"You eat, drink, and sleep your molecule"
(Phil S. Baran)
Guillaume Barbe
Charette’s Laboratories
Université de Montréal
October 30th 2006
Phil S. Baran
Date/Place of Birth: 10 Aug 1977 / Denville, NJ, USA
Education
1991 - 1995 Simultaneous high school graduation from Mt. Dora High School and
A.A. degree with honors from Lake Sumter Community College, Florida
1995 - 1997 B.S. with Honors in Chemistry, New York University
Advisor: Professor D.I. Schuster
1997 - 2001 Ph.D. graduate student in Chemistry, The Scripps Research Institute
Advisor: Professor K.C. Nicolaou
2001 - 2003 Postdoctoral Associate, Harvard University
Advisor: Professor E.J. Corey
Career
July, 2006 Associate Professor of Chemistry (with Tenure)
June, 2003 Assistant Professor of Chemistry
Phil S. Baran: Awards
Pre 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: Awards
Pre 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: Awards
Independent 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
Fullerene Chemistry
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, 83638364.
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.
Baran’s Publications: Nicolaou
H
O
O
O
O
O
O
O
CO2H
CP-263,114
O
O
O
O
HO H
O
OH
O
CO2H
CP-225,917
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.
Baran’s Publications: Nicolaou
Iodine(V) Reactions
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, 202206.
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.
Baran’s Publications: Nicolaou
Synthesis of Hindered a-Diazoketones via Acyl Mesylates
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.
a-Sulfonated Ketones
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.
Mild and Selective Homologation of Hindered Aldehydes
in the Presence of Ketones
16. Nicolaou, K.C.; Vassilikogiannakis, G.; Kranich, R.; Baran, P.S.; Zhong, Y.L.; Natarajan, S. Org. Lett.
2000, 2, 1895-1898.
The Art and Science of Total Synthesis
at the Dawn of the Twenty-first Century
21. Nicolaou, K.C.; Vourloumis, D.; Winssinger, N.; Baran, P.S. Angew. Chem. Int. Ed. 2000, 39, 44-122.
Baran’s Publications: Nicolaou
OH O
OH O
O
HO
O HO
O
O
O
HO
OH
O
O
HO
OH
OH O
O
HO
OH O
O
Bisorbicillinol
Trichodimerol
Bisorbibutenolide
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.
Baran’s Publications: Corey
O
N
O
N
O
H
O
H
N
O
N
N Me
H
Me
(+)-Deoxyisoaustamide
O
N
H
Me Me
(+)-austamide
O
H
N
OH
N
O
N
H
Me Me
(+)-Hydratoaustamide
38. Baran, P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 7904 - 7905.
Me
Me
OH
N
H
O
N
H
O
N
H
N Me
H
Me
Okaramine N
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.
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 (CJ17,665) 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
H2N
Br
Br
O
N
H
HN
H
N
H
N
O
(+)-Sceptrin
H
N
Cl
N
Br
O
NH2
N
H
HN
H
N
NH
H
N
H
N
N
H
N
H
NH2
Br
O
(-)-Ageliferin
N
Br
N
NH
Cl
H2N
TFA
TFA
NH2
Br
O
TFA
N
N
H
HN
H
N
H
N
H
N
N
H
TFA
NH2
O
Nagelamide E
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, 26742677.
42. Baran, P.S.; Zografos, A.L.; O'Malley, D.P. Short Total Synthesis of Sceptrin, J. Am. Chem. Soc. 2004, 126,
3726-3727.
Baran’s Publications
O
R
R'
N
Br
NN
Br
N
H
R = R' = Br
R = H, R' = Br
R = R' = H
Cl
Me
Me
Chartelline A
Chartelline B
Chartelline C
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.
HO
HO
HO
N
H
Houamine A
HO
51. Baran, P. S.; Burns, N. Z. Total Synthesis of (±)-Haouamine A. J. Am. Chem. Soc.; 2006; 128; 3908 - 3909.
Baran’s Publications
Me
SCN
H
Me
Me
C N
H
H
N
H
Hapalindole Q
N
H
Cl
H
Me
Me
(+)-Fischerindole G
Me
C N
Me
Cl
SCN
H
N
H
H
Me
Me
(-)-Fischerindole I
Me
N
H
H
Me
Me
(-)-12-epi-Fischerindole U
C
Cl
H
Me
Me
O
N
N
H
(+)-Welwitindolinone A
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.
CP Molecules
H
O
O
O
O
O
O
O
CO2H
CP-263,114
O
O
O
O
HO H
O
OH
O
CO2H
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.”
Stinson, S. Chem. Eng. News 1995, 73, 29.
CP Molecules: Setting the floor to Baran
[3,3]-sigmatropic rearrangement approach
1)
O
DABCO cat.
H2C=O, THF
0 °C - rt, 30 %
PMBO
2) PMBOC(NH)CCl3
CSA, DCM, rt
78 %
1) n-BuLi, THF, ald
-40 °C - 0 °C
86 %
1) NaHMDS, PhNTf2
THF, -40 °C
60 %
O
2)
SnMe3
PMBO
Me3SnSnMe3
Pd(PPh3)4, LiCl
THF, 60 °C
73 %
O
O
MeO
OTBS
TBAF, THF
0 °C - rt, 95 %
2) PPh3, DEAD
PhCO2H, THF
-20 °C - rt, 95 %
O
MeO
PMBO
H
OTBS
OTBS
PMBO
NaOMe, MeOH
rt, 93 %
4)
TBSOTf
2,6-lutidine
DCM, -78 °C to 0 °C
86 %
2)
TPAP, NMO
MS 4Å, DCM, rt
H
PMBO
H
OTBS
MeMgBr, THF
0 °C
2)
TPAP, NMO
MS 4Å, DCM, rt
OTBS
MeO
O
1)
O
DIBAL, DCM
-78 °C, 86 %
DBU, DCM
0 °C - rt, 95 %
O
3)
1)
N2
OTBS
1) KHMDS, PhCO2Me PMBO
THF, -78 °C - rt, 93 %
2)
MeO
H
PMBO
1)
Rh2(OAc)4
DCM, 0 °C, 87 %
6.7:1 ratio
OTBS
PMBO
TBSCl, Im
DMF, 50 °C
94 %
1) CSA, MeOH/H2O 3) NaOCl2, NaH2PO4
2-methyl-2-butene
0 °C, 91 %
2) (COCl)2, DMSO
THF/H2O/tBuOH, 0 °C
4) CH2N2, Et2O, rt
TEA, DCM
-78 °C
87 % over 3 steps
H
TBSO
2)
O
Me
93 % over 3 steps
PMBO
H
OTBS
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
OTES
O
Me
H
KHMDS, TESCl
TEA, THF, -78 °C
OTBS
PMBO
OTES
THF
-78 °C to 45 °C
H
OTBS
PMBO
H
OTBS
PMBO
TBAF, THF
0 °C - rt
95 % over 2 steps
O
O
DDQ
DCM:H2O, rt
SPh
SPh
85 %
H
HO
O
PhSSPh, Bu3P
PhH, rt
H
65 % brsm
H
PMBO
PMBO
OH
BrCH2CO2H, DCC
4-DMAP, DCM
rt, 81 %
O
SPh
O
Me3SnSnMe3, hv
PhH, 35 °C, 61 %
O
SPh
O
H
O
Br
O
O
O
H
O
Nicolaou, K. C.; Postema, M. H. D.; Yang, G. Angew. Chem. Int. Ed. 1997, 36, 2821-2823.
CP Molecules: Setting the floor to Baran
Diels-Alder approach
TBSCl, NaH
THF, 0 °C
HO
OH
TBSO
OH
90 %
1) SO3-Py, DMSO
TEA, DCM, 0 °C
80 %
TBSO
N
2)Cyclohexylamine
MS 4 Å
Benzene, rt
1) LDA, Allyl-Br
THF, -78 °C to rt
2)
1)
TBSO
i) LDA, Butanal
THF, -78 °C to rt
ii) Oxalic Acid
water, rt
74 %
O
H
OTBS
OBn
N
3)
TBAF, H2O/THF
rt, 96 %
I2, PPh3, Im
DCM, rt, 78 %
NaBH4
MeOH, rt
58 % over 3 steps
TBSO
3)Cyclohexylamine
MS 4 Å
Benzene, rt, 98 %
OBn
OH
OTMS
1) i) KH, DME, 0 °C
ii)
Me2SO4
HMPA, 0 °C
96 %
2)
BnBr, NaH
TBAI, DMF, 0 °C
88 %
2)
O3, DCM;
PPh3
-78 °C - rt, 84 %
CN
i) LiHMDS, THF
-78 °C - 0 °C
MeO
ii)
I
OBn
TBAF
THF/H2O, 0 °C
86 %
MeO
O
OBn
Nicolaou, K. C.; Härter, M. W.; Boulton, L.; Jandeleit, B. Angew. Chem. Int. Ed. 1997, 36, 1194-1196.
CP Molecules: Setting the floor to Baran
Diels-Alder approach
O
MeO
OBn
Me2AlCl
DCM, -10 °C
86 %
3 : 1 ratio
Et
Et
Et
Et
MeO
OMe
O
CH2OBn
O
CH2OBn
MeO
O
BnO
Et
Et
Et
OMe
O
Et
OBn
Nicolaou, K. C.; Härter, M. W.; Boulton, L.; Jandeleit, B. Angew. Chem. Int. Ed. 1997, 36, 1194-1196.
CP Molecules: Diels-Alder Scale Up
1)
MeO
OMe
O
O
2)
I(CH2)3OTBS
NaH, THF, 80 °C
90 %
Allyl-Br
NaH, DME, rt
95 %
TBSO
1)
MeO
OMe
O
LiBH4, THF
0 °C - rt, 80 %
TBSO
2) Me2C(OMe)2
CSA, DCM, rt
82 %
O
O
i)
O3, DCM
-20 °C
ii)
PPh3
-78 °C - rt
95 %
O
1)
O
PMBO
O
Me2AlCl, DCM
-10 °C, 90 %
2)
C8H15
C8H15
O
O
3)
O
4)
TIPSO
a) O3; MeOH
b) Schlosser-modified Wittig
c) TsOH
O
Cyclohexylamine
Benzene, 80 °C
2) i) LDA, C9H17CHO
Et2O, -78 °C to -30 °C
ii) Oxalic Acid
water, rt
60 % overall
TIPSO
OTPS
O
O
1)
I
PMBO
O
H
TBSO
KH, PMBCl
DME/HMPA, 0 °C
78 %
TBAF, THF
0 °C, 82 %
n-BuLi, THF
-78 °C, 92 %
SO3-Py, DMSO
TEA, DCM
rt, 76 %
H
TBSO
O
C8H15
O
O
O
H
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.
CP Molecules: The Maleic Anhydride Hurdle
PMBO
O
O
OTPS
O
C8H15
O
PMBO
O
O
O
H
OTPS
O
O
O
O
O
O
O
C8H15
O
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… »
Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
CP Molecules: Maleic Anhydride Strategy
O
PMBO
O
O
O
OTPS
PMBO
O
O
C8H15
O
OTPS
C8H15
O
Molecular oxygen
Autoxidaton
H2N
O
"Molecular sponge"
HN
O
N HO
5-exo-dig cyclisation
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.
CP Molecules: Maleic Anhydride Synthesis
PMBO
O
O
O
OTPS
C8H15
OTf
KHMDS, PhNTf2
Pd(OAc)2, PPh3
MeOH, CO
THF, 0 °C
95 %
TEA, DMF, 50 °C
76 %
OH
OMe
DIBAL
Toluene, -78 °C
95 %
O
V(O)(acac)2, tBuOOH
Benzene, rt
85 %, 3.7:1 ratio
N
OAc
1)
Ac2O
2) Martin Sulfurane
90 %
OH
N
OH
HO
O
Et2AlCN
Toluene, 0 °C - rt
68 %
“With the a,b-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.”
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.
CP Molecules: Maleic Anhydride Synthesis
“It would take another seven weeks before we finally found reliable conditions for the conversion
of cyanodiol [] into maleic anhydride []…”
OH
N
HO
1)
MsCl, TEA
THF, 0 °C
2) K2CO3, MeOH, rt
3) 10 % oxalic acid
Et2O, air, rt
60 %
O
O
PMBO
O
O
O
OTPS
O
O
C8H15
O
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.
CP Molecules: Maleic Anhydride Synthesis
OH
N
HO
-
OMs
N
N
N
HO
O
O
Base
H
Proven intermediate
HN
O
O
OH
H2N
O
HN
O
H+
Path A
Proven intermediate
Path B
H2N
O
O
O
O
O
O
OH
H2N
O
O
O
O
H
N
O
H
N
O
OH
O
H
N
OH
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.
CP Molecules: Maleic Anhydride Synthesis
“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.”
Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
CP Molecules: g-Hydroxylactone Hurdle
OTPS
PMBO
O
O
C8H15
O
O
O
O
C8H15
O
H
O
O
OTPS
HO
O
DDQ
DCM/H2O
rt, 50 %
O
O
O
CO2H
CP-263,114
X
O
O
X
OTPS
C8H15
O
“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…”
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.
CP Molecules: g-Hydroxylactone Hurdle
Br
OTPS
O
O
HO
OTPS
PMBO
O
NaH, 2-Br-BnBr
DMF, rt
75 %
O
C8H15
HO
C8H15
H
O
O
O
O
C8H15
O
1)
O
O
O
CO2H
CP-263,114
Br
O
O
O
2 N HCl, THF
rt, 90 %
2) DMP, NaHCO3
DCM, rt, 90 % (5:1)
3) NaClO2, NaH2PO4
2-methyl-2-butene
THF/tBuOH/H2O, rt;
then CH2N2, 0 °C, 85 %
O
O
OTPS
n-Bu3SnH, AIBN
Benzene, 80 °C
80 %
O
O
O
X
O
OTPS
O
MeO
HO
OTPS
HO
O
DDQ
DCM/H2O
rt, 50 %
C8H15
MeO
HO
C8H15
X
OTPS
C8H15
O
“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…”
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.
CP Molecules: g-Hydroxylactone Hurdle
PMBO O
MeO
OTPS
O
C8H15
PMP
Me
1)
2 N HCl, THF
rt, 90 %
2)
DDQ, MS 4 Å
DCM, rt, 81 %
O
OTPS
O O
O O
C8H15
1)
PivCl, TEA
4-DMAP
DCM, rt, 90 %
2)
CSA
MeOH, rt, 90 %
HO
OTPS
HO O
MeO
HO
C8H15
PivO
DMP (10 equiv)
DCM, rt, 82 %
X
MeO
O
O OH
OTPS
O O
OTPS
MeO
O
MeO
O
OH
OTPS
O
C8H15
PivO
TEMPO, KBr, NaOCl
Cyclooctene
Acetone/5% NaHCO3
0 °C, 68 %
C8H15
PivO
X = OH, H
C8H15
PivO
Proven intermediate
X=O
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.
CP Molecules: g-Hydroxylactone Hurdle
HO O
O
OTPS
O
HO
C 8H 15
SO3 -Pyr, DMSO
TEA, DCM, -78 °C
O
HO
O
O
OTPS
O
90 %
C 8H 15
PivO
PivO
TEMPO, KBr, NaOCl
Cyclooctene
Acetone/5% NaHCO 3
0 °C, 75-85 %
HO O
O
OTPS
O
HO
C 8H 15
(COCl) 2, DMSO
TEA, DCM, 0 °C
PivO
O
X
O
OH
OTPS
C 8H 15
Oxidant
DCM, 25-35 °C
PivO
C 8H 15
O
O
O
70-90 %
Oxidant = PDC, DMP, PCC, BaMnO4
OTPS
C 8H 15
PivO
O
HO
O
O
82 %
PivO
HO O
O
O
O
OTPS
O
O
O
O
OH
OTPS
C 8H 15
PivO
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.
CP Molecules: g-Hydroxylactone Hurdle
OTPS
PMBO O
O
O
O
C 8H 15
TiCl4
1,3-propanedithiol
cyclooctene
DCM, -15 °C, 84 %
AcO O
O
O
TESO
O
OTPS
1)
C 8H 15
TESO
TESCl, Im
DCM, rt, 84 %
2)
Ac2 O
TEA, 4-DMAP
DCM, rt, 97 %
O
AcO O
O
TESO
OTPS
C 8H 15
TESO
1) TiCl4, cyclooctene
DCM, -78 °C
67 % (3.8:1)
2)
DMP, DCM
rt, 94 %
3) TiCl4, cyclooctene
1,3-propanedithiol
DCM, -78 °C to -15 °C,
71 %
O
X
O
O
O
OH
OTPS
1) (CF2 CO 3) 2IPh
MeCN, rt, 80 %
C 8H 15
TESO
2) TEMPO, KBr
NaOCl, Cyclooctene
Acetone/5% NaHCO 3
0 °C, 70 %
O
S
S
O
TESO
O O
OTPS
1) K2CO3 , MeOH
rt, 89 %
C 8H 15
2)
PDC, DCM
rt, 90 %
O
S
S
AcO O
O
TESO
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.
OTPS
C 8H 15
CP Molecules: Real Model Synthesis
S
S
PMBO
O
O
OTPS
1)
C 8H 15
O
PMBO
O
TBAF, THF
rt, 93 %
2) DMP, NaHCO3
DCM, rt, 92 %
H
O
O
1)
C 8H 15
O
SS
Li
THF, -78 °C
93 % (11:1)
2) NaH, TESOTf
THF, 0 °C to rt
86 %
PMBO TESO
O
O
C 8H 15
O
1) Vinyltriflate
(95 % vs 95 %)
2) Carboxymethylation
(78% vs 76 %)
OO
PMBO TESO
O
O
O
O
R
C 8H 15
O
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 %)
SS
OO
PMBO TESO
R
O
R
C 8H 15
O
PhI(OCOCF3) 2
CaCO3 , MeOH
rt, 81 %
PMBO TESO
R
O
R
C 8H 15
O
R = CO 2Me
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.
CP Molecules: Real Model Synthesis
OO
PMBO TESO
O
O
O
O
1) 90 % AcOH, rt
2) Me 2C(OMe)2
CSA, DCM, rt
77 % (2 steps)
R
3)
TBSOTf
2,6-lutidine, DCM
-20 °C to 0 °C
90 %
C 8H 15
O
O
PMBO TBSO
O
O
O
O
O
R
C 8H 15
1)
DDQ
DCM/H2 O
64 %
2) PDC, DCM, rt
89 %
O TBSO
O
O
O
O
O
R
C 8H 15
O
1) 80 % aq AcOH
rt, 82 %
2)
TESOTf
2,6-lutidine
0 °C, 92 %
O
O
O
O
O
TBSO
O OH
O
R
PhI(OAc)2
TEMPO, MeCN
rt, 74 %
O
HO
C 8H 15
TESO
O
O
TBSO
O OH
O
R
DMP
Benzene
80 °C, 63 %
O
C 8H 15
TESO
O
O
TBSO
O OH
R
C 8H 15
TESO
“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…”
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.
CP Molecules: Homologation
O
O
O
O
O
TBSO
O OH
R
2)
C 8H 15
TESO
1)
H
TFA
DCM / H2 O, rt
CH3 SO3H
CHCl3 , rt
50 % overall
DMP, NaHCO3
DCM, rt, 95 %
OO
O
O
O
OO
O
O
O
O
R
C 8H 15
HO
O
H
O
R
H
C 8H 15
H O
R
H
C 8H 15
H
O
O
OO
O
O
O
O
O
OO
O
O
O
O
O
O
R
C 8H 15
O
OH
“My (K.C.N.) first reaction was to attribute this failure to the “inadequate” experimental skills of my coworkers; 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!”
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.
CP Molecules: Homologation
PMP
O
PMBO TBSO
O
O
O
R
1) 90 % AcOH
rt, 85 %
2)
O
C8H15
O
TBSO
O O O O
DDQ
Ph-F, rt, 57 %
O
PMP
O
R
1) DMP, NaHCO3
DCM, rt, 90 %
O
2) NaClO2, NaH2PO4
2-methyl-2-butene
t-BuOH/H2O
rt, 80 %
C8H15
HO
O
TBSO
O O O O
R
C8H15
O
OH
1) MsCl, TEA
THF, 0 °C
2)
CH2N2
THF/Et2O
0 °C - rt
PMP
O
O
HO
HO TBSO
O
O
R
C8H15
1) PhNH2, EDC
4-DMAP
DCM, rt, 85 %
O
TBSO
O O O O
2) 80 % AcOH
rt, 89 %
R
C8H15
OH
NHPh
O
PMP
O
O
Ag2O
DMF/H2O
120 °C, 1 min.
O
O
TBSO
O O O O
38 % overall
R
C8H15
O
N2
“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…”
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.
CP Molecules: DMP Surprise
O
TBSO
HO O
O
O
HO
H
N
O
R
DMP
Benzene, rt
90 %
O
TBSO
O OH
O
O
C 8H 15
O
O
TBSO
O OH
O
O
HO
O
O
H
N
R
C 8H 15
O
R
DMP
Benzene, 80 °C
NH O
DMP
Benzene, 80 °C
O
O
O
O
R
C 8H 15
H
N
O
O
TBSO
O OH
C 8H 15
O
TBSO
O OH
O
O
45 %
N
O
R
C 8H 15
O
“…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.”
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.
CP Molecules: Testing Baran!
“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...””
Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
CP Molecules: Final Route
O
O
HO
O
O
O
H
TBSO
O OH
R
1)
2)
C 8H 15
TESO
TFA
DCM/H 2O, rt
MeSO 3H
CHCl3, rt
83 % overall
O
HO
O
O
OO
1)
DMP
Benzene, rt
90 %
R
2)
C 8H 15
HO
TBSOTf
2,6-lutidine, DCM
-20 °C to 0 °C
85 %
H
OO
O
O
O
TBSO
O
R
C 8H 15
O
H
NaClO 2, NaH 2 PO 4
2-methyl-2-butene
t -BuOH/H 2O
rt, 90 %
H
O
TBSO
OO
O
O
O
R
C 8H 15
Indoline
EDC, 4-DMAP
DCM, rt, 85 %
H
O
TBSO
OO
O
O
O
1)
R
O
C 8H 15
N
OH
O
MsCl, TEA
THF, 0 °C
2)
CH 2N 2
THF/Et2 O, 0 °C
3)
Ag 2O
DMF/H 2O
120 °C, 1 min.
35 % overall
H
O
O
O
TBSO
OO
O
R
C 8H 15
O
OH
“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!”
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.
CP Molecules: Final Route
H
O
TBSO
OO
O
O
O
1)
R
C8H15
O
H
TFA
DCM/H2O
rt, 95 %
OO
O
O
O
O
2) DMP, NaHCO3
DCM, rt, 80 %
R
p-chloranil
Toluene
70 °C, 70 %
H
O
O
O
OO
O
O
C8H15
R
C8H15
O
N
“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
O
N
N
LiOH
THF/H2O, rt;
10 % NaH2PO4
72 %
H
O
O
O
O
OO
O
R
C8H15
O
OH
CP-263,114
MeSO3OH
CDCl3, rt, 72 %
LiOH
THF/H2O, rt
90 %
O
O
O
O
HO
O OH
O
R
C8H15
O
OH
CP-225,917
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.
Triumphant CP-Team
Nicolaou, K.C.; Baran, P.S. Angew. Chem. Int. Ed. 2002, 41, 2678 - 2720.
Total Synthesis of Haouamine A
HO
HO
HO
N
H
Haouamine A
HO
51. Baran, P. S.; Burns, N. Z. Total Synthesis of (±)-Haouamine A. J. Am. Chem. Soc.; 2006; 128; 3908 - 3909.
Total Synthesis of Haouamine A
MeO
1)
OMe
O
+
I
2)
Br
O
OMe OMe
OMe
KHMDS
THF / DMPU
-78 °C - rt, 54 %
Br
i)
OMe
N
OH
Br
OMe
OMe
Br
HO-NH3 Cl
NaOAc / EtOH
75 %
OMe
Br
Br
DCE, 0 °C
30 min.
N
OH
ii)
OMe OMe
OMe OMe
iii) In powder
H 4NCl sat.
EtOH, reflux
OMe
N
H H
Br
57 % overall
N
H
OH
NaBH4
EtOH, 50 °C
1h
OMe
OMe
Br
Baran, P. S.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908 - 3909.
Br
OMe
iii) In powder
H 4NCl sat.
EtOH, reflux
OMe
Br
57 % overall
H
N
OH
Br
Total Synthesis of Haouamine A
Boc 2 O
DCM
OMe
OMe OMe
OMe
OMe
O
Br
N
H H
SnMe 3
OMe OMe
OMe OMe
Pd(Ph3 )4 , CuI
Toluene, reflux
44 % overall
Br
N
H Boc
OMe
O
OMe
N
H Boc
O
O
i) TFA / DCM
TsO
AcO
HO
AcO
HO
N
O
N
2) K2CO3 , MeOH
H
H
21 % (30 % sm)
OMe OMe
O
OMe
1) DCB (0.001 M)
BHT
250 °C ( W) AcO
HO
i) BBr3 , DCM
-78 °C - rt
ii)
Ac 2O, py
67 %
Houamine A
HO
ii) A , K2CO3
MeCN, ref lux
70 %
A
AcO
Baran, P. S.; Burns, N. Z. J. Am. Chem. Soc. 2006, 128, 3908 - 3909.
H
OMe
N
O
O
Total Synthesis of Chartelline
O
R
R'
N
Br
NN
Br
N
H
Cl
Me
Me
R = R' = Br
R = H, R' = Br
R = R' = H
Chartelline A
Chartelline B
Chartelline C
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.
Total Synthesis of Chartelline
OTBS
NH2
CO2Me
OTBS
NH2
MgBr
THF, -78 °C
93 %
O
Me
Me
i) KNCS, H4NCl
toluene
105 °C - 110 °C
OTBS
N
ii) 6 N HCl, rt
iii) H2O2, THF, rt;
2 M NaOH
NaHCO3 sat.
iV) TBSCl, TEA
DCM, rt
84 % overall
Me
N
Me H
OTBS
1) NaIO4, OsO4
THF/H2O, rt
N
2) Ohira's reagent
K2CO3
MeOH, rt
63 %
N
Me H
Me
MeO2C
Br
N
Boc
O
P(O)(OEt)2
N
H
O
N
Boc
N
N
H
Pd(PPh3)4, CuI
DIPA, DME
70 °C, 71 %
CO2Me
CO2Me
H
1)
Me
Me
LiOH
THF / H2O, rt
2) BOPCl, DIPEA
0 °C, 86 %
O
N
Boc
N
N
H
MeO2C
H
1)
H2 / Pd/C
MgSO4, EtOH, rt
2)
TBAF, THF
0 °C - rt
MnO2, DCM
rt, 98 %
Me
Me
3)
Baran, P. S.; Shenvi, R.A.; Mitsos, C.A. Angew. Chem. Int. Ed. 2005, 44, 3714-3717.
TBSO
N
NH
N
Boc
Me
Me
Total Synthesis of Chartelline
O
P(O)(OEt)2
N
H
O
N
Boc
N
O
O
CO2Me
NH
CO2Me
N
H
LiCl, DIPEA
Me
N
Boc
N
MeCN, 70 °C
75 %
Me
Me
Me
1)
180 °C
2)
NBS, KHCO3
THF / H2O
88 %
NN
N
H
N
H
N
H
CO2Me
Me
Me
Selected Dead-End Routes to the Chartelline Carbocyclic Skeleton
O
O
NH
O
OH
NH2
CO2Me
NH
CO2Me
O
N
R
N
N
H
Me
Me
=> Ring-Closing Metathesis
N
H
N
R
Me
N
Me
N
H
N
H
=> Macrolactamization
N
Me
Me
=> Heck-type coupling
Baran, P. S.; Shenvi, R.A.; Mitsos, C.A. Angew. Chem. Int. Ed. 2005, 44, 3714-3717.
Total Synthesis of Chartelline
O
O
NH
MeO2C
CO2R
NH
i) Br2, CaCO3
PhH, rt
I
Br
N
Boc
N
Boc
N
Br
R = TMSE
Me
Me
ii)
Br
Br
NBA
PhH, rt
36 %
N
H
N
Boc
N
Me
Me
N
H
Br
iv)
v)
i) 185 °C, 1.5 min
ii) NBS, MS 3Å
MeCN, rt
iii) 18-C-6, K2CO3
MeCN, rt, 1 h
O
N
N
NN
Br
Chartelline C
O
Br
N
H
Cl
Me
Me
i) TFA / DCE, rt
ii) o-DCB, 200 C
64 %
Baran, P. S.; Shenvi, R. A. J. Am. Chem. Soc. 2006, 128, in press.
CO2R
NN
Br
Br
N
H
NaHCO3 sat.
Brine, 15 min
93 %
CO2R
Cl
Me
Me
Total Synthesis of Sceptrin
H2N
Br
Br
O
N
H
HN
H
N
H
N
O
(+)-Sceptrin
H
N
Cl
N
Br
O
NH2
N
H
HN
H
N
NH
H
N
H
N
N
H
N
H
NH2
Br
O
(-)-Ageliferin
N
Br
N
NH
Cl
H2N
TFA
TFA
NH2
Br
O
TFA
N
N
H
HN
H
N
H
N
H
N
N
H
TFA
NH2
O
Nagelamide E
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, 26742677.
42. Baran, P.S.; Zografos, A.L.; O'Malley, D.P. Short Total Synthesis of Sceptrin, J. Am. Chem. Soc. 2004, 126,
3726-3727.
Total Synthesis of rac-Sceptrin
O
O Me
MeO2C
MeO2C
Me
H2SO4, MeOH
50 %
MeO2C
MeO2C
O
O
Me
1) HC(OMe)3, PTSA
MeOH, 50 °C
HO
Me
Me
2)
HO
Me
O
DIBAL
DCM, -78 °C;
AcOH, H2O
100 %
1)
N
H
H
N
Br
H
N
HN
NH
H
N
NH
O
N
H
Cl
1)
NH2
2)
Cl
NH2
3)
(CHO)2NNa
35 °C
HCl
MeOH, rt
Br
O
N
H
H
N
H2N-CN
H2O, 95 °C
72 % overall
O
Br
N3
Me
CCl3
1) HC(OMe)3, PTSA
MeOH, 50 °C
2)
H2, Lindlar
MeOH
3)
X, MeCN
70 % overall
Br
O
Ph
HN
Cl
H
N
Cl
O
Me
O
N
H
O
NaN3
DMF, 50 °C
N3
O
Br
Br
2)
MsCl, py
0 °C - rt
O
NMe3
MeO
N
H
H
N
ICl2
THF, 60 °C
97 %
HN
Me
H
N
Me
MeO
O
Br
rac-Sceptrin
Baran, P. S.; Zografos, A. L.; O'Malley, D. P. J. Am. Chem. Soc. 2004, 126, 3726-3727.
O
OMe
OMe
Total Synthesis of (+)-Sceptrin
1) i)
O Me
MeO2C
PLE, pH = 8
Acetone, rt
MeO2C Me
100 %, 75 % ee
O Me
O Me
MeO2C
BnNH2, DMT-MM
MeO2C
THF, 92 %
BnHNOC Me
HO2C Me
N
MeO
N
Cl
OMe
N
h, THF
H2SO4
THF / MeOH MeO2C
45-50 %
2)
PTSA
MeOH / PhMe MeO2C
105 °C, 50 %
75 % ee
>95 % ee
ii)
DMT-MM
N Me
O
Mechanism ???
O
O Me
MeO2C
BnHNOC Me
1)
MeO2C
O
Me
Me
BnHNOC
2)
MeO2C
Me
Me
MeO2C
O
Baran, P. S.; Li, K.; O'Malley, D. P.; Mitsos, C. Angew. Chem. Int. Ed. 2006, 45, 249 –252.
O
O
Me
Me
O
Total Synthesis of (+)-Sceptrin
O
O Me
MeO2C
MeO2C
1)
BnHNOC Me
O
MeO2C
2)
Me
Me
BnHNOC
Me
Me
MeO2C
O
O Me
MeO2C
Me
O Me
h
BnHNOC Me
MeO2C
BnHNC
O Me
+
H
O
H+
MeO2C
H
Me
BnHNO
OH
O
MeO2C
MeOC
Me
Me
MeO2C
MeO2C
H2O
OH
O
Me
BnHN
O
Me
NBn
O Me
OH
MeOC
O
H+
MeOH
O
O
MeO2C
Me
Me
BnHNOC
O
Baran, P. S.; Li, K.; O'Malley, D. P.; Mitsos, C. Angew. Chem. Int. Ed. 2006, 45, 249 –252.
O
(-)-Ageliferin and Nagelamide E
H2N
N
Br
O
N
H
H
N
Br
Br
O
H
N
N
H
HN
NH
H
N
H
N
NH
O
N
H
Cl
Cl
N
HN
H
N
H
N
N
H
Cl
NH2
O
Br
NH2
H2O, microwave
200 °C, 5 min.
(-)-Ageliferin
40 %
Cl
NH2
H2N
N
Br
O
(+)-Sceptrin
50 %
Br
N
H
HN
H
N
H
N
Cl
N
H
N
Cl
NH2
N
H
O
Nagelamide E
2%
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.
(-)-Ageliferin and Nagelamide E
H
N
R
Cl
H
N
NH2
NH
R
NH
R
NH
Cl
NH
N
H
Sceptrin
Cl
NH2
N
N
Cl
NH2
TFA
N
NH2
radical
R
H2N
R
H
N
R
N
H
TFA
NH2
Ageliferin and Nagelamide
ionic
H
N
R
N
R
NH
N
Cl
NH2
Cl
NH2
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.
(-)-Ageliferin and Nagelamide E
H
N
R
Cl
NH2
R
NH
Cl
NH
R
N
H
Cl
H
N
H
H
H
NH2
N
NH
R
NH2
N
R
N
R
Cl
NH
N
NH3
Cl
NH
NH2
N
Cl
Sceptrin
H2N
N
H2N
Cl
N
N
N
R
Cl
H
N
Cl
R
N
N
H
Cl
NH3
NH2
R
R
N
R
N
N
R
NH3
Cl
NH
N
NH2
Cl
Ageliferin and Nagelamide
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.
Baran’s Methodology
Me
SCN
H
Me
Me
C N
H
H
N
H
Hapalindole Q
N
H
Cl
H
Me
Me
(+)-Fischerindole G
Me
C N
Me
Cl
SCN
H
N
H
H
Me
Me
(-)-Fischerindole I
Me
N
H
H
Me
Me
(-)-12-epi-Fischerindole U
C
Cl
H
Me
Me
O
N
N
H
(+)-Welwitindolinone A
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.
Baran’s Methodology
Me
Me
SCN
H
O
O
H
Me
H
Me
+
Me
N
H
Me
N
H
H
N
H
Hapalindole Q
Indole
Me
C N
H
N
H
Cl
H
Me
Me
(+)-Fischerindole G
Me
C N
SCN
H
N
H
H
Me
Me
(-)-Fischerindole I
Me
Me
Cl
N
H
H
Me
Me
(-)-12-epi-Fischerindole U
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.
Carvone
C
Cl
H
Me
Me
O
N
N
H
(+)-Welwitindolinone A
Baran’s Methodology
Me
O
O
H
Me
+
Me
Me
N
H
H
N
H
Indole
Carvone
O
O
Me
Me
+
N
+
Me
N
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.
Me
Baran’s Methodology
O
LiHMDS (3 equiv)
Copper(II) 2-ethylhexanoate
(1.5 equiv)
X
R3
R1
+
R2
N
H
1 equiv
2 equiv
N
H
O
Me
NH
Me
H
N
H
Me
R2
Me
Me
Ph
43 % (dr = 5:1)
HN
NH
H
33 %a (dr = >25:1)
R1
NH
Ot-Bu
H
N
S
OO
O
N
H
H
54 %
O
N
HO
O
53 % (70)a
O
O
Me O
H
O
R1
X
THF, -78 °C
Me
O
H
O
R3 R2
Me
H
R1 = H; R2 = Hb
R1 = F; R2 = H
R1 = H; R2 = Me
R1 = H; R2 = OMeb
64 %a
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 material
b) LDA used
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.
Baran’s Methodology
OH
Me
i)
O
H
Me
H
N
H
ii)
iii)
LiHMDS
THF, -78 °C
L-Selectride
Me
Me
O
H
CH3CHO
-78 °C - rt
Me
H
Martin
Sulfurane
CHCl3
O
H
75 % overall
N
H
Me
Me
Me
H
TMSOTf
MeOH / DCM
0 °C
75 % brsm
O
H
N
H
N
H
NaBH3CN
H4NOAc
MeOH / THF
150 °C, W
61 %
Me
SCN
H
Me
CS(imid)2
DCM
0 °C - rt
63 %
H
N
H
Hapalindole Q
33 %
Me
H2N
H
Me
Me
SCN
H
H
N
H
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450-7451.
H
Me
Me
N
H
H
Me
Me
(-)-12-epi-Fischerindole U
Baran’s Methodology
O
O
i)
Me
O
Me
ii)
LiHMDS
THF, -78 °C
MgBr
O
PPh3, NCS
THF, 55 %
Me
HO
Me
Me
Cl
Me
-15 °C, 30 %
R-carvone oxide
LiHMDS
Copper(II) 2-ethylhexanoate
THF, -78 °C - rt
55 %
Me
H2N
H
N
H
Me
Me
Cl
NaBH3CN
H4NOAc
H
Me
Me
O
H
MeOH / THF
26 %
N
H
Cl
H
Me
Me
Mont. K-10
DCE, W
120 °C
40 %
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005; 127, 15394-15396.
Cl
O
H
Me
H
N
H
Baran’s Methodology
Me
Cl
H2N
H
N
H
HCO2H
DMT-MM
4-DMAP, NMM
H
Me
Me
Me
O
H
H
N
H
Me
Cl
DCM, rt
98 %
N
H
H
Me
Me
i)
tBuOCl
TEA, THF
0 °C
C N
ii) SiO2, TEA
(PTLC)
iii) Burgess, rt
47 % overall
N
H
Cl
H
Me
Me
(+)-Fischerindole I
Me
O
H
N
H
1)
Me
Cl
H
Me
Me
i)
NaBH4
MeOH, 0 °C
ii)
Ms2O, Py
69 %
H2N
H
N
H
Cl
H
Me
Me
HCO2H
DMT-MM
4-DMAP, NMM
DCM, rt, 87 %
2)
Burgess
PhH, rt
82 %
Me
C N
H
N
H
Cl
H
Me
Me
(-)-Fischerindole G
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005; 127, 15394-15396.
Baran’s Methodology
Me
C N
N
H
Cl
H
Me
Me
(-)-Fischerindole I
Me
i)
ii)
tBuOCl
TEA, THF
-30 °C
TFA
THF / H2O
28 %
C
Cl
H
Me
Me
O
N
N
H
(+)-Welwitindolinone A
Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005; 127, 15394-15396.
Baran’s Methodology
LiHMDS (4 equiv)
Copper(II) 2-ethylhexanoate
(1.5 equiv)
O
R3
R1
+
N
H
R2
1 equiv
N
H
THF
-78 °C to -60 °C to 0 °C
R2
R3
R1
O
3 equiv
Me
Me
Me
Me
H
O
O
Ot-Bu
Me
N
S
OO
O
NH
O
Me
Me
H
N
H
Me
Me
57 % (dr = 1:1)
R2
R3
H
H
Me
Me
Me
41 %
Ph
NH
Me
Me
N
H
R1
O
Me
NH
NH
42 % (dr = 14:1)
NMe
O
Me
Me
a
O
Me
R1 = R2 = R3 = H
R1 = R2 = Me; R3 = H
R1 = R2 = Me; R3 = Et
R1 = Et; R2 = R3 = H
42 % (dr = 1:1)
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
54 %a (dr = >20:1)
Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem. Int. Ed. 2005, 44, 609-612.
Baran’s Methodology
i)
OH
N
O
TEA, MeOCOCl
THF, 0 °C
Me Me
H
ii)
LiN
OS
O
Me Me
H
O
N
N
OS
O
100 %
LiHMDS, TEA
THF
-78 °C - 12 °C
65 % brsm
Fe+ PF6-
O
H
N
Aux
O
S-ketorolac (NSAID)
i)
BzCl, 70 °C
ii)
TBAH, H2O2
2-methyl-2-butene
DME, -10 °C
38 %
H
N
Aux
O
Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem. Int. Ed. 2005, 44, 609-612.
Baran’s Methodology
O
O
R3
R1
R2
+
R4
R6
N
R5
1 equiv
R4
R7
O
O
O
O H
Ph
Me
H
O
O
O
N
R1
Ph
52 % (dr = 2.7:1)
59 % (dr = 2.8:1)
Me
R2
Me
N
O
Ph
Ph
O
N
R5 R7 R6 R1
O
O
O
N
2
1 equiv
Me
O
R3 R
O
LDA;
Fe(acac)3
O
Ph
R1 = a-Bn; R2 = H
R1 = a-Bn; R2 = OMe
R1 = b-iPr; R2 = Br
R1 = b-iPr; R2 = H
R1 = b-iPr; R2 = OMe
57 %; a-H dr = 2.8:1
67 %; a-H dr = 2.5:1
55 %; b-H dr = 2.5:1
66 %; b-H dr = 2.1:1
65 %; b-H dr = 2.3:1
O
O
H
R2
Me
H
N O
R1
R1 = R2 = Me
R1 = R2 = Me
R1 = MOM; R2 = Prenyl
91 %; dr = 1.2:1
60 %; dr = 1.2:1
54 %; dr = 1.0:1
R2
N
R1 O
R1 = R2 = Me
R1 = MOM; R2 = Prenyl
Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, in press.
O
72 %; dr = 2.6:1
73 %; dr = 2.0:1
Baran’s Methodology
O
O
R3
R1
+
R4
R2
1 equiv
N
R5
R6
R4
R7
2
O
N
R5 R7 R6 R1
1 equiv
O
O
O
R3 R
O
LDA;
Cu(II) 2-ethylhexanoate
O
O
Bn
Bn
OR
N
O
N
iPr
O
iPr
Bn
O
O
54 %; dr = 2.4:1
R = Me
R = tBu
R = tBu
Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, in press.
51 %; dr = 1.0:1
51 %; dr = 1.6:1
53 %; dr = 1.6:1
Baran’s Methodology
OMe
O
O
O
O
CO2tBu
N
iPr
O
+
O
OMe
LDA, LiCl
Copper(II) 2-ethylhexanoate
OMe
PhMe
-78 °C
O
O
N
OMe
CO2tBu
iPr
O
O
LiBH4
MeOH / THF
-78 °C to -10 °C
OMe
OMe
OMe
O
(-)-bursehernin
41 % overall
single diastereomer
DBU, PhMe
110 °C
O
OH
OMe
CO2tBu
O
O
O
Baran, P. S.; DeMartino, M. P. Angew. Chem. Int. Ed. 2006, 45, in press.
O
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…
Small Molecule Natural Products in the Discovery of Therapeutic Agents:
The Synthesis Connection
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.