Organocatalytic, Asymmetric Eliminative [4+2] Cycloaddition of Allylidene Malononitriles with Enals: Rapid Entry to Cyclohexadiene-Embedding Linear and Angular Polycycles.

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,ß-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.

Pushing the boundaries of vinylogous reactivity: catalytic enantioselective mukaiyama aldol reactions of highly unsaturated 2-silyloxyindoles.

The first example of catalytic, enantioselective hypervinylogous Mukaiyama aldol reaction (HVMAR) involving multiply unsaturated 2-silyloxyindoles is reported. The reaction utilizes a chiral Lewis base-catalyzed Lewis acid-mediated technology to deliver homoallylic 3-polyenylidene 2-oxindoles with extraordinary levels of regio-, enantio-, and geometrical selectivity. This work highlights a subtle yet decisive influence of the indole N-substituents on the propagation of the vinylogous reactivity space of the donor substrates up to ten bonds away from the origin of the vinylogy effect. Analysis of the (13) C NMR chemical shifts of the C-ω remote site within homologous silyloxyindole donors enabled rationalization of the results and easy qualitative prediction of the HVMAR reactivity/inertia toward a given aldehyde acceptor.

Exploring the vinylogous reactivity of cyclohexenylidene malononitriles: switchable regioselectivity in the organocatalytic asymmetric addition to enals giving highly enantioenriched carbabicyclic structures.

Modulation of the complex reactivity of cyclohexenylidene malononitriles using diverse ß-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.

Synthesis, structure and inhibitory activity of a stereoisomer of oseltamivir carboxylate.

A stereodivergent plan is presented leading to all eight stereoisomers of oseltamivir carboxylate (OC). Key chemical manoeuvers are (1) a three-component vinylogous Mukaiyama-Mannich reaction, which sets the whole carbon skeleton and heteroatom substituents, and (2) an intramolecular, silylative Mukaiyama aldol reaction, which creates the targeted carbocycle. The viability of the plan was demonstrated by the first total synthesis of 4-epi-oseltamivir carboxylate (6), accessed in 15 steps from glyceraldehyde, o-anisidine and pyrrole siloxydiene precursors. Compound 6 inhibits influenza A virus strains H1N1 and H3N2 at the µM level, about 150 000-fold less than the OC reference, testifying that the stereodisposition of the C4 acetamido function is key for enzyme recognition. Guided by in-depth structural evaluation including NMR solution studies, molecular mechanics simulations, docking analyses and X-ray crystallography, rationalization of the biological verdict was established.

3-Alkenyl-2-silyloxyindoles in vinylogous Mannich reactions: synthesis of aminated indole-based scaffolds and products.

The first Lewis acid catalyzed vinylogous Mukaiyama-type Mannich addition of 3-alkenyl-2-silyloxyindoles to in situ generated N-Boc imines has been established, which affords chiral α-alkylidene-δ-amino-2-oxindole products with good efficiency and complete γ-site- and Z-selectivity. The reaction is wide in scope, as it can be applied with equal convenience to different silyloxyindole donors and aromatic or aliphatic aminal-derived aldimine acceptors. The utility of these scaffolds is demonstrated by their easy transformation into either spirocyclopropane oxindole or homotryptamine-like products, featuring nontraditional indole-based skeleton connections.

Design, synthesis, and biological evaluation of novel cRGD-paclitaxel conjugates for integrin-assisted drug delivery.

The efficacy of taxane-based antitumor therapy is limited by several drawbacks which result in a poor therapeutic index. Thus, the development of approaches that favor selective delivery of taxane drugs (e.g., paclitaxel, PTX) to the disease area represents a truly challenging goal. On the basis of the strategic role of integrins in tumor cell survival and tumor progression, as well as on integrin expression in tumors, novel molecular conjugates were prepared where PTX is covalently attached to either cyclic AbaRGD (Azabicycloalkane-RGD) or AmproRGD (Aminoproline-RGD) integrin-recognizing matrices via structurally diverse connections. Receptor-binding assays indicated satisfactory-to-excellent α(V)ß(3) binding capabilities for most conjugates, while in vitro growth inhibition assays on a panel of human tumor cell lines revealed outstanding cell sensitivity values. Among the nine conjugate ensemble, derivative 21, bearing a robust triazole ring connected to ethylene glycol units by an amide function and showing excellent cell sensitivity properties, was selected for in vivo studies in an ovarian carcinoma model xenografted in immunodeficient mice. Remarkable antitumor activity was attained, superior to that of PTX itself, which was associated with a marked induction of aberrant mitoses, consistent with the mechanism of action of spindle poisons. Overall, the novel cRGD-PTX conjugates disclosed here represent promising candidates for further advancement in the domain of targeted antitumor therapy.

Diastereo- and enantioselective catalytic vinylogous Mukaiyama-Mannich reactions of pyrrole-based silyl dienolates with alkyl-substituted aldehydes.

A reliable, catalytic asymmetric vinylogous Mukaiyama-Mannich reaction of pyrrole-based silyl dienolates is introduced that is particularly apt for alkyl- and α-alkoxyalkyl-substituted aldehydes. The reaction course is effectively orchestrated by the Hoveyda-Snapper amino acid-based chiral ligand/silver(I) catalyst combination to produce valuable vicinal diamino carbonyl compounds in high yields, with virtually complete γ-site- and anti-selectivity and significant catalyst-to-product chirality transfer. The utility of the Mannich products can be seen in the synthesis of an unprecedented perhydrofuro[3,2-b]pyrrolone product, an aza-analogue of naturally occurring (+)-goniofufurone.

Catalytic, asymmetric hypervinylogous Mukaiyama aldol reactions of extended furan-based silyl enolates.

Virtually perfect transmittal of the enolate reactivity up to five conjugated double bonds from the origin allows a series of furan-based silyloxypolyenes to add to aldehyde carbonyls at the most distant point of the molecule. Denmark's axially chiral bisphosphoramide/SiCl(4) combination catalyzes these scantly precedented, long-range Mukaiyama-type vinylogous aldol reactions efficiently, providing a palette of extended γ-alkylidene butenolide carbinols with complete ω-site selectivity and good to excellent levels of enantioselectivity.

anti-Selective, catalytic asymmetric vinylogous Mukaiyama Mannich reactions of pyrrole-based silyl dienolates with N-aryl aldimines.

Pyrrole-based silyl dienolates undergo asymmetric vinylogous Mukaiyama Mannich reactions with a series of N-aryl aldimines in the presence of the Hoveyda-Snapper amino acid-derived silver(I) catalysts. The Mannich products-α,ß-unsaturated δ-amino-γ-butyrolactams-are typically obtained in high yields, excellent γ-site selectivities and anti-diastereoselectivities, and up to 80% enantioselectivity.

Uncatalyzed, diastereoselective vinylogous Mukaiyama aldol reactions on aqueous media: pyrrole vs furan 2-silyloxy dienes.

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.

Asymmetric total synthesis of 1-deoxy-7,8-di-epi-castanospermine.

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.

4-Aminoproline-based arginine-glycine-aspartate integrin binders with exposed ligation points: practical in-solution synthesis, conjugation and binding affinity evaluation.

An expedient and practical in-solution synthesis of three new 4-aminoproline-based arginine-glycine-aspartate integrin binders--compounds 15, 17 and 19--is presented. Two candidates carrying exposed azide and amine functional points were further advanced to trimeric platform 21 as well as fluorescein- and DOTA-conjugates 23 and 25. The new compounds were assayed for their binding affinity towards human alpha(V)beta3 and alpha(V)beta5 integrin receptors. Both monomeric candidates and covalent conjugates revealed potent ligand competence for the alpha(V)beta3 receptor in the one-digit nanomolar range (IC50 alpha(V)beta3 = 0.2-8.0 nM; IC50 alpha(V)beta5 = 5.0-1621 nM), thus demonstrating that conjugation does not impair the exquisite binding profile of this new generation of integrin ligands.

Vicarious silylative Mukaiyama aldol reaction: a vinylogous extension.

A vinylogous, silylative, and direct variant of the venerable Mukaiyama aldol reaction has been developed. Exploiting N-Boc-pyrrol-2(5H)-one as the conjugate donor, several aldehyde and ketone acceptors were scrutinized under the guidance of suitable dual Lewis acid-Lewis base activators to provide a varied repertoire of functionality-rich alpha,beta-unsaturated-gamma-amino-delta-silyloxy carbonyl structures, in useful yields and often with an exquisite level of diastereoselection.

Discovery of subnanomolar arginine-glycine-aspartate-based alphaVbeta3/alphaVbeta5 integrin binders embedding 4-aminoproline residues.

The embodiment of 4-aminoproline residues (Amp) into the arginine-glycine-aspartate (RGD) sequence led to the discovery of a novel class of high-affinity alpha Vbeta 3/alpha Vbeta 5 integrin binders [IC 50 h (alpha Vbeta 3) 0.03-5.12 nM; IC 50 h (alpha Vbeta 5) 0.88-154 nM]. A total of eight cyclopeptides of type cyclo-[-Arg-Gly-Asp-Amp-], 5- 12, were assembled by a standard solid-phase peptide synthesis protocol that involved the C2-carboxyl and C4-amino functionalities of the proline scaffolds, leaving the N (alpha)-nuclear site untouched. Functionalization of this vacant proline site with either alkyl or acyl substituents proved feasible, with significant benefit to the integrin binding capabilities of the ligands. Notably, six out of eight cyclopeptide inhibitors, 5- 7 and 9- 11, showed moderate yet significant selectivity toward the alpha Vbeta 3 receptor. The three-dimensional structure in water was determined by NMR techniques and molecular dynamics calculations. Docking studies to the X-ray crystal structure of the extracellular segment of integrin alpha Vbeta 3 complexed with reference compound 1 were also performed on selected analogues to highlight the structural features required for potent ligand binding affinity.

Diastereoselective synthesis of 4,5'-bis-proline compounds via reductive dimerization of N-acyloxyiminium ions.

A short, practical synthesis of novel, unsymmetrical 4,5'-bis-proline compounds has been achieved, highlighted by the application of an unprecedented samarium diiodide-driven regio- and diastereocontrolled reductive dimerization of N-acyloxyiminium ions generated from readily available 2-methoxy-5-silyloxymethyl-N-Boc pyrrolidines. The title proline dimers proved to be pertinent metal-free catalysts in aldol and Mannich reactions.

Streamlined, asymmetric synthesis of 8,4'-oxyneolignans.

Highly direct, modular syntheses of several natural 8,4'-oxyneolignans [(-)-1, (+)-1, (-)-2, and (-)-3] and some related variants [(-)-26, (+)-26, (+)-27, and (-)-28] are reported. Utilizing (S)- or (R)-methyl lactate as the chiral sources, two complementary syn- or anti-oriented routes were designed, encompassing nine and five steps, which were carried out to deliver the targets in an enantiomerically pure form. The embodiment of the two independent aryl and aryloxy moieties onto the lactate frame was performed according to a diversity-oriented protocol from the common precursors, aldehydes 6 and ent-6 for the syn-oriented routes and mesyl esters 19 and ent-19 for the anti-oriented routes. These syntheses set the stage for the generation of a wide and diverse repertoire of 8,4'-oxyneolignan compounds and the broad biological interrogation of its members.

New enantioselective entry to cycloheptane amino acid polyols.

[reaction: see text] A diversity-oriented protocol has been developed for the assembly of densely hydroxylated cycloheptane amino acids via succession of a vinylogous Mukaiyama aldol reaction (VMAR), a Morita-Baylis-Hillman reaction (MBHR), and an intramolecular pinacol coupling reaction (IPCR). The plan utilizes D- or L-configured glyceraldehyde derivatives as "chiral" surrogates of glyoxal and N-[(tert-butoxycarbonyl)-2-(tert-butyldimethylsilyl)oxy]pyrrole as the synthetic equivalent of the alpha,gamma-dianion of gamma-aminobutanoic acid. The parallel, asymmetric syntheses of four cycloheptane representatives proceed with high diastereocontrol and virtually complete enantioselectivity in ten steps and overall yields of 15-37%.

Grafting aminocyclopentane carboxylic acids onto the RGD tripeptide sequence generates low nanomolar alphaVbeta3/alphaVbeta5 integrin dual binders.

Eleven gamma-aminocyclopentane carboxylic acid (Acpca) platforms, including four dihydroxy representatives (19-22), three hydroxy analogues (34-36), and four deoxy derivatives (30-33), were prepared in a chiral nonracemic format. These simple units were then grafted onto an Arg-Gly-Asp (RGD) tripeptide framework by a mixed solid phase/solution protocol delivering an ensemble of 11 macrocyclic analogues of type cyclo-[-Arg-Gly-Asp-Acpca-], 1-11. The individual compounds were evaluated for their binding affinity toward the alphaVbeta3 and alphaVbeta5 integrin receptors. The analogue 10 exhibited a very interesting activity profile (IC50/alphaVbeta3= 1.5 nM; IC50/alphaVbeta5= 0.59 nM), comparable to that of reference compounds EMD121974 and ST1646. Closely related congeners 6, 8, and 9 also proved to be excellent dual binders with activity levels in the low nanomolar range. The three-dimensional (3D) NMR solution structures were determined, and docking studies to X-ray crystal structure of the extracellular segment of integrin alphaVbeta3 in complex with the reference compound EMD121974 were performed on selected analogues to elucidate the interplay between structure and function in these systems and to evidence the subtle bases for receptorial recognition. The results prove that the principle of isosteric dipeptide replacement for peptidomimetics design and synthesis can be violated, without detriment to the development of highly effective integrin binders.