Letters in Organic Chemistry - Volume 15, Issue 5, 2018

In the search for synthetic routes for the preparation of cis- and trans- decahydroquinolin-2- ones, a procedure for the generation of enantiopure trans-hydrochromene lactones, by treatment of (R)- phenylglycinol-derived oxazoloquinolone lactams with Na/liq. NH3 followed by acidification, has been developed.

A novel bis(1,2,4-triazin-3-yl)-dppz (dipyridophenazine) BTPhen ligand has been synthesised and screened for its ability to selectively extract Am(III) selectively from Eu(III) from 0.001 M – 2 M HNO3. The ligand showed preferential extraction for Am(III) over Eu(III) as the [HNO3] increased towards 2 M with a reported separation factor (SFAm/Eu) of ∼225. The synthesis towards the dppz-BTPhen ligand employs a truncated synthetic approach, involving two one-pot reactions.

The addition of but-3-enylmagnesium bromide and pent-4-enylmagnesium bromide to N-tert-butanesulfinyl aldimines in toluene as solvent proceeds with high diastereoselectivity to yield the corresponding products of homoallylation and bis-homoallylation, respectively. The reactions are diastereoselective, and the configuration of the sulfur atom of the sulfinyl group determined the stereochemical outcome. The reaction products are aminoalkene derivatives of potential synthetic interest as precursors of nitrogen containing heterocycles.

2-Azidocyclopropane-1,1-dicarboxylic esters were transformed into orthogonally N-protected alkyl 1-amino-2-azidocyclopropanecarboxylates via stereoselective monosaponification and subsequent Curtius reaction. Following deprotection of the ester function or the Boc-protected amino group, the first derivatives of a novel class of conformationally constrained cyclopropane α,β-diamino carboxylic acids were made accessible.

The Mitsunobu reaction was employed in a key step during the development of a convenient synthetic route for the enantioselective preparation of pyrrolidine-sulfamide ligands from (R)- or (S)- [(S)-1-benzylpyrrolidin-2-yl](phenyl)methanol, and employing tert-butyl pyrrolidin-1-yl-sulfonylcarbamate as a non-conventional nucleophilic source. Although it is well documented that the exposure of this type of diastereomeric amino alcohols to the above-mentioned nucleophile usually leads to the formation of piperidines via ring expansion, either through classical nucleophilic substitution or the Mitsunobu version, only the pyrrolidine derivatives were generated with retention of configuration on the exocyclic stereocenter, owing to the neighboring group participation (internal backside nucleophilic substitution, SNib). Final removal of the N-Boc protecting group from the sulfamide fragment afforded chiral compounds with significant potential as chiral ligands in asymmetric catalysis.

An efficient procedure for the direct arylation of pyrrolidine with phenols and naphtols is reported. Upon reaction with catalytic amounts of a binuclear copper(II)-7-azaindole complex under an atmosphere of oxygen, pyrrolidine is smoothly oxidized to the corresponding imine which can be trapped in situ by a series of phenols and naphtols in fair to good yields. This copper-catalyzed direct oxidative arylation of pyrrolidine offers an efficient entry to α-aryl-pyrrolidines in a single step and without the need for protecting or directing groups.

O-Unsaturated alkoxyamines are versatile compounds that can be cyclized to heterocyclic 5-membered rings by using onium ions, transition metals, Brønsted and Lewis acids. O-Allylic and O-homoallylic alkoxyamines can be transformed to isoxazolidines, O-allenyl alkoxyamines to isoxazolidines as well as to 2-isoxazolines and O-alkynyl alkoxyamines to 2- or 3-isoxazolines as well as to isoxazoles.

Direct hydroxymethylation of C=N double bonds including imines, nitrones, oximes, hydrazones and iminium salts is a less explored synthetic approach to 1,2-amino alcohols that provides good alternatives to the classical methods. The review deals with nucleophilic additions of organometallic hydroxymethyl reagents and lithiated alkoxyallenes to C=N double bonds. Reductive cross couplings between C=N double bonds and aldehydes or ketones are also discussed.

Secondary phosphine oxides (SPOs) are important starting materials in organophosphorus syntheses, and may be the ligands in transition metal complexes. SPOs are obtained from phosphorus trichloride via double substitution by a Grignard reagent followed by hydrolysis, or from dialkyl phosphites by reaction with two equivalents of a Grignard reagent. The preparation of SPOs with two different substituents is of special importance. This minireview gives useful hints for the synthesis of a variety of SPOs that are useful intermediates.

Organocatalyzed (4+2) cycloadditions (Diels-Alder reactions) are reviewed in this manuscript. Among the different catalytic alternatives, reactions involving α,β-unsaturated ketones and alkenes are considered. In these processes, substituted cyclohexanones are obtained via HOMO activation generated by amine organocatalysis that generate transient dienamine species. Both concerted and stepwise mechanisms are described. In most cases, excellent regio-, diastereo- and enantiocontrol have been observed.

trans-Fused octahydroisoindole-1-carboxylic acids are bicyclic proline analogues of potential interest in the search for new drugs. Within this work, the trans-fused octahydroisoindole system has been constructed using methyl trans-2-(hydroxymethyl)cyclohexane-1-carboxylate as the key synthetic precursor, in turn readily prepared from inexpensive cis-cyclohexane-1,2-dicarboxylic anhydride. Both the (1S*,3aR*,7aR*)- and the (1R*,3aR*,7aR*)-octahydroisoindole-1-carboxylic acids were prepared through the Strecker reaction of methyl trans-2-formylcyclohexane-1-carboxylate as the key step. Finally, (1S*,3aR*,7aR*)-octahydroisoindole-1-carboxylic acid was obtained with good yields in a highly stereoselective manner using (3aR*,7aR*)-octahydroisoindole-1-one as a suitable scaffold.

Acetone-d6 has been transformed for the first time to 4,4-bis(methylthio)but-3-en-2-one- 1,1,1,3-d4. This tetradeutero-α-oxoketenedithioacetal is shown to be an excellent 1,3-dielectrophilic building block for the synthesis of 5- and 6-membered deuterated heterocycles and aromatics.

The first examples of intramolecular Pauson-Khand reactions involving ketenimines are reported. The alkyne-ketenimines participate through the C=C bond of the ketenimine fragment in the [2+2+1] cyclization process giving rise to cyclopenta[b]quinolin-2-ones. In the absence of metal carbonyl complexes, two competitive periselective cycloadditions occur when the alkyne-ketenimines are heated in benzene solution: a [4+2] process leading to benz[b]acridines as the major products, and a [2+2] route giving minor amounts of cyclobuta[b]quinolines.

Macrobicycles comprising a central diazacrown structural unit were modified with two 3-bromobenzyl substituents and the resulting compounds were introduced in Pd(0)-catalyzed macrocyclization reactions with trioxadiamine, to give cryptand-like macrotricycles. In the second approach, diazacrown ethers were substituted with two 3,5-dibromobenzyl groups and their Pd(0)-catalyzed double macrocyclization with a series of oxadiamines produced a new family of trimacrocyclic compounds; the Pd(dba)2/RuPhos catalytic system was found to be the most efficient. The decoration of one trimacrocycle with four dansyl fluorophore groups produced a fluorescent molecular probe for Cu(II) and Al(III) cations.

Enantiopure exo-4-nitro-3,5-diphenylproline reacts with aldehydes and electrophilic alkenes, in good yields, through a multicomponent 1,3-dipolar cycloaddition where the intermediate azomethine ylide is generated by the decarboxylative route. The reactions with maleimides afford diastereoselectively nitropyrrolizidines. Dimethyl fumarate and 1,2-bis(phenylsulfonyl)ethylene also give variable mixtures of diastereoisomeric nitropyrrolizidines. The replacement of aldehydes by phenyl-3-buten-2- one also affords satisfactory results with high diastereoselection although in lower yields. The stereochemical outcome is studied and defined according to the absolute configuration of the resulting cycloadducts.

A new synthesis of unsymmetrically substituted imidazo[1,2-a]quinoxalines via regioselective displacement of 3-chloro group in 2-(methylthio)-3-chloroquinoxalines by aminoacetaldehyde dimethylacetal and subsequent-acid mediated intramolecular cyclization of the resulting adducts is reported in this study. The utility of the 3-(methylthio) group in these imidazoquinoxalines is also demonstrated by conversion of one of the 2-(methylthio)quinoxalines to 2-(methylsulfonyl) derivative and its subsequent displacement by hydroxy-, phenoxy- and n-butylamino groups, thus affording various 2-substituted imidazo[1,2-a]quinoxalines.

The present work reports a study on the isomerization reactions of several alkyl epoxides to the corresponding allylic alcohols or bicyclic alcohols under microwave irradiation. The reaction occurred in the presence of lithium diisopropylamide as a base and different experimental conditions in terms of solvent, amount of the base, times and temperatures. The traditional heating with an oil-bath and the use of alternative organometallic bases, as the Lochmann-Schlosser bases, have been furthermore compared with the microwave heating. The results obtained show that the use of microwave irradiations on promoting the isomerization of epoxides gives access to a series of synthetically useful products, among which allylic alcohols and bicyclic alcohols, depending on the starting substrate.

We have recently developed three antitrypanosomal leads that feature a unit of huprine or (6-chloro-)tacrine linked to a 8-cyanooctyl side chain, which, unfortunately, exhibit very potent (low nanomolar) acetylcholinesterase (AChE) inhibitory activity, which might lead to unwanted cholinergic side-effects. Because huprine and tacrine moieties impart high acetylcholinesterasic potency, we have explored their replacement by alternative heteroaromatic systems (thiazolylbenzamido, quinoxalinecarboxamido, benzimidazolecarboxamido, and benzothiazolylamino moieties), while retaining the 8- cyanooctyl side chain. These structural modifications led to the desired drop in AChE inhibitory activity (low micromolar), albeit at the expense of the antitrypanosomal potency. However, despite the lower AChE inhibitory activity of the novel compounds compared to that of the initial leads, their potency is comparable to that of some AChE inhibitors currently approved for Alzheimer's disease (AD) treatment. They are brain permeable and less lipophilic than the leads, thereby emerging as interesting novel hits for future AChE inhibitor-based AD drug discovery programs.