Catalytic Asymmetric Total Syntheses of Quinine and Quinidine OMe 3 - - PowerPoint PPT Presentation

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Catalytic Asymmetric Total Syntheses of Quinine and Quinidine OMe 3 - - PowerPoint PPT Presentation

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Catalytic Asymmetric Total Syntheses of Quinine and Quinidine OMe 3 3 2 2 OMe 4 4 OH 7 7 5 5 N N 8 9 1 1 6 6 8 N OH 9 N Quinine Quinidine Zhensheng Ding January 22 2004 Chinese New Year Day 1. Jacobsen, E., N. J. Am.

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SLIDE 1

Catalytic Asymmetric Total Syntheses of Quinine and Quinidine

Zhensheng Ding January 22 2004 Chinese New Year Day

  • 1. Jacobsen, E., N. J. Am. Chem. Soc. 2004, ASAP
  • 2. Stork, G.; Niu, D. J. Am. Chem. Soc. 2001, 123, 3239
  • 3. Nicolaou, K., C. Classics in Total Synthesis II: More Targets,

Strategies, Methods, Wiley-VCH: Weinheim, Germany, 2003, Ch. 15

N OMe OH N

Quinine

1 2 3 4 5 6 7 8 9 N OMe N

Quinidine

1 2 3 4 5 6 7 8 9 OH

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SLIDE 2
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SLIDE 3

1

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SLIDE 4
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SLIDE 5
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SLIDE 6

1 2

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SLIDE 7

1 Pasteur Pasteur’s ’s Degradation Degradation Reaction Reaction of

  • f Quinine

Quinine

N OMe OH H N H2SO4 N OMe OH H N H H2O N OMe OH HN N OMe O HN

quinine quinotoxine 3 4 5

Classics Classics in in Total Total Synthesis Synthesis II, II, Wiley-VCH,Germany, Wiley-VCH,Germany, 2003, 2003, Ch.

  • Ch. 15

15

Louis Pasteur (1822 - 1895)

Chance favors only the prepared mind.

—Louis Pasteur

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SLIDE 8

5 6 7 8 1

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SLIDE 9

Formal Formal Synthesis Synthesis of

  • f Quinine

Quinine By By Woodward Woodward and and Doering Doering

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SLIDE 10

HN N N OMe O N MeO CO2Et BzN O OEt H H N OMe OH H

Condensation

OH CHO AcN H H Me O AcN Me OH N Me OH

quinine quinotoxine Rabe route

+

1 5 9 10 11 12 13 14 Woodward/Doering Woodward/Doering’ Retrosynthetic Retrosynthetic Analysis Analysis and and Strategy Strategy

J.

  • J. Am.
  • Am. Chem.
  • Chem. Soc.
  • Soc. 1945,

1945, 67, 67, 860 860 J.

  • J. Am.
  • Am. Chem.
  • Chem. Soc.
  • Soc. 1944,

1944, 66, 66, 849 849

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SLIDE 11

14 15 16 16 17 13 12

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SLIDE 12

12 11

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SLIDE 13

11 18 19 20 21 22

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SLIDE 14

22 23 10 9 5

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SLIDE 15

What What we we can can learn learn from from Woodward Woodward’s s Synthesis Synthesis

  • 1. The formation, modification, and eventual cleavage of carbon

frameworks in cyclic settings to generate acyclic stereochemical elements

  • 2. Rapid construction of the carbon framework in the target

molecule

  • 3. The application of nitrite ester cleavage protocol can prevent

epimerization, directly afford the requisite ester side chain, and make it easy to make double bond

AcN H H Me O BzN O OEt H H

10 11

N OH

17

N

  • vs. BzN

O OEt H H

10

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SLIDE 16
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SLIDE 17

The The First First Stereoselective Stereoselective Total Total Synthesis Synthesis of

  • f Quinine

Quinine By By Stork Stork

Gilbert Stork (Emeritus)

Department of Chemistry Columbia University Box 3118, Havemeyer Hall New York, NY 10027 (212) 854-2178 gjs8@columbia.edu

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SLIDE 18

Stork Stork’s ’s Retrosynthetic Retrosynthetic Analysis Analysis and and Strategy Strategy

J.

  • J. Am.
  • Am. Chem.
  • Chem. Soc
  • Soc. 2001,

2001, 123, 123, 3239 3239

N OMe OH H N O N OMe N N OMe N OR N OMe N OR N OMe N3 OR O N OMe N3 OR HO

Alkylation

N OMe N OMe Me N OMe N OR H H NH OR N3 O RO

1: quinine 24: deoxyquinine

8 +

Reduction and imine formation Nucleophilic addition Selective hydride delivery 25 26 27 28 29 30

1 6

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SLIDE 19

31 32 33 34 35 30

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SLIDE 20

29 30 28 26 25 24 1

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SLIDE 21

What What we we can can learn learn from from Stork Stork’s ’s Synthesis Synthesis

  • 1. Conformational analysis shows that the two pseudo-chair forms
  • f the synthetic precursor are of similar energy, and makes the C-8

non-stereoselective.

  • 2. Follow the words of wisdom by Robert Ireland: “All too often

the most convenient way to draw a molecule on paper belies the most efficient synthetic approach.” This helps to construct the C-8 stereocenter.

  • 3. Install C-9 stereocenter by oxygenation which utilize the steric

bulk of the bridgehead nitrogen in the quinuclidine ring.

N OMe HN 8 N OMe HN

vs.

8 N OMe N OMe N OR H H NH OR 8 8

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SLIDE 22

Catalytic Catalytic Asymmetric Asymmetric Synthesis Synthesis of

  • f Quinine

Quinine and and Quinidine Quinidine By By Jacobsen Jacobsen

Eric N. Jacobsen

Sheldon Emery Professor of Chemistry

Harvard University Department of Chemistry, 12 Oxford Street Cambridge, MA 02138 (617) 496-3690 (Assistant)

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SLIDE 23

J.

  • J. Am.
  • Am. Chem.
  • Chem. Soc.
  • Soc. 2004,

2004, ASAP ASAP

Yesterday Yesterday Once Once More: More: N1-C8 N1-C8 Disconnection Disconnection Jacobsen Jacobsen’s s Retrosynthetic Retrosynthetic Analysis Analysis and and Strategy Strategy

N OMe OH N N OMe PN O N H CO2Me O COPh CN PO N H Ph O O PO N OMe PN H H M N P N OMe X

quinine Intramolecular SN2 Suzuki coupling Enantioselective conjugate addition Sharpless dihydroxylation

+ 8 1

1 21 20 5 4 6 9

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SLIDE 24

J.

  • J. Am.
  • Am. Chem.
  • Chem. Soc
  • Soc. 2004,

2004, ASAP ASAP

Jacobsen Jacobsen’s s Total Total Synthesis Synthesis of

  • f Quinine

Quinine

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SLIDE 25

J.

  • J. Am.
  • Am. Chem.
  • Chem. Soc
  • Soc. 2004,

2004, ASAP ASAP

Jacobsen Jacobsen’s s Total Total Synthesis Synthesis of

  • f Quinine

Quinine

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SLIDE 26

J.

  • J. Am.
  • Am. Chem.
  • Chem. Soc
  • Soc. 2004,

2004, ASAP ASAP

N OMe N OH

2

Jacobsen Jacobsen’s s Total Total Synthesis Synthesis of

  • f Quinidine

Quinidine

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SLIDE 27

What What we we can can learn learn from from Jacobsen Jacobsen’s s Synthesis Synthesis

  • 1. Application of recently developed (salen)Al-Catalyzed conjugate

addition of methyl cyanoacetate to construct C4 stereocenter efficiently.

  • 2. C8 & C9 chiral center can be formed by Sharpless

dihydroxylation with high dr.

  • 3. Yes, disconnection of N1-C8 bond provides a way to asymmetric

total synthesis of quinine

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SLIDE 28

Date Group Step Yield Reality Key Step 2001 Stork 16 7% Stereoselective C8 High Stereospecific reduction set C8 2004 Jacobsen 16 5% Catalytic, Asymmetric C4, C8 and C9 High, Sharpless dihydroxylation

Comparison Comparison of

  • f the

the Two Two Steroselective Steroselective Total Total Synthesis Synthesis of

  • f Quinine

Quinine

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SLIDE 29

Large-Scale Synthesis of VANOL Park, O. S, Jang, B. S. Archives of Phar.Research, 1995, 18, 277

Method IV to intermediate 20

Ph OH O OH Ph OEt O OH Ph Ph O CO2Et Ph O Br CO2Et 2) Addition to ketone Hydrolysis + + Zn 1) Reformatsky reaction + BnMgCl 28 40 41 42 43 Ph O MeO Br CO2Et PhH Ph OEt O OH MeO + Zn, I2, 96% 44 45 Ph O Br CO2Et PhH, Et2O, 4h Ph OEt O OH + Zn, I2, worked 41 42 28 Ph OH O OH 28

 Successful examples:  Synthesis of 20 from b-hydroxyester  Can this condition be used for my compound?

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SLIDE 30

Large-Scale Synthesis of VANOL

Future Work: Synthesis of VANOL and Resolution

OH OH Ph Ph OH Ph O O Ph Ph P O OH 5 3 190oC air, 32h 1) POCl3 2) H2O 1) (-)-brucine 2) resolution 3) reduction (+) and (-)VANOL 33 N O N O MeO MeO H H H H (-)-brucine

Key point: monomer 5 must be pure for oxidative coupling

Bao, J.; Wulff, W. D. et al J. Am. Chem. Soc., 1996, 118, 3392

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SLIDE 31

Large-Scale Synthesis of VANOL

Conclusions

1) A new synthetic approach of VANOL was studied. This new method provides a cheap, efficient way for large scale synthesis of VANOL ligand. 2) Conditions for Michael addition, hydrolysis and Friedel-Crafts reaction were

  • ptimized.

3) Michael addition was scaled up successfully in high yields. More work is needed to scale up Friedel-Crafts reactions. 4) Dehydrogenation reaction was studied and optimization of the conditions is in progress. 5) Some new methods have been briefly discussed.