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The Future of Total Synthesis

The Future of Total Synthesis 24
The Future of Total Synthesis Jason M. Stevens 01.26.2012The Future of Total Synthesis a brief forward ■ The idea for tonights topic was from discussions with all of you over the past 1.5 years ■ The intent of presentation is to: ■ Discuss a brief history of total synthesis for the purpose of context ■ Briefly review the the best current work in the field of total synthesis ■ Present examples that underscore the transitions occurring in total synthesis for the purpose of discussionTotal Synthesis of Natural Products a brief history ■ It all began with urea... ■ Wöhlers synthesis of urea demonstrated that organic matter could be produced synthetically ■ Discredited vitalism, the theory that organic matter possessed a vital force inherent to living things O H N NH 2 2 urea Friedrich Wöhler (1828). "Ueber künstliche Bildung des Harnstoffs". Annalen der Physik und Chemie 88 (2): 253–256.Total Synthesis of Natural Products a brief history ■ Gustaf Komppa’s industrial synthesis of camphor in 1903 via semisynthesis from pinene ■ Camphor was a scarce natural product with a worldwide demand ■ Important milestone in synthetic organic chemistry Me Me Me O camphorTotal Synthesis of Natural Products a brief history ■ The modern era of total synthesis began with Woodward’s synthesis of quinine ■ The ability to utilize a predictive set of known reactions to execute a synthetic plan ■ Ushered in the modern era of total synthesis HO N MeO N quinine Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc. 1944, 66: 849849.Total Synthesis of Natural Products why we’ve made molecules since 1828 ■ Three driving forces for undertaking the total synthesis of natural products Potential Societal Impact Assist Structural Identification Inspire New Methods N HO H N N MeO H H O O H N originally proposed skeleton quinine strychnine of cholesterolTotal Synthesis of Natural Products why we make molecules in 2012 ■ Modern analytical methods have largely eliminated the need to verify structure through synthesis ■ We’re now entering an era where chemists can make molecules with unprecedented efficiency ■ Focus is largely shifting toward the synthesis of molecules that have the potential for societal impact Potential Societal Impact Assist Structural Identification Inspire New Methods N HO H N N MeO H H O O H N originally proposed skeleton quinine strychnine of cholesterolWhat is the Future of Total Synthesis topics for discussion ■ Brief discussion of how the field of total synthesis has changed over the past 50 years ■ Discussion will be limited to active research groups located at U.S. institutions since 1960 ■ Highlight recent literature that contrast the past and present of total synthesis ■ Use insights from these examples to look toward the future Potential Societal Impact Assist Structural Identification Inspire New Methods N HO H N N MeO H H O O H N originally proposed skeleton quinine strychnine of cholesterolKey Research Programs in Total Synthesis programs initiated from 19611972 Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972) Also: Phil Magnus, James Marshall, Albert Padwa, James White ■ Equipped with the knowledge that complex molecules can be made ■ The goals of synthetic efforts from this group largely focused on accessing the desired target Syntheses completed by 1972 Strychnine Woodward Prostaglandin Corey Reserpine Woodward Progesterone W. S. JohnsonKey Research Programs in Total Synthesis programs initiated from 19611972 Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972) Also: Phil Magnus, James Marshall, Albert Padwa, James White ■ Equipped with the knowledge that complex molecules can be made ■ Only a limited selection of reliable “synthons” Reactions and Reagents that Didn’t Exist in 1972 Active areas of research at that time Chiral Auxiliaries Hydroboration Heck, KumadaCorriu, Stille, and Suzuki Couplings Controlling enolate geometry Sharpless epoxidation Organic photochemistry TBSCl Crosscoupling reactionsKey Research Programs in Total Synthesis programs initiated from 19611972 Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972) ■ Throughout their careers they produced many total syntheses which, at the time their programs began, were seeming impossible R Cl O O O HO OH Cl O O H H H O N N N N N N Me H H H Me HN O O O HO C 2 NH Me 2 OH Vancomycin (Evans 1998) HO OH Evans, D. A.; Wood, M. R.; Trotter, W. B.; Richardson, T. I.; Barrow, J. C.; Katz, J. L. Angew. Chem. Int. Ed. 1998, 37, 27002704.Key Research Programs in Total Synthesis programs initiated from 19611972 Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972) ■ Devoted much of their careers to developing new methods to enable the synthesis of natural products Me OH HO Me H O HO O O O OR All stereocenters set by asymmetric Me Me HO O N OH aldol, alkylation or epoxidation O O Me Me Ph Me OHO OH cytovaricin (Evans 1990) Me H Me Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 70017031.Key Research Programs in Total Synthesis programs initiated from 19611972 Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972) ■ Pioneered many fundamental advances and applications for transition metal chemistry Me TsMeN H N O NH quadrigemine C H N H N Me Me N (Overman 2002) Bn N N TfO OTf Bn N N N N Me Me N H H H H HN O N H NMeTs Me Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc. 2002, 124, 90089009.Key Research Programs in Total Synthesis programs initiated from 19611972 Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972) ■ Executed syntheses of natural products with the aim of exploring its therapeutic potential OH Me HO HO O H H H Me O O H OMe spongistatin 1 X = Cl O HO O OH spongistatin 2 X = H O H H O Me (Evans 1998, Smith 2001) OH O H O X Me AcO OAc Me OHKey Research Programs in Total Synthesis programs initiated from 19611972 Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972) ■ Famous molecules as a benchmark for total synthesis and a continued source of inspiration N H N H H O O H strychnine Magnus, Overman, Padwa (Woodward)Key Research Programs in Total Synthesis programs initiated from 19731984 K.C. Nicolaou (1976) Paul Wender (1976) Dale Boger (1979) Stuart Schreiber (1981) Also: James Cook, Mike Crimmins, Gary Keck, Tom Hoye, Stephen Martin, Viresh Rawal, Bill Roush, Bob Williams Dave Williams and Jeffrey Winkler ■ Applied some of the most vigorously studied research in organic chemistry toward natural products ■ Completed brilliant total syntheses of some of the most complicated molecules ever isolated Ph H endiandric acids AD (Nicolaou 1982) H H CO H H 2 HO OH H Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 55555557.Key Research Programs in Total Synthesis programs initiated from 19731984 K.C. Nicolaou (1976) Paul Wender (1976) Dale Boger (1979) Stuart Schreiber (1981) Also: James Cook, Mike Crimmins, Gary Keck, Tom Hoye, Stephen Martin, Viresh Rawal, Bill Roush, Bob Williams Dave Williams and Jeffrey Winkler ■ Applied some of the most vigorously studied research in organic chemistry toward natural products ■ Completed brilliant total syntheses of some of the most complicated molecules ever isolated O O CO Et 2 O HO O O CO Et HO 2 O O O CMe O 3 Me Me hν TESO HO Me O TESO O Me Me Me Me ginkolide B (Crimmins 1999) Crimmins, M. T. et al. J. Am. Chem. Soc. 1999, 121, 1024910250.Key Research Programs in Total Synthesis programs initiated from 19731984 K.C. Nicolaou (1976) Paul Wender (1976) Dale Boger (1979) Stuart Schreiber (1981) Also: James Cook, Mike Crimmins, Gary Keck, Tom Hoye, Stephen Martin, Viresh Rawal, Bill Roush, Bob Williams Dave Williams and Jeffrey Winkler ■ During their careers the “synthetic toolkit” had expanded drastically ■ New transformations provided increased access to exceptionally complicated structures O HO H H Me H O Me H Me O Me O H H H H H O H O O O H O O H H O H H H O H H brevetoxin A (Nicolaou 1998, Crimmins 2008)Key Research Programs in Total Synthesis programs initiated from 19731984 K.C. Nicolaou (1976) Paul Wender (1976) Dale Boger (1979) Stuart Schreiber (1981) Also: James Cook, Mike Crimmins, Gary Keck, Tom Hoye, Stephen Martin, Viresh Rawal, Bill Roush, Bob Williams Dave Williams and Jeffrey Winkler ■ During their careers the “synthetic toolkit” had expanded drastically ■ The synthesis of Nature’s most complicated therapeutic leads became a worthy endeavor Ph AcO O OH Me HN O Ph Me OHO O Me O H HO OBz OAc taxol (Nicolaou 1994, Wender 1997)Key Research Programs in Total Synthesis programs initiated from 19731984 K.C. Nicolaou (1976) Paul Wender (1976) Dale Boger (1979) Stuart Schreiber (1981) Also: James Cook, Mike Crimmins, Gary Keck, Tom Hoye, Stephen Martin, Viresh Rawal, Bill Roush, Bob Williams Dave Williams and Jeffrey Winkler most synthetic efforts largely focused on accessing the desired target Key Research Programs in Total Synthesis programs initiated between 19851996 Andrew Myers (1986) Scott Rychnovsky (1988) Peter Wipf (1990) John Wood (1993) Also: Arun Ghosh, John Montgomery, James Panek, Tom Pettus and John Rainier ■ The goals of synthetic efforts from this group largely focused on accessing the desired target ■ Constructed molecules of incredible complexity with innovative methods OTMS Me Me H H CO H CO TIPS 2 2 OH O HN N O O O OMe OMe OTMS OTMS H H OH O OH O dynemicin (Myers 1995) Myers, A. G.; Fraley, M. E.; Tom, N. J. J. Am. Chem. Soc. 1994, 116, 1155611557.Key Research Programs in Total Synthesis programs initiated between 19851996 Andrew Myers (1986) Scott Rychnovsky (1988) Peter Wipf (1990) John Wood (1993) Also: Arun Ghosh, John Montgomery, James Panek, Tom Pettus and John Rainier ■ The goals of synthetic efforts from this group largely focused on accessing the desired target ■ Continued the traditions of building molecules of incredible complexity Me Me O Me Me H HO HO HO ingenol (Wood 2004) HO Nickel, A,; Maruyama, T.; Tang, H.; Murphy, P. D.; Green, B. Yusuff, N. Wood, J. L. J. Am. Chem. Soc. 2004, 126, 1630016301.Key Research Programs in Total Synthesis programs initiated between 19851996 Andrew Myers (1986) Scott Rychnovsky (1988) Peter Wipf (1990) John Wood (1993) Also: Arun Ghosh, John Montgomery, James Panek, Tom Pettus and John Rainier ■ The goals of synthetic efforts from this group largely focused on accessing the desired target ■ Continued the traditions of building molecules of incredible complexity Me OH NMe 2 HO H H OH NH 2 OH OH O OH O tetracycline (Myers 2005) Charest, M. G.; Siegel, D. R.; Myers, A. G.; J. Am. Chem. Soc. 2005, 127, 82928293.A Paradigm Shift in Total Synthesis “can we make everything” becomes “how well can we make everything” ■ A significant aim of the synthetic community from 1940 to 1995 entailed accessing the desired structure ■ Once the synthetic natural product was obtained the project was over ■ Recent years have placed additional focus on how well we access desired targets ■ The shift is evident (not ubiquitous) with total synthesis programs initiated after this period ■ This shift is being increasingly adopted by the research groups initiated before this periodA Paradigm Shift in Total Synthesis why the mid1990’s ■ In 1990 Corey wins the Nobel Prize in Chemistry for the... “...development of the theory and methodology of organic synthesis”.A Paradigm Shift in Total Synthesis why the mid1990’s ■ A high profile introspective analysis concerning synthetic efficiency was published in 1991. Atom Economy Trost B. M. Science 1991 254, 14711477.A Paradigm Shift in Total Synthesis why the mid1990’s ■ The taxol problem exemplified the limitations total synthesis for assembling structures that carry the potential to have societal impact (35 groups worked on taxol) Sam Danishefsky (1996) Paul Wender (1997) Robert Holton (1994) K.C. Nicolaou (1994) 46 longest linear steps 42 longest linear steps 49 longest linear steps 37 longest linear steps Ph AcO O OH Me HN O Ph Me OHO O Me O H HO OBz OAc taxolA Paradigm Shift in Total Synthesis why the mid1990’s ■ The taxol problem exemplified the limitations total synthesis for assembling structures that carry the potential to have societal impact (35 groups worked on taxol) Sam Danishefsky (1996) Paul Wender (1997) Robert Holton (1994) K.C. Nicolaou (1994) 46 steps 55 steps 49 steps 37 steps Consideration of the chemical complexity of baccatin III, which in suitably protected form would be the likely synthetic intermediate en route to taxol, should have engendered considerable skepticism and even disbelief that total synthesis would supplant natural sources as a route to the drug. More plausible, though as yet unrealized in practice, is the prospect that mastery of the synthesis of baccatin III will bring with it new nuclei which, upon suitable conjugation with biologically critical side chains, might provide medically promising variants of taxol. Samuel DanishefskyKey Research Programs in Total Synthesis programs initiated from 19972008 David MacMillan (1998) Erik Sorensen (2001) Phil Baran (2003) Mo Movassaghi (2003) Also: Martin Burke, Steve Castle, Jef De Brabander, Justin Du Bois, Greg Dudley, Paul Floreancig, Neil Garg, Timothy Jamison, Jeff Johnson, Jeff Johnston, Glen Micalizio, Jon Njardarson, Sarah Reisman, Richmond Sarpong, Karl Scheidt, Matthew Shair, Scott Snyder, Brian Stoltz, Regan Thomson, Chris Vanderwal, Lawrence Williams, Armen Zakarian. ■ Breakthroughs in catalysis have opened new doors for powerful synthetic methods ■ Previous efforts in total synthesis have provided a framework for new researchers to build on ■ The result is that highly complex targets are being synthesized with incredible efficiencyKey Research Programs in Total Synthesis programs initiated from 19972008 David MacMillan (1998) Erik Sorensen (2001) Phil Baran (2003) Mo Movassaghi (2003) Also: Martin Burke, Steve Castle, Jef De Brabander, Justin Du Bois, Greg Dudley, Paul Floreancig, Neil Garg, Timothy Jamison, Jeff Johnson, Jeff Johnston, Glen Micalizio, Jon Njardarson, Sarah Reisman, Richmond Sarpong, Karl Scheidt, Matthew Shair, Scott Snyder, Brian Stoltz, Regan Thomson, Chris Vanderwal, Lawrence Williams, Armen Zakarian. ■ Examples of powerful synthetic methods for total synthesis developed in the last 10 years H H H H H HO Me O O water O O Me 70 °C, 72 h O HO O O O H H H H H 71 common ladder toxin subunit Vilotijevic, I.; Jamison, T. J. Science 2007 317, 11891192 Key Research Programs in Total Synthesis programs initiated from 19972008 David MacMillan (1998) Erik Sorensen (2001) Phil Baran (2003) Mo Movassaghi (2003) Also: Martin Burke, Steve Castle, Jef De Brabander, Justin Du Bois, Greg Dudley, Paul Floreancig, Neil Garg, Timothy Jamison, Jeff Johnson, Jeff Johnston, Glen Micalizio, Jon Njardarson, Sarah Reisman, Richmond Sarpong, Karl Scheidt, Matthew Shair, Scott Snyder, Brian Stoltz, Regan Thomson, Chris Vanderwal, Lawrence Williams, Armen Zakarian. ■ Examples of powerful synthetic methods for total synthesis developed in the last 10 years Me Bn OH O O MgBr O CO tBu H 2 TBSO tBuO C TBS H 2 OAc O H CO tBu 2 H CO tBu THF tBuO C 2 2 CO H Bn O 2 OTBS 2 equiv 78 to 45 °C CO H O 2 HO C Me 50 2 OH zaragozic acid C Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C. Johnson, J. S. J. Am. Chem. Soc. 2008 130, 1728117283.Key Research Programs in Total Synthesis programs initiated from 19972008 David MacMillan (1998) Erik Sorensen (2001) Phil Baran (2003) Mo Movassaghi (2003) Also: Martin Burke, Steve Castle, Jef De Brabander, Justin Du Bois, Greg Dudley, Paul Floreancig, Neil Garg, Timothy Jamison, Jeff Johnson, Jeff Johnston, Glen Micalizio, Jon Njardarson, Sarah Reisman, Richmond Sarpong, Karl Scheidt, Matthew Shair, Scott Snyder, Brian Stoltz, Regan Thomson, Chris Vanderwal, Lawrence Williams, Armen Zakarian. ■ Examples of powerful synthetic methods for total synthesis developed in the last 10 years O NBoc NHBoc Me O O ·TBA N 1Nap ()strychnine N SeMe N tBu 82, 97 ee N H PMB PMB 20 mol Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011 850, 183188.Key Research Programs in Total Synthesis programs initiated from 19972008 David MacMillan (1998) Erik Sorensen (2001) Phil Baran (2003) Mo Movassaghi (2003) Also: Martin Burke, Steve Castle, Jef De Brabander, Justin Du Bois, Greg Dudley, Paul Floreancig, Neil Garg, Timothy Jamison, Jeff Johnson, Jeff Johnston, Glen Micalizio, Jon Njardarson, Sarah Reisman, Richmond Sarpong, Karl Scheidt, Matthew Shair, Scott Snyder, Brian Stoltz, Regan Thomson, Chris Vanderwal, Lawrence Williams, Armen Zakarian. ■ Examples of powerful synthetic methods for total synthesis developed in the last 10 years PhO S 2 O O H H N N O Me Me N S N Me Br N N O N O S Me Me N Me Me Me S O N CoCl(PPh ) O N 3 3 N N N S O 46 SO Ph 2 Me Me N N H H H O O SO Ph 2 (+)11,11’dideoxyverticillin A Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science 2011 324, 238241.Key Research Programs in Total Synthesis programs initiated from 19972008 David MacMillan (1998) Erik Sorensen (2001) Phil Baran (2003) Mo Movassaghi (2003) Also: Martin Burke, Steve Castle, Jef De Brabander, Justin Du Bois, Greg Dudley, Paul Floreancig, Neil Garg, Timothy Jamison, Jeff Johnson, Jeff Johnston, Glen Micalizio, Jon Njardarson, Sarah Reisman, Richmond Sarpong, Karl Scheidt, Matthew Shair, Scott Snyder, Brian Stoltz, Regan Thomson, Chris Vanderwal, Lawrence Williams, Armen Zakarian. ■ Advances in new methodologies and synthetic strategies have changed how we view total syntheses ■ Greater emphasis on striving for an “ideal synthesis” ■ To a growing extent, attaining the natural product is no longer the final goal ■ Total synthesis is starting to become an auxiliary function of new research in chemistryThe Future of Total Synthesis representation of what we strive to accomplish in total synthesis Me Bn O H H N Me N S N O N O S Me H H OAc O H Me S N O N CO H H H Bn 2 O N S CO H O 2 O Me O N H HO C H Me 2 H OH O zaragozic acid C (+)11,11’dideoxyverticillin A strychnine ■ Two syntheses outlined broadly applicable concepts (cascade catalysis, controlled oligimerization) ■ All outlined powerful methods to deliver the natural product in short order(1015 steps) ■ Two syntheses are of molecules with promising bioactivityThe Future of Total Synthesis representation of what we strive to accomplish in total synthesis Me Bn O H H N Me N S N O N O S Me H H OAc O H Me S N O N CO H H H Bn 2 O N S CO H O 2 O Me O N H HO C H Me 2 H OH O zaragozic acid C (+)11,11’dideoxyverticillin A strychnineThe Future of Total Synthesis representation of what we strive to accomplish in total synthesis Me Bn O H H N Me N S N O N O S Me H H OAc O H Me S N O N CO H H H Bn 2 O N S CO H O 2 O Me O N H HO C H Me 2 H OH O zaragozic acid C (+)11,11’dideoxyverticillin A strychnine Many some would argue most natural products can now be synthesized if suitable resources are provided. The challenge in synthesis is therefore increasingly not whether a molecule can be made, but whether it can be made in a practical fashion, in sufficient quantities for the needs of research and/ or society, and in a way that is environmentally friendly if not ‘ideal’. Paul WenderThe Future of Total Synthesis representation of what we strive to accomplish in total synthesis Me Bn O H H N Me N S N O N O S Me H H OAc O H Me S N O N CO H H H Bn 2 O N S CO H O 2 O Me O N H HO C H Me 2 H OH O zaragozic acid C (+)11,11’dideoxyverticillin A strychnine ■ These represent premier total syntheses for our time ■ In general, these syntheses are atypical from most syntheses that are published in top journals ■ While they embody what we strive to accomplish as synthetic chemists, they are only a small but rapidly growing representation of current work in the field of total synthesisThe Future of Total Synthesis insights from three recent total syntheses of groups from three different era’s ■ Three molecules that highlight the perceived divisions for the modern role of total synthesis ■ Which natural products do we make ■ All, some, any Structurally interesting, biologically active ■ What holds more value ■ The structure, method employed, lessons learned, or future prospects OH Me Me O HO HO Me + H N O 2 H H H H O Me O NH O O HO H OMe HN O Me HO O NH O HO 2 O OH N NH HO O O O H H O Me + NH OH O H 2 O OMe O Cl Me AcO OAc OH Me OH resiniferatoxin spongistatin 1 (+)saxitoxinWender's Synthesis of Daphnane Diterpene Orthoesters Me O Me H O O Me HO O O O OMe resiniferatoxin OH ■ Plants containing DDOs have been used medicinally for over 2000 years ■ Many DDOs are leads for treatment of cancer, diabetes, neurodegenerative disease and pain. ■ Resiniferatoxin has advanced into Phase II clinical trials ■ Study and use of DDOs are hampered by supply and cost issues Wender, P. A.; Buschmann, N.; Cardin, N. B.; Jones, L. R.; Kan, C.; Kee, J.M.; Kowalski, J. A.; Longcore, K. E.; Nature Chem. 2011, 3, 615619.Wender's Synthesis of Daphnane Diterpene Orthoesters the first synthesis of a daphnane diterpene by Wender in 1997 Me O HO Me Me OAc H O Me OH Me H OBn O Me H OBn H H O HO O O O Me Ph RO O OTMS OTBS OMe O TBSO resiniferatoxin OH OAc OAc OAc Me Me Me OBn OBn O OBn O H O O O HO OAc OTBS OTBS ■ Total synthesis featured 46 stop and go steps, tour de force ■ Key disconnections: oxidopyrilium cycloaddition. Enyne ring closure. Applied in highly complex system ■ Wender’s total synthesis is widely regarded as a “classic” Wender, P. A.; Jesudason, C. D.; Nikahira, H.; Tamura, N.; Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 1297612977.Wender's Synthesis of Daphnane Diterpene Orthoesters function oriented synthesis ■ Original total synthesis not ideal from an efficiency or a structural diversification perspective Me PMP Me Me O R 1 O Me R 1 O O OH H O H O H OR O Me H O Me O Me R 2 HO O O O HO OR O O O HO O O OMe O O PMP OH major subset of DDOs resiniferatoxin (X = H, 73 congeners) ■ Key question: ■ Is a more structurally diverse DDO collection accessible to probe function ■ Can analog synthesis reveal a more synthetically accessible structure that retains function Wender, P. A.; Buschmann, N.; Cardin, N. B.; Jones, L. R.; Kan, C.; Kee, J.M.; Kowalski, J. A.; Longcore, K. E.; Nature Chem. 2011, 3, 615619.Wender's Synthesis of Daphnane Diterpene Orthoesters function oriented synthesis ■ Original total synthesis not ideal from an efficiency or a structural diversification perspective Me O Me H O O Me HO O O O OMe OH resiniferatoxin ■ Key question: ■ Is a more structurally diverse DDO collection accessible to probe function ■ Can analog synthesis reveal a more synthetically accessible structure that retains function Wender, P. A.; Buschmann, N.; Cardin, N. B.; Jones, L. R.; Kan, C.; Kee, J.M.; Kowalski, J. A.; Longcore, K. E.; Nature Chem. 2011, 3, 615619.Wender's Synthesis of Daphnane Diterpene Orthoesters function oriented synthesis PMP Me Me O R O 1 OH R 1 O H OBn H O H Me O O Me R 2 O O O HO OR O O HO O O PMP major subset of DDOs general precursor (X = H, 73 congeners) (22 steps from commercial) Me Me Me HO O OAc O OH Me H OBn OBn OBn O vs H H O H O O O Ph TBSO HO OTBS Br TBSO TBSO 10 steps from tartrate revised cycloadduct original cycloadduct Wender, P. A.; Buschmann, N.; Cardin, N. B.; Jones, L. R.; Kan, C.; Kee, J.M.; Kowalski, J. A.; Longcore, K. E.; Nature Chem. 2011, 3, 615619.Wender's Synthesis of Daphnane Diterpene Orthoesters probing the function of the “B” ring PMP Me O Me Me Me O AcO AcO AcO OH O O O Me Me Me H OBn H H H O O O H Me O B O O O Me Me Me Ph Ph Ph (19 steps) O O O O HO HO HO O OH OH OH O O O O HO HO HO O PMP general precursor (22 steps) 1 2 3 a a PK PKC C a affi ffin niity ty,, K K (n (nM) M) C Ce ellllu ulla ar r g gr ro ow wth th iin nh hiib biiti tio on n ii b c A549 EC (nm) K562 EC (nm) 50 50 1 0.48 +/ 0.07 150 +/ 30 7 +/ 1 2 343 +/ 6 10,000 10,000 3 1.6 +/ 0.1 1500 +/ 60 87 +/ 5 a b c PKC = protein kinase C, a family of serine/threonine kinases A549 = human lung carcinoma K562 = human chronic myleogenous leukaemia. ■ Screen of analogs revealed the high potency of DDO’s as a ligand for PKC ■ Carries the potential for treatment of cancer, alzheimers, and AIDS. Wender's Synthesis of Daphnane Diterpene Orthoesters probing the function of the “B” ring PMP Me O Me Me Me O AcO AcO AcO OH O O O Me Me Me H OBn H H H O O O H Me O B O O O Me Me Me Ph Ph Ph (19 steps) O O O O HO HO HO O OH OH OH O O O O HO HO HO O PMP general precursor (22 steps) 1 2 3 a a PK PKC C a affi ffin niity ty,, K K (n (nM) M) C Ce ellllu ulla ar r g gr ro ow wth th iin nh hiib biiti tio on n ii b c A549 EC (nm) K562 EC (nm) 50 50 1 0.48 +/ 0.07 150 +/ 30 7 +/ 1 2 343 +/ 6 10,000 10,000 3 1.6 +/ 0.1 1500 +/ 60 87 +/ 5 a b c PKC = protein kinase C, a family of serine/threonine kinases A549 = human lung carcinoma K562 = human chronic myleogenous leukaemia. ■ An assay against both cancer cell lines reveals the importance of the epoxide stereochemistry ■ Interestingly, the simplified desepoxy analog is activeWender's Synthesis of Daphnane Diterpene Orthoesters probing the function of the “B” ring PMP Me O Me Me Me O AcO AcO AcO OH O O O Me Me Me H OBn H H H O O O H Me O B O O O Me Me Me Ph Ph Ph (19 steps) O O O O HO HO HO O OH OH OH O O O O HO HO HO O PMP general precursor (22 steps) 1 2 3 ■ Calculations showed a preservation of the oxygen spatial arrangement between 1 and 3 ■ The βepoxide of 2, significantly perturbs the orientation of the hydoxymethyl relative to 1Wender's Synthesis of Daphnane Diterpene Orthoesters a model for the future PMP Me O Me Me Me O AcO AcO AcO OH O O O Me Me Me H OBn H H H O O O H Me O B O O O Me Me Me Ph Ph Ph (19 steps) O O O O HO HO HO O OH OH OH O O O O HO HO HO O PMP general precursor (22 steps) 1 2 3 ■ Original synthesis was a tour de force, 46 steps, of an incredibly complicated molecule ■ They delivered an improved synthesis of a more complicated and functionally versatile molecule ■ Is the tour de force synthesis relevant if it delivers additional compound for testing ■ Is the second generation route more valuable than the synthesis of another natural product ■ Does a molecules potential for societal impact alter how we perceive its total synthesisSmiths' Synthesis of the Spongistatins OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O X Me AcO OAc Me OH spongistatin 1 X = Cl spongistatin 2 X = H Smith, A. B., III; Doughty, V. A.; Lin, Q.; Zhuang, L; McBriar, M. D.; Boldi, A. M.; Moser, W. H.; Murase, N.; Nakayama, K. Angew. Chem. Int. Ed. 2001, 40, 196199. Smith, A. B., III; Lin, Q.; Doughty, V. A.; Zhuang, L; McBriar, M. D.; Kerns, J. K.; Brook, C. S.; Murase, N.; Nakayama, K. Angew. Chem. Int. Ed. 2001, 40, 197201. Smith, A. B., III; Zhu, W.; Shirakami, S.; Sfouggatakis, C.; Doughty, V. A.; Bennett, C. S.; Sakamoto, Y. Org. Lett. 2003, 5, 761764.Smiths' Synthesis of the Spongistatins history of the spongistatins OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O X Me AcO OAc Me OH spongistatin 1 X = Cl spongistatin 2 X = H ■ Isolated in the early 1990's by the Pettit, Fusetani, and Kitagawa laboratories ■ Pettit’s attempted reisolation delivered 35 mg of spongistatin 1 from 13 TONS of sponge ■ Two spiroketals, two tetrahydropyrans, hemiketal, 42 membered macrolideSmiths' Synthesis of the Spongistatins history of the spongistatins OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O X Me AcO OAc Me OH spongistatin 1 X = Cl spongistatin 2 X = H ■ Spongistatin 1 has been recognized as one of the most selective cytotoxic agents known ■ Average IC value of 0.12 nM against the NCI panel of 60 human cancer cell lines 50 ■ Proposed to bind βtubulin near, but distinct from, the vinca domain where vinca alkaloids bindSmiths' Synthesis of the Spongistatins history of the spongistatins OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O X Me AcO OAc Me OH spongistatin 1 X = Cl spongistatin 2 X = H ■ Promising therapeutic potential and daunting structure drew much interest as a synthetic target ■ Total syntheses of 1 and 2: Kishi Evans (1998), Smith, Paterson, Crimmins, Ley, Heathcock and others ■ Smith completed the total synthesis of spongistatin 2 in 2001 and 1 in 2003 (48 longest linear steps)Smiths' Synthesis of the Spongistatins Smiths’ first generation synthesis ■ Retrosynthetic analysis OH Me OTBS HO E Me HO PPh I 3 O MeO E O H H H H TESO Me O H O O H H H OMe D Me F O O OMe D O HO H C F O OTIPSTBSO C OH OTMS O O H H O OTMS O H Me H O OH O H Me O A O H Me Cl OTMS A O AcO B Me OAc Cl AcO B OAc Me OH Me OH ■ Late stage Yamaguchi macrolactonization to form the macrocycle ■ A Wittig olefination unites the eastern and western halves of the moleculeSmiths' Synthesis of the Spongistatins Smiths’ first generation synthesis ■ Retrosynthetic analysis OH Me OTBS HO E Me HO PPh I 3 O MeO E O H H H H TESO Me O H O O H H H OMe Me F O O OMe O HO H F O OTIPSTBSO OH OTMS O O H H O OTMS O H Me H O OH O H Me O O H Me Cl OTMS O AcO Me OAc Cl AcO OAc Me OH Me OH Me Me OTBS SnBu 3 S O O O Me OTES H OBn MeO E Me S TESO O O F H H OTMS E Me OBn O Cl F OPMB OTESSmiths' Synthesis of the Spongistatins Smiths’ first generation synthesis ■ Retrosynthetic analysis OH Me OTBS HO Me HO PPh I 3 O MeO O H H H H TESO Me O H O O H H H OMe D Me O O D OMe O HO H C O OTIPSTBSO C OH OTMS O O H H O OTMS O H Me H O OH O H Me O A O H Me Cl OTMS A O AcO B Me OAc Cl AcO B OAc Me OH Me OHSmiths' Synthesis of the Spongistatins Smiths’ first generation synthesis ■ Retrosynthetic analysis BnO O H H H O BPSO OMe D O D OMe TBSO C O MeO H O O OTIPSTBSO A C Me I O H O B Me OBOM O H Me H O Me OH Me O H Me O A Me PhO S ODMB 2 AcO B OAc Me OHSmiths' Synthesis of the Spongistatins Smiths’ first generation synthesis ■ Retrosynthetic analysis BnO O H H H O BPSO OMe O OMe TBSO O MeO H O O OTIPSTBSO A Me I O H O B Me OBOM O H Me H O Me OH Me O H Me O A Me PhO S ODMB 2 AcO B OAc Me OH Me Me OH O OH OH OTBS OH O O Me S S Me S S O A OTs BPSO BPSO TBS BSmiths' Synthesis of the Spongistatins Smiths’ first generation synthesis ■ Retrosynthetic analysis BnO O H H H O BPSO OMe D O D OMe TBSO C O MeO H O O OTIPSTBSO C Me I O H O Me OBOM O H Me H O Me OH Me O H Me O Me PhO S ODMB 2 AcO OAc Me OH BnO H Me S S Me Me O TBSO TBSO OMe O D OMe S S TBSO O Me C BnO O D O O C H I DMP Me Me O OTBS O O O S S BnO TBSSmiths' Synthesis of the Spongistatins anion relay chemistry ■ A versatile method for polyketide synthesis used to form AB and CD fragments O S S S S TBS dianion phosgene equivalent umpole S S OTBS S S S S R Si 3 S S R O 1,3Brook base TBS TBS O rearrangement R R “anion relay” bifunctional nucleophile linchpin OH O OTBS OH OTBS R R S S 1 R R 1 O readily accessible R 1Smiths' Synthesis of the Spongistatins review of their initial synthetic efforts ■ Overview of their entire synthesis and strategy OH Me Wittig (64) OTBS O H HO HO Me H O PPh I 3 H H H MeO O Me TESO OMe O O O H H H OMe OTIPSTBSO Me O O HO O H O O H OH 48 steps H O O H OTMS Me H O O H Me OTMS O OH O H Me O 5 steps AcO Me Cl OAc AcO OTMS OAc Me OH Cl Me OH Yamaguchi (81) Alkylation (92) 24 steps, 0.3 43 steps O H H O OMe BPSO TBSO O O MeO H O H Me I O O Me Me 19 steps Me OTES Me PhO S OAc 2 11 steps 24 stepsSmiths' Synthesis of the Spongistatins review of their initial synthetic efforts ■ Overview of their synthesis and strategy OH Me Wittig (64) OTBS O H HO HO Me H O PPh I 3 H H H MeO O Me TESO OMe O O O H H H OMe OTIPSTBSO Me O O HO O H O O H OH H O O H OTMS Me H O O H Me OTMS O OH O H Me O 5 steps AcO Me Cl OAc AcO OTMS OAc Me OH Cl Me OH Yamaguchi (81) Alkylation (92) 24 steps, 0.3 43 steps ■ Versatile synthetic route that accommodated necessary changes in routes and strategies ■ Methods employed in the synthesis were designed to access many structurally diverse natural products ■ Methods employed were not ideally suited for this specific molecule ■ Allowed them to complete the total synthesis, not ideal for scale up or analog synthesisSmiths' Synthesis of the Spongistatins review of their initial synthetic efforts ■ Overview of their synthesis and strategy OH Me Wittig (64) OTBS O H HO HO Me H O PPh I 3 H H H MeO O Me TESO OMe O O O H H H OMe OTIPSTBSO Me O O HO O H O O H OH H O O H OTMS Me H O O H Me OTMS O OH O H Me O 5 steps AcO Me Cl OAc AcO OTMS OAc Me OH Cl Me OH Yamaguchi (81) Alkylation (92) 24 steps, 0.3 53 steps ■ Should we attempt the total synthesis of molecules this large and complex ■ Are these types of tour de force syntheses worth undertaking in 2012 ■ Should versatile methods (diverse array of accessible structures) continue to be employed ■ Should methods be more ideally suited (and scalable) for a specific moleculeSmiths' Synthesis of the Spongistatins review of their second generation synthesis ■ Vastly Improved Second Generation Synthesis OH Me Wittig (Crimmins, 64) OTBS O H HO HO Me H O PPh I 3 H H H MeO O Me TESO OMe O O O H H H OMe OTIPSTBSO Me O O HO O H O O H OH H O O H OTMS Me H O O H Me OTMS O OH O H Me O 4 steps AcO Me Cl OAc AcO OTMS OAc Paterson Aldol Me OH Cl Me OH Evans, Crimmins 1.009 g prepared Paterson, Heathcock 24 steps, 9.5 yield 22 steps, 6.5 yield 5.8 g prepared ■ Took cues from previous syntheses to revise their overall retrosynthetic strategy ■ Adopted changes to fragment syntheses that were more specifically tuned toward this molecule ■ Vastly improved efficiency and scalability Smith, A. B., III; Tomioka, T.; Risatti, C. A.; Sperry, J. B.; Sfouggatakis, C. Org. Lett. 2008, 10, 43594362.Smiths' Synthesis of the Spongistatins review of their second generation synthesis ■ Vastly Improved Second Generation Synthesis OH Me OTBS O H HO HO Me H O PPh I 3 H H H MeO O Me TESO OMe O O O H H H OMe OTIPSTBSO Me O O HO O H O O H OH H O O H OTMS Me H O O H Me OTMS O OH O H Me O 4 steps AcO Me Cl OAc AcO OTMS OAc Me OH Cl Me OH 1.009 g prepared 24 steps, 9.5 yield 22 steps, 6.5 yield O H O OH O Me 20 (L)proline O O BPSO BPSO H H Me H DMF, 4 °C OBn Me Me OBn 84, 5:1 anti/syn 68 g preparedSmiths' Synthesis of the Spongistatins review of their second generation synthesis ■ Vastly Improved Second Generation Synthesis OH Me OTBS O H HO HO Me H O PPh I 3 H H H MeO O Me TESO OMe O O O H H H OMe OTIPSTBSO Me O O HO O H O O H OH H O O H OTMS Me H O O H Me OTMS O OH O H Me O 4 steps AcO Me Cl OAc AcO OTMS OAc Me OH Cl Me OH 1.009 g prepared 24 steps, 9.5 yield 22 steps, 6.5 yield ■ How important is efficiency in a gram scale total synthesis of a bioactive natural product of low availability ■ Do 2nd Gen syntheses have value for identifying more robust methods (proline aldol vs dithiane) ■ Since earlier tour de force efforts enabled a highly efficient synthesis, do they hold more value Smiths' Synthesis of the Spongistatins analog syntheses from multiple groups provide insight regarding bioactivity ■ What was known about structural features required for activity OH OH C23 epimer Me Me (200 nm) HO HO HO HO O O H H H H H H Me Me O O O O H H OMe OMe O HO O HO O O OH OH O H O H H O H O Me Me OH O H OH O H O O Me Cl Me Cl AcO AcO OAc OAc Me OH Me OH spongistatin 1 Diene section required for activitySmiths' Synthesis of the Spongistatins analog syntheses from multiple groups provide insight regarding bioactivity ■ What was known about structural features required for activity OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O Cl Me AcO OAc Me OH spongistatin 1Smiths' Synthesis of the Spongistatins analog syntheses from multiple groups provide insight regarding bioactivity ■ Appeared that the CD spiroketal wasn’t critical but does play some role OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O Cl Me AcO OAc Me OH spongistatin 1Smiths' Synthesis of the Spongistatins analog syntheses from multiple groups provide insight regarding bioactivity ■ Appeared that the CD spiroketal wasn’t critical but does play some role OH OH Me Me HO HO HO HO O O H H H H H Me Me O O O H H OMe O HO O O OH OH O H O H O H Me OH O H OH O H O O ( ) Cl Me Cl 5 AcO AcO OAc Me OH Me OH spongistatin 1 480 nm (Heathcock)Smiths' Synthesis of the Spongistatins analog syntheses from multiple groups provide insight regarding bioactivity ■ Appeared that the CD spiroketal wasn’t critical but does play some role OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O Cl Me AcO OAc Me OH spongistatin 1Smiths' Synthesis of the Spongistatins analog syntheses from multiple groups provide insight regarding bioactivity ■ Also appears that the AB spiroketal wasn’t critical but does play some role OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O Cl Me AcO OAc Me OH spongistatin 1Smiths' Synthesis of the Spongistatins analog syntheses from multiple groups provide insight regarding bioactivity ■ Also appears that the AB spiroketal wasn’t critical but does play some role OH OH Me Me HO HO HO HO O O H H H H H Me Me O O O H OMe H O HO O O OH OH O H O H O Me OH O H OH O Cl Me Cl AcO OAc Me OH spongistatin 1 460 nm (Heathcock)Smiths' Synthesis of the Spongistatins analog syntheses from multiple groups provide insight regarding bioactivity ■ Also appears that the AB spiroketal wasn’t critical but does play some role OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O Cl Me AcO OAc Me OH spongistatin 1Smiths' Synthesis of the Spongistatins analog syntheses from multiple groups provide insight regarding bioactivity ■ The “western” portion of spongistatin (diene E, F rings) constitute the recognition domain ■ The “eastern” portion of spongistatin (A,B and C,Dspiroketals) imparts conformational restraints on the western portion OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O Cl Me AcO OAc Me OH spongistatin 1Smiths' Synthesis of the Spongistatins examining the conformational restraint hypothesis ■ How can the hypothesis of conformational restraint imparted by the eastern half be tested ■ Random analog synthesis seemed cumbersome and unattractive ■ Molecular modeling may provide some insights OH Me HO HO O H H H Me O O H OMe O HO O OH O H H O Me OH O H O Cl Me AcO OAc Me OH spongistatin 1 Smith, A. B., III; Risatti, C. A.; Atasoylu, O.; Bennett, C. S.; Liu, J.; Cheng, H.; TenDyke, K. Xu, Q. J. Am. Chem. Soc. 2011, 133, 1404214053.Smiths' Synthesis of the Spongistatins insights from molecular modeling ■ Molecular modeling revealed two major an two minor conformations ■ Chloroform “Flat” maximized intramolecular hydrogen bonds ■ Water “Twisted” oxygens oriented toward solventSmiths' Synthesis of the Spongistatins insights from molecular modeling ■ Molecular modeling revealed two major an two minor conformations ■ DMSO Acetonitrile “Saddle” ■ Kitagawa original solution state structure from isolation reportSmiths' Synthesis of the Spongistatins molecular dynamics simulations ■ Focused on water as the solvent ■ Used molecular dynamics simulations to identify rigid and flexible regions ■ Lead to the development of “DISCON” (DIstrubution of Solution CONformations) MD software Smiths' Synthesis of the Spongistatins molecular dynamics simulations ■ Focused on water as the solvent ■ Used molecular dynamics simulations to identify rigid and flexible regions ■ Lead to the development of “DISCON” (DIstrubution of Solution CONformations) MD software ■ Red = Rigid, Blue = Intermediate, Green = Flexible; Number indicates bond pair where torsions change togetherSmiths' Synthesis of the Spongistatins molecular dynamics simulations ■ The EFAB region is extremely rigid whereas the CD region is very flexible ■ The only rigidity in the “eastern” half comes from the CD spiroketal ■ The ends of the EFAB region tend to move as a single unit ■ Red = Rigid, Blue = Intermediate, Green = Flexible; Number indicates bond pair where torsions change togetherSmiths' Synthesis of the Spongistatins molecular dynamics simulations ■ The EFAB region is extremely rigid whereas the CD region is very flexible ■ The only rigidity in the “eastern” half comes from the CD spiroketal ■ The ends of the EFAB region tend to move as a single unit ■ Explains why the C23 epimer results in loss of activity even as its not involved in recognition OH C23 epimer Me (200 nm) HO E HO O H H H Me O O H D OMe F O HO C O OH O H H O Me OH O H O A Me Cl AcO B OAc Me OHSmiths' Synthesis of the Spongistatins molecular dynamics simulations ■ An overlay of all the most populated solution state conformations is revealing ■ The rigid EFAB region is highly conservedSmiths' Synthesis of the Spongistatins molecular dynamics simulations ■ The tether employed by Heathcock didn’t impart enough conformational restraint on the EFAB region ■ Can an appropriate tether be designed to simplify the structure while maintaining activity OH OH Me Me HO HO HO HO O O H H H H H Me Me O O O H H OMe O HO O O OH OH O H O H O H Me OH O H OH O H O O ( ) Cl Me Cl 5 AcO AcO OAc Me OH Me OH spongistatin 1 ABEF analog (Heathcock) 1 nm 480 nm (Heathcock)Smiths' Synthesis of the Spongistatins computationally aided analog design ■ Computationally aided analog design found ABEF analog with high structural homology to spongistatin OH OH Me Me HO HO E E E HO HO O O H H H H H Me Me O O O H H OMe F F F O HO O O O OH OH O H O H O H O Me OH O H OH O H O O Cl Me Cl AcO AcO OAc Me OH Me OH spongistatin 1 ABEF analog (Smith) macrolide strain energy = 8.3 kJ/mol macrolide strain energy = 9.1 kJ/molSmiths' Synthesis of the Spongistatins computationally aided analog design ■ Computationally aided analog design found ABEF analog with high structural homology to spongistatin OH OH Me Me HO HO E E E HO HO O O H H H H H Me Me O O O H H OMe F F F O HO O O O OH OH O H O H O H O Me OH O H OH O H O O Cl Me Cl AcO AcO OAc Me OH Me OH spongistatin 1 ABEF analog (Smith) macrolide strain energy = 8.3 kJ/mol macrolide strain energy = 9.1 kJ/molSmiths' Synthesis of the Spongistatins a highly potent spongistatin analog ■ Similar activity present after having deleted nearly 1/3 of the original structure ■ ABEF analog determined to have the same mode of action OH OH Me Me HO HO HO HO O O H H H H H Me Me O O O H H OMe O HO O O O OH OH O H O H O H O Me OH O H OH O H O O Cl Me Cl AcO AcO OAc Me OH Me OH spongistatin 1 ABEF analog (Smith) MDAMB435 HT29 H522T1 U937 spongistatin 0.0225 0.058 0.16 0.059 ABEF analog 82.8 161.2 297.2 60.5Smiths' Synthesis of the Spongistatins a review of their analog work OTBS OH Me Me PPh I 3 MeO HO TESO HO O O H H H H Me Me O O H CHO H OTES O O OTIPS OTES OH O O H O O 5 steps H O OTBS OH O H O O H Cl Cl O AcO AcO Me OH Me OTES 29 steps (20 steps shorter) ■ Are the post total synthesis opportunities in computational chemistry and analog design worth the effort ■ Do 2nd Gen syntheses have value for identifying more robust methods (proline aldol vs dithiane) ■ Since earlier tour de force efforts enabled a highly efficient synthesis, do they hold more value ■ Are these types of projects worth undertaking in 2012 DuBois' Total Synthesis of Saxitoxin + H N 2 O NH HO HN HO O NH 2 N NH + NH 2 (+)saxitoxin ■ A highly oxidized and polar neurotoxic agent ■ Toxicity arises from disabling ionic conductance through voltagegated sodium channel. ■ Exhibits nanomolar affinity for binding the extracellular mouth of the ion channel. Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 99649975.DuBois' Total Synthesis of Saxitoxin ■ Why synthesize a neurotoxic agent + H N 2 O NH HO HN HO O NH 2 N NH + NH 2 (+)saxitoxin ■ Ion flux is crucial for many important biochemical processes ■ Small molecules that modulate ion flux may provide the discovery of new drugs ■ Chemically modified guanidinium toxin could be used to probe structure and function of ion channels Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 99649975.DuBois' Total Synthesis of Saxitoxin Rhodium catalyzed CH amination O O O O 2 mol Rh (OAc) 2 2 S S PhI(OAc) , MgO 2 H N O HN O 2 Me Me CH Cl 2 2 Me Me Me Me Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 69356936. + H N 2 O NH HO HN HO O NH 2 N NH + NH 2DuBois' Total Synthesis of Saxitoxin Rhodium catalyzed CH amination O O O O 2 mol Rh (OAc) 2 2 S S PhI(OAc) , MgO 2 H N O HN O 2 Me Me CH Cl 2 2 Me Me Me Me Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 69356936. O O S O O HN O S 0.3 mol Rh (esp) 2 2 H N O 2 PhI(OAc) , MgO 2 O O CH Cl O 2 2 Me O Me 76 Me Me Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 99649975.DuBois' Total Synthesis of Saxitoxin Rhodium catalyzed CH amination O O O O 2 mol Rh (OAc) 2 2 S S PhI(OAc) , MgO 2 H N O HN O 2 Me Me CH Cl 2 2 Me Me Me Me Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 69356936. O O O O S O O HN O S S 0.3 mol Rh (esp) 2 2 HN O H N O 2 R ZnCl PhI(OAc) , MgO 2 O O BF ·OEt 3 2 CH Cl O 2 2 Me OH O Me 76 Me Me OTs Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 99649975.DuBois' Total Synthesis of Saxitoxin first generation total synthesis NMbs NMbs O O H N NH OH 2 S H N NH 2 HN O AgNO 3 OH NH 11 steps iPrNEt NH 2 2 MbsN OH NMbs 65 N N MeS H OTs H Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 99649975.DuBois' Total Synthesis of Saxitoxin first generation total synthesis NMbs NMbs O O H N NH OH 2 S H N NH 2 HN O AgNO 3 OH NH 11 steps iPrNEt NH 2 2 MbsN OH NMbs 65 N N MeS H OTs H NMbs NMbs O NH O 2 H N NH 2 NH 1. Cl CC(O)NCO HO 3 2 OsCl HO 3 O O NH 2 oxone, Na CO 2 3 2. K CO , MeOH 2 3 NH N NH 62, 12:1 + 82 NMbs NH N 2 H Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 99649975.DuBois' Total Synthesis of Saxitoxin first generation total synthesis NMbs NMbs O O H N NH OH 2 S H N NH 2 HN O AgNO 3 OH NH 11 steps iPrNEt NH 2 2 MbsN OH NMbs 65 N N MeS H OTs H NMbs NMbs O NH O 2 H N NH 2 NH 1. Cl CC(O)NCO HO 3 2 OsCl HO 3 O O NH 2 oxone, Na CO 2 3 2. K CO , MeOH 2 3 NH N NH 62, 12:1 + 82 NMbs NH N 2 H + H N + 2 H N 2 NH O NH O DMSO, DCC H HO HN B(O CCF ) 2 3 3 HN HO pyridine·TFA HO O NH 2 O NH 2 70 N NH TFA, 0 °C to rt N NH 82 + NH + 2 (+)saxitoxin NH 2 20 steps Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 99649975.DuBois' Total Synthesis of Saxitoxin first generation recap + H N 2 O NH HO HN HO O NH 2 N NH + NH 2 (+)saxitoxin ■ Utilizing their CH amination method in a total synthesis fostered the development of a better catalyst ■ The first enantioselective synthesis ■ Du Bois synthesis was longer than both the Kishi and Jacobi racemic syntheses (17 and 15 steps)DuBois' Total Synthesis of Saxitoxin rethinking their original route NMbs O O H N NH OH 2 S HN O NH 11 steps 2 MbsN OH N MeS OTs H 14 steps Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 99649975.DuBois' Total Synthesis of Saxitoxin rethinking their original route NMbs O O H N NH OH 2 S HN O NH 11 steps 2 MbsN OH N MeS OTs H 14 steps PMB OH N PMB O O N OTBDPS MeO OH SMe NHBoc H OTBDPS NHBoc NHBoc N NMbs H NBoc serine methyl ester Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 99649975.DuBois' Total Synthesis of Saxitoxin 14 step second generation total synthesis PMB OH N alkyne O PMB O iPrMgCl OTBDPS N MeO OH SMe NHBoc THF, 78 °C 3 steps H OTBDPS NHBoc 78, 5:1 anti/syn N NMbs NHBoc H NBoc serine methyl ester NMbs + H N 2 H N NH 2 O NH H OH HO HN HO O NH 2 NH N NH 6 steps 4 steps NMbs N + H NH 2 10 steps vs 16 steps (+)saxitoxin Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 99649975.DuBois' Total Synthesis of Saxitoxin second generation recap + H N 2 O NH HO HN HO O NH 2 N NH + NH 2 (+)saxitoxin ■ Their second generation approach provided the most efficient synthesis of the (+)saxitoxin ■ The second generation synthesis was scalable, preparing 5 g of the 9 membered ring ■ Provided enough material to initiate ion channel studies.Saxitoxin as a Small Molecule Probe for Ion Channel Studies ■ Difficulty in chemically modifing natural saxitoxin limits its use as a small molecular probe ■ Through de novo total synthesis an array of diverse molecular probes can be synthesized readily 7,8,9guanidine residue proposed to bind the selectivity filter carbomyl group proposed to be H bond donor Andersen, B. M.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 1252412525.Saxitoxin as a Small Molecule Probe for Ion Channel Studies initial question ■ Is the carbamate, specifically as an Hbond donor, important for saxitoxin binding the ion channel + + H N H N 2 2 NH O NH O H H HO HO HN HN Me HO O NH HO O N 2 N NH N NH Me + + NH NH 2 2 (+)saxitoxin N,Ndimethyl(+)saxitoxinSaxitoxin as a Small Molecule Probe for Ion Channel Studies initial question ■ Is the carbamate, specifically as an Hbond donor, important for saxitoxin binding the ion channel + + H N H N 2 2 NH O NH O H H HO HO HN HN Me HO O NH HO O N 2 N NH N NH Me + + NH NH 2 2 (+)saxitoxin N,Ndimethyl(+)saxitoxin ■ Strategy: Remove the hydrogen bonds and measure the voltage across the ion channel Saxitoxin as a Small Molecule Probe for Ion Channel Studies initial question ■ Is the carbamate, specifically as an Hbond donor, important for saxitoxin binding the ion channel + + H N H N 2 2 NH O NH O H H HO HO HN HN Me HO O NH HO O N 2 N NH N NH Me + + NH NH 2 2 (+)saxitoxin N,Ndimethyl(+)saxitoxin ■ Increasing conc. of both saxitoxin and N,Ndimethylsaxitoxin result in decreased peak current carbomyl unit not likely a hydrogen bond donorSaxitoxin as a Small Molecule Probe for Ion Channel Studies initial question ■ Do further modifications to the carbomyl unit effect binding R IC (nM) 50 C H 26 +/ 3 7 15 + H N iPr 83 +/ 13 2 NH O H HO + HN C H NH 19 +/ 0.8 R 6 12 3 HO O N N NH H C H CO 135 +/ 7 5 10 2 + O NH 2 87 +/ 9 N H O ■ Despite steric, electronic, and polar modifications, all retained activity within 11.5 orders of magnitude ■ Allowed for the installation of the first saxitoxin photoaffinity probeSaxitoxin as a Small Molecule Probe for Ion Channel Studies additional modifications to the carbamate ■ Use of a carbamate tethered amine will allow installation of structurally complex payloads ■ Fluorogenic groups ■ Cofactors ■ Having access to synthetic saxitoxin should provide unique insights in ion channel structure and function + H N 2 + H N 2 NH O H HO NH O H pFC H C(O)NHS 6 4 HN H HO N HN + ( ) NH HO O N 5 3 ( ) HO O N 5 N NH H N NH H F CH CN/H O 3 2 + NH 2 + NH 2 pH = 9.5 IC = 46 +/ 7 nm 50 O O N O O F pFC H C(O)NHS 6 4DuBois' Total Synthesis of Saxitoxin overview of saxitoxin synthesis + H N 2 O NH HO HN HO O NH 2 N NH + NH 2 (+)saxitoxin ■ Their initial synthesis enabled a very elegant and scalable synthesis of an important molecule ■ Application of their chemistry toward a total synthesis identified a better CH amination catalyst ■ The result of their work enabled a new area of academic research on ion channels.DuBois' Total Synthesis of Saxitoxin overview of saxitoxin synthesis + H N 2 O NH HO HN HO O NH 2 N NH + NH 2 (+)saxitoxin ■ Should total syntheses be used to apply methodology if the resulting initial synthesis isn’t the “best” ■ Is post synthetic research becoming mainstreamThe Future of Total Synthesis summary of themes from selected examples ■ Three molecules that highlight the perceived divisions for the modern role of total synthesis ■ Which natural products do we make ■ All, some, any Structurally interesting, biologically active ■ What holds more value ■ The structure, method employed, lessons learned, or future prospects OH Me Me O HO HO Me + H N O 2 H H H H O Me O NH O O HO H OMe HN O Me HO O NH O HO 2 O OH N NH HO O O O H H O Me + NH OH O H 2 O OMe O Cl Me AcO OAc OH Me OH resiniferatoxin spongistatin 1 (+)saxitoxinThe Future of Total Synthesis final thoughts ■ Wender’s synthesis of resiniferatoxin ■ Which natural products to we make ■ A tour de force synthesis is worth undertaking if the target is important and the goal of the research is to understand the SAR of the molecule to provide new therapeutic leads ■ What holds more value ■ The structure and future prospects are what drives the value in these types of syntheses OH Me Me O HO HO Me + H N O 2 H H H H O Me O NH O O HO H OMe HN O Me HO O NH O HO 2 O OH N NH HO O O O H H O Me + NH OH O H 2 O OMe O Cl Me AcO OAc OH Me OH resiniferatoxin spongistatin 1 (+)saxitoxinThe Future of Total Synthesis final thoughts ■ Smiths synthesis of spongistatin 1 ■ Which natural products to we make ■ Focused efforts toward very complex and important molecules offer a testing ground for synthetic methods and provided multiple opportunities for post total synthesis research ■ What holds more value ■ The structure, method employed, lessons learned, and future prospects all provided value OH Me Me O HO HO Me + H N O 2 H H H H O Me O NH O O HO H OMe HN O Me HO O NH O HO 2 O OH N NH HO O O O H H O Me + NH OH O H 2 O OMe O Cl Me AcO OAc OH Me OH resiniferatoxin spongistatin 1 (+)saxitoxinThe Future of Total Synthesis final thoughts ■ Du Bois synthesis of saxitoxin ■ Which natural products to we make ■ Focused efforts toward very complex and important molecules often leads to improvements in synthetic methods and provide opportunities for post total synthesis research ■ What holds more value ■ Methods employed, lessons learned, and future prospects drove the value of this program OH Me Me O HO HO Me + H N O 2 H H H H O Me O NH O O HO H OMe HN O Me HO O NH O HO 2 O OH N NH HO O O O H H O Me + NH OH O H 2 O OMe O Cl Me AcO OAc OH Me OH resiniferatoxin spongistatin 1 (+)saxitoxinThe Future of Total Synthesis final thoughts ■ All three examples entailed focused research programs directed toward a single natural product ■ They all provided additional supplies of valuable targets that initiated further research ■ They all encountered pitfalls in synthetic strategies that facilitated future focused efforts ■ They all generated an improved synthetic transformation or method for fragment synthesis OH Me Me O HO HO Me + H N O 2 H H H H O Me O NH O O HO H OMe HN O Me HO O NH O HO 2 O OH N NH HO O O O H H O Me + NH OH O H 2 O OMe O Cl Me AcO OAc OH Me OH resiniferatoxin spongistatin 1 (+)saxitoxinThe Future of Total Synthesis final thoughts ■ Powerful new methods will continue to push toward the ideal total synthesis Me Bn O H H N Me N S N O N O S Me H H OAc O H Me S N O N CO H H H Bn 2 O N S CO H O 2 O Me O N H HO C H Me 2 H OH O zaragozic acid C (+)11,11’dideoxyverticillin A strychnineThe Future of Total Synthesis final thoughts ■ Focused efforts toward a single natural product will continue to be a productive area of research OH Me Me O HO HO Me + H N O 2 H H H H O Me O NH O O HO H OMe HN O Me HO O NH O HO 2 O OH N NH HO O O O H H O Me + NH OH O H 2 O OMe O Cl Me AcO OAc OH Me OH resiniferatoxin spongistatin 1 (+)saxitoxin new areas of researchThe Future of Total Synthesis final thoughts ■ Focused efforts toward a single natural product will continue to be a productive area of research Last total syntheses to be published in Science O H H OAc N Me Me Me OH NMe 2 S N H H H Me Me OH N O S H Me Me NH 2 OH S O N Me OH N S OH O OH O O HO OH Me N O H H O prostratin (Wender) ()doxycycline (Myers) dideoxyverticillin A (Movassaghi) new areas of researchThe Future of Total Synthesis final thoughts ■ Groups that undertake impractical syntheses of many different targets will become irrelevantThe Future of Total Synthesis final thoughts ■ These sentiments are being increasingly observed across the spectrum of total synthesis ■ More focused efforts toward fewer targets is likely the future of total synthesis Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972) OH Me Me HO Me OR HO MeO C 2 O HO O O O H H H Me OAc O O OH O Me H OMe O H O HO O OH O AcO OH Me O O O H H H O Me Me H OH O H Me Me RO OH Me O Cl Me AcO OAc CO Me 2 bryostatin 1 macfarlandin spongistatin 1 Me OHThe Future of Total Synthesis final thoughts ■ These sentiments are being increasingly observed across the spectrum of total synthesis ■ More focused efforts toward fewer targets is likely the future of total synthesis K. C. Nicolaou (1976) Paul Wender (1976) Dale Boger Stuart Schreiber R Me Me HO Cl O OR MeO C 2 O O OAc Me O O HO OH Me Me OH Cl O O O H H H H O N N N OH N N N Me OH Me O O Me H H H Me HN O O O Me HO OH HO C 2 O Me RO OH NH Me 2 CO Me 2 OH HO OH bryostatin 1 prostratin vancomycinThe Future of Total Synthesis final thoughts ■ These sentiments are being increasingly observed across the spectrum of total synthesis ■ More focused efforts toward fewer targets is likely the future of total synthesis Andrew Myers (1986) Scott Rychnovsky (1988) Peter Wipf (1990) John Wood (1993) Me Me Me Me OH NMe 2 H H H Me OH H Me H NH 2 OH H OH O OH O O HO doxycyclin cholesterolThe Future of Total Synthesis final thoughts ■ These sentiments are being increasingly observed across the spectrum of total synthesis ■ More focused efforts toward fewer targets is likely the future of total synthesis + H N Me OMe O OMe 2 O NH OH HO N HN H H HO O NH OH O Me 2 Me Me Me N NH H HO + NH H 2 O OH irciniastatin A HO saxitoxin (Du Bois) (Floreancig, De Brabander) Me OH O Me O OH HO Me OH O OH H Me H OH N Me O OH H H H HO O OH OH OH OH O O N Me H Me H OH Me O O O Me O O OH cephalostatin 1 (Shair) amphotericin B (Burke) Me HO OH Me NH 2The Future of Total Synthesis final thoughts ■ If the overall goal is for chemistry to benefit society and if natural products are to play a role... ■ Continuing to strive for new reactions will deliver increasingly complex targets in short order ■ Applying methods in complex settings will lead to better and more useful methods ■ Focused efforts toward fewer targets will lead to better targets and more active areas of research ■ Whether or not total synthesis directly benefits society, and thus it’s future, depends on the targets we choose and what we choose to do with those targets...The Future of Total Synthesis final thoughts ■ If the overall goal is for chemistry to benefit society and if natural products are to play a role... ■ Continuing to strive for new reactions will deliver increasingly complex targets in short order ■ Applying methods in complex settings will lead to better and more useful methods ■ Focused efforts toward fewer targets will lead to better targets and more active areas of research ■ Whether or not total synthesis directly benefits society, and thus it’s future, depends on the targets we choose and what we choose to do with those targets... which is entirely up to us
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