Selective sp C-H HydroxylationSelective sp3 C-H Hydroxylation Xin Zhang Department of Chemistry Michigan State University 11/10/2010 Wednesday, November 10, 2010

Selective sp3 C-H Hydroxylation

Xin ZhangDepartment of ChemistryMichigan State University

11/10/2010

Wednesday, November 10, 2010

Content

• Introduction

• Tertiary sp3 C-H Hydroxylation

• Secondary sp3 C-H Hydroxylation

• Primary sp3 C-H Hydroxylation

• Example of sp3 C-H Hydroxylation in Total Synthesis


The Versatility and Application of Alcohol in Chemistry


The Versatility and Demand of Alcohol in Industry and Daily Life

Reed, T. B.; Lerner, R. M.; Science 1973, 182, 1299.Worldwatch Institute and Center for American Progress (2006). American energy: The renewable path to energy security

Isopropanol is good solvent and anticeptic


http://images1.americanprogress.org/il80web20037/americanenergynow/AmericanEnergy.pdf

http://images1.americanprogress.org/il80web20037/americanenergynow/AmericanEnergy.pdf

Petroleum reserves on the earth

<Petroleum Resources Management System>, Society of Petroleum Engineers. 2007. Retrieved 2008-04-20.http://www.spe.org/industry/reserves/prms.php

The Advantage of Hydroxylation from sp3 C-H


http://www.spe.org/spe-app/spe/industry/reserves/prms.htm

http://www.spe.org/spe-app/spe/industry/reserves/prms.htm

http://www.spe.org/industry/reserves/prms.php

http://www.spe.org/industry/reserves/prms.php

The Advantage of Hydroxylation from sp3 C-H

6-Deoxyerythronolide B

Corey, E. J.; Trybulski, E. J.; Melvin, L. S.; Nicolaou, K. C. et al. J. Am. Chem. Soc. 1987, 100, 4620.Stang, E. M.; White, M. C. Nature Chemistry 2009, 1, 547.


Challenges in C-H Oxidation

95 96.5 98 99.5 101

primary sp3 C-H

secondary sp3 C-H

tertiary sp3 C-H

C-H Bond dissociation energy/ kcal/mol

Berkowitz, J.; Ellison, G. B.; Gutman, D. J. Phys. Chem. 1994, 98, 2744.

The inertness of C-H bond



The over oxidation of alcohol product

Mello, R.; Fiorentino, M.; Fusco, C.; Curc, R.; J. Am. Chem. Soc. 1989, 111, 6749.



The selective oxidation of specific one type

Nomura, K.; Uemura, S. J. Chem. Soc., Chem. Commun. 1994, 129.


Content

• Introduction






Tertiary sp3 C-H Hydroxylation with Ru Catalyst

McNeill, E.; Bois, J. D. J. Am. Chem. Soc. 2010, 132, 10202.

Mechanism of this Reaction

2RuCl3+5KBrO3+3H2O = 2RuO4+5KBrO2+6HCl


Substrate Scope of the Ru Catalyzed Reaction

McNeill, E.; Bois, J. D. J. Am. Chem. Soc. 2010, 132, 10202.


More Complex Case with Multiple Tertiary C-H Centers

4-epiajanol dihydroxyeudesmane pygmol

Chen, K.; Baran, P. S. Nature 2009, 459, 824.

common intermediate 3

13C NMR of ‘3’13C NMR of ‘3’13C NMR of ‘3’13C NMR of ‘3’13C NMR of ‘3’13C NMR of ‘3’carbon C-H1 C-H2 C-H3 C-H4 C-H5

δ(ppm) 27.5 55.2 73.6 50.2 26.6

C-H1 and C-H5 is most likely to be oxidized with electrophilic oxidant


Total Synthesis of Dihydroxyeudesmane



Selective Hydroxylation of H5

Chen, K.; Baran, P. S. Nature 2009, 459, 824.Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247.

Crystal structure of ‘3’


Chen, K.; Baran, P. S. Nature 2009, 459, 824.Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247.



Total Synthesis of 4-epiajanol



‘Strain release’ is proposed to be the keyin this selective hydroxylation on H1




Strain Release of 1,3-Diaxial Interaction

Bath, R. D.; Andri, J. L.; Su, M.-D.; McDouall, J. J. W. J. Am. Chem. Soc. 1993, 115, 5768. Chen, K.; Baran, P. S. Nature 2009, 459, 824.

δ+ δ- δ. δ.

sp3 sp2 Tetrahedral Planar

6-3lG* CalculationCharged or radical transition state


Total Synthesis of pygmol



Total Synthesis of pygmol



Content

• Introduction






Over Oxidation of Secondary C-H Hydroxylation

Mello, R.; Fiorentino, M.; Fusco, C.; Curc, R.; J. Am. Chem. Soc. 1989, 111, 6749.

Over oxidation on secondary C-HIs there any method to avoid the over oxidation?


Secondary sp3 C-H Hydroxylation with Rh Catalyst

Nomura, K.; Uemura, S. J. Chem. Soc., Chem. Commun. 1994, 129.


Secondary sp3 C-H Hydroxylation without Rh Catalyst

Moody, C. J. ; O’Connell, J. L. Chem. Commun. 2000, 1311.

0

0.075

0.15

0.225

0.3

0 3 6 9 12

GC

sig

nal o

f pro

duct

Reaction time/h

cyclohexane oxidation product comparison

With Rh Without Rh


Mechanism of Hydroxylation with Peroxy Acid

Moody, C. J. ; O’Connell, J. L. Chem. Commun. 2000, 1311.


Directing Group in Secondary Hydroxylation

Wong, M.-K.; Chung, N.-W.; He, L.; Yang, D. J. Am. Chem. Soc. 2003, 125, 158.


Mechanism of Carbonyl Directed Intramolecular Hydroxylation



Rationale of Trans Stereoselectivity of2-Methyl Substrate




Rationale of Cis Stereoselectivity of3-Methyl Substrate



Rationale of Ttans Stereoselectivity of4-Methyl Substrate


Bulky Group Strongly Favor One Stereochemistry



Oxygen Substituent at C-3

Inverse the Stereoselectivity


Why the stereoselectivity is inversed?


Rationale of Inverse Stereoselectivity



Secondary C-H Hydroxylation Activated by alkene group

Chen, M. S.;Prabagaran, N.; Labenz, N. A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970


Mechanism of Pd Catalyzed C-H Oxidation




Substrate Scope of Pd Catalyzed Reaction


Secondary Hydroxylation by Bulky Polyoxometalate

Kamata, K.; Yonehara, K.; Nakagawa, Y.; Uehara, K. and Mizuno, N.; Nature chemistry, 2010, 2, 478.


Crystal Structure of the Metal Catalyst

[HPV2W10O40]4-

OVWP



m/z=3583{[nBu4N]4[H2PV2W10O40]}+

m/z=3599{[nBu4N]4[HPV2W10O39(OOH)]}+

Catalytic Cycle of C-H Hydroxylation



Kinetic Study for the Catalytic Cycle

Step 11A+H2O2 1B+H2O


0

0.043

0.085

0.128

0.17

0 0.175 0.35 0.525 0.7

[H2O2]/[H2O]

[1B]/[1A]


Kinetic Study for the Catalytic Cycle

1A+H2O2 1B+H2O 1B 1C+H2O

+ 1A+H2O2 1C+2H2O


0

0.013

0.025

0.038

0.05

0 0.002 0.004 0.005 0.007[H2O2]/[H2O]2

[1C]/[1A]


Kinetic Isotope Effect of the Hydroxylation Reaction



Substrate Scope of the Hydroxylation Reaction

Kamata, K.; Yonehara, K.; Nakagawa, Y.; Uehara, K. and Mizuno, N.; Nature chemistry, 2010, 2, 478.Wednesday, November 10, 2010

Content

• Introduction

• Tertiary sp3 C-H hydroxylation

• Secondary sp3 C-H hydroxylation

• Primary sp3 C-H hydroxylation

• Example of sp3 C-H hydroxylation in total synthesis


Primary sp3 C-H Hydroxylation : Barton Reaction

Barton, D. H. R.; Beato, J. M. J. Am. Chem. Soc. 1960, 82, 2640.Reese, P. B. Steroids 2001, 66, 481.


Stepwise Hydroxylation of Primary C-H

Chen,H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science, 2000, 287, 1995.Wei, C. S.; Jimenez-Hoyos, C. A.; Videa, M. F.; Hartwig,J. F.; Hall, M. B. J. Am. Chem. Soc. 2010, 132, 3078.

0.5 mol%Cp*Rh(η4-C6Me6)

Primary alcohol is obtained


Calculated Energy Diagram for Boration Reaction

Chen,H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science, 2000, 287, 1995.Wei, C. S.; Jimenez-Hoyos, C. A.; Videa, M. F.; Hartwig,J. F.; Hall, M. B. J. Am. Chem. Soc. 2010, 132, 3078.


Content

• Introduction






Previous Strategy of Total Synthesis of 6-Deoxyerythronolide B

Corey, E. J.; Trybulski, E. J.; Melvin, L. S.; Nicolaou, K. C. et al. J. Am. Chem. Soc. 1987, 100, 4620.

6-Deoxyerythronolide B


Total Synthesis of 6-Deoxyerythronolide B with Late-Stage sp3 C-H Oxidation Strategy

Stang, E. M.; White, M. C. Nature Chemistry, 2009, 1, 547.

6-Deoxyerythronolide B intermediate 2Task 1: C-H oxidationTask 2: StereochemistryTask 3: Lactonization


Total Synthesis of 6-Deoxyerythronolide B



Energy Difference between ‘3’ and ‘epi-3’

‘3’ is calculated (MMFF94s force-field) to be 3 kcal/mol

more stable than ‘epi-3’



The Macrolactonization is Proposed to be a Closed Transition State

‘Chelated’, product-like structure

‘Non-chelated’


More stable


Total Synthesis of 6-Deoxyerythronolide B



‘Non-Chelated’ Leads to Poor Stereoselectivity



Proof of Stereochemistry : Crystal Structure of Derivative of the 6-Deoxyerythronolide B



Summary:

1. Tertiary hydroxylation could be selectively achieved with one or more tertiary centers present by the electronic, steric factors.

2. Secondary hydroxylation could be selectively achieved with directing group, protecting group, alkene activation or steric factors.

3. Primary hydroxylation could be selectively achieved with directing group or stepwise method.


Acknowledgement

• Dr. Wulff

• Dr. Jackson

• Dr. Maleczka

• Anil, Dima, Li, Munmun, Nilanjana, Yong, Hong, Wynter, Wenjun

• Jason, Zhe, Greg, Li, Yimeng


Thank you for your attention


Documents

Selective sp C-H HydroxylationSelective sp3 C-H Hydroxylation Xin Zhang Department of Chemistry Michigan State University 11/10/2010 Wednesday, November 10, 2010