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

Transcript of Synthesis and Utility of α-Aminoboranes and α Topic Talk 5-17-12 full.pdf · Some drugs contain...

Page 1: Synthesis and Utility of α-Aminoboranes and α Topic Talk 5-17-12 full.pdf · Some drugs contain α- ... carbonyl, amine, or methoxy group. ... Examples of Utility of Acyltrifluoroboronates

Synthesis and Utility of α-Aminoboranes

and α-Hydroxyboranes

Morken Group Literature Meeting Thomas C. Caya

May 17, 2012

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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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