Synthesis of (±)-Actinophyllic Acid and Analogs: … 11-Steps Total Synthesis of Magellanine...

A 11-Steps Total Synthesis of Magellanine through a Gold(І)-Catalyzed

Dehydro Diels-Alder Reaction

Reporter: Hong-Qiang Shen Checker: Cong Liu Date: 2017/06/19

McGee, P.; Bétournay, G.; Barabé, F.; Barriault, L. Angew. Chem. Int. Ed. 2017, 56, 6280-6283.

Literature Report

Introduction

Total synthesis of (-)-magellanine by Yang

Total synthesis of (+/-)-magellanine by Barriault

Summary

Contents

CV of Louis Barriault

Position: Full Professor

in University of Ottawa

Education:

1993 B. Sc., University of Sherbrooke

1997 Ph. D., Chemistry, University of Sherbrooke

1999 Postdoctoral Fellow, Ohio State University

2000 Assistant Professor, University of Ottawa

2010 Full Professor, University of Ottawa

Lycopodium Alkaloids

HO

N

O

H

HH

AB

C

DN

OH

H

HH

AB

C

DH H

O

N

H

HH

AB

C

DH

O

Paniculatine Magellanine Magellaninone

O

Magellanine

Isolated from Lycopodium magellanicum in 1976

Treatment of Alzheimer’s disease and myasthenia gravis

Six contiguous stereocenters, polycyclic framework

N

OH

H

HH

AB

C

DHO

Magellanine Lycopodium 石松

Proposed Retrosynthesis

N

OH

H

HH

AB

C

DHO

NTs

O

H

OHH

AB

DH

TBSO

NTs

O

HA

B

DH

TBSOO

NO

Ts

A

DO SPh

A +N

I

Ts

D

Removalof OH

Site-selectivealdol

magellanine

1 2 3

13 10

C

Yang, Y.-R. et al. Org. Lett. 2014, 16, 5612.

Synthesis of Key Intermediate 7

NTs

OTBS

H

NO

TsO SPh

a) NaH, DMF, 2, 80%

b) mCPBA, DCM, then CaCO3, Toluene, reflux

TiCl4, Allyl-TMS

DCM, -78 oC to rt

NO

TsOsO4, NMO86%

NO

Ts

HO

OHa) TBSCl, Imidazolea) MsCl, DMAP

O

NO

Ts

TBSO

OH

85%

b) AcOH, H2O/THF69%67%

b) tBuOK,THF

81%1 3

4

567

AD

A

A

D

B

N

I

Ts2

NTs

OTBS

H

O

a) NaBH4, MeOHb) TBSOTf, Et3N

c) TBAF,THF

NTs

OH

H

TBSO

a) PCC, Celiteb) HF·Py, THF

NTs

O

H

HO69%

77%

7 8 9

AB

D


NTs

OH

H

TBSOa) BH3·Me2S

NTs

O

H

TBSOOH

tBuOK, Toluene

NTs

O

H

OHHH

TBSOH

NTs

O

H

HHH

TBSO

NTs

O

H

HTBSOBurgess reagent H2, Pd/C

b) PCC, 4 Å MS65%

68%

8 10d.r. = 2:1

11

12 13

80% 88%

AB

D


Burgess Reagent

O N

O

SN

OO

R1

HR2

R3

OH

SNCO2MeEt3N

O O

H

O

SNCO2Me

OO

R2 R3R1

R1 R2

R3

It is used to convert secondary and tertiary alcohol with an adjacent proton into alkenes. Primary alcohols do not work well. The reagent is soluble in common organic solvents and alcohol dehydration takes place with syn elimination through an intramolecular elimination reaction.

a) NaBH4 a) TBAF

NTs

O

H

HTBSO

a) LDA, Cl(Ph)S=NtBu HMPA

NTs

OMOM

H

HTBSO

Na-Naph then HCHONaBH3CN, 62%

NTs

OMOM

H

HO

N

OMOM

H

HOb) 10% HCl (aq)

N

OH

H

HO

DIAD, PPh3, PhCO2H,NaOH

N

OH

H

HO

b) MOMCl iPr2NEt

95%

b) PCC, 4 Å MS81%

65%

13 14 15

1617(-)-magellanine

HH

HH

HHHH

HH

HH

75%

Synthesis of Magellanine

Mukaiyama Method

LDA

N

OMOM

H

HO

N

OH

H

HO

16 17

N

OMOM

H

HLiOCl(Ph)S=NtBu

N

OMOM

H

HO

SPh

NH

tBu

HH

HH

HH H

H

Mukaiyama, T. et al. Chem. Lett. 2000, 1250.

Dehydro Diels-Alder Reaction (DDA)

+dehydro Diels-Alder

reaction (DDA)

RO

[LAu]

n

OR

n

ORH

H

nRO-[LAu]

n

H

[LAu]

Barriault, L. et al. Angew. Chem. Int. Ed. 2017, 56, 6280.

N N

iPr

iPr iPr

iPr

L1

iPr

iPriPr

OMe

PCy2MeOPtBu2

L2 L3

iPr

iPriPr

PtBu2

L4

iPr

iPriPr

OMe

PAr2MeO

L6Ar = 3,5-CF3C6H3

N

PAd2

L5

O

EtO2C CO2Et

TIPSO

[LAuNCMe]SbF6

PhMe, rt, 16h

EtO2C CO2EtH

TIPSO

EtO2C CO2EtH

TIPSO+ +

EtO2C CO2EtH

TIPSO

18 19a 19b 19c


Entry Ligand Loading (mol %) 19a:19b:19ca Yield (%)a

1 L1 2.5 6:6:1 98 2 L1 1.0 6:6:1 98 3 L1 0.5 6:6:1 51 4 L1 0.1 6:6:1 18 5b L1 1 13:0:1 98 6b L2 1 12:0:1 98 7b L3 1 9:0:1 98 8b L4 1 5:0:1 98 9b Ph3PAuNTf2 1 > 20:0:1 68 10b L5 1 > 20:0:1 49 11b L6 1 > 20:0:1 98 (96)c

a Determined by 1H NMR analysis of the crude reaction mixture using mesitylene as internal standard. b One equivalent of CSA was added to the reaction mixture only after all the starting material was consumed. c Isolated yield .


E E

TIPSO

R2

[L6AuNCMe]SbF6 (1 mol%)PhMe, 16h

then CSA (1 equiv)

E EH

R2

TIPSO

R1

R1

n n

E = CO2Et

E EH

TIPSO

nE EH

TIPSO

nE EH

TIPSO

E EH

TIPSO

Ph

n = 2 n = 3

79% yield 61% yield 91% yield 81% yield[b]

E EH

TIPSO

93% yield[c]

EE

93% yield[c]

HTIPSO

E EH

TIPSO

86% yield, d.r. = 1:1[b]E EH

TIPSO

89% yield[b,d]

O

[a] Isolated yields, ratio 5-exo/6-endo and d.r. > 20:1. [b] Reaction run using 2 mol% of catalyst. [c] Reaction run using 1 mol% of [L1AuNCMe]SbF6. [d] No addtion of CSA.


Proposed Retrosynthesis

NOH

H

H

O

TsN

TIPSO

E E

Au(I)-DDA 1,4-addition

EE

E = CO2Et

+

TsN

OMitsunobu/Diels-Alder

Oxidation/AldolHO +

TsNH

20 21

222324

TsN

OTsNH

HOTMAD, TBP,then 150 oC

TsN

H

Hd.r. = 1:1

TsN a) OsO4, NMO, NaIO4

b) Piperidine, HOAc

[gram scale][gram scale]

a) TIPSOTf, DMS then

21, LiHMDS, THF, -78 oC

EEE = CO2Et

TsN

TIPSO

E E

[L6AuNCMe][SbF6] (1 mol%)then CSA, 91%

[gram scale]

[gram scale]

TsN

TIPSO

H E E

a) TBAF, 60 oC, then, LiOH 140 oC

b) DMP, DCMTsN

O

H CO2H

PtO2, H2

TsN

O

H CO2H

24 25 26 22

20 27

28 29

70%

58%

81%

80%84%


TsN

O

H CO2H

iPrC(O)Cl, NMM,Et3N, Toluene, 0oC

S

N S

OH

TsN

O

H

OO

NS

S

TsN

O

H

LED(365 nm), O2

CH3(CH2)8C(CH3)2SH then PPh3

OHH

TsN

O

H HOH

DIAD, HCO2H, Ph3Pthen LiOH

TsN

O

H OHH

TsN

O

H OHH

Na, C10H8, THF

then HOAc, CH2ONaBH3CN N

O

H OHH

LDA, TMSCl

then Cl(Ph)S=NtBuHCl

N

O

H OHH

29 30 31 (29%)

32 (26%) 31 (59%)

31 32 (+/-)-magellanine74% 64%


Radical Oxidative Decarboxylation

N S

SO

O

R

NS

S SR'

+

CO2

R

O2

ROOR'SH

ROOH+

PPh3 ROH

RCOO

TsN

O

H CO2H

iPrC(O)Cl, NMM,Et3N, Toluene, 0oC

S

NS

OH

TsN

O

H

OO

NS

S

TsN

O

H

LED(365 nm), O2

CH3(CH2)8C(CH3)2SH then, PPh3

29 30

R'S

OH

Zard, S. Z. et al. Tetrahedron 1998, 54, 6751.

Summary

27 steps, 1.1% overall yield Aldol cyclization Dehydration through Burgess reagent

11 steps, 2.7% overall yield Au-catalyzed cycloaddition Radical oxidative decarboxylation

Yang, Y.-R. et al. Org. Lett. 2014, 16, 5612.

Barriault, L. et al. Angew. Chem. Int. Ed. 2017, 56, 6280.

N

OH

H

HH

AB

C

DHO

The First Paragraph

The development of new transformations for the efficient

synthesis of architecturally complex scaffolds via operationally

simple and practical protocols is of paramount importance. In this

regard, the specific affinity of cationic gold complexes for π-system

and their ability to stabilize neighboring cationic charges have

stimulated the development of efficient and reliable methods for the

construction of C-C bonds.

The First Paragraph

The cycloaddition between an enyne and a olefin known as the

dehydro Diels–Alder reaction (DDA) is a expedient process for the

synthesis of cyclohexadienes and related carbocycles. While the

thermal DDA reaction is well documented, the use of transition

metals to catalyze this reaction remains marginal.

The Last Paragraph

In conclusion, we have developed an innovative and

operationally facile methodology for the formation of carbocycles

via a gold(I)-catalyzed cycloaddition. This reaction gives access to

various complex angular fused-ring systems in high

diastereoselectivities. The practicality of this Au-catalyzed

transformation was validated in the total synthesis of (+/-)-

magellanine 7 which was accomplished in only 11 steps from

alcohol 18, one of the shortest total syntheses known to date.

Further applications of this transformation in natural product

synthesis are currently ongoing and will be reported in due course.

Synthesis of (±)-Actinophyllic Acid and Analogs: … 11-Steps Total Synthesis of Magellanine...

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Transcript of Synthesis of (±)-Actinophyllic Acid and Analogs: … 11-Steps Total Synthesis of Magellanine...