Transition metal-catalyzed cross-coupling reactions of alkyl metals and aryl halides or pseudohalides have emerged as a powerful methodology for the formation of Csp3-Csp2 bonds over the past decades.1 However, significant attention has also been focused on Pdand Ni-catalyzed Csp3-Csp2 bond-forming reactions that involve aryl metals and haloalkyl compounds lacking -hydrogen atoms as cross-coupling partners.2 In contrast, until a few years ago, few examples were reported in the literature concerning transition metalcatalyzed reactions of aryl metals with functionalized alkyl halides including R-halocarbonyl compounds and R-bromosulfones bearing -hydrogen atoms,3 and a single example of Pd-catalyzed cross-coupling reaction of aryl metals and unfunctionalized alkyl halides bearing -hydrogen atoms had been described.4 Only in recent years, successful procedures for the Pd-,5 Ni-,6 Rh-,7 Fe-,8 V-,9 Co-,10 and Cu-catalyzed11 cross-coupling reactions of aryl metals and unfunctionalized alkyl halides bearing -hydrogen atoms have been developed.12 Nevertheless, new, effective, and more environmentallybenignmethodologiesfortheformationof(cyclo)alkyl-aryl bonds, which require a reduced number of synthetic operations, have emerged as valuable alternatives to the conventional cross-coupling reactions. These methodologies (Scheme 1) are based on transition metal-catalyzed simple or 2-fold C-H bond functionalization according to the following approaches: (a) highly regioselective Pd-catalyzed direct arylation reactions of unactivated sp3-hybridized C-H bonds with aryl halides (eq a, Scheme 1);13 (b) Pd-catalyzed direct alkylation reactions of aryl C-H bonds with alkyl metals (eq b, Scheme 1);14 Au-15 or Pdcatalyzed16 direct alkylation reactions of aryl C-H bonds with alkyl halides or pseudohalides (eq c, Scheme 1); (d) Pd-catalyzed arylations of unactivated sp3-hybridized C-H bonds with aryl metals (eq d, Scheme 1);14c (e) Pd-, Ru-, or Cu-catalyzed cross-coupling reactions of sp3-hybridized C-H bonds with arylboronic acids using air as oxidant (eq d, Scheme 1);17 and (f) cross-dehydrogenative coupling of alkyl and aryl C-H bonds (eq e, Scheme 1).18 Finally, great attention, particularly in the past decade, has also been focused on the design, development, and application of transition metal-catalyzed coupling reactions of aryl halides and pseudohalides with a wide variety of substrates containing activated sp3-hybridized C-H bonds (eq f, Scheme 1). A mini-review on this topic was published by Scolastico and Poli in 1999,19 and three excellent reviews that concern the results obtained in this rapidly growing area of extensive research by the groups of Miura, Natsume, Hartwig, and Buchwald up to the end of 2002 were published by Miura,20 Hartwig,21 and Lloyd-Jones22 a few years later. However, the reviews by Miura20 and Hartwig21 were limited in that they fundamentally emphasized the author’s own work and * To whom correspondence should be addressed. E-mail: rossi@dcci.unipi.it. Chem. Rev. 2010, 110, 1082–1146 1082

Transition metal-catalyzed direct arylation of substrates with activated sp3-hybridized C-H bonds and some of their synthetic equivalents with aryl halides and pseudohalides.

Kepa Ruiz-Mirazo,†,∥ Carlos Briones,‡,∥ and Andreś de la Escosura* †Biophysics Unit (CSIC-UPV/EHU), Leioa, and Department of Logic and Philosophy of Science, University of the Basque Country, Avenida de Tolosa 70, 20080 Donostia−San Sebastiań, Spain ‡Department of Molecular Evolution, Centro de Astrobiología (CSIC−INTA, associated to the NASA Astrobiology Institute), Carretera de Ajalvir, Km 4, 28850 Torrejoń de Ardoz, Madrid, Spain Organic Chemistry Department, Universidad Autońoma de Madrid, Cantoblanco, 28049 Madrid, Spain

Prebiotic systems chemistry: new perspectives for the origins of life.

Mechanochemistry is becoming more widespread as a technique for molecular synthesis with new mechanochemical reactions being discovered at increasing frequency. Whilst mechanochemical methods are solvent free and can therefore lead to improved sustainability metrics, it is more likely that the significant differences between reaction outcomes, reaction selectivities and reduced reaction times will make it a technique of interest to synthetic chemists. Herein, we provide an overview of mechanochemistry reaction examples, with ‘direct’ comparators to solvent based reactions, which collectively seemingly show that solid state grinding can lead to reduced reaction times, different reaction outcomes in product selectivity and in some instances different reaction products, including products not accessible in solution.

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Mechanochemistry as an emerging tool for molecular synthesis: what can it offer?

We report experimental results that show a large and symmetric population of D and L crystals moving
into complete chiral purity, with one of the enantiomers completely disappearing. The results indicate (i) a
new symmetry breaking process incompatible with the hypothesis of an initial single chiral phase or
‘‘mother crystal,’’ (ii) that total symmetry breaking and complete chiral purity can be achieved from a
system that initially includes both enantiomers, and (iii) that this is achieved through a nonlinear
autocatalytic-recycling process.

Chiral Symmetry Breaking during Crystallization: Complete Chiral Purity induced by Nonlinear Autocatalysis and Recycling

The general notion of an "RNA World" is that, in the early development of life on the Earth, genetic continuity was assured by the replication of RNA and genetically encoded proteins were not involved as catalysts. There is now strong evidence indicating that an RNA World did indeed exist before DNA- and protein-based life. However, arguments regarding whether life on Earth began with RNA are more tenuous. It might be imagined that all of the components of RNA were available in some prebiotic pool, and that these components assembled into replicating, evolving polynucleotides without the prior existence of any evolved macromolecules. A thorough consideration of this "RNA-first" view of the origin of life must reconcile concerns regarding the intractable mixtures that are obtained in experiments designed to simulate the chemistry of the primitive Earth. Perhaps these concerns will eventually be resolved, and recent experimental findings provide some reason for optimism. However, the problem of the origin of the RNA World is far from being solved, and it is fruitful to consider the alternative possibility that RNA was preceded by some other replicating, evolving molecule, just as DNA and proteins were preceded by RNA.

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The Origins of the RNA World

The evolution of a single chiral solid state is reported for an amino acid derivative starting from a nearly racemic mixture of solid left- and right-handed crystals Attrition-enhanced dissolution and recrystallization processes based on solubility considerations of the Gibbs−Thomson rule, coupled with solution-phase racemization, drive this near-equilibrium system inexorably to single chirality in the solid phase

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Emergence of a single solid chiral state from a nearly racemic amino acid derivative.

The amount of research activity concerning alpha-methylene-gamma-butyrolactones and alpha-alkylidene-gamma-butyrolactones has increased dramatically in recent years. This Review summarizes the structural types, biological activities, and biosynthesis of these compounds, concentrating on publications from the past 10 years. Traditional approaches to alpha-methylene-gamma-butyrolactones and alpha-alkylidene-gamma-butyrolactones are then reviewed together with novel approaches, including those from our own research group, reported more recently.

The Renaissance of α‐Methylene‐γ‐butyrolactones: New Synthetic Approaches

3‐Alkenyl‐oxindoles: Natural Products, Pharmaceuticals, and Recent Synthetic Advances in Tandem/Telescoped Approaches

Direct resolution by crystallization of racemic mixtures, induced by seeding or by adding tailor-made additives, constitutes an attractive alternative to separation using diastereomeric salts. Unfortunately, the yield in a single resolution step is low and the overall yield limited to 50% of each enantiomer. Combination of a direct resolution with racemization in the solution permits a total enantiomeric transformation. Complete resolution in a single operation would be of great practical use but examples have been limited. Recently, Viedma has demonstrated the total resolution of an intrinsically achiral molecule, NaClO3, by means of abrasive grinding. Inspired by Viedma, proof of principle was given with a solid phase of a chiral amino acid derivative in contact with a solution in which racemization occurs; this evolved smoothly to a single chiral solid end state on abrasive grinding. This was demonstrated for the conglomerate N-(2-methylbenzylidene)-phenylglycine amide (1) (Scheme 1). Starting the process with a mixture slightly enriched in one enantiomer in the solid phase, the solid phase is completely converted into the major enantiomer through the solution-phase racemization reaction. Within a few weeks either solid enantiomer can be obtained quantitatively with ee> 99.9%. Monte Carlo simulations led to a model that showed that two processes are responsible for the deracemization: continuous attrition of crystals and Ostwald ripening, which leads to growth of large crystals at the cost of smaller ones. Here we explore the parameters of this deracemization process as derived from theory by varying the experimental conditions. The insight obtained also allows definition of suitable conditions to increase the deracemization rate drastically. The Monte Carlo simulation model is expressed in terms of the experimental parameters. In the model three parameters are crucial. First, the rate at which molecules racemize in solution is described by the racemization efficiency c. Second, the continuous ablation of crystals is determined by an attrition probability z, and, third, the growth of larger crystals at the cost of smaller proceeds according to the Ostwald ripening probability k. The simulation results confirmed the experimentally observed exponential behavior typical for asymmetric autocatalysis of the time evolution of the enantiomeric excess ee in the solid state according to Equation (1) for not too small values of the initial enantiomeric excess ee(0).

Complete deracemization by attrition enhanced Ostwald ripening elucidated

Seit einigen Jahren erlebt die Forschung an α-Methylen-γ-butyrolactonen einen enormen Aufschwung. Diese Ubersicht beschreibt die Strukturen, die biologische Aktivitat und die Biosynthese der Substanzen mit dem Schwerpunkt auf Veroffentlichungen aus den letzten zehn Jahren. Thematisiert werden sowohl die klassischen Herstellungsmethoden von α-Methylen-γ-butyrolactonen und α-Alkyliden-γ-butyrolactonen als auch neue Syntheseansatze, die unter anderem von uns entwickelt worden sind.

Alessia Millemaggi

Papers

Emergence of a single solid chiral state from a nearly racemic amino acid derivative.

The Renaissance of α‐Methylene‐γ‐butyrolactones: New Synthetic Approaches

3‐Alkenyl‐oxindoles: Natural Products, Pharmaceuticals, and Recent Synthetic Advances in Tandem/Telescoped Approaches

Complete deracemization by attrition enhanced Ostwald ripening elucidated

Die Renaissance der α‐Methylen‐γ‐butyrolactone: neue Syntheseansätze