Synthesis of Solid-phase Supported Chiral Amines and Investigation of Stereoselectivity of Aldol Reactions of Amine-free Tropinone Enolate

Author(s): Aneta Nodzewska*, Agnieszka Wadolowska, Katarzyna Podgorska, Damian Pawelski, Ryszard Lazny

Journal Name: Current Organic Chemistry

Volume 23 , Issue 17 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Seven selected chiral mono-, di-, and tridentate amines supported on insoluble polymer were effectively prepared from corresponding primary amines or secondary amino alcohols and Merrifield resin. The reaction of the polymer-supported amines with excess n-butyllithium gave the corresponding lithium amide bases, which were tested in the aldol reactions of tropinone with benzaldehyde. The deprotonation reactions were carried out with or without separation of the lithium enolate from polymer-supported reagents. Using the procedure with separation of lithium enolate from supported chiral reagent different results were obtained with or without the addition of LiCl despite the fact that aggregate formation of Merrifield resin supported Li-amides is hindered. Without the additive, the aldol products were obtained in low diastereoselectivity and enantioselectivity, whereas the addition of LiCl resulted in a significant increase of de and ee even when LiCl was added after the deprotonation step and separation of the chiral amine.

Keywords: Amine immobilization, chiral lithium amide, enolate separation, deprotonation, aldol reaction, stereoselective synthesis, benzaldehyde.

a) Simpkins, N.S.; Weller, M.D. Asymmetric transformations by deprotonation using chiral lithium amides. Org. React., 2013, 79(2004), 317-636.
b) O’Brien, P. Recent advances in asymmetric synthesis using chiral lithium amide bases. J. Chem. Soc., Perkin Trans., 1998, 1, 1439-1458.
c) Pettersen, D.; Amedjkouh, M.; Ahlberg, P. Chiral lithium amides in asymmetric synthesis. Chem. Organolithium Compounds, 2006, 2, 411-477.
d) Eames, J. Recent developments in enantioselective deprotonation mediated by sub-stoichiometric quantities of chiral bases. Eur. J. Org. Chem., 2002, 2002, 393-401.
e) Harrison-Marchand, A.; Maddaluno, J. Advances in the chemistry of chiral lithium amides. Lithium Compounds Org. Synthesis, 2014, 297-328.
a) Valnot, J-Y.; Maddaluno, J. Aspects of the synthesis, structure and reactivity of lithium enolates. Chem. Organolithium Comp., 2006, 2, 526-647.
b) Majewski, M. Enantioselective deprotonation of cyclic ketones. Advances in Asymmetric Synthesis., 1998, vol. 3, 39-76.
a) Sienkiewicz, M.; Wilkaniec, U.; Lazny, R. Enantioselective route to ferrugine and its methyl analogue via aldol deoxygenation. Tetrahedron Lett., 2009, 50, 7196-7198.
b) Majewski, M.; Zheng, G-Z. Enantioselective deprotonation of tropinone and reactions of tropinone lithium enolate. Synlett, 1991, 173-175.
c) Majewski, M.; Lazny, R. Stereoselective synthesis of tropane alkaloids: Physoperuvine and dihydroxytropanes. Synlett, 1996, 785-786.
d) Simpkins, N.S.; Weller, M.D. Asymmetric deprotonations using chiral lithium amide bases. Stereochemical Aspects Organolithium Compounds, 2010, 26, 1-52.
e) Lazny, R.; Wolosewicz, K.; Zielinska, P.; Urbanczyk-Lipkowska, Z.; Kalicki, P. Diastereo- and enantioselective aldol reaction of granatanone (pseudopelletierine). Tetrahedron, 2011, 67, 9433-9439.
Hilmersson, G.; Granander, J. Structure and dynamics of chiral lithium amides. Chem.Organolithium Comp., 2006, 2, 382-410.
Sugasawa, K.; Shindo, M.; Noguchi, H.; Koga, K. Solution structures of a monodentate chiral lithium amide in the presence of lithium halide. Tetrahedron Lett., 1996, 37, 7377-7380.
a) Seebach, D. Structure and reactivity of lithium enolates. From pinacolone to selective C-alkylations of peptides. Difficulties and opportunities afforded by complex structures. Angew. Chem. Int. Ed. Engl., 1988, 27, 1624-1654.
b) Juaristi, E.; Beck, A.K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.; Simson, M.; Seebach, D. Enantioselective aldol and michael additions of achiral enolates in the presence of chiral lithium amides and amines. Synthesis, 1993, 1271-1290.
c) Seebach, D.B.A.K.; Studer, A. Some effects of lithium salts, of strong bases, and of the cosolvent DMPU in peptide chemistry, and elsewhere. Modern Synthetic Methods, 1995, 1995, 1-178.
d) Braun, M. Modern Enolate Chemistry: From Preparation to Applications in Asymmetric Synthesis; John Wiley & Sons, 2016.
e) Braun, M. Lithium enolates: ‘Capricious’ structures - Reliable reagents for synthesis. Helv. Chim. Acta, 2015, 98, 1-31.
Li, D.; Sun, C.; Williard, P.G. Characterization of a chiral enolate aggregate and observation of 6Li-1H scalar coupling. J. Am. Chem. Soc., 2008, 130(35), 11726-11736.
[] [PMID: 18693723]
Majewski, M.; Lazny, R.; Nowak, P. Effect of lithium salts on enantioselective deprotonation of cyclic ketones. Tetrahedron Lett., 1995, 36, 5465-5468.
a) Majewski, M.; Lazny, R. Synthesis of tropane alkaloids via enantioselective deprotonation of tropinone. J. Org. Chem., 1995, 60, 5825-5830.
b) Bunn, B.J.; Simpkins, N.S. An enhancement of enantioselectivity in chiral lithium amide deprotonations due to lithium chloride. J. Org. Chem., 1993, 58, 533-534.
a) Koga, K. Asymmetric synthesis mediated by chiral ligands. Pure Appl. Chem., 1994, 66, 1487-1492.
b) Lazny, R.; Sienkiewicz, M.; Olenski, T.; Urbanczyk-Lipkowska, Z.; Kalicki, P. Approaches to the enantioselective synthesis of ferrugine and its analogues. Tetrahedron, 2012, 68, 8236-8244.
a) Asami, M. Asymmetric transformation of meso-epoxides by chiral lithium amides. J. Synth. Org. Chem. Jpn., 1996, 54, 188-199.
b) Asami, M. An asymmetric transformation of cyclohexene oxide to (S)-2-cyclohexen-1-ol by chiral lithium amides. Chem. Lett., 1984, 13, 829-832.
a) Majewski, M.; Ulaczyk-Lesanko, A.; Wang, F. Chiral lithium amides on polymer support - Synthesis and use in deprotonation of ketones. Can. J. Chem., 2006, 84, 257-268.
b) Majewski, M.; Ulaczyk, A.; Wang, F. Chiral lithium amides on solid support: synthesis and applications in enantioselective deprotonation of cyclic ketones. Tetrahedron Lett., 1999, 40, 8755-8758.
Lazny, R.; Michalak, M. Application of piperazine-derived hydrazone linkers for alkylation of solid-phase immobilized ketones. Synlett, 2002, 1931-1934.
Ma, L.; Williard, P.G. Synthesis of polymer-supported chiral lithium amide bases and application in asymmetric deprotonation of prochiral cyclic ketones. Tetrahedron Asymmetry, 2006, 17(21), 3021-3029.
[] [PMID: 18026563]
Bodanszky, M.; Badanszky, A. The Practice of Peptide Synthesis, (2nd Ed); , 1994.
Myers, A.G.; Yang, B.H.; David, K.J. Lithium amidotrihydroborate, a powerful new reductant. Transformation of tertiary amides to primary alcohols. Tetrahedron Lett., 1996, 37, 3623-3626.
Shirai, R.; Aoki, K.; Sato, D. Kim.H.-D.; Murakata, M.; T., Y.; Koga, K. Stereoselective reactions. XXII. Design and synthesis of chiral chelated lithium amides for enantioselective reactions. Chem. Pharm. Bull. (Tokyo), 1994, 42, 690-693.
McKennon, M.J.; Meyers, A.I.; Drauz, K.; Schwarm, M. A convenient reduction of amino acids and their derivatives. J. Org. Chem., 1993, 58, 3568-3571.
Lazny, R.; Sienkiewicz, M.; Bräse, S. Application of triazenes for protection of secondary amines. Tetrahedron, 2001, 57, 5825-5832.
Lazny, R.; Ratkiewicz, A.; Brzezinski, K.; Nodzewska, A.; Sidorowicz, K. An investigation of the enolization and isomeric products distribution in the water promoted aldol reaction of tropinone and granatanone. J. Chem, 2016, 1-15. Article ID 4674901
Lazny, R.; Wolosewicz, K. An expedient preparation of amine-free lithium enolates using immobilized amide reagents. Tetrahedron Lett., 2013, 54, 1103-1106.
a) Majewski, M.; Lazny, R. Synthesis of pyranotropanes via enantioselective deprotonation strategy. Tetrahedron Lett., 1994, 35, 3653-3656.
b) Bunn, B.J.; Simpkins, N.S.; Spavold, Z.; Crimmin, M.J. The effect of added salts on enantioselective transformations of cyclic ketones by chiral lithium amide bases. J. Chem. Soc., Perkin Trans. 1, 1993, 3113-3116.
Toriyama, M.; Sugasawa, K.; Shindo, M.; Tokutake, N.; Koga, K. Stereochemistry of enantioselective deprotonation of 4-substituted cyclohexanones by chiral bidentate lithium amides. Tetrahedron Lett., 1997, 38, 567-570.
Lazny, R.; Ratkiewicz, A.; Nodzewska, A.; Wysocka, J. A DFT study of the origins of the stereoselectivity in the aldol reaction of bicyclic amino ketones in the presence of water. Tetrahedron Lett., 2012, 53, 5871-5874.
Lazny, R.; Nodzewska, A.; Wolosewicz, K. New simple polymeric supports with hydrazone linkers for solid-phase synthesis of ketones and primary amines. Synthesis, 2003, 2858-2864.
Pajouhesh, H.; Pajouhesh, H.; Ding, Y.; Snutch, T.P. Urea derivatives as calcium channel blockers, NeuroMed Technologies Inc. Patent, US2006/0063775 A1. 2006.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [1867 - 1879]
Pages: 13
DOI: 10.2174/1385272823666190916145332
Price: $58

Article Metrics

PDF: 18
PRC: 1