Exploiting a "Beast" in Carbenoid Chemistry: Development of a Straightforward Direct Nucleophilic Fluoromethylation Strategy.

The first direct and straightforward nucleophilic fluoromethylation of organic compounds is reported. The tactic employs a "fleeting" lithium fluorocarbenoid (LiCH2F) generated from commercially available fluoroiodomethane. Precise reaction conditions were developed for the generation and synthetic exploitation of such a labile species. The versatility of the strategy is showcased in ca. 50 examples involving a plethora of electrophiles. Highly valuable chemicals such as fluoroalcohols, fluoroamines, and fluoromethylated oxygenated heterocycles could be prepared in very good yields through a single synthetic operation. The scalability of the reaction and its application to complex molecular architectures (e.g., steroids) are documented.

A greener and efficient access to substituted four- and six-membered sulfur-bearing heterocycles.

The regioselective functionalization of four- and six-membered cyclic sulfones was investigated using a lithiation/electrophile trapping strategy. The protocol features an interesting eco-compatibility profile because of the use of 2-MeTHF as a solvent (more eco-friendly than other organic solvents) and n-hexyllithium as a lithiating agent safer than other alkyllithium compounds. Several derivatives were prepared with different stereochemistry and substitution patterns. A number of selected derivatives, spanning a range of 5 log P units, were characterized for their lipophilicity through RP-HPLC. A good linear correlation, with a slope close to 1.0, was observed between the experimentally determined RP-HPLC lipophilicity parameters (log k'w) and calculated log P (clog P) values, whereas a systematic difference in absolute values between the chromatographic parameters and in silico lipophilicity descriptors can be attributed mainly to silanophilic interactions between the H-bond acceptor SO2 group and free silanol groups on silica-based C18 columns, which results in increased retention times.

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis.

Microreactor technology and flow chemistry could play an important role in the development of green and sustainable synthetic processes. In this review, some recent relevant examples in the field of flash chemistry, catalysis, hazardous chemistry and continuous flow processing are described. Selected examples highlight the role that flow chemistry could play in the near future for a sustainable development.

The Use of the Comins-Meyers Amide in Synthetic Chemistry: an Overview.

Formylation reactions are fundamental operations in synthetic chemistry allowing the incorporation into a given structure formyl groups amenable to further deiivatization. Conceptually, the introduction of such groups through the reaction between an electrophilic donor and a nucleophilic acceptor (i.e. organometallic reagent) constitutes a reliable technique with widespread applications. In this Highlight, we summarize the effectiveness of the so called Comnins-Meyers amide - [2-(N-methyl-N-formylamino]pyridine - in such a chemistry with vistas to the synthesis of natural products and biologically active substrates.

Regio- and Stereoselective Synthesis of Sulfur-Bearing Four-Membered Heterocycles: Direct Access to 2,4-Disubstituted Thietane 1-Oxides.

Starting from readily available C2-substituted thietane 1-oxides, a straightforward synthesis of new C2,C4-disubstituted thietane 1-oxides has been developed by using a lithiation/electrophilic trapping sequence. The chemical and configurational stability of lithiated C2-substituted thietane 1-oxides has been investigated as well as the stereochemical implications for this process. The results demonstrate that a stereoselective functionalization at the C2, C4 positions of a thietane is feasible, leaving intact the four-membered ring.

Easy access to constrained peptidomimetics and 2,2-disubstituted azetidines by the unexpected reactivity profile of α-lithiated N-Boc-azetidines.

The reactivity profile of lithiated N-Boc-2-arylazetidines has been investigated filling a gap in the chemistry of this class of four-membered heterocycles. Two unexpected and unprecedented results have been observed: an "ortho-effect" accounting for the regioselective functionalization of the azetidine ring, and self-condensation leading to new and interesting azetidine-based peptidomimetics.

Nitrogen Stereodynamics and Complexation Phenomena as Key Factors in the Deprotonative Dynamic Resolution of Alkylideneaziridines: A Spectroscopic and Computational Study.

The present work is aimed at shedding light on the origin of the stereoselectivity observed in the reactions of chiral heterosubstituted organolithiums, generated by lithiation of alkylideneaziridines. Factors such as the nitrogen inversion barrier, the stereochemistry at the nitrogen atom, the substitution pattern of the alkylideneaziridines, and the reaction conditions are taken into consideration. The interplay between nitrogen stereodynamics and complexation phenomena seems to be crucial in determining the stereochemical outcome of the lithiation/trapping sequence. The findings were rationalized by a synergistic use of NMR experiments, run on the lithiated intermediates, alongside computational data. It has been demonstrated that, in such systems, the stereochemistry-determining step is the deprotonation reaction, and a model based on a deprotonative dynamic resolution has been proposed. Such findings could find application in dynamic systems other than aziridines.

[Normal urine levels of the aminoterminal telopeptide of type I collagen (NTx) in premature newborns in the first week of life]. / Livelli normali urinari del telopeptide aminoterminale del collagene di tipo I (NTx) nei neonati prematuri durante la prima settimana di vita.

Urinary excretion of type I collagen cross-linked aminoterminal telopeptide (NTx) is a specific index of bone resorption. The Authors have studied urinary NTx concentrations in 60 urine samples of preterm infants, from 32 to 36 weeks of gestation, to evaluate the trend of the bone marker in the first week of life. Urine samples were collected at 1, 3 and 7 days of life. NTx was measured by ELISA (OSTEOMARK) and the values expressed in nmol Bone Collagen Equivalent (BCE)/mmol u-creatinine and the mean values (+/- 1 SD) were compared by ANOVA. NTx levels showed a progressive increase from 1 to 7 days of life in every group (P = 0.002 at 32, 0.040 at 33, 0.019 at 34, 0.010 at 35 and 0.000 at 36 weeks of gestation). Moreover, by comparing the mean values in every day (1st, 3rd and 7th) in the whole period under investigation, significant variations were noticed at 1 and 7 days (P = 0.045 and P = 0.021) and highly significant variation on the 3r day (P =0.000). We found a inverse relationship between gestational age and NTx concentrations, with significantly higher values in preterm infants of 32-34 weeks compared to those found in the following weeks of life and to those of full term infants. Preterm infants have a higher bone turnover rate that seems to be responsible of the major risk of osteopenia. In conclusion, the trend of NTx at different gestational ages reflects the peculiar balance of mineral metabolism. The unexpected interruption of nutritional supply and of mineral triggers the turbulent combination of processes of bone formation and especially of bone resorption, that becomes more evident as more premature is the delivery.