"You eat, drink, and sleep your molecule" (Phil S. Baran)
Guillaume Barbe
Charette’s Laboratories
Université de MontréalOctober 30th 2006
Phil S. BaranDate/Place of Birth: 10 Aug 1977 / Denville, NJ, USA
Education
1991 - 1995 Simultaneous high school graduation from Mt. Dora High School andA.A. degree with honors from Lake Sumter Community College, Florida
1995 - 1997 B.S. with Honors in Chemistry, New York UniversityAdvisor: Professor D.I. Schuster
1997 - 2001 Ph.D. graduate student in Chemistry, The Scripps Research InstituteAdvisor: Professor K.C. Nicolaou
2001 - 2003 Postdoctoral Associate, Harvard UniversityAdvisor: Professor E.J. CoreyCareer
July, 2006 Associate Professor of Chemistry (with Tenure)June, 2003 Assistant Professor of Chemistry
Phil S. Baran: AwardsPre to PostDoctoral
• Nobel Laureate Signature Award in Chemistry, ACS, 2003
• National Institutes of Health Post-Doctoral Fellowship Award, Harvard, 2001-2003• Hoffmann-La Roche Award for Excellence in Organic Chemistry, 2000• Lesly Starr Shelton Award for Excellence in Chemistry Graduate Studies, 2000• National Science Foundation Pre-Doctoral Fellowship Award, Scripps, 1998–2001• William and Sharon Bauce Family Foundation Fellowship Award, Scripps, 1997• Dean’s Undergraduate Research Fund Award in Chemistry, NYU, 1996-1997• George Granger Brown Award for Excellence in Chemistry, NYU, 1996-1997• NYU College of Art and Sciences Scholarship, 1995-1997• Herman and Margaret Sokol Chemistry Fellowship, NYU, 1995-1997
Phil S. Baran: AwardsPre and PostDoctoral
Nobel Laureate Signature Award in Chemistry
Purpose: To recognize an outstanding graduate student and her or his preceptor(s), in the field of chemistry, as broadly defined.
"Phil Baran was a phenomenal student. Tenacious, enthusiastic, brilliant, and imaginative. I think he is now a formidable synthetic chemist with an exciting career ahead of him." (Nicolaou)
"Phil has a towering intellect and is a young person of great originality and motivation. I feel certain that he is destined to be one of the superstars of organic chemistry for years to come." (Corey)
C&EN : January 6, 2003, Volume 81, Number 01, pp. 38-43
Phil S. Baran: AwardsIndependent career
• National Fresenius Award, 2007• Pfizer Award for Creativity in Organic Synthesis, 2006• Beckman Foundation Fellow, 2006 – 2008• Alfred P. Sloan Foundation Fellow, 2006 – 2008• BMS Unrestricted “Freedom to Discover” Grant, 2006 – 2010• NSF CAREER award, 2006 – 2010• Eli Lilly Young Investigator Award, 2005-2006• AstraZeneca Excellence in Chemistry Award, 2005• DuPont Young Professor Award, 2005• Roche Excellence in Chemistry Award, 2005• Amgen Young Investigator Award, 2005• Searle Scholar Award, 2005• GlaxoSmithKline Chemistry Scholar Award, 2005-2006
Baran’s Publications: Schuster
27. MacMahon, S.; Fong, R.; Baran, P.S.; Safonov, I.; Wilson, S.R.; Schuster, D.I. J. Org. Chem. 2001, 66; 5449-5455. 24. Wilson, S.R.; Baran, Phil S.; Schuster, D.I.; Goh, S.K.; Marynick, D.S. manuscript in preparation. 14. Baran, P.S.; Khan, A.U.; Schuster, D.I. Sci. Tech. 1999, 7, 921-925. 4. Schuster, D.I.; Baran, P.S.; Hatch, R.K.; Khan, A.U.; Wilson, S.R. Chem. Commun. 1998, 22, 2493-2494. 3. Safonov, I.G.; Baran, P.S.; Schuster, D.I. Tetrahedron Lett. 1997, 38, 8133-8136. 2. Baran, P.S.; Monaco, R.R.; Khan, A.U.; Schuster, D.I.; Wilson, S.R. J. Am. Chem. Soc. 1997, 119, 8363-8364. 1. Baran, P.S.; Monaco, R.R.; Khan, A.U.; Schuster, D.I.; Soulas, P.; Echegoyen, L. Proc. - Electrochem. Soc. 1997, 97-14 (Recent Advances in the Chemistry and Physics of Fullerenes and Related Materials), 25-36.
Fullerene Chemistry
Baran’s Publications: Nicolaou
39. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720. 35. Nicolaou, K.C.; Jung, J.; Yoon, W. H.; Fong, K. C.; Choi, H.; He, Y.; Zhong, Y. L.; Baran, P. S. J. Am. Chem. Soc. 2002, 124, 2183 - 2189. 34. Nicolaou, K.C.; Baran, P. S., Zhong, Y. L.; Fong, K. C.; Choi, H. J. Am. Chem. Soc. 2002, 124, 2190 - 2201. 33. Nicolaou, K.C.; Zhong, Y. L.; Baran, P. S.; Jung, J.; Choi, H.; Yoon, W. H. J. Am. Chem. Soc. 2002, 124, 2202 - 2211. 17. Nicolaou, K.C.; Jung, J.-K.; Yoon, W.-Y.; He, Y.; Zhong, Y.-L.; Baran, P.S. Angew. Chem. Int. Ed. 2000, 39, 1829-1832. 8. Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Choi, H.-S.; Yoon, W.H.; He, Y.; Fong, K.C. Angew. Chem. Int. Ed. 1999, 38, 1669-1675. 7. Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Fong, K.C.; He, Y.; Yoon, W.H.; Choi, H.S. Angew. Chem. Int. Ed. 1999, 38, 1676-1678. 6. Nicolaou, K.C.; He, Y.; Fong, K.C.; Yoon, W.H.; Choi, H.-S.; Zhong, Y.-L.; Baran, P.S. Org. Lett. 1999, 1, 63-66. 5. Nicolaou, K.C.; Baran, P.S.; Jautelat, R.; He, Y.; Fong, K.C.; Choi, H.-S.; Yoon, W.H.; Zhong, Y.-L. A Angew. Chem. Int. Ed. 1999, 38, 549-552.
OO
O
OO
O
HO
CO2H
OO
O
OO
OH
HO
CO2H
HO
CP-263,114 CP-225,917
Baran’s Publications: Nicolaou
37. Nicolaou, K.C.; Montagnon, T.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 1386-1389. 36. Nicolaou, K.C.; Montagnon, T.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 993 - 996.32. Nicolaou, K.C.; Baran, P. S.; Zhong, Y. L.; Sugita, K. J. Am. Chem. Soc. 2002, 124, 2212 - 2220. 31. Nicolaou, K.C.; Sugita, K.; Baran, P. S.; Zhong, Y. L. J. Am. Chem. Soc. 2002, 124, 2221 - 2232. 30. Nicolaou, K.C.; Baran, P. S.; Zhong, Y. L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am. Chem. Soc. 2002, 124, 2233 - 2244. 29. Nicolaou, K.C.; Montagnon, T.; Baran, P. S.; Zhong, Y. L. J. Am. Chem. Soc. 2002, 124, 2245 - 2258. 26. Nicolaou, K.C.; Baran, P.S.; Zhong, Y.L. J. Am. Chem. Soc. 2001, 123, 3183 - 3185. 25. Nicolaou, K.C.; Zhong, Y. L.; Baran, P.S.; Sugita, K. Angew. Chem. Int. Ed. 2001, 40, 2145. 23. Nicolaou, K.C.; Sugita, K.; Baran, P.S; Zhong, Y.-L. Angew. Chem. Int. Ed. 2001, 40, 207-210. 22. Nicolaou, K.C.; Baran, P.S.; Kranich, R.; Zhong, Y.L.; Sugita, K.; Zou, N. Angew. Chem. Int. Ed. 2001, 40, 202-206. 19. Nicolaou, K.C.; Zhong, Y.-L.; Baran, Phil S. J. Am. Chem. Soc. 2000, 122, 7596-7597. 18. Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Vega, J.A. Angew. Chem. Int. Ed. 2000, 39, 2525-2529. 13. Nicolaou, K.C.; Zhong, Y.-L.; Baran, P.S. Angew. Chem. Int. Ed. 2000, 39, 622-625. 12. Nicolaou, K.C.; Zhong, Y.-L.; Baran, P.S. Angew. Chem. Int. Ed. 2000, 39, 625-628.
Iodine(V) Reactions
Baran’s Publications: Nicolaou
28. Nicolaou, K.C.; Montagnon, T.; Ulven, T.; Baran, P. S.; Zhong, Y. L.; Sarabia, F. J. Am. Chem. Soc. 2002, 124, 5718 - 5728. 20. Nicolaou, K.C.; Baran, P.S.; Zhong, Y.L. J. Am. Chem. Soc. 2000, 122, 10246-10248.
Synthesis of Hindered -Diazoketones via Acyl Mesylates
16. Nicolaou, K.C.; Vassilikogiannakis, G.; Kranich, R.; Baran, P.S.; Zhong, Y.L.; Natarajan, S. Org. Lett. 2000, 2, 1895-1898.
9. Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Choi, H.-S.; Fong, K.C.; He, Y.; Yoon, W.H. Org. Lett. 1999, 1, 883-886.
-Sulfonated Ketones
Mild and Selective Homologation of Hindered Aldehydes in the Presence of Ketones
21. Nicolaou, K.C.; Vourloumis, D.; Winssinger, N.; Baran, P.S. Angew. Chem. Int. Ed. 2000, 39, 44-122.
The Art and Science of Total Synthesis at the Dawn of the Twenty-first Century
Baran’s Publications: Nicolaou
15. Nicolaou, K.C.; Vassilikogiannakis, G.; Simonsen, K.B.; Baran, P.S.; Zhong, Y.-L.; Vidali, V.P.; Pitsinos, E.N.; Couladouros, E.A. J. Am. Chem. Soc. 2000, 122, 3071 - 3079. 11. Nicolaou, K.C.; Jautelat, R.; Vassilikogiannakis, G.; Baran, P.S.; Simonsen, K. Chem. Eur. J. 1999, 5, 3651-3665. 10. Nicolaou, K.C.; Simonsen, K.S.; Vassilikogiannakis, G.; Baran, P.S.; Vidali, V.P.; Pitsinos, E.N.; Couladouros, E.A. Angew. Chem. Int. Ed. 1999, 38, 3555-3559.
OOH
HOO
HO
O
O
HO
OOH
HOO
O
Bisorbicillinol
Bisorbibutenolide
OOH
O
HOO O
O O
OH
OH
OH
Trichodimerol
Baran’s Publications: Corey
40. Baran, P. S.; Guerrero, C. A.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 5628 - 5629.41. Baran, P. S.; Guerrero, C. A.; Corey, E. J. Org. Lett. 2003, 5, 1999 - 2001.
NH
N
N
OO
MeMe
H
(+)-Deoxyisoaustamide
NH
(+)-austamide
N
NO
O
MeMe
O H
NH
(+)-Hydratoaustamide
N
NO
O
MeMe
O H OH
38. Baran, P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 7904 - 7905.
NH
N
N
OO
MeMe
H
Okaramine N
H
NMeMe
H
OH
Baran’s Publications
53. Baran, P.S.; Hafensteiner, B.D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. Enantioselective Total Synthesis of Avrainvillamide and the Stephacidins. J. Am. Chem. Soc. 2006, 128, 8678-8693.
48. Baran, P. S.; Guerrero, C.A.; Hafensteiner, B.D.; Ambhaikar, N.B. Total synthesis of Avrainvillamide (CJ-17,665) and Stephacidin B, Angew. Chem. Int. Ed. 2005, 44, 3892-3895.
46. Baran, P. S.; Guerrero, C.A.; Ambhaikar, N.B.; Hafensteiner, B.D. Short, Enantioselective Total Synthesis of Stephacidin A, Angew. Chem. Int. Ed. 2005, 44, 606-609.
Baran’s Publications
52. Northrop, B.H.; O'Malley, D.P.; Zografos A. L.; Baran, P.S.; Houk, K. N. Mechanism of the Vinylcyclobutane Rearrangement of Sceptrin to Ageliferin and Nagelamide E. Angew. Chem. Int. Ed. 2006, 45, 4126 –4130.
50. Baran, P. S.; Li, K; O'Malley, D.P.; Mitsos, C. Short, Enantioselective Total Synthesis of Sceptrin and Ageliferin by Programmed Oxaquadricyclane Fragmentation. Angew. Chem. Int. Ed. 2006, 45, 249 –252.
43. Baran, P.S.; O'Malley, D.P.; Zografos, A.L. Sceptrin as a Potential Biosynthetic Precursor to Complex Pyrrole-Imidazole Alkaloids: The Total Synthesis of Ageliferin, Angew. Chem. Int. Ed. 2004, 43, 2674-2677.
42. Baran, P.S.; Zografos, A.L.; O'Malley, D.P. Short Total Synthesis of Sceptrin, J. Am. Chem. Soc. 2004, 126, 3726-3727.
NH
HN
NH
NH
HN
HN
NH2
NH2
HN
NH
Br O
OBr
Cl
Cl
(+)-Sceptrin
HN
HN
HN
NH
Br O
OBr
NN
NH
HN
H2N
NH2
TFA
TFA
(-)-Ageliferin
HN
HN
HN
NH
Br O
OBr
NN
NH
HN
H2N
NH2
TFA
TFA
Nagelamide E
Baran’s Publications
55. Baran, P. S.; Shenvi, R. A. Total Synthesis of (±)–Chartelline C, J. Am. Chem. Soc. 2006, 128, in press.
47. Baran, P. S.; Shenvi, R.A.; Mitsos, C.A. A Remarkable Ring Contraction En Route to the Chartelline Alkaloids, Angew. Chem. Int. Ed. 2005, 44, 3714-3717.
N
N
N
NH
Cl
O
R
R'
Br
Br MeMe
R = R' = Br Chartelline AR = H, R' = Br Chartelline BR = R' = H Chartelline C
51. Baran, P. S.; Burns, N. Z. Total Synthesis of (±)-Haouamine A. J. Am. Chem. Soc.; 2006; 128; 3908 - 3909.
Houamine A
N
HO
HO
HO
H
HO
Baran’s Publications
54. Baran, P. S.; DeMartino, M. P. Intermolecular Enolate Heterocoupling, Angew. Chem. Int. Ed. 2006, 45, in press.
49. Baran, P. S.; Richter, J. M. Enantioselective Total Syntheses of Welwitindolinone A and Fischerindoles I and G, J. Am. Chem. Soc.; 2005; 127(44); 15394-15396.
45. Baran, P.S.; Richter, J.M.; Lin, D.W. Direct Coupling of Pyrroles with Carbonyl Compounds: Short, Enantioselective Synthesis of (S)-Ketorolac, Angew. Chem. Int. Ed. 2005, 44, 609-612.
44. Baran, P.S.; Richter, J.M. Direct Coupling of Indoles with Carbonyl Compounds: Short, Enantioselective, Gram-Scale Synthetic Entry into the Hapalindole and Fischerindole Alkaloid Families, J. Am. Chem. Soc. 2004, 126, 7450-7451.
NH
Cl
Me
Me
H
Me
NC
(-)-Fischerindole I
NH
Cl
Me
Me
H
MeNC
(+)-Welwitindolinone A
ONH
Cl
Me
Me
H
Me
NC
(+)-Fischerindole G
H
NH
Me
Me
H
Me
(-)-12-epi-Fischerindole U
H
SCN
Hapalindole Q
NH
Me
H
H
SCN
Me
CP Molecules
Stinson, S. Chem. Eng. News 1995, 73, 29.
OO
O
OO
O
HO
CO2H
OO
O
OO
OH
HO
CO2H
HO
CP-263,114 CP-225,917
“New natural products have unusual structures”
“Fermentation broths of a still-unidentified fungus have yielded two compounds that are promising leads to drugs for lowering serum cholesterol and treating cancer. In addition to their medicinal promise, the two compounds have unusual structures that make them attractive synthetic targets.”
“Both compounds inhibit the enzymes squalene synthase and farnesyl protein transferase. Squalene synthase catalyzes condensation of two molecules of the C15 sesquiterpenoid farnesyl pyrophosphate to squalene, with presqualene pyrophosphate as a step on the way. This reaction is one in the overall biosynthesis of cholesterol. The hope is that such compounds will lead to new cholesterol-lowering drugs. Farnesyl protein 1 transferase mediates farnesylation of the protein p21, which is the product of the ras oncogene. A one-amino acid mutation of p21 renders it permanently activated, so that it pushes regulation of cell growth and division out of control. Here, the hope is that the Pfizer compounds will inhibit a step that may be essential to p21 activity and thus to the carcinogenic process.”
CP Molecules: Setting the floor to Baran[3,3]-sigmatropic rearrangement approach
PMBO
O O
SnMe3PMBO PMBOOTBS
OTBS
PMBOOTBS
O
MeO
PMBOOTBS
O
MeON2
MeOO
OTBS
HPMBO
MeOO
H
OTBSPMBO
HO
H
OTBSPMBO
MeO
H
OTBSPMBO
DABCO cat.H2C=O, THF
0 °C - rt, 30 %
1)
PMBOC(NH)CCl3CSA, DCM, rt
78 %
2)
NaHMDS, PhNTf2THF, -40 °C
60 %
1)
Me3SnSnMe3Pd(PPh3)4, LiCl
THF, 60 °C73 %
2)
n-BuLi, THF, ald-40 °C - 0 °C
86 %
1)
TBSCl, ImDMF, 50 °C
94 %
2)
TBSO H
O
CSA, MeOH/H2O0 °C, 91 %
1)
(COCl)2, DMSOTEA, DCM
-78 °C
2)
NaOCl2, NaH2PO42-methyl-2-butene
THF/H2O/tBuOH, 0 °C
3)
CH2N2, Et2O, rt87 % over 3 steps
4)
KHMDS, PhCO2MeTHF, -78 °C - rt, 93 %
1)
DBU, DCM0 °C - rt, 95 %
2)
Rh2(OAc)4DCM, 0 °C, 87 %
6.7:1 ratio
TBAF, THF0 °C - rt, 95 %
1)
PPh3, DEADPhCO2H, THF
-20 °C - rt, 95 %
2)
NaOMe, MeOHrt, 93 %
3)
TBSOTf2,6-lutidine
DCM, -78 °C to 0 °C86 %
4)
DIBAL, DCM-78 °C, 86 %
1)
TPAP, NMOMS 4Å, DCM, rt
2)
MeMgBr, THF0 °C
1)
TPAP, NMOMS 4Å, DCM, rt
2)
93 % over 3 steps
Nicolaou, K. C.; Postema, M. H. D.; Yang, G. Angew. Chem. Int. Ed. 1997, 36, 2821-2823.
CP Molecules: Setting the floor to Baran[3,3]-sigmatropic rearrangement approach
Nicolaou, K. C.; Postema, M. H. D.; Yang, G. Angew. Chem. Int. Ed. 1997, 36, 2821-2823.
MeO
H
OTBSPMBO
OTES
H
OTBSPMBO
OTES
H
OTBSPMBO
O
PMBO OH
H
O
PMBO H
SPh
O
HO H
SPh
O
O H
SPh
OBr
O
H
SPh
O
O
O
O
O
KHMDS, TESClTEA, THF, -78 °C
THF-78 °C to 45 °C
TBAF, THF0 °C - rt
95 % over 2 steps
PhSSPh, Bu3PPhH, rt
65 % brsm
DDQDCM:H2O, rt
85 %
BrCH2CO2H, DCC4-DMAP, DCM
rt, 81 %
Me3SnSnMe3, hvPhH, 35 °C, 61 %
CP Molecules: Setting the floor to BaranDiels-Alder approach
Nicolaou, K. C.; Härter, M. W.; Boulton, L.; Jandeleit, B. Angew. Chem. Int. Ed. 1997, 36, 1194-1196.
HOOH
TBSOOH
TBSON
TBSO
OH
TBSO N
OBn
OBn
HO
OBn
MeO
OBn
MeO
CN
OTMS
TBSCl, NaHTHF, 0 °C
90 %
SO3-Py, DMSOTEA, DCM, 0 °C
80 %
1)
CyclohexylamineMS 4 Å
Benzene, rt
2)
LDA, Allyl-BrTHF, -78 °C to rt
1)
NaBH4MeOH, rt
2)
58 % over 3 steps
BnBr, NaHTBAI, DMF, 0 °C
88 %
1)
O3, DCM;PPh3
-78 °C - rt, 84 %
2)
CyclohexylamineMS 4 Å
Benzene, rt, 98 %
3)LDA, Butanal
THF, -78 °C to rti)
Oxalic Acidwater, rt
ii)
74 %
KH, DME, 0 °Ci)Me2SO4
HMPA, 0 °Cii)
96 %
1)
TBAF, H2O/THFrt, 96 %
2)
I2, PPh3, ImDCM, rt, 78 %
3)OTBS IO
LiHMDS, THF-78 °C - 0 °C
i)
TBAFTHF/H2O, 0 °C
ii)
86 %
CP Molecules: Setting the floor to BaranDiels-Alder approach
Nicolaou, K. C.; Härter, M. W.; Boulton, L.; Jandeleit, B. Angew. Chem. Int. Ed. 1997, 36, 1194-1196.
OBn
MeOO
MeO
Et
Et
CH2OBn
O
CH2OBn
O
Et
OMe
Et
MeO
Et
EtBnO
OOMe
Et
Et
OBn
O
Me2AlClDCM, -10 °C
86 %3 : 1 ratio
CP Molecules: Diels-Alder Scale Up
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Choi, H.-S.; Yoon, W.H.; He, Y.; Fong, K.C. Angew. Chem. Int. Ed. 1999, 38, 1669-1675.
MeO
O
OMe
OMeO
O
OMe
O
TBSO
O O
TBSO
O O
TBSOOH
O O
TBSOOH
C8H15
O O
PMBO
C8H15
O
TIPSO
PMBO OTPS
C8H15O
O
O
I(CH2)3OTBSNaH, THF, 80 °C
90 %
1)
Allyl-BrNaH, DME, rt
95 %
2)
LiBH4, THF0 °C - rt, 80 %
1)
Me2C(OMe)2CSA, DCM, rt
82 %
2)
O3, DCM-20 °C
i)
PPh3-78 °C - rt
95 %
ii)
CyclohexylamineBenzene, 80 °C
1)
2) LDA, C9H17CHOEt2O, -78 °C to -30 °Ci)
Oxalic Acidwater, rt
ii)
60 % overallKH, PMBCl
DME/HMPA, 0 °C78 %
1)
2) TBAF, THF0 °C, 82 %
n-BuLi, THF-78 °C, 92 %
3)
SO3-Py, DMSOTEA, DCM
rt, 76 %
4)
Me2AlCl, DCM-10 °C, 90 %
O3; MeOHa)
Schlosser-modified Wittigb)c)
H
OTsOH
TIPSO
I
CP Molecules: The Maleic Anhydride Hurdle
Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
OO
OPMBO OTPS
C8H15O
O
PMBO OTPS
C8H15O
O
OO
OO
OO
O
HO
CO2H
CP-263,114
• While improving and scaling up the Diels-Alder sequence (hundreds of grams), many approach to the anhydride met with failure.
• Mid-September 1997, the CP-team halted the studies on the anhydride formation to conclude the scale up.
• Beginning of December, 1997, the studies directed toward the maleic anhydride problem resumed.
• « Shortly before New Year’s eve, 1997, a rather daring strategy towards the anhydride moiety was conceived… »
CP Molecules: Maleic Anhydride Strategy
Nicolaou, K.C.; Baran, P.S.; Jautelat, R.; He, Y.; Fong, K.C.; Choi, H.-S.; Yoon, W.H.; Zhong, Y.-L. A Angew. Chem. Int. Ed. 1999, 38, 549-552.
OO
OPMBO OTPS
C8H15O
O
PMBO OTPS
C8H15O
O
O
HON
5-exo-dig cyclisation
OHN
OH2N
Molecular oxygenAutoxidaton
"Molecular sponge"
CP Molecules: Maleic Anhydride Synthesis
PMBO OTPS
C8H15O
O
OOTf
OOMe OH
OHO
OHHO
N
KHMDS, PhNTf2
THF, 0 °C95 %
Pd(OAc)2, PPh3MeOH, CO
TEA, DMF, 50 °C76 %
DIBAL
Toluene, -78 °C95 %
V(O)(acac)2, tBuOOHBenzene, rt
85 %, 3.7:1 ratio
Toluene, 0 °C - rt68 %
Martin Sulfurane90 %
1)
2)Et2AlCN
Ac2OOAcN
Nicolaou, K.C.; Baran, P.S.; Jautelat, R.; He, Y.; Fong, K.C.; Choi, H.-S.; Yoon, W.H.; Zhong, Y.-L. A Angew. Chem. Int. Ed. 1999, 38, 549-552. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
“With the a,-unsaturated ester in hand, we proceeded at a furious pace which reached a climax at 2:00 a.m. on January 1, 1998, wherein we had synthesized the cyanodiol…”
“One of us (K.C.N.) will never forget the scene in the laboratory on that day in January 1998, who upon arrival at 8:00 a.m. found the other (P.S.B.) fast asleep on his desk with a clean NMR spectrum of compound [] by his side.”
CP Molecules: Maleic Anhydride Synthesis
OHHO
N O OO O
OO
PMBO OTPS
C8H15O
O
MsCl, TEATHF, 0 °C
K2CO3, MeOH, rt
1)
10 % oxalic acidEt2O, air, rt
60 %
2)
3)
Nicolaou, K.C.; Baran, P.S.; Jautelat, R.; He, Y.; Fong, K.C.; Choi, H.-S.; Yoon, W.H.; Zhong, Y.-L. A Angew. Chem. Int. Ed. 1999, 38, 549-552. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
“It would take another seven weeks before we finally found reliable conditions for the conversion of cyanodiol [] into maleic anhydride []…”
CP Molecules: Maleic Anhydride Synthesis
Nicolaou, K.C.; Baran, P.S.; Jautelat, R.; He, Y.; Fong, K.C.; Choi, H.-S.; Yoon, W.H.; Zhong, Y.-L. A Angew. Chem. Int. Ed. 1999, 38, 549-552.
OHHO
N
O OO
OMsHO
NO
N
H
N-O
OHN
Proven intermediate
Proven intermediate
OH2N
Base
H+
OHN
OOH
Path BPath A
OH2N
O OO
H2NO
OH
HN
OO
OH
HN
OOH
HN
OO
CP Molecules: Maleic Anhydride Synthesis
Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
“Despite the extraordinary chemistry involved in this cascade in which maleic anhydride is formed, we restrained ourselves from submitting a paper describing the results until later on in 1998 when further progress toward the CP molecules was made.”
CP Molecules: -Hydroxylactone Hurdle
Nicolaou, K.C.; He, Y.; Fong, K.C.; Yoon, W.H.; Choi, H.-S.; Zhong, Y.-L.; Baran, P.S. Org. Lett. 1999, 1, 63-66. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
PMBO OTPS
C8H15O
O
O
HO OTPS
C8H15O
O
O
X OTPS
C8H15O
O
OX
DDQDCM/H2Ort, 50 %
“One of us took a trip downstairs to discuss this problem with Professor Erik Sorensen, he drew our attention to a paper of D. P. Curran…”
OO
O
OO
O
HO
CO2H
CP-263,114
CP Molecules: -Hydroxylactone Hurdle
Nicolaou, K.C.; He, Y.; Fong, K.C.; Yoon, W.H.; Choi, H.-S.; Zhong, Y.-L.; Baran, P.S. Org. Lett. 1999, 1, 63-66. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
PMBO OTPS
C8H15O
O
O
HO OTPS
C8H15O
O
O
X OTPS
C8H15O
O
OX
O OTPS
C8H15HO
HO
O
Br
O OTPS
C8H15MeO
HO
O
Br
O
OTPS
C8H15MeO
HO
OO
O
DDQDCM/H2Ort, 50 %
NaH, 2-Br-BnBrDMF, rt75 %
2 N HCl, THFrt, 90 %
1)
DMP, NaHCO3DCM, rt, 90 % (5:1)
2)
NaClO2, NaH2PO42-methyl-2-butene
THF/tBuOH/H2O, rt;then CH2N2, 0 °C, 85 %
3)
n-Bu3SnH, AIBNBenzene, 80 °C
80 %
“One of us took a trip downstairs to discuss this problem with Professor Erik Sorensen, he drew our attention to a paper of D. P. Curran…”
OO
O
OO
O
HO
CO2H
CP-263,114
CP Molecules: -Hydroxylactone Hurdle
Nicolaou, K.C.; He, Y.; Fong, K.C.; Yoon, W.H.; Choi, H.-S.; Zhong, Y.-L.; Baran, P.S. Org. Lett. 1999, 1, 63-66.
PMBO OTPS
C8H15O
O
MeOO O OTPS
C8H15
HO
OOMe
O
PMP
HO OTPS
C8H15HO
PivO
MeOO
OHOTPS
C8H15
O
PivO
MeOO
Proven intermediate
O OTPS
C8H15
O
PivO
MeOOOTPS
C8H15
X
PivO
MeOO OH
O
X = OH, H
X = O
2 N HCl, THFrt, 90 %
1)
DDQ, MS 4 ÅDCM, rt, 81 %
2)
PivCl, TEA4-DMAP
DCM, rt, 90 %
1)
CSAMeOH, rt, 90 %
2)
DMP (10 equiv)DCM, rt, 82 %
TEMPO, KBr, NaOClCyclooctene
Acetone/5% NaHCO30 °C, 68 %
CP Molecules: -Hydroxylactone Hurdle
Nicolaou, K.C.; He, Y.; Fong, K.C.; Yoon, W.H.; Choi, H.-S.; Zhong, Y.-L.; Baran, P.S. Org. Lett. 1999, 1, 63-66.
HO OTPS
C8H15HO
PivO
OO
OHOTPS
C8H15
O
PivO
OO
OTPS
C8H15
X
PivO
OO OH
O
O
O
O
OTPS
C8H15
HO
PivO
OO
OOSO3-Pyr, DMSO
TEA, DCM, -78 °C
90 %
HO OTPS
C8H15HO
PivO
OO
O
OTPS
C8H15
O
PivO
OO
OO(COCl)2, DMSOTEA, DCM, 0 °C
82 %
HO OTPS
C8H15HO
PivO
OO
OOxidant
DCM, 25-35 °C
70-90 %
Oxidant = PDC, DMP, PCC, BaMnO4
TEMPO, KBr, NaOClCyclooctene
Acetone/5% NaHCO30 °C, 75-85 %
CP Molecules: -Hydroxylactone Hurdle
Nicolaou, K.C.; He, Y.; Fong, K.C.; Yoon, W.H.; Choi, H.-S.; Zhong, Y.-L.; Baran, P.S. Org. Lett. 1999, 1, 63-66.
PMBO OTPS
C8H15O
O
OO
O
AcO OTPS
C8H15TESO
TESO
OO
O
AcO OTPS
C8H15
TESO
OO
OSS
OTPS
C8H15
X
TESO
OO OH
OO
TiCl41,3-propanedithiol
cyclooctene
DCM, -15 °C, 84 %
AcO OTPS
C8H15TESO
TESO
OO
OTESCl, Im
DCM, rt, 84 %1)
Ac2OTEA, 4-DMAPDCM, rt, 97 %
2)
TiCl4, cycloocteneDCM, -78 °C67 % (3.8:1)
1)
DMP, DCMrt, 94 %
2)
K2CO3, MeOHrt, 89 %
3) TiCl4, cyclooctene1,3-propanedithiol
DCM, -78 °C to -15 °C,71 %
1)
PDC, DCMrt, 90 %
2)
O OTPS
C8H15
TESO
OO
OSS
(CF2CO3)2IPhMeCN, rt, 80 %
1)
2) TEMPO, KBrNaOCl, Cyclooctene
Acetone/5% NaHCO30 °C, 70 %
CP Molecules: Real Model Synthesis
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Choi, H.-S.; Yoon, W.H.; He, Y.; Fong, K.C. Angew. Chem. Int. Ed. 1999, 38, 1669-1675.
PMBO OTPS
C8H15O
O
O
PMBO O
C8H15O
O
OH
PMBO
C8H15O
O
R
TESOR
SS
PMBO
C8H15O
O
O
TESO
SS
PMBO
C8H15O
O
R
TESOR
OO
R = CO2Me
PMBO
C8H15O
O
TESOR
OO
OO O
TBAF, THFrt, 93 %
1)
DMP, NaHCO3DCM, rt, 92 %
2)
THF, -78 °C93 % (11:1)
1)
NaH, TESOTfTHF, 0 °C to rt
86 %
2)
SS
Li
1) Vinyltriflate(95 % vs 95 %)
2) Carboxymethylation(78% vs 76 %)
PhI(OCOCF3)2CaCO3, MeOH
rt, 81 %
1) Reduction(95 % vs 95 %)
2) Epoxidation(83 % vs 85 %)(10:1 vs 3.7:1)
3) Cyanation(73 % vs 68 %)
4) Anhydride(56 % vs 60 %)
CP Molecules: Real Model Synthesis
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Choi, H.-S.; Yoon, W.H.; He, Y.; Fong, K.C. Angew. Chem. Int. Ed. 1999, 38, 1669-1675. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
PMBO
C8H15O
O
TESOR
OO
OO O
PMBO
C8H15O
O
TBSOR
O
OO O O
C8H15O
O
TBSOR
O
OO O
OH
C8H15
TESO
TBSOR
O
OO OO
OH
C8H15
TESO
TBSOR
O
OO OO
OH
C8H15
TESO
TBSOR
O
OO OO
HOO
90 % AcOH, rt1)
Me2C(OMe)2CSA, DCM, rt77 % (2 steps)
2)
TBSOTf2,6-lutidine, DCM
-20 °C to 0 °C90 %
3)
DDQDCM/H2O
64 %
1)
PDC, DCM, rt89 %
2)
80 % aq AcOHrt, 82 %
1)
TESOTf2,6-lutidine0 °C, 92 %
2)
DMPBenzene
80 °C, 63 %
PhI(OAc)2TEMPO, MeCN
rt, 74 %
“In the midst of their desperation and hope, Yong-Li Zhong and Phil […] proceeded to design, in complete secrecy (from K.C.N.), an experiment […] in refluxing benzene with excess DMP! […] had they informed me […], I would have most likely instructed them […]against this course of action in light of the assumption that DMP could possibly be explosive at high temperatures. Their plot was, therefore, perfect…”
CP Molecules: Homologation
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Choi, H.-S.; Yoon, W.H.; He, Y.; Fong, K.C. Angew. Chem. Int. Ed. 1999, 38, 1669-1675. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
“My (K.C.N.) first reaction was to attribute this failure to the “inadequate” experimental skills of my co-workers; after all, I said, “This is a textbook example of the easiest transformations in organic chemistry!” However, despite repeated attempts, […] we were consistently unsuccessful. I was wrong and I apologized profusely to my very capable co-workers!”
OH
C8H15
TESO
TBSOR
O
OO OO
O
O
C8H15
HO
R
O
OO OO
O
HO
C8H15
O
R
O
OO OO
O
H
H
O
C8H15
O
R
O
OO OO
O
H
OH
TFADCM / H2O, rt
1)
CH3SO3HCHCl3 , rt
50 % overall
2)
DMP, NaHCO3DCM, rt, 95 %
O
C8H15
O
R
O
OO OO
O
H
OH
CP Molecules: Homologation
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Choi, H.-S.; Yoon, W.H.; He, Y.; Fong, K.C. Angew. Chem. Int. Ed. 1999, 38, 1669-1675. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
“In the midst of this chaos when everyone was following their own intuition, I (K.C.N.) approached Phil and asked what strategy he was following. “I have an idea,” he said. “It’s simple.” What he had in mind was the use of an amide as a protecting group for the carboxylic acid…”
PMBO
C8H15O
O
TBSOR
O
OO O
O
C8H15
O
HO
TBSOR
O
OO O
PMP
O
C8H15
O
O
TBSOR
O
OO O
PMP
OH
O
C8H15
OTBSO
R
O
OO O
PMP
O
N2
O
C8H15
OTBSO
R
O
OO O
PMP
O
OH
90 % AcOHrt, 85 %
1)
DDQPh-F, rt, 57 %
2)
DMP, NaHCO3DCM, rt, 90 %
1)
NaClO2, NaH2PO42-methyl-2-butenet-BuOH/H2O
rt, 80 %
2)
MsCl, TEATHF, 0 °C
1)
2) CH2N2THF/Et2O0 °C - rt
Ag2ODMF/H2O
120 °C, 1 min.
38 % overall
HO
C8H15
HO
TBSOR
O
OO O
O
NHPh
PhNH2, EDC4-DMAP
DCM, rt, 85 %
80 % AcOHrt, 89 %
1)
2)
CP Molecules: DMP Surprise
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Choi, H.-S.; Yoon, W.H.; He, Y.; Fong, K.C. Angew. Chem. Int. Ed. 1999, 38, 1669-1675. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
“…it did not help us at the time and we decided to put this strange discovery on the shelf (but not under the carpet!) until after the total synthesis was complete.”
HO
C8H15
TBSOR
O
OO O
HO
O
HN
OH
C8H15
TBSOR
O
OO OO
O
HN
OH
C8H15
TBSOR
O
OO OO
O
HN
HO
DMPBenzene, rt
90 %
DMPBenzene, 80 °C
OH
C8H15
TBSOR
O
OO OO
O
N O
OH
C8H15
TBSOR
O
OO OO
O
N OH
DMPBenzene, 80 °C
45 %
CP Molecules: Testing Baran!
Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
“Early one morning, after another failure, I (K.C.N.) called Phil to my office, sat him down and said, “This project is always in shambles, and it is very painful to everyone. I think we should cut our losses and just forget about the CP molecules. I would not think any less of you if you stop now.”
“Phil’s eyes widened and he immediately declared, “Impossible, I will never stop until CP has fallen and I know Zhong feels the same way. This is what a PhD is all about, isn’t it?”
“OK, good, you passed the test. Now you can go back to work...””
CP Molecules: Final Route
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Fong, K.C.; He, Y.; Yoon, W.H.; Choi, H.S. Angew. Chem. Int. Ed. 1999, 38, 1676-1678. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
“During this period, I (K.C.N.) would often find Zhong and Phil either fast asleep in the mornings or working in eight-hour shifts exchanging material back and forth. As one rested, the other worked; my contribution was to bring them occasional sustenance in the form of sandwiches in the lab!”
OH
C8H15
TESO
TBSOR
O
OO OO
HO
O
C8H15
HO
R
O
OO OO
HO
HO
C8H15
R
O
OO OO
TBSO
H
HO
O
C8H15
R
O
OO OO
TBSO
H
OHO
O
C8H15
R
O
OO OO
TBSO
H
O
OH
O
C8H15
R
O
OO OO
TBSO
H
N
O
TFADCM/H2O, rt
TBSOTf2,6-lutidine, DCM
-20 °C to 0 °C85 %
1)
MeSO3HCHCl3, rt
83 % overall
2)
DMPBenzene, rt
90 %
1)
2)
NaClO2, NaH2PO42-methyl-2-butenet -BuOH/H2O
rt, 90 %
MsCl, TEATHF, 0 °C
1)
2) CH2N2THF/Et2O, 0 °C
Ag2ODMF/H2O
120 °C, 1 min.35 % overall
3)
IndolineEDC, 4-DMAPDCM, rt, 85 %
CP Molecules: Final Route
Nicolaou, K.C.; Baran, P.S.; Zhong, Y.-L.; Fong, K.C.; He, Y.; Yoon, W.H.; Choi, H.S. Angew. Chem. Int. Ed. 1999, 38, 1676-1678. Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
“The final reaction was set up at 1:00 a.m. on April 12, 1999. A few hours later it was done […]! I (K.C.N.) was to learn of the athlos upon my arrival in the lab at 8:00 a.m. that day. Needless to say, pure adrenaline kept Phil and Zhong awake past the successful isolation of CP-225,917( 2) and its subsequent conversion into CP-263,114 (1). Within 24 hours of that final blow, two communications were dispatched to Angewandte Chemie.”
O
C8H15
R
O
OO OO
TBSO
H
N
O
O
C8H15
R
O
OO OO
O
H
N
O
O
C8H15
R
O
OO OO
O
H
N
O
OH
C8H15
R
O
OO OO
O
HO
OH
O
CP-225,917
O
C8H15
R
O
OO OO
O
H
OH
O
CP-263,114
TFADCM/H2Ort, 95 %
1)
DMP, NaHCO3DCM, rt, 80 %
2)
p-chloranilToluene
70 °C, 70 %
LiOHTHF/H2O, rt;
10 % NaH2PO472 %
MeSO3OHCDCl3, rt, 72 %
LiOHTHF/H2O, rt
90 %
Triumphant CP-Team
Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
Total Synthesis of Haouamine A
51. Baran, P. S.; Burns, N. Z. Total Synthesis of (±)-Haouamine A. J. Am. Chem. Soc.; 2006; 128; 3908 - 3909.
Haouamine A
N
HO
HO
HO
H
HO
Total Synthesis of Haouamine A
Baran, P. S.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908 - 3909.
OMe
MeO
OI
OMe
Br
+
KHMDSTHF / DMPU
-78 °C - rt, 54 %OMe
OMe
Br
OMe
N
OH
1)
HO-NH3ClNaOAc / EtOH
75 %
2) DCE, 0 °C30 min.
OMe
OMe
N
OH
i)
Br Br
Br BrO
BrBr
OMe
OMe
OMe
NBr
OMe
HOH
57 % overall
iii)
NaBH4EtOH, 50 °C
1 h
ii)
In powderH4NCl sat.
EtOH, reflux
OMe
OMe
Br
OMe
N
OHH57 % overall
iii) In powderH4NCl sat.
EtOH, reflux
OMe
OMe
Br
OMe
NHH
Total Synthesis of Haouamine A
Boc2ODCM
Pd(Ph3)4, CuIToluene, reflux
44 % overall
i)
TFA / DCMi)
BBr3, DCM-78 °C - rt
OMe
OMe
Br
OMe
NHH
OMe
OMe
Br
OMe
NBocH
OMe
OMeOMe
NBocH
O O
OMe
O O
OMe
SnMe3
OMe
OMeOMe
NH
O O
OMe
A, K2CO3MeCN, ref lux
70 %
ii)TsO A
N
AcO
AcO
AcO
H
N
HO
HO
HO
H
HO
O
AcOO
ii) Ac2O, py67 %
DCB (0.001 M)BHT
250 °C (W)
1)
K2CO3, MeOH
21 % (30 % sm)
2)
Houamine A
Baran, P. S.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908 - 3909.
Total Synthesis of Chartelline
55. Baran, P. S.; Shenvi, R. A. Total Synthesis of (±)–Chartelline C, J. Am. Chem. Soc. 2006, 128, in press.
47. Baran, P. S.; Shenvi, R.A.; Mitsos, C.A. A Remarkable Ring Contraction En Route to the Chartelline Alkaloids, Angew. Chem. Int. Ed. 2005, 44, 3714-3717.
N
N
N
NH
Cl
O
R
R'
Br
Br MeMe
R = R' = Br Chartelline AR = H, R' = Br Chartelline BR = R' = H Chartelline C
Total Synthesis of Chartelline
Baran, P. S.; Shenvi, R.A.; Mitsos, C.A. Angew. Chem. Int. Ed. 2005, 44, 3714-3717.
OTBS
CO2Me
NH2
OTBS
NH2
OMeMe
OTBS
MeMeNH
N
OTBS
MeMeNH
N
THF, -78 °C93 %
MgBrKNCS, H4NCl
toluene105 °C - 110 °C
i)
6 N HCl, rtii)
H2O2, THF, rt;2 M NaOH
NaHCO3 sat.
iii)
TBSCl, TEADCM, rt
84 % overall
iV)
NaIO4, OsO4THF/H2O, rt
1)
Ohira's reagentK2CO3
MeOH, rt63 %
2)
NBoc
MeO2C
BrPd(PPh3)4, CuI
DIPA, DME70 °C, 71 %
TBSO
MeMe
NH
N
NBoc
MeO2C
NBoc
O
N
NH
H
Me
Me
CO2Me
H2 / Pd/CMgSO4, EtOH, rt
1)
TBAF, THF0 °C - rt
2)
MnO2, DCMrt, 98 %
3)
NBoc
O
N
NH
H
Me
Me
LiOHTHF / H2O, rt
1)
BOPCl, DIPEA0 °C, 86 %
2)
O
NH
CO2Me
P(O)(OEt)2
Total Synthesis of Chartelline
Baran, P. S.; Shenvi, R.A.; Mitsos, C.A. Angew. Chem. Int. Ed. 2005, 44, 3714-3717.
NBoc
O
N
NH
H
Me
Me
180 °C1)
NBS, KHCO3THF / H2O
88 %
2)
O
NH
CO2Me
P(O)(OEt)2
LiCl, DIPEA
MeCN, 70 °C75 %
N
N
N
NH
O
MeMe
NBoc
N
NH
Me
Me
O
NH CO2MeCO2Me
NR N
NH
Me
Me
O
NH CO2Me
NH
N
NH
Me
Me
O
O
NH2
OH
NR N
NH
Me
Me
O
NH CO2Me
=> Ring-Closing Metathesis => Macrolactamization => Heck-type coupling
Selected Dead-End Routes to the Chartelline Carbocyclic Skeleton
Total Synthesis of Chartelline
Baran, P. S.; Shenvi, R. A. J. Am. Chem. Soc. 2006, 128, in press.
NBoc
N
NH
Me
Me
O
NH CO2R
NBoc
Br
MeO2C
IBr
R = TMSE
Br2, CaCO3PhH, rt
i)
NBAPhH, rt36 %
ii) NBoc
N
NH
Me
Me
O
NH CO2R
Br
Br
Br
185 °C, 1.5 mini)NBS, MS 3Å
MeCN, rtii)
18-C-6, K2CO3MeCN, rt, 1 h
iii)
NaHCO3 sat.iv)Brine, 15 minv)
93 %
N
N
N
NH
O
MeMe
CO2R
ClBr
Br
TFA / DCE, rti)
o-DCB, 200 C64 %
ii)N
N
N
NH
O
MeMe
ClBr
BrChartelline C
Total Synthesis of Sceptrin
52. Northrop, B.H.; O'Malley, D.P.; Zografos A. L.; Baran, P.S.; Houk, K. N. Mechanism of the Vinylcyclobutane Rearrangement of Sceptrin to Ageliferin and Nagelamide E. Angew. Chem. Int. Ed. 2006, 45, 4126 –4130.
50. Baran, P. S.; Li, K; O'Malley, D.P.; Mitsos, C. Short, Enantioselective Total Synthesis of Sceptrin and Ageliferin by Programmed Oxaquadricyclane Fragmentation. Angew. Chem. Int. Ed. 2006, 45, 249 –252.
43. Baran, P.S.; O'Malley, D.P.; Zografos, A.L. Sceptrin as a Potential Biosynthetic Precursor to Complex Pyrrole-Imidazole Alkaloids: The Total Synthesis of Ageliferin, Angew. Chem. Int. Ed. 2004, 43, 2674-2677.
42. Baran, P.S.; Zografos, A.L.; O'Malley, D.P. Short Total Synthesis of Sceptrin, J. Am. Chem. Soc. 2004, 126, 3726-3727.
NH
HN
NH
NH
HN
HN
NH2
NH2
HN
NH
Br O
OBr
Cl
Cl
(+)-Sceptrin
HN
HN
HN
NH
Br O
OBr
NN
NH
HN
H2N
NH2
TFA
TFA
(-)-Ageliferin
HN
HN
HN
NH
Br O
OBr
NN
NH
HN
H2N
NH2
TFA
TFA
Nagelamide E
Total Synthesis of rac-Sceptrin
Baran, P. S.; Zografos, A. L.; O'Malley, D. P. J. Am. Chem. Soc. 2004, 126, 3726-3727.
OMeO2C
MeO2C
Me
Me
HC(OMe)3, PTSAMeOH, 50 °C
1)
DIBALDCM, -78 °C;AcOH, H2O
100 %
2)
H2SO4, MeOH
50 %MeO2C
MeO2CMe
O
Me
O
Me
O
Me
O
HO
HOMsCl, py0 °C - rt
1)
NaN3DMF, 50 °C
2)
Me
O
Me
O
N3
N3
HN
HN
HN
NH
Br O
OBr
Me
Me
MeO OMe
OMeMeO
HC(OMe)3, PTSAMeOH, 50 °C
1)
H2, LindlarMeOH
2)
X, MeCN70 % overall
3)CCl3N
H
Br O
HN
HN
HN
NH
Br O
OBr
THF, 60 °C97 %
Ph NMe3
ICl2
Cl
Cl
O
O
(CHO)2NNa35 °C
1)
HClMeOH, rt
2)
H2N-CNH2O, 95 °C72 % overall
3)
NH
HN
NH
NH
HN
HN
NH2
NH2
HN
NH
Br O
OBr
Cl
Cl
rac-Sceptrin
Total Synthesis of (+)-Sceptrin
Baran, P. S.; Li, K.; O'Malley, D. P.; Mitsos, C. Angew. Chem. Int. Ed. 2006, 45, 249 –252.
MeO2C
MeO2CMe
O
Me
O
h, THF
OMeO2C
BnHNOC
Me
Me
OMeO2C
MeO2C
Me
Me
OMeO2C
HO2C
Me
Me100 %, 75 % ee
PLE, pH = 8Acetone, rt BnNH2, DMT-MM
THF, 92 %
i)
ii) H2SO4THF / MeOH
45-50 %
1)
2) PTSAMeOH / PhMe105 °C, 50 %
75 % ee >95 % ee
N N
NMeO OMe
N
O
MeCl
DMT-MM
Mechanism ???
BnHNOC
MeO2CMe
O
Me
O
OMeO2C
BnHNOC
Me
Me
1)
MeO2C
MeO2CMe
O
Me
O
2)
Total Synthesis of (+)-Sceptrin
Baran, P. S.; Li, K.; O'Malley, D. P.; Mitsos, C. Angew. Chem. Int. Ed. 2006, 45, 249 –252.
OMeO2C
BnHNC
Me
Me
MeO2C H
Me
OOH
BnHNO
Me
MeOC
Me
OO
BnHN
Me
H+ H2OOHO
MeO2C
BnHNOC
Me
Me
h
O+H
O
BnHNOC
MeO2CMe
O
Me
O
H+
MeOH
MeO2C
MeO2CMe
O
Me
O
NBnMeO2C
MeOC
O
Me
OH
BnHNOC
MeO2CMe
O
Me
O
OMeO2C
BnHNOC
Me
Me
1)
MeO2C
MeO2CMe
O
Me
O
2)
(-)-Ageliferin and Nagelamide E
Baran, P. S.; O'Malley, D. P.; Zografos, A. L. Angew. Chem. Int. Ed. 2004, 43, 2674-2677. Northrop, B. H.; O'Malley, D. P.; Zografos A. L.; Baran, P. S.; Houk, K. N. Angew. Chem. Int. Ed. 2006, 45, 4126 –4130.
NH
HN
NH
NH
HN
HN
NH2
NH2
HN
NH
Br O
OBr
Cl
Cl
(+)-Sceptrin
HN
HN
HN
NH
Br O
OBr
NN
NH
HN
H2N
NH2
Cl
Cl
(-)-Ageliferin
HN
HN
HN
NH
Br O
OBr
NN
NH
HN
H2N
NH2
Cl
Cl
Nagelamide E
H2O, microwave200 °C, 5 min.
50 %
40 %
2 %
(-)-Ageliferin and Nagelamide E
Baran, P. S.; O'Malley, D. P.; Zografos, A. L. Angew. Chem. Int. Ed. 2004, 43, 2674-2677. Northrop, B. H.; O'Malley, D. P.; Zografos A. L.; Baran, P. S.; Houk, K. N. Angew. Chem. Int. Ed. 2006, 45, 4126 –4130.
R
R NH
HN
NH
NH
NH2
NH2
Cl
Cl
Sceptrin
R
R NH
HN
N
NH
NH2
NH2
Cl
Cl
R
R
NN
NH
HN
H2N
NH2
TFA
TFA
Ageliferin and Nagelamide
R
R N
HN
N
NH
NH2
NH2
Cl
Cl
radical
ionic
(-)-Ageliferin and Nagelamide E
Baran, P. S.; O'Malley, D. P.; Zografos, A. L. Angew. Chem. Int. Ed. 2004, 43, 2674-2677. Northrop, B. H.; O'Malley, D. P.; Zografos A. L.; Baran, P. S.; Houk, K. N. Angew. Chem. Int. Ed. 2006, 45, 4126 –4130.
R
R NH
HN
NH
NH
NH2
NH2
Cl
Cl
Sceptrin
R
R
NN
N
N
H2N
NH3
Cl
Cl
R
R N
HN
N
NH
NH2
NH
Cl
ClH
H
ClR
R
N
NH
NH3
N
NH
NH2
Cl
ClR
R
N
N
NH3
N
NH
NH2
Cl
R
R
NN
NH
HN
H2N
NH2
Cl
Cl
Ageliferin and Nagelamide
Baran’s Methodology
54. Baran, P. S.; DeMartino, M. P. Intermolecular Enolate Heterocoupling, Angew. Chem. Int. Ed. 2006, 45, in press.
49. Baran, P. S.; Richter, J. M. Enantioselective Total Syntheses of Welwitindolinone A and Fischerindoles I and G, J. Am. Chem. Soc.; 2005; 127(44); 15394-15396.
45. Baran, P.S.; Richter, J.M.; Lin, D.W. Direct Coupling of Pyrroles with Carbonyl Compounds: Short, Enantioselective Synthesis of (S)-Ketorolac, Angew. Chem. Int. Ed. 2005, 44, 609-612.
44. Baran, P.S.; Richter, J.M. Direct Coupling of Indoles with Carbonyl Compounds: Short, Enantioselective, Gram-Scale Synthetic Entry into the Hapalindole and Fischerindole Alkaloid Families, J. Am. Chem. Soc. 2004, 126, 7450-7451.
NH
Cl
Me
Me
H
Me
NC
(-)-Fischerindole I
NH
Cl
Me
Me
H
MeNC
(+)-Welwitindolinone A
ONH
Cl
Me
Me
H
Me
NC
(+)-Fischerindole G
H
NH
Me
Me
H
Me
(-)-12-epi-Fischerindole U
H
SCN
Hapalindole Q
NH
Me
H
H
SCN
Me
Baran’s Methodology
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.
Hapalindole Q
NH
Me
H
H
SCN
Me
NH
H
H
O
Me
Me
NH
O
Me
Me+
Indole Carvone
NH
Cl
Me
Me
H
Me
NC
(-)-Fischerindole I
NH
Cl
Me
Me
H
MeNC
(+)-Welwitindolinone A
ONH
Cl
Me
Me
H
Me
NC
(+)-Fischerindole G
H
NH
Me
Me
H
Me
(-)-12-epi-Fischerindole U
H
SCN
Baran’s Methodology
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.
NH
H
H
O
Me
Me
NH
O
Me
Me+
Indole Carvone
N
O
Me
Me+
N
O
Me
Me+
Baran’s Methodology
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.
NH
H
H
O
Me
Me
R1R3
R2
O
NH
+
X
1 equiv 2 equiv
LiHMDS (3 equiv)Copper(II) 2-ethylhexanoate
(1.5 equiv)
THF, -78 °CNH
X
R3R2
R1
O
53 % (70)a
O
ONH
54 %
H
H H
Me H
Me
HO
O
NH
33 %a (dr = >25:1)
NH
Ot-Bu
O
64 %a
NO
Ph
O O
Me
NH
43 % (dr = 5:1)
H
NSOO
O
Me
HN
R1
R2MeMe R1 = H; R2 = Hb
R1 = F; R2 = H
R1 = H; R2 = Me
R1 = H; R2 = OMeb
48 % (60)a ; dr = >20:1
30 % (90)a ; dr = 10:1
36 % (96)a ; dr = 10:1
37 % (49)a ; dr = >20:1
a) Yield based on recovered starting materialb) LDA used
Baran’s Methodology
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.
Hapalindole Q
NH
H
H
O
Me
Me
NH
Me
Me
H
Me
(-)-12-epi-Fischerindole U
H
SCN
LiHMDSTHF, -78 °C
i)
L-Selectrideii)
CH3CHO-78 °C - rt
iii)
NH
H
H
O
Me
MeMartin
SulfuraneCHCl3
75 % overall
OHMe
NH
H
H
O
Me
Me
TMSOTfMeOH / DCM
0 °C
75 % brsm
NH
Me
Me
H
Me
H
O
NaBH3CNH4NOAc
MeOH / THF150 °C, W
61 %
NH
H
H
H2N
Me
MeCS(imid)2DCM
0 °C - rt63 %
NH
H
H
SCN
Me
Me
33 %
Baran’s Methodology
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005; 127, 15394-15396.
O
MeO
Me
R-carvone oxide
LiHMDSTHF, -78 °C
i)
-15 °C, 30 %
ii) MgBr
O
MeMe
HO
PPh3, NCSTHF, 55 %
O
MeMe
Cl
LiHMDSCopper(II) 2-ethylhexanoate
THF, -78 °C - rt55 %
NH
H
H
O
Me
MeClMont. K-10
DCE, W120 °C
40 %
NH
Me
Me
H
Me
H
OCl
NaBH3CNH4NOAc
NH
Me
Me
H
Me
H
H2NCl
MeOH / THF26 %
Baran’s Methodology
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005; 127, 15394-15396.
HCO2HDMT-MM
4-DMAP, NMM
NH
Me
Me
H
Me
H
H2NCl
DCM, rt98 %
tBuOClTEA, THF
0 °C
NH
Me
Me
H
Me
H
HN
Cl
H
O i)
SiO2, TEA(PTLC)
ii)
Burgess, rt47 % overall
iii) NH
Cl
Me
Me
H
Me
NC
(+)-Fischerindole I
NH
Me
Me
H
Me
H
OCl
NH
Me
Me
H
Me
H
H2NCl
NaBH4MeOH, 0 °C
i)
Ms2O, Py69 %
ii)
NH
Me
Me
H
Me
H
NCl
1)
BurgessPhH, rt82 %
2)
HCO2HDMT-MM
4-DMAP, NMMDCM, rt, 87 %
C
(-)-Fischerindole G
Baran’s Methodology
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005; 127, 15394-15396.
tBuOClTEA, THF
-30 °C
i)
TFATHF / H2O
28 %
ii)
NH
Cl
Me
Me
H
Me
NC
(-)-Fischerindole I
NH
Cl
Me
Me
H
MeNC
(+)-Welwitindolinone A
O
Baran’s Methodology
Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem. Int. Ed. 2005, 44, 609-612.
NHH
O
Me
Me
R1R3
R2
O
NH
+
1 equiv 3 equiv
LiHMDS (4 equiv)Copper(II) 2-ethylhexanoate
(1.5 equiv)
THF-78 °C to -60 °C to 0 °C
54 %a (dr = >20:1)
42 %a (dr = 14:1) 41 %
H
NSOO
O
Me
NH
MeMe
R1 = R2 = R3 = H
R1 = R2 = Me; R3 = H
R1 = R2 = Me; R3 = Et
R1 = Et; R2 = R3 = H
53 %; dr = >20:1
67 %a; dr = >20:1
54 %; dr = >20:1
42 %a; dr = >20:1
a) Yield based on recovered starting material
NH
R2
R3
OR1
NHH
HO
Me
Me
Ph R3 R2
R1
NH
Ot-Bu
O
Me
Me
MeNH
Me
Me
Me
O
O
Me
NH
Me
Me
Me
NMe
O
Me
57 % (dr = 1:1) 42 % (dr = 1:1)
Baran’s Methodology
Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem. Int. Ed. 2005, 44, 609-612.
TEA, MeOCOClTHF, 0 °C
100 %
NOH
O
i)
H
LiNSOO
MeMeii)
H
NSOO
MeMeO
N
O
N H
OAux
N H
OAux
Fe+ PF6-
LiHMDS, TEATHF
-78 °C - 12 °C65 % brsm
BzCl, 70 °Ci)
TBAH, H2O22-methyl-2-butene
DME, -10 °C38 %
ii)
S-ketorolac (NSAID)
Baran’s Methodology
Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, in press.
H
H
O
Me
Me
R1R3
R2
O
+
1 equiv 1 equiv
LDA;Fe(acac)3
R3 R2
R1
O
NO
Ph
O O
Ph
52 % (dr = 2.7:1)
NR6
R7
O
R4
R5 R6R7
N
O
R5
R4
ONO
Ph
O O
Ph
59 % (dr = 2.8:1)
ONO
O O
PhR1
Me
O
R2
R1 = -Bn; R2 = H
R1 = -Bn; R2 = OMe
R1 = -iPr; R2 = Br
R1 = -iPr; R2 = H
57 %; -H dr = 2.8:1
67 %; -H dr = 2.5:1
55 %; -H dr = 2.5:1
66 %; -H dr = 2.1:1
R1 = -iPr; R2 = OMe 65 %; -H dr = 2.3:1
N
H
H
O
Me
Me
O
R1
R2
R1 = R2 = Me
R1 = R2 = Me
R1 = MOM; R2 = Prenyl
91 %; dr = 1.2:1
60 %; dr = 1.2:1
54 %; dr = 1.0:1N O
O
OR1
R2
R1 = R2 = Me
R1 = MOM; R2 = Prenyl
72 %; dr = 2.6:1
73 %; dr = 2.0:1
Baran’s Methodology
Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, in press.
R1R3
R2
O
+
1 equiv 1 equiv
LDA;Cu(II) 2-ethylhexanoate
R3 R2
R1
ON
R6
R7
O
R4
R5 R6R7
N
O
R5
R4
ONO
iPr
O O
Bn
NO
O O
BniPr
BnOR
O
R = Me
R = tBu
R = tBu
51 %; dr = 1.0:1
51 %; dr = 1.6:1
53 %; dr = 1.6:1
O
54 %; dr = 2.4:1
Baran’s Methodology
Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, in press.
NO
iPr
O O
O
O OMe
OMe
CO2tBu
+
LDA, LiClCopper(II) 2-ethylhexanoate
PhMe-78 °C
NO
iPr
O O
O
O
CO2tBu
OMe
OMe
LiBH4MeOH / THF
-78 °C to -10 °C
OH
O
O
CO2tBu
OMe
OMeDBU, PhMe
110 °CO
O
OMe
OMe
O
O
(-)-bursehernin
41 % overallsingle diastereomer
Race for Molecular Summits
Robert F. Service Science 9 July 1999 : Vol. 285. no. 5425, pp. 184 - 187
In a branch of chemistry called TOTAL SYNTHESIS, glory goes to the first team to reproduce a complex molecule from simple ingredients. But some wonder whether the competition is healthy.
“It used to be that the way to learn the principles was to engage in the second exercise,” says [Nicolaou]. “That is less and less true. There's the rub.”
“That much I'm ready to concede,” says Danishefsky. The chemistry that is developed on the climb up the mountain “doesn't impact as many other projects” as the discoveries made in previous decades, he says.
“I'm sure that's true,” agrees Scripps total synthesis chemist Dale Boger. “At some point, [the chemistry] becomes so well developed that it becomes harder to justify chemistry for chemistry's sake.”
“The quickest way to make a molecule is not to discover new reactions, but to use known reactions,” says Jacobsen. “Rarely do you see a lot of new chemistry come out of that effort.”
Final quote…
The main case for SMNPs as a means of discovering valuable leads is that such structures often allow for entry into the discovery progression at a much more advanced stage than does the screening of standard diversity libraries which lack comparable pedigree or intellectual coherence.
Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71, 8329-8351.
Small Molecule Natural Products in the Discovery of Therapeutic Agents: The Synthesis Connection