From Stereodefined Cyclobutenes to Dienes: Total Syntheses of Ieodomycin D and the Southern Fragment of Macrolactin A.

A copper-promoted flexible synthesis of cyclobutenes carrying simple alkyl chains, enabling even the most hindered nucleophiles to be employed, has been developed. The versatility of this approach was exemplified by a short total synthesis of ieodomycin D and a straightforward preparation of the southeastern fragment of macrolactin A. The latter features a late-stage, double cyclobutene electrocyclic ring opening that directly delivers a bis-diene of defined geometry.

Direct synthesis of stereodefined and functionalized dienes as valuable building blocks.

We have reported a direct and stereoselective synthesis of functionalized dienoic carboxylates from the simple bicyclic lactone 1. The use of oxygen- or nitrogen-based nucleophiles in a domino allylic alkylation/4π-electrocyclic ring opening affords reliable access to dienes with interesting functionalities. Alternatively, halide substitution offers synthesis of other classes of functionalized dienoic acids. Herein, we demonstrate the utility of such dienoic products as key building blocks in various transformations as well as natural product synthesis.

Asymmetric palladium-catalyzed allylic alkylation using dialkylzinc reagents: a remarkable ligand effect.

A serendipitously discovered palladium-catalyzed asymmetric allylic alkylation reaction with diorganozinc reagents, which displays broad functional group compatibility, is reported. This novel transformation hinges on a remarkable ligand effect which overrides the standard "umpolung" reactivity of allyl-palladium intermediates in the presence of dialkylzincs. Owing to its mild conditions, enantioselective allylic alkylations of racemic allylic electrophiles are possible in the presence of sensitive functional groups.

Regio- and enantioselective cyclobutene allylations.

Catalytic asymmetric allylation of lactone 1 with allyl boronates leads to functionalized cyclobutenes in high regio- and stereoselectivity.

An atom-economical and stereoselective domino synthesis of functionalised dienes.

Open sesame: A direct synthesis of functionalised and stereodefined dienes, relying on a domino allylic alkylation/electrocyclic ring-opening sequence, is reported. This method allows concise access to doubly vinylogous esters. A further systematic study of ring-opening rates of carbon-substituted cyclobutenes allowed the design of substrates amenable to sequential pericyclic reactions (see scheme).

Diastereodivergent de-epimerization in catalytic asymmetric allylic alkylation.

Diastereomers made to order: In an unprecedented ligand-controlled process a racemic mixture of four stereoisomers can be converted with high selectivity into each one of the diastereomers of the product, at will (see scheme). The mechanism of this deracemization of epimers, that is, a de-epimerization, was also studied.

Catalytic asymmetric diastereodivergent deracemization.

Your wish is my command: Deracemization is a powerful strategy wherein a racemate is converted into a 100 % yield of a single enantiopure product. A new concept in catalytic deracemization is presented, in which a racemate with n stereogenic elements can be selectively converted into each one of 2(m) (m = number of chiral centers of the product) different enantiopure products, by simple tuning of the reaction conditions.

Biomimetic cyclization of geraniol derivatives, a useful tool in the total synthesis of bioactive monocyclic terpenoids.

This review is a detailed account of authors' work in the field of biomimetic cyclization of geraniol-like dienes. The very high regio- and enantioselectivity achieved made these elegant reactions a viable tool for the synthesis of monocyclic building blocks used in the synthesis of valued terpenoids, like the precious aroma and perfume constituents' ionones and irones.

Gold(I)-catalyzed diastereo- and enantioselective 1,3-dipolar cycloaddition and Mannich reactions of azlactones.

Azlactones participate in stereoselective reactions with electron-deficient alkenes and N-sulfonyl aldimines to give products of 1,3-dipolar cycloaddition and Mannich addition reactions, respectively. Both of these reactions proceed with good to excellent diastereo- and enantioselectivity using a single class of gold catalysts, namely C(2)-symmetric bis(phosphinegold(I) carboxylate) complexes. The development of the azlactone Mannich reaction to provide fully protected anti-α,ß-diamino acid derivatives is described. 1,3-Dipolar cycloaddition reactions of several acyclic 1,2-disubstituted alkenes and the chemistry of the resultant cycloadducts are examined to probe the stereochemical course of this reaction. Reaction kinetics and tandem mass spectrometry studies of both the cycloaddition and Mannich reactions are reported. These studies support a mechanism in which the gold complexes catalyze addition reactions through nucleophile activation rather than the more typical activation of the electrophilic reaction component.

Enantioselective synthesis and olfactory evaluation of bicyclic alpha- and gamma-ionone derivatives: the 3D arrangement of key molecular features relevant to the violet odor of ionones.

Violet smelling ionones 1-3, occurring in the headspace of different flowers, are well-known perfumery raw materials. With the goal to recognize the still ill-defined spatial arrangement of structural features relevant to the binding of ionones to olfactory G-protein coupled receptors, through B3LYP/6-31G(d) modeling studies we identified bicyclic compounds 7-9 as conformationally constrained 13-alkyl-substituted analogues of monocyclic alpha- and gamma-ionones. They were thus synthesized to evaluate the olfactory properties. The enantioselective syntheses of 7-9 entailed two common key steps: (i) a Diels-Alder reaction to construct the octalinic core and (ii) a Julia-Lythgoe olefination to install the alpha,beta-enone side chain. The odor thresholds of synthetic 7 and 9 were significantly lower than the corresponding parent ionones, and 9 showed the lowest threshold value among violet-smelling odorants examined so far. Modeling studies suggested a nearly identical spatial orientation of key hydrophobic and polar moieties of compounds 1, 3, and 4-9. Presumably, interaction of these moieties with ionone olfactory receptors (ORs) triggers a similar receptor code that is ultimately interpreted by the human brain as a pleasant woody-violet smell. These results open the way to studies aimed at identifying and modeling complementary binding sites on alpha-helical domains of ionone receptor proteins.

A simple and versatile re-catalyzed Meyer-Schuster rearrangement of propargylic alcohols to alpha,beta-unsaturated carbonyl compounds.

Rhenium does the job! A readily available rhenium complex efficiently catalyzed the direct Meyer-Schuster-like rearrangement of different alkyl- and aryl-substituted propargylic secondary and tertiary alcohols to the corresponding alpha,beta-unsaturated compounds, which were produced with virtually complete E stereoselectivity. The reaction proceeded under neutral conditions and no racemization of potentially enolizable stereocenters was observed.

Enantioselective synthesis and olfactory evaluation of 13-alkyl-substituted alpha-ionones.

To study the influence of the steric bulk of the substituents at C(5) on the olfactory characteristics of alpha-ionone, the (S)-antipodes of compounds 8-10 were synthesized starting from (S)-alpha-cyclogeraniol (14a). The latter was available in useful preparative yield with 95% ee by enantioselective lipase-PS-mediated acetylation of the racemic mixture. Key step in the conversion of 14a to 8-10 was an S(N)2'-type reaction of an organocuprate on the allylic phosphate 20, which appears to be a general method for the introduction of an alkyl substituent at the cyclohexene C=C bond of ionones. Olfactory evaluation showed that, compared to the parent (S)-alpha-ionone (1), the odor strength and fragrance facets of the three analogues 8-10 are significantly influenced by the bulkiness of the substituent at C(13), giving further evidence that hydrophobic interactions of this group play a significant role in the chemoreception of ionones. In particular, the odor of the ethyl derivative 8 was found to be significantly stronger than that of the parent (S)-alpha-ionone (1).

1,2-Bisanionic coupling approach to 2,3-disubstituted cyclopentenols and cyclopentenones.

[reaction: see text] We describe a new approach to 2,3-disubstituted cyclopentenols and cyclopentenones through two consecutive regioselective additions of equal or different electrophiles to a cyclopentene bisanionic synthon. Indeed, on exposure to BuLi, 3-bromo-2-iodocyclopent-2-enol O-TBS ether undergoes iodine-lithium permutation with complete regioselectivity. Successive reaction of the monolithium anion with different C(sp(2))- and C(sp(3))-electrophiles affords the corresponding 2-substituted-3-bromocyclopentenol derivative. Subsequent bromo-lithium exchange with t-BuLi, followed by reaction with an equal or different electrophile, affords the desired 2,3-disubstituted cyclopentenol.

[Study on the appropriateness of utilization of dermatological consultants in emergency unit]. / Appropriatezza delle richieste di consulenza dermatologica in Pronto Soccorso in una Azienda Ospedaliera piemontese.

The aim of this study is to evaluate the rate of appropriate use of dermatologist consultants, in order to identify its determinants and to define its economic impact. We analysed 1750 dermatological procedures performed in the emergency room of the Azienda Ospedaliera "Maggiore della Carità" in Novara. The 87,64% of the procedures were inappropriate. We also observed low rates of diagnostic agreement between emergency unit and dermatology unit; 40.88% of discordant diagnoses were due to severe mistakes. The rate of inappropriate dermatological procedures was related to the clinical diagnosis and to patient's access time. The economical analysis was performed using the Activity Based Costing methodology. We measured an average expenditure of euro 7 for procedure (total expenditure euro 9.850). As possible determinants of inappropriateness, we identified the lack of "filter action" by general practitioners, the incorrect behaviour of patients and the professional uncertainty phenomena.