Diastereo- and Enantioselective Synthesis of α,β-Disubstituted γ-Bisalkoxycarbonyl Sulfonates

Abstract

The asymmetric synthesis of a,b-disubstituted g-bisalkoxycarbonyl sulfonates is reported. The synthesis is based on the Michael addition of a lithiated enantiopure sulfonate bearing a cheap chiral sugar auxiliary to Knoevenagel acceptors. The reaction proceeds with high asymmetric inductions (ds = 69-96%) and good yields (62-79%). The absolute configuration was determined by Xray crystal-structure analysis.Sulfonic acid derivatives constitute an important class of organic compounds, which exist in a large number of natural products. They are also present in synthetic compounds with important biological or pharmacological activities, such as antiulcer, antibacterial, antipseudomonal, and squalene synthase inhibition activities. 1 On the other hand, sulfonates are of interest as bioactive isosteres of carboxylates, phosphates, and sulfates such as phospholipids, sulfated steroid conjugates, and oligonucleotides. 2 However, only a few asymmetric syntheses of this important class of compounds are described in the literature. 3 In continuation of our research on the asymmetric synthesis of sulfonic acid derivatives, 4 we now wish to report a convenient diastereo-and enantioselective approach for the synthesis of a,b-disubstituted g-bisalkoxycarbonyl sulfonates.The asymmetric synthesis of the title compounds is based on a stoichiometric approach employing 1,2:5,6-di-O-isopropylidene-a-D-allofuranose as a cheap chiral sugar auxiliary. As shown in Scheme 1, the enantiopure sulfonate 1 was deprotonated with n-butyllithium in THF and allowed to react with the Knoevenagel acceptor 2a to give the Michael adduct 3a in good yield (79%) and high diastereoselectivity (77%).We explored the generality of this reaction with a wide range of Michael acceptors bearing different substituents. The desired products 3a-j were obtained with one exception in good yields (10, 62-79%) and high diastereoselectivities (ds = 69-96%). The results are summarized in Table 1.The variation of the substituents of the Michael acceptors indicated a strong influence on the diastereoselectivity of the reaction. Michael acceptors containing heterocycles (2e,f) afforded the Michael products in good yields (62% and 69%, respectively) and excellent diastereoselectivities (82% and 96%, respectively). The more sterically hindered alkene 2g reacted with sulfonate 1 in high diastereoselectivity (87%), whereas the aliphatic Michael acceptor 2h gave only a moderate diastereoselectivity (69%). The effect of the electron-withdrawing groups of the Michael acceptor was also investigated. The replacement of an ester group with a cyanide function did not lead to any significant changes in yield and diastereoselectivity (entry 9). A significant difference was observed, however, when two tert-butyl ester groups instead of the two methyl ester were used (entry 10). This result may be explained by the steric hindrance caused by the two tert-butyl groups.In all of these cases, only three out of four possible diastereomers could be detected. The major diastereomers could be i...

Synthesis and styrene copolymerization of novel ring-substituted isobutyl phenylcyanoacrylates

“…2-Methylphenyl ring-substituted phenylcyanoacrylate was reported in cyclopropanation of electron-deficient alkenes with 2-bromo-1,3-propanedione compounds [1]; in synthesis of ethyl 3-amino-1-aryl-1H-benzo[f]chromene-2-carboxylates in aqueous media [2]; in conjugate hydrocyanation of α-cyanoacrylates using potassium hexacyanoferrate(II) [3]; synthesis of novel 3,4-dihydrophthalazin-2(1H)-yl-4-phenyl-4H-pyrans [4]; in diastereoand enantioselective synthesis of α,β-disubstituted γ-bisalkoxycarbonyl sulfonates [5]; in synthesis and study of binding affinities of methylvesamicol analogs for the acetylcholine transporter and sigma receptor [6]. 4-Phenoxy ring-substituted phenylcyanoacrylate was involved in DBU-mediated [4 + 2] annulations of cyclopropanes with 3-aryl-2cyanoacrylates for the synthesis of fully substituted anilines [7], and in studies on quinolin-2(1H)-one derivatives related to synthetic access to pyrano [3,2-c] quinoline and 3substituted quinoline derivatives [8].…”

Copper-Mediated Fluoroalkylation of Aryl Iodides Enables Facile Access to Diverse Fluorinated Compounds: The Important Role of the (2-Pyridyl)sulfonyl Group

“…Simple treatment of the product with t -BuOK in DMF furnished the desired monofluoroalkene with an eight-member ring in 80% yield (Scheme , b) . Moreover, the fluorinated sulfinates are important precursors for fluorinated sulfonic acids and fluorinated sulfones, which found wide application in modern functional materials and biologically active compounds . Monofluorinated sulfinate could be easily generated by a t -BuSNa-mediated depyridination and could be trapped in situ with CH 3 I to furnish the corresponding methyl sulfone ( 10 ) in 85% yield (Scheme , c)…”

From Difluoromethyl 2‐Pyridyl Sulfone to Difluorinated Sulfonates: A Protocol for Nucleophilic Difluoro(sulfonato)methylation

“…[1] The sulfonic acid functional group has not only found its use in modern materials such as proton-exchange membranes and surfactants, [2] but also in synthetic molecules with important biological and pharmacological activities such as antiulcer, antibacterial, antipseudomonal, and squalene synthase inhibition activities. [3] Based on this scenario, a,a-difluorinated sulfonate derivatives, as an important subclass of lightly fluorinated compounds, are of great interest in life and materials sciences. Furthermore, owing to the isopolar and isosteric characters of the difluoromethylene group to an oxygen atom, difluorinated sulfonates can be exploited to replace the labile sulfate esters.…”

“…Surprisingly, by applying the reported optimal reaction conditions for the nucleophilic substitution of difluoromethyl phenyl sulfone with alkyl iodides, [12] only difluoromethyl 2-pyridyl sulfone 1 b gave a detectable amount of substituted product ( Table 1, entries [1][2][3][4]. In all cases, the decomposition of the difluoromethyl sulfones was observed as the predominant outcome.…”