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

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. 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

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Pasteur Pasteur’s ’s Degradation Degradation Reaction Reaction of of Quinine Quinine OMe OMe HN N 1 H 2 SO 4 5 O OH H N N quinotoxine quinine OMe OMe Louis Pasteur N HN (1822 - 1895) H OH OH H N N Chance favors only H 2 O 4 the prepared mind. 3 —Louis Pasteur Classics Classics in in Total Total Synthesis Synthesis II, II, Wiley-VCH,Germany, Wiley-VCH,Germany, 2003, 2003, Ch. Ch. 15 15

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Formal Formal Synthesis Synthesis of of Quinine Quinine By By Woodward Woodward and and Doering Doering

Woodward/Doering’ Retrosynthetic Woodward/Doering Retrosynthetic Analysis Analysis and and Strategy Strategy OMe OMe OEt CO 2 Et Rabe H HN N MeO route O + O BzN OH H N N H N Condensation quinotoxine quinine 9 5 10 1 H CHO AcN AcN N O OH OH H Me OH Me Me 12 14 13 11 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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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 OEt H H O AcN BzN O H Me H 10 11 2. Rapid construction of the carbon framework in the target molecule OEt H O N vs. BzN OH H N 17 10 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

The The First First Stereoselective Stereoselective Total Total Synthesis Synthesis of of 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

Stork Stork’s ’s Retrosynthetic Retrosynthetic Analysis Analysis and and Strategy Strategy OMe OMe OMe NH O N N 8 1 OR 6 OH H Alkylation N N N 24: deoxyquinine 1: quinine Selective hydride OMe OMe delivery OMe N H N N OR OR OR N N H N 25 26 Reduction and imine formation OMe RO OMe OMe + Me O HO N 3 N 3 N 3 O OR OR N N N Nucleophilic addition 30 27 29 28 J. J. Am. Am. Chem. Chem. Soc Soc. 2001, 2001, 123, 123, 3239 3239

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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 of the synthetic precursor are of similar energy, and makes the C-8 non-stereoselective. OMe OMe 8 HN HN vs. N 8 N 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. OMe OMe N H NH 8 8 OR OR N H N 3. Install C-9 stereocenter by oxygenation which utilize the steric bulk of the bridgehead nitrogen in the quinuclidine ring.

Catalytic Catalytic Asymmetric Asymmetric Synthesis Synthesis of of 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)

Yesterday Once Yesterday Once More: More: N1-C8 N1-C8 Disconnection Disconnection Jacobsen Jacobsen’s s Retrosynthetic Retrosynthetic Analysis Analysis and and Strategy Strategy OMe OMe OMe PN N 1 N O 8 P OH N N Suzuki Intramolecular N Sharpless coupling S N 2 dihydroxylation quinine 20 21 1 O COPh OMe N O O H H PO CN N Ph M H X CO 2 Me + PN Enantioselective PO H N conjugate addition 9 6 4 5 J. Am. J. Am. Chem. Chem. Soc. Soc. 2004, 2004, ASAP ASAP

Jacobsen’s Jacobsen s Total Total Synthesis Synthesis of of Quinine Quinine J. J. Am. Am. Chem. Chem. Soc Soc. 2004, 2004, ASAP ASAP

Jacobsen’s Jacobsen s Total Total Synthesis Synthesis of of Quinine Quinine J. J. Am. Am. Chem. Chem. Soc Soc. 2004, 2004, ASAP ASAP

OMe Jacobsen’s Jacobsen s Total Total Synthesis Synthesis of of Quinidine Quinidine OH N N 2 J. Am. J. Am. Chem. Chem. Soc Soc. 2004, 2004, ASAP ASAP

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

Comparison Comparison of of the the Two Two Steroselective Steroselective Total Total Synthesis Synthesis of of Quinine Quinine Date Group Step Yield Reality Key Step 2001 Stork 16 7% Stereoselective C8 High Stereospecific reduction set C8 2004 Jacobsen 16 5% Catalytic, C4, C8 and C9 High, Sharpless Asymmetric dihydroxylation

Large-Scale Synthesis of VANOL Method IV to intermediate 20  Synthesis of 20 from b-hydroxyester O Br CO 2 Et + Zn + Ph OEt OH Ph O 42 O 41 Hydrolysis OH OH 1) Reformatsky reaction OH Ph Ph O + BnMgCl O 40 28 CO 2 Et OH Ph Ph 43 2) Addition to ketone 28  Successful examples: OEt MeO MeO O O Zn, I 2 , OH + Br CO 2 Et 96% PhH Ph Ph 45 44  Can this condition be used for my compound? OEt O O Zn, I 2 , Br CO 2 Et + OH PhH, Et 2 O, 4h Ph worked Ph 42 28 41 Park, O. S, Jang, B. S. Archives of Phar.Research , 1995, 18, 277

Large-Scale Synthesis of VANOL Future Work: Synthesis of VANOL and Resolution 1) POCl 3 190 o C O Ph OH Ph O (+) and 1) (-)-brucine P air, 32h Ph OH (-)VANOL Ph O 2) resolution 2) H 2 O OH Ph OH 3) reduction 33 5 3 Key point: monomer 5 must be pure for oxidative coupling MeO N MeO H H N H O O H (-)-brucine Bao, J.; Wulff, W. D. et al J. Am. Chem. Soc. , 1996, 118 , 3392

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 optimized. 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.