Double Diastereoselection in Aldol Reactions Mediated by Dicyclohexylchloroborane between Chiral Aldehydes and a Chiral Ethyl Ketone Derived from l-Erythrulose. Synthesis of a C1−C9 Fragment of the Structure of the Antifungal Metabolite Soraphen A1α

Both matched and mismatched diastereoselections have been observed in the aldol reactions of a range of chiral aldehydes with the dicyclohexylboron enolate of a chiral ethyl ketone related to l-erythrulose. As was previously observed in the corresponding aldol reactions with l-erythrulose derivatives, the Felkin−Anh model provides an adequate explanation for the stereochemical outcome of reactions with chiral α-methyl aldehydes. However, a satisfactory account of the results observed with α-oxygenated aldehydes was only possible with the Cornforth model. As a practical application of the methodology described herein, a C1−C9 fragment of the structure of the antifungal macrolide soraphen A1α…

Organocatalytic Enantioselective Intramolecular (Hetero)Michael Additions in Desymmetrization Processes

Synthesis, spectroscopic studies and biological evaluation of acridine derivatives: The role of aggregation on the photodynamic efficiency.

Two new photoactive compounds (1 and 2) derived from the 9-amidoacridine chromophore have been synthesized and fully characterized. Their abilities to produce singlet oxygen upon irradiation have been compared. The synthesized compounds show very different self-aggregating properties since only 1 present a strong tendency to aggregate in water. Biological assays were conducted with two cell types: hepatoma cells (Hep3B) and human umbilical vein endothelial cells (HUVEC). Photodynamic therapy (PDT) studies carried out with Hep3B cells showed that non-aggregating compound 2 showed photoxicity, ascribed to the production of singlet oxygen, being aggregating compound 1 photochemically inactive.…

Stereoselective Synthesis and Structural Correction of the Naturally Occurring Lactone Stagonolide G

A convergent synthesis of the structure proposed for the naturally occurring lactone stagonolide G is described. All three stereocenters were created with the aid of asymmetric Brown allylations. The lactone ring was built by means of a ring-closing metathesis (RCM). The synthetic and the natural compound differed in their spectral properties. A new structure is now proposed for stagonolide G and demonstrated by means of a chemical transformation.

Stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide A.

A stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide A has been performed. The preparation of a cis-2,6-disubstituted tetrahydropyran ring via stereoselective reduction of an intermediate cyclic hemiacetal was one key feature of the synthesis. The macrocyclic lactone ring was created by means of a ring-closing metathesis (RCM), whereby the new C=C bond displayed exclusively the undesired Z configuration. Conversion to the required E configuration was achieved via photochemical isomerization.

Synthesis and Biological Evaluation of α-Tubulin-Binding Pironetin Analogues with Enhanced Lipophilicity

Financial support has been granted to M. C. by the Spanish Ministry of Education and Science (project numbers CTQ2008-02800 and CTQ2011-27560), by the Conselleria d'Empresa, Universitat i Ciencia de la Generalitat Valenciana (ACOMP09/113) and by the BANCAJA-UJI Foundation (P1-1B2002-06, P1-1B-2008-14 and PI-1B2011-37). The biological work has been supported in part by grants from the Spanish Ministry of Education and Science (grant number BIO2010-16351) and from the Comunidad de Madrid (grant number S2010/BMD-2457 BIPEDD2-CM), both to J. F. D. We further thank the Matadero Municipal Vicente de Lucas in Segovia for providing the calf brains, which were the source of tubulin.

Double diastereoselection in aldol reactions mediated by dicyclohexylchloroborane between L-erythrulose derivatives and chiral aldehydes. The Felkin-Anh versus Cornforth dichotomy.

Both matched and mismatched diastereoselections have been observed in aldol reactions of the B,B-dicyclohexylboron enolate of a protected l-erythrulose derivative with a range of chiral aldehydes. The stereochemical outcome of reactions with alpha-methyl aldehydes can be adequately explained within the Felkin-Anh paradigm. In the case of alpha-oxygenated aldehydes, however, strict adherence to this model does not allow for a satisfactory account of the observed results. In such cases, the Cornforth model provides a much better explanation.

Design and synthesis of pironetin analogue/colchicine hybrids and study of their cytotoxic activity and mechanisms of interaction with tubulin

We here report the synthesis of a series of 12 hybrid molecules composed of a colchicine moiety and a pironetin analogue fragment. The two fragments are connected through an ester-amide spacer of variable length. The cytotoxic activities of these compounds and their interactions with tubulin have been investigated. Relations between the structure and activity are discussed. Since the spacer is not long enough to permit a simultaneous binding of the hybrid molecules to the colchicine and pironetin sites on tubulin, a further feature investigated was whether these molecules would interact with the latter through the pironetin end (irreversible covalent binding) or through the colchicine end (…