Xavier Verdaguer

Regioselective ring opening of chiral epoxyalcohols by primary amines

Abstract A reinvestigation of the titanium(IV)-mediated reaction of primary amines with chiral 2,3-epoxyalcohols shows that, contrary to previous reports, this reaction constitutes a general and practical process for the enantioselective synthesis of 3-amino-1,2-diols.

Primary and Secondary Aminophosphines as Novel P-Stereogenic Building Blocks for Ligand Synthesis†

Chiral phosphine ligands are central to asymmetric metal catalysis. The effect of the majority of these ligands arises from the chirality of their backbones; however, P-stereogenic (P*) ligands have garnered renewed interest. After the decisive work of Knowles and co-workers with PAMP and DIPAMP ligands, several efficient syntheses of all-carbon P* compounds have been reported. In contrast, P* compounds that contain heteroatoms directly linked to the phosphorus center are scarce, and have found little application in catalysis. This class of substances includes secondary phosphine oxides, which exist in equilibrium with their trivalent phosphinite form. P* aminophosphines, which are the corresponding nitrogen analogues, are even more rare, as free primary aminophosphines tend to dimerize with the evolution of ammonia. However, Kolodiazhnyi et al. have reported that borane aminophosphines of type I are stable and that they can be obtained in diastereomerically pure form using 2-phenylethylamine as a chiral amine (Scheme 1). Nonetheless, type I compounds do not have any reported applications in asymmetric catalysis, nor has their hydrogenolysis been described. We envisioned that reductive cleavage of the arylethyl fragment should provide boraneprotected primary aminophosphines of type II, which would be amenable to further transformations and become useful P* building blocks in catalysis. Herein, we report the synthesis of enantiopure P-chiral primary and secondary aminophosphines (II) and diphosphinoamines (III). We began by investigating the hydrogenolysis of the known compound 1a, which contains a tert-butyl(phenyl)phosphinamine moiety (Scheme 2), under various

Stereoselective Synthesis of P-Stereogenic Aminophosphines: Ring Opening of Bulky Oxazaphospholidines

A highly diastereoselective and efficient synthesis of P-stereogenic bulky alkyl and aryl aminophosphines that relies on ring opening of tert-butyl-oxazaphospholidine 2 is described. Ring opening with several organometallic reagents takes place with inversion of configuration at the phosphorus center as it has been demonstrated by X-ray analysis of two ring-opened intermediates. The unprecedented reactivity observed is attributed to the presence of a free NH functionality that facilitates the attack of the organometallic reagent in an S(N)2@P-type process.

Toward the understanding of the mechanism and enantioselectivity of the Pauson-Khand reaction. Theoretical and experimental studies*

Semiempirical and density functional theory (DFT) calculations have been performed on the key steps of the commonly accepted mechanism of the PausonKhand reaction (PKR). In this context, the high reactivity of ynamine complexes in the cycloaddition process has been rationalized on the basis of an anomerically assisted dissociation of CO. Moreover, an explanation has been provided for the correlation between olefin strain and reactivity in the PKR. Inspired by these results, new selective syntheses of cyclopentanones and phenols based on PKR with cyclopropene have been developed. On the other hand, the theoretical analysis of phosphine-substituted dicobalt carbonyl complexes of alkynes has helped in the development of efficient chelating (P,N) and bridging (P,S) ligands for the stereochemical control of the reaction and in the understanding of their action modes.

Synthesis of prostaglandin and phytoprostane B1 via regioselective intermolecular Pauson-Khand reactions.

A new approach to the synthesis of prostaglandin and phytoprostanes B(1) is described. The key step is an intermolecular Pauson-Khand reaction between a silyl-protected propargyl acetylene and ethylene. This reaction, promoted by NMO in the presence of 4 A molecular sieves, afforded the 3-tert-butyldimethylsilyloxymethyl-2-substituted-cyclopent-2-en-1-ones (III) in good yield and with complete regioselectivity. Deprotection of the silyl ether, followed by Swern oxidation, gave 3-formyl-2-substituted-cyclopent-2-en-1-ones (II). Julia olefination of the aldehydes II with the suitable chiral sulfone enabled preparation of PPB(1) type I and PGB(1).

Enantioselective Syntheses of Carbanucleosides from the Pauson-Khand Adduct of Trimethylsilylacetylene and Norbornadiene

A new enantioselective approach to carbanucleosides from Pauson-Khand (PK) adduct 1 is disclosed. The chiral cyclopentenone 1 is readily accessible in enantiomerically pure form via PK reaction of trimethylsilylacetylene and norbornadiene using N-benzyl-N-diphenylphosphino-tert-butyl-sulfinamide as a chiral P,S ligand. (-)-Carbavir and (-)-Abacavir were enantioselectively synthesized starting from (-)-1. The key steps of the sequence are a photochemical conjugate addition of a hydroxymethyl radical, a retro-Diels-Alder reaction, and a palladium catalyzed allylic substitution to introduce the nucleobase.

N-Phosphino-p-tolylsulfinamide Ligands: Synthesis, Stability, and Application to the Intermolecular Pauson−Khand Reaction

Here we synthesized a family of racemic and optically pure N-phosphino-p-tolylsulfinamide (PNSO) ligands. Their stability and coordination behavior toward dicobalt-alkyne complexes was evaluated. Selectivities of up to 3:1 were achieved in the ligand exchange process with (mu-TMSC2H)Co2(CO)6. The resulting optically pure major complexes were tested in the asymmetric intermolecular Pauson-Khand reaction and yielded up to 94% ee. X-ray studies of the major complex 18a indicated that the presence of an aryl group on the sulfinamide reduces the hemilabile character of the PNSO ligands.

A versatile enantiospecific approach to 3-azetidinols and aziridines

Abstract Treatment with triethylamine of mono- and dimesylates derived from N-diphenylmethyl 3-amino-1,2-diols of high enantiomeric purity affords 3-azetidinols or aziridines, respectively, in a stereospecific fashion.

Asymmetric Intermolecular Pauson−Khand Reaction of Symmetrically Substituted Alkynes

The asymmetric intermolecular Pauson-Khand reaction of symmetric alkynes has been accomplished for the first time. N-Phosphino-p-tolylsulfinamide (PNSO) ligands have been identified as efficient ligands in this process. The chirality of the cobalt S-bonded sulfinyl moiety was found to direct olefin insertion into one of the two possible cobalt-carbon bonds in the alkyne complex. Reaction of symmetric alkynes allows for a simplified experimental protocol since there is no need for separation of diastereomeric complexes.

Total Synthesis and Biological Activity of 13,14‐Dehydro‐12‐Oxo‐Phytodienoic Acids (Deoxy‐J1‐Phytoprostanes)

In plants, almost all abiotic and biotic stresses are associated with enhanced endogenous production of reactive oxygen species and free radicals. Free radicals in turn readily attack unsaturated fatty acids in membrane lipids that can be non-enzymatically oxidised to a variety of products in situ. Eventually oxidised lipids are released from membrane stores. It becomes increasingly clear that several of these oxidised lipids, such as malondialdehyde and the recently discovered phytoprostanes that occur ubiquitously in plants, can be induced by oxidative stress and display potent biological activities. 2] Consequently it has been postulated that oxidised lipids represent archetype mediators of oxidative stress, not only in plants but also in animals. The major metabolites of the phytoprostane pathway are deoxy-J1-phytoprostanes (dPPJ1), which structurally resemble potent, enzymatically formed defence mediators in plants and animals such as 12-oxo-phytodienoic acid (OPDA) and 15deoxy-D-prostaglandin J2 (dPGJ2; Scheme 1). Notably, these cyclopentenone phytoprostanes are more abundant than OPDA even in young and unstressed plants. However, it is not known whether the recently discovered dPPJ1s are merely markers of oxidative stress or are biologically active stress metabolites. It was the aim of this study to systematically prepare and evaluate these cyclopentenone phytoprostanes. In 1976, Pryor and co-workers discovered that a-linolenic acid is prone to undergoing autoxidation to yield a series of prostaglandin-like compounds by a free-radical-catalysed lipidperoxidation process in vitro. This finding remained a laboratory curiosity until 1990, when it was shown that arachidonic acid undergoes a similar radical-catalysed oxidation to yield