total synthesis of (-)- himandrine · total synthesis of (-)-himandrine movassaghi, m.; ... ii....

41
Total Synthesis of (-)- Himandrine Movassaghi, M.; Tjandra, M.; Qi, J. J. Am. Chem. Soc. 2009, 131, 9648-9650. Jason M. Stevens - 07.29.2009

Upload: dokhuong

Post on 20-Aug-2018

246 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Total Synthesis of (-)-Himandrine

Movassaghi, M.; Tjandra, M.; Qi, J.J. Am. Chem. Soc. 2009, 131, 9648-9650.

Jason M. Stevens - 07.29.2009

Page 2: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Galbulimima Alkaloids

2

OMeN

Me

HO

OBzCO2Me

(-)-himandrine

NHMe

HO

O

GalbulimimaAlkaloid 13

OMeN

Me

HO

OH

himgaline

Movassaghi MovassaghiSchering PloughEvansMander

Schering-PloughEvans

O

O

Me H

H H

H

N

Me

H

himbacine himbeline

O

O

Me H

H H

H

HN

Me

HMe

Hart and Kozikowski

Page 3: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

• Isolated from the bark of Galbulimima belgraveana (New Guinea/Australia)

• Galbulimima Alkaloids have shown to be useful as antithrombotic agents and possible agents for offsetting Alzheimer’s disease

• This work is ~75% the same as for GB-13

About (-)-Himandrine

Page 4: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Retrosynthesis

OMeN

Me

HO

OBzCO2Me(-)-himandrine

OMeNHMe

HO

N O

OMe

O

N ON

Me

Me

NOMeMe

TBSO

OO

+

4

Page 5: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Retrosynthesis

OMeN

Me

HO

OBzCO2Me(-)-himandrine

OMeNHMe

HO

N O

OMe

O

N ON

Me

Me

NOMeMe

TBSO

OO

+

4

Responsible for setting everystereocenter in the molecule

Page 6: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

HO OHO

i. D-ProlinePhNOCH2Cl2, 0 oC

ii. NaBH4, MeOH

90%, 98.4% eeHO O NHPh

Zn, AcOH

EtOH

80%

Page 7: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

HO OHO

i. D-ProlinePhNOCH2Cl2, 0 oC

ii. NaBH4, MeOH

90%, 98.4% eeHO O NHPh

Zn, AcOH

EtOH

80%

O N HN

Ph

RCO2

-

Page 8: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

HO OHO

i. D-ProlinePhNOCH2Cl2, 0 oC

ii. NaBH4, MeOH

90%, 98.4% eeHO O NHPh

Zn, AcOH

EtOH

80%

O N HN

Ph

RCO2

-

Why C-O bond formation andnot C-N bond formation?

Page 9: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

O OMeHO OMe

TBSO OMeTBSO OH

TBSClimidazole, DMAP

DMF, 0 oC

94%

Me3O.BF4Proton Sponge

4Å-MS, CH2Cl2

93%

HCl

MeOH

98%

SO3.pyridine

i-Pr2NEt, DMSO

CH2Cl2

CBr4, PPh3

CH2Cl2, 0 oC

65% (2 steps)

HO OH

BrBr

OMe

Page 10: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

O OMeHO OMe

TBSO OMeTBSO OH

TBSClimidazole, DMAP

DMF, 0 oC

94%

Me3O.BF4Proton Sponge

4Å-MS, CH2Cl2

93%

HCl

MeOH

98%

SO3.pyridine

i-Pr2NEt, DMSO

CH2Cl2

CBr4, PPh3

CH2Cl2, 0 oC

65% (2 steps)

HO OH

BrBr

OMe

Why Meerwein conditions?

Page 11: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

BrBr

OMe (HO)2B

Me

OTBS

BrOMeMe

TBSOPd(PPh3)4, Tl2CO3

THF, H2O

97%

Page 12: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

BrBr

OMe (HO)2B

Me

OTBS

BrOMeMe

TBSOPd(PPh3)4, Tl2CO3

THF, H2O

97%

Why is there complete selectivity for the “E”-Br?

Page 13: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

BrBr

OMe (HO)2B

Me

OTBS

BrOMeMe

TBSOPd(PPh3)4, Tl2CO3

THF, H2O

97%

Why is there complete selectivity for the “E”-Br?

What is the role of the Tl2CO3?

Page 14: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

R Br RBr

PdCl2(dppf)

R1MgBr

RBrR R1+ +

Page 15: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

R Br RBr

PdCl2(dppf)

R1MgBr

RBrR R1+ +

Generally, E-vinyl bromides are much more reactive than Z-vinyl bromides

Page 16: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

Pd(0)

BrBr

OMe

BrPdIIBr

OMePdIIBr

OMe

Me

OTBS

BrOMeMe

TBSO

B(OH)2

Me

OTBS

HO

KOH: rel rate = 1TlOH: rel rate = 1000

(HO)2B

Me

OTBS

M-OH

If oxidative addition is the slow step then this intermediate is short lived and quickly consumed.

If transmetallation is the slow step then this intermediate is long livedand eventually decomposes

TlOH significantly accelerates thetransmetallation step thus fixingoxidative addition as the slow step

Page 17: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

CuI, K2CO3,β-lactam MeNH(CH2)2NHMe

Toluene, 120 oC

85%BrOMeMe

TBSO

NOMeMe

TBSO

O

What is this even for?

Page 18: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

NOMeMe

TBSO

O

NOMeMe

HO

O

NOMeMe

O

O

TBAF, THF

0 oC to rt

DMSO, i-Pr2NEtSO3

.pyridine

CH2Cl2

80% (2 steps)

NOMeTBSO

O

TBSOTf, NEt3

CH2Cl2, -78 oC

82%

acrolein4,5-DihydroIMES-Cl2Ru=CH(o-Oi-Pr)Ph(10 mol%)

CH2Cl2 1 h

85%N

OMeTBSO

O

O

NOMeMe

O

O

Page 19: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

TBSO

OHH

NO

H OMe

N,N-Diethylaniline

BHT, MeCN95 oC, 7 h

75%

H

NO

H OMe

OHH

H1. TiCl4 4Å-MS CH2Cl2, -78 oC

2. Martin Sulfurane benzene, rt

57% (2 steps)

NOMeTBSO

O

O

Page 20: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

TBSO

OHH

NO

H OMe

N,N-Diethylaniline

BHT, MeCN95 oC, 7 h

75%

H

NO

H OMe

OHH

H1. TiCl4 4Å-MS CH2Cl2, -78 oC

2. Martin Sulfurane benzene, rt

57% (2 steps)

NOMeTBSO

O

O

What is this for?

Page 21: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

TBSO

OHH

NO

H OMe

N,N-Diethylaniline

BHT, MeCN95 oC, 7 h

75%

H

NO

H OMe

OHH

H1. TiCl4 4Å-MS CH2Cl2, -78 oC

2. Martin Sulfurane benzene, rt

57% (2 steps)

NOMeTBSO

O

O

What is this for?

Enforces s-cis geometry

Page 22: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

TBSO

OHH

NO

H OMe

N,N-Diethylaniline

BHT, MeCN95 oC, 7 h

75%

H

NO

H OMe

OHH

H1. TiCl4 4Å-MS CH2Cl2, -78 oC

2. Martin Sulfurane benzene, rt

57% (2 steps)

NOMeTBSO

O

O

What is this for?

What is BHT for?

Enforces s-cis geometry

Page 23: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

TBSO

OHH

NO

H OMe

N,N-Diethylaniline

BHT, MeCN95 oC, 7 h

75%

H

NO

H OMe

OHH

H1. TiCl4 4Å-MS CH2Cl2, -78 oC

2. Martin Sulfurane benzene, rt

57% (2 steps)

NOMeTBSO

O

O

What is this for?

What is BHT for?

Enforces s-cis geometry

Protected carbonyl

Page 24: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Building the trans-Decalin

TBSO

OHH

NO

H OMe

N,N-Diethylaniline

BHT, MeCN95 oC, 7 h

75%

H

NO

H OMe

OHH

H1. TiCl4 4Å-MS CH2Cl2, -78 oC

2. Martin Sulfurane benzene, rt

57% (2 steps)

NOMeTBSO

O

O

What is this for?

What is BHT for?

Why Martin Sulfurane?

Enforces s-cis geometry

Protected carbonyl

Ph2SOC(CF3)2Ph

OC(CF3)2Ph

Page 25: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

The Cyclohexylamine

OMe

O

N ON

Me

Me

n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH

Page 26: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

The Cyclohexylamine

OMe

O

N ON

Me

Me

n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe

NRMe

O

N O

Page 27: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

The Cyclohexylamine

OMe

O

N ON

Me

Me

n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe

NRMe

O

N O

OMeNRMe

O

N O

Page 28: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

The Cyclohexylamine

OMe

O

N ON

Me

Me

n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe

NRMe

O

N O

OMeNRMe

O

N O

OMeN

HMe

HO

N O NaBH4

EtOH, 0 oC

Page 29: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

The Cyclohexylamine

OMe

O

N ON

Me

Me

n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe

NRMe

O

N O

OMeNRMe

O

N O

OMeN

HMe

HO

N O NaBH4

EtOH, 0 oCOMe

NHMe

HO

N O

Page 30: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

The Cyclohexylamine

OMe

O

N ON

Me

Me

n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe

NRMe

O

N O

OMeNRMe

O

N O

OMeN

HMe

HO

N O NaBH4

EtOH, 0 oCOMe

NHMe

HO

N O

complete selectivity

Page 31: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

The Cyclohexylamine

OMe

O

N ON

Me

Me

n-BuLi, THF;CuBr.Me2S, -78 to -40 oC;enone; -78 to -10 oC; PhSH OMe

NRMe

O

N O

OMeNRMe

O

N O

OMeN

HMe

HO

N O NaBH4

EtOH, 0 oCOMe

NHMe

HO

N O

complete selectivity

2-azetidinone still in placeto protect the carbonyl

Page 32: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

PG Adjustments

CBzClK2CO3, i-PrNEt2

THF, H2O, 0 oC to rt

50% (3 steps)OMe

NCbzMe

HOTsOH.H2O

benzene

81%

O

OMeN

CbzMe

HO

N O

OMeN

HMe

HO

N O

still rockin the2-azetidinone

Page 33: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Installing the Methyl EsterPOCl3, DMF

CH2Cl2, 0 oC to rt

71%OMe

NCbzMe

HO

O

Page 34: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Installing the Methyl Ester

POCl3, DMF

CH2Cl2, 0 oC to rt

71%

OMeNZ

Me

O O

OMeN

CbzMe

HO

OH

N+

Cl

Me Me

OMeNZ

Me

HO

O

N+MeMe

H

OMeNZ

Me

O O

NMe2H

OMeNZ

Me

O O

H

B

OMeN

CbzMe

HO

O

POCl3, DMF

CH2Cl2, 0 oC to rt

71%OMe

NCbzMe

HO

O

Page 35: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Getting Rid of the Enol

DDQ, SiO2

MeCN, waterOMeNZ

Me

O O

OMeNZ

Me

HO

O

O

Would anyone like to suggest a mechanism?

Page 36: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Installing the Methyl Ester

OMeNZ

Me

HO

O

OOMe

NZ

Me

HO

O

CO2H

NaClO2, NaH2PO42-methyl-2-butene

H2O, t-BuOH OMeNZ

Me

HO

O

CO2Me

CH2N2

THF, 0 oC

61% (3 steps)

TMSIDTBMP

CH2Cl2, 0 oC

66%OMe

NH

Me

TMSO

O

CO2Me

Et3N.(HF)3

THF

90%OMe

NHMe

HO

O

CO2MeOMeNZ

Me

HO

O

CO2Me

Page 37: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Almost There!

OMeNHMe

HO

O

CO2Me

N-chlorosuccinimide

MeCN, 45 min

89%

Page 38: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Almost There!

OMeNHMe

HO

O

CO2Me OMeNHMe

HO

OHOMeO

N-chlorosuccinimide

MeCN, 45 min

89%OMe

NHMe

HO

OOMeO

Cl

OMeN

Me

HO

OE

OMeNHMe

HO

O

CO2Me

N-chlorosuccinimide

MeCN, 45 min

89%

Page 39: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Also of Interest

OMeNHMe

HO

OE

N-chlorosuccinimide

CH3CN

stop reaction at 10 minOMe

NMe

HO

OECl

OMeN

Me

HO

OE

OMeN

Me

HO

OE

CH3CN

SM

CH3CNOMe

NMe

HO

OE

PDT PDT

can't form dienol!

H

OMeNDMe

HO

OE

D

MeOH MeOD

cyclohexylamine iscapable deprotonatingC9 to give the dienol

Page 40: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Finished

OMeN

Me

HO

OEOMe

NMe

HO

OHCO2Me

H

OMeN

Me

HO

OBzCO2Me

NaBH4

EtOH, 0 oC

90%

BzCl

pyridine, 7 d

87%

Yet another completelyselective NaBH4 reduction

Page 41: Total Synthesis of (-)- Himandrine · Total Synthesis of (-)-Himandrine Movassaghi, M.; ... ii. NaBH4, MeOH 90%, 98.4% ee HO ONHPh ... Building the trans-Decalin Br Br OMe (HO)2B

Conclusions

• Total synthesis completed in 27 steps.

• Proline catalyzed alpha-aldehyde oxidation provided the stereocenter that lead to the formation of all other stereocenters under substrate control.

• Demonstrated sequential cross-coupling reactions from a dibromoolefin.

• Transannular IMDA.

• Conjugate addition-Mannich reaction to incorporate the cyclohexylamine.

• NCS mediated late stage ring closure.