Synthesis and Utility of α-aminoboranes and α-hydroxyboranes. Morken Group Literature Meeting Thomas C. Caya May 17, 2012

Transcription

1 Synthesis and Utility of α-aminoboranes and α-hydroxyboranes Morken Group Literature Meeting Thomas C. Caya May 17, 2012

2 2 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.

3 3 Boron in Medicine 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 sp 2 and sp 3 configuration under physiological conditions. Matteson, D. S. Tetrahedron 1989, 45, Yang, W.; Gao, X.; Wang, B. Med. Res. Rev. 2003, 23, 346.

4 4 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.

5 5 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.

6 6 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.

7 7 α-amino Cyclic Boronates as Treatments for Hepatitis C Cyclic boronates incorporated into unnatural amino acids have shown potential use as serine protease inhibitors in Hepatitis C treaments. Li, X. et al. Bioorg. Med. Chem. Lett. 2010, 20, Li, X. et al. Bioorg. Med. Chem. Lett. 2010, 20, 5695.

8 8 Synthetic Applications 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. Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597.

9 9 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, Awano, T.; Ohmura, T.; Suginome, M. J. Am. Chem. Soc. 2011, 133, 20738

10 10 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.

11 11 α-amino boronates clearly have an important role in medicine and synthesis. So how does one go about making them?

12 12 The Matteson Homologation Used in the synthesis of peptides, both natural and unnatural. Catalyzed by ZnCl 2 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, 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.

13 13 Example from Li Li, X. et al. Bioorg. Med. Chem. Lett. 2010, 20, 3550.

14 14 Baker s Method: Diboration of Aldimines Several limitations: Only works for diaryl aldimines. Product is a racemic mixture. Cannot selectively deboronate the nitrogen-boron bond. Mann, G.; John, K. D.; Baker, R. T. Org. Lett. 2000, 2, 2105.

15 15 Srebnik: Synthesis from Aminoboranes and Aminocyanoboranes Uses sbuli to deprotonate aminoboranes and aminocyanoboranes, then adds an electrophilic boron compound. Short reaction times and good yields, but not enantioselective. Shibli, A.; Srebnik, M. Eur. J. Inorg. Chem. 2006, 8, 1686.

16 16 Boration of N-tert-Butanesulfinyl Aldimines Reaction is diastereoselective and uses mild conditions. Possible downsides include: Long reaction time. Product is not stable and can break down on silica gel. Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6910.

17 Greener, B. S.; Millan, D.S. Modern Drug Synthesis; Wiley: Hoboken, NJ, 2010; Chapter 8 17 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.

18 18 Ellman s Synthesis of Bortezomib Considerably shorter than the traditional synthesis. Overall yield is 30%. Lower than the traditional synthesis, but fewer steps and the starting materials are affordable. Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 6910.

19 19 Fernández: Boration of Tosylaldimines 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). Solé, C.; Gulyás, H.; Fernández, E. Chem. Commun. 2012, 48, 3769.

20 20 Fernández: Boration of Tosylaldimines Solé, C.; Gulyás, H.; Fernández, E. Chem. Commun. 2012, 48, 3769.

21 21 Other Options: Hydroboration of Enamines Westcott and coworkers report a mixture of products when RhCl (PPh 3 ) 3 is used as the catalyst. Rh(acac)(dppb) results in 97% yield of the branched, α-aminoboron product. Geier, M. J.; Vogels, C. M.; Decken, A.; Westcott, S. A. J. Organomet. Chem. 2009, 694, 3154.

22 22 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.

23 23 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.

24 24 Diboration/Hydroboration of Thiocarbonyls 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, B 2 cat 2, and aqueous workup. Westcott, S. A. et al. Organometallics 2001, 20, 2130.

25 25 α-alkoxyorganostannanes 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. Carmès, L.; Carreaux, F.; Carboni, B.; Mortier, J. Tetrahedron Lett. 1998, 39, 555.

26 26 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.

27 27 Sadighi: Catalytic Diboration of Aldehydes 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. Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128,

28 28 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.

29 29 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.

30 30 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.

31 31 Acyltrifluoroborates Reaction conditions are similar to those for benzoyltrifluoroborates. B(OMe) 3 is used to trap an anion, then treatment with KHF 2 leads to the formation of the acyltrifluoroborate. Can be performed in one pot. Dumas, A. M.; Bode, J. W. Org. Lett. 2012, 14, 2138.

32 32 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.

33 33 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 SiO 2 gave an α- hydroxyboronate. Bode s synthesis of acyltrifluoroboronates. Could be used to form α-hydroxyboronates. Products have similar reactivity to aldehydes and ketones.