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The discovery of chemical methods enabling the construction of carbocycle-fused uracils which embody a three-dimensional and functional-group-rich architecture is a useful tool in medicinal chemistry oriented synthesis. In this work, an unprecedented amine-catalyzed [4+2] cross-cycloaddition is documented; it involves remotely enolizable 6-methyluracil-5-carbaldehydes and β-aryl enals, and chemoselectively produces two novel bicyclic and tricyclic fused uracil chemotypes in good yields with a maximum level of enantiocontrol. In-depth mechanistic investigations and control experiments support an intriguing homo-synergistic organocatalytic approach, where the same amine organocatalyst concomitantly engages both aldehyde partners in a stepwise eliminative [4+2] cycloaddition, whose vinylogous iminium ion intermediate product may diverge-depending upon conditions-to either bicyclic targets by hydrolysis or tricyclic products by a second homo-synergistic trienamine-mediated stepwise [4+2] cycloaddition.

A direct aminocatalytic synthesis has been developed for the chemo-, regio-, diastereo-, and enantioselective construction of densely substituted polycyclic carbaldehydes containing fused cyclohexadiene rings. The chemistry utilizes, for the first time, remotely enolizable π-extended allylidenemalononitriles as electron-rich 1,3-diene precursors in a direct eliminative [4+2] cycloaddition with both aromatic and aliphatic α,β-unsaturated aldehydes. The generality of the process is demonstrated by approaching 6,6-, 5,6-, 7,6-, 6,6,6-, and 6,5,6-fused ring systems, as well as biorelevant steroid-like 6,6,6,6,5- and 6,6,6,5,6-rings. A stepwise reaction mechanism for the key [4+2] addition is proposed as a domino bis-vinylogous Michael/Michael/retro-Michael reaction cascade. The utility of the malononitrile moiety as traceless activating group of the dicyano nucleophilic substrates is demonstrated.

Polycyclic indole architectures, including carbazole and hydrocarbazole skeletons, represent privileged structural motifs found in a number of natural alkaloids, many of which displaying interesting activities against a diverse set of biological targets.[1] Accordingly, the search for efficient methods for the assembly of these structures has drawn a great deal of attention in the synthetic organic chemistry community.[2,3] An unprecedented technique for the in situ generation of indolyl ortho-quinodimethanes from 2-methylindole-based methylenemalononitriles 1 by amine-mediated remote C(sp3)-H deprotonation was developed. These intermediates were efficiently trapped by diverse enals to provide a rapid entry to 2,9-dihydro-1H-carbazole-3-carboxyaldehyde structures 3 through a formal asymmetric [4+2] eliminative cycloaddition governed by a ?,?-diphenylprolinol trimethylsilyl ether catalyst.[4] A stepwise reaction mechanism of the formal catalytic asymmetric [4+2] cycloaddition of methylenemalononitrile 1a with enal 2a catalyzed by (S)-C1 is proposed. Parole chiave: asymmetric synthesis, cycloaddition heterocycles, organocatalysis, vinylogy Riferimenti: 1) A. G?uszynska, Eur. J. Med. Chem. 2015, 94, 405. 2) N. H. Krishna, A. P. Saraswati, M. Sathish, N. Shankaraiah, A. Kamal, Chem. Commun. 2016, 52, 4581. 3) Y. Li, F. Tur, R. P. Nielsen, H. Jiang, F. Jensen, K. A. Jørgensen, Angew. Chem. Int. Ed. 2016, 55, 1020; Angew. Chem. 2016, 128, 1032. 4) G. Rassu, C. Curti, V. Zambrano, L. Pinna, N. Brindani, G. Pelosi, and F. Zanardi, Chem. Eur. J. 2016, 22, 12637 - 12640 Ringraziamenti: Financial support provided by the Università degli Studi di Parma.

While several protocols exist for the asymmetric functionalization of pyrazolinones at the alfa-position relying on nucleophilic addition or annulation procedures, use of alfa-ethylidene electron-rich analogues in asymmetric vinylogous coupling to carbon electrophiles is substantially an uncharted domain. We now report, for the first time, that ethylidenepyrazolinones carrying an enolizable carbon at the gamma-position efficiently participate in direct and asymmetric, catalytic vinylogous Michael-type addition to nitroolefins providing the expected adducts in high yields, with complete gamma-site selectivity and with an extraordinary level of geometrical and enantioselectivity. Either R- or S- configured adducts were equally accessed by employing a quasi-enantiomeric quinine- or quinidine-based thiourea catalyst pair.

Previously elusive 2,9-dihydro-1H-carbazoles become accessible by a novel enantioselective catalytic [4 + 2] eliminative cycloaddition of indolyl methylenemalononitriles with various cinnamaldehydes.

3-Alkylidene oxindoles (methyleneindolinones), be they natural or man-made substances, occupy a preeminent position among the various classes of chemically and medicinally relevant small-molecule scaffolds. Their plural functional architecture featuring a lactam carbonyl flanked by a highly substituted exocyclic double bond renders them enabling intermediates to be elaborated into a myriad of useful nitrogen heterocycles of varied complexity. For example, 3-alkylidene oxindoles can be viewed as electrophilic Michael acceptors, which react with carbon-centered anions to give bsubstituted oxindoles of type A (Scheme 1a). In addition, they can act as electron-poor components in synchronous (Scheme 1b) or stepwise (Scheme 1c) cycloadditive functionalizations, thus opening the way to a wide range of highly valuable 3,3-spirocyclic structures of type B or C. Whereas these protocols have been largely pursued and formed the basis of many synthetic achievements, an “umpolung” option could also be envisaged (Scheme 1d), and capitalizes on the vinylogous pro-nucleophilic character of the alkyl group attached at the b-position of the ylidene. By reacting with the proper acceptors, these nucleophiles furnish olefinic oxindoles of type D, which are functionalized at the most distant point of the molecule (Cγ).

The first uncatalyzed, diastereoselective vinylogous Mukaiyama aldol reaction is reported, between pyrrole/furan-based dienoxy silanes and aromatic aldehydes on salty water/methanol medium, at almost human body temperature, under ultrasonic irradiation. With pyrrole dienes the reaction is anti-selective, while that of furan dienes is syn-selective. The dual role of water as both reaction medium and promoter is highlighted.

A two-step, one-pot sequence under chiral amine—NHC catalysis allows the approach to spiro[4.5]decanone structures in a diastereoselective manner with high e.e.

The feasibility of sequential vinylogous aldol (intermolecular)/silylative aldol (intramolecular) addition reactions involving furan- and pyrrole-based dienoxysilanes, 6 and 12, in the synthesis of carbasugar frameworks is illustrated by the preparation of the scantily investigated carbaseptanose and carbaoctanose representatives of this class of compounds. The target compounds, 1, 2, 3, ent-2, ent-3, and 4, were obtained from readily available carbohydrate precursors (5 and 19) in yields of 21-30% over 8-12 steps. The irreversible silylative ring-closing aldolisation of gamma-substituted dihydro-5H-furan-2-one and pyrrolidin-2-one aldehydes (9, 16, ent-16, and 22) driven by the TBSOTf/Pr(i)(2)EtN Lewis acid-Lewis base couple was shown to be a practical, diastereoselective maneuver to forge the densely functionalized, medium-sized core carbocycles.

A concise, diastereoselective synthesis of 2- C -methyl-4a-carba-β- d -lyxofuranose 13 and 2- C -methyl-4a-carba-β- d -arabinofuranose 14 , two novel representatives of the branched-chain carbasugar family, is presented. The construction is based on the sequential execution of two strategic carbon–carbon bond-forming reactions, a vinylogous crossed aldol addition ( 1 + 2 → 3 ), and a rare silylative cycloaldolization ( 8 → 9 + 10 ).

A chiral, divergent synthesis of two carbafuranosylamines, 1 and 2, two carbapyranosylamines, 3 and 4, two carbafuranosylamino acids, 5 and 6, and two carbapyranosylamino acids, 7 and 8, has been achieved. Highlights of the procedure include the following: a diastereoselective crossed vinylogous Mukaiyama aldol coupling between N-(tert-butoxycarbonyl)-2-[(tert-butyldimethylsilyl)oxy]pyrrole (TBSOP, 9) and 2,3-O-isopropylidene-d-glyceraldehyde (10) for the assembly of the target compound carbon backbone; a high-yielding silylative cycloaldolization that gives the cyclopentanoid and cyclohexanoid motifs; and a reductive or hydrolytic breakage of the lactam C(O)−N link to liberate the carbasugar and install the desired pseudo-anomeric amine and the hydroxymethyl or carboxyl functionalities. The sequences leading to trans-configured carbafuranosyl compounds 1 and 5 and carbapyranosyl compounds 3 and 7 were 12- and 13-step processes, with overall yields of 34%, 35%, 17%, and 16%. Cis-configured isomers 2, 4, ...

The reactions proceed with high to excellent Z-selectivity and can be scaled-up without loss of stereoselectivity.

Modulation of the complex reactivity of cyclohexenylidene malononitriles using diverse β-aryl-substituted enals and proper organocatalytic modalities resulted in divergent asymmetric reaction patterns to furnish angularly fused or bridged carbabicyclic frameworks. In particular, use of remotely enolizable dicyanodienes 1, under one-pot sequential amine/NHC catalysis, led to [3 + 2] cycloaddition to afford ε,δ-bonded spiro[4.5]decanone structures 5. Alternatively, modifying the standard amine catalysis by adding a suitable chemical stimulus (p-nitrophenol cocatalyst) switched the reactivity decidedly toward a domino [4 + 2] cycloaddition to afford γ',δ-bonded bicyclo[2.2.2]octane carbaldehydes 8. Products invariably formed in good yields, with rigorous chemo-, regio-, diastereo-, and enantiocontrol. Experimental evidence, including carbon isotope effects measured by (13)C NMR, were indicative of the rate (and stereochemistry) determining step of these transformations and suggested a stepwise mechanism for the [4 + 2] cycloadditive pathway.

Complex periodic and aperiodic behaviours are reported in an unstirred Belousov-Zhabotinsky oscillatory reaction performed at temperatures varying between 0°C and 8°C. A route to chaos following a Ruelle-Takens-Newhouse (RTN) scenario is identified. Thus, temperature effects on the coupling between chemical kinetics, diffusion and convection, seem to be responsible for the observed RTN scenario. In this Letter we demonstrate that the temperature is a bifurcation parameter for the sequence period-1 -> quasiperiodicity -> chaos.

The asymmetric Michael addition of prochiral 3-alkylideneoxindoles to nitroolefins is realized in the presence of a dihydroquinine derived thiourea catalyst.

3-Alkylidene-2-oxindoles represent a simple, yet enabling sub-family of indole alkaloids, and their ability to react as electron-poor acceptors has largely been investigated. In contrast, their utility as nucleophilic or pronucleophilic synthons remains elusive. In this context, this article describes the successful execution of the direct, organocatalytic asymmetric Michael addition of prostereogenic 3-alkylidene oxindoles to nitroolefins, through which a variety of ?-substituted alkylidene oxindoles chiral at both the ?- and ?-carbon sites were assembled with excellent stereoselectivity and without olefin isomerization or stereochemical ablation.

3-Alkylidene oxindoles (methyleneindolinones), be they natural or man-made substances, occupy a preeminent position among the various classes of chemically and medicinally relevant small-molecule scaffolds. Their plural functional architecture featuring a lactam carbonyl flanked by a highly substituted exocyclic double bond renders them enabling intermediates to be elaborated into a myriad of useful nitrogen heterocycles of varied complexity. For example, 3-alkylidene oxindoles can be viewed as electrophilic Michael acceptors, which react with carbon-centered anions to give bsubstituted oxindoles of type A (Scheme 1a). In addition, they can act as electron-poor components in synchronous (Scheme 1b) or stepwise (Scheme 1c) cycloadditive functionalizations, thus opening the way to a wide range of highly valuable 3,3-spirocyclic structures of type B or C. Whereas these protocols have been largely pursued and formed the basis of many synthetic achievements, an “umpolung” option could also be envisaged (Scheme 1d), and capitalizes on the vinylogous pro-nucleophilic character of the alkyl group attached at the b-position of the ylidene. By reacting with the proper acceptors, these nucleophiles furnish olefinic oxindoles of type D, which are functionalized at the most distant point of the molecule (Cγ).

The title alkenyl(siloxy)indoles (III) serve as suitable substrates in the vinylogous Mukaiyama aldol reaction with aromatic aldehydes to furnish hydroxylated alkylideneoxindoles (V) in good yields with virtually complete γ-site selectivity and high Z-selectivity.

We introduce novel 3-alkenyl-2-silyloxyindole nucleophiles and demonstrate their utility by developing an unprecedented vinylogous Mukaiyama-type aldol reaction with aromatic aldehydes. This reaction displays excellent levels of γ- site selectivity and diastereoselectivity and delivers valuable hydroxylated oxindoles bearing a substituted exocyclic double bond at the C-3 position. A preliminary trial of an asymmetric, catalytic version was conducted, and it showed promising enantioselectivity for the desired vinylogous aldol products.

The coupling of the pyrrole proceeds with good antiselectivity, while that of the furan (IV) is syn-selective.

A short and practical entry to optically pure 5a-carbahexopyranose and 1-thio-5a-carbahexopyranose representatives is described. Besides a few functional group and protecting group manipulations, the synthetic scheme counts on two fundamental carbon−carbon bond-forming reactions, namely (i) a regio- and stereoselective aldol addition between heterocyclic (silyloxy)diene donors (6 or 13) and D-glyceraldehyde as the acceptor (7) and (ii) a chemo- and stereoselective silylative cycloaldolization involving bifunctional aldehydes (10, 16, and 21). The 1H NMR based configurational and conformational assignment of target structures 1−5 and bicyclic intermediates 11, 12, 17, 18, and 22 is discussed. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

An efficient, stereocontrolled synthesis of (6S,7S,8S,8aR)-6,7,8-trihydroxyindolizidine (alias 1-deoxy-7,8-di-epi-castanospermine) (14) has been developed, which exploits an asymmetric vinylogous Mukaiyama aldol reaction (VMAR) between N-(tert-butoxycarbonyl)-2-(tert-butyldimethylsilyloxy)pyrrole (1) and 2,3-O-isopropylidene-D-glyceraldehyde (2) to construct the initial pyrrolidine building block 3, and an ene-ene ring closing metathesis reaction (RCM) (9 to 10) to install the indolizidine skeleton. The synthetic sequence was 13 steps, proceeding in 19.5% overall yield. The configurational and conformational structure of 14 was ascertained unambiguously and confronted to previously published assignments of rac-14 and ent-14.

Denmark’s chiral bisphosphoramide/silicon tetrachloride system performs as an excellent Lewis base-Lewis acid catalyst for the vinylogous Mukaiyama aldol reaction of pyrrole- and furan-based dienoxy silanes with aromatic and heteroaromatic aldehydes. This asymmetric methodology provides a powerful synthetic entry to a variety of δ-hydroxylated γ-butenolide-type frameworks with high efficiency and valuable margins of regio-, diastereo-, and enantioselectivity. Notably, the nature of the heteroatom within the vinylogous dienoxy silane donor heavily impacts the diastereocontrol, with syn -configured aldol adducts emerging from pyrroles bearing electron-withdrawing N -protecting groups (Boc, Ts, and Cbz) and anti -configured adducts prevailing when furan- or N -alkyl/alkenylpyrrole donors are involved.

A rare silylative hydroxyalkylation of amide compounds with chiral aldehydes has been developed utilizing a Lewis acid–Lewis base promoter system consisting of an equimolecular mixture of tert -butyldimethylsilyl trifluoromethanesulfonate and N -diisopropylethylamine. This approach culminated in the synthesis of several enantiopure acyclic nucleoside representatives comprising thymidine analogues 6 , 7 , 9 , 10 , 12 and 13 , uridine analogues 15 and 16 , and 6-chloropurine derivatives 18 and 19 .

Efficient, total syntheses of novel 2-deoxy-2-amino-5a-carba-beta-L-mannopyranuronic acid (1) and 2-deoxy-2-amino-5a-carba-beta-L-mannopyranose (2), a positional stereoisomer of validamine, have been achieved in 28% and 24% overall yields and in 12 steps and 13 steps, respectively, from 2-[(tert-butyldimethylsilyl)oxy]furan (3) and (2S)-2,3-O-isopropylideneglyceraldehyde N-benzyl imine (4) via two highly diastereoselective Mukaiyama aldol-related chemical maneuvers. The strategy, which furnishes the targeted carbasugars in enantiopure forms, allows for complete control of the configuration at all five contiguous stereocenters of the targets by utilizing the sole element of chirality present in the aldimine progenitor 4.

A short and practical entry to optically pure 5a-carbahexopyranose and 1-thio-5a-carbahexopyranose representatives is described. Besides a few functional group and protecting group manipulations, the synthetic scheme counts on two fundamental carbon−carbon bond-forming reactions, namely (i) a regio- and stereoselective aldol addition between heterocyclic (silyloxy)diene donors (6 or 13) and D-glyceraldehyde as the acceptor (7) and (ii) a chemo- and stereoselective silylative cycloaldolization involving bifunctional aldehydes (10, 16, and 21). The 1H NMR based configurational and conformational assignment of target structures 1−5 and bicyclic intermediates 11, 12, 17, 18, and 22 is discussed. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

A chiral, divergent synthesis of two carbafuranosylamines, 1 and 2, two carbapyranosylamines, 3 and 4, two carbafuranosylamino acids, 5 and 6, and two carbapyranosylamino acids, 7 and 8, has been achieved. Highlights of the procedure include the following: a diastereoselective crossed vinylogous Mukaiyama aldol coupling between N-(tert-butoxycarbonyl)-2-[(tert-butyldimethylsilyl)oxy]pyrrole (TBSOP, 9) and 2,3-O-isopropylidene-D-glyceraldehyde (10) for the assembly of the target compound carbon backbone; a high-yielding silylative cycloaldolization that gives the cyclopentanoid and cyclohexanoid motifs; and a reductive or hydrolytic breakage of the lactam C(O)-N link to liberate the carbasugar and install the desired pseudo-anomeric amine and the hydroxymethyl or carboxyl functionalities. The sequences leading to trans-configured carbafuranosyl compounds 1 and 5 and carbapyranosyl compounds 3 and 7 were 12- and 13-step processes, with overall yields of 34%, 35%, 17%, and 16%. Cis-configured isomers 2, 4, 6, and 8 were obtained only in minor yields.