Roberto Fernández de la Pradilla

Update 1 of: α,β-Diamino Acids: Biological Significance and Synthetic Approaches

The discovery of nonproteinogenic amino acids among natural products, either in native state or as fragments of complex molecules, has increased the level of interest in this family of molecules from different scientific standpoints. Compounds with valuable biological properties can be found among these atypical amino acids. In addition, they have served as building blocks for the synthesis of new molecules or as surrogates of native amino acids in known peptidic entities to modulate their biological behavior. In this context, R, -diamino acids and their derivatives esters and amides, have attracted a great deal of attention among organic chemists and biochemists through the years. This interest has been due to the ubiquitous nature of R, -diamino acids as key structural fragments of biologically active compounds. Beyond this focus, the simplest compound, 2,3-diaminopropionic acid, has recently found application in the environmentally safe production of hydrogen for fuel cells, as a selective carrier of CO2 through gel membranes.1a Also, it has served to assemble a molecular device that produces propelling motion upon IR irradiation1b and, lately, in the context of food chemistry, 2,3-diaminopropionic acid has been identified as an inhibitor of polyphenol oxidase, the enzyme responsible for the browning of fruits and vegetables1c and as an enhancer of Maillard browning.1d In spite of the incidence of these molecules in an increasing number of areas, this review will deal with the biological significance, the therapeutic uses, and other interesting applications of R, -diamino acids and their derivatives found in the existing literature. Additionally, aside from the above considerations, the structural complexity of these molecules, having two vicinal chiral centers has also represented a challenge for synthetic organic chemists, especially the synthesis of enantiopure materials. Therefore, the aim of this article will also be to provide a deep and general view of the existing methodology for the synthesis of aliphatic R, or 2,3-diamino acids and their simple derivatives, esters, * To whom correspondence should be addressed. E-mail: iqov379@ iqog.csic.es. Alma Viso was born in Madrid (Spain) in 1964. She obtained a B.S. degree in Chemistry in 1987 and a Ph.D. in 1992 from Universidad Complutense de Madrid (UCM). In 1992, she moved to Massachusetts Institute of Technology (MIT) as a Fulbright fellow to work with Stephen L. Buchwald for 18 months. She joined the faculty at UCM (Madrid) in 1993 as an Assistant Professor and was promoted to Associate Professor in May 2002. In December 2002, she joined Instituto de Quı́mica Orgánica General, CSIC, as a Staff Researcher (Cientı́fico Titular) and was promoted to Senior Staff Researcher (Investigador Cientı́fico) in 2007. Her current research interests are focused in two main areas, the development of new methodologies in asymmetric synthesis using sulfoxides and sulfinamides and the application of these novel methods to efficient syntheses of therapeutically valuable products. Chem. Rev. PR1

Stereocontrolled synthesis of enantiomerically pure 2-dienyl sulfoxides via palladium-catalyzed coupling reactions☆

Abstract Enantiopure 2-sulfinyl dienes can be prepared via regio- and stereoselective hydrostannylation of alkynylsulfoxides; after conversion to the corresponding vinyliodides these substrates may be coupled with vinylstannanes via Stille methodology in the presence of BHT.

Regio- and stereospecific synthesis of substituted cyclohexenediols from 7-oxabicyclo[2.2.1]hept-5-en-2-ols and organolithium reagents

Abstract The bridge opening reactions of 7-oxabicyclo[2.2.1]hept-5-en-2-ols,4 and6 with organolithium reagents proceed with complete regio- and stereoselectivity to produce highly functionalized cyclohexene derivatives5 and7, respectively.

[2,3]-Sigmatropic rearrangements of 3-sulfinyl dihydropyrans: application to the syntheses of the cores of ent-dysiherbaine and deoxymalayamicin A.

The [2,3]-sigmatropic rearrangement of a variety of configurationally stable diastereomeric allylic sulfinyl dihydropyrans, produced by base-promoted cyclization of sulfinyl dienols, has been studied. In some cases, the efficient transformation of these substrates into dihydropyranols required an in-depth study of reaction conditions, with the preferred protocol relying on the use of DABCO in warm toluene. This methodology has been applied to the syntheses of the cores of ent-dysiherbaine and deoxymalayamicin A by means of efficient tethered aminohydroxylations.

Regio- and stereocontrolled synthesis of hydroxycyclohexenyl sulfones from oxanorbornenes

Abstract Organolithium reagents and lithium aluminum hydride undergo conjugate additions to oxanorbornenic vinyl sulfones 9-12 with concomitant cleavage of the oxygen bridge, to generate highly functionalized cyclohexenyl phenyl sulfones 13-16 in high yields and in a regio- and stereocontrolled fashion.

An Approach to the Stereoselective Synthesis of Enantiopure Dihydropyrroles and Aziridines from a Common Sulfinyl-Sulfinamide Intermediate

The diastereoselective addition of lithiated vinyl sulfoxides to enantiopure sulfinimines provides direct access to a wide assortment of allylic sulfinamides in good yields and excellent selectivities. These adducts are key precursors to differently functionalized cis- and trans-dihydropyrroles. Modulation of the protecting group on nitrogen prior to cyclization has a significant impact on the stereochemical outcome, allowing for the selective preparation of 2,5-cis- or 2,5-trans-3-sulfinyl disubstituted dihydropyrroles from a common sulfinamide intermediate. Further research on halocyclization conditions has also yielded a stereoselective synthesis of trisubstituted vinyl aziridines from these chiral sulfinamides, simply by changing the halogenating agent.

Development of Chromanes as Novel Inhibitors of the Uncoupling Proteins

The uncoupling proteins (UCPs) are mitochondrial carriers that modulate the energetic efficiency and, as a result, can lower superoxide levels. Here, we describe the discovery of a small-molecule inhibitor of the UCPs. Screening of potential UCP1 regulators led to the identification of chromane derivatives that inhibit its proton conductance. Members of the UCP family can act as a defense against oxidative stress and, thus, UCP2 plays a protective role in tumor cells. High UCP2 levels have been associated with chemoresistance. We demonstrate that chromanes also inhibit UCP2 and, in HT-29 human carcinoma cells, cause oxidative stress. The chromane derivatives can act synergistically with chemotherapeutic agents; for instance, they increase the toxicity of arsenic trioxide in HT-29 cells. These findings open a promising line in the development of novel anticancer agents.

Enantiopure 1,4-diols and 1,4-aminoalcohols via stereoselective acyclic sulfoxide-sulfenate rearrangement.

Treatment of acyclic α-hydroxy and α-tosylamino sulfinyl dienes with amines affords enantiopure 1,4-diol or 1,4-hydroxysulfonamide derivatives in good yields and diastereoselectivities. This one-pot procedure entails a conjugate addition that triggers a diastereoselective sulfoxide-sulfenate [2,3]-sigmatropic rearrangement.

Gold Sulfinyl Mesoionic Carbenes: Synthesis, Structure, and Catalytic Activity

Gold mesoionic carbenes having a chiral sulfoxide group attached to the C4 position of the five membered ring have been prepared and tested as catalysts in the cycloisomerization of enynes. These new catalysts are very efficient, with the sulfoxide moiety playing a key role in their activity and the N1-substituent in control of the regioselectivity of these processes.

Highly Diastereoselective Katsuki−Jacobsen Oxidation−Epoxidation of α-Silyloxy Sulfinyl Dienes: Synthetic Applications

Katsuki-Jacobsen oxidation-epoxidation of acyclic alpha-silyloxy sulfinyl dienes, followed by acid-promoted cyclization, leads to 2,5-trans-sulfonyl dihydrofurans with good selectivities. As an application, the formal syntheses of (6S,7S,9R,10R)- and (6S,7S,9S,10S)-6,9-epoxynonadec-18-ene-7,10-diols is reported.