Alkaloids 7/11/2020 Overman 1999 Fukuyama 2000 SiMe H KH, 18-C-6 2 OTIPS OTIPS OK then ClCO Me SiMe H Cl 2 O O 2 CO2Me 8 steps then KOH H2O2 + Et AlCl KF, 53% HN CN 81% N N O + 2 88% X O aza-Cope Cl Bn X= Auxiliary rearrangement Sm(OTf)3 H MeOH, 99% O CO Me X= OMe 2 CHO 1. Br2 O OK OH OSiEt3 2. TFA N N Cl 3 steps MeAl(OAr)2 N O t-Bu CO2Me MeO2C H H Et3SiO MeO2C mechanism? Br CO2Me Ar = Me O 31 steps 24 steps O 0.86% overall yield N t-Bu Pd2(dba)3 enantioselective MOM I gelsemine 4 steps Ag3PO4, Et3N Fukuyama Angew. Chem. Int. Ed. 2000, 39, 4073. N N OMe 61-78% early studies (1988) MeO C 2 MeO2C cationic condition OMe OMe Br Br OMe (CH2O)n 76%

11:1 dr NHMe NMe NMe DBU NMOM 6 steps NMOM 90 oC SEM O OH O N 80% O SEM O N Pd2(dba)3, Et3N N OMe N retro-aldol/aldol , 110 oC MeO C Br 2 Me 89-95% Br CN N N MOM MeO C 2 dr 8:1 MeO2C O O N Br Br NMOM NMOM

O SEM N O N N O N OH O Me Me CN Me CN NH 3 steps 26 steps gelsemine N 1.2% overall yield MeO C 2 OH Overman Angew. Chem. Int. Ed. 1999, 38, 2934. 17 Baran Group Meeting Yang Gao Total Syntheses of Gelsemium Alkaloids 7/11/2020 Danishefsky 2002 EtO P O NO 2 O N EtO H 2 t O2N t O Bu H t O Bu H OtBu O Bu 14 steps MeO2CHN Al2O3 O NO O NaOMe H 2 74% O O CbzHN OMe CbzHN Cbz NO2 H Me NMe2 N BF3•Et2O 7 steps OMe 64% 30 - 40% NMe2 11 steps N N N O N OH OH Eschenmoser-Claisen MeO C MeO C MeO C 2 MeO2C rearrangement 2 2 gelsemine OPiv OPiv OPiv 36 steps Danishefsky J. Am. Chem. Soc. 2002, 124, 9812. 0.019% overall yield Qin 2012 OMe OMe OMe OMe O N O N MOMO OMe 1. LDA MOMO OMe LDA CN CN 75% O 20 LDA, PhSeCl CN MeO CN 75% 6 O H 2. SOCl2 N then NaIO + N 4 O 90% MeN OMe MeN OMe N N 70% OMe OMe OMe Me Me OMOM OMOM Z : E = 1.5:1 OMe OMe OMe O O HO OMe N N N O Lindlar cat. OMe CN N NC NC CN N 10:1 dr CN H2, 90% H H p-TsOH + 73% OH N MeN OMe MeN OMe Me O N N O Me O OMe OMe Me gelsemine 3 steps OMOM 1:2 OMOM 25 steps 1% overall yield asymmetric Qin Angew. Chem. Int. Ed. 2012, 51, 4909. Baran Group Meeting Yang Gao Total Syntheses of Gelsemium Alkaloids 7/11/2020

Zhai 2015 t-Bu Ph DBU, 97% Ph 1. DIBAL-H pTSA HN O TFA 2. MOMPPh Cl OH 3 KHMDS Cbz Cbz CHO Ph Cbz Cbz then pTSA N O N O + N N O + H + 93% OMe then NaBH4 CO2Me N O H 13:1 OMe Cbz organocatalytic CO2Me Diels-Alder rxn 30% 47% O3; NaOMe Me MOM Me Cbz O O N Me 60% N N O HO LDA, Et AlCl O O N 2 N 5 steps Cbz OMs OMe N 32% OH OH OMe N piperidine OMs N single isomer O O O MOM 86% O H MOM Intramolecular SN2 mixture of four isomers 12 steps 5% overall yield asymmetric Zhai Nat. Commun. 2015, 6, 7204. Gelsedine-type Alkaloids

O O O O O HO N N N OMe N OMe OMe N OMe OMe O H H H O H O O O H O NH H N N NH H N H Me Me O oxabicyclo[3.2.2]nonane core gelsedine gelsenicine gelsedilam gelsemoxonine spiro-N-methoxyindolinone diverse N-heterocycle

2019 2018 Takayama 1999 2011 2015 2016 2016 Ma (-)-14-hydroxygelsedilam 2013 Fukuyama Hiemstra Fukuyama Carreira Ferreira Zhao (-)-gelsenicine 13-19 steps (+)-gelsedine (-)-gelsemoxonine (-)-gelsenicine (-)-gelsenicine (-)-gelsedilam (-)-gelsedine (+/-)-gelsemoxonine (-)-gelsedine 23 steps 30 steps 21 steps 13 steps 18 steps (-)-gelsedilam (-)-gelsedilam (-)-gelsemoxonine 24-25 steps 11-13 steps Baran Group Meeting Yang Gao Total Syntheses of Gelsemium Alkaloids 7/11/2020

Hiemestra 1999 • HCO2 O OTBS TfO OTBS TfO OTBS o OCHO HO HCO2H, 85 C 2 steps LiHMDS HO 5 steps • H H 79% H PhNTf2 H H H N H N HO2C CO2H EtO N O N N Bn O Bn O Bn O (S)-malic acid Bn Bn O not observed NaI HCO2H

1. (Chx)2BH; O O I OCHO O NaOH/H O , 79% 7 steps N 2 2 N Br N Pd(PPh3)4 Me Me N 5 steps 2. Hg(OTf)2, 88% MeO Me 90% H n H H O 3. Bu3SnH, AIBN O H H H N H N O N H 80% H HN Bn O H Intramolecular Bn O Bn O Me N Heck cyclization ent-gelsedine Bn O 42% + 34% ketone 28 steps Hiemstra Angew. Chem. Int. Ed. 1999, 38, 2214. 0.09% overall yield Fukuyama 2011 TMSO O Tol, 70 oC OH 11 steps H O then TBAF O O 3 4 steps O 7 N O O divinylcyclopropane OMe H N N OMe PivO OMe -cycloheptadiene O 5 OTMS rearrangement O OPiv H O OPiv HO2C O N OMe

1. (COCl)2 O 6 steps O O 2. NaN3 O O 1. TMSI HO N 3. BnOH N OMe OMe N OMe 2. EtOH O 82% reflux O H H O CbzHN H 79% N O CbzHN O H Curtius rearrangement Biomimetic cyclization (-)-gelsemoxonine 26 steps 2.3% overall yield

Fukuyama, J. Am. Chem. Soc. 2011, 133, 17634 Baran Group Meeting Yang Gao Total Syntheses of Gelsemium Alkaloids 7/11/2020 Carreira 2013 Ferreira 2015 Ph O O NH H HO CO Et O 4 steps 2 O 3 steps O CO2Me 2 mol% A O OH H 93% O O HN O H mechanism? CO2Et Me O H SO (cat.), O O H 2 4 H BocO H MeOH HgSO (cat.) HO O O CO2Me Ph 4 TFA, MeCN CO2Et 5 steps o 60 C THF/H2O o H 80 C O Ph 50 oC, 68% 75% CO Me 40 - 45% N N H O 2 H Boc Me ring contraction Me O O O O O O Ph rac- BocO 4 steps BocO Ph Ph N [PPh3CuH]6 5 stepsH 82% O H Br O OH OH CO Me 74% H H 2 CO2Me O NH N N 4:1 dr. N Boc Boc O OMe Me Me Me OBz

1. PdCl (MeCN) 2 2 O HCO H, 72% O (Me2SiH)2NH 2 HO O PhI(OCOCF3)2 N 2. NaH, MeI, 92% N OMe then OMe AIBN H n N OMe [RuCl2(C6H6)2]2 86% Bu3SnH 3. K2CO3, MeOH N H O 58% O 66% H 87% O Boc directed N N H reductive hydrosilylation Me OBz Me Heck cyclization (-)-gelsenicine 1. KHF , Ac O 2 2 O t-Bu 13 steps H2O2, 65% O 4.2% overall yield gelsemoxonine Si N t-Bu P Au NCMe 2. 3 M HCl OMe 26 steps 97% SbF6 0.33% overall yield H Fleming-Tamao N O Boc oxidation A

Carreira J. Am. Chem. Soc. 2013, 135, 8500. Carreira J. Am. Chem. Soc. 2015, 137, 6084. Ferreira J. Am. Chem. Soc. 2016, 138, 108. Baran Group Meeting Yang Gao Total Syntheses of Gelsemium Alkaloids 7/11/2020

Fukuyama 2016 2.6 :1 then O TMSCN, DBU O O 1. TMSI O MeOH 2. DBU THF, rt N N N OMe N OMe OMe OMe H 73% H NC O OHC O O O NH H NHCbz NHCbz TMSO NHCbz MeO O O (-)-gelsedilam 21 steps 57% desired from furfuryl then O O O 1. EtMgBr TBAF H2, PtO2 2. IBX N N N Pd(OAc)2, Et3SiH OMe 79% OMe EtOH, rt OMe 65% Et N, DCM, rt Et 3 H 95% H O H O H O HN N NH OSiEt3 Me Me CO2SiEt3 O (-)-gelsenicine (-)-gelsedine N OMe Zhao 2016 O O 1. OsO4 O O EtSH O HO 9 steps EtS NHCbz Cs CO Et 2. Pd(OAc) N OMe O N 2 3 N 2 HO OMe Et3SiH, Et3N N OMe 3. CsF 1. Triton B H O OMe O O conjugate addition O O N O TBHP, 95% 42% Me /aldol rxn OH 2. TMSI (-)-14,15-dihydroxygelsenicine 3. SmI2 AIBN O O NH2OH•HCl n 5 steps Bu3SnH N N OMe OMe Sm O 47% O O then MeOH HO O O MeO2C O N N OMe OH O OMe H Et 37% O O N H O NiCl2•6H2O O NH2 Me O NaBH Sm (-)-14-hydroxygelsenicine N OMe 4 N OMe then silica gel H H O NH 49% MeO C O 18 steps O 2 N 1.8% overall yield (-)-gelsedilam HO Fukuyama Org. Lett. 2016, 18, 4622. Zhao Chem. Eur. J. 2016, 22, 18339. Baran Group Meeting Yang Gao Total Syntheses of Gelsemium Alkaloids 7/11/2020 Ma 2018

MeO RO O N O NO2 RO O RO Cs2CO3 RO O NCS + O N HO N OMe N O 95% OMe aldol rxn 1:1 dr O OMe R = (-)-menthol O NO OH NO2 3 steps 4 steps asymmetric NO2 2 from gramine from L-arabinose Michael addition silica gel Et3N [3.3.1] [3.2.2] 90%

O (-)-gelsenicine O O RO O AlCl3 RO (-)-gelsedine 4-5 steps O Tol/Et2O (-)-gelsedilam N HO HO o HO N (-)-gelsemoxonine OMe N OMe N OMe 95 C OMe divergent O 86% NO O O NO O heterocyclization 2 NO2 NO2 pinacol rearrangement 2

Ma J. Am. Chem. Soc. 2018, 140, 11608.

Takayama 2019 Br TBDPSO O O OTBDPS OMe 5 steps 3 steps N HO O LiHMDS HO Pd(PPh3)4 O NHPMB N OMe 98% N H 84% O intramolecular O aza-Michael O PMB O N H addition N H Heck cyclization O PMB O PMB O 1. Hg(TFA)2, 78% HO 1-6 steps six biogenetically related 2. NaBH ; O , 86% N OMe 4 2 Gelsemium alkaloids 3. TFA, 77% H O oxymercuration NH O (-)-14-Hydroxygelsedilam 13 steps 8.5% overall yield

Takayama Org. Lett. 2019, 21, 7134.