synthesis and utility of α-aminoboranes and α topic talk 5-17-12 full.pdf · some drugs contain...
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Synthesis and Utility of α-Aminoboranes
and α-Hydroxyboranes
Morken Group Literature Meeting Thomas C. Caya
May 17, 2012
α-Amino and β-Amino Boronates • Few methods to make these
compounds.
• Great potential in synthesis and pharmaceuticals. ▫ Some drugs contain α-
aminoboron functionality. ▫ Other simple structures are
being studied for treatment for ailments such as certain types of cancer.
• Can be made stereoselectively.
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Boron in Medicine
Matteson, D. S. Tetrahedron 1989, 45, 1859. Yang, W.; Gao, X.; Wang, B. Med. Res. Rev. 2003, 23, 346.
• Carbon-boron bonds can be made easily, allowing boron to be incorporated into pharmaceuticals.
• Boron acts as a good substitute for carbon, in terms of size.
• Boronic acids and esters are usually non-toxic.
• Lewis-acidic nature of boron allows it to convert between sp2 and sp3 configuration under physiological conditions.
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Boron in Medicine
• Most commonly used as a serine protease inhibitor and an enzyme inhibitor.
• Potential use in cancer treatment as a neutron-capture agent (with Boron-10, specifically).
Yang, W.; Gao, X.; Wang, B. Med. Res. Rev. 2003, 23, 346.
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Bortezomib: For Treatment of Multiple Myeloma
• Multiple myeloma is a plasma cell cancer. Cancerous cells start to build up in bone marrow, interfering with normal blood cell production. ▫ Survival rate is 3-7 years, and relapse is common.
• Developed by Millennium Pharmaceuticals, it serves as a treatment option for patients with a relapse in multiple myeloma.
Raab, M. S.; Podar, K.; Breitkreutz, I.; Richardson, P. G.; Anderson, K. C. Lancet 2009, 374, 324. Richardson, P. G.; Mitsiades, C.; Hideshima, T.; Anderson, K. C. Annu. Rev. Med. 2006, 57, 33.
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Bortezomib: Mechanism of Action
• Bortezomib is a serine protease inhibitor that reversibly binds to the 26S proteasome, a large complex that allows the cell to break down proteins.
• Cancer cells are unable to break down proteins needed for cell functions and proliferation. Ultimately leads to cell death.
Richardson, P. G.; Mitsiades, C.; Hideshima, T.; Anderson, K. C. Annu. Rev. Med. 2006, 57, 33.
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α-Amino Cyclic Boronates as Treatments for Hepatitis C
Li, X. et al. Bioorg. Med. Chem. Lett. 2010, 20, 3550. Li, X. et al. Bioorg. Med. Chem. Lett. 2010, 20, 5695.
• Cyclic boronates incorporated into unnatural amino acids have shown potential use as serine protease inhibitors in Hepatitis C treaments.
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Synthetic Applications
Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597.
• α-aminoboranes can also be used in synthetic applications. • Prime example is a Suzuki-Miyaura cross-coupling reaction, first
published by Molander. ▫ Tertiary amines are always used for the coupling reaction. ▫ A variety of substituents are tolerated, where R’ can be a methyl,
cyano, nitro, carbonyl, amine, or methoxy group. ▫ Aromatic group could also contain a heteroatom.
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Synthetic Applications
• A few years after Mollander, Suginome reported a Suzuki-Miyaura cross-coupling using α-(acylamino)benzylboronic esters.
• Reaction used enantioenriched starting material, which gave product with the opposite configuration.
• In 2011, Suginome found that adding 0.5 equivalents of Zr(OiPr)4·iPrOH resulted in retention of configuration.
Ohmura, T.; Awano, T.; Suginome, M. J. Am. Chem. Soc. 2010, 132, 13191. Awano, T.; Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2011, 133, 20738
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Synthetic Applications
• α-Aminoboronates could also be used to prepare synthetically useful 1,2-amino alcohols.
• Fernández was able to convert a relatively simple α-aminoboronate to the 1,2-amino alcohol without affecting the initial stereochemistry.
Ager, D. J.; Prakash, I.; Schaad, D.R. Chem. Rev. 1996, 96, 835. Solé, C.; Gulyás, H.; Fernández, E. Chem. Commun. 2012, 48, 3769.
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α-amino boronates clearly have an important role in medicine and synthesis.
So how does one go about making them?
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The Matteson Homologation
• Used in the synthesis of peptides, both natural and unnatural. • Catalyzed by ZnCl2 • Takes advantage of pinanediol in order to direct stereochemistry. • Disadvantages include: ▫ Multiple steps necessary. ▫ Conditions are not always practical (may require very low temperatures).
Matteson, D. S.; Beedle, E. C. Tetrahedron Letters 1987, 28, 4499. Matteson, D.S.; Sadhu, K. M.; Peterson, M. L. J. Am. Chem. Soc. 1986, 108, 810.
Thomas, S. P.; French, R. M.; Jheengut, V.; Aggarwal, V. K. The Chemical Record 2009, 9, 24.
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Example from Li
Li, X. et al. Bioorg. Med. Chem. Lett. 2010, 20, 3550.
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Baker’s Method: Diboration of Aldimines
Mann, G.; John, K. D.; Baker, R. T. Org. Lett. 2000, 2, 2105.
• Several limitations: ▫ Only works for diaryl aldimines. ▫ Product is a racemic mixture. ▫ Cannot selectively deboronate the nitrogen-boron bond.
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Srebnik: Synthesis from Aminoboranes and Aminocyanoboranes
Shibli, A.; Srebnik, M. Eur. J. Inorg. Chem. 2006, 8, 1686.
• Uses sBuLi to deprotonate aminoboranes and aminocyanoboranes, then adds an electrophilic boron compound.
• Short reaction times and good yields, but not enantioselective.
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Boration of N-tert-Butanesulfinyl Aldimines
Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6910.
• Reaction is diastereoselective and uses mild conditions. • Possible downsides include: ▫ Long reaction time. ▫ Product is not stable and can break down on silica gel.
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Traditional Synthesis of Bortezomib
• About 35% yield over eight steps. • Relies on Matteson’s chemistry. • Reaction conditions (such as temperatures required) are not always
practical. Greener, B. S.; Millan, D.S. Modern Drug Synthesis; Wiley: Hoboken, NJ, 2010; Chapter 8
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Ellman’s Synthesis of Bortezomib
Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6910.
• Considerably shorter than the traditional synthesis. • Overall yield is 30%. ▫ Lower than the traditional synthesis, but fewer steps and the starting
materials are affordable.
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Fernández: Boration of Tosylaldimines
Solé, C.; Gulyás, H.; Fernández, E. Chem. Commun. 2012, 48, 3769.
• Chiral phosphines:
• Tested a wide variety of phosphines and general conditions. • In initial experiments, products with high e.e. had low conversion,
and vice-versa (R=Ph).
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Fernández: Boration of Tosylaldimines
Solé, C.; Gulyás, H.; Fernández, E. Chem. Commun. 2012, 48, 3769.
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Other Options: Hydroboration of Enamines
Geier, M. J.; Vogels, C. M.; Decken, A.; Westcott, S. A. J. Organomet. Chem. 2009, 694, 3154.
• Westcott and coworkers report a mixture of products when RhCl(PPh3)3 is used as the catalyst.
• Rh(acac)(dppb) results in 97% yield of the branched, α-aminoboron product.
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Summary of α-Aminoboranes
• Useful in a variety of pharmaceutical settings. • Matteson homolygation/alkylation. ▫ Common way to make these compounds.
• Methods by Baker, Srebnik, Ellman, and Fernández. ▫ Catalytic. ▫ Some are stereoselective.
• Hydroboration of enamines by Westcott. ▫ α-aminoboron product obtained with proper catalyst. ▫ Racemic product.
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α-Hydroxyboranes
• The usefulness of α-aminoboranes in medicine and synthesis has fueled an interest in how to make other α-heteroboranes.
• Like α-aminoboranes, such compounds could be potentially useful in pharmaceutical compounds or in synthesis of new compounds.
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Diboration/Hydroboration of Thiocarbonyls
Westcott, S. A. et al. Organometallics 2001, 20, 2130.
• First reported by Westcott in 2001, this work spurred an interest in boration of carbonyls.
• A few routes are available to α-thioboronates, which could be used in biologically active molecules. ▫ One method requires a rhodium catalyst, B2cat2, and aqueous workup.
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α-Alkoxyorganostannanes
Carmès, L.; Carreaux, F.; Carboni, B.; Mortier, J. Tetrahedron Lett. 1998, 39, 555.
• Prior to Westcott’s work with thiocarbonyls, one method to prepare α-alkoxy boranes was by using tin-based reagents.
• Transmetallation with lithium, followed by borylation, results in the formation of a stable product.
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The Need for Improvements
• Multiple steps involved. • Yields for this reaction tend to be low, with reported yields as low as
30%. • Stereochemistry is retained in only two cyclic substrates:
• Toxicity of tin makes it unlikely this process could be used in an industrial process.
Carmès, L.; Carreaux, F.; Carboni, B.; Mortier, J. Tetrahedron Lett. 1998, 39, 555.
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Sadighi: Catalytic Diboration of Aldehydes
Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128, 11036.
• Using a copper catalyst, a (ICy)CuBpin complex is generated in situ. • Good yields obtained on a variety of substrates. • However, the process is not stereoselective. • In some cases, purification on silica gel cleaved O-B bond.
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Diboration of Ketones
• Very similar to Sadighi’s diboration of ketones. ▫ Utilizes a similar catalyst
system generated in situ from (ICy)CuCl and NaOt-Bu. ▫ Purification on silica gel
severed the O-B bond, providing the α-hydroxy boronate.
McIntosh, M. L.; Moore, C. M.; Clark, T. B. Org. Lett. 2010, 12, 1996.
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Diastereoselectivity
• Chiral ketones gave α-hydroxy boronates in high diastereomeric ratios.
• Bulkiness of the Bpin group probably forces the boronate group away from large substituents.
McIntosh, M. L.; Moore, C. M.; Clark, T. B. Org. Lett. 2010, 12, 1996.
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Acyltrifluoroborates
• Acyltrifluoroborates are extremely difficult to synthesize. • Bode recently reported a method where benzoyltrifluoroborates
could be made from N,O-acetals in one pot. • Carried further to see if acyltrifluoroborates could be similarly
prepared.
Dumas, A. M.; Bode, J. W. Org. Lett. 2012, 14, 2138.
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Acyltrifluoroborates
• Reaction conditions are similar to those for benzoyltrifluoroborates. • B(OMe)3 is used to trap an anion, then treatment with KHF2 leads to
the formation of the acyltrifluoroborate. • Can be performed in one pot.
Dumas, A. M.; Bode, J. W. Org. Lett. 2012, 14, 2138.
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Examples of Utility of Acyltrifluoroboronates
• Bode discovered that acyltrifluoroboronates have similar reactivity to carbonyls and that the boronate group is stable to some chemical transformations.
Dumas, A. M.; Bode, J. W. Org. Lett. 2012, 14, 2138.
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Summary of α-Heteroboronates and Related Compounds
• Westcott’s diboration of thiocarbonyls. ▫ Showed that diboration could occur over carbon-heteroatom
bonds (where heteroatom is not nitrogen). • Diboration of aldehydes and ketones. ▫ Using a copper catalyst, Sadighi and Clark proved that diboration
could take place across carbon-oxygen double bonds. ▫ Clark also discovered that purification on SiO2 gave an α-
hydroxyboronate. • Bode’s synthesis of acyltrifluoroboronates. ▫ Could be used to form α-hydroxyboronates. ▫ Products have similar reactivity to aldehydes and ketones.
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