Atom Economical Multi-Substituted Pyrrole Synthesis from Aziridine.

Multi-substituted pyrroles are synthesized from regiospecific aziridine ring-opening and subsequent intramolecular cyclization with a carbonyl group at the γ-position in the presence of Lewis acid or protic acid. This method is highly atom economical where all the atoms of the reactants are incorporated into the final product with the removal of water. This new protocol is applied to the synthesis of various pyrroles, including natural products.

Preface to "Aziridine Chemistry".

Aziridine is a nitrogen-containing three-membered ring with similar ring strain energy as other three-membered ring compounds, including cyclopropane and oxirane [...].

Synthetic Applications of Aziridinium Ions.

Nonactivated aziridine with an electron-donating group at the ring nitrogen should be activated to an aziridinium ion prior to being converted to cyclic and acyclic nitrogen-containing molecules. This review describes ways to generate aziridinium ions and their utilization for synthetic purposes. Specifically, the intra- and intermolecular formation of aziridinium ions with proper electrophiles are classified, and their regio- and stereoselective transformations with nucleophiles are described on the basis of recent developments.

Alkylative Aziridine Ring-Opening Reactions.

In this study, the highly strained three-membered aziridine ring was successfully activated as the aziridinium ion by alkylation of the ring nitrogen with a methyl, ethyl or allyl group, which was followed by ring opening with external nucleophiles such as acetate and azide. Such alkylative aziridine ring opening provides an easy route for the synthesis of various N-alkylated amine-containing molecules with concomitant introduction of an external nucleophile at either its α- or ß-position.

Stereoselective synthesis of 2,6-disubstituted piperidine alkaloids.

Among the large number of structurally diverse alkaloids, 2,6-disubstituted piperidine and its analogs have often been targeted when exploiting new synthetic techniques perhaps because of their strong pharmacological properties. This review outlines synthetic strategies to build the 2,6-disubstituted piperidine structural motif with a focus on stereochemical control of two substituents at C2 and C6. The key reactions in this process are then classified on the basis of how the piperidine rings were built with specific examples of natural products that control the stereochemical outcomes and their transition states.

Lewis acid-mediated synthesis of mono- and tris-indole adducts from chiral aziridines.

Lewis acid-mediated regio- and stereoselective nucleophilic addition of 2- or 3-substituted indoles to non-activated aziridine-2-carboxaldehydes in dioxane afforded 2-(indol-3-ylhydroxymethyl)aziridines whose ring opening with various nucleophiles rendered multi-substituted tryptamine derivatives. The reaction of the same aziridine-2-carboxaldehyde with three moles of indole in dichloromethane yielded tris-indole adducts ß-(3,3'-bisindolyl)methyl (BIM) tryptamines from sequential steps including nucleophilic addition to aldehyde, Michael type Friedel-Crafts alkylation of the mono-adduct followed by regio- and stereoselective ring-opening of the aziridine ring.

Total Synthesis and Absolute Stereochemical Assignment of Microgrewiapine A and Its Stereoisomers.

Total synthesis of both enantiomers of (-)-(2 S,3 R,6 S)- and (+)-(2 R,3 S,6 R)-microgrewiapine A along with (+)-microcosamine A and (-)-6- epi-microgrewiapine A from chiral 1-(α-methylbenzyl)-aziridine-2-carboxylate was accomplished for the first time. Key steps involved in this synthesis include one-pot reductive ring-opening of aziridine, debenzylation, intramolecular N-alkylation to obtain the key piperidine ring, and Julia-Kociensky olefination. The absolute configuration of natural microgrewiapine A is assigned as (+)-(2 R,3 S,6 R), which is opposite to the originally proposed structure by comparing optical rotation data of both synthetic enantiomers.

Metal-free aza-Claisen type ring expansion of vinyl aziridines: an expeditious synthesis of seven membered N-heterocycles.

A metal-free approach for the synthesis of 7-membered aza-heterocycles has been developed by the intermolecular [5 + 2] cycloaddition of non-activated vinylaziridines and alkynes. This method has a broad substrate scope under mild reaction conditions to afford structurally diverse 7-membered N-heterocycles in high yield up to 92%.

Preparation of Chiral Contiguous Epoxyaziridines and Their Regioselective Ring-Opening for Drug Syntheses.

Synthetically valuable chiral (aziridin-2-yl)oxirane-3-carbaldehydes bearing three consecutive functional groups including aziridine, epoxide, and aldehyde were prepared from the stereoselective epoxidation of (aziridin-2-yl)acrylaldehydes with H2 O2 using organocatalyst (2R)- or (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as organocatalyst. The regioselective ring opening of aziridines and epoxides enabled us to achieve the highly efficient asymmetric synthesis of the antibiotic edeine D fragment 3-hydroxy-4,5-diaminopenatanoic acid, an intermediate for the formal synthesis of non-proteinogenic amino acid (-)-galantinic acid, and for potent antifungal agent (+)-preussin, and the medicinally important framework 3-hydroxy-2-hydroxymethylpyrrolidine.

Morita-Baylis-Hillman reaction of a chiral aziridine aldehyde.

The Morita-Baylis-Hillman reaction of (R)-1-((R)-1-phenylethyl)aziridine-2-carbaldehyde with alkyl acrylate was carried out under various conditions by changing solvents, bases, and alcohol additives. The reaction at room temperature under neat conditions (no solvent) with quinuclidine as an amine nucleophile, in the presence of benzyl alcohol as an additive, afforded a product, γ-(aziridin-2-yl)-ß-hydroxy-α-methylene butanoate, in 97% yield with a diastereomeric ratio of anti and syn as 86 : 14.

Theoretical insight into the regioselective ring-expansions of bicyclic aziridinium ions.

Transient bicyclic aziridinium ions are known to undergo ring-expansion reactions, paving the way to functionalized nitrogen-containing heterocycles. In this study, the regioselectivity observed in the ring-expansion reactions of 1-azoniabicyclo[n.1.0]alkanes was investigated from a computational viewpoint to study the ring-expansion pathways of two bicyclic systems with different ring sizes. Moreover, several nucleophiles leading to different experimental results were investigated. The effect of solvation was taken into account using both explicit and implicit solvent models. This theoretical rationalization provides valuable insight into the observed regioselectivity and may be used as a predictive tool in future studies.

Mixed Monosilyl Acetals and Catalyst-Dependent Chemoselective Mukaiyama Aldol Reactions.

We report a direct, simple, and straightforward approach for the construction of a mixed monosilyl acetal as a new and synthetically valuable functional group by mixing an aldehyde, sodium tert-butoxide, and trimethylsilyl azide. We also demonstrate a catalyst-dependent chemoselective reaction between mixed monosilyl acetals and silyl ketene acetals through Mukaiyama aldol reactions to give different structures of O-protected ß-hydroxy esters in excellent yields with high chemoselectivities. This study provided the existence of an oxonium ion intermediate and of its kinetically controlled reaction with the pre-equilibrated silyl enol ether obtained from (E)- and (Z)-isomerization.

Selective Ring-Opening of N-Alkyl Pyrrolidines with Chloroformates to 4-Chlorobutyl Carbamates.

Our study shows that among aza-heterocycles of various ring sizes, including aziridines, azetidines, pyrrolidines, and piperidines, only N-alkyl pyrrolidines undergo competitive reaction pathways with chloroformates to yield N-dealkylated pyrrolidines and 4-chlorobutyl carbamates. The pathway taken depends on the substituent on the nitrogen, i.e., ring-opening with methyl and ethyl substituents and dealkylation with a benzyl substituent. Computational calculations support the substituent-dependent product formation by showing the energy difference between the transition states of both reaction pathways. Selective ring-opening reactions of N-methyl and N-ethyl pyrrolidine derivatives with chloroformates were utilized to prepare various 4-chlorobutyl carbamate derivatives as valuable 1,4-bifunctional compounds.

One-pot multiple reactions: asymmetric synthesis of 2,6-cis-disubstituted piperidine alkaloids from chiral aziridine.

A divergent, new, and highly stereoselective synthesis of cis-2,6-disubstituted piperidine natural products including isosolenopsins, deoxocassine, and spectaline was achieved from chiral aziridine decorated with appropriate alkyl chains for isosolenopsins or alkynyl groups for deoxocassine and spectaline at C2. The characteristic feature of this synthesis is one-pot sequential reactions under atmospheric hydrogen including the reduction of alkyne (for deoxocassine and spectaline), reductive ring-opening of aziridine, debenzylation, and intramolecular reductive amination in high yields. The prerequisite aziridines were elaborated from commercially available (2S)-hydroxymethylaziridine through oxidation, Wittig olefination, and the Grignard reaction for isosolenopsins or substrate-controlled lithium alkynylate addition for deoxocassine and spectaline.

Stereoselective Pd-catalyzed etherification and asymmetric synthesis of furanomycin and its analogues from a chiral aziridine.

A chiral aziridine was utilized for the synthesis of the anti-bacterial natural amino acid L-(+)-furanomycin, and its analogues including 5'-epi-furanomycin and norfuranomycin. Key steps of this synthesis are the stereoselective Pd-catalyzed etherification for diallyl ethers and ring closing metathesis.

Simple preparation of new [(18) F]F-labeled synthetic amino acid derivatives with two click reactions in one-pot and SPE purification.

New [(18) F]fluorinated 1,2,3-triazolyl amino acid derivatives were efficiently prepared from Huisgen 1,3-dipolar cycloaddition reactions, well known as click reaction. We developed two simultaneous click reactions in one-pot with a simple solid-phase extraction (SPE) purification method. [(18) F]fluoro-1-propyne was obtained at a 45% non-decay corrected radiochemical yield based on the [(18) F]fluoride ion. The one-pot and simultaneous two click reactions were performed with unprotected azido-alkyl amino acid, [(18) F]fluoro-1-propyne, and lipophilic additive alkyne to produce three synthetic amino acid derivatives, AMC-101 ([(18) F]-6a), AMC-102 ([(18) F]-6b), and AMC-103 ([(18) F]-6c) with 29%, 28%, and 24% of non-decay corrected radiochemical yields, respectively. All radiotracers indicated that radiochemical purities were >95% without any residual organic solvent. Our new method involving two click reactions in one-pot showed high radiochemical and chemical purity by easy removal of the residual precursor from the simultaneous two click reactions.

CAL-B catalyzed desymmetrization of 3-alkylglutarate: "olefin effect" and asymmetric synthesis of pregabalin.

CAL-B catalyzed desymmetrization of prochiral 3-alkylglutaric acid diesters was performed to prepare optically active 3-alkylglutaric acid monoesters bearing various alkyl substituents, including methyl, ethyl, propyl and allyl groups. Allyl esters showed far better stereoselectivity among the alkyl esters, suggesting possible π-π interactions between the olefin of the substrate and the Trp104 or His224 side chains at the enzyme active site. Based on this reaction, the synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (pregabalin) was achieved with a 70% overall yield.

Highly stereoselective directed reactions and an efficient synthesis of azafuranoses from a chiral aziridine.

Polyhydroxylated pyrrolidines, such as biologically important azafuranoses represented by the natural product (+)-2,5-imino-2,5,6-trideoxy-gulo-heptitol and its C(3)-epimer, were elaborated from a commercially available enantiomerically pure (2R)-hydroxymethylaziridine by highly stereoselective directed reactions in more than 61% overall yield. At first, the nucleophile 2-trimethylsilyloxyfuran was directed to (2R)-aziridine-2-carboxaldehyde by ZnBr2 to yield the unusual anti-addition product as a single isomer via the chelation-controlled transition. The ring opening of aziridine was followed by conjugate addition to give a cis-fused bicycle, which was converted to the target molecule after the required reductive operations.

Regioselectivity in the ring opening of non-activated aziridines.

In this critical review, the ring opening of non-activated 2-substituted aziridines via intermediate aziridinium salts will be dealt with. Emphasis will be put on the relationship between the observed regioselectivity and inherent structural features such as the nature of the C2 aziridine substituent and the nature of the electrophile and the nucleophile. This overview should allow chemists to gain insight into the factors governing the regioselectivity in aziridinium ring openings (81 references).

Recent advances in synthesizing and utilizing nitrogen-containing heterocycles.

The use of organocatalysts and a pot economy has strengthened recent organic syntheses. Synthetic methodologies may be applicable in laboratory preparation or in the industrial production of valuable organic compounds. In most cases, synthetic challenges are overcome by highly efficient and environmentally benign organocatalysts in a pot-economical manner. This is exemplified by the recent synthesis of tetrahydropyridine-containing (-)-quinine.