Deoxygenation of Aliphatic Alcoholsalexanian.chem.unc.edu/img/Seminars/CaitlinDeoxygenation.pdf ·...
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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.