Total Synthesis of the Securinega Alkaloid ()-Secu'amamine A Liu, P.; - - PowerPoint PPT Presentation

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total synthesis of the securinega alkaloid secu amamine a
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Total Synthesis of the Securinega Alkaloid ()-Secu'amamine A Liu, P.; - - PowerPoint PPT Presentation

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Total Synthesis of the Securinega Alkaloid ()-Secu'amamine A Liu, P.; Hong, S.; Weinreb, S. M. J. Am. Chem. Soc. 2008 , 130 , 7562-7563 HO O O NH Enantioselective Total Syntheses of Nankakurines A and B: Confirmation of Structure and

slide-1
SLIDE 1

Total Synthesis of the Securinega Alkaloid (–)-Secu'amamine A Enantioselective Total Syntheses of Nankakurines A and B: Confirmation of Structure and Establishment of Absolute Stereochemistry

Liu, P.; Hong, S.; Weinreb, S. M. J. Am. Chem. Soc. 2008, 130, 7562-7563 Nilsson, B. L.; Overman, L. E.; de Alaniz, J. R.; Rohde, J. M. J. Am. Chem. Soc. 2008, 130, 11297-11299

NH HO O O R N Me N Me

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SLIDE 2

Total Synthesis of (–)-Secu'amamine A

Biogenetic Origin from Allosecurinine Mangus, P.; Padilla, A. I. Org. Lett. 2006, 8, 3569

  • Isolated in 2003 by Ohaki and coworkers
  • Securinega family of alkaloids
  • New structural framework

NH HO O O

(–)-secu'amamine A

N O O H

securinine

N O O H

allosecurinine

  • GABA receptor antagonist
  • antimalarial
  • antibacterial

N O O H HO N O O H

H2O H2O

NH HO O O N O O H HO

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SLIDE 3

Total Synthesis of (–)-Secu'amamine A

  • Isolated in 2003 by Ohaki and coworkers
  • Securinega family of alkaloids
  • New structural framework

NH HO O O

(–)-secu'amamine A

N O O H

securinine

N O O H

allosecurinine

  • GABA receptor antagonist
  • antimalarial
  • antibacterial

N MOMO H H O O MeO2C N MOMO H H O O MeO2C

conjugate addition

NH O MOM OH O H CO2Me NH O MOM O O O H NH O MOM O CO2Me O

aldol –MeOH Base-Promoted Cascade

slide-4
SLIDE 4

N Tr H CHO BrMg OTBDPS N Tr H OTBDPS OMOM

  • 1. THF
  • 2. MOMBr, DIEA

CH2Cl2 +

Total Synthesis of (–)-Secu'amamine A

  • 1. TBAF, AcOH, 95%
  • 2. HOAc, MeOH
  • 3. Boc2O, DIEA, MeOH, 89%

N Boc H OH OMOM

DMP

N Boc H O OMOM (MeO)2P(O) O CO2Me

NaH, THF, rt 70% (2 steps)

N Boc H OMOM O CO2Me N Boc H O OMOM O CO2Me

X

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SLIDE 5

Total Synthesis of (–)-Secu'amamine A

N Boc H OMOM O CO2Me

  • 1. TFA, CH2Cl2
  • 2. DIEA, CH2Cl2

–78 ºC, 70%

NH O MOM O CO2Me

+

NH O MOM H O CO2Me

desired (5:1)

N MOMO H H O MeO2C N MOMO H H O MeO2C NH O MOM O CO2Me NH O MOM O CO2Me NH O MOM H O MeO2C NH O MOM H O MeO2C

+ Proposed Mechanism

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SLIDE 6

Total Synthesis of (–)-Secu'amamine A

NH O MOM O CO2Me NH O MOM O CO2Me O

OsO4, NaIO4 H2O, THF, NMO 63% NaOMe, MeOH rt, 12 h

NH O MOM O O O H NH O MOM OH O H CO2Me

75% 15% + desired NaOMe MeOH 90%

NH O MOM O O O H NH O MOM O OTf O H

KHMDS PhNTf2 THF 85%

NH O MOM O O H

Pd(OAc)2 PPh3 H2CO2H DIEA, DMF 95%

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SLIDE 7

Total Synthesis of (–)-Secu'amamine A

NH O MOM O O H

LDA, PhSeCl THF 86%

NH O MOM O O H SePh

NaIO4, NaHCO3 MeOH, H2O 84%

NH O MOM O O

HCl, MeOH 60 ºC 93%

NH HO O O

(–)-secu'amamine A 15 steps 9% overall yield

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SLIDE 8

Total Syntheses of Nankakurines A and B

NH Me N Me

2004 Proposed Structure nankakurine A

R N Me N Me

nankakurine A (R = H) nankakurine B (R = Me) 2006 Proposed Structure

  • Lycopodium family of alkaloids
  • Induces secretion of neurotrophic factors
  • Isolated in 0.0002-0.0003%
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SLIDE 9

NHR Me N R

aza-Prins

NHR H H R Me Me N N R R

[3+2]

Total Syntheses of Nankakurines A and B

NH Me N Me

2004 Proposed Structure nankakurine A

R N Me N Me

nankakurine A (R = H) nankakurine B (R = Me) 2006 Proposed Structure

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SLIDE 10

TsHN(H2C)4 H

2.5 mol % Grubbs II ethylene (300 psi) CH2Cl2, 25 ºC 90%

TsHN(H2C)4 O Me

50 mol % EtAlCl2 CH2Cl2, PhMe, 25 ºC 74% (1:1 - 1:3 cis:trans)

O H H TsHN(H2C)4 Me

Total Syntheses of Nankakurines A and B

  • 1. HONH2•HCl, MeOH

KOH, 25 ºC, 56%

  • 2. MoO3, NaBH4

MeOH, 25 ºC, 98%

NH2 H H TsHN(H2C)4 Me

  • 1. ClCO2Me, Et3N, CH2Cl2

25 ºC, 56%

  • 2. (CH2O)n, TFA, CHCl3

25 ºC, 20%

NTs CO2Me N Me NHTs Me N MeO2C

aza-Prins

NH Me N Me

  • 1. Na, NH3, THF

–78 ºC, 98%

  • 2. LiAlH4, THF

25 ºC, 65%

1H and 13C NMR spectra

DO NOT MATCH

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SLIDE 11

Total Syntheses of Nankakurines A and B

BnO(H2C)4 H

2.5 mol % Grubbs II ethylene (300 psi) CH2Cl2, 25 ºC 90%

BnO(H2C)4 O Me

10 mol % TMSOTf CH2Cl2, 25 ºC, 90%

TMSO OTMS H BnO(H2C)4 Me O O H

FeCl3/SiO2 acetone, 25 ºC 99%

H BnO(H2C)4 Me H O

  • i. H2NNHCOPh, MeOH
  • ii. NaCNBH3, MeOH

HCl, 25 ºC, 80%

H BnO(H2C)4 Me H HN H N O Ph

(CH2O)n, 4 Å MS, (i-Pr)2NEt PhMe, 115 ºC, 82%

Me N N Ph O BnO(H2C)4 Me N N BnO(H2C)4 Bz

[3+2]

  • i. SmI2, 9:1, 80%
  • II. 37% aq. formaldehyde,

NaCNBH3, MeOH HCl, 25 ºC

Me N Me NBz BnO

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SLIDE 12

Total Syntheses of Nankakurines A and B

Me N Me NBz BnO

  • 1. H2, 10 mol % Pd(OH)2

HCl, MeOH, 25 ºC, 97%

  • 2. AlH3, THF, 25 ºC, 74%

Me N Me NBn HO

37% aq. formaldehyde, NaCNBH3, MeOH HCl, 25 ºC

Me N Me N Me

(+)-nankakurine B 80%

  • i. MsCl, Et3N, CH2Cl2,

–40 ºC, 96%

  • ii. H2, 10 mol % Pd/C,

HCl, MeOH, 25 ºC, 99%

H N Me N Me

(+)-nankakurine A 13 steps 20% overall yield 14 steps 16% overall yield