Deoxygenation of

Aliphatic Alcohols Caitlin McMahon

Alexanian Group Meeting

June 12, 2014

Importance of Deoxygenation

• Ubiquitous in total synthesis & modification of natural products

• Deoxygenation in synthesis of potent insecticide (functional group tolerant)

• Deoxygenation/elimination in Mukaiyama’s Taxol synthesis

Frank, S. A.; Roush, W. R. J. Org. Chem. 2002, 67, 4316–4324.

Mukaiyama, T., et al; Chem. – Eur. J. 1999, 5, 121–161.

Importance of Deoxygenation

• Carbohydrate & aminoglycoside chemistry

• Enzymes deactivate hydroxy-group of antibiotics

• Deoxygenation of nucleosides

• Deoxygenations of carbohydrates often used to obtain

intermediates from the “chiral pool”

Arya, D. P. Aminoglycoside Antibiotics: From Chemical Biology to Drug Discovery; 2007

Saito, I., et al J. Am. Chem. Soc. 1986, 108, 3115–3117.

Outline

• Overview of historical methods of deoxygenation

• Barton-McCombie Deoxygenation & Variations

• Photochemical Deoxygenation

• Direct Deoxygenation

• Areas for exploration

Methods of Deoxygenation

• Challenge: Strong C-O bond (85-91 kcal/mol)

Herrmann, J. M.; König, B. Eur. J. Org. Chem. 2013, 2013, 7017–7027.

Historical Methods & Limitations

• Conversion to alcohol derivatives reduction

• Conversion to halide or thiolate reduction

• Dehydration hydrogenation

• Substitution reactions limited to 1° alcohols

(or unhindered 2°)

• Rearrangements and undesired eliminations common

Hartwig, W. Tetrahedron 1983, 39, 2609–2645.

Benchmark Discovery

• Barton-McCombie Deoxygenation (1975)

• Widely utilized

• Radical mechanism avoids elimination and

rearrangement pathways

Derek H.R. Barton

1918-1998

Imperial College

Nobel Laureate (1969)

Stuart W. McCombie

Imperial College

(Post-doc) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc. [Perkin 1] 1975, 1574–1585.

Limitations & Drawbacks

Problems

• Organotin hydrides are toxic

• Organotin hydrides are expensive

• Tin byproducts are difficult to separate from products

• Issues with stability with 3° xanthates

Solution

Make it catalytic in tin

Solution

Use different H-source

McCombie, S. W.; Motherwell, W. B.; Tozer, M. J. In Organic Reactions; John Wiley & Sons, Inc., 2004.

Improving the Barton Deoxygenation

• Alternative H-donors

• Silanes

• Phosphines

• Hypophosphorous acid

Barton, D. H. R.; et al Tetrahedron Lett. 1990, 31, 4681-4684.

Barton, D. H. R.; Jacob, M. Tetrahedron Lett. 1998, 39, 1331–1334.

Izawa, K. et al Tetrahedron Lett. 2001, 42, 7605–7608.

Improving the Barton Deoxygenation

• Alternative H-donors

• Diphenylphosphine oxide

• Borane/H2O

Jang, D.; HyanCho, D.; Kim, J. Synth. Commun. 1998, 28, 3559–3565.

Wood, J. L. et al J. Am. Chem. Soc. 2005, 127, 12513–12515.

Catalytic Barton Deoxygenation

• First report - Fu (1997)

• Proposed catalytic cycle:

• Examples of polymer-supported catalytic tin hydrides

used to further aid in separation

Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949–6950.

Dumartin, G.; Pereyre, M.; et al Tetrahedron Lett. 2000, 41, 3377–3380.

Alcohol Derivatives – Beyond Xanthates

• Trifluoroacetates:

• Toluates:

Jang, D. O.; Cho, D. H. Tetrahedron Lett. 2002, 43, 5921–5924.

Kim, J.-G.; Cho, D. H.; Jang, D. O. Tetrahedron Lett. 2004, 45, 3031–3033.

Lam, K.; Markó, I. E. Org. Lett. 2008, 10, 2773–2776.

Alcohol Derivatives – Beyond Xanthates

• Phosphites:

• Site-selective peptide-catalyzed phosphitylation

Jordan, P. A.; Miller, S. J. Angew. Chem. Int. Ed. 2012, 51, 2907–2911.

Electrochemical Deoxygenation

• Reduction of phosphinate derivatives

• Probable mechanism:

Lam, K.; Marko, I. E. Org. Lett. 2011, 13, 406–409.

Photo-catalyzed Deoxygenation

• Early example:

• Proposed mechanism

Saito, I.; et al J. Am. Chem. Soc. 1986, 108, 3115–3117.

Photo-catalyzed Deoxygenation

• Batch to flow deoxygenation via iodide intermediate

• Deoxygenation & functionalization of N-phthalimidoyl oxalates

Stephenson, C. R. J.; et al Chem. Commun. 2013, 49, 4352–4354.

Overman, L. E.; et al J. Am. Chem. Soc. 2013, 135, 15342-15345.

Direct Reductions of Alcohols

• Lewis acid-catalyzed direct deoxygenation

• Chemoselective deoxygenation of a primary alcohol in the

presence of a secondary alcohol:

Gevorgyan, V.; Rubin, M.; Benson, S.; Liu, J.-X.; Yamamoto, Y. J. Org. Chem. 2000, 65, 6179–6186.

Denancé, M.; Guyot, M.; Samadi, M. Steroids 2006, 71, 599–602.

Direct Reductions of Alcohols

• InCl3-catalyzed direct dehydroxylation

• Chemoselectivity:

• Iridium-catalyzed direct dehydroxylation

(via oxidation/Wolff-Kishner sequence) Baba, A.; et al J. Org. Chem. 2001, 66, 7741–7744.

Huang, J.-L.; Dai, X.-J.; Li, C.-J. Eur. J. Org. Chem. 2013, 2013, 6496–6500.

Direct Reductions of Alcohols

• Titanium(III)-mediated direct deoxygenation

• Proposed mechanism:

Barrero, A. F. et al J. Am. Chem. Soc. 2010, 132, 254–259.

Conclusions

• Deoxygenation is important in chemical synthesis, especially useful in carbohydrate chemistry.

• The Barton-McCombie deoxygenation was a benchmark discovery and countless variations and improvements have been reported, making it extremely useful in synthesis.

• Various other photoredox and metal-catalyzed methods for deoxygenation have emerged as useful instruments in the chemical toolbox.

• The C-O bond remains an interesting target for activation and functionalization.