Total synthesis of natural products ppt

total synthesis of cholesterol ppt and total synthesis natural product ppt
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MarthaKelly,Mexico,Researcher
Published Date:12-07-2017
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The Future of Total Synthesis Jason M. Stevens 01.26.2012Total 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 cholesterolA 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 mid-1990’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 mid-1990’s ■ A high profile introspective analysis concerning synthetic efficiency was published in 1991. Atom Economy Trost B. M. Science 1991 254, 1471-1477.A Paradigm Shift in Total Synthesis why the mid-1990’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 mid-1990’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 1997-2008 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 1997-2008 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, 1189-1192 Key Research Programs in Total Synthesis programs initiated from 1997-2008 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 t-Bu H 2 TBSO t-BuO C TBS H 2 OAc O H CO t-Bu 2 H CO t-Bu THF t-BuO 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, 17281-17283.Key Research Programs in Total Synthesis programs initiated from 1997-2008 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 1-Nap (-)-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, 183-188.Key Research Programs in Total Synthesis programs initiated from 1997-2008 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, 238-241.Key Research Programs in Total Synthesis programs initiated from 1997-2008 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(10-15 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 (+)-saxitoxin