total synthesis of (+)-corymine

Total Synthesis of(+)-Corymine

2020.9.12. Literature SeminarB4 Hibiki Asai

1. Introduction

2. Total synthesis of (-)-Vincorine(by MacMillan Group)

3. Total synthesis of (+)-Corymine(by Li Group)

Contents

2

Akuammiline Alkaloids

1) Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 4037. 2) Eckermann, R.; Gaich, T. Synthesis 2013, 45, 2813.

3

32N

N21

16

OMe

CO2MeHH

• migration of C3-N bond to C2-N• strained 7-membered azepanyl ring

A

B

D

E

C

32

16N

CO2Me

NC D

EB

A

akuammilinealkaloids

HN

N

OMe

CO2MeHH

Boc Cl(1) TMSOTf, 2,6-lutidine CH2Cl2(2) K2CO3, KI MeCN, 60 °Cconstruction of D-ring

(3) HCHO, NaBH3CN MeCN, AcOH

(-)-vincorine

by Ma Group

Vincorine and Corymine

1) Mokry,J.;Dubravkova,L.;Šefcǒvic,P.Experientia1962,18, 564. 2) Kiang, A. K.; Smith, G. F. Proc. Chem. Soc. 1962, 298.3) Zhang, M.; Huang, X.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2009, 131, 6013.4) Zi, W.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2012, 134, 4037.5) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.6) Zhang, B.; Wang, X.; Cheng, C.; Sun, D.; Li, C. Angew. Chem., Int. Ed. 2017, 56, 74847) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.8) Eckermann, R.; Gaich, T. Synthesis 2013, 45, 2813.

4

32N

N

O CO2Me

OH

16

H

32N

N

16

OMe

CO2MeHH

(-)-vincorine (+)-corymineVinca minor (1962) 1) Hunteria corymbosa (1962) 2)Isolation:

Structual features: pentacyclic caged structurestrained 7-membered azepanyl ring

hexacyclic caged structurestrained 7-membeed azepanyl ringC16 extra carbon

Total synthesis: Qin (2009 (35 steps, racemic)) 3)

Ma (2012 (18 steps, enantioselective)) 4)

MacMillan (2013 (9 steps, enantioselective)) 5)

Li (2017 (21 steps, racemic), 2020 (11 steps, 99% ee)) 6) 7)

A A

B B

D DE E

C C

Introduction of Prof. MacMillan and Li

1) https://macmillan.princeton.edu2) http://www.fluorinelab.ac.cn/ketizu.jsp?name=李超忠 5

Prof. David W. C. MacMillan

1991 B.S. @ University of Glasgow1996 Ph.D @ the University of California, Irvine (Prof. Larry E. Overman)1996- Postdoctral fellow

@ Harvard University (Prof.David A. Evans) 1998- @ the University of California, Berkeley2000- @ the California Institute of Technology2004- Professor @ the California Institute of Technology2006- Professor @ Princeton University2011- Distinguished professor @ Princeton University

Research topic: photoredox, organocatalysis, total synthesis

Prof. Chaozhong Li

1988 B.S @ University of Science and Technology of China1993 Ph.D @ Shanghai Institute of Organic Chemistry1993- Assistant Researcher @ Shanghai Institute of Organic Chemistry1994- Postdoctral fellow @ Iowa State University1999- Associate professor @ Shanghai Institute of Organic Chemistry2000- Professor @ Shanghai Institute of Organic Chemistry

Research topic: free radical chemistry, organofluorine chemistry,organometallic chemistry, natural product synthesis

Retrosynthetic Analysis

1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.2) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269. 6

3N15

N 20

O CO2MeOH

16

H

N15

N 20

OMe

CO2MeH

N

OMe

NH

BocN

N

OMe

CO2MeHX

H

3N

NO

CO2Me16

CO2Me

Br

HN NBr

CO2MeCO2Me

O R

HNN

R

Br

7-memberedcyclization

; Hemiacetalization7-memberedcyclization

asymmetricalkylation

asymmetricDiels-Aider reaction

(-)-vincorine

(+)-corymine

MeO2C Oby MacMillan

by Li

D

E

D

E

CC

C

C

E

E

Y

1. Introduction



Contents

7

Synthesis of Diene

1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.2) Biscoe, M. R.; Fros, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686. 8

HN

OMe

NH

Boc

commercially available

NaH, DMF, 0 °C; MeI

N

OMe

NH

Boc

n-BuLi1,2-dimethoxyethane, -40°C

; ZnCl2, -78 °C to rt I

N

OMe

NH

Boc

PdII

NH2

Cl

XPhos precatalyst

Negishi coupling

; XPhos precatalyst,N

OMe

NH

BocZnCl

ortho metalation

96%

PCy

CyAr

Ar =

i-Pr

i-Pr

i-Pr

71%

Diels-Alder/Cyclization Cascade (I)

1) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458.2) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442. 9

N

OMe

NH

BocMeO2C O

catalyst (20 mol%)MeCN, -20 °C

N

OMeHN

CO2Me

CHO

Boc

N

HN

OMe

CO2MeHCHO

H

Boc

N

N

OMe

CO2MeHCHO

H

Boc

N

NHPh

Me

Me

MeO

catalyst

Diels-Alderreaction

+H+

-H+MeO2C O

70% yieled, 95% ee

E

E

E

C

catalyst HBF4

Diels-Alder/Cyclization Cascade (II)

1) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458.2) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.

10

N

NH Me

MeO

MeO2C

N

N Me

MeO

CO2Me

N

NH

H Me

MeO

MeO2C OH H

Diels-Alder

N

OMeHN

CO2Me

Boc

NNMe

O

Me

N

HNBoc

OMe

N

OMeHN

CO2Me

CHO

Boc

N

N

OMe

CO2MeHCHO

H

Boc

+H2O-H+

Me Me Me

Me

Ph

EZ

largeallylic strain

smallallylic strain

electrophilic

nucleophilic

H

Ph Ph Ph

Enantioselectivity of Diels-Alder

1) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458.2) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.

11

N

HN BocOMe

CO2Me

N

OMe

HNBoc

N

CO2Me

NMe

OMeMe

PhN

OMe

HNBoc

N

CO2Me

NMe

OMeMe

Ph

N

NMe O

Me

Ph

Me

N

OMeHN

CO2Me

CHO

Boc

‡ ‡

hydrolysis

Synthesis of Radical Cyclization Precursor

1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.12

N

N

OMe

CO2MeHCHO

H

Boc

N

N

OMe

CO2MeHCO2H

H

Boc

N

N

OMe

CO2MeHCOTePh

H

Boc

N

N

OMe

CO2MeHCOTePh

H

NaClO2,THF/t-BuOH/H2O, 0 °C

Cl O

O

N-methylmorpholineTHF, -10 °C;

(PhTe)2, NaBH4THF/MeOH, -10 °C

(1) CF3CO2H

(2)O

St-Bu

NaBH(OAc)3CH2Cl2

acyl telluridation

N

N

OMe

CO2MeH

H

Boc

O

O

O

O

96%

87%

65% (2 steps)

St-Bu

Radical Cyclization (I)

1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442. 2) Chen, C.; Crich, D.; Papadatos, A. J. Am. Chem. Soc. 1992, 114, 8313. 13

N

N

OMe

CO2MeH

H N

N C

OMe

CO2MeHH

X

O radical cyclization

X condition solvent yield[%]

SePh

TePh

120 °C, 5 hBu6Sn2, hν (Hg lamp)

200 °C, 10 h

St-Bu

chlorobenzene(5 mM)

1,2-dichlorobenzene(0.5 mM)

conversion[%]

85

100

17a

51b

a Yield based on 1H NMR analysis. b Isolated yield.

D

Radical Cyclization (II)

1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.2) Chen, C.; Crich, D.; Papadatos, A. J. Am. Chem. Soc. 1992, 114, 8313. 14

N

N

OMe

CO2MeH

H

N

N C

OMe

CO2MeHH

TePh

O

St-Bu

N

N

OMe

CO2MeH

H

O

St-Bu

N

N

OMe

CO2MeH

St-Bu

-t-BuS

-CO

H

-PhTe

Δ

7-exo

Total Synthesis of (-)-Vincorine

1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442. 15

N

N

N C

OMe

CO2MeHH

Pd/C, H2THF, -15 °C

N

N

OMe

CO2MeHH

hydrgenetion fromless hindered face

80% (-)-vincorine

H H

H H

H H

H H

MeO2C

H

CN C

MeO2C

boat skewed-boat

Short Summary

1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.16

N

N

OMe

CO2MeHH

(-)-vincorine

N

OMe

NH

Boc N

N

OMe

CO2MeHCHO

H

Boc

N

N

OMe

CO2MeHCOTePh

H

2 steps fromcommercially available

compound

asymmetricDiels-Alder reaction

MeO2C O

radical cyclization

St-Bu

• 9 steps syntesis• asymmetric Diels-Alder reaction• radical cyclization using acyl telluride

C

D

E

1. Introduction



Contents

17

Retrosynthesis

1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269. 18

N

N

O CO2Me

OHH

N

NO

CO2MeCO2Me

N

NO

CO2MeCO2Me

Br

N NBr

CO2MeCO2Me

RHN N

BrO

Br

R

hemiacetalization 7-menberedcyclization

constructionof C, E-rings

chain extension;asymmetric addition

C

E

(+)-corymine

D

O OEtEtO

Synthesis of 3-bromooxindole


HNNH

Ns HNN

Ns

Br

BrBr

NBS, H2Ot-BuOH/THF

commercially available

K2CO3DMF

HN N

O

Br

Ns

Br95%

(2 steps)

HNN

Ns

Br

OH

Br

Cu-Catalyzed Enantioselective Alkylation

1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.2) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stolz, B. M. Angew. Chem. , Int. Ed. 2009. 48, 8037. 20

HN NBr

CO2MeCO2Me

O NsMeO2C CO2Me

[Cu], i-Pr2NEt, MS3ACH2Cl2, -20 °C

CuIIN

N

O

O

Ph

Ph

[Cu]

asymmetric alkylation

HN NBrO

Br

Ns

> 99% eerecrystallization, 90%

2 SbF6

65% yield, 91% ee

2

Proposed Mechanism ofCu-Catalyzed Alkylation (I)

1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.2) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stolz, B. M. Angew. Chem. , Int. Ed. 2009. 48, 8037.3) D. M. Barnes, J. Ji, M. G. Fickes, M. A. Fitzgerald, S. A. King, H. E. Morton, F. A. Plagge, M. Preskill, S. H. Wagaw, S. J. Wittenberger, J. Zhang, J.

Am. Chem. Soc. 2002, 124, 13097 21

N

CuII

N

OO

Ph Ph

N

CuIIN

OO

Ph PhO O

MeO OMe

N

CuIIN

OO

Ph PhO O

MeO OMe

+H+

-H+

N NBrO

Br

Ns

H

NEt(i-Pr)2

H

i-Pr2EtNN R

O

Br=R

NO

R+H+

-H+ -Br-

22

Proposed Mechanism ofCu-Catalyzed Alkylation (II)


Am. Chem. Soc. 2002, 124, 13097 22

CuII

O O

NR OMe

CO2Me

NCuIIN

OO

Ph Ph

CuII

O O

MeO OMeH

CuII

O O

MeO OMe

MeO2C CO2Me

NO

R

HNO

RBr

-HBr

-H+

iPr2EtN H

HNO

R

CO2MeCO2Me

CuII

O O

MeO OMe

N

O

R

N N N N

NNNN

2

2

Proposed Mechanism ofCu-Catalyzed Alkylation (III)


Am. Chem. Soc. 2002, 124, 13097 23

HN

R

O

N

CuIIN

OO

Ph PhO O

MeO OMe

N

CuIIN

OO

Ph PhO O

MeO OMe

stericrepulsion

HN

R

O

CuII

O O

MeO OMe

N

O

R

CuII

O O

NR OMe

CO2Me

‡ ‡

N N N N

Installation of Alkyl Chain


HN NBr

CO2MeCO2Me

O Ns alkyllithiumGrignard reagent

N

3

NBr

OEtEtO

CO2MeCO2Me

Ns

N NBr

CO2MeCO2Me

OTf Ns

Tf2O2,6-lutidine

CH2Cl2, -78 °C

EtO

OEt

B

Pd(PPh3)4, (o-tolyl)3Pborane A, K2CO3

THF, 75 °C

borane A

Suzuki coupling

N3

NBr

O OEtEtO

CO2MeCO2Me

Ns

MnO2CH2Cl2

oxidation of C3

54%, 2 steps(73% brsm, 2 steps)

65%

Attempted Construction of C,E-Rings


N N

O OEtEtO

CO2Me

CO2Me

Ns p-thiocresolK2CO3, MeCN

N

CO2MeCO2Me

NBr

O

undesired

N N

O OEtEtO

CO2Me

CO2Me

N-deprotection

BrBr

N N

OEtO

CO2Me

CO2MeBr

E1cBeliminiation

8-endo

-EtOHHN

NO

CO2MeCO2Me

Br

desired

C

OEtOEt

5-exo

H

82%

Construction of C,E-Rings (II)


N N

O OEtEtO

CO2Me

CO2Me

NsN

O

CO2MeCO2Me

OEt

N

Br

Ns

HN

NO

CO2MeCO2Me

Br

OEt

desired

; p-thiocresol

5-exo

Br

EtONaTHF N N

OEtO

CO2Me

CO2Me

Ns

Br

E

NO

CO2MeCO2Me

OEt

N

Br

E

C

E1cB 6-endo

66%

Formation of 7-membered Ring (I)

1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.27

HN

NO

CO2MeCO2Me

Br

OEt N

NO

CO2MeCO2Me

Br

OEt

N

NO

CO2MeCO2Me

Br

N

N

OCO2Me

CO2Me

; TMSOTf

Bu3SnH or (TMS)3SiH-mediated,photoredox-catalyzed,

or cobalt-catalyzedradical cyclization

Me3O•BF4 CH2Cl2

D

72%

Formation of 7-membered Ring (II)

1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.2) Sole, D.; Cancho, Y.; Llebaria, A.; Moreto, J. M.; Delgado, A. J. Am. Chem. Soc. 1994. 116, 12133.3) Nicolaou, K. C.; Roecker, A. J.; Follmann, M.; Baati, R. Angew. Chem., Int. Ed. 2002, 41, 2107.4) Okamura, H.; Mori, N.; Watanabe, H; Takikawa, H. Tetraherdon Lett. 2018, 59, 4397.

28

N

NO

CO2MeCO2Me

Br

N

N

OCO2Me

CO2Me

N

N

OCO2Me

CO2Mereductive Heck coupling

undesired

desired

Pd(OAc)2 (20 mol%)K2CO3, Bu4NCl, HCO2Na

DMF, 80 °C

Ni(cod)2 (6 eq.)NaI (10 eq.), Mg(OTf)2 (2 eq.)

DMF, 80 °C

Ni-mediated cyclyzation

Ni0

Ni0(cod)2

D

50%

46%

Ni(cod)2-Mediated Cyclization

1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.2) Sole, D.; Cancho, Y.; Llebaria, A.; Moreto, J. M.; Delgado, A. J. Am. Chem. Soc. 1994. 116, 12133.3) Nicolaou, K. C.; Roecker, A. J.; Follmann, M.; Baati, R. Angew. Chem., Int. Ed. 2002, 41, 2107.4) Okamura, H.; Mori, N.; Watanabe, H; Takikawa, H. Tetraherdon Lett. 2018, 59, 4397.

29

N

NO

CO2MeCO2Me

Br

N

N

OCO2Me

CO2Me

N

NO

CO2MeCO2Me

NiIILnX

oxidativeaddition

activationof enone

N

NO

CO2MeCO2Me

NiIILnX

transferinsertion

work up

X = Br or I or OTfNi0Ln MgII

X

X

N

NO

CO2MeCO2Me

NiIILnXMgIIX

MgIIX

eliminationof NiII

N

NO

CO2MeCO2Me

MgIIX

-NiIILnX2

X

X

Total Synthesis of (+)-Corimine


N

N

OCO2Me

CO2Me

N

N

HO CO2MeCO2Me

from less hindered face

lactonization

; i-Bu2AlH-78 °C

from lesshindered face

(+)-coryimne

KBH4MeOH

Cs2CO3toluene, 100 °C

KBH495%

82%

N

N

O CO2Me

O

N

N

O CO2Me

OH2

H BH3

N

N

O CO2Me

OHH

Extension to Other Family

1) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.31

OHN

NO

CO2MeCO2Me

N

N

HO CO2MeCO2Me

N

N

HO CO2MeH

(-)-deformylcorymine

(1) CS2, NaH, MeI THF, 0 °C to rt(2) (TMS)3SiH, AIBN benzene, 80 °C

N

N

CO2MeH

(-)-10-demethoxyvincorine

i-Bu2AlHtoluene, -78 °C

N

N

CO2Me

OH

HO

N

N

CO2Me

OAc

H

Ac2O/Py; CF3CO2H

(-)-3-epi-dihydrocormine-17-acetate

N

N

OCO2Me

H

N

N

CO2MeH

(1) SmI2 THF/MeOH(2) BF3•OEt2, Et3SiH CH2Cl2

(-)-2(S)-cathafoline

LiCl, DMF, 120 °C

KBH4MeOH

LiClDMF, 120 °C

95%

71%

82%70%

80%

77%

62%

Short Summary


N

N

O CO2Me

OHH

N

NO

CO2MeCO2Me

N

NO

CO2MeCO2Me

Br

N N

O OEtEtO

CO2Me

CO2Me

NsHN N

CO2Me

CO2Me

O NsHN N

O

Br

Ns

hemiacetalization Ni-mediatedcyclization

nucleophiliccyclizatoin

Suzukicouplingasymmetric

addition

• 11 steps synthesis• Cu-catalyzed asymmetric addition• construction of C, E-rings on one step• Ni-mediated 7-endo cyclization

Br Br Br

2 steps fromcommercially available

compound

(+)-corymine

CD

E

N

N

O CO2Me

OHH

N

N

OMe

CO2MeHH

N

OMe

NH

Boc

N

N

OMe

CO2MeHCOTePh

H

StBu

N

NO

CO2MeCO2Me

Br

HN N

CO2Me

CO2Me

O Ns

HNN

Ns

Br

radicalcyclization

Ni-mediatedcyclization

; Hemiacetalization

asymmetricalkylationasymmetric

Diels-Aider reaction

(-)-vincorine (+)-corymine

achiral indol derivative

N

N

OMe

CO2MeHCHO

H

Boc

Br

by MacMillan by Li

CDE

CD

E

Summary

1) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442.2) Zhang, B.; Wang, X.; Li, C. J. Am. Chem. Soc. 2020, 142, 3269.

33

total synthesis of (+)-corymine

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