Enantioselective synthesis of α-aryl α-hydrazino phosphonates.

Catalysts generated in situ by the combination of pyridine-hydrazone N,N-ligands and Pd(TFA)2 have been applied to the addition of arylboronic acids to formylphosphonate-derived hydrazones, yielding α-aryl α-hydrazino phosphonates in excellent enantioselectivities (96 → 99% ee). Subsequent removal of the benzyloxycarbonyl (Cbz) N-protecting group afforded key building blocks en route to appealing artificial peptides, herbicides and antitumoral derivatives. Experimental and computational data support a stereochemical model based on aryl-palladium intermediates in which the phosphono hydrazone coordinates in its Z-configuration, maximizing the interactions between the substrate and the pyridine-hydrazone ligand.

Asymmetric Dearomatization of Phthalazines by Anion-Binding Catalysis.

A straightforward methodology for the enantioselective synthesis of 1,2-dihydrophthalazines via dearomatization of phthalazines by anion-binding catalysis has been developed. The process involves the Mannich-type addition of silyl ketene acetals to in situ generated N-acylphthalazinium chlorides using a tert-leucine derived thiourea as a H-bond donor catalyst. Ensuing selective and high-yielding transformations provide appealing dihydro- and tetrahydro-phthalazines, phthalazones, and piperazic acid homologues, en route to biologically relevant molecules.

Silver-Free Gold-Catalyzed Heterocyclizations through Intermolecular H-Bonding Activation.

Modulable monosulfonyl squaramides have been shown to exert activation of gold(I) chloride complexes through H-bonding in an intermolecular way. Combinations of (PPh3)AuCl or IPrAuCl complexes and an optimal sulfonyl squaramide cocatalyst bearing two 3,5-bis(trifluoromethyl)phenyl groups efficiently catalyzed diverse heterocyclizations and a cyclopropanation reaction, avoiding in all cases undesired side reactions. Computational studies indicate that the Au-Cl bond breaks by transligation to the triple bond in a ternary complex formed by the actual AuCl···HBD catalyst and the substrate.

Asymmetric cross-aldol reactions of α-keto hydrazones and α,ß-unsaturated γ-keto hydrazones with trifluoromethyl ketones.

α-Keto hydrazones and α,ß-unsaturated γ-keto hydrazones are suitable pro-nucleophiles for asymmetric cross-aldol reactions with trifluoromethyl ketones via aza-di(tri)enamine-type intermediates. A quinidine-derived primary amine catalyst affords tertiary trifluoromethylated alcohols in good-to-excellent yields and high enantioselectivities. Subsequent transformations of hydrazono moieties yield appealing fluorinated carboxylic acids, 1,4-dicarbonyls and γ-keto acids.

Enantio- and Diastereoselective Nucleophilic Addition of N-tert-Butylhydrazones to Isoquinolinium Ions through Anion-Binding Catalysis.

A highly enantio- and diastereoselective thiourea-catalyzed dearomatization of isoquinolines employing N-tert-butylhydrazones as neutral α-azo carbanions and masked acyl anion equivalents has been developed. Experimental and computational data supports the generation of highly ordered complexes wherein the chloride behaves as a template for the catalyst, the hydrazone reagent, and the isoquinolinium cation, providing excellent stereocontrol in the formation of two contiguous stereogenic centers. The ensuing selective and high-yielding transformations provide appealing dihydroisoquinoline derivatives.

Formaldehyde tert-butyl hydrazone as a formyl anion equivalent: asymmetric addition to carbonyl compounds.

The asymmetric 1,2-addition of formyl anion equivalents to carbonyl compounds is a powerful synthetic tool that ideally provide access to highly functionalizable α-hydroxy aldehydes in an enantioselective fashion. In this context, the nucleophilic character of formaldehyde hydrazones, together with their remarkable stability as monomeric species, has been exploited for the functionalization of diverse carbonyl compounds, using initially auxiliary-based methodologies and, more recently, catalytic enantioselective versions. This feature article highlights our research progress employing formaldehyde tert-butyl hydrazone as a versatile formyl anion equivalent, in combination with bifunctional H-bonding organocatalysis. The design and optimization of different catalytic systems, focusing on a dual activation of both reagents, is reviewed, as well as the racemization free unmasking of the formyl group and representative product transformations for the construction of valuable, densely functionalyzed chiral building blocks.

Catalytic enantioselective synthesis of α-aryl α-hydrazino esters and amides.

Catalysts generated by combinations of Pd(TFA)2 and pyridine-hydrazone ligands have allowed the asymmetric 1,2-addition of aryl boronic acids to N-carbamoyl (Cbz and Fmoc) protected glyoxylate-derived hydrazones, yielding α-aryl α-hydrazino esters/amides in high enantioselectivities. Subsequent removal of the carbamoyl moiety affords key building blocks en route to hydrazinopeptides, N-aminopeptides and peptidomimetics thereof.

Bifunctional Squaramide Organocatalysts for the Asymmetric Addition of Formaldehyde tert-Butylhydrazone to Simple Aldehydes.

The nucleophilic addition of formaldehyde tert-butylhydrazone to simple aldehydes (a formal hetero-carbonyl-ene reaction) can be performed with good reactivity and excellent enantioselectivity by virtue of the dual hydrogen-bonding activation exerted by amide-squaramide organocatalysts. The resulting hydroxydiazenes (azo alcohols) were isolated in high yields as enantiomerically enriched azoxy compounds after a regioselective azo-to-azoxy transformation. Subsequent derivatization provides an entry to relevant amino alcohols, oxazolidinones, and derivatives thereof.

Asymmetric organocatalytic synthesis of tertiary azomethyl alcohols: key intermediates towards azoxy compounds and α-hydroxy-ß-amino esters.

A series of peracylated glycosamine-derived thioureas have been synthesized and their behavior as bifunctional organocatalysts has been tested in the enantioselective nucleophilic addition of formaldehyde tert-butyl hydrazone to aliphatic α-keto esters for the synthesis of tertiary azomethyl alcohols. Using the 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-ß-d-glucosamine derived 3,5-bis-(trifluoromethyl)phenyl thiourea the reaction could be accomplished with high yields (75-98%) and moderate enantioselectivities (50-64% ee). Subsequent high-yielding and racemization-free tranformations of both aromatic- and aliphatic-substituted diazene products in a one pot fashion provide a direct entry to valuable azoxy compounds and α-hydroxy-ß-amino esters.

Hydrazones as Singular Reagents in Asymmetric Organocatalysis.

This Minireview summarizes strategies and developments regarding the use of hydrazones as reagents in asymmetric organocatalysis, their distinct roles in nucleophile-electrophile, cycloaddition, and cyclization reactions. The key structural elements governing the reactivity of these reagents in a preferred pathway will be discussed, as well as their different interactions with organocatalysts, leading to diverse activation modes. Along these studies, the synthetic equivalence of N-monoalkyl, N,N-dialkyl, and N-acyl hydrazones with several synthons is also highlighted. Emphasis is also put on the mechanistic studies performed to understand the observed reactivities. Finally, the functional group transformations performed from the available products has also been analyzed, highlighting the synthetic value of these methodologies, which served to access numerous families of valuable multifunctional compounds and nitrogen-containing heterocycles.

Pyridine-Hydrazones as N,N'-Ligands in Asymmetric Catalysis: Pd(II)-Catalyzed Addition of Boronic Acids to Cyclic Sulfonylketimines.

The design, synthesis, and coordination features of a novel class of chiral pyridine-hydrazone ligands are described. As a first application, L/Pd(TFA)2 complexes served as catalysts in the 1,2-addition of arylboronic acids to saccharin-derived cyclic ketimines, affording products in high yields and enantioselectivities. The method was also applied to more challenging 3,4-disubstituted 1,2,5-thiadiazole 1,1-dioxides, affording again high yields and enantioselectivities along with high regioselectivities for unsymmetrically substituted derivatives.

Masked unsaturated esters/amides in asymmetric organocatalysis.

This Concept article summarizes strategies and developments regarding the use of masked unsaturated esters/amides in asymmetric organocatalysis. Useful substrates are categorized by the design of their inherent carboxylate template. This template group not only enables their functionality as ester surrogates, but also define their accessibilities, modes of interactions with catalysts and the simplicity with which they transform back to the parent carboxylates. Both covalent and noncovalent catalytic systems are discussed and examples showing the entire process (from substrates-to-functionalized ester/amides) are given.

Asymmetric organocatalytic synthesis of quaternary α-hydroxy phosphonates: en route to α-aryl phosphaisoserines.

The dual activation of acyl phosphonates and formaldehyde tert-butyl hydrazone by a BINAM-derived bis-urea catalyst is the key to achieve high reactivities and enantioselectivities in the synthesis of densely functionalized quaternary α-hydroxy phosphonates. Subsequent high-yielding transformations in a 'one-pot' fashion provide direct access to valuable azoxy compounds and quaternary α-aryl-phosphaisoserines.

Asymmetric organocatalytic Strecker-type reactions of aliphatic N,N-dialkylhydrazones.

The enantioselective organocatalytic Strecker-type reaction of aliphatic N,N-dialkylhydrazones is presented. Using trimethylsilyl cyanide (TMSCN) as the cyanide source, the reaction can be efficiently catalyzed by a tert-leucine-derived bifunctional thiourea to afford the corresponding hydrazino nitriles in good to excellent yields (50-96%) and moderate to good enantioselectivities, up to 86% ee. Further transformations of the nitrile functionality allow access to useful protected hydrazino acids and imidazolidinones. Interestingly, some of the hydrazino nitriles and their derivatives could be recrystallized in high recovery, yielding essentially pure enantiomers.

Dual organocatalytic activation of isatins and formaldehyde tert-butyl hydrazone: asymmetric synthesis of functionalized 3-hydroxy-2-oxindoles.

Two is better than one! Dual activation of isatins and formaldehyde tert-butyl hydrazone by 2,2'-diamino-1,1'-binaphthalene (BINAM)-derived bis(ureas) is the key to achieve high reactivity and excellent enantioselectivities in the synthesis of azo- and azoxy-functionalized 3-hydroxy-2-oxindoles (see scheme).

Synthesis of enantioenriched azo compounds: organocatalytic Michael addition of formaldehyde N-tert-butyl hydrazone to nitroalkenes.

The unprecedented diaza-ene reaction of formaldehyde N-tert-butyl hydrazone with nitroalkenes can be efficiently catalyzed by an axially chiral bis-thiourea to afford the corresponding diazenes in good to excellent yields (60-96%) and moderate enantioselectivities, up to 84 : 16 er; additional transformation of diazenes into their tautomeric hydrazones proved to be operationally simple and high-yielding, affording bifunctional compounds which represent useful intermediates for the synthesis of enantioenriched ß-nitro-nitriles and derivatives thereof.

Asymmetric formal carbonyl-ene reactions of formaldehyde tert-butyl hydrazone with α-keto esters: dual activation by bis-urea catalysts.

The dual activation of α-keto esters and formaldehyde tert-butyl hydrazone by BINAM-derived bis-ureas is the key to achieve high reactivity and excellent enantioselectivities in nucleophilic addition (formal carbonyl-ene reaction) to functionalized tertiary carbinols. Ensuing high-yielding diazene-to-aldehyde tranformations and subsequent derivatizations provides a direct entry to a variety of densely functionalized products.

Synthesis of 1,2,4-triazolines: base-catalyzed hydrazination/cyclization cascade of α-isocyano esters and amides.

A convenient, efficient synthesis of 1,2,4-triazolines from α-isocyano esters/amides and azodicarboxylates is presented. The developed reaction cascade is based on a base-catalyzed hydrazination-type reaction followed by a subsequent cyclization providing the triazolines in good to excellent yields (75-99%). Phosphine-catalyzed and preliminary asymmetric phase-transfer catalysis approaches have also been investigated.

Asymmetric one-pot sequential organo- and gold catalysis for the enantioselective synthesis of dihydropyrrole derivatives.

A direct asymmetric one-pot synthesis of optically active 2,3-dihydropyrroles from propargylated malononitrile and N-Boc-protected (Boc = tert-butoxycarbonyl) imines is presented. The approach is based on a bifunctional organocatalytic Mannich-type reaction and a subsequent gold-catalyzed alkyne hydroamination and isomerization. The compatibility of both catalytic systems is presented and the overall transformation results in good yields (up to 70 %) with high selectivities (endo/exo > 10:1) and enantioselectivities (up to 88 % ee). The absolute configuration of the final products is unambiguously established by X-ray analysis. To highlight the synthetic potential of the accessed heterocyclic compounds, their transformation into 1-pyrrolines, which represent direct precursors of pyrrolidines, is presented.