N-acyl Aziridines Research Articles

The reactivity and conformational control of cyclic tetrapeptides derived from aziridine-containing amino acids.

Among the smallest of the macrocyclic peptides, 12- and 13-membered cyclic tetrapeptides are particularly noteworthy because they exhibit a broad spectrum of biological activities due to their innate capacity to mimic β-turns in proteins. In this report, we demonstrate that aziridine-containing cyclic tetrapeptides offer a platform to interrogate the conformational properties of tetrapeptides. We show that aziridine ring-opening of 12-membered cyclic tetrapeptides yields exclusively 13-membered α3β macrocycles, regardless of peptide sequence, nucleophile, aziridine β-carbon substitution, or stereochemistry. NMR and computational studies on two related aziridine-containing cyclic tetrapeptides revealed that the amide conformations of their N-acyl aziridines are similar, and are likely the determinant of the observed ring-opening regioselectivity. Interestingly, some of the resulting 13-membered α3β macrocycles were found to be conformationally heterogeneous. This study on the reactivity and conformational control of aziridine-containing cyclic tetrapeptides provides useful insight on the design and development of macrocyclic therapeutics.

ChemInform Abstract: A General Synthesis of Sphinganines Through Multicomponent Catalytic Asymmetric Aziridination.

A catalytic asymmetric synthesis of all four stereoisomers of sphinganine is described starting from hexadecanal. Utilizing either the (R) or (S) enantiomer of a BOROX catalyst, a multicomponent reaction of this aldehyde with an amine and ethyl diazoacetate gives rise to enantiomeric aziridine-2-carboxylates. Access to all diastereomers of sphinganine is realized upon ring opening of the enantiopure aziridine-2-carboxylate at the C-3 position by direct SN2 attack of an oxygen nucleophile, which occurs with inversion of configuration and by ring expansion of an N-acyl aziridine to an oxazolidinone and then hydrolysis. Overall, this process results in the formal ring opening of the aziridine with an oxygen nucleophile with retention of configuration.

Solid-phase synthesis of piperazinones via disrupted Ugi condensation.

The first application of aziridine aldehyde dimers in solid-phase synthesis is reported. The solid-supported disrupted Ugi condensation between an aziridine aldehyde dimer, isonitrile, and backbone-anchored amino acids delivered N-acyl aziridine intermediates, which were reacted with nucleophiles to yield the corresponding piperazinones. Subsequent cleavage from the resin provided a diverse set of 2,3,6-trisubstituted piperazinones starting from various amino acids, aziridine aldehydes, and nucleophiles.

Fe(NO3)3 as an efficient catalyst for regio- and stereo-controlled ring expansion of 1,2-diaroyl-3-arylaziridines

Several 1,2-diaroyl-3-arylaziridines were previously prepared conveniently and used in the preparation of 5-benzoyl-2,4-diaryl oxazolines in the presence of NaI. In this work, synthesis of some trans-4-benzoyl-2,5-diaryl oxazolines by a regio- and stereo-controlled reaction in the presence of Iron (III) nitrate at room temperature is reported. A plausible mechanism has been proposed for ring expansion of N-acyl aziridines to oxazolines.

Preparation of the Geranyl-α-pyrone (±)-Aurantiacone via a New Pyrone Synthesis

The structure of the leaf resin geranyl-α-pyrone auranti-acone isolated from Mimulus ( = Diplacus) aurantiacus (Curtis) Jeps. (Scrophulariaceae) was confirmed through synthesis. The key step is lactonization of the sensitive 5-hydroxy-3-oxopent-4-enoic acid under mild conditions, which can be released from the corresponding bispotassium salt. The latter is accessible in a few steps from an N-acyl aziridine and an ethyl acetoacetate.

A General Process for the Haloamidation of Olefins. Scope and Mechanism

A methodology is described for the addition of a bromine atom and an amide nitrogen in a trans sense to an olefinic double bond. The process, which is illustrated by numerous examples, involves the use of an N-bromoamide and a Lewis acid as a source of Br+ which reacts with the olefin. The amide group is derived from a nitrile and a water molecule which serve as nucleophiles for the overall three-component reaction. The bromoamidation is general for a broad range of olefins and nitriles. This reaction pathway provides access not only to vicinal bromoamides but also to N-acyl aziridines and oxazolines. From these, many types of amines and amino alcohols can be prepared. Examples are provided which delineate diastereo- and regioselectivity preferences. An analogous chloroamidation reaction is also described.

Studies of Acyl Nitrene Insertions. A Stereocontrolled Route toward Lankacidin Antibiotics.

Photochemically generated acyl nitrenes undergo facile addition to 4,5-dihydrofurans 20 and 24b to yield the novel 2-ethoxyoxazolines 21 and 25. The regiocontrolled C=C insertion has provided for introduction of the sterically hindered C-3 amido appendage of the lankacidins 1-4 with high stereoselectivity. High chemoselectivity for the C=C insertion pathway was demonstrated upon production of the acyl nitrene intermediate from azide 33b. Intramolecular competition for allylic C(3)-H insertion versus C=C addition yielded exclusive formation of seven-membered N-acyl aziridines 34a,b. The latent aldehydic functionality of oxazolines such as 21 and 25 is exposed upon a brief hydrolysis, permitting further chemical elaboration. Wittig condensation of the lactol from 25 has led to the synthesis of the lactone fragment 5, containing all of the necessary stereochemistry and functionality for incorporation into the lankacidin antibiotics. The acyl nitrene insertion into 4,5-dihydrofurans affords a route toward unusual beta-amido acids and amino sugar derivatives as shown via stereocontrolled formation of the amidofuranose derivatives 31 and 32. The three-step process of acyl nitrene addition, hydrolysis of the resulting 2,5-dialkoxy oxazoline intermediates, and Wittig carbon chain elongation provides the stereocontrolled formation of novel beta-amido esters.

Ring expansion of N-acyl aziridine-2-imides to oxazoline-4-imides, useful precursors of pure β-Hydroxy α-aminoacids

Optically active N-acyl aziridine 2-imides or 2-carboxylates rearrange to oxazoline-4-imides or 4-carboxylates with high regio and stereo control. This ring expansion followed by mild hydrolisis allows the synthesis of enantiomerically pure β-hydroxy α-aminoacid precursors.

N-acyl aziridines - C-acylating agents for the preparation of polyketides

A one-pot synthesis of N-acylaziridines from carboxylic acids has been developed, and their reaction with dianions derived from β-ketoesters studied. The aziridines were found to be efficient C-acylating agents, giving polyketide-like products in good overall yields.

A convenient synthesis of chiral N-Boc-amino ethers as potential peptide bond surrogate units

Boron triflouride etherate and zinc triflate have been found to be effective catalysists for the synthetic route to chiral N-Boc-amino ethers via a Lewis acid-catalyzed ring-opening of N-acyl aziridines, derived from chiral amino acids.

An investigation of the mitsunobu reaction in the preparation of peptide oxazolines, thiazolines, and aziridines

The diisopropyl azodicarboxylate-triphenylphosphine mediated cyclization of serine and allo-threonine derivatives provides peptide oxazolines, whereas cyclization of threonine containing substrates leads to N-acyl aziridines. In the thiopeptide series, only thiazolines are obtained. The presence of a moderately strong base is necessary for the formation of aziridines from threonine peptides.

Wittig olefination in the absence of an exogenous base: A new synthesis of α-substituted primary allylic amines.

A new synthesis of α-substituted primary allylic amines through the in situ generation and trapping of an ylide from the reaction of an N-acyl aziridine, triphenylphosphine, and an aldehyde in refluxing isopropanol is reported. These compounds can be prepared enantioselectively (>94.6% ee) by employing a chiral nonracemic N-acyl aziridine.

The Stereospecific Cyclization of A Threo α-Benzamide Alcohol to A Cis N-Acyl Aziridine

Abstract Treatment of threo α-benzamide alcohol 3b with triphenylphosphine and diethyl azodicarboxylate gave solely the cis N-acyl aziridine 5b.

Nucleophilic ring opening of aziridine-2-carboxylates with Wittig reagents; an enantioefficient synthesis of unsaturated amino acids

Reaction of N-tosyl- or N-acyl aziridine-(2S)-carboxylate esters with carbonyl stabilized Wittig reagents provides an isolable phosphorus ylide resulting from opening of the aziridine ring; this ylide reacts with carbonyl compounds to provide a novel synthesis of optically pure unsaturated amino acids, exemplified by enantioefficient syntheses of the naturally occuring (2S)-γ-methyleneglutamic acid and (E)-(2S)-4-ethylideneglutamic acid.

Reactions with aziridines XXI The (Michaelis-)arbusov reaction with N-acyl aziridines and other amidoethylations at phosphorus.

Heating trialkyl phosphites with N-acyl aziridines produces dialkyl 2-amidoethyl-phosphonates bearing one of the phosphite alkyl groups on nitrogen. Other alkoxy phosphines behave analogously. Dialkyl phosphites furnish the same type of products devoid of the N-alkyl group.