The academic Synthetic Chemist s Dilemma. Lecture outline

Transcription

1 IASC XV Synthephilia: For the love of natural product synthesis Stephen anessian University of Montreal, Canada University of California, Irvine, USA Wednesday, September 26, 2012 C Relevant Chemistry in the anessian Group Website: atural Product Synthesis Borrelidin J. Am. Chem. Soc. 2003, 125, a Carbohydrates P R Ac Drug Prototypes C 2 Asymmetric Synthesis asymmetric conjugate addition asymmetric cyclopropanation asymmetric olefination asymmetric aziridination asymmetric phosphonates Molecular Recognition and Self-Assembly Supraminols J. Am. Chem. Soc. 1995, 117, 7630 E-Selectin Antagonist J. rg. Chem. 2002, 67, scillarin J. Am. Chem. Soc. 2004, 126, Peptides J. Am. Chem. Soc. 1998, 120, J. rg. Chem. 2000, 65, 5623 Chem. Rev. 1997, 97, Boc euraminidase Inhibitor J. Am. Chem. Soc. 2002, 124, 4716 airpin Structure Chem. Eur. J. 2002, 8, 111 C 2 (1982) 2 Bu Renin Inhibitor J. rg. Chem. 2002, 67, 4261 Morphinomimetic Angew. Chem., Int. Ed , 40, 3810 Chemical Diversity 2C Ar Tubular Superstructure J.rg.Chem. 2008, 73,1181 C C 2 Tetrahedron Lett. 2002, 43, 9441 Targeted Drug Delivery Fe Catalysis 99% ee 3 Super paramagnetic iron oxide nanopolymer Bioorg.d.Chem 2008,16, rg. Lett. 2006, 8, 4787, 2000, 2,,2975 RA Ligands and Antibiotics Aminoglycosides Angew. Chem., Int. Ed. 2004, 43, 6735 Lecture outline Definitions The Why, What, and ow of synthesis The visual dialogue with molecules The psychobiology of heuristic synthesis planning Living through a total synthesis Synthesis: from whence we came, to where we are going Ciao The academic Synthetic Chemist s Dilemma 1. Incentives, reasons, and rationales for synthesis (The Why of synthesis) 2. Which molecule should I synthesize? (The What of synthesis ) 3. ow can I make sure I have an efficient and viable route? (The ow of synthesis) 4. Where and with what do I begin?

2 The Why of Synthesis 18 Chapters ver 900 pages Expected before end of 2012 ature: the provider, the healer and the enticer (new antibiotics) The supply problem (practical syntheses of sparse compounds) Synthesis as a seeker of truth (correction of misassigned structures) Beyond the molecule (buckeyballs and friends) Exploring new dimensions in methodology (efficiency and practicality) Creating new entities and materials (nanomolecules and beyond) The What of Synthesis Selected ighlights in Total Synthesis Fascinating Molecular Shapes Cubane Adamantane omopentaprismane Dodecahedrane Bullvalene Twistane 2 C atone Corannulene C 60 f ullerene CP-263,114 (omoidride B)

3 Selected ighlights in Total Synthesis of Complex atural Products Selected ighlights in Total Synthesis of Complex atural Products 2 Tetrodotoxin Kishi, 1972 Erythronolide B Corey, P C Co C 2 Gibberellic acid Corey, V itamin B 12 Woodward and Eschenmoser, 1973 Ac C 2 Vindoline Büchi, 1975 Erythromycin A Woodward, Strychnine Magnus, 1992* Stork, 1992* verman, 1993 Kuehne, 1993*, 1998 Rawal, 1994* Martin, 1996* Bonjoch, 1999 Vollhardt, 2000* Shibasaki, 2002 Bodwell, 2002* Mori, 2002 Fukuyama, 2004 Padwa, 2006* Andrade 2010* Reissig 2010* Vanderwal 2011 MacMillan 2011 Ginkgolide B Corey, 1988 Crimmins, Ptylomycalin A verman, 1995 Bz Ac Taxol icolaou, 1994 olton, 1994 Danishefsky, 1995 Wender, 1997 Mukaiyama, 1998 Kuwajima, 1998 orbol Bz Ac Wender, 1997 Cha, 2001 Selected ighlights in Total Synthesis of Complex atural Products Selected ighlights in Total Synthesis of ighly xygenated Complex atural Products 2C 2 Cl Cl 2 V ancomycin icolaou, 1998 Evans (aglycon), 1998 Boger (aglycon), C Azaspiracid-1 icolaou, 2005 Evans, 20007

4 Selected ighlights in Total Synthesis of ighly xygenated Complex atural Products Selected ighlights in Total Synthesis of ighly xygenated Complex atural Products Swinholide A Paterson, 1994 icolaou, 1996 Cytovaricin Evans, 1990 alichondrin B Kishi, 1992 Ac 2 C C 2 Azadirachtin Ley, 2007 ighlights in Total Synthesis of ighly xygenated Complex atural Products Selected examples of recently marketed drugs produced by total synthesis 2 Palytoxin Kishi, 1989 & 1994

5 The ow of Synthesis tal-catalyzed Chemistry Asymmetric Synthesis: Resident-chirality control (substrate control) Reagent or catalyst control (external control). a. tal and ligand-based; b. tal-free based (organocatalysis) The Chiron Approach : (Structural and stereochemical elements dictate strategy) Maximizing chirality and structural convergence using nature s chiral non-racemic molecules (amino acids, carbohydrates, hydroxy acids, terpenes) The Synthon Approach (Reaction feasibility dictates strategy) Biomimetic Synthesis Bryostatin 16 B.M. Trost Br rganocatalysis in atural Product Synthesis Boc + t-bu 1. (20 mol%), Ts 2. ab 4, 78% 2 steps Br Boc ME t-bu Ts Biomimetic Cascade Reactions in Total Synthesis R* Br Boc Br Boc 5 steps Br D.W.C. MacMillan Flustramine B

6 Biomimetic Cascade Reactions in Total Synthesis disrotatory 6 electrocyclization C 2 R conrotatory 8 electrocyclization C 2 Diels-Alder Endiandric acid B icolaou, K. C.; Petasis,. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5555 C 2 R C 2 C Living Through a Total Synthesis A. Choice of target molecule B. Perceptive powers and seeing through the mind s eye C. Emergence of a strategy D. Generation of a synthesis plan E. Execution F. Endurance G. Contribution to science. Recognition I. Lasting value Bafilomycin A 1 (2001) Borreledin (2003) 2 C Reserpine (1997) Relevance euristics, open-eyed serendipity, and personal bias Individual prowess, creativity Attention to detail, possible fixation (beware!) Efficiency, practicality What price synthesis? ew concepts, reactions, reagents, etc. Fame, fortune, legacy Coworker training R Ca Ionomycin Ca salt (1990) Avermectin B 1a (1986) C Total Synthesis Scenarios (synthephilia) The ike approach: Just do it The Kekulé approach: I dreamed of it The Archimedes approach: Eureka, eureka The Sinatra approach: I did it my way 2 C Reserpine (1997) Borrelidin (2003) R R R Bafilomycin A 1 (2001) Manassantin A, B (2006) Avermectin B 1a (1986) Ca Ionomycin (1990) VISUAL AD REFLEXIVE TARGET MLECULE Analysis, discovery, connectivity, stereochemical and functional decoding, strategic bond-breaking, etc. Reflex action (instinctive) Key reaction type Suitable blueprint (reaction, reagents, schemes) Laboratory (execution) Subunit analysis (analogic) VISUAL Suitable building block (template fitting synthon or chiron) VISUAL AD RELATIAL LGISTIC, AALYTIC, LIEAR MAUAL, TEMPRAL, LISTIC

7 The psychobiology of heuristic synthesis planning: Visual and mental thought processing Essentials of the Chiron Approach August 17 issue, 2012 Whereas the left hemisphere of the brain analyses over time, the right hemisphere synthesizes over space idiolactones: The synthesis in a capsule Visual relational and visual reflexive thought processing from eye to mind s eye Catalytic Reformatsky Burgess dehydration 12 Baylis-illman C 2 R Stereoselective methylation X xidation Functionalization Epoxidation Bromolactonization Elimination C 2 Wieland-Miescher Ketone with Boyer,.; Reddy, G. J.; Deschenes-Simard, B. rg Lett. 2009, 11, 4640 As an entity, the target molecule is different from the sum its parts, but the visual chasm that separates the two gradually disappears, as the synthesis plan takes shape, like a progressive epiphany of thoughts and images Dihydromevinolin intramolecular Diels-Alder reaction nitronate anion 1,4-conjugate addition R' R A Baeyer-Villiger oxidation D E F endo-transition state vs. B R' exo-transition state + R TBDPS C 2 "" 2 "" C C L-glutamic acid with Roy, P.; Petrini, M.; odges, P. J.; Di Fabio, R.; Carganico, G. J. rg. Chem. 1990, 55, 5766

8 Synthesis and the mind s eye Synthesis and the mind s eye 2 C Vincamine [L-Aspartic acid]. Rappoport L. A. Paquette chanism and knowledge-based visual relational thinking Key strategic bond construction -based visual reflexive thinking. iemstra ent-gelsedine [L-Malic acid] The False Mirror R.Magritte (1928) W. C. Still Functional group and chiral template-based visual relational thinking Pactamycin Unique interactions Isolation Isolated in 1961 from Streptomyces pactum by scientists at the former Upjohn Company. Proposed structure of pactamycin was reported in 1970 and corrected in 1972 with help of X-ray crystallographic studies. Structure: Biology Exhibits activity against Gram positive and Gram negative bacteria. Potent in vivo and in vitro cytotoxic effects as well as antimicrobial activity. Potent protein synthesis inhibitory activity in prokaryotes as well as in eukaryotes. Wiley, P. F., et al. J. rg. Chem. 1970, 35, Duchamp, D. J., et al. American Crystallographic Association eting. 1972, April, p. 23. Isolation and biological activity: Bhuyan, B. K., et al. Antimicrob. Agents Chemother., 1961, 184. Argoudelis, A. D., et al. Antimicrob. Agents Chemother., 1961, Aromatic stacking in pactamycin mimics two consecutive mra bases. Pactamycin displaces mra in the E-site, preventing movement through the 30S subunit. Ramakrishnan, V. et al. Cell 2000, 103, 1143

9 Major challenge: ow to orchestrate the sequence and type of reactions? Claisen condensation Yb(Tf) 3 -mediated epoxide opening Cyclopentenone core 2 2 A C 2 isocyanate coupling 1 ester oxazoline 3 R Claisen condensation B 4 extension to ketone Grignard oxidation, then intramolecular aldol with methyl ketone ketene-mediated esterification Ar C R Absolute configuration Epoxidation and Reduction PMP TES 2 2,a 88% TBDPS PMP TES TBDPS conditions PMP TES TBDPS PMP TES TBDPS ab 4, CeCl 3 > 20 : 1 ab : 1 LiB 4 10 : 1 KB 4 5 : 1 Zn(B) 4 > 20 : 1 B 3. TF decomposition TBDPS TES 2.47% E 2.11% E no E observed

10 Introduction of azide First major setback: wrong epoxide! expected = obtained Epoxide inversion via solvolysis Good epoxide! 3 PMP 1. TBDPSCl, TEA DMAP, DCM 2. Tf 2, pyridine, DMAP, DCM 96% 2steps 3 PMP TBDPS

11 Epoxide opening 2 Pactamycin and Pactamycate 3 2 (10 eq.) Yb(Tf) 3, toluene TBDPS 80 o C 81% (91% bsmr) 3 TBDPS pactamycin pactamycate mp [ ] D 210 o C (decomp.) +26 o (in DMF) Wiley, P.F.; Jahnke,.K.; MacKellar, F.; Kelly, R.B.; Argoudelis, A.D. J. rg.chem. 1969, 35, Crystalline pactamycate! C 3 Lindlar, 2 K 2 C 3, DMA : Et 98% 83% C 2 Synthetic pactamycate 3 earing the summit? TBDPS 1. 2 Cl, 63%, 83% bsmr 2. DIBAL, DCM, 90% TBDPS Esterification method, Porco, J. A et al rg.lett. 2002, 4, Cl 63%, 83% bsmr 3 PMBz 2 TBDPS

12 D### Carbamate! Extreme proximity effects 3 PMBz 2 TBDPS Cl 3 CCCl, TEA activated charcoal TF 91% 3 PMBz TBDPS A very uncooperative amine! More surprises PMP TBDPS 2 Cl, TF, r.t. 63% 3 PMBz 2 TBDPS a, BnBr TBAI, TF 84% 3 PMBz 2 TBDPS Bn Bn Cl 3 CCCl, TEA activated charcoal TF 85% PMBz 3 C Bn TBDPS Bn 2 neat 96% PMBz 3 2 Bn TBDPS Bn

13 eutralizing the enemy Pactamycin: reaching the summit! PMP 3 TBDPS 1. 2 Cl,TF, r.t. 63% (93% bsmr) 2. TASF, TF 0 o C to r.t., 95% PMBz 2 3 2,2-DMP : DCM (1:5) CSA, r.t. 86% 3 PMBz 1. DIBAL, DCM, -78 o C, 90% 2. Lemieux-Johnson 80% 3. TFA: C: 2 (5:1:1), 0 o C to r.t. 85% PMBz 2 3 via: Cl 3 CCCl activated charcoal TEA, TF then 2 neat 86% PMBz C 3 PMBz C 2, K 2 C 3, DMA 2. Lindlar, 2, : Et (1:1) 82%, 2 steps 29 linear steps, 3% overall yield 700 Mz nmr, PLC, RMS; optical rotation The long and arduous climb to the summit 2 isocyanate coupling Claisen condensation Grignard ketene-mediated esterif ication Yb(Tf) 3 -mediated epoxide opening Ca J. Am. Chem. Soc. 1990, 112, 5276 C C 2 J. Am. Chem. Soc. 2003, 125, rg. Lett. 2006, 8, 5477 J. rg. Chem. 1990, 55, C J. rg. Chem. 1991, 56, 2947 rg. Lett. 2005, 7, 3989 with Vakiti, R.R.; Dorich, S.; Banerjee, S.; Lecomte, F.; Del Valle, J. R.; Zhang, J.; Deschesnes-Simard, B. Angew. Chem. Int. Ed. 2011, 50, 3497