Total Syntheses of Gelsemium Alkaloids Baran Group Meeting...+30% epimer Si 1. TBAF 2. Hg(OTf) 2 3. NaBH 4 N Me N O O O SEM 80% 1. TBAF, 90% 2. AlH 3, 50% Yang Gao Baran Group Meeting

Yang Gao Total Syntheses of Gelsemium Alkaloids Baran Group Meeting7/11/2020

NH

N

H

H

H

OH

koumidine

NH

N

OH

H

Me

taberpsychine

N

NMe

H

Okoumine

O

N

NH

H HO

OMe

rankinidine

O

NH H

O

OMe

Ngelsecine

O

NH H

O

OMe

NHHgelsedine

Sarpagine type Koumine type

Gelsedine type

O

N

NMe

H HO

OMe

humantenine

Humantenine type

NMe

O

HNO

NMe

O

HNO

O

gelsemine 21-oxogelsemine

Gelsemine type

Six subclasses of the Gelsemium alkaloids

No total synthesis reported to date

genus Gelsemium

Gelsemium elegansnickname "heartbreak grass" Gelsemium rankinii Gelsemium sempervirens

yellow jasmine

Native to China and Southeast Asia Native to North America

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

For total synthesis of Sarpagine alkaloidssee: Ajmaline and Sarpagine alkaloids(Baran GM, Newhouse, 2006)

For total synthesis of kouminesee: Philip D. Magnus (Baran GM, Yan, 2012)

N

N

semperivirine

Yohimbane type

For reviews on syntheses of Gelsemium alkaloidssee: Danishefsky et al. Angew. Chem. Int. Ed. 2003, 42, 36.Carter et al. Angew. Chem. Int. Ed. 2019, 58, 681.

Semi-synthesis, formal synthesis and synthetic effortsare not covered in this GM.

ONMe

HNO

1994Johnsonracemic29 steps

1994Speckamp

racemic19 steps

1996Fukuyama

racemic32 steps

1997Hart

racemic23 steps

1999Overmanracemic26 steps

2000Fukuyamaasymmetric

31 steps

2002Danishefsky

racemic36 steps

2012Qin

asymmetric25 steps

2015Zhai & Qiuasymmetric

12 steps

gelsemine

Chronology of the total syntheses of gelsemine


♦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 1959via NMR and X-ray crystallography

ONMe

HNO

[3.2.1] bicyclic ring system

ONMe

HNO

spirooxindole motifwith a quaternary center

Structural features and synthetic challenges

ONMe

HNO

ONMe

HNO

THP moiety N-heterocycle

720

5

6

16 17

34

14218

hv, -N2

Speckamp 1994

OH

+ N Me

O

O N

H

O

MeOEt

TIPSO

6 steps

NCHO

O

Me

BF3•Et2O70% N

O

MeOTIPS

5 steps

NOTDS

O

Me

NHO Br

1. SEMCl2. Pd2(dba)3

NMe

NO

O

OTDS

SEM

60%+30% epimer

Si

1. TBAF2. Hg(OTf)23. NaBH4 N

Me

NO

O

O

SEM

80%

1. TBAF, 90%2. AlH3, 50%

Yang GaoBaran Group Meeting

7/11/2020

NNN

OMe

TMS

LDA; nBuLi;65%

ONO

NOMe

NN

ONMe

O

MeON

N N+

Me

O

MeO2C CO2Me hv 53%

H

O

CO2MeCO2Me

Johnson 1994

5 steps

H

TIPSO

O

N

OMe

OMeBr

ONMe

O

Br

OTIPSTFA74%

ONMe

O

R

O

nBu3SnH70%

R = Br

R = H

ONMe

NMeO

O

12% desired + 24% epimer

gelsemine

oxymercuration-reductionTDS=

Total Syntheses of Gelsemium Alkaloids

intramolecularMannich cyclization

oxindole synthesis

Johnson J. Chem. Soc., Chem. Commun. 1994, 763.Johnson J. Chem. Soc., Chem. Commun. 1994, 765.

29 steps0.58% overall yield

Speckamp J. Chem. Soc., Chem. Commun. 1994, 767.

intramolecularMannich cyclization

intramolecularHeck cyclization


1. HCl2. DIBAL-H gelsemine

H

O

CO2MeO

TBSO

PhSeTMSZnI294%

HCO2Me

O

TBSO OTMS

PhSe

3 stepsH

CO2MeO

TBSO O

MeNH2MeOH86%

H

TIPSO

O

HN

OMe

CO2Me7 steps

[2+2]

516

ONMe

O

MeON

Fukuyama 1996

OEt

O O

O

OEt N2

Cu(acac)2

CO2Me

O

O

4 stepsCO2Me

HO

NHO

I

MeO2C

NH

I

OPhMe/MeCN

90 oC98%

divinylcyclopropane-cycloheptadienerearrangement

12 steps

CO2Me

N

NOMOM

Me

ClO

NHCO2Et

CO2MeN

NO

MOM

Me

O

EtO2CHNHO2 steps

NMe

NO

O

OH

MOM

1. Hg(OTf)22. NaBH4

63%ON

Me

NOMOM

O

2 steps gelsemine

Fukuyama J. Am. Chem. Soc. 1996, 118, 7426

Hart 1997TMSO

CH2CH2OTHP

N

O

O

Me +8 steps

N

SPh

O

Me

HO

O

OBnCO2Et

AIBNnBu3SnH

61%N

Me

BnO

O

CO2Et

O

O

NMe

BnO

OO

O

4 steps

NMe

BnO

O

Ph2(MeO)C

OAc

O

NAc

Br nBu3SnH, hv40% desired

NMe

BnO

O

Ph2(MeO)C

OAc

NOAc

3 steps

O


EtO68%

AgOTf52%

32 steps0.67% overall yieldOxymercuration

O

CO2Me

OAc

HO

4-iodooxindolepiperidine (cat.)

89%

CO2MeO

NHO

I

OAcDCC, DMSO;Et3N, 91%

oxindole 4:1 E:Z, photochemical isomerization 1:1 E:Z4-bromooxindole exlusively Z, but debromination failed

MeO2C

NH

I

OO

MeO2C

NH

I

OO

a

b

Hart J. Am. Chem. Soc. 1994, 116, 6943.

gelsemine23 steps

0.25% overall yield

CO2EtH

NMe

BnO

OO

NOAc

OH

5 steps

Overman 1999

OTIPS

+ CO2Me 8 stepsOTIPS

HN CN

KH, 18-C-6then ClCO2Me

then KOH81%

OK

N

NOK

H

NO

H

CO2Me1. Br22. TFA

NMeO2C

OH

Br

NMeO2C

O

Br

4 steps

NMeO2CBr

OMe

NMOM

O

11:1 dr

6 steps

N

OHNMOM

O

Me CN

DBU90 oC80%

ONMe

NOMOM

NH3 stepsgelsemine

Fukuyama 2000

N O

OO

Cl Bn

+

SiMe2H

Et2AlCl88%

SiMe2HCl

O

OH

CO2Me

XX= Auxiliary

X= OMeSm(OTf)3MeOH, 99%

H2O2KF, 53%

ClOSiEt3

MeO2C

3 steps O

Ar = Me

t-Bu

t-Bu

Et3SiOCO2Me

CHO

24 steps

gelsemine


7/11/2020Total Syntheses of Gelsemium Alkaloids

aza-Coperearrangement

Overman Angew. Chem. Int. Ed. 1999, 38, 2934.


retro-aldol/aldol

MeAl(OAr)2

mechanism?


enantioselectiveFukuyama Angew. Chem. Int. Ed. 2000, 39, 4073.

NMeO2CBr

OMe

NMOM

O

I Pd2(dba)3Ag3PO4, Et3N

61-78%

N

NMOM

O

Me CNO N

Me CN

NMOMO

OH

cationic conditionearly studies (1988)

OMe

NHMe

(CH2O)nOMe

NMe

OMe

NMe

76%

NMeO2CBr

O

NSEM

Br

Pd2(dba)3, Et3N toluene, 110 oC

89-95% NMeO2CBr

SEMNO

dr 8:1

NMeO2C

SEMNO

OH17

Danishefsky 2002

OtBu

OAl2O3

OtBu

O

NO2PEtOEtO

O

NaOMe74%

OtBu H

H NO2

HOtBu O2N14 steps

H

O

MeO2CHN

O2N

NMeO2C OH

H NO2BF3•Et2O

64%N

MeO2C

OPiv

7 steps

OH

CbzHNMe

OMe

OMeNMe2

30 - 40%N

MeO2C

OPiv

O

CbzHN

NMe2N

MeO2C

OPiv

N

OCbz

gelsemine

11 steps

Qin 2012

NMe

O

CNMOMO

OMe

OMe

+ NOMe

O

1. LDA 75%

2. SOCl290%

NMe

CNMOMO

OMe

OMe

NOMeO


LDA 75%

MeN

OMOM

OMe

H

OMe

NOCN

LDA, PhSeClthen NaIO4

70% MeN

OMOM

OMeOMe

NOCN

OMe OMe

Lindlar cat.H2, 90%

MeN

OMOM

OMeOMe

NO

NC

OMe

H

MeN

OMOM

OMeOMe

NO

NC

OMe

H+

1:2

p-TsOH73%

O

N

OH

OMe

NMe

CN

ONMe

CN NHO OMe

ONMe

CN NO OMe

10:1 dr

3 stepsgelsemine

Eschenmoser-Claisenrearrangement

36 steps0.019% overall yieldDanishefsky J. Am. Chem. Soc. 2002, 124 , 9812.

25 steps1% overall yield

asymmetricQin Angew. Chem. Int. Ed. 2012, 51, 4909.

Z : E = 1.5:1

20 6


7/11/2020

Zhai 2015

CHO

CO2Me+

NCbz

HN O

t-Bu PhPh

PhTFA

then NaBH4

NCbz

OH

CO2Me

NCbz

O

O30% 47%

DBU, 97%

+

1. DIBAL-H2. MOMPPh3ClKHMDSthen pTSA N

CbzO

OMe

HN

CbzO

H

OMe +

13:193%

O3; NaOMe60%

NCbz

H

OMeO

HOO

OMe

NCbz

O

OH

ONMe

OMsOH

5 steps

NO

MOM

piperidine86%

ONMe

OMsNOMOM

LDA, Et2AlCl

32%single isomer

ONMe

NOMOM

organocatalyticDiels-Alder rxn

ON OMe

O

ON OMe

ONH

HMe

ON OMe

ONHH

HO

HO

NH

HO

gelsenicine gelsedilam gelsemoxonine

2011Fukuyama

(-)-gelsemoxonine30 steps

2013Carreira

(+/-)-gelsemoxonine21 steps

2015Ferreira

(-)-gelsenicine13 steps

2016Fukuyama

(-)-gelsenicine(-)-gelsedine(-)-gelsedilam24-25 steps

2016Zhao

(-)-gelsedilam18 steps

2018Ma

(-)-gelsenicine(-)-gelsedine(-)-gelsedilam

(-)-gelsemoxonine11-13 steps

Gelsedine-type Alkaloids

2019Takayama

(-)-14-hydroxygelsedilam13-19 steps


Zhai Nat. Commun. 2015, 6, 7204.

12 steps5% overall yield

asymmetric

pTSA

Intramolecular SN2 mixture of four isomers

ON OMe

ONoxabicyclo[3.2.2]nonane corespiro-N-methoxyindolinone

diverse N-heterocycle

ON OMe

ONHH

HMe

gelsedine

1999Hiemstra

(+)-gelsedine23 steps

Yang Gao Total Syntheses of Gelsemium AlkaloidsBaran Group Meeting

7/11/2020

Hiemestra 1999

HO2C CO2H

HO

(S)-malic acid

5 steps

N OBn

EtO

HO•

NaIHCO2H

42% + 34% ketone

NMe

O NH

H

•

NH

Bn O

OCHOHCO2 OTBS

NH

HOBn

O

Pd(PPh3)4

90%

ONMeO

O HNH

HMeBn O

1. (Chx)2BH;NaOH/H2O2, 79%2. Hg(OTf)2, 88%3. nBu3SnH, AIBN80%

NMe

O NH

HBn O

O7 steps

ent-gelsedine

Fukuyama 2011

OOH 11 steps

OTMSO

H

HPivO

NOOMe

Tol, 70 oCthen TBAFO

OTMS

N

OOMe

OPiv

ON OMe

O

O

OPiv

divinylcyclopropane-cycloheptadienerearrangement

4 steps ON OMe

OH

O

HO2C

1. (COCl)22. NaN33. BnOH

82%

ON OMe

OH

O

CbzHN

6 steps ON OMe

OHCbzHN

O

O

1. TMSI2. EtOHreflux 79%

ON OMe

O

HO

NH

HO

(-)-gelsemoxonine

Hiemstra Angew. Chem. Int. Ed. 1999, 38, 2214.

Fukuyama, J. Am. Chem. Soc. 2011, 133 , 17634



HCO2H, 85 oC

79%

OCHO

NH

HOBn

I

OTBS

NH

HOBn

TfO2 steps LiHMDS

PhNTf2

OTBS

NH

HOBn

TfO

not observed

5 steps

NH

HOBn

ON

MeBr

IntramolecularHeck cyclization

Curtius rearrangement Biomimetic cyclization

73

5


7/11/2020

Carreira 2013

O

O 4 steps

O

NHO

HOH

CO2Et

TFA, MeCN80 oC

40 - 45%

OHO

NH

O

HCO2Et

OHO H

CO2Et

OHN

5 stepsO

BocO

NBoc

HO

OH

rac-proline82%

OBocO

NBoc

H

OOH

4 steps OBocO

NBoc

H

O

NOH Br

ON OMe

O

HO

NBoc

H

2. NaH, MeI, 92%3. K2CO3, MeOH

87%

1. PdCl2(MeCN)2HCO2H, 72% (Me2SiH)2NH

then[RuCl2(C6H6)2]2

58%

ON OMe

O

O

NBoc

H

Si

1. KHF2, Ac2OH2O2, 65%

2. 3 M HCl97%

gelsemoxonine

Ferreira 2015

directedhydrosilylation

OO

H

3 steps O

Me

Ph

CO2Me

Pt-Bu

t-Bu Au NCMe

SbF6

93%

O

Me

Ph

CO2Me

OH

Me

Ph

CO2Me

H

MeOH60 oC75%

H2SO4 (cat.), HgSO4 (cat.)

THF/H2O50 oC, 68%

OPh

CO2MeO

Me

[PPh3CuH]674%

OPh

CO2Me

H

MeO4:1 dr.

5 steps

OPh

H

NMe OBz

NHOOMe

PhI(OCOCF3)286%

ON OMe

OH

NOBzMe

AIBNnBu3SnH

66%

ON OMe

ONH

HMe

(-)-gelsenicine



Carreira J. Am. Chem. Soc. 2013, 135 , 8500.Carreira J. Am. Chem. Soc. 2015, 137 , 6084.


Ferreira J. Am. Chem. Soc. 2016, 138 , 108.

ring contraction

Fleming-Tamaooxidation

reductiveHeck cyclization

A

2 mol% A

mechanism?


7/11/2020

Fukuyama 2016

ON OMe

ONHCbz

OHC

21 stepsfrom furfuryl alcohol

TMSCN, DBUTHF, rt

then MeOH

ON OMe

ONHCbz

H

MeO O

2.6 :1

1. TMSI2. DBU

73%

ON OMe

ONHH

HO

(-)-gelsedilam

1. EtMgBr2. IBX

65%

ON OMe

OEt

O

57% desired

ON OMe

ONHCbzTMSO

NC

Pd(OAc)2, Et3SiHEt3N, DCM, rt

ON OMe

OHNOSiEt3

Et

CO2SiEt3

thenTBAF O

N OMe

ONH

HMe

(-)-gelsenicine

79%H2, PtO2

EtOH, rt95%

ON OMe

ONHH

HMe

(-)-gelsedine

1. OsO4

2. Pd(OAc)2 Et3SiH, Et3N3. CsF

42%

ON OMe

ON

HO

HMe

HO

(-)-14,15-dihydroxygelsenicine

1. Triton BTBHP, 95%2. TMSI3. SmI2

ON OMe

ONH2O

Et

Sm

OSm then

MeOH37%

ON OMe

ON

H

HMe

HO

(-)-14-hydroxygelsenicine

Zhao 2016

NOMe

O9 steps O

N OMe

OOO

EtSHCs2CO3

ON

OMeOO

OH

EtS

AIBNnBu3SnH

47%

ON

OMe

OOOH

5 steps ON

OMe

OO

MeO2C

NH2OH•HCl

ON

OMe

ONMeO2C

HO

NiCl2•6H2ONaBH4

then silica gel49%

ON OMe

ONHH H

O(-)-gelsedilam

conjugate addition/aldol rxn

Zhao Chem. Eur. J. 2016, 22, 18339.


Fukuyama Org. Lett. 2016, 18 , 4622.


NHCbz


7/11/2020

Ma 2018

NOMe

NO2 O

O

RO

R = (-)-menthol

Cs2CO3

95%1:1 dr

O

O

RO+

NMeO

NO2

NCSO

O

RO

N

OH

OMe

NO2

O

HO

RO

N

O

OMe

NO2

silica gelEt3N90%

O

HO

RO

N

O

OMe

NO2

AlCl3Tol/Et2O

95 oC86%

O

HO

RO

N

O

OMe

NO2

O

HO N

O

OMe

NO2

ON

OMe

ONO2

O4-5 steps

divergentheterocyclization

(-)-gelsenicine(-)-gelsedine(-)-gelsedilam(-)-gelsemoxonine

3 stepsfrom gramine

4 stepsfrom L-arabinose

Takayama 2019TBDPSO

N HPMBO

OOO

5 stepsO

OTBDPSNHPMB

O

LiHMDS98%

3 steps HO

N HPMBO

N

O

OMe

Br

Pd(PPh3)4 HON OMe

ON H

84%

O PMB1. Hg(TFA)2, 78%2. NaBH4; O2, 86%3. TFA, 77%

N OMe

ONH HO

OHO

(-)-14-Hydroxygelsedilam

1-6 stepssix biogenetically related

Gelsemium alkaloids


asymmetric Michael addition

aldol rxn

pinacol rearrangement

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

[3.3.1] [3.2.2]

aza-Michaeladdition

intramolecularHeck cyclization

oxymercuration

Takayama Org. Lett. 2019, 21, 7134.


Documents

Total Syntheses of Gelsemium Alkaloids Baran Group Meeting...+30% epimer Si 1. TBAF 2. Hg(OTf) 2 3. NaBH 4 N Me N O O O SEM 80% 1. TBAF, 90% 2. AlH 3, 50% Yang Gao Baran Group Meeting