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Optimized conditions allow the enantioselective synthesis of the title compounds from racemic α-hydroxycyclobutanone and N-alkylaniline derivatives via a tandem condensation/keto-enol tautomerization process.

An overview of the most important synthetic strategies currently available for the preparation of cyclopent-2-enones is presented and illustrated with recent applications. 1 Introduction 2 Multicomponent Ring Assembly 3 Cyclizations 4 Transformations of Existing Cyclic Systems 5 Miscellaneous Methods 6 Conclusions

All four stereoisomers of 2-(aminomethyl)cyclobutane-1-carboxylic acid have been prepared starting from a single chirally derivatized unsaturated γ-lactam. A photochemical [2+2] cycloaddition reaction of this compound with ethylene was employed to create the four-membered ring exclusively with a cis ring configuration. The two diastereoisomers were separated conveniently by chromatography then the chiral appendage replaced by the more convenient Boc protecting group. Base-mediated lactam hydrolysis provided each of the cis target structures as single enantiomers. An efficient, tandem epimerization/hydrolysis protocol was applied to a carboxamide derivative of each cis compound, to furnish the corresponding trans compounds as single isomers, for the first time.

Peptide formation on the N-terminal of 1-aminoazetidine-2-carboxylic acid is rendered problematic due to a ring opening reaction. However C-terminal development is possible and two diastereomeric mixed hydrazino dipeptides were prepared. Solution-state studies of these compounds suggest the presence of intramolecular hydrogen bonding, consistent with a hydrazino turn, and the crystal structure of one of these compounds shows a horse-shoe conformation, centered around what appears to be a hydrazino turn involving three hydrogen bond acceptors.

A bottom-up design rationale was adopted to devise β/γ-peptide foldamer manifolds which would adopt preferred 13-helix conformations, relying on minimal steric imposition brought by the constituent amino acid residues. In this way, a well-defined 13-helix conformer was revealed for short oligomers of trans-2-aminocyclobutanecarboxylic acid and γ(4)-amino acids in alternation, which gave good topological superposition upon an α-helix motif.

A major current challenge in bioorganic chemistry is the identification of effective mimics of protein secondary structures that act as inhibitors of protein–protein interactions (PPIs). In this work, trans‐2‐aminocyclobutanecarboxylic acid (tACBC) was used as the key β‐amino acid component in the design of α/β/γ‐peptides to structurally mimic a native α‐helix. Suitably functionalized α/β/γ‐peptides assume an α‐helix‐mimicking 12,13‐helix conformation in solution, exhibit enhanced proteolytic stability in comparison to the wild‐type α‐peptide parent sequence from which they are derived, and act as selective inhibitors of the p53/hDM2 interaction.

International audience; The complexation of uranium and europium, in oxidation states +VI and +III, respectively, was investigated with pertinent bio-inorganic systems. Three aspartate-rich pentapeptides with different structural properties were selected for study to rationalize the structure–affinity relationships. Thermodynamic results, crosschecked by both isothermal titration calorimetry and time-resolved laser fluorescence spectroscopy, showed different affinity depending on the peptide for both Eu(III) and U(VI). The thermodynamic aspects were correlated to structural predictions, which were acquired by density functional theory quantum chemical calculations and from IR and extended X-ray absorption fine structure experiments. The combination of these microscopic properties revealed that carbonyl–metal interactions affected the entropy in the case of europium, while the larger uranyl cation was mostly affected by preorganization and steric effects, so that the affinity was enhanced through enthalpy. The approach described here revealed various microscopic aspects governing peptide actinide affinity. Highlighting these mechanisms should certainly contribute to the rational synthesis of higher affinity biomimetic aspartic ligands.

International audience; Conformationally restricted glutamate analogues have been pharmacologically characterized at AMPA and kainate receptors and the crystal structures have been solved of the ligand (2S,10R,20S)-2-(20-carboxycyclobutyl) glycine (CBG-IV) in complex with the ligand binding domains of the AMPA receptor GluA2 and the kainate receptor GluK3. These structures show that CBG-IV interacts with the binding pocket in the same way as (S)-glutamate. The binding affinities reveal that CBG-IV has high affinity at the AMPA and kainate receptor subtypes. Appreciable binding affinity of CBG-IV was not observed at NMDA receptors, where the introduction of the carbocyclic ring is expected to lead to a steric clash with binding site residues. CBG-IV was demonstrated to be an agonist at both GluA2 and the kainate receptor GluK1. CBG-IV showed high affinity binding to GluK1 compared to GluA2, GluK2 and GluK3, which exhibited lower affinity for CBG-IV. The structure of GluA2 LBD and GluK3 LBD in complex with CBG-IV revealed similar binding site interactions to those of (S)-glutamate. No major conformational rearrangements compared to the (S)-glutamate bound conformation were found in GluK3 in order to accommodate CBG-IV, in contrast with GluA2 where a shift in lobe D2 binding site residues occurs, leading to an increased binding cavity volume compared to the (S)-glutamate bound structure.

The effect of ring size of four- to six-membered cyclic β-amino acid on the hybridization properties of pyrrolidinyl peptide nucleic acid with an alternating α/β peptide backbone is reported. The cyclobutane derivatives (acbcPNA) show the highest T(m) and excellent specificity with cDNA and RNA.

L-Tryptophan has been shown to catalyse the enantio- selective aldol reaction between 2-hydroxycyclobutanone and an aromatic aldehyde in DMF solution. The reaction is completely re- gioselective and gives the 2,2-disubstituted cyclobutanone in up to 80% yield. The major adduct is obtained with ee values up to 67%, and has an anti relative configuration which contrasts with the se- lectivity of organocatalysed aldol reactions conducted on acyclic hydroxyacetone substrates.

A polystyrene-supported α-aminonitrile has been prepared and its successive mono- and dialkylations achieved. Complementary procedures allow cleavage of the alkylated moities in either carbonyl or acetal form.

An enantioselective synthesis of a N-Boc-protected trans-cyclopropane gamma-amino acid is reported. The key chiral aldehyde intermediate is prepared in enantiomerically pure form using a three-step aldol-cyclopropanation-retro-aldol protocol.

The 4-hydroxy-2-cyclopentenone moiety is a highly valued molecular scaffold; it is bestowed with a wide-ranging chemical reactivity profile which synthetic chemists have exploited increasingly over the last few decades. This review summarises the methods available for the preparation of simple building blocks which contain this core, then illustrates the diversity of chemical transformations which can be conducted with them, by highlighting applications in multistep syntheses of complex target molecules.

The photochemical reactivity of enantiomerically pure bicyclo[3.1.0]hept-3-en-2-ones has been examined to determine whether a [2+2] cycloaddition with an alkene could be achieved without interference from a photochemically induced skeletal rearrangement. The formation of a tricyclo[5.2.0.0 2,5 ]nonan-6-one was indeed the major pathway, exclusively providing the cis - anti - cis isomer. However, the formation of norbornenones was also observed, as was stereochemical scrambling at C6 in the starting material.

A selection of 4-hydroxycyclopent-2-enone derivatives were prepared in enantiomerically pure form, and their photochemical [2+2] cycloaddition reactions with a variety of alkenes were studied, with a view to providing diversely functionalized bicyclo[3.2.0]heptanes. Intermolecular reactions provided the target structures in reasonable yields as a mixture of exo and endo adducts, in proportions which varied very little as a function of the steric bulk of the reactants or the reaction conditions. The system was suitably adapted for an intramolecular reaction, which provided a single, stereochemically pure product, the convenient precursor of a rigid, concave, trioxygenated skeleton. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

A short, convergent, formal total synthesis of cyclotheonamide C is described. The key linear pentapeptide intermediate is assembled at the same time as the elaboration of the alpha-hydroxyhomoarginine (H-hArg) residue via a three-component Passerini reaction-amine deprotection-O,N-acyl migration strategy.

The total synthesis of cyclotheonamide C (3), a macrocyclic pentapeptide incorporating an alpha-keto homoarginine (k-Arg) and a vinylogous dehydrotyrosine (V-deltaTyr) unit, has been achieved. For comparison of macrocyclisation feasibility, two linear pentapeptides bearing free ketone functions at the k-Arg units were prepared, by use of tandem oxidation/coupling reactions on alpha-keto cyanophosphorane precursors as the key processes for pentapeptide elaboration. Successful activation and coupling at the pentapeptide V-deltaTyr C terminus led to the target molecule core, and thus provided a short total synthesis of the target compound

A very short and efficient synthesis of protected derivatives of APTO and AETD, the complex polyhydroxylated beta-amino acid residues present in microsclerodermins C, D, and E, is described. The targets are obtained in only five steps, in 23% and 16% overall yields, respectively. The key transformation involves the completely diastereoselective two-carbon homologation of appropriately selected intermediate chiral sulfinimines.

N-Aminoguanidine (Amgu) was examined for its behaviour as a ligand for platinum(II) and palladium(II). Protonated AmguH+ can coordinate platinum as a monodentate ligand bound via the N4 amino group. Deprotonated, electrically neutral Amgu forms chelate complexes with both PtII and PdII; in these complexes Amgu is coordinated to the metal by the N4 amino group and the deprotonated N1 imino group, forming a five-membered ring. K[PtCl3(dmso)] reacted with Amgu·HCl to yield a chelate complex with N1 bound trans to S, suggesting that an exchange between the N1 and N4 binding sites followed the primary nucleophilic attack of N4 on platinum. Whereas reactions between K2PdCl4 and Amgu·HCl were rapid and straightforward, K2PtCl4 was easily reduced to metallic platinum by Amgu·HCl, especially in stoichiometric conditions. Solution NMR and X-ray crystallographic characterization is presented for five new complexes: trans-[PtCl2(AmguH-N4)2]Cl2·21/2H2O (3), trans-[Pt(Amgu-N1,N4)2](NO3)2 (4), [PtCl(Amgu-N1,N4)(dmso)]Cl·2H2O (5), [PdCl2(AmguH-N1,N4)] (6), and trans-[Pd(Amgu-N1,N4)2]Cl2 (7)

An organocatalytic enantioselective synthesis of α-(benzylamino)cyclobutanones has been achieved by employing a tandem condensation/intramolecular rearrangement/proton transfer reaction and starting from racemic α-hydroxycyclobutanone and a selection of benzylamines. This reaction sequence afforded the products in good to high yields with moderate to high enantioselectivities.

The de novo design of a β/γ-peptidic foldamer motif has led to the discovery of an unprecedented 9/8-ribbon featuring an uninterrupted alternating C9/C8 hydrogen-bonding network. The ribbons adopt partially curved topologies determined synchronistically by the β-residue configuration and the γ-residue conformation sets.

An original synthetic protocol has been developed for the preparation of highly functionalized tryptamines from 2-hydroxycyclobutanone and secondary arylamines via a solvent-free Bronsted acid catalysed two-step reaction sequence.

The reaction provides 3-alkyl/aryl-2-(2-nitro-1-alkyl/aryl)cyclo-1-butanones as mixture of the two diastereomers bearing a trans-ring configuration.

The [2 + 2]-photocycloaddition reactions of maleic anhydride (II) with either allyl alcohol (I) or propargyl alcohol (XII) is elaborated to provide access to 1,2,3-trifunctionalized cyclobutanes with three differentiated one-carbon substituents and complementary stereochemical pattern.

The UV irradiation of N -benzyl-2-phenyl-1,2-dihydropyridin-3-one furnished trans -1-benzyl-4-phenyl-3-vinylazetidin-2-one, a structural isomer, as the main product. A novel tandem mechanism involving a [4+2] photocycloreversion followed by a Staudinger cycloaddition reaction is proposed, and is supported with the trapping of the purported vinylketene intermediate by other imines. This process predominates in the presence of ethylene, precluding the formation of an intermolecular [2+2] cyclobutane adduct.

A synthetic equivalent of the southern segment of cyclotheonamide C, a cyclopentapeptide isolated from the sponge Theonella , has been synthesized via complementary Wadsworth–Emmons or palladium-catalysed methodologies followed by tandem oxidation/vinylogation in 41% overall yield (five steps) from readily available starting materials.

(S)-4-Oxopipecolic acid has been prepared in enantiomerically pure form from two readily accessible starting materials, (R)-N-(cyanomethyl)-4-phenyloxazolidine (2) and 2-(methoxymethoxy)allyl chloride, (3, MOM-allyl chloride). This strategy exploits the complementary electrophile/nucleophile reactivity at each end of this pair of 3-atom unit building blocks. Thus, alkylation of the anion of 2 with 3 (creation of the piperidine C-2−C-3 bond) followed by Lewis acid induced cyclisation (creation of the C-5−C-6 bond), leads principally to a bicyclic intermediate 5 which incorporates a protected form of the title compound. Subsequent chemical transformations lead to the target molecule in an overall yield of 20% for the five-step sequence. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Semi-empirical quantum chemical studies using PM3 suggest that the preferred reaction between a Grignard reagent and a combined aminonitrile–oxazolidine system involves initial formation of a Lewis acid–base complex between magnesium and the central nitrogen atom, followed by preferred reaction with the aminonitrile function; model studies confirm that this reaction proceeds by addition rather than substitution.

The title compound types are structural isomers. The absence of literature studies dealing with the mass spectrometric gas-phase behavior of such compounds prompted a search for the best conditions for differentiation between the two prototype examples (R,R)-5,10-diphenyl-1,6-diaza-3,8-dioxabi-cyclo[4.4.1]undecane and N,N'-methylenebis[(R)-4-phenyloxazolidine]. Attempts to differentiate between the isomers by NMR were inconclusive and X-ray crystallography had to be used. The best mass spectrometric results were obtained using gas-phase ionization techniques, particularly chemical ionization, whereby protonated molecules were observed. The fragmentation pathways were elucidated from MS/MS studies and from experiments performed on hexadeuterated samples of each compound.

The (+)-(1R,2S) and (−)-(1S,2R) stereoisomers of 2-(aminomethyl)cyclobutane-1-carboxylic acid have been prepared using a short and efficient strategy, which employs the photochemical [2+2] cycloaddition reaction between ethylene and an unsaturated γ-lactam as the key step.

Short synthetic sequences commencing with the photosensitized [2 + 2]-cycloaddition reactions of maleic anhydride with either allyl alcohol or propargyl alcohol have been elaborated to provide access to 1,2,3-trisubstituted cyclobutanes with three differentiated one-carbon substituents and complementary stereochemical patterns. These intermediates were used to prepare three discrete stereo- and regioisomers of hydroxymethylated cyclobutane β-amino acids in orthogonally protected form.

Optimized conditions allow the enantioselective synthesis of the title compounds from racemic α-hydroxycyclobutanone and N-alkylaniline derivatives via a tandem condensation/keto-enol tautomerization process.

An overview of the most important synthetic strategies currently available for the preparation of cyclopent-2-enones is presented and illustrated with recent applications. 1 Introduction 2 Multicomponent Ring Assembly 3 Cyclizations 4 Transformations of Existing Cyclic Systems 5 Miscellaneous Methods 6 Conclusions

A convenient and rapid synthesis of the title compound is described, requiring three steps with no chromatographic purification; the key procedure is a double Curtius rearrangement.

Coronamic acid and norcoronamic acid have been prepared in racemic form in 11% and 20% overall yields, respectively, from (E)- methanohomoserine, while the (1S,2R)-isomer of the latter allows the preparation of enantiomerically pure (1S,2R)- allocoronamic acid in 37% overall yield. Care is required to avoid intramolecular cyclisation reactions during side chain manipulation.

International audience; A study of the reaction of phenyl magnesium bromide with various N-(cyanomethyl)oxazolidines showed that product formation (essentially 3-imidazolines and 2-aminomorpholines) is highly sensitive to the substitution pattern and stereochemistry, and appears to involve initial complexation of the Grignard reagent to ring-oxygen.

This themed issue of NJC features a collection of papers highlighting the latest developments in foldamer chemistry.

Simple N -protected di- and tri-peptide methyl esters incorporating (±)-( Z )-2,3-methanoaspartic acid were prepared by oxidation of the corresponding (±)-( Z )-2,3-methanohomoserine-derived peptides.

Chiral 2-(aminomethyl)oxazolines 3 and 7, in which the heterocycle is derived from (R)-phenylglycinol, are synthesized and studied in alkylation reactions involving strong base and alkyl halides. The tertiary amine derivative 3 is alkylated efficiently at the α-carbon centre with no stereochemical induction, while the tertiary carbamate 7 is alkylated in moderate yield and reasonable diastereomeric excess. The stereochemical control observed in the latter case can be explained by the preferred formation of an E-enolate during the deprotonation step by prior complexation of the carbamate carbonyl group to the base.

Four model compounds and four dipeptides containing N-aminoazetidinecarboxylic acid (AAzC) and a particular stereoisomer of 2-aminocyclobutanecarboxylic acid (ACBC) were studied to establish their solution state conformational preferences, particularly regarding the ability of AAzC to induce a three-center hydrogen-bonded folding feature known as a "hydrazino turn". On the basis of IR and NMR experiments, supported by molecular modeling, the AAzC residue adopted a trans configuration amenable to the formation of a cyclic eight-membered hydrogen bond conformation in solution, in all cases studied. The implication of the heterocyclic nitrogen atom of AAzC in the trans-like structure was demonstrated via a refined (1)H-(15)N HMBC experiment giving exploitable data at natural (15)N isotopic abundance, providing unprecedented evidence for the solution state hydrazino turn conformation. The predominance of this secondary structural feature depended on the configuration of the neighboring ACBC residue in the dipeptides: while the trans-ACBC derivatives prefer the hydrazino turn, the cis-ACBC derivatives may also populate low-energy 10-membered hydrogen-bonded ring structures. X-ray diffraction analysis of three compounds confirmed the presence of a solid state hydrazino turn in two cases, with geometries similar to those deduced from the solution state studies, but in the third compound, no intramolecular hydrogen-bonding feature was in evidence.

International audience; Two new head-to-head cyclobutane photodimers have been obtained in single stereoisomeric form by irradiation of 5-phenyl- and 6-phenyluracils in acetone solution. While the latter substrate gives a cis-anti-cis adduct, the former provides, for the first time in a solution phase reaction, a cis-syn-cis photodimer as the only product.

A new synthesis of trans -1,2-diaminocyclobutane 1 is described, in which the key feature is the novel stereoselective borane-induced reductive ring-expansion reaction of the cyclopropane-iminonitrile 2 to give the cyclobutane 4 . This latter intermediate was also used to prepare a trans -fused rigid analogue of moclobemide.

Propylbenzene is metalated regioseleclively at the α-carbon using the n -BuLi- t -BuOK-TMEDA super-base combination; the resulting carbanion condenses with functionalised benzophenones to provide direct syntheses of tamoxifen and 4-hydroxytamoxifen.

The Polonovski-Potier reaction was carried out on the N-oxide of amopyroquin in an attempt to mimic the metabolic process. The major reaction product was the previously unknown aldehyde. The dihydrobenzoxazine, potentially the unidentified non-polar metabolite, was prepared by an alternative route. Neither of these compounds was the metabolite sought.

N-Phenylsulfonyl (S)-proline catalyzes the direct aldol reaction of 3-substituted cyclobutanones and aryl aldehydes in good yield and with excellent diastereoselectivity and enantioselectivity. This desymmetrization process provides highly functionalized cyclobutanones with control over three contiguous stereogenic centers.