Retrosynthe*cAnalysis

A11-StepTotalSynthesisofMagellaninethroughaGold(I)-CatalyzedDehydroDiels-AlderReac*on

PhilippeMcGee,GenevièveBétournay,FrancisBarabé,andLouisBarriault*

N

O

OHHAB C

D

(+/-)Magellanine (7)

Ka#eBoknevitzProfessorS.-Y.Liu

02/23/2017

Angew.Chem.Int.Ed.2017,56,Earlyview.

•  Alkaloidisolatedfromtheclubmoss,LycopodiumMagellanicum

•  Tetracyclicangularcarbonframework•  Sixcon*nguousstereogeniccenters•  Applica*onofGold-catalyzedDDAreac*on

1

N

O

OHHAB C

D

NTsA

B

TIPSO

E EE

E

E = CO2Et

NTs

O

HO NH

Ts

(+/-)Magellanine (7)15

17

161918

Au(I)-DDA 1,4-addition

Mitsunobu/Diels-Alder

oxidation/aldol

2

ForwardSynthesisOverview

NH

Ts

HO

NH

H

TsN OTs

a) TMAD, TBP

then 150 °C70 %

b) OsO4, NMO, NaIO4

c) Piperidine, HOAc, MePh58% over 2 steps

d) TIPSOTf, DMS then

LiHMDS, THF, –78 °C81%

EE

NTs

TIPSO

E E

E = CO2Et

N

TIPSO

Ts H EE

e) [L6AuNCMe][SbF6](1 mol%)then CSA91%

f) TBAF, 60 °Cthen LiOH, 140 °C

92%

g) DMP, CH2Cl287%NTs H

O

CO2H

h) PtO2, H2,

EtOAc84%NTs H

O

CO2H

i) iPrC(O)Cl, NMM,Et3N, Toluene, 0 °C

N

S

OH

S

NTs H

O

OO

NS

S

LED (365nm), O2

CH3(CH2)8C(CH3)2SHthen PPh3

26% (27) + 29% (28)NTs H

O

YX

27 X=H, Y=OH28 X=OH, Y=H

N H

O

OH

k) Na, C10H8,THF

then HOAc, CH2O,NaBH3CN

74%N H

O

OH

l) LDA, TMSCl

then LDA,

64%N

StBuCl

Ph

j) DIAD, HCO3H, Ph3Pthen LiOH, 59%

NTs

18

19

20

21 16

2324

25

26 29 30

1715

22

(+/-)Magellanine (7)

ForwardSynthesisMechanisms

3

E

E Br

Pd(PPh3)4 (2 mol%)

CuI (4 mol%), DIPEATHF

EE

Pd0R–X

R–PdII–X

CuX

R'H

R'Cu

R–PdII R'

NH(iPr)2(Et)XN(iPr)2(Et)

R'RSynthesis of 17: Sonogashira Coupling

17E = CO2Et

OA

TM

RE

O

Oethyl sorbate

1) LDA, THF, HMPA

2) LiAlH4

OH

18

O

O

H

NLi

O

O

PONN

N

HMPA

H+

O

O

1)

2) H–OH

18

Determines selectivity of enolate formation

Synthesis of 18: Isomerization/Reduction

O

OHtautomerization

NH

Ts

HO

NH

H

Ts

a) TMAD, TBP

then 150 °C70 %

1:1.6 mixture ofdiastereomers

b) OsO4, NMO, NaIO4

18

19

21

N OTs

16

c) Piperidine, HOAc, MePh

58% over 2 stepsN

H

H

Ts

21aO

O

TMAD: TetramethylazodicarboxamideTBP: Tributylphosphine

NNO

NO

N

18 to 21: Mitsunobu/Diels-Alder

NNO

NO

NPR3

R3P

ROH H

NNO

NO

NPR3

RO

ROPR3

18

NH

Ts

NTs

20–H+

NH

H

Ts

21

4

21 to 21a: Lemieux-Johnson protocol

OsO

O

O

O

R

R

R

R

O OsO

OO

OsO

OH

O

HO

N

O

O

N

O+ H2O

2 H2O

R

R

OHOH

NaIO4R

R

O IO

HO OOHO

Na

2x PT

NH

H

Ts

21a OO

NaIO3H2O

21a to 22: Aldol Condensation

PT N OTs

16

R

R

21aO

OH

R

R

O

OHHN

– H2O R

R

O

N

R

R

OH

NR

ROH

N

H – H2O

R

R

N + H2O

– amine

5

R

TIPSO

E ER

[Au]+

R

TIPSO

E ER

[Au]

R

R

TIPSO

E E

[Au]

R

R

TIPSO

H E E

[Au]

HH

R

R

TIPSO

H E E

[Au]

N

TIPSO

Ts H E E

22

15

15 to 22: Gold-catalyzed Dehydro-Diels Alder

R

R

TIPSO

E E

[Au]

H

MeO PAr Ar

OMe

iPr

iPriPr

JackiePhos (L6)

*Diastereoselec#vetransforma#on(>95:5)

N OTs d) TIPSOTf, DMS then

LiHMDS, THF, –78 °C81%

EE

NTs

TIPSO

E E

E = CO2Et

1617 15

N

TIPSO

Ts H E E

22

e) [L6AuNCMe][SbF6](1 mol%)

then CSA91%

O

16

R

R

SiOTf

S

OR

RS

TIPS

EE

EE

17

H

NTs

TIPSO

E E

15LiHMDS

16 to 15: 1,4-addition

N

TIPSO

Ts H E E

f) TBAF, 60 °C

then LiOH, 140 °C92% NTs H

O

CO2H

h) PtO2, H2,

EtOAc84% NTs H

O

CO2H23 2422

g) DMP, CH2Cl2

87%NTs H

HO

CO2H22a

OR

RSi

N 4F

22

OR

R= O

RO

OEtOOEt

+ 2 LiOHO

RO

OOO

∆

– CO2NTs H

O

OO

NTs H

O

CO2 NTs H

O

CO2NTs H

HO

CO2H22a

2 H+

– 2 EtOH

22 to 22a: One-pot desilylation/saponification/decarboxylation

HOR

R

22a

OI

O

OAcOAc

AcO

OI

O

OAcO

AcO

RR

H

– H+

OAc

– HOAc– AcO– NTs H

O

CO2H23

22a to 23: Dess-Martin oxidation

6

NTs H

O

CO2H24

i) iPrC(O)Cl, NMM,Et3N, Toluene, 0 °C

N

S

OH

S

25

NTs H

O

OO

NS

S

26

LED (365nm), O2

CH3(CH2)8C(CH3)2SHthen PPh3

26% (27) + 29% (28)NTs H

O

YX

27 X=H, Y=OH28 X=OH, Y=H

j) DIAD, HCO3H, Ph3Pthen LiOH, 59%

HO

RR

R

i-PrO N NO

Oi-Pr

ODIAD

PPh3

i-PrO N NO

Oi-Pr

O

PPh3

HO OH

O

i-PrO NH

NO

Oi-Pr

O

PPh3

HO O

O

27

i-PrO NH

HN

OOi-Pr

O

O

RR

R

PPh3 OH NTs H

O

OH

28

27 to 28: Mitsunobu reaction

7

R

RR

OOH

Cl

OR

RR

OO

O24

HO

N

O

N HCl

R

RR

OO

O

N

S

HO

S

OO

NS

S

26

RR

R

HO

O

C9H19 S

R

S

OO

RR

R– CO2

RR

R

O O

RR

R O O

H

RR

R O OH

R

S

PPh3

RR

R O

O PPh3

HNTs H

O

YX

27 X=H, Y=OH28 X=OH, Y=H

O=PPh3

24 to 27/28: Radical oxidative decarboxylation

PT

NTs H

O

N H

O

OH

k) Na, C10H8,THF

then HOAc, CH2O,NaBH3CN

74%N H

O

OH

l) LDA, TMSCl

then LDA,

64%N StBu Cl

Ph

29 (+/-)Magellanine (7)28

OH

NS

RR

O

ONa2

N

RR

SO2Na

O

O HO

HH

O

HH

H

N

RR

OH

H

N

RR

OH2 H2O

N

RR

H BH2CNNa

N H

O

OH

29

28 to 29: One-pot detosylation/reductive amination

N H

O

OH

29

NLi

H

N H

O

OH

SiCl

N H

O

OH

Si

NS tBuCl

Ph

N H

O

OH

SN

Ph

tBuCl H

NLi

N H

O

OH

(+/-)Magellanine (7)

29 to 7: Oxidation

8Conclusion:Finaltargetachievedin11stepsfromknowncompounds.