Application of the asymmetric hetero Diels-Alder reaction for synthesising carbohydrate derivatives and glycosidase inhibitors

This review provides a discussion of recent developments in the asymmetric hetero Diels-Alder reaction (AHDAR), with particular emphasis on the synthesis of carbohydrates, their derivatives, and inhibitors of carbohydrate processing enzymes.

SYNTHESIS AND RETRO AZA DIELS-ALDER REACTION OF SOME NEW ISOQUINUCLIDINE DERIVATIVES

N-Benzyl- and N-(alpha-methoxycarbonylethyl)-2,4,6-triphenyl-1,2-dihydropyridines were submitted to Diels-Alder reactions with maleic anhydride or N-phenylmaleimide yielding, diastereoselectively, the corresponding endo-anti adducts. These novel isoquinuclidines showed to be resistant to N-alkylation or N-protonation, undergoing an unexpected fragmentation via a retro aza Diels-Alder process.

Microwave-Mediated Hetero Diels-Alder reaction: Synthesis of biologically active compounds

Heterocyclic compounds represent almost two-thirds of all the known organic compounds: they are widely distributed in nature and play a key role in a huge number of biologically important molecules including some of the most significant for human beings. A powerful tool for the synthesis of such compounds is the hetero Diels-Alder reaction (HDA), that involve a [4+2] cycloaddition reaction between heterodienes and suitable dienophiles. Among heterodienes to be used in such six-membered heterocyclic construction strategy, 3-trialkylsilyloxy-2-aza-1,3-dienes (Fig 1) has been demonstrated particularly attractive. In this thesis work, HDA reactions between 2-azadienes and carbonylic and/or olefinic dienophiles, are described. Moreover, substitution of conventional heating by the corresponding dielectric heating as been explored in the frame of Microwave-Assisted-Organic-Synthesis (MAOS) which constitutes an up-to-grade research field of great interest both from an academic and industrial point of view. Reaction of the azadiene 1 (Fig 1) will be described using as dienophiles carbonyl compounds as aldehyde and ketones. The six-membered adducts thus obtained (Scheme 1) have been elaborated to biologically active compounds like 1,3-aminols which constitutes the scaffold for a wide range of drugs (Prozac®, Duloxetine, Venlafaxine) with large applications in the treatment of severe diseases of nervous central system (NCS). Scheme 1 The reaction provides the formation of three new stereogenic centres (C-2; C-5; C-6). The diastereoselective outcome of these reactions has been deeply investigated by the use of various combination of achiral and chiral azadienes and aliphatic, aromatic or heteroaromatic aldehydes. The same approach, basically, has been used in the synthesis of piperidin-2-one scaffold substituting the carbonyl dienophile with an electron poor olefin. Scheme 2 As a matter of fact, this scaffold is present in a very large number of natural substances and, more interesting, is a required scaffold for an huge variety of biologically active compounds. Activated olefins bearing one or two sulfone groups, were choose as dienophiles both for the intrinsic characteristic flexibility of the “sulfone group” which may be easily removed or elaborated to more complex decorations of the heterocyclic ring, and for the electron poor property of this dienophiles which makes the resulting HDA reaction of the type “normal electron demand”. Synthesis of natural compounds like racemic (±)-Anabasine (alkaloid of Tobacco’s leaves) and (R)- and (S)-Conhydrine (alkaloid of Conium Maculatum’s seeds and leaves) and its congeners, are described (Fig 2).

Asymmetric Diels-Alder Reactions of Chiral Acrylates of Cholic Acid Derivatives

New steroid-based chiral auxiliaries 6, 9, and 12 have been synthesized from readily available cholic acid. These new chiral auxiliaries place the reactive and the shielding sites in a 1,5 relationship to each other. Diels-Alder reaction of cyclopentadiene with corresponding acrylate esters (7, 10, and 13) have been examined. Acrylates 7 and 10 yielded cycloadducts with 29-88% diastereomeric excess with excellent endo selectivity in the presence of an excess of Lewis acids such as AlCl3, BF3.OEt(2), FeCl3, SnCl4, TiCl4, and ZnCl2. Treatment of acrylate 7 with cyclopentadiene in the presence of BF3.OEt(2) at -80 degrees C gave the endo adduct (>99%) with 88% de. Lewis acid catalyzed and uncatalyzed reactions of acrylates 7 and 10 with cyclopentadiene yielded cycloadducts with opposite stereochemistry. The chiral auxiliary was recovered in a nondestructive manner only via iodolactonization. Acrylate ester of alcohol 12 did not show any selectivity in either catalyzed and uncatalyzed reactions with cyclopentadiene. The presence of a flat aromatic surface at C-7 of the steroid was found to be essential to effect high diastereoselection.

电子反常供需型Diels-Alder反应合成2-吡啶基吡啶

电子反常供需型Diels-Alder反应(inverse electron demabd Diels-Alder reaction,IDA)因其在天然生物碱及类似物合成中的应用,在近20年来已经逐渐引起关注[1].含氮芳杂环体系1,2,4-三嗪由于其特有的缺电子特征,作为双烯体非常适于进行这类反应[2].本文利用IDA反应从3-吡啶基-5,6-二取代-1,2,4-三嗪出发,设计出一条简捷、低成本的合成路线,成功地合成出不对称取代的2,3′-联吡啶和2,4′-联吡啶.这一类化合物已被应用于药物中间体或有机配体.

Recyclable copper catalysts based on imidazolium-tagged bis(oxazolines): A marked enhancement in rate and enantioselectivity for Diels-Alder reactions in ionic liquid

Imidazolium-tagged bis(oxazolines) have been prepared and used as chiral ligands in the copper(II)-catalysed Diels-Alder reaction of N-acryloyl- and N-crotonoyloxazolidinones with cyclopentadiene and 1,3-cyclohexadiene in the ionic liquid 1-ethyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide, [emim][NTf2]. A significant and substantial enhancement in the rate and enantioselectivity was achieved in [emim][NTf2] compared with dichloromethane. For example, complete conversion and enantioselectivities up to 95 % were obtained for the reaction between N-acryloyloxazolidinone and cyclopentadiene within 2 min in [emim][NTf2] whereas the corresponding reaction in dichloromethane required 60 min to reach completion and gave an ee of only 16 %. The enhanced rates obtained in the ionic liquid enabled a catalyst loading as low as 0.5 mol % to give complete conversion within 2 min while retaining the same level of enantioselectivity. The imidazolium-tagged catalysts can be recycled ten times without any loss in activity or enantioselectivity and showed much higher affinity for the ionic liquid phase during the recycle procedure than the analogous uncharged ligand.

Highly efficient asymmetric hetero-Diels-Alder reactions of carbonyl compounds catalyzed by Lewis acid platinum complexes of conformationally flexible NUPHOS-type diphosphines

Conformationally flexible NUPHOS-type diphosphines have been resolved as their diastereopure platinum BINOLate complexes delta- and lambda-[(NUPHOS)Pt{(S)-BINOL}] and the corresponding enantiopure Lewis acids delta- and lambda-[(NUPHOS)Pt(OTf)(2)], being generated by protonation with trifluoromethanesulfonic acid, act as highly efficient catalysts for the hetero-Diels-Alder reaction of nonactivated conjugated dienes with aryl glyoxals and glyoxylate esters, giving ee's as high as 99%.

Studies on chemo- and diastereo-selectivity of the Diels-Alder reactions of sulfinyltoluquinones with cyclopentadiene

Sulfinyltoluquinones (2a-2c) were submitted to thermal or catalyzed [4+2] cycloaddition reactions with cyclopentadiene. For p-tolylsulfinyltoluquinones (2b) and (2c), almost complete C2-C3-chemo- and unlike-diastereoselectivity was achieved by catalysis with ZnBr(2), yielding adducts 6. Under thermal conditions, Diels-Alder reaction took place at the C5-C6 double bonds of quinones 2a-2c, generating mixtures of diastereoisomeric like- and unlike-adducts 4.

Stereoselective synthesis of novel diels-alder adducts of p-substituted Methyl Thiocinnamates and Cyclopentadiene

This article describes the Diels-Alder reaction between methyl thiocinnamates, substituted at the para position by electron-donating and electron-withdrawing groups, with cyclopentadiene in the presence of catechol boron bromide (CBB) as a Lewis acid catalyst. The adduct configuration was confirmed by H-1 NMR coupling constants and single-crystal x-ray diffraction. Total endo stereoselectivity was observed in all reactions and was attributed to the effective secondary interaction between the boron atom and the incipient double bond in the norbonene resulting from the planar geometry of the catalyst. C-13 NMR chemical shifts of the coordinated dienophile carbonyl carbons with CBB compared to those of the non coordinated thiocinammates suggest a strong complexation with the catalyst.

Novos protocolos teóricos utilizados nos estudos das ligações hidrogênio-hidrogênio, na estabilidade do tetraedrano, seus derivados e das reações de diels-alder e na quantificação da afinidade de fármacos

This thesis was performed in four chapters, at the theoretical level, focused mainly on electronic density. In the first chapter, we have applied an undergraduate minicourse of Diels-Alder reaction in Federal University of Rio Grande do Norte. By using computational chemistry tools students could build the knowledge by themselves and they could associate important aspects of physical-chemistry with Organic Chemistry. In the second chapter, we studied a new type of chemical bond between a pair of identical or similar hydrogen atoms that are close to electrical neutrality, known as hydrogen-hydrogen (H-H) bond. In this study performed with complexed alkanes, provides new and important information about their stability involving this type of interaction. We show that the H-H bond playing a secondary role in the stability of branched alkanes in comparison with linear or less branched isomers. In the third chapter, we study the electronic structure and the stability of tetrahedrane, substituted tetrahedranes and silicon and germanium parents, it was evaluated the substituent effect on the carbon cage in the tetrahedrane derivatives and the results indicate that stronger electron withdrawing groups (EWG) makes the tetrahedrane cage slightly unstable while slight EWG causes a greater instability in the tetrahedrane cage. We showed that the sigma aromaticity EWG and electron donating groups (EDG) results in decrease and increase, respectively, of NICS and D3BIA aromaticity indices. In addition, another factor can be utilized to explain the stability of tetra-tert-butyltetrahedrane as well as HH bond. GVB and ADMP were also used to explain the stability effect of the substituents bonded to the carbon of the tetrahedrane cage. In the fourth chapter, we performed a theoretical investigation of the inhibitory effect of the drug abiraterone (ABE), used in the prostate cancer treatment as CYP17 inhibitor, comparing the interaction energies and electron density of the ABE with the natural substrate, pregnenolone (PREG). Molecular dynamics and docking were used to obtain the CYP1ABE and CYP17-PREG complexes. From molecular dynamics was obtained that the ABE has higher diffusion trend water CYP17 binding site compared to the PREG. With the ONIOM (B3LYP:AMBER) method, we find that the interaction electronic energy of ABE is 21.38 kcal mol-1 more stable than PREG. The results obtained by QTAIM indicate that such stability is due a higher electronic density of interactions between ABE and CYP17