Tetramisole promotes the catalytic asymmetric intramolecular Michael addition-lactonization of a variety of enone acids, giving carbo- and heterocyclic products with high diastereo- and enantiocontrol (up to 99:1 dr, up to 99% ee) that are readily derivatized to afford functionalized indene and dihydrobenzofuran carboxylates. Chiral isothioureas also promote the catalytic asymmetric intermolecular Michael addition-lactonization of arylacetic acids and α-keto-β,γ-unsaturated esters, giving anti-dihydropyranones with high diastereo- and enantiocontrol (up to 98:2 dr, up to 99% ee).
Peptides and proteins are attractive initial leads for the rational design of bioactive molecules. Several natural cyclic peptides have recently emerged as templates for drug design due to their resistance to chemical or enzymatic hydrolysis and high selectivity to receptors. The development of practical protocols that mimic the power of nature's strategies remains paramount for the advancement of novel peptide-based drugs. The de novo design of peptide mimetics (nonpeptide molecules or cyclic peptides) for the synthesis of linear or cyclic peptides has enhanced the progress of therapeutics and diverse areas of science and technology. In the case of metabolically unstable peptide ligands, the rational design and synthesis of cyclic peptide analogues has turned into an alternative approach for improved biological activity.
The rational design and mechanistic understanding of catalytic systems capable of generating quaternary stereocenters in an asymmetric fashion is a recognized challenge in synthesis.[1] A number of asymmetric Lewis base mediated processes have been developed within this area, [2] in which enantiomerically pure derivatives of 4-(pyrrolidino)pyridine (PPY) and 4-dimethylaminopyridine (DMAP) are elegantly employed by the Fu, [3] Vedejs, [4] and Richards groups, [5] as asymmetric catalysts for the rearrangement of 5-oxazolyl carbonates into 4-carboxyazlactones (Scheme 1).[6] This process delivers C-carboxyazlactones bearing a quaternary stereocenter with excellent enantiocontrol. [7] Among the recent developments in Lewis base catalysis, the ability of isothioureas to efficiently promote alcohol acylation has been demonstrated. Birman and Li first showed that tetramisole and its benzannulated analogue BTM could catalyze effective kinetic resolution [8] and desymmetrization protocols (Scheme 2).[9] Independent studies by Kobayashi and Okamoto, and Birman et al. subsequently introduced DHPB, [10] before Birman and Li developed HBTM (1) for the kinetic resolution of aryl cycloalkanols.[11] Building upon these studies, [12,13] Dietz and Gröger have utilized tetramisole (32 mol %) to promote a modestly enantioselective rearrangement of an oxazolyl acetate (63 % ee at 80 % conversion), [14] and we have shown that DHPB represents the optimal catalyst substructure for the carboxyl group transfer reaction of oxazolyl carbonates in the racemic series. [15] As part of a research program concerned with utilizing Lewis bases as catalysts, [16] we hoped to build upon these precedents by using chiral isothioureas, such as 1, to promote the Steglich rearrangement with high enantioselectivity. The incorporation of a stereodirecting group at C4, adjacent to the nucleophilic nitrogen atom, is imperative in these catalyst architectures; this contrasts the recognized derogatory effect of the 2-substitution of DMAP or PPY derivatives upon catalytic turnover in acylation reactions. [4a, 17] Upon formation of an N-carboxy derivative within the Steglich reaction, this stereodirecting group was predicted to adopt a pseudoaxial conformation.[18] It was anticipated that asymmetric induction would arise from discrimination between the prochiral faces of an azlactone enolate upon addition to this intermediate, preferably anti to the C4 stereodirecting unit, with the axial C3 À H aiding differentiation between the planar aromatic and aliphatic quadrants (Figure 1).Initial studies evaluated isothiourea 1 to promote the asymmetric O-to C-carboxyl group transfer of a range of alkyl and aryl oxazolyl carbonates 2-4, with the transfer of the
The asymmetric annulation of a range of a,b-unsaturated acyl ammonium intermediates, formed from isothiourea HBTM 2.1 and anhydrides with either 1,3-dicarbonyls, b-ketoesters or azaaryl ketones gives either functionalised esters (upon ring opening), dihydropyranones or dihydropyridones in good yields (up to 93%) and high enantioselectivity (up to 97% ee).
The piperidine and dihydropyridone motifs are a recognized feature of numerous structurally diverse natural products and bioactive pharmaceuticals. [1] Among the synthetic methods developed for the preparation of these derivatives in enantiomerically pure form, [2] the aza-Diels-Alder reaction is an important and versatile route. [3] Since the introduction of uncatalyzed inverse-electron-demand aza-Diels-Alder cycloaddition processes by Boger and Kasper, [4] and Hsung and Berry, [5] few catalytic asymmetric methods for the promotion of this reaction have been developed. [6,7] The state-of-the-art N-heterocyclic carbene promoted [8] organocatalytic methods of Bode and co-workers (using enals and N-sulfonyl-a,bunsaturated aldimines), [9] and those of Ye and co-workers (arylalkylketenes and N-sulfonyl butenoates) [10] furnish dihydropyridones with high diastereo-and enantioselectivity; on the otherhand Chen and co-workers have employed enamine [11] and dienamine [12] catalysis in the transformation of Nsulfonyl-a,b-unsaturated ketimines [13] into pyridinols with high enantioselectivity. To date, processes that utilize enolate equivalents that have been prepared directly from readily available and bench-stable carboxylic acids have not been developed. [14] Within this area, Romo and co-workers, [15] and ourselves [16] have utilized Lewis base catalyzed [17] in situ activation of a carboxylic acid, [18] in combination with chiral isothioureas [19] (introduced as acyl transfer catalysts by Birman et al.), [20] to promote asymmetric aldol-and Michael/lactonization processes, respectively. To date, the only intermolecular process using this strategy requires aketo-b,g-unsaturated esters as the Michael acceptor, with chalcones being unreactive. To build upon this work, we envisaged that the electron-withdrawing N-sulfonyl group within N-tosyl-a,b-unsaturated ketimine derivatives would facilitate intermolecular organocatalytic Michael/lactamization, furnishing directly stereodefined dihydropyridones from arylacetic acids under isothiourea-mediated catalysis. We detail herein our studies toward this goal, as well as a range of derivatization procedures and a new N-to C-sulfonyl photoisomerization process, for the efficient asymmetric synthesis of polysubstituted dihydropyridones, dihydropyridines, piper-Scheme 1. Versatile route to N-and O-heterocyclic building blocks. Ts = p-toluenesulfonyl, LB = Lewis base.
The rational design and mechanistic understanding of catalytic systems capable of generating quaternary stereocenters in an asymmetric fashion is a recognized challenge in synthesis. [1] A number of asymmetric Lewis base mediated processes have been developed within this area, [2] in which enantiomerically pure derivatives of 4-(pyrrolidino)pyridine (PPY) and 4-dimethylaminopyridine (DMAP) are elegantly employed by the Fu, [3] Vedejs, [4] and Richards groups, [5] as asymmetric catalysts for the rearrangement of 5-oxazolyl carbonates into 4-carboxyazlactones (Scheme 1). [6] This process delivers C-carboxyazlactones bearing a quaternary stereocenter with excellent enantiocontrol. [7] Among the recent developments in Lewis base catalysis, the ability of isothioureas to efficiently promote alcohol acylation has been demonstrated. Birman and Li first showed that tetramisole and its benzannulated analogue BTM could catalyze effective kinetic resolution [8] and desymmetrization protocols (Scheme 2). [9] Independent studies by Kobayashi and Okamoto, and Birman et al. subsequently introduced DHPB, [10] before Birman and Li developed HBTM (1) for the kinetic resolution of aryl cycloalkanols. [11] Building upon these studies, [12,13] Dietz and Gröger have utilized tetramisole (32 mol %) to promote a modestly enantioselective rearrangement of an oxazolyl acetate (63 % ee at 80 % conversion), [14] and we have shown that DHPB represents the optimal catalyst substructure for the carboxyl group transfer reaction of oxazolyl carbonates in the racemic series. [15] As part of a research program concerned with utilizing Lewis bases as catalysts, [16] we hoped to build upon these precedents by using chiral isothioureas, such as 1, to promote the Steglich rearrangement with high enantioselectivity. The incorporation of a stereodirecting group at C4, adjacent to the nucleophilic nitrogen atom, is imperative in these catalyst architectures; this contrasts the recognized derogatory effect of the 2-substitution of DMAP or PPY derivatives upon catalytic turnover in acylation reactions. [4a, 17] Upon formation of an N-carboxy derivative within the Steglich reaction, this stereodirecting group was predicted to adopt a pseudoaxial conformation. [18] It was anticipated that asymmetric induction would arise from discrimination between the prochiral faces of an azlactone enolate upon addition to this intermediate, preferably anti to the C4 stereodirecting unit, with the axial C3 À H aiding differentiation between the planar aromatic and aliphatic quadrants (Figure 1).Initial studies evaluated isothiourea 1 to promote the asymmetric O-to C-carboxyl group transfer of a range of alkyl and aryl oxazolyl carbonates 2-4, with the transfer of the Scheme 1. The asymmetric Steglich rearrangement. Scheme 2. Evolution of isothiourea catalysts.Figure 1. Proposed stereodefined N-carboxy intermediate. The stereodirecting unit at C4 is imperative; the stereodefined N-carboxy intermediate has a pseudoaxial directing substituent; and discrimination between the...
[reaction: see text] The photoinduced metalation of nonactivated C-Cl bonds of O-acetyl chlorohydrins is promoted by samarium diiodide. As a result of this, beta-elimination of O-acetyl chlorohydrins is achieved, affording the corresponding (Z)-alkenes with total or high stereoselectivity.
Encephalitogenic T cells are heavily implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Their stimulation is triggered by the formation of a trimolecular complex between the human leukocyte antigen (HLA), an immunodominant myelin basic protein (MBP) epitope, and the T cell receptor (TCR). We detail herein our studies directed towards the rational design and synthesis of non-peptide mimetic molecules, based on the immunodominant MBP83–96 epitope that is recognized by the TCR in complex with HLA. We focused our attention on the inhibition of the trimolecular complex formation and consequently the inhibition of proliferation of activated T cells. A structure-based pharmacophore model was generated, in view of the interactions between the TCR and the HLA-MBP83–96 complex. As a result, new candidate molecules were designed based on lead compounds obtained through the ZINC database. Moreover, semi-empirical and density functional theory methods were applied for the prediction of the binding energy between the proposed non-peptide mimetics and the TCR. We synthesized six molecules that were further evaluated in vitro as TCR antagonists. Analogues 15 and 16 were able to inhibit to some extent the stimulation of T cells by the immunodominant MBP83–99 peptide from immunized mice. Inhibition was followed to a lesser degree by analogues 17 and 18 and then by analogue 19. These studies show that lead compounds 15 and 16 may be used for immunotherapy against MS.
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