Juan M. Cuerva

Understanding the Exceptional Hydrogen-Atom Donor Characteristics of Water in TiIII-Mediated Free-Radical Chemistry

In recent years solid evidence of HAT reactions involving water as hydrogen atom source have been presented. In this work we demonstrate that the efficiency of titanocene(III) aqua complexes as an unique class of HAT reagents is based on two key features: (a) excellent binding capabilities of water toward titanocene(III) complexes and (b) a low activation energy for the HAT step. The theory has predictive capabilities fitting well with the experimental results and may aid to find more examples of this remarkable radical reaction.

Intramolecular coupling of allyl carboxylates with allyl stannanes and allyl silanes: A new type of reductive elimination reaction?

The palladium-catalyzed intramolecular coupling of allyl stannanes with allyl carboxylates provides a general synthesis of five- and six-membered-ring carbocycles. The intramolecular coupling leads selectively to trans five-membered carbocycles and cis six-membered carbocycles, regardless of the cis or trans configuration of the allylic functions in the starting material. For example, the stereoselective synthesis of 10-epi-elemol demonstrated the cis configuration of the six-membered carbocycles. The related Oppolzer cyclization leads to lower yields, or fails completely, with substrates substituted at C-3 of the allyl and/or alkene terminus. The palladium-catalyzed intramolecular coupling of allyl silanes with allyl trifluoroacetates allows the synthesis of trans five-membered-ring carbocycles and requires the use of a bicyclic phosphite as the ligand. DFT calculations suggest that the preferred pathway for the intramolecular allyl/allyl coupling is by formation of the Cbond;C bond between the C-3 termini of the allyl ligands of bis(eta(3)-allyl)palladium complexes.

Ti‐Catalyzed Barbier‐Type Allylations and Related Reactions

Titanocene(III) complexes, easily generated in situ from commercial Ti(IV) precursors, catalyze Barbier-type allylations, intramolecular crotylations (cyclizations), and prenylations of a wide range of aldehydes and ketones. The reaction displays surprising and unprecedented mechanistic subtleties. In cyclizations a fast and irreversible addition of an allyl radical to a Ti(III)-coordinated carbonyl group seems to occur. Intermolecular additions to conjugated aldehydes proceed through a coupling of a Ti(IV)-bound ketyl radical with an allyl radical. Reactions of ketones with allylic halides take place by the classical addition of an allylic organometallic reagent. The radical coupling processes enable transformations such as the highly regioselective alpha-prenylation that are otherwise difficult to achieve. The mild reaction conditions and the possibility to employ titanocene complexes in only catalytic quantities are highly attractive features of our protocol. These unusual properties have been taken advantage of for the straightforward synthesis of the natural products rosiridol, shikalkin, and 12-hydroxysqualene.

Unprecedented Barbier-type reactions catalysed by titanocene(III)

Selective Barbier-type allylations, benzylations and propargylations of aldehydes and ketones can be carried out under extremely mild conditions employing titanocene(III) complexes as catalysts. In this way, chiral titanocene catalysts provided yields ranging from 50-80% of optically active products.

Divergent Titanium‐Mediated Allylations with Modulation by Nickel or Palladium

Titanocene(III)-mediated radical processes are important tools for the formation of C C bonds under mild conditions, and are compatible with many functional groups. Moreover, titanium(III) complexes can be used substoichiometrically, which has allowed the development of enantioselective versions of these reactions. A serious limitation of these radical processes, however, derives from the fact that titanium(III)-mediated radical generation requires reactive substrates, such as allylic halides, which are often cumbersome in introduction and manipulation. Allylic carbonates and carboxylates, in contrast, are easily prepared and handled but are inert against titanocene(III) complexes. Nevertheless, it is known that nickel and palladium complexes can readily activate allylic carbonates and carboxylates I (Scheme 1) to form h-allylmetal complexes (II). On the basis of these results, we deemed that the combination of palladium or nickel derivatives with titanocene(III) complexes would facilitate the development of novel allylation processes using accessible allyl carbonates or carboxylates. In the case of palladium catalysis, it is known that the Oppolzer-type cyclization of organometallic species (II, M = Pd, Scheme 1) to cyclic derivatives (VI) is relatively slow at room temperature. Thus, reduction of II by a singleelectron-transfer reagent, such as [Cp2TiCl], [6] could lead to the allylic radical III, which might be eventually trapped by a second [Cp2TiCl] species to give an allylic titanium(IV) complex IV. Finally, nucleophilic attack of the organometallic derivative IV on an aldehyde or other electrophilic reagent would provide the corresponding allylation product V. On the other hand, nickel-catalyzed carbocyclizations, via intermediates such as II (M = Ni, Scheme 1) to cyclic derivatives VI, are relatively fast at room temperature. Once formed, VI might be reduced by [Cp2TiCl] to a primary radical VII, which could be trapped by a second [Cp2TiCl] species to give an alkyl titanium(IV) complex VIII. Hydrolysis of the organometallic derivative VIII would yield carbocycles IX. Thus, we anticipated that the use of palladium or nickel catalysts could modulate titanium(III) to drive allylation reactions with allyl carboxylates by two different pathways, either through intermolecular coupling with electrophilic reagents or to give carbocyclic derivatives by an intramolecular allylation. To check our hypothesis, we chose allylic carbonate E-1 as a model allylation reagent. Thus, reaction of decanal with carbonate E-1 and an excess of [Cp2TiCl] (2.0 equiv), [8] in the presence of PdCl2 (20 mol%) and triphenylphosphine, [9] gave the expected coupling product 2 as a single stereoisomer in 76% yield (Scheme 2). In contrast, when carbonate E-1 was treated with an excess of [Cp2TiCl] (2.0 equiv) in the presence of [NiCl2(PPh3)2] (20 mol%), a mixture of carbocycles 3 and 4 (4:1 ratio) was obtained in almost quantitative Scheme 1. Mechanism for palladium-catalyzed, titanocene-mediated allylation of carbonyl compounds and nickel-catalyzed, titanocenemediated carbocylization of allylic carboxylates. [M] = transition metal catalyst; Cp = cyclopentadienyl; E = electrophilic reagent (e.g. aldehyde).R = OEt, Me, or Ph.

Unexpected TiIII/Mn-Promoted Pinacol Coupling of Ketones

Titanocene(III) chemistry has emerged in the last decades as an indispensable tool in C-C bond-forming reactions. In this context, pinacol and related reactions allow the stereoselective synthesis of vicinal diols. In this work, we present new applications of these reactions using as starting materials aromatic ketones. Simple and smooth reaction conditions have been developed and have been applied for inter- and intramolecular processes. We also describe that although Cp(2)TiCl is usually used as a monoelectronic reducing agent, it can be also used as an efficient Lewis acid.

Recent applications of Cp2TiCl in natural product synthesis

This review highlights the recent applications of titanocene(III) complexes in the field of natural product synthesis from the seminal precedents to the development of modern catalytic methods. The power of the titanocene(III)-based approaches is demonstrated by the straightforward syntheses of many natural products from readily available starting materials.

Water control over the chemoselectivity of a Ti/Ni multimetallic system: Heck- or reductive-type cyclization reactions of alkyl iodides.

A versatile Ti/Ni multimetallic protocol is described for the efficient catalysis of two different reactions, namely a Heck- and reductive-type cyclization of alkyl iodides, in the absence or presence of water, respectively. Noteworthy, the versatility of Ti(III) chemistry allows an oxidative ending step under reductive conditions to give Heck-type products, and the good H-atom transfer capabilities of Ti(III)-aqua complexes ensure reductive-type cyclizations.

Bassianolone: an antimicrobial precursor of cephalosporolides E and F from the entomoparasitic fungus Beauveria bassiana.

We have established the chemical structure of (+)-bassianolone (3), the antimicrobial compound precursor of cephalosporolides E and F, and that of the furan metabolite 4 from the entomopathogenic fungus Beauveria bassiana.

Ti/Pd Bimetallic Systems for the Efficient Allylation of Carbonyl Compounds and Homocoupling Reactions

The allylation, crotylation and prenylation of aldehydes and ketones with stable and easily handled allylic carbonates is promoted by a Ti/Pd catalytic system. This Ti/Pd bimetallic system is especially convenient for the allylation of ketones, which are infrequent substrates in other related protocols, and can be carried out intramolecularly to yield five- and six-membered cyclic products with good stereoselectivities. In addition, Ti/Pd-mediated reductions and Würtz-type dimerisation reactions can be readily carried out from allyl carbonates and carboxylates.