Synthesis, NMR studies and conformational analysis of oxazolidine derivatives of the β-adrenoreceptor antagonists metoprolol, atenolol and timolol

Enantioselective Formal [3+2] Cycloaddition of Epoxides with Imines under Brønsted Base Catalysis: Synthesis of 1,3‐Oxazolidines with Quaternary Stereogenic Center

“…Finally,( M)-1d·HCl, which had 1-naphthyl groups on the spirocyclic rings and tBu groups on the nitrogen atom of the guanidine moieties,was found to be the best precatalyst to provide 4aa in 88 %y ield, upon isolation, with 93 % ee (entry 12). [18] Next, the scope with respect to the N-Boc imines was examined by using 2a as as ubstrate (entries [9][10][11][12][13][14]. Thea bsolute configuration of 4aa was unambiguously determined to be (2R,4R)bysingle-crystal X-ray diffraction analysis of racemic 4aa and the enantioenriched amino alcohol 7, derived from enantioenriched 4aa.…”

“…Thed riving force for this step would be the release of ring strain. [10] Therefore,t he intended reaction would provide new and efficient access to enantioenriched 1,3-oxazolidines that are difficult to synthesize by other methods. This intermediate would then formally serve as the synthetic equivalent of a1 ,3-dipole,a nd the cycloaddition with the imine 3 would proceed in astepwise fashion, that is,a ddition of B to 3 followed by intramolecular aza-Michael addition of the intermediate C to afford the 1,3oxazolidine 4.The main challenge of the intended reaction is the stereocontrol of the two stereogenic centers.T othis end, we expected that as uitable choice of in the chiral Brønsted base would enable the enantioselective addition of B to 3 although such precedents are rather limited.…”

“…[15] Thei nitial experiment was conducted with the catalyst generated in situ by treating 11 mol %(M)-1a·HBr with 10 mol %KN(SiMe 3 ) 2 prior to use.H owever, 4aa was not formed, and instead 5aa was obtained quantitatively with 82 % ee for the major Z isomer (entry 5). To increase the enantioselectivity,o ther precatalysts [(M)-1·HX] having different substituents were examined (entries [10][11][12]. We assumed that the failure of the aza-Michael addition was attributed to the detrimental effect of alkali metal cations,such as the potassium cation and sodium cation, which would reduce the requisite nucleophilicity of the anion of 5aa.B ased on this hypothesis,w en ext attempted the reaction by using KN(SiMe 3 ) 2 with 30 mol %18-crown-6 as an additive.A saresult, the formal [3+ +2] cycloaddition proceeded to afford 4aa in good yield as as ingle diastereomer with 75 % ee (entry 8), which is as imilar level of enantioselectivity to that of 5aawithout 18-crown-6 (entries 5versus 8).…”

The Determination of the Stoichiometry of Cyclodextrin Inclusion Complexes by Spectral Methods: Possibilities and Limitations

“…8), a beta-blocker drug used in the treatment of cardiovascular diseases (Bontchev et al, 2000;Castro et al, 1998;Esteves de Castro et al, 2007;Moloney et al, 1998;Pandeeswaran & Elango, 1009;Pulgarin et al, 1998;Ranta et al, 2002), is a very flexible molecule, consisting of fragments with different features: an amido-substituted aromatic ring, a flexible three-carbon chain (Siqintuya et al, 2007) and a dimethyl-substituted amino group.…”

Ring Expansion of Epoxides under Brønsted Base Catalysis: Formal [3+2] Cycloaddition of β,γ‐Epoxy Esters with Imines Providing 2,4,5‐Trisubstituted 1,3‐Oxazolidines

“…This intermediate would then formally serve as the synthetic equivalent of the 1,3-dipole,a nd the cycloaddition reaction with unsaturated compounds (X = Y) would proceed in as tepwise fashion, that is,t he addition of the alkoxide moiety to the unsaturated compounds followed by cyclization of the resulting anion to the electron-deficient alkene moiety, to provide five-membered ring compound E. [5,6] In our investigation, imines were chosen as ap otential partner of the formal 1,3-dipole in light of the synthetic value of the adduct, 2,4,5-trisubstituted 1,3-oxazolidines.1,3-Oxazolidines can be utilized as versatile intermediates in organic synthesis, as chiral auxiliaries in asymmetric synthesis, [7] and as ligands in transition metal catalysis. [9] Whereas several catalytic [3+ +2] cycloaddition reactions of epoxides with imines have been developed, [10] the synthesis of 2,4,5trisubstituted 1,3-oxazolidines is rather limited because of the difficulty of using 2,3-disubstituted epoxides in most cases. [9] Whereas several catalytic [3+ +2] cycloaddition reactions of epoxides with imines have been developed, [10] the synthesis of 2,4,5trisubstituted 1,3-oxazolidines is rather limited because of the difficulty of using 2,3-disubstituted epoxides in most cases.…”