"You eat, drink, and sleep your molecule" (Phil S. Baran) Guillaume Barbe Charette’s Laboratories

"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


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


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


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.


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


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


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.”


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 []…”


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



“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


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


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 %



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 %



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


“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)


O

C8H15

O

R

O

OO OO

O

H

OH

CP Molecules: Homologation


“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)


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


“…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!


“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)


2)

p-chloranilToluene

70 °C, 70 %

LiOHTHF/H2O, rt;

10 % NaH2PO472 %

MeSO3OHCDCl3, rt, 72 %

LiOHTHF/H2O, rt

90 %

Triumphant CP-Team


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


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


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


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


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


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 %



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



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


ONH

Cl

Me

Me

H

Me

NC

(+)-Fischerindole G

H

NH

Me

Me

H

Me


H

SCN

Hapalindole Q

NH

Me

H

H

SCN

Me


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


ONH

Cl

Me

Me

H

Me

NC

(+)-Fischerindole G

H

NH

Me

Me

H

Me


H

SCN



NH

H

H

O

Me

Me

NH

O

Me

Me+

Indole Carvone

N

O

Me

Me+

N

O

Me

Me+



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



Hapalindole Q

NH

H

H

O

Me

Me

NH

Me

Me

H

Me


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, 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 %



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



tBuOClTEA, THF

-30 °C

i)

TFATHF / H2O

28 %

ii)

NH

Cl

Me

Me

H

Me

NC

(-)-Fischerindole I

NH

Cl

Me

Me

H

MeNC


O


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, 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, 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



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



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

"You eat, drink, and sleep your molecule" (Phil S. Baran) Guillaume Barbe Charette’s Laboratories

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