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In the last decade a certain number of new cyclobutane and cyclobutanone synthesis and functionalization protocols have been published. Organo- and biocatalyzed eco-friendly approaches to cyclobutane-containing molecules have been developed with interesting results. Also, successful new total synthesis of bioactive compounds and drugs have been recently reported where a four membered ring represented the key intermediate. Therefore, the rising interest in this field represents a great point of discussion for the scientific community, disclosing the synthetic potential of strained four membered ring carbocyclic compounds. Herein we report a critical survey on the literature concerning the enantiocontrolled synthesis and functionalization of cyclobutane derivatives, with particular attention to metal-free, low impact methodologies, published during the period 2000-2013.

A novel synthesis of optically active α-arylamino ketones through an organocatalytic enantioselective Amadori-Heyns rearrangement is described.

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.

An unprecedented and conceptually novel chiral Brønsted base/Brønsted acid catalytic method for the enantioselective synthesis of α-amino thioesters through a tandem condensation-intramolecular rearrangement-protonation has been developed which provides a number of important synthetic building blocks in good yield and with moderate to good enantioselectivities.

The high versatility of 1-phenylsulfenyl- or 1-phenylsulfonyl-cyclopropylketones has been exploited for the regioselective synthesis of trans-2,3-disubstituted cyclobutanones, 2,4,5-trisubstituted 3,6-dihydro-2H-pyrans and cis-2-alkyl- or cis-2-aryl-cyclopropylphenylsulfones.

[reaction: see text] Acid-catalyzed ring expansion of chiral cyclopropyl and cyclobutyl derivatives for the synthesis of carbo- and heterocyclic compounds is reported. The starting materials have been successfully prepared by l-proline-catalyzed direct asymmetric aldol reactions of 1-phenylthiocycloalkyl carboxaldehydes with ketones.

The current burden of allergic diseases, estimated by both direct and indirect costs, is very relevant. In fact the cost estimation for rhinitis amount globally to 4-10 billion dollars/year in the U.S. and to an average annual cost of 1089 euros per child/adolescent and 1543 euros per adult in Europe. The estimated annual costs in Northern America for asthma amounted to 14 billion dollars. Consequently, preventive strategies aimed at reducing the clinical severity of allergy are potentially able to reduce its costs. Among them, specific immunotherapy (SIT) joins to the preventive capacity the carryover effect once treatment is discontinued. A number of studies, mainly conducted in the US and Germany demonstrated a favourable cost-benefit balance. In the nineties, most surveys on patients with allergic rhinitis and asthma reported significant reductions of the direct and indirect costs in subjects treated with SIT compared to those treated with symptomatic drugs. This is fully confirmed in recent studies conducted in European countries: in Denmark the direct cost per patient/year of the standard care was more than halved following SIT; in Italy a study on Parietaria allergic patients demonstrated a significant difference in favor of SIT plus drug treatment for three years versus drug treatment alone, with a cost reduction starting from the 2nd year and increasing to 48% at the 3rd year, with a highly statistical significance which was maintained up to the 6th year, i.e. 3 years after stopping immunotherapy, corresponding to a net saving for each patient at the final evaluation of 623 euros per year; in France a cost/efficacy analysis comparing SIT and current symptomatic treatment in adults and children with dust mite and pollen allergy showed remarkable savings with SIT for both allergies in adults and children.

Allergic rhinitis and asthma constitute a global health problem because of their very high prevalence and the consequent burden of disease, concerning medical and economical issues. Among the treatments of allergy, specific immunotherapy has the capacity to favourably alter the natural history of the disease both during and after its performance and thus to reduce the direct and indirect costs of allergic rhinitis and asthma. A number of studies reported such cost reduction for traditional, subcutaneous immunotherapy and recent data demonstrate that also sublingual immunotherapy (SLIT) is associated to economic advantages and/or monetary savings, specifically in terms of reduction of disease economic burden. Only few formal economic assessments of SLIT have been carried out so far, this article will present and discuss the published studies addressed to this issue. The data obtained, although the number of studies is still limited, provide preliminary evidence supporting a SLIT effect on sparing costs for respiratory allergy.

[reactions: see text] Regioselective synthesis of 2,4,5- or 3,4,5-trisubstituted 2,3-dihydrofurans has been realized by using donor-acceptor cyclopropanes or by a Corey ylide reaction with alpha-sulfenyl-, alpha-sulfinyl-, or alpha-sulfonylenones. The method allowed a straightforward synthesis of the natural product calyxolane B.

2,2-dimethyl cyclopentanones are readily prepared by acid catalyzed ring expansion of isopropenylcyclobutanols; the method allows ready access to the family of sesquiterpenes cuparanes and herbertanes, as demonstrated by the synthesis of (+/-)-alpha-cuparenone and the direct precursor of (+/-)-herbertene.

[reaction: see text] The stereochemistry of the cyclobutanones 3, obtained by lithium salt catalyzed ring expansion of the optically pure oxaspiropentanes 2, depends not only on the lithium salt but also on the stereochemistry of 2. They constitute the starting material for the syntheses of the acetogenin (-)-(4R,5R)-muricatacin and the pheromone (R)-japonilure.

[reaction: see text] The thionium ion, generated through a cyclopropylcarbinyl-cyclobutyl ring expansion, is, for the first time, intramolecularly intercepted by activated aromatic rings to generate new versatile 2a-methyl-8b-(phenylsulfanyl-1,2a,3,8b-tetrahydro-2H-cyclobuta[c]chromenes.

[reaction: see text]. Enantiomerically pure (S)-cleonin, a key component of the antitumor antibiotic cleomycin, was prepared starting from (R)-serine. The Kulinkovich cyclopropanation of the methyl ester of N-Cbz serine acetonide gave the hydroxycyclopropyl moiety. The amino alcohol region was further oxidized to amino acid. The Kulinkovich cyclopropanation allowed also the preparation of other non-natural substituted cyclopropylglycines.

The Authors mark a case of penile metastasis in a man 70 years old suffering from bladder cancer. They emphasize the rarity of this manifestation. They discuss about symptomatology, diagnosis and pathogenesis even today debated. They mark therapeutical indications about the short expectation of life, that these patients have from appearance of the metastases.