Palladium-Mediated Approach to Coumarin-Functionalized Amino Acids.

Incorporation of the fluorogenic l-(7-hydroxycoumarin-4-yl)ethylglycine into proteins is a valuable biological tool. Coumarins are typically accessed via the Pechmann reaction, which requires acidic conditions and lacks substrate flexibility. A Pd-mediated coupling is described between o-methoxyboronic acids and a glutamic acid derived (Z)-vinyl triflate, forming latent coumarins. Global deprotection with BBr3 forms the coumarin scaffold in a single step. This mild and scalable route yielded five analogues, including a probe suitable for use at lower pH.

A highly stereoselective synthesis of glycidic amides based on a new class of chiral sulfonium salts: applications in asymmetric synthesis.

A new type of chiral sulfonium salts that are characterized by a bicyclic system has been designed and synthesized from α-amino acids. Their corresponding ylides, which were prepared by basic treatment of the sulfonium salts, reacted smoothly with a broad array of simple and chiral aldehydes to provide trans-epoxy amides in reasonable to very good yields and excellent stereoselectivities (>98%). The obtained epoxy amides were found to be useful as synthetic building blocks. Thus, they were reduced into their corresponding epoxy alcohols and subjected to oxirane-ring-opening reactions with different types of nucleophiles.

Solid phase synthesis of globomycin and SF-1902 A5.

The syntheses of the natural lipocyclodepsipeptide-type antibiotics globomycin and SF-1902 A(5) are reported, utilizing solid phase technology for the construction of the peptidic fragment and a new asymmetric methodology of epoxidation for the preparation of the lipidic chain. The linkage between both fragments was successfully achieved in solid phase to complete the syntheses via a macrolactonization reaction executed prior to the cleavage of the acyclic precursors from the solid support. These syntheses provide access to the rapid generation of a library of analogues via modification of the amino acid residues as well as the lipidic chain, thus facilitating the identification of new antibiotics with interesting mechanisms of action based upon the inhibition of the enzyme signal peptidase II.

Chiral sulfur ylides for the synthesis of bengamide E and analogues.

A new synthetic methodology of asymmetric epoxidation developed in our laboratories has been employed for the stereoselective synthesis of bengamide E (16) and analogues at the terminal olefinic position. In the event, the chiral sulfonium salt 30 was transformed into its corresponding sulfur ylide and reacted with aldehydes 21 and 44 to efficiently provide epoxy amides 31 and 45, respectively. To access the bengamides from these epoxy amides, we combined a synthetic strategy previously reported by us, using an olefin cross metathesis reaction to introduce various alkyl substituents at the terminal olefinic position of amide 33, with reactions mediated by palladium (Negishi or Suzuki couplings) from amide 49. This latter route of introduction of alkyl groups proved to be more efficient than the metathesis approach and allowed access to the generation of a wide array of new bengamide analogues.

A highly efficient methodology of asymmetric epoxidation based on a novel chiral sulfur ylide.

A new type of chiral sulfur ylides has been synthesized and their reactivities against carbonyl compounds tested, showing a high degree of stereoselectivity in the formation of trans epoxy amides under very mild reaction conditions.

Epoxyamide-based strategy for the synthesis of polypropionate-type frameworks.

A new approach to the stereoselective synthesis of polypropionate-type frameworks is reported utilizing reactions of amide-stabilized sulfur ylides with chiral aldehydes. To establish a new strategy for macrolide fragment synthesis, the stereoselectivity of these reactions in the construction of epoxy amides was the most important aspect of this study. In this aspect, we found a strong influence of the protecting groups employed in the starting aldehydes upon the stereochemical outcome of their reactions with the sulfur ylide 1. Thus, numerous aldehydes showed remarkable stereofacial differentiation, providing a major diastereoisomer, in contrast to others that displayed a poor or no stereoselectivity. Despite the difficulties encountered for some cases with respect to their diastereomeric yields, we were able to prepare various stereotetrads and stereopentads, thus enhancing the synthetic value of this new methodology for the preparation of typical polypropionate frameworks found in many natural products, in particular the macrolide class of antibiotics.

Stereoselective synthesis of macrolide-type antibiotics from epoxy amides. Synthesis of the polypropionate chain of streptovaricin u.

The synthesis of the polypropionate chain of Streptovaricin U (1) is described utilizing a new approach for the stereoselective synthesis of the macrolide-type antibiotics via sulfur ylides.

Synthetic studies on stevastelins. 1. Total synthesis of stevastelins B and B3.

[Chemical reaction: See text] The synthesis of stevastelin B3 (2) and B (5) are described. In a first approach, epoxy cyclodepsipeptide 8 was considered as a promising candidate for the synthesis of the [15]-membered ring members of the stevastelins; however, the oxirane ring opening, required for the completion of the natural stevastelin synthesis, failed. Thus, we synthesized stevastelin B (5), carrying out the oxirane ring opening earlier in the synthesis and following a synthetic scheme capable of delivering analogues. On the other hand, a translactonization reaction of the [15]-membered ring derivative 59 led to the total synthesis of the natural [13]-membered ring component of the stevastelins family, stevastelin B3 (2).

Synthetic studies on stevastelins. 2. Synthesis of lipidic- and peptidic-modified analogues.

[Chemical reaction: See text] The synthesis of a series of stevastelin analogues with modification of the susbstituent at the C-2 position of the stearic acid chain (compounds 28 and 31), variation of the amino acids (compounds 41, 42, 73, and 78), or lacking the lipidic chain (compound 91) is described. The replacement of L-valine and L-threonine with other amino acids proceeded without difficulties for the synthesis of analogues 41 and 42; however, the substitution of L-serine with simple amino acids, such as glycine or L-alanine, proved to be elusive, which was adscribed to factors of conformational flexibility. Finally, the substitution with L-valine or L-threonine proceeded without difficulties to provide the analogues 73 and 78 respectively.

Stereoselective synthesis of E-64 and related cysteine proteases inhibitors from 2,3-epoxyamides.

The stereoselective synthesis of cathepsin inhibitors from indoline type epoxyamides is described. The use of this type of epoxyamides permitted the preparation of E-64 and CA-074 related compounds depending on the order in which the key steps, the oxidation of indoline amides to indole amides and oxidative acetal cleavage were undertaken. By taking advantage of the facile substitution of the indole of the corresponding indole epoxyamides, with various nucleophiles, we were able to prepare different epoxysuccinic acids derivatives as potential cathepsin inhibitors.

Chemistry and biology of cyclic depsipeptides of medicinal and biological interest.

Cyclodepsipeptides comprise a wide variety of cyclic peptides of natural origin and are characterized by the occurrence of at least one ester linkage. The great interest that this class of natural products has elicited in scientific community is explained by their wide range of biological activities, intriguing mechanisms of action and attractive molecular architecture. For example, they display a variety of biological effects, such as immunosuppressant, antibiotic, antifungi, antiinflammatory or antitumoral activities. In addition, many of these cyclic depsipeptides represent useful tools for the research of biological processes involved in cellular regulation. The present review deals with the most interesting aspects of the biology and the chemistry of some of these compounds.