The Future of Total SynthesisJason M. Stevens
01.26.2012
The Future of Total Synthesisa 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 discussion
Total Synthesis of Natural Productsa brief history
■ It all began with urea...
Friedrich Wöhler (1828). "Ueber künstliche Bildung des Harnstoffs". Annalen der Physik und Chemie 88 (2): 253–256.
H2N
O
NH2
■ Wöhlers synthesis of urea demonstrated that organic matter could be produced synthetically
urea
■ Discredited vitalism, the theory that organic matter possessed a vital force inherent to living things
Total Synthesis of Natural Productsa brief history
■ Gustaf Komppa’s industrial synthesis of camphor in 1903 via semi-synthesis from pinene
■ Camphor was a scarce natural product with a worldwide demand
camphor
■ Important milestone in synthetic organic chemistry
Me Me
OMe
Total Synthesis of Natural Productsa brief history
■ The modern era of total synthesis began with Woodward’s synthesis of quinine
Woodward, R. B.; Doering, W. E. J. Am. Chem. Soc. 1944, 66: 849-849.
■ The ability to utilize a predictive set of known reactions to execute a synthetic plan
quinine
■ Ushered in the modern era of total synthesis
NHO
N
MeO
Total Synthesis of Natural Productswhy we’ve made molecules since 1828
NHO
N
MeO
Potential Societal Impact Inspire New Methods
N
O
N
OH
H
H
H
quinine originally proposed skeletonof cholesterol strychnine
■ Three driving forces for undertaking the total synthesis of natural products
Assist Structural Identification
Total Synthesis of Natural Productswhy we make molecules in 2012
Assist Structural IdentificationPotential Societal Impact
N
O
N
OH
H
H
H
strychnine
■ 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
Inspire New Methods
originally proposed skeletonof cholesterol
NHO
N
MeO
quinine
What is the Future of Total Synthesis?topics for discussion
Assist Structural IdentificationPotential Societal Impact
N
O
N
OH
H
H
H
strychnine
■ 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
Inspire New Methods
originally proposed skeletonof cholesterol
NHO
N
MeO
quinine
Key Research Programs in Total Synthesis
Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972)
Also: Phil Magnus, James Marshall, Albert Padwa, James White
programs initiated from 1961-1972
■ Equipped with the knowledge that complex molecules can be made
Syntheses completed by 1972
Strychnine - Woodward Prostaglandin - Corey
Reserpine - Woodward Progesterone - W. S. Johnson
■ The goals of synthetic efforts from this group largely focused on accessing the desired target
Key Research Programs in Total Synthesis
Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972)
Also: Phil Magnus, James Marshall, Albert Padwa, James White
programs initiated from 1961-1972
Reactions and Reagents that Didn’t Exist in 1972
■ Equipped with the knowledge that complex molecules can be made
■ Only a limited selection of reliable “synthons”
Heck, Kumada-Corriu, Stille, and Suzuki Couplings
Chiral Auxiliaries
Sharpless epoxidation
TBSCl
Active areas of research at that time
Hydroboration
Controlling enolate geometry
Organic photochemistry
Cross-coupling reactions
Key Research Programs in Total Synthesis
Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972)
programs initiated from 1961-1972
■ Throughout their careers they produced many total syntheses which, at the time their programs began, were seeming impossible
OOO
NH
HN
O
OHN
O
NH2
ONH
OOH
Cl
HN
MeMe
Me
NH
HOCl
HNHO2C
O
OHOHHO
R
Vancomycin (Evans 1998)
Evans, D. A.; Wood, M. R.; Trotter, W. B.; Richardson, T. I.; Barrow, J. C.; Katz, J. L. Angew. Chem. Int. Ed. 1998, 37, 2700-2704.
Key Research Programs in Total Synthesis
Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972)
programs initiated from 1961-1972
■ Devoted much of their careers to developing new methods to enable the synthesis of natural products
cytovaricin (Evans 1990)
NMe
O O
O
Ph Me
All stereocenters set by asymmetricaldol, alkylation or epoxidation
ORHO
HOMe
OHMeHO
OO
OOMe
O OH
Me
MeOH
Me
OH
Me
H
H
Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001-7031.
Key Research Programs in Total Synthesis
Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972)
programs initiated from 1961-1972
■ Pioneered many fundamental advances and applications for transition metal chemistry
NH
NMe
HN
N
NHNH
Me
Me
H
HNN
HMe
quadrigemine C(Overman 2002)
Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc. 2002, 124, 9008-9009.
NH
NMe
HN
NMe
H
NMeTs
O
NBn
OTf
TsMeN
O
NBn TfO
Key Research Programs in Total Synthesis
Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972)
programs initiated from 1961-1972
■ Executed syntheses of natural products with the aim of exploring its therapeutic potential
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHX
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1 X = Cl
spongistatin 2 X = H
(Evans 1998, Smith 2001)
Key Research Programs in Total Synthesis
Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972)
programs initiated from 1961-1972
■ Famous molecules as a benchmark for total synthesis and a continued source of inspiration
Magnus, Overman, Padwa (Woodward)
N
O
N
OH
H
H
H
strychnine
Key Research Programs in Total Synthesis
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 WilliamsDave Williams and Jeffrey Winkler
programs initiated from 1973-1984
■ 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
PhH
H HHCO2H
H
endiandric acids A-D(Nicolaou 1982)
HO OH
Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am. Chem. Soc. 1982, 104, 5555-5557.
Key Research Programs in Total Synthesis
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 WilliamsDave Williams and Jeffrey Winkler
programs initiated from 1973-1984
■ 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
OO
O
O
CMe3
OHO
HOO
MeHOO
ginkolide B (Crimmins 1999)
O
TESO
OCO2Et
MeMeMe
OCO2EtO
TESOMe
MeMe
hν
Crimmins, M. T. et al. J. Am. Chem. Soc. 1999, 121, 10249-10250.
Key Research Programs in Total Synthesis
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 WilliamsDave Williams and Jeffrey Winkler
programs initiated from 1973-1984
■ During their careers the “synthetic toolkit” had expanded drastically
■ New transformations provided increased access to exceptionally complicated structures
O
OO
O
O
O
O
O
OOH
Me HH HMe
H MeH
HHO H
HH
HH
HHHHHH
O
O
Me
brevetoxin A (Nicolaou 1998, Crimmins 2008)
Key Research Programs in Total Synthesis
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 WilliamsDave Williams and Jeffrey Winkler
programs initiated from 1973-1984
■ During their careers the “synthetic toolkit” had expanded drastically
■ The synthesis of Nature’s most complicated therapeutic leads became a worthy endeavor
MeMe
OAcOMe
OH
OHO OBz
H
O
O
HO
HNPh
OPh
OAc
taxol (Nicolaou 1994, Wender 1997)
Key Research Programs in Total Synthesis
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 WilliamsDave Williams and Jeffrey Winkler
programs initiated from 1973-1984
most synthetic efforts largely focused on accessing the desired target
Key Research Programs in Total Synthesis
Andrew Myers (1986) Scott Rychnovsky (1988) Peter Wipf (1990) John Wood (1993)
Also: Arun Ghosh, John Montgomery, James Panek, Tom Pettus and John Rainier
programs initiated between 1985-1996
■ The goals of synthetic efforts from this group largely focused on accessing the desired target
dynemicin (Myers 1995)
O
O
HNO
CO2H
OMe
OH
OH
OH
H
HMe
■ Constructed molecules of incredible complexity with innovative methods
OTMS
OTMS
O
OTMS
NO
CO2TIPS
OMe
O
H
HMe
Myers, A. G.; Fraley, M. E.; Tom, N. J. J. Am. Chem. Soc. 1994, 116, 11556-11557.
Key Research Programs in Total Synthesis
Andrew Myers (1986) Scott Rychnovsky (1988) Peter Wipf (1990) John Wood (1993)
Also: Arun Ghosh, John Montgomery, James Panek, Tom Pettus and John Rainier
programs initiated between 1985-1996
■ The goals of synthetic efforts from this group largely focused on accessing the desired target
O
HOHO
HMe
Me
MeMe
HOHO
ingenol (Wood 2004)
■ Continued the traditions of building molecules of incredible complexity
Nickel, A,; Maruyama, T.; Tang, H.; Murphy, P. D.; Green, B. Yusuff, N. Wood, J. L. J. Am. Chem. Soc. 2004, 126, 16300-16301.
Key Research Programs in Total Synthesis
Andrew Myers (1986) Scott Rychnovsky (1988) Peter Wipf (1990) John Wood (1993)
Also: Arun Ghosh, John Montgomery, James Panek, Tom Pettus and John Rainier
programs initiated between 1985-1996
■ The goals of synthetic efforts from this group largely focused on accessing the desired target
OH O
HMe OH
HNMe2
OH
O
NH2OH
OH
HO
tetracycline (Myers 2005)
■ Continued the traditions of building molecules of incredible complexity
Charest, M. G.; Siegel, D. R.; Myers, A. G.; J. Am. Chem. Soc. 2005, 127, 8292-8293.
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
■ Recent years have placed additional focus on how well we access desired targets
■ Once the synthetic natural product was obtained the project was over
■ 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 period
A Paradigm Shift in Total Synthesiswhy 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 Synthesiswhy 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 Synthesiswhy 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)
MeMe
OAcOMe
OH
OHO OBz
H
O
O
HO
HNPh
OPh
OAc
taxol
Robert Holton (1994) K.C. Nicolaou (1994) Sam Danishefsky (1996) Paul Wender (1997)
37 longest linear steps49 longest linear steps46 longest linear steps 42 longest linear steps
A Paradigm Shift in Total Synthesiswhy the mid-1990’s
Robert Holton (1994) K.C. Nicolaou (1994) Sam Danishefsky (1996) Paul Wender (1997)
37 steps49 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 Danishefsky
46 steps 55 steps
■ The taxol problem exemplified the limitations total synthesis for assembling structures that carry the potential to have societal impact (35 groups worked on taxol)
Key Research Programs in Total Synthesis
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.
programs initiated from 1997-2008
■ 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 efficiency
Key Research Programs in Total Synthesis
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.
programs initiated from 1997-2008
■ Examples of powerful synthetic methods for total synthesis developed in the last 10 years
MeO
O
OO
HOH
H
O
O
O
OHO
MeH H H H
HHHH
water
70 °C, 72 h71%
Vilotijevic, I.; Jamison, T. J. Science 2007 317, 1189-1192
common ladder toxin subunit
Key Research Programs in Total Synthesis
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.
programs initiated from 1997-2008
■ Examples of powerful synthetic methods for total synthesis developed in the last 10 years
Nicewicz, D. A.; Satterfield, A. D.; Schmitt, D. C. Johnson, J. S. J. Am. Chem. Soc. 2008 130, 17281-17283.
OO
HO2CCO2H
OH
HCO2H
O H
O
Me Bn
OAcBn
Me
TBSOt-BuO2C
CO2t-BuOTBS
OH
CO2t-BuHH CO2t-Bu
O
2 equiv
MgBr
t-BuO2C TBS
O
THF
50%-78 to -45 °C
zaragozic acid C
Key Research Programs in Total Synthesis
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.
programs initiated from 1997-2008
■ Examples of powerful synthetic methods for total synthesis developed in the last 10 years
Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011 850, 183-188.
(-)-strychnineN SeMePMB
NHBocO N
NH
tBu
Me O
1-Nap·TBA
20 mol%
NPMB
NBoc O
82%, 97% ee
Key Research Programs in Total Synthesis
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.
programs initiated from 1997-2008
■ Examples of powerful synthetic methods for total synthesis developed in the last 10 years
Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science 2011 324, 238-241.
N
NN
Me
OMe
O
SO2Ph
Br
NN
NN
H
NMe
OMe
O N
O
O
Me
Me
PhO2S
SO2PhNH
N
HN
N
H
NMe
OMe
O N
O
O
Me
Me
SS
SS
H
CoCl(PPh3)3
46%
(+)-11,11’-dideoxyverticillin A
Key Research Programs in Total Synthesis
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.
programs initiated from 1997-2008
■ Advances in new methodologies and synthetic strategies have changed how we view total syntheses
■ To a growing extent, attaining the natural product is no longer the final goal
■ Greater emphasis on striving for an “ideal synthesis”
■ Total synthesis is starting to become an auxiliary function of new research in chemistry
The Future of Total Synthesisrepresentation of what we strive to accomplish in total synthesis
■ Two syntheses outlined broadly applicable concepts (cascade catalysis, controlled oligimerization)
■ Two syntheses are of molecules with promising bioactivity
■ All outlined powerful methods to deliver the natural product in short order(10-15 steps)
OO
HO2CCO2H
OH
HCO2H
O H
O
Me Bn
OAcBn
Me
zaragozic acid C
NH
N
HN
N
H
NMe
OMe
O N
O
O
Me
Me
SS
SS
H
(+)-11,11’-dideoxyverticillin A
N
O
N
OH
H
H
H
strychnine
The Future of Total Synthesisrepresentation of what we strive to accomplish in total synthesis
OO
HO2CCO2H
OH
HCO2H
O H
O
Me Bn
OAcBn
Me
zaragozic acid C
NH
N
HN
N
H
NMe
OMe
O N
O
O
Me
Me
SS
SS
H
(+)-11,11’-dideoxyverticillin A
N
O
N
OH
H
H
H
strychnine
The Future of Total Synthesisrepresentation of what we strive to accomplish in total synthesis
OO
HO2CCO2H
OH
HCO2H
O H
O
Me Bn
OAcBn
Me
zaragozic acid C
NH
N
HN
N
H
NMe
OMe
O N
O
O
Me
Me
SS
SS
H
(+)-11,11’-dideoxyverticillin A
N
O
N
OH
H
H
H
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 Wender
The Future of Total Synthesisrepresentation of what we strive to accomplish in total synthesis
■ These represent premier total syntheses for our time
■ 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 synthesis
■ In general, these syntheses are atypical from most syntheses that are published in top journals
OO
HO2CCO2H
OH
HCO2H
O H
O
Me Bn
OAcBn
Me
zaragozic acid C
NH
N
HN
N
H
NMe
OMe
O N
O
O
Me
Me
SS
SS
H
(+)-11,11’-dideoxyverticillin A
N
O
N
OH
H
H
H
strychnine
The Future of Total Synthesisinsights from three recent total syntheses of groups from three different era’s
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OH
resiniferatoxin
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
(+)-saxitoxin
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
■ 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?
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, 615-619.
Wender's Synthesis of Daphnane Diterpene Orthoesters
■ 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
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OHresiniferatoxin
Wender's Synthesis of Daphnane Diterpene Orthoesters
■ Total synthesis featured 46 stop and go steps, tour de force■ Key disconnections: oxidopyrilium cycloaddition. Enyne ring closure. Applied in highly complex system
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OH
resiniferatoxin
Me
O
OBn
OTBS
OAc
O H
Me
O
OBn
OTBS
OAc
O
OAc
■ 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, 12976-12977.
the first synthesis of a daphnane diterpene by Wender in 1997
O
Me
H
OTMS
OHMe
Me
O
OBn
OTBS
H
O
MeOBn
OAc
HO
OBn
TBSO
H
OH
HO
Me
ROPh
OAc
Wender's Synthesis of Daphnane Diterpene Orthoesters
■ Original total synthesis not ideal from an efficiency or a structural diversification perspective
■ Is a more structurally diverse DDO collection accessible to probe function?
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OHresiniferatoxin
■ Can analog synthesis reveal a more synthetically accessible structure that retains function
function oriented synthesis
O
Me
H
HO
O
Me
O
O
OR
R2
HO
R1
O
R1 OH
OR
OO
Me
H
OH
MeO
O
PMP
PMP
OO
O
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, 615-619.
■ Key question:
major subset of DDOs(X = H, 73 congeners)
Wender's Synthesis of Daphnane Diterpene Orthoesters
■ Original total synthesis not ideal from an efficiency or a structural diversification perspective
■ Is a more structurally diverse DDO collection accessible to probe function?
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OH
■ Can analog synthesis reveal a more synthetically accessible structure that retains function
function oriented synthesis
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, 615-619.
■ Key question:
resiniferatoxin
Wender's Synthesis of Daphnane Diterpene Orthoestersfunction oriented synthesis
O
Me
H
HO
O
Me
O
O
OR
R2
HO
R1
O
R1
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, 615-619.
OH
OBn
OO
Me
H
OH
MeO
O
PMP
PMP
OO
O
OH
OBn
BrTBSO
H
OH
MeHO
HOPh
general precursor(22 steps from commercial)
OBn
TBSO
OHO
OO
MeMe
TBSO
revised cycloadduct
major subset of DDOs(X = H, 73 congeners)
Me
O
OBn
OTBS
OAc
O Hvs
original cycloadduct10 steps from tartrate
OH
OBn
OO
Me
H
OH
MeO
O
PMP
PMP
OO
O
general precursor (22 steps)
O
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
OO
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
OO
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
1 2 3
Wender's Synthesis of Daphnane Diterpene Orthoestersprobing the function of the “B” ring
PKC affinity, Ki (nM)aPKC affinity, Ki (nM)a Cellular growth inhibitionCellular growth inhibition
A549 EC50 (nm)b K562 EC50 (nm)c
1 0.48 +/- 0.07 150 +/- 30 7 +/- 1
2 343 +/- 6 > 10,000 > 10,000
3 1.6 +/- 0.1 1500 +/- 60 87 +/- 5aPKC = protein kinase C, a family of serine/threonine kinases bA549 = human lung carcinoma cK562 = 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.
B(19 steps)
Wender's Synthesis of Daphnane Diterpene Orthoestersprobing the function of the “B” ring
PKC affinity, Ki (nM)aPKC affinity, Ki (nM)a Cellular growth inhibitionCellular growth inhibition
A549 EC50 (nm)b K562 EC50 (nm)c
1 0.48 +/- 0.07 150 +/- 30 7 +/- 1
2 343 +/- 6 > 10,000 > 10,000
3 1.6 +/- 0.1 1500 +/- 60 87 +/- 5aPKC = protein kinase C, a family of serine/threonine kinases bA549 = human lung carcinoma cK562 = human chronic myleogenous leukaemia.
■ An assay against both cancer cell lines reveals the importance of the epoxide stereochemistry
■ Interestingly, the simplified des-epoxy analog is active
OH
OBn
OO
Me
H
OH
MeO
O
PMP
PMP
OO
O
general precursor (22 steps)
O
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
OO
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
OO
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
1 2 3
B(19 steps)
Wender's Synthesis of Daphnane Diterpene Orthoestersprobing the function of the “B” ring
■ Calculations showed a preservation of the oxygen spatial arrangement between 1 and 3
■ The β-epoxide of 2, significantly perturbs the orientation of the hydoxymethyl relative to 1
OH
OBn
OO
Me
H
OH
MeO
O
PMP
PMP
OO
O
general precursor (22 steps)
O
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
OO
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
OO
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
1 2 3
B(19 steps)
Wender's Synthesis of Daphnane Diterpene Orthoestersa model for the future?
■ 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 synthesis?
OH
OBn
OO
Me
H
OH
MeO
O
PMP
PMP
OO
O
general precursor (22 steps)
O
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
OO
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
OO
Me
H
HO
OMe
Me
O
O
OH
Ph
HO
AcO
1 2 3
B(19 steps)
Smiths' Synthesis of the Spongistatins
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHX
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 2 X = Hspongistatin 1 X = Cl
Smith, A. B., III; Zhu, W.; Shirakami, S.; Sfouggatakis, C.; Doughty, V. A.; Bennett, C. S.; Sakamoto, Y. Org. Lett. 2003, 5, 761-764.
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, 197-201.
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, 196-199.
Smiths' Synthesis of the Spongistatinshistory of the spongistatins
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHX
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 2 X = Hspongistatin 1 X = Cl
■ Isolated in the early 1990's by the Pettit, Fusetani, and Kitagawa laboratories
■ Pettit’s attempted re-isolation delivered 35 mg of spongistatin 1 from 13 TONS of sponge!
■ Two spiroketals, two tetrahydropyrans, hemiketal, 42 membered macrolide
Smiths' Synthesis of the Spongistatinshistory of the spongistatins
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHX
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
■ Spongistatin 1 has been recognized as one of the most selective cytotoxic agents known
■ Average IC50 value of 0.12 nM against the NCI panel of 60 human cancer cell lines
■ Proposed to bind β-tubulin near, but distinct from, the vinca domain where vinca alkaloids bind
spongistatin 2 X = Hspongistatin 1 X = Cl
Smiths' Synthesis of the Spongistatinshistory of the spongistatins
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHX
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
■ 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)
spongistatin 2 X = Hspongistatin 1 X = Cl
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Smiths' Synthesis of the SpongistatinsSmiths’ first generation synthesis
■ Retrosynthetic analysis
O
OTMS
O
Me
OTMSCl
Me
OTMS
TESO
OTBS
H
H
H
MeOPPh3I
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
■ Late stage Yamaguchi macrolactonization to form the macrocycle
■ A Wittig olefination unites the eastern and western halves of the molecule
AB
CD
E
F
E
F DC
AB
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Smiths' Synthesis of the SpongistatinsSmiths’ first generation synthesis
■ Retrosynthetic analysis
O
OTMS
O
Me
OTMSCl
Me
OTMS
TESO
OTBS
H
H
H
MeOPPh3I
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
SnBu3
OTMSCl
O
OTES
O
Me
Me
TESO
OTBS
HH
MeOOTES
OBn
OMe
OH
OPMB
OBnO O
MeMe
S
S
EE
FF
E
FEF
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Smiths' Synthesis of the SpongistatinsSmiths’ first generation synthesis
■ Retrosynthetic analysis
O
OTMS
O
Me
OTMSCl
Me
OTMS
TESO
OTBS
H
H
H
MeOPPh3I
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
DC
BA
DC
BA
Smiths' Synthesis of the SpongistatinsSmiths’ first generation synthesis
■ Retrosynthetic analysis
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
OMeO
Me
O
H
OH
OMeMe
BPSO
I
O
O
MeODMB
Me
PhO2S
TBSOOMe
H
OBOMH
BnO
DC
BA
DC
BA
Smiths' Synthesis of the SpongistatinsSmiths’ first generation synthesis
■ Retrosynthetic analysis
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
OMeO
Me
O
H
OH
OMeMe
BPSO
I
O
O
MeODMB
Me
PhO2S
TBSOOMe
H
OBOMH
BnO
BPSOOTs
OH OHSS
OTBSMe
OH
BPSO
OHO
SS
TBS
MeO OO
MeMe
AB
AB
B
A
Smiths' Synthesis of the SpongistatinsSmiths’ first generation synthesis
■ Retrosynthetic analysis
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
OMeO
Me
O
H
OH
OMeMe
BPSO
I
O
O
MeODMB
Me
PhO2S
TBSOOMe
H
OBOMH
BnO
DC
DC
O OMe
SS
DMP
Me O
OTBSO
OMe
HBnO
HI
BnOTBSO TBSO
SSOMe
OO
MeMe
BnOOTBS
O SS
TBS
O OO
MeMe
DC
CD
Smiths' Synthesis of the Spongistatinsanion relay chemistry
S S
TBS
S S
dianionequivalent
O
phosgeneumpole
S S
TBS
bifunctional nucleophile linchpin
S S
TBSbase O
R
S SR3Si
OR
1,3-Brookrearrangement
“anion relay”
S SOTBS
R
O
R1
S SOTBS
ROH
R1readily accessible
OTBSR
OHR1
O
■ A versatile method for polyketide synthesis - used to form AB and CD fragments
■ Overview of their entire synthesis and strategy
O
O
MeOAc
Me
PhO2S
TBSOOMe
H
OH
HO
OMeO
Me
O
H
OTES
OMeMe
BPSO
I
11 steps 24 steps
19 steps
Smiths' Synthesis of the Spongistatins
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Yamaguchi (81%)
review of their initial synthetic efforts
48 steps
Alkylation (92%)
Wittig (64%)
5 steps
O
OTMS
O
Me
OTMSCl
Me
OTMS
TESO
OTBS
H
H
H
MeOPPh3I
24 steps, 0.3%
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
43 steps
■ Overview of their synthesis and strategy
Alkylation (92%)
O
OTMS
O
Me
OTMSCl
Me
OTMS
TESO
OTBS
H
H
H
MeOPPh3I
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
5 steps
Smiths' Synthesis of the Spongistatins
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HOWittig (64%)
review of their initial synthetic efforts
■ Versatile synthetic route that accommodated necessary changes in routes and strategies
■ Allowed them to complete the total synthesis, not ideal for scale up or analog synthesis
■ Methods employed in the synthesis were designed to access many structurally diverse natural products
■ Methods employed were not ideally suited for this specific molecule
24 steps, 0.3% 43 stepsYamaguchi (81%)
■ Overview of their synthesis and strategy
Alkylation (92%)
O
OTMS
O
Me
OTMSCl
Me
OTMS
TESO
OTBS
H
H
H
MeOPPh3I
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
5 steps
Smiths' Synthesis of the Spongistatins
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HOWittig (64%)
review of their initial synthetic efforts
■ Should we attempt the total synthesis of molecules this large and complex?
■ Should methods be more ideally suited (and scalable) for a specific molecule?
■ Are these types of tour de force syntheses worth undertaking in 2012?
■ Should versatile methods (diverse array of accessible structures) continue to be employed?
24 steps, 0.3% 53 stepsYamaguchi (81%)
■ Vastly Improved Second Generation Synthesis
24 steps, 9.5% yield
Smiths' Synthesis of the Spongistatins
5.8 g prepared
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Paterson Aldol
review of their second generation synthesis
■ Vastly improved efficiency and scalability
■ Took cues from previous syntheses to revise their overall retrosynthetic strategy
■ Adopted changes to fragment syntheses that were more specifically tuned toward this molecule
O
OTMS
O
Me
OTMSCl
Me
OTMS
TESO
OTBS
H
H
H
MeOPPh3I
Wittig (Crimmins, 64%)
4 steps
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
22 steps, 6.5% yield1.009 g prepared
Evans, CrimminsPaterson, Heathcock
Smith, A. B., III; Tomioka, T.; Risatti, C. A.; Sperry, J. B.; Sfouggatakis, C. Org. Lett. 2008, 10, 4359-4362.
■ Vastly Improved Second Generation Synthesis
Smiths' Synthesis of the Spongistatins
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
review of their second generation synthesis
BPSOH
OH
O
MeH
O
Me
OHBPSO O
OBnOBn
Me
OH
Me
68 g prepared
20% (L)-proline
DMF, 4 °C
84%, 5:1 anti/syn
O
OTMS
O
Me
OTMSCl
Me
OTMS
TESO
OTBS
H
H
H
MeOPPh3I
4 steps
24 steps, 9.5% yield 22 steps, 6.5% yield1.009 g prepared
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
■ Vastly Improved Second Generation Synthesis
Smiths' Synthesis of the Spongistatinsreview of their second generation synthesis
■ 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?
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
O
OTMS
O
Me
OTMSCl
Me
OTMS
TESO
OTBS
H
H
H
MeOPPh3I
4 steps
24 steps, 9.5% yield 22 steps, 6.5% yield1.009 g prepared
O
O
MeOAc
MeO
O
OTIPSTBSOOMe
H
Me
H
AcO
OO
H
H
OH
HO
■ What was known about structural features required for activity
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Diene sectionrequired for activity
C23 epimer(200 nm)
Smiths' Synthesis of the Spongistatinsanalog syntheses from multiple groups provide insight regarding bioactivity
■ What was known about structural features required for activity
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
Smiths' Synthesis of the Spongistatinsanalog syntheses from multiple groups provide insight regarding bioactivity
■ Appeared that the CD spiroketal wasn’t critical but does play some role
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Smiths' Synthesis of the Spongistatinsanalog syntheses from multiple groups provide insight regarding bioactivity
spongistatin 1
■ Appeared that the CD spiroketal wasn’t critical but does play some role
O
OO
O
O
Me
Me
H
AcO
OHCl
O
Me
OH
HO
OH
H
H
OH
H
H
HO
( )5
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
480 nm (Heathcock)
Smiths' Synthesis of the Spongistatinsanalog syntheses from multiple groups provide insight regarding bioactivity
spongistatin 1
■ Appeared that the CD spiroketal wasn’t critical but does play some role
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Smiths' Synthesis of the Spongistatinsanalog syntheses from multiple groups provide insight regarding bioactivity
spongistatin 1
■ Also appears that the AB spiroketal wasn’t critical but does play some role
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Smiths' Synthesis of the Spongistatinsanalog syntheses from multiple groups provide insight regarding bioactivity
spongistatin 1
■ Also appears that the AB spiroketal wasn’t critical but does play some role
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
O
O
O
Me
OHCl
O
Me
OH
HO
OH
H
H
H
HO
460 nm (Heathcock)
Smiths' Synthesis of the Spongistatinsanalog syntheses from multiple groups provide insight regarding bioactivity
spongistatin 1
■ Also appears that the AB spiroketal wasn’t critical but does play some role
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Smiths' Synthesis of the Spongistatinsanalog syntheses from multiple groups provide insight regarding bioactivity
spongistatin 1
■ The “western” portion of spongistatin (diene & E, F rings) constitute the recognition domain
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
■ The “eastern” portion of spongistatin (A,B and C,D-spiroketals) imparts conformational restraints on the western portion
Smiths' Synthesis of the Spongistatinsanalog syntheses from multiple groups provide insight regarding bioactivity
spongistatin 1
■ Random analog synthesis seemed cumbersome and unattractive
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
■ Molecular modeling may provide some insights
examining the conformational restraint hypothesis
■ How can the hypothesis of conformational restraint imparted by the eastern half be tested?
Smiths' Synthesis of the Spongistatins
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, 14042-14053.
insights from molecular modeling
■ Molecular modeling revealed two major an two minor conformations
■ Chloroform - “Flat” maximized intramolecular hydrogen bonds
■ Water - “Twisted” oxygens oriented toward solvent
Smiths' 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 report
Smiths' Synthesis of the Spongistatins
molecular dynamics simulations
■ Focused on water as the solvent
■ Used molecular dynamics simulations to identify rigid and flexible regions
Smiths' Synthesis of the Spongistatins
■ Lead to the development of “DISCON” (DIstrubution of Solution CONformations) MD software
molecular dynamics simulations
■ Focused on water as the solvent
■ Used molecular dynamics simulations to identify rigid and flexible regions
■ Red = Rigid, Blue = Intermediate, Green = Flexible; Number indicates bond pair where torsions change together
Smiths' Synthesis of the Spongistatins
■ 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 together
■ 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
Smiths' Synthesis of the Spongistatinsmolecular 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
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HOC23 epimer
(200 nm)
■ Explains why the C23 epimer results in loss of activity even as its not involved in recognition
Smiths' Synthesis of the Spongistatinsmolecular dynamics simulations
DC
AB
E
F
■ An overlay of all the most populated solution state conformations is revealing
■ The rigid EFAB region is highly conserved
Smiths' Synthesis of the Spongistatinsmolecular dynamics simulations
O
OO
O
O
Me
Me
H
AcO
OHCl
O
Me
OH
HO
OH
H
H
OH
H
H
HO
( )5
480 nm (Heathcock)
■ 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?
Smiths' Synthesis of the Spongistatinsmolecular dynamics simulations
spongistatin 1
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
< 1 nm
ABEF analog (Heathcock)
computationally aided analog design
O
OO
O
O
Me
Me
H
AcO
OHCl
O
Me
OH
HO
OH
H
H
OH
H
H
HO
O
O
■ Computationally aided analog design found ABEF analog with high structural homology to spongistatin
macrolide strain energy = 8.3 kJ/mol macrolide strain energy = 9.1 kJ/mol
E
F
EE
F F
ABEF analog (Smith)
Smiths' Synthesis of the Spongistatins
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
computationally aided analog design
O
OO
O
O
Me
Me
H
AcO
OHCl
O
Me
OH
HO
OH
H
H
OH
H
H
HO
O
O
■ Computationally aided analog design found ABEF analog with high structural homology to spongistatin
macrolide strain energy = 8.3 kJ/mol macrolide strain energy = 9.1 kJ/mol
E
F
EE
F F
ABEF analog (Smith)
Smiths' Synthesis of the Spongistatins
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
a highly potent spongistatin analog
O
OO
O
O
Me
Me
H
AcO
OHCl
O
Me
OH
HO
OH
H
H
OH
H
H
HO
O
O
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
MDA-MB-435 HT-29 H522-T1 U937
spongistatin 0.0225 0.058 0.16 0.059
ABEF analog 82.8 161.2 297.2 60.5
spongistatin 1
■ Similar activity present after having deleted nearly 1/3 of the original structure
■ ABEF analog determined to have the same mode of action
Smiths' Synthesis of the Spongistatins
ABEF analog (Smith)
O
OTES
O
Me
OTBSCl
Me
OTES
TESO
OTBS
H
H
H
MeOPPh3I
OO
Me
H
AcO
O
H
OTES
O
O
OTIPS
CHO
O
OO
O
O
Me
Me
H
AcO
OHCl
O
Me
OH
HO
OH
H
H
OH
H
H
HO
O
O5 steps
29 steps(20 steps shorter!!!)
a review of their analog workSmiths' Synthesis of the Spongistatins
■ 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
Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975.
■ A highly oxidized and polar neurotoxic agent
■ Toxicity arises from disabling ionic conductance through voltage-gated sodium channel.
■ Exhibits nanomolar affinity for binding the extracellular mouth of the ion channel.
(+)-saxitoxin
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
DuBois' Total Synthesis of Saxitoxin
Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975.
(+)-saxitoxin
■ Why synthesize a neurotoxic agent?
■ 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
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
2 mol% Rh2(OAc)2PhI(OAc)2, MgO
CH2Cl2 Me
OHNMeMe
SOO
Rhodium catalyzed C-H aminationDuBois' Total Synthesis of Saxitoxin
Me
OH2NMeMe
SOO
Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935-6936.
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
2 mol% Rh2(OAc)2PhI(OAc)2, MgO
CH2Cl2 Me
OHNMeMe
SOO
Rhodium catalyzed C-H aminationDuBois' Total Synthesis of Saxitoxin
Me
OH2NMeMe
SOO
Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935-6936.
OH2NSOO
OO
MeMe
0.3 mol% Rh2(esp)2
PhI(OAc)2, MgOCH2Cl2
76%
OHNSOO
OO
MeMe
Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975.
2 mol% Rh2(OAc)2PhI(OAc)2, MgO
CH2Cl2 Me
OHNMeMe
SOO
Rhodium catalyzed C-H aminationDuBois' Total Synthesis of Saxitoxin
Me
OH2NMeMe
SOO
Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935-6936.
OH2NSOO
OO
MeMe
0.3 mol% Rh2(esp)2
PhI(OAc)2, MgOCH2Cl2
76%
OHNSOO
OO
MeMe
HN
OH
S
OTs
O
OO
ZnClR
BF3·OEt2
Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975.
HN
OH
S
OTs
O
OO
11 steps
AgNO3
i-PrNEt2
65% NH
NH
NHOH
NMbs
H2N
NMbs
Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975.
DuBois' Total Synthesis of Saxitoxinfirst generation total synthesis
NH
NH2
OH
NH
MbsN
MeS
H2N
NMbs
HN
OH
S
OTs
O
OO
11 steps
AgNO3
i-PrNEt2
65% NH
NH
NHOH
NMbs
H2N
NMbs
1. Cl3CC(O)NCO
2. K2CO3, MeOH
82% NH
NH
NHO
NMbs
H2N
NMbs
NH2
O
Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975.
DuBois' Total Synthesis of Saxitoxinfirst generation total synthesis
NH
NH2
OH
NH
MbsN
MeS
H2N
NMbs
OsCl3oxone, Na2CO3
62%, 12:1N NH
O
O
NH2
NH2+
HOHONH2
NMbs
HN
OH
S
OTs
O
OO
11 steps
AgNO3
i-PrNEt2
65% NH
NH
NHOH
NMbs
H2N
NMbs
1. Cl3CC(O)NCO
2. K2CO3, MeOH
82% NH
NH
NHO
NMbs
H2N
NMbs
NH2
O
OsCl3oxone, Na2CO3
62%, 12:1N NH
O
O
NH2
NH2+
HOHONH2
NMbs
Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975.
DuBois' Total Synthesis of Saxitoxin
B(O2CCF3)3
TFA, 0 °C to rt82%
N NH
NHHN
+H2N
O
O
NH2
NH2+
HODMSO, DCCpyridine·TFA
70% N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
H
(+)-saxitoxin20 steps
first generation total synthesis
NH
NH2
OH
NH
MbsN
MeS
H2N
NMbs
DuBois' Total Synthesis of Saxitoxin
(+)-saxitoxin
■ Utilizing their C-H 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)
first generation recap
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975.
DuBois' Total Synthesis of Saxitoxinrethinking their original route
HN
OH
S
OTs
O
OO
11 steps
NH
NH2
OH
NH
MbsN
MeS
H2N
NMbs
14 steps
Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975.
DuBois' Total Synthesis of Saxitoxinrethinking their original route
HN
OH
S
OTs
O
OO
11 steps
NH
NH2
OH
NH
MbsN
MeS
H2N
NMbs
N
NHBocOTBDPS
OHPMB
NH
SMe
NMbs
H
N
NHBocOTBDPS
OPMB
MeO
O
NHBocOH
methyl esterN-Boc serine
14 steps
14 step second generation total synthesisDuBois' Total Synthesis of Saxitoxin
MeO
O
NHBocOH
3 steps H
N
NHBocOTBDPS
OPMBalkyne
i-PrMgClTHF, -78 °C
78%, 5:1 anti/syn
N
NHBocOTBDPS
OHPMB
NH
SMe
NMbs
NH
NH
NHOH
NMbs
H2N
NMbs
4 steps6 steps N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
H
(+)-saxitoxin
methyl esterN-Boc serine
Fleming, J. J.; McReynolds, M. D.; Du Bois, J. J. Am. Chem. Soc. 2007, 129, 9964-9975.
10 steps vs 16 steps
DuBois' Total Synthesis of Saxitoxin
(+)-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.
second generation recap
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
carbomyl group proposed to be H bond donor7,8,9-guanidine residue
proposed to bind the selectivity filter
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
Andersen, B. M.; Du Bois, J. J. Am. Chem. Soc. 2009, 131, 12524-12525.
■ Is the carbamate, specifically as an H-bond donor, important for saxitoxin binding the ion channel?
initial question
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
H
N NH
NHHN
+H2N
O
O
N
NH2+
HO
HO
HMe
Me
Saxitoxin as a Small Molecule Probe for Ion Channel Studies
N,N-dimethyl-(+)-saxitoxin(+)-saxitoxin
■ Is the carbamate, specifically as an H-bond donor, important for saxitoxin binding the ion channel?
■ Strategy: Remove the hydrogen bonds and measure the voltage across the ion channel
initial question
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
H
N NH
NHHN
+H2N
O
O
N
NH2+
HO
HO
HMe
Me
Saxitoxin as a Small Molecule Probe for Ion Channel Studies
N,N-dimethyl-(+)-saxitoxin(+)-saxitoxin
■ Is the carbamate, specifically as an H-bond donor, important for saxitoxin binding the ion channel?
initial question
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
H
N NH
NHHN
+H2N
O
O
N
NH2+
HO
HO
HMe
Me
(+)-saxitoxin N,N-dimethyl-(+)-saxitoxin
■ Increasing conc. of both saxitoxin and N,N-dimethylsaxitoxin result in decreased peak current
carbomyl unit not likely a hydrogen bond donor
Saxitoxin as a Small Molecule Probe for Ion Channel Studies
■ Do further modifications to the carbomyl unit effect binding?
initial question
N NH
NHHN
+H2N
O
O
N
NH2+
HO
HO
HR
H
C7H15
i-Pr
C6H12NH3+
C5H10CO2-
NH
O
O
R
26 +/- 3
83 +/- 13
19 +/- 0.8
135 +/- 7
87 +/- 9
IC50 (nM)
■ Despite steric, electronic, and polar modifications, all retained activity within 1-1.5 orders of magnitude
■ Allowed for the installation of the first saxitoxin photoaffinity probe
Saxitoxin 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
( )5N NH
NHHN
+H2N
O
O
N
NH2+
HO
HO
H
H
NH3+p-FC6H4C(O)NHS
CH3CN/H2O
pH = 9.5IC50 = 46 +/- 7 nm
( )5N NH
NHHN
+H2N
O
O
N
NH2+
HO
HO
H
H
HN
F
■ Cofactors
Saxitoxin as a Small Molecule Probe for Ion Channel Studies
■ Having access to synthetic saxitoxin should provide unique insights in ion channel structure and function
F
O
ON
O
O
p-FC6H4C(O)NHS
DuBois' Total Synthesis of Saxitoxin
(+)-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 C-H amination catalyst
■ The result of their work enabled a new area of academic research on ion channels.
overview of saxitoxin synthesis
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
DuBois' Total Synthesis of Saxitoxin
(+)-saxitoxin
■ Should total syntheses be used to apply methodology if the resulting initial synthesis isn’t the “best”?
overview of saxitoxin synthesis
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
■ Is post synthetic research becoming mainstream?
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OH
resiniferatoxin
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
(+)-saxitoxin
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
■ 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?
summary of themes from selected examplesThe Future of Total Synthesis
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OH
resiniferatoxin
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
(+)-saxitoxin
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
■ 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
final thoughtsThe Future of Total Synthesis
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OH
resiniferatoxin
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
(+)-saxitoxin
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
■ 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
final thoughtsThe Future of Total Synthesis
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OH
resiniferatoxin
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
(+)-saxitoxin
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
■ 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
final thoughtsThe Future of Total Synthesis
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OH
resiniferatoxin
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
(+)-saxitoxin
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
■ 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
final thoughtsThe Future of Total Synthesis
final thoughts
■ Powerful new methods will continue to push toward the ideal total synthesis
The Future of Total Synthesis
OO
HO2CCO2H
OH
HCO2H
O H
O
Me Bn
OAcBn
Me
zaragozic acid C
NH
N
HN
N
H
NMe
OMe
O N
O
O
Me
Me
SS
SS
H
(+)-11,11’-dideoxyverticillin A
N
O
N
OH
H
H
H
strychnine
final thoughts
■ Focused efforts toward a single natural product will continue to be a productive area of research
The Future of Total Synthesis
O
Me
H
HO
OMe
Me
O
O
O
O OMe
OHresiniferatoxin
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
(+)-saxitoxin
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
spongistatin 1
new areas of research
final thoughts
■ Focused efforts toward a single natural product will continue to be a productive area of research
The Future of Total Synthesis
new areas of research
NH
N
HN
N
H
NMe
OMe
O N
O
O
Me
Me
SS
SS
H
dideoxyverticillin A (Movassaghi)
O
Me
H
HO
Me
OH
OH
MeMe
OAc
prostratin (Wender) (-)-doxycycline (Myers)
OH O
HMe OH
HNMe2
OH
O
NH2OH
OH
H
O
Last total syntheses to be published in Science
final thoughts
■ Groups that undertake impractical syntheses of many different targets will become irrelevant
The Future of Total Synthesis
final thoughts
■ These sentiments are being increasingly observed across the spectrum of total synthesis
The Future of Total Synthesis
Barry Trost (1965) David Evans (1967) Larry Overman (1970) Amos Smith (1972)
■ More focused efforts toward fewer targets is likely the future of total synthesis
spongistatin 1
O
O
O
MeOAc
MeO
O
O
O
Me
HOOMe
H
Me
H
AcO
OHCl
OO
Me
OH
HO
OH
H
H
H
OH
H
H
HO
Me Me
H
H
Me
O
O
O
OAc
AcOH
macfarlandin
OMeO2C
MeMe
O
MeMeHOOR
OH
O
O
Me OH
OOH
RO
CO2Mebryostatin 1
final thoughts
■ These sentiments are being increasingly observed across the spectrum of total synthesis
The Future of Total Synthesis
K. C. Nicolaou (1976) Paul Wender (1976) Dale Boger Stuart Schreiber
■ More focused efforts toward fewer targets is likely the future of total synthesis
vancomycinprostratin
OMeO2C
MeMe
O
MeMeHOOR
OH
O
O
Me OH
OOH
RO
CO2Mebryostatin 1
O
Me
H
HO
Me
OH
OH
MeMe
OAc
OOO
NH
HN
O
OHN
O
NH2
ONH
OOH
Cl
HN
MeMe
Me
NH
HOCl
HNHO2C
O
OHOHHO
R
final thoughts
■ These sentiments are being increasingly observed across the spectrum of total synthesis
The Future of Total Synthesis
Andrew Myers (1986) Scott Rychnovsky (1988) Peter Wipf (1990) John Wood (1993)
■ More focused efforts toward fewer targets is likely the future of total synthesis
cholesteroldoxycyclin
OH O
HMe OH
HNMe2
OH
O
NH2OH
OH
H
OHO
Me H
H
H
MeMe
Me
Me
final thoughts
■ These sentiments are being increasingly observed across the spectrum of total synthesis
The Future of Total Synthesis
■ More focused efforts toward fewer targets is likely the future of total synthesis
irciniastatin A(Floreancig, De Brabander)
amphotericin B (Burke)
N NH
NHHN
+H2N
O
O
NH2
NH2+
HO
HO
O
O
MeHO
OH
Me
OH
OMeMe
OHH
OMe
NH
O
OH
OMeMe
H
H
MeO O
HONH2
OH
Me
O O
OH
OHOH
O
OHOH
OH
OHOHO
Me
MeHO
saxitoxin (Du Bois)
N
NOMe
Me
H
H
HH
H
H
OHMe
O
H
OMeHO
MeHO
OH
OO
MeMe
OHcephalostatin 1 (Shair)
final thoughts
■ If the overall goal is for chemistry to benefit society and if natural products are to play a role...
The Future of Total Synthesis
■ Focused efforts toward fewer targets will lead to better targets and more active areas of research
■ Continuing to strive for new reactions will deliver increasingly complex targets in short order
■ 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...
■ Applying methods in complex settings will lead to better and more useful methods
final thoughts
■ If the overall goal is for chemistry to benefit society and if natural products are to play a role...
The Future of Total Synthesis
■ Focused efforts toward fewer targets will lead to better targets and more active areas of research
■ Continuing to strive for new reactions will deliver increasingly complex targets in short order
■ 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
■ Applying methods in complex settings will lead to better and more useful methods